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2 Special Edition: Corrective and Preventive Action

TABLE OF CONTENTS
CORRECTIVE & PREVENTATIVE ACTIONS

4 The Old vs. the New: A Breakdown of the Corrective and Preventive Action Requirements
in the New Quality System Regulation
by Karen Abney Coleman

7 AbyDeeper Look at Corrective Action

Fred Hooten

10 AbyTeam Approach to Medical Device Failure Investigation and Resolution: A Case Study
John E. Lincoln

23 Failure Analysis & Corrective Action for an IV Catheter Component Problem: Case Study
by John Rodriguez and Don Wood

28 Beyond Compliance: Exceeding Requirements with Systematic Corrective Action

by Michael Clark, Wade Speir, and David Sandahl

34 Implementing Corrective Action: An Escalation Approach to Compliance and Business Value

by Michael Clark, Wade Speir, and David Sandahl

44 Corrective and Preventative Actions (CAPA): A Medical Device Case Study

by John E. Lincoln

55 Implementing Corrective Actions for FDA Observations

by Shahid T. Dara

67 Non-Conformance,
by David A. Manalan
The Corrective and Preventive Action (CPA) Initiator

71 Corrective and Preventative Action: Planning to Achieve Sustainable GMP Compliance

by John E. Snyder

82 Be SMART With Your Corrective and Preventive Actions (CAPA)

by Larry Nold

Special Edition: Corrective and Preventive Action 3

 The Old
vs.
The New
A breakdown of the
Corrective and
T he opportunity is finally here
to start learning and under-
standing the Quality System
Regulation. I find it is easier to
learn regulations by breaking
Preventive Action them down into smaller sections
or parts, so I will discuss
Subpart J-Corrective and
Requirements in the Preventive Action. Ill compare
the old cGMP section to the
New Quality System new section in the Quality
System Regulation in an effort to
help readers understand the
Regulation new regulation.
A brief comparison of the two
sections quickly reveals that the
new Quality System Regulation
is more prescriptive and
detailed. For reference pur-
poses, the old cGMP sections
are quoted below:
820.20(a) (3) Identifying,
recommending, or providing
solutions for quality assurance
problems and verifying the
implementation of such solu-
tions; and
820.162 Failure investiga-
By tion After a device has been
Karen Abney Coleman released for distribution, any
failure of that device or any of
National Device Expert its components to meet perfor-
USFDA mance specifications shall be
4 Special Edition: Corrective and Preventive Action
investigated. A writ-
ten record of the
investigation,
including
conclusions
and fol-
low-up,
shall be
made.
The Quality System Reg-
ulation section states:
820.100 Corrective and
Preventive Action.
(a) Each manufacturer shall
establish and maintain
procedures for implement-
ing corrective and preven-
tive action. The procedures
shall include requirements
for:
(1) Analyzing processes,
work operations, conces-
sions, quality audit re-
ports, quality records,
service records, com-
plaints, returned product,
and other sources of
quality data to identify
existing and potential
causes of nonconforming
 Karen Abney Coleman

product, or other quality problems.
Appropriate statistical methodology shall
be employed where necessary to detect
recurring quality problems.
Device manufacturers need to look at this sec-
tion very closely. A manufacturer must understand
that identifying and correcting potential causes of
nonconforming processes and products is crucial
to preventing systemic quality system problems.
Manufacturers that understand this usually do not
have significant compliance problems with the
FDA. This does not mean that problems never
occur. But if problems do occur, the manufacturer
will have a system in place to adequately identify
potential causes of nonconforming products, verify
corrective action, and take action to prevent recur-
ring problems.
Many manufacturers fall victim to relying on a
procedure that directs the employees to review
records in specific areas. If no problems are seen
during the review of records in
these specified areas, then they
consider this an adequate investiga- A manufacturer must understand that
tion. A review of records does not
appear to meet the intent of this identifying and correcting potential causes
regulation. According to the Quality
System Regulation, the manufac-
of nonconforming processes and products
turer shall include requirements is crucial to preventing systemic
for: (1) analyzing processes ser-
vice records, complaints, returned quality system problems.
product, and other sources of qual-
ity data to identify existing and
potential causes of nonconforming
products or quality problems.
According to the next requirement, Appropriate
statistical methodology shall be employed where
necessary to detect recurring quality problems.
Have you considered this as an option to analyze
or evaluate a problem product or process? Many
device manufacturers are currently using statistical
process controls which can aid in fulfilling this
requirement.
(2) Investigating the cause of nonconformi-
ties relating to product, processes, and
the quality system;
(3) Identifying the action(s) needed to cor-
rect and prevent recurrence of noncon-
forming product and other quality prob-
lems;
After identifying the potential cause, a manufac-
turer must investigate how the nonconformity
relates to the product, processes, and the impact
on other quality areas. If the potential cause and
its relationship to the product or process has not
been identified, a manufacturer cannot identify the
corrective action(s) needed to prevent recurrence
of the quality problems or nonconforming product.
Many manufacturers do not understand that their
failure to complete these key areas in a failure
investigation will impede them from finding the cor-
rect solution(s) for preventing recurrence of the
quality problems.
(4) Verifying or validating the corrective and
preventive action to ensure that such
action is effective and does not adversely
affect the finished device;
Manufacturers should have data and supporting
documents to show how they verified or validated
the corrective and preventive action. The docu-
ments should show the corrective action taken was
effective and does not adversely affect the finished
device. Preventive action that is not verified to
assure it is effective will allow similar failures or
complaints to continue after unverified corrective
actions were implemented.
(5) Implementing and recording changes in
methods and procedures needed to correct
and prevent identified quality problems;
After the elements in (2), (3) and (4) are met,
then the processes and procedures should be cor-
rected to reflect the required changes. The
changes should be implemented through a docu-
ment change control procedure. A summary of

5 Special Edition: Corrective and Preventive Action 5

 Karen Abney Coleman

these document changes should be included in the
investigation report.
(6) Ensuring that information related to qual-
ity problems or nonconforming product is
disseminated to those directly responsible
for assuring the quality of such product or
the prevention of such problems;
Each manufacturer should have a mechanism
for communicating quality related issues to
employees who are directly responsible for product
quality and implementing corrective actions.
(7) Submitting relevant information on identi-
fied quality problems, as well as correc-
tive and preventive actions, for manage-
ment review.
tions 820.20(a)(3) and 820.162 provided FDA investi-
gators with many observations and deficiencies
because of numerous recalls, product replacements,
or frequent upgrades.
The more prescriptive text in the Quality System
Regulation should assist manufacturers who did
not really understand what was required under the
old cGMP. However, it will also make it easier for
an investigator to show where a manufacturer has
failed to comply with the regulation and how it
impacts the product.
These comments are provided to aid manufac-
turers in developing a better understanding in
applying and complying with the new Quality
System Regulation. They are not intended to be
construed as Agency policy. The comments pro-
vided are based on my experiences as an investi-
gator conducting inspections and audits of device
manufacturers over the past 19 years.

The job is not completed until

the paperwork is done!
References
1. 21 CFR 820 Good Manufacturing Practice for Medical
Devices: General (July 21, 1978)
There should be some system/procedure that 2. 21 CFR 820 Quality System Regulation (October 7,
1996)
states the who, what, when, where and how the
management review will be handled by the device
manufacturer.

(b) All activities required under this section,

and their results, shall be documented.

Last but not least the job is not completed

until the paperwork is done! All steps taken dur-
ing the investigation should be documented
according to the steps outlined above and
included in the report. An SOP should be in
place to provide directions and for completing the
required documentation.

Conclusion

Learning and understanding Subpart J

Corrective and Preventive Action of the new Quality
System Regulation can be facilitated by comparing it
to the 1978 cGMP. Understand that FDA field investi-
gators will recognize Subpart J as including the two
sections of the old cGMP quoted above. Device
manufacturers who did not comply with cGMP sec-

6 Special Edition: Corrective and Preventive Action

 Hooten
A Deeper Look at
Corrective
Action
T he Corrective and Preventive
Action (Section 820.100)
requirements are some of the
more important quality system
elements required by the Quality
System Regulation (QS Reg).
This section requires manufactur-
ers to identify all sources of qual-
ity data (e.g., complaints, returned
devices, service records, in-pro-
cess rejects and incoming com-
ponents). The data must then be
compiled and statistically ana-
lyzed which usually means
trending and any trends or sys-
temic problems must be identi-
fied. The trends then must be
evaluated and corrective action
taken where appropriate. This
section is the heart of the regula-
tion, and compli-
ance with
the
Highlights
by Fred Hooten
requirements is necessary to
identify quality problems and fos-
ter continuous improvement.
Identifying and resolving
quality problems are the objec-
tives of these requirements, so
a manufacturers activities in
this area will be of special
interest to FDA investigators.
However, certain clarifications
in the QS Reg Preamble have
created controversy concerning
whether the FDA actually has
access to the results of the cor-
rective action program.
The FDA states in Comment
#160 of the Preamble, the FDA
wants to make it clear that cor-
rective and preventive actions, to
include the documentation of
these activities, which result
from internal audits and man-
agement reviews are not covered
under Section 820.180(c).
Section 820.180(c) of the QS
Reg exempts quality audits, sup-
plier audits and management
reviews from review and copying
by FDA investigators during the
FDA quality system inspections.
The clarification appears to
revoke the exemption. Industry
was not provided an opportunity
Special Edition: Corrective and Preventive Action
to comment on the clarification
before the QS Reg was final-
ized, and as a result, there have
been objections to this FDA
position.
Allegedly, a request has
been made to FDA to exempt all
corrective action from FDA re-
view on the basis that it is part
of the management review and
quality audit activities.
The clarifications apparent
intent was to put manufacturers
on notice that they cant claim
corrective actions relating to
quality problems, that may be
identified during management
reviews and audits, are exempt
from FDA review. If this were the
case, the FDA might not have
access to any of the records of
corrective action a firm may
take. While this might appear
attractive to some, it aint going
to happen. However, the issue
does highlight an important
change from the previous cGMP
regulation (i.e., the exemptions
are no longer administrative
policy).
The exemptions provided by
Section 820.180(c) are a contin-
uation of policy established by
7 75
 Fred Hooten
the FDA in the 1978 cGMP reg-
ulation. When the 1978 Good
Manufacturing Practices regula-
tion was drafted, the cGMP
Advisory Committee recom-
mended that the FDA not seek
to review a companys internal
audit results. The committee
believed that internal audits
would not be useful or meaning-
ful to a firms management as a
self-inspection tool if the audit
Allegedly, a request has been made to
FDA to exempt all corrective action
from FDA review on the basis that it
is part of the management review
and quality audit activities.
report was available to FDA.1
The Agency agreed with the
Committee that general access
to audit reports would tend to
weaken the audit system. The
Agency stated in the Preamble
to the 1978 cGMP regulation
that, as a matter of administra-
tive policy, the FDA would not
request inspection and copying
of internal audit reports, but they
reserved the right to access
these reports if there was litiga-
tion with access sought under
applicable procedural rules (e.g.,
such as discovery).2
The exemptions provided in
Section 820.180(c) of the QS
Reg were intended to maintain
this philosophy. However, the
exemptions are now no longer
FDA administrative policy,
which the FDA could revoke
without opportunity for industry
comment. The exemptions are
8 Special Edition: Corrective and Preventive Action
now part of the regulation, not
the Preamble, and the FDA
cannot withdraw the exemp-
tions without revising the regu-
lation through the notice and
comment rulemaking process
(not an easy matter). Therefore,
it appears clear that the FDA
does not have access to qual-
ity audit, management review
and supplier audit reports.
However, no exemptions are
granted for the corrective and
preventive action program.
The 1978 cGMP regulation
anticipated that industry might
attempt to shield product failures
and corrective action data from
the investigator under the guise
that the data were part of the
quality audit results. To avoid
this, the definition of audit was
designed to prohibit this
approach. The definition of the
term audit in the 1978 cGMP
[Section 820.3(b)], included the
statement: Audit does not
include surveillance or inspec-
tion activities performed for the
purpose of conducting a quality
assurance program or undertak-
ing complaint investigations of
failure analyses of a device.
So, the 1978 cGMP rule sug-
gested that manufacturers can-
not shield corrective action data
and associated information from
FDA review behind the veil of
internal audit information.
However, the definition of
Quality Audit that appears in
the 1996 QS Reg no longer
includes such qualifying infor-
mation, so the FDA has clari-
fied in the Preamble that cor-
rective and preventive actions,
including the documentation of
these activities, are not
included in the exemptions
granted in Section 820.180(c).
Manufacturers are required
by Section 820.100(a)(7) of the
QS Reg to evaluate the results
of the corrective and preventive
action program as part of the
management review function.
This does not mean, however,
that the corrective and preven-
tive action information is
intended to be used only in the
management review function.
This information is simply one
of many data inputs to the man-
agement review function. The
primary purpose of the correc-
tive and preventive action pro-
gram is to, on a routine basis,
identify quality problems and
generate corrective action data
that is used by the QA, produc-
tion and design activities to
make corrections and improve-
ments in the product design,
production and quality assur-
ance procedures and methods.
There is no exemption in the
QS Reg to prevent the FDA
from reviewing and copying
documents and records that
manufacturers use to implement
these activities.
Of course, quality problems
identified by corrective and pre-
ventive action programs may be
resolved during management
reviews or quality audits, and
its clear that such deliberations,

and the results of these reviews
would be exempt from FDA
review and copying. However,
the identification and resolution
of quality problems are not the
primary responsibilities of man-
agement reviews and quality
audits. This responsibility is
intended to be assigned to the
corrective and preventive action
program required by Section
820.100 of the QS Reg. The
responsibilities of the quality
audits and management
reviews are to ensure that an
adequate system is in place to
identify and resolve quality
problems. If the decisions made
during management reviews or
audits are intended to be used
to satisfy the QS Reg corrective
action requirements (i.e., to
identify the actions needed to
correct and prevent recurrence
of quality problems, and the
documentation of these activi-
ties), the decisions become part
of the effort to comply with
Section 820.100, and are sub-
ject to FDA review and copying.
All quality problems must be
resolved, and controls must be in
place, to provide evidence that
corrective actions are effective.
This is the purpose of the correc-
tive and preventive action pro-
gram, and the results of the pro-
gram are subject to FDA review.
In any event, its fruitless to
attempt to identify loopholes to
keep failure information from the
FDA, as there are many
sources from which the FDA can
obtain failure information, (e.g.
engineering change notices, pro-
duction records and complaint
files). Once the FDA finds a
problem, the Agency will expect
to see documentation that pro-
vides evidence that the problem
Fred Hooten
was properly investigated, ments for a corrective and pre-
resolved, and included in the ventive action program and the
corrective and preventive action management reviews and quality
program. If the FDA finds that audits are separate, and FDA
quality problems are being iden- access to each is very clear in
tified via the management the regulation.
review and audits, and not
included in the corrective and
preventive action program, the
Agency can site the firm for an
ineffective program. A manufac- References
turers best defense is to be able
1. Manufacture, Packing, Storage
to demonstrate that there is an and Installation of Medical
effective program in place for Devices, Regulations Estab-
identifying and resolving quality lishing Good Manufacturing
problems. Practices, Federal Register, vol.
43, No. 141, Friday 21, 1978 ,
pg. 31510, Disclosure of inter-
Summary nal audits.
2. Manufacture, Packing, Storage
Controversy has developed and Installation of Medical
over the language that the FDA Devices; Regulations Estab-
used to clarify that corrective lishing Good Manufacturing
Practices, Federal Register,
and preventive action informa- vol. 43, No. 141, Friday 21,
tion is not covered by the 1978, pg. 31516, Comment #
exemptions stated in Section 37.
820.180(c) of the QS Reg. There
was really no need for the clarifi-
cation. The wording simply mud-
died already clear requirements.
The FDA inspectional program is
designed to determine if manu-
facturers have effective quality
problem identification and cor-
rective action programs. The
FDA always has reviewed and
evaluated the adequacy of a
manufacturers procedures for
identifying and investigating
quality problems, as well as the
effectiveness of the corrective
action. Its not likely that the FDA
will allow manufacturers to
shield the information necessary
to make this determination from
the FDA investigator, under the
pretense that the problems and
corrective actions are exempt
because they are part of man-
agement reviews, quality audits
or supplier audits. The require-
Special Edition: Corrective and Preventive Action 9 77
 A Team Approach to Medical
Device Failure Investigation
and Resolution
A CASE STUDY
T
he article published in
the January 1998 issue
The following case of the Journal of cGMP
Compliance, Setting Up and
study illustrates Running a Failure Investigation
System, outlined some of the
specific steps and techniques available to a com-
issues encountered pany desiring to set up or
improve their failure investiga-
by a team in tion and corrective action pro-
gram. The following case study
developing and illustrates specific steps and
issues encountered by a team
implementing in one company using device
complaint data in developing
effective and implementing effective cor-
rective action.
corrective action A medical device firms man-
agement desired to reduce cus-
tomer complaints, rework costs,
failure rates, uncertain delivery
dates, and lot quantities for a 2.5
million unit per-year medical
device they manufactured. This
product had been plagued with
problems (in-house rejects, cus-
tomer complaints) for many
years, even though it had under-
gone numerous part and process
modifications to make it more reli-
able to manufacture.
The Product
by The product was a medical
John E. Lincoln device used to control fluid flow.
Principal It consisted of two body halves,
John E. Lincoln and Associates molded in-house, with a vendor-
10 Special Edition: Corrective and Preventive Action
supplied gasket in-between. The
halves had to be able to rotate
but remain leak proof (see
Figure 1). Assembly consisted of
mechanically inserting the gas-
ket into one of the body halves,
manually orienting and combin-
ing the parts, oven curing the
assembly, then ultrasonic weld-
ing (swaging) the parts
together, making them leak-
proof, while still allowing motion
between the assemblies. The
completed assembly then would
be positive air pressure-tested
for leaks, flow tested for flow rate
and/or blockages, and subjec-
tively manually tested for torque
resistance. Acceptable product
was shipped to other sites for
incorporation into sets and fin-
ished packaging/labeling.
The Problem
This medical device had been
manufactured by this plant for
over ten years and had a history
of wide swings in quality.
Acceptable outgoing quality lev-
els were achieved only by fre-
quent batch or lot rework, con-
sisting mainly of 100% testing
and sorting, resultant high/costly
scrap rates, missed delivery
dates, and final lot quantities sub-
stantially less than forecast. The
product exhibited erratic process
John E. Lincoln

Figure 1
Medical Device Assembly Process (Simplified)

Inspected/Cleaned Inspected/Siliconed Inspected/Cleaned

Body Half Gasket Body Half

Silkscreen Gasket Assembly Silkscreen

Imprinting (Machine) Imprinting

Hand
Assembly

Oven
Cure

Ultrasonic
Swaging

Test:
Air/Water/ Fail Rework Retest Fail Scrap
Torque

Pass

Package/Inspect/
Ship Pass Pass

and lot quality variability, necessitating rework and
retest at both the shipping and receiving (sister)
plants, resulting in shipping delays, additional pro-
cessing steps, returns of lots to the assembly plant
for rework, scheduling difficulties, and high fall-
off/scrap rates. The poor product quality and high
cost wasnt fully visible until the data was formatted
and trended during the project (see Figure 2).
The key functional defects were:
Failure to shut-off.
Body Leaks.
Plugs (in a gasket passage, and in body
lumens and fluid pathways).
The defect rate had, on occasion, exceeded
66,000 defects per million (DPM). This was not the
rate the customer saw, because that in-house rate ini-
tiated lot rework by 100% to 300% retest, but as with
any quality effort based on inspection, rework/retest,
and reinspection, all defects were not caught. This
was confirmed by the complaint rate (both from sister
plants and, to a lesser degree, by the end-user),
which was substantially lower than the in-house QC

Special Edition: Corrective and Preventive Action 11


rates, but reflected the same types of defects in the
same relative proportions. Incidentally, this field data
did reflect the data initially found in-house, two to three
months later, but by a reduced amount. This indicated
that in-house testing was addressing and finding the
key field concerns/complaints.
Some engineering changes had also recently
been tested and implemented, including the re-
placing of hand siliconing of the gasket with bulk,
machine-siliconing, and some body mold tooling
modifications to aid gasket retention. Concurrently,
freon washing of the parts was being phased out
due to environmental concerns with freon.
The Goal
The initial goal of the project was to identify all
sources of product and process variability, and
take controlled actions in reducing it. Furthermore,
the team was to define the defects per million rate,
bring it down into a 400 500 DPM range desired
by the receiving (sister) plants, and achieve this
rate without rework/retest.
Data
The first step in the product improvement/defect
reduction project was evaluating existing data
sources and associated reports for past builds (pro-
duction and work order documentation, control
charts, maintenance and equipment parameter
sheets, in-coming, in-process, and final QC data,
etc). In-process and final QC testing had always
been a part of this product line, with sampling and
AQL-based (the old Mil Std 105D and -E; replaced
by ANSI/ASQ[C] Z 1.4) acceptance and rejection of
lots. Lot size was approximately 125,000, and func-
tional samples per month averaged 9,000 during the
project period. Testing consisted of the visual review
of parts, dimensional checking of key areas on the
individual molded and purchased parts, then func-
tional testing of the assembled unit (see Figure 1).
Unfortunately, as is so often true of such test data,
it was only used for lot acceptance/rejection, not for
in-process monitoring, reaction, and corrective action.
The Team
An early step was assembling a product qual-
ity/productivity improvement team. With the
approval of affected department managers, a cross-
functional team was formed, with a representative
12 Special Edition: Corrective and Preventive Action
John E. Lincoln
each from R&D, Manufacturing Engineering (engi-
neer and technician), Production (supervisor, line
technician, and operators as needed), Molding, In-
Process/Manufacturing QA/QAE (engineer, techni-
cian, and inspector), Material Management
(scheduling/planning and purchasing), Facilities and
Maintenance (mechanics/supervisor, as needed).
Individuals from these disciplines were selected
and invited to commit to weekly meetings and
assignments, as required, to improve the product
quality and the process productivity. The project
was estimated to take one year to complete.
The project leader looked for individuals who
would get excited over such a project, were open
to new ideas, had a good understanding of their
portion of the products assembly and test prac-
tices, and would be a good fit to the team. Team
members had to be willing to direct their competi-
tive spirit to the problem and its solution(s), not
against each other (individual or departmental),
look at product and processes with fresh eyes,
learn new techniques, and change their mindsets.
They also had to be willing to change, to make and
accept mistakes (with the project leader taking any
management heat in order to shield the team and
foster a risk-taking environment, as opposed to the
previous risk-adverse environment).
Not all individuals originally selected worked out,
and some personnel adjustments/substitutions were
required during the course of the project (approxi-
mately one year, part-time).This assignment was in
addition to their existing workload. So, individuals
had to be good time managers, hard workers, moti-
vated by challenges and the excitement of creating
something new (new solutions). They had to move
from doing a job, to train in and learn new tools,
solve problems, pose and evaluate/test solutions,
institutionalize and document positive change. In
doing so, they would personally benefit by enjoying
personal and professional growth.
The cross-functional team became a key ele-
ment in the projects ultimate success. Individual
members had a personal stake in the outcome.
They became deeply involved and personally com-
mitted. They had permission to make mistakes
(once, not repeatedly, for the same mistake) in
attacking problems with attempted solutions. With
permission came protection from management
(Dr. Demings drive out fear).
They learned new problem-solving tools. This
generated excitement that became the basic glue
that kept the team going, even though their team
John E. Lincoln
responsibilities were in addition to their normal
jobs. The mission was clearly stated, results
would be measurable, and the importance to the
business unit (in dollars saved, with scrap and
rework almost eliminated, customers pleased, and
lot quantities and delivery dates made predictable)
had managements attention. There was a clear
and compelling reason for the teams existence.
During the course of the project, with its interim
successes, some operators attitudes changed
from saying they wouldnt want the product used on
themselves or loved ones, to it becoming the preferred
product. As the project progressed and initial goals
were met, team members pushed to raise the bar,
the standards. Their confidence in themselves, in each
other, and the teams synergy caused them to chal-
lenge perceptions, to push the envelope. It was excit-
ing and infectious. Unfortunately, it only lasted as long
as the need/problem existed. Once the problem was
solved to managements satisfaction, the teams
emphasis shifted, and the excitement ebbed.
The Tools
The team was familiarized with the seven tools
for improvement mentioned in the January 1998
issue of the Journal of cGMP Compliance:
Ishikawa (Cause and Effect, or Fishbone)
diagram.
Flow charting.
Pareto charts.
Run/Trend charts.
Histograms.
Scatter diagrams.
Control charts.
Familiarization occurred as each tool was incor-
porated, with a general discussion of the tool, its
use, underlying assumptions, but with real learning
only developing through actual use and interpreta-
tion. Project trend charts and histograms were
included in a new monthly product quality report
(see Figures 5 7).
The Meeting Format
The team meetings were scheduled once a week,
for one hour or less. The project leader published a
minutes memo at the conclusion of the previous
weeks meeting, outlining what had been discussed,
project status, what was agreed to for future work,
responsible parties, estimated deadlines, and com-
pletion dates. Supplemental Gantt charts for sub-pro-
jects were appended as needed. Although any of the
project management software packages could have
been used, the team used a standard word process-
ing program using keyboard symbols (e.g., |, , >,
=, x...), to develop the Gantt charts and their up-
dates, with headings, such as, Description, Resp.
(Responsible), and the time line by month.
When an assignment fell behind schedule, the
Gantt chart was modified accordingly and redis-
tributed, and appropriate comments were made in
the weekly memo. The memo was distributed to all
participants and other individuals in management
who had a vested interest in the project within a
day after the meeting. Elements of the minutes
were extracted and disseminated to cognizant ven-
dors and/or receiving plants.
The weekly meetings, the meeting minutes
memos, and the Gantt chart(s) became key project
management tools, supplemented by additional
unscheduled visits and hallway meetings as
needed with appropriate individuals/functions.
AQL to DPM
The existing data was taken and incorporated into
a monthly report. The data was changed from AQL
(Acceptable Quality Level) to DPM (Defects per
Million; Defects/Sampled units x 1,000,000, see
Figure 2) for each of the qualities being measured.
The team preferred the more precise, easier to relate
to measurement data resulting from DPM for the
measurement and reporting of product quality and
effects of component or process changes.
Trending
(Pareto and Histogram; Figures 4 7)
The device was inspected for visual (printing and
molding) defects and functional problems (leaks,
blockages, and torque) with the failure logged.
Engineering then further evaluated actual failed units
and made tested, verified/validated changes as
required through the plants change control system.
However, trending of the source of the failure was not
being conducted. Such trending was then developed,
made part of the monthly report, and copies of the
charts were posted in the manufacturing area.
Trending was by category of defect. A monthly pro-
duction floor meeting, approximately 15 minutes long,
was held when a new chart was posted to explain the
Special Edition: Corrective and Preventive Action 13
 John E. Lincoln

Figure 2
FI Project Year One
Functional Defects Per Million
Defects Per Million (Thousands) 60,000

50,000

40,000

30,000

20,000

10,000

0,000
JAN FEB MAR APR MAY JUN JULY AUG SEPT OCT NOV DEC

Air Test Referee FQA

Note: January is a partial-build month due to a two week line shut down in December.

trends and what was being done to address the ber gasket. Key dimensions were checked by mold-
problems, and how each workers efforts best suited ing QC on the in-house molded parts, and by incom-
the projects needs. This discussion, supported by ing QC on the vendor-supplied gasket. Buy-offs of
real data and not opinion, was presented in a highly some non-conformances were routinely practiced.
visual format (the charts). This proved to be another Key component inputs were:
major contributor to the projects success.
Raw material variability (rubber durometer,
The Ishikawa (Cause and Effect, plastic resin lot variability, resin drying,
Fishbone) Diagram (Figure 3) regrind percentages, et al).
Molding parameters of the three components
A major activity for the team was defining the key (barrel, tool dwell, temps, pressure).
product and process inputs. This was done with an Cavity-to-cavity variability (multiple cavity tool-
Ishikawa diagram on a white board in the confer- ing used for all three parts).
ence room during brainstorming sessions (Figure Secondary processes, e.g., deflashing, mold
3 presents a simplified version). All viable inputs release, cleaning, handling.
were recorded, then deleted or retained, as data Key in-house assembly process inputs were:
became available and was analyzed to verify the
key inputs that affected product/process variability. Parts injection molding.
Parts washing.
Key Inputs Gasket siliconing.
Oven curing.
As mentioned, the major device components con- Gasket assembly machine.
sisted of the two outer molded plastic parts (injection Manual assembly.
molded) and a vendor-supplied molded natural rub- Ultrasonic welder (unit assembly) parameters,

14 Special Edition: Corrective and Preventive Action

John E. Lincoln

Figure 3
Ishikawa Cause and Effect Diagram Abbreviated
Documentation Materials Process

Body M Environmental
Drawings Gasket Temp/Hum Mold Release
Body F Foreign Objects
SOPs Ink Siliconing
Freon Particulate
QA Reports Raw Materials GRR

QC Test Data W.O. Packages Washing

Deflash
Other Documentation Molding
Maintenance
Records Problem Statement
Tooling / Cavities / Parameters
Reduce Variability.
Reduce Defect Level
from 50-60000+
Training Air/Leak Packaging DPM to 4-500 DPM
Follow SOPs Torque Visual
Welder 1 Tweaking
Supervision Gram Force Appropriate
Welder 2 Air
Three Shifts Water Referee Dims
Welder 3 Electricity
Experienced Equipment
Oven Gasket Assembly
Parameters
Silkscreen
Fixturing
People Tests Machines

including booster, pre-pressure, weld and hold Key inputs by defect:

times, weld pressure, and collapse distance.
Ultrasonic welder inputs: Air pressure and
electricity; nest and horn design and material.
Personnel (assembly, set-up/maintenance, and
test) inputs included:
Training.
Experience.
Person to person, shift to shift, and within
(single) person variability.
Plugs: Gasket rotation, particulate, gasket
misplacement, silicone variation.
Body Leaks: Welding/swaging variation
(between u/s welders, 3 E, between shifts [3],
and within welder.
Failure to Shut Off: Damaged parts,
improper silk-screen orientation, particu-
late.
Off Gauge: Print misalignment (screen shift,
part/mandrel shift).

Test methodology: Evaluation of input by the team, with supple-

Tests: Torque, air/leak, functional/water leak
(referee test for air test failures), visual (silk-
screen print quality).
Test SOPs.
Test equipment.
Appropriateness.
GRR gauge (equipment, process, person-
nel) repeatability, subjectivity, and reproducibility.
mental testing and re-evaluation as required
allowed the real key inputs to be isolated, modified,
if required, with results tracked.
Communication
At the start of the project, only a monthly quality
report on the product line was available and pub-
lished. The project added the following:

Special Edition: Corrective and Preventive Action 15

 John E. Lincoln

Figure 4
Best and Worse Welder Analysis

DEFECT TRENDS

Number of Defects
500

400

300
Number

200

100

0
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC
Welder 1

Shut Off Body Leak Plug

DEFECT TRENDS

Number of Defects
500

400

300
Number

200

100

0
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC
Welder 2

Shut Off Body Leak Plug

Note: January a partial-build month due to a two week line shut down in December.

16 Special Edition: Corrective and Preventive Action

John E. Lincoln

Figure 5 The Fix(es)

Monthly QAE Report The goal was to analyze the part each of these
TOC and Summary inputs contributed to the problem (or lack of). DOE
(design of experiments) was not a familiar tool at
May Table of Contents the plant, so the problem was initially attacked by
Page means of reducing/eliminating variability by the
A. Monthly Summary 1 cheaper, easier-to-implement fixes first. The theory
B. Manufacturing Inspection being that if it can be demonstrated not to add an
1. Percent Defective by Welder 2 unknown variable to the process and, a priori,
2. Air Test % Defective 3 appeared to be a fix, it was validated/imple-
C. In-Process QA Inspection mented (under change control), and then moni-
tored after the fact. Some examples were the air
1. Percent Lots Nonconforming 4
surge tanks, the electrical uninterruptible power
2. Percent Defective 5 supply (UPS), standardization of welder parame-
3. Defect Analysis 7 ters (see Figure 4). More critical changes (e.g.,
D. FQA Inspection molded part modifications, new process parame-
1. Flow Rate FQA 8 ters, addition/deletion of a process step) were pilot
2. Packaging Percent Defective 9 tested off-line prior to validation and then imple-
E. NCMRs 10 mented (also under change control).
A change of philosophy was immediately insti-
tuted. Inspection procedures were changed to
Excerpt from Monthly QAE Report Summary, Jan. mandate immediate reaction to declining air test
May, two years later: data, rather than to the less sensitive follow-on
Functional Defects Per Million: functional fluid testing (the referee test), previ-
Current Month YTD Defects/ ously used to retest an air test failure prior to for-
Million Rate mally accepting/rejecting a unit.
Total Total Year An important, but hard-to-implement, change
Quantity Functl. Quantity Functl Current to was eliminating intuitive equipment adjust-
Inspecd Defects Inspecd Defects Month Date ments (process tweaking, modifying, interfer-
Air Test 9,750 14 41,000 47 1,436 1,146 ing, altering), even within previously allowable
Referee 9,750* 0 41,000 6 0 146 ranges, by operators/mechanics (Dr. Demings
(water) famous tampering with a stable system mar-
In-Process 52 0 296 0 0 0 bles-in-a-funnel demonstration), that only serves
QC** to increase variation.
FQC 320 0 1,740 0 0 0 Future process adjustments, if needed, would
be authorized by the team after being tested and
validated by engineering (ME and QAE).
Quantity Inspected under air test; only air test failures
were referee tested with water. Total sample size is re- The initial steps taken were multi-faceted. The
tained for referee test to maintain DPM rate correlation. gasket vendor was visited/audited and assisted to
** Visual/packaging inspection only. characterize their incoming raw material and
reduce variability in their molding process by
implementing written SOPs for process parame-
Monthly defects/million report.
ters. Line clearance and head covering procedures
Weekly QPI meetings/minutes.
were implemented with shop floor personnel.
Weekly defects reports.
The deflashing and parts washing/cleaning
Weekly pareto charts.
operations were flow charted and modified/up-
Monthly defects/lot graph, with copies posted
graded (equipment enhancements, fluid filtration,
in production area.
PM program) to reduce a source of gasket block-
Meeting with production personnel as
ages. When plant IQC testing was changed, incor-
required.
porating a more sensitive measurement of gasket
Jawboning for a culture change.
material hardness than durometer, resulting in an

Special Edition: Corrective and Preventive Action 17

 John E. Lincoln

Figure 6
Monthly QAE Report Operation Inspection, Manufacturing QC

Air Tester Manufacturing

Percent of Mfg/Referee Failures
Percentage Defective by Welder 0.6%
Current Month
5.0% 0.5%

4.0% 0.4%
Percentage

Percentage
3.0% 0.3%

2.0% 0.2%

1.0% 0.1%

0.0% 0.0%
# # # Total JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC YTD

Body Leak Shut Off Plugs

Defect Analysis by Welder Manufacturing Air/Referee Testing

Welder Qty. Totals Shut-Off Leak Plug
Quantity Inspected #1 #2 #3 Total Month Insp. Def. % Def Def % Def % Def Def % Def
JAN 5,375 0 0.00% 0 0.00% 0 0.00% 0 0.00%
Quantity Inspected 4,375 4,500 875 9,750 FEB 9,275 1 0.01% 0 0.00% 1 0.01% 0 0.00%
Body Leak 0 0 0 0 MAR 10,750 0 0.00% 0 0.00% 0 0.00% 0 0.00%
0.00% 0.00% 0.00% 0.00% APR 5,250 5 0.10% 1 0.02% 4 0.08% 0 0.00%
Shut Off 12 1 1 14 MAY 9,750 0 0.00% 0 0.00% 0 0.00% 0 0.00%
0.27% 0.02% 0.11% 0.14% JUN
JUL
Plugs 0 0 0 0 AUG
0.00% 0.00% 0.00% 0.00% SEP
Total 12 1 1 14 OCT
0.27% 0.02% 0.11% 0.14% NOV
DEC
YTD 41,000 6 0.01% 1 0.00% 5 0.01% 0 0.00%
Previous Years Avg. 0.04% 0.01% 0.03% 0.00%

in-house developed gram-force measurement fix-
ture, a duplicate test fixture was made and sent to
the vendor with a copy of the SOP to facilitate
speaking the same language. Tooling modifica-
tions were made to better equalize the cavities
within and between tools and to add a test button
cavity to each tool (for more accurate gram-force
measurements).
Changes were instituted to plant SOPs, allowing
immediate reaction to negative data by stopping
the line and evaluating the problem/corrective
action prior to resuming production. This minimized
continued production of questionable product. In
this case, the frequent reworks of marginal produc-
tion builds consumed more time/money than the
new policy of shutting the line down, so it was
accepted by management. The frequency of need
for such a drastic measure decreased as the pro-
ject continued and problems were defined, located,
and reduced/eliminated.

18 Special Edition: Corrective and Preventive Action

John E. Lincoln

Figure 6 (Continued)
Monthly QAE Report Operation Inspection, Manufacturing QC

Lot Nonconformance MQA Percent Defective

50% 2.6
2.4
2.2
Percent of Lots Nonconforming

40% 2.0
1.8
30% 1.6

Percentage
1.4
1.2
20% 1.0
0.8
0.6
10%
0.4
0.2
0% 0.0
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC YTD JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC YTD

FUNCTIONAL COSMETIC

MQA/FDA Functional Lot Nonconformance MQA Functional Percent Defective

Lots Guaranteed Qty. Total Functional Cosmetic
Month Inspected Lots Percent Defect Description Insp. Defects % Defects % Defects %
JAN 3 0 0.0% JAN 240 0 0.0% 0 0.0% 0 0.0%
FEB 7 0 0.0% FEB 530 0 0.0% 0 0.0% 0 0.0%
MAR 6 0 0.0% MAR 410 0 0.0% 0 0.0% 0 0.0%
APR 3 0 0.0% APR 240 0 0.0% 0 0.0% 0 0.0%
MAY 4 0 0.0% MAY 320 0 0.0% 0 0.0% 0 0.0%
JUN JUN
JUL JUL
AUG AUG
SEP SEP
OCT OCT
NOV NOV
DEC
DEC
YTD 1,740 0 0.0% 0 0.0% 0 0.0%
YTD 23 0 0.0%
Previous Years Avg. 0.0% 0.0% 0.0%
Previous Years Avg 3.9%

The in-house vendor, the molding department, That process had been demonstrated to plug a
validated their molding processes on the presses critical orifice with particulate (even after adding fil-
that were dedicated to this products parts. A tration of the cleaning solution to attempt to elimi-
clean parts program was developed, imple- nate the problem).
mented, and validated, consisting of enclosed and Cavity-to-cavity variation of all parts and defect-
filtered air-bathed conveyors. (This project was by-cavity were tracked/logged and statistically ana-
helped along by the need to phase out the use of lyzed by histograms, scatter diagrams, and regres-
freon for the cleaning, and no acceptable substi- sion analysis to ID key variables within and
tute had yet been identified.) This change virtually between cavities and correct/eliminate them.
eliminated the need for molded parts cleaning. Assembly process variability was reduced by

Special Edition: Corrective and Preventive Action 19

 John E. Lincoln

Figure 7
Monthly QAE Report Manufacturing QC; Final QC
Total Non-Conforming Material Reports (NCMRs)
Average Flow Rate FQA
By Setting
Defective by Category 150
MQA 140
130 124.0 123.0 120.0
1.00%
120 123.2 119.6
0.90% 110
0.80% 100
100.1
0.70% 90
Percentage

Percentage
0.60% 80
70 64.4 63.1
60 64.3 61.1 69.5

0.50%
0.40% 50 54.25
0.30% 40
31.3 30.0 29.1
30
0.20%
20

31.0

26.2

29.6
0.10% 10
0.00% 0
Flow Leak Shut Off Plug Other JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC YTD AVG.
125 Setting
Month Year-to-date 30 Setting 60 Setting

MQA Functional Defects by Category Flow Rate for the Month

Flow Leak Shut-Off Plug Other 30 Setting 60 Setting 120 Setting
JAN 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% AVG 29.1 61.1 120.0
FEB 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% STD 3.6 4.9 10.9
MAR 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% MIN 22.0 50.0 91.0
APR 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% MAX 37.0 75.0 145.0
MAY 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% RANGE 15.0 25.0 54.0
JUN PERCENT ERROR -3.0% 1.8% -4.0%
JUL COV 0.125 0.081 0.090
AUG
SEP AVERAGE PERCENTAGE
OCT ERROR FOR THE YEAR -1.47% 2.47% -4.13%
NOV PREVIOUS YEARS -3.72% 0.24% -2.57%
DEC
YTD 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00%
Prev.Years Avg. 0.00% 0.00% 0.00% 0.00% 0.00%

tracking the production defects from each of the department). An air holding (surge) tank was
three ultrasonic welders (see Figure 4), and initially added to the air supply lines to each welder, elimi-
standardizing the welder parameters to the best nating the same type of air supply surges in the
welder (with minor variations due to any unique plant. An electric filter was added to the vibration
characteristics of a particular welder, horn, and bowl on the gasket assembly machine to further
nest combination). Further consistency was condition its power.
achieved by adding UPS to the ultrasonic welders The three welder changes had a major impact
reducing power surges/spikes that occurred when on assembled part consistency and after imple-
plant and grid power demands fluctuated (this mentation, we noted a marked decrease in the
trended information was obtained from the facilities defect per million rate that month, which held in

20 Special Edition: Corrective and Preventive Action

John E. Lincoln

Figure 7 (Continued)
Monthly QAE Report Manufacturing QC
Total Non-Conforming Material Reports (NCMRs)
Air Tester Manufacturing
Percentage of Mfg/Referee Failures
10
Percentage Defective by Category 9
1.5%
1.4% 8
1.3%
1.2% 7
Percentage Defective

Number of NCMRs
1.1% 6
1.0%
0.9% 5
0.8%
0.7% 4
0.6%
0.5% 3
0.4% 2
0.3%
0.2% 1
0.1%
0.0% 0
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC YTD JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC.

30 Setting 60 Setting 125 Setting

NCMR Analysis
MQA Packaging Defects Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec YTD
Mold 0 0 0 0 0 0
Qty. Total Defect Description Dimen. 0 1 0 0 0 1
Inspect. Defects % Specs. 3 0 0 0 0 3
JAN 26 0 0.0% Durom. 1 0 2 0 0 3
FEB 101 0 0.0% Other 0 0 0 0 0 0
Subtotal 4 1 2 0 0 7
MAR 78 0 0.0%
In-Process QA
APR 39 0 0.0% Durom. 2 0 0 0 0 2
MAY 52 0 0.0% Parameter 0 0 0 0 0 0
JUN Flow 0 *1 0 0 0 0
JUL Leak 0 0 0 0 0 0
Plug 0 0 0 0 0 0
AUG Visual 0 0 0 0 0 0
SEP Dimens. 0 0 0 0 0 0
OCT Other 1 0 0 1 0 2
NOV Subtotal 3 1 0 1 0 5
Total 7 2 2 1 0 12
DEC
MRDRs
YTD 296 0 0.0% Prod. 0 10 3 4 6 23
1992 Avg. 0.2% MQA 0 0 0 0 0 0
Comments: Case Inspection Only / 125 Unit Inspection Per Lot. Partial Build NCMRd / Scrap Other: Particulate on gaskets

subsequent months. of gasket silicone, mentioned earlier, was further

An upgrade of welder fixture prepressure dies
was initiated and accomplished, to even radial and
compressive pressure on the assembled compo-
nents prior to ultrasonic welding, and to further
ensure consistency (especially torque and flow
rate), device to device.
Silk-screen printer mandrels were modified for
consistency and mating part fitment reducing par-
ticulate generation. The change to bulk application
improved with the addition of a recirculating filtra-
tion system minimizing particulate migration.
Training of production operators and QC per-
sonnel was enhanced. This was performed by
Manufacturing and QA Engineering personnel, with
the same trainers instructing all three shifts to
refine and improve upon their previous on-the-job
training (OJT) (which had proved inconsistent at
best).

Special Edition: Corrective and Preventive Action 21


All these improvements were implemented in
stages. This allowed the effect of each change on
the DPM rate each month to be monitored, and
any adjustments/refinements to be made and veri-
fied prior to implementation of the next major
improvement. As mentioned above, if several
planned changes were certain to have no negative
effects on the process a priori they were imple-
mented as a package, and monitored accordingly.
In such cases, only the cumulative effect of such
grouped change(s) would be observable in future
DPM rate shifts.
Interestingly, near the end of the project, the
product enjoyed zero defects for one six-month
period (thats with approximately 9,000 samples
functionally tested per month). Then the DPM rate
bounced between 25 and 84 DPM for another six
months, after which the project was deemed com-
pleted by management. Subsequent variability
was tracked primarily to incoming parts (gasket)
variability. Although this was substantially reduced,
it was never eliminated, due to the inherent vari-
ability of natural rubber. No suitable alternative had
been identified that met all the design specifica-
tions, so the variability from this source continued.
Epilogue
Although this narrative portrays a smooth pro-
gression, the process was messy. There were
some fits and starts and steps backward (espe-
cially with the hands-off, no tweaking of equip-
ment policy). Some personnel left, some changed
responsibilities, so others had to be recruited and
brought quickly up to speed. Other responsibilities
and demands on constrained resources constantly
intruded.
Initially, the gasket vendor was reluctant to
cooperate. They blamed the companys own parts
and production personnel/equipment for problems
and would not react to requests for changes. This
was solved by three events: 1) Refining the data to
clearly pinpoint the source of problems, and quan-
tify rejects by source (the Pareto) that clearly
demonstrated what percentage of the total rejects
was due to their part; 2) A contraction in the rubber
molding industry, making the remaining vendors
more customer-focused; and 3) Increased quality
demands by the gasket vendors other customers
(aerospace and automotive) for the same kind of
quality improvements we were demanding.
Not all of plant management was solidly behind
22 Special Edition: Corrective and Preventive Action
John E. Lincoln
the project, even after it began to show some initial
success. However, as the successes crystallized
and became long-term, there was more support
and recognition. The team was recognized with
pictures and an article in the division newspaper,
increasing compliments from the receiving (sister)
plants, and a request (accomplished) for a presen-
tation of the teams efforts/results to corporate
management.
The product quality improved with proper atten-
tion and resources focused on it, based on factual
information/data, but started to degrade somewhat
whenever it was taken for granted and not main-
tained by programs of continuous improvement,
such as those utilized in the project outlined above.
Another year later, this process had defect rates
averaging approximately 1,100 DPM per month
(see Figures 5-7). While this was a vast improve-
ment over the rate prior to the start of the project, it
was nowhere near what was sustainable when
more attention and a team effort was focused on it.
The assumption is false that once a project to
improve quality achieves its goal, it can end. True,
the intensity/urgency may be decreased somewhat
(with some company cultures, this may not be a
possibility) while still maintaining continuous
improvement. But, ceasing such methods alto-
gether does not leave the process and product at
the level of quality achieved, but allows (encour-
ages) its slow degradation process/product
entropy.
Concurrently, somewhere, globally, a competitor
is intensely/urgently refining their product/ process.
The message is obvious.
 Case Study
Failure Analysis
& Corrective Action
for an IV Catheter Component Problem
W
e are all faced with dif-
ficult situations that
Understanding require quick response
and rapid corrective action. The
customer following case study outlines a
situation that any company could
specification face and methods used to cor-
rect the problem. The authors are
relationships and serious proponents of design
control and use design control
methodology are not only as a means of develop-
the basis of ing new products, but for analyz-
ing and correcting problems.
this study. Understanding customer specifi-
cation relationships and method-
ology are the basis of this study.
Background
A customer needed an intra-
by venous catheter applicable for
John Rodriguez use in both short term and con-
Manager of Process tinuous infusion therapy. To meet
Design and Development this requirement, the firms cur-
Becton Dickinson Infusion rent product was modified to
Therapy Systems include a PRN, a rubber injec-
and tion port, for use in short-term
Don Wood therapy. The PRN was designed
Director of Equipment to be a removable adapter
and Process Design which, once removed, exposed a
Development luer for connection to an IV set
Becton Dickinson Infusion for continuous therapy. A luer
Therapy Systems connection is defined in ANSI
Special Edition: Corrective and Preventive Action
standards and must meet cer-
tain dimensional and functional
requirements. The functional
requirements include such char-
acteristics as the ability to with-
stand pressure without leaking,
disconnection force, etc.
Situation
After the product went into
production, final inspection
detected adapters that were dif-
ficult to remove. The release
criteria was based on the
inspectors ability to remove the
adapter manually. Initially, the
lots were released based on a
secondary evaluation of the lots
by engineering who found that
they were able to remove the
adapters by hand. After several
months the situation worsened
and the engineers were unable
to remove the PRN. As a result,
production was unable to pro-
duce a product that met the cri-
teria of easily removable and
the production lines were shut
down. The situation intensified
as production blamed the prod-
uct design, the designers
blamed production and the pro-
23

cess engineers, and in the mean time, the prod-
uct was not available for sale. A team was
formed to evaluate and resolve the problem. A
summary of initial test results is presented in
Figure 1.
The Remedial Journey
The team took a broad view of the problem
since the cause was not readily apparent. Analysis
of the production lots over time revealed a deterio-
rating condition that may have been caused by
poor design, unstable processes, or uncontrolled
production methods. The team decided to do a
design review and determine if good design con-
trol methods had been used during product devel-
opment. An overview of the design control system
employed is shown in Figure 2.
As the design review progressed, team mem-
bers became aware of an ambiguous design
requirement, specifically, the term easily remov-
able had not been defined quantitatively. Without a
measurable specification, there was no chance
that the balance of the development activities could
be linked back to customer requirements, and no
method of checking the validity of product dimen-
sions or processing factors. As a result of this dis-
covery, the team developed a plan of attack. The
plan included determining what the customer
24 Special Edition: Corrective and Preventive Action
John Rodriguez & Don Wood
meant by the term easily removable, converting
that information into an input specification, and
evaluating the product design and process factors
against the new specification.
Developing the Input Specification
In order to understand the input specification,
customers were engaged in a way that would lead
to a quantifiable characteristic. From the cus-
tomers point of view, the PRN is removed by
twisting so that the adapter unscrews from the
body of the product. From an engineering per-
spective, this would relate to torque. A variety of
samples were assembled that had varying, but
known, removal torque. By having customers
remove the adapter and give feedback on accept-
ability, a relationship between removal torque and
customer acceptance was developed. This is
demonstrated in Figure 3.
An additional important design requirement
was that the adapter must not leak. The team
tested the adapter and product for leaks at vari-
ous torque values. From the customer tests and
lab tests, an input specification was developed for
torque that took both requirements into account.
The team now had a method of measuring their
success as they corrected the product and pro-
cess designs.
John Rodriguez & Don Wood

Figure 2
Design Control System

Product
Verification Specification Verification
(Design Output)

Identify Create Complete Implement

Customer Input Development Design
Needs Specifications Tasks Verification Output

Manufacturing
Specification
(Design Output)

Desired Actual
Outcome Design Validation Outcome

Field Conditions

In order to modify the product design, the team
needed to determine which design factors had the
most impact on removal torque. A statistically
designed experiment was conducted to evaluate
the design factors as compared to the input specifi-
cation. After completing the evaluation, the team
discovered that surface finish had the most effect
(see Pareto Analysis shown in Figure 4). With this
knowledge, the team was able to relate surface fin-
Figure 3
Customer Acceptance
Various Removal Torque
100.0%
80.0%
Percentage Acceptance
ish to the input specification and develop a specifi-
cation for molded parts.
Since the greatest impact of the components
by the product design changes were injection
molded, the team then determined how to mold
the right surface finish. This required the team to
determine how the finish on the steel core pin
transferred to the plastic component during the
molding process. The team manufactured core
pins with a variety of finishes and measured the
plastic finishes produced as the parts were
molded. Using this data, the team established a
correlative (see Figure 5) between steel finish and
plastic finish that followed a well-behaved mathe-
matical function.
The team then established core pin specifica-
tions based on this function. As this work was pro-
gressing, the molding department was establishing

60.0%
how to accurately measure surface finish and
machine core pins that met the specification.
40.0% In the assembly department, the team wanted
to eliminate causes of variation affecting the
20.0%
input specification. Through experiments, the
0.0%
team determined that assembly torque had the
E H
Removal Torque
L R greatest impact. This is demonstrated in

Special Edition: Corrective and Preventive Action 25

 John Rodriguez & Don Wood

Figure 6. By providing the

Figure 4 assemblers with tools that limited
Pareto Analysis of Critical Factors as Function torque to within a certain range,
of Various Surface Finish the main source of variability was
eliminated. The assemblers were
trained in the new assembly
technique and production began.
Pareto Condition 1 Removal Torque
Factor 1
Results of the
Factor 2

Factor 2 x Factor 1
Remedial Journey
Factor 3

Factor 4
The effect of the teams effort
Factor

Factor 4 x Factor 1
was immediately felt throughout
Factor 3 x Factor 1
the organization. The molding
Factor 4 x Factor 3
department was able to measure
Factor 4 x Factor 3 x Factor 1
whether or not acceptable parts
Factor 2 x Factor 3
were produced by monitoring the
Factor 2 x Factor 3 x Factor 1 surface finish of the core pin
0 1 2 3 4 5 6 steel. Assembly assured their
Effect
work quality by properly setting
up their assembly tools. At final
release, a measurable release
Pareto Condition 2 Removal Torque
criteria allowed release deci-
Factor 3
Factor 2
sions to become consistent.
Factor 1 x Factor 2 After manufacture of approxi-
Factor 4 mately six production lots follow-
Factor 4 x Factor 2
Factor 3 x Factor 2
ing the implementation of cor-
rective action, the team evalu-
Factor

Factor 3 x Factor 1
Factor 1 ated their work by summarizing
Factor 3 x Factor 1 x Factor 2
Factor 3 x Factor 4 x Factor 2
each lot in the form of his-
Factor 3 x Factor 4 tograms of removal torque (see
Factor 1 x Factor 4 Figure 7.)
Factor 1 x Factor 4 x Factor 2
Factor 3 x Factor 1 x Factor 4
In every case, the product
0 0.5 1 1.5 2 2.5 behaved consistently both in
Effect
terms of control (predictability)
and capability (meeting specifica-
tion). By achieving this state, a
Figure 5 stable supply of product meeting
specifications was created.
Regression Analysis Throughout the life of this correc-
Plastic vs. Steel Surface Finish tive action project, the principles
50.0
Line FIt Plot of design control and validation
were utilized. Design reviews at

40.0 y = 0.8568 x + 1,6703 the appropriate times resulted in a
better solution than could have
30.0
been achieved without an inde-
Plastic

pendent look.

20.0

Over a year after implementing

10.0

corrective actions, every produc-
tion lot has successfully met
0.0 release criteria established by the
0.0 10.0 20.0 30.0 40.0 50.0
Steel project team.

26 Special Edition: Corrective and Preventive Action

John Rodriguez & Don Wood

Special Edition: Corrective and Preventive Action 27

Beyond Compliance:
Exceeding Requirements
with
Systematic Corrective Action
Our thesis is that
any organization
that manages
its production
processes to
maximize efficient
Paradigm One
FDA regulations will choke
our business. Requirements,
changing all too often, generate
extra work and mountains of
paper. FDA auditors have no
understanding of our business
and appear intent on slowing or
shutting us down. We prepare
for site visits in fear that some
unknown discrepancy will earn
us a Warning Letter.
improving our operations.
We proactively search for per-
formance that deviates from our
standards. We effectively priori-
tize the deviations we detect,
assigning corrective action teams
to find cause, develop solutions,
and manage risks when we
make changes. Concise, thor-
ough documentation guides our
improvement efforts.

use of its resources Our production is not like other
manufacturing. Based in biolog-
will, by default, ics, it is unpredictable, more an
meet cGMP art than a science. We try to mini-
mize reporting deviations, be-
requirements. cause the paperwork burden they
generate is a distraction from
what we must do here. Our devia-
tion reporting is designed to sat-
by isfy the inspectors.
Michael Clark
Consultant Paradigm Two
Kepner-Tregoe
and Our business is run to maxi-
Wade Speir mize production efficiency. FDA
Consultant audits are seldom a real prob-
Kepner-Tregoe lem and provide useful insights
and about what we can improve. It is
David Sandahl easy to document deviations,
Partner which is part of our systematic
Kepner-Tregoe approach to continuously
W
hich paradigm is more
like yours? Which is
the one that you hear
more about, especially far from
the ears of FDA inspectors? Are
these paradigms inevitably in
conflict, or is there a reasonable
way to reconcile the two views?
Our thesis is that any organi-
zation that manages its produc-
tion processes to maximize effi-
cient use of its resources will, by
default, meet cGMP require-
ments. In our view, compliance
should not be seen as a detrac-
tor from production efficiency, but
rather as a powerful lever ensur-
ing the best possible production
with the least possible waste.1
With this view, compliance
does not mean merely meeting
FDA cGMP requirements. Real

28 Special Edition: Corrective and Preventive Action


good manufacturing practices means systematic
use of corrective action methods that not only meet,
but exceed established production standards. We
describe below how compliance management can
be harmonized with manufacturing management
methods that optimize productivity and quality.
Assumptions
The purpose of a manufacturing organization is
maximizing productivity the highest possible ratio
of outputs to inputs. It is an ideal; easy to state and
difficult to attain.
From the earliest uneasy cooperation between
hunters and gatherers, a major part of the human
quest has been to produce more output with less
input. We are only the latest participants in a contin-
uing revolution sweeping from the earliest hunters to
the first farmers, from mercantilist sea traders to the
great industrialists of the last century. Accompanying
an ever-increasing ability to produce more with less
is a profound increase in the wealth and well-being
of ever increasing numbers of people.
But revolution is not without cost. Converting
inputs to useful outputs often generates byproducts
that are neither intentional nor desirable. Econo-
mists use the term externalities to describe some of
the costly byproducts to society generated by
unregulated market forces.2 No one can be oblivi-
ous to the unintentional, undesirable byproducts of
manufacturing called pollution. In healthcare manu-
facturing, no one can be oblivious to the uninten-
tional, undesirable consequences that unsafe medi-
cal devices and pharmaceuticals can cause.
Almost everyone would agree on the need to pro-
tect public health and safety
in the development, manu- Figure 1
facture, and use of medical
devices and pharmaceuti-
cals. Most would argue at
the same time that regula-
tory requirements inherently
impede efficient business
Follow-Up
process management.
Much of the management
effort directed toward cGMP
compliance reflects this ten-
sion. Often, the emphasis Report
is on taking action any
action to reduce attention
from the FDA.
We believe much of the Copyright Kepner-Tregoe, Inc. reproduced by permission.
Special Edition: Corrective and Preventive Action
Michael Clark & Wade Speir & David Sandahl
management time and attention spent on this
approach to cGMP compliance is wasted.
Resource-efficient processes and regulation are not
opposing forces. In fact, we believe that systematic
use of corrective action techniques can help most
healthcare manufacturing organizations achieve
cGMP compliance with superior business results.
Systematic Corrective Action
An organization that seeks to efficiently maxi-
mize the use of its resources will comply with
cGMP standards by default. Within such organi-
zations, compliance means to minimize deviation
from standards. These standards are the consis-
tently and predictably obtained levels of perfor-
mance for each manufacturing process, which, in
turn, serve as a guide toward a state of superior
efficiency.
We propose a proactive model for achieving
cGMP compliance: managing resource-efficient
processes to provide predictable, documented
results. At its core is systematic corrective action.
The Logic of the Model
It goes without saying that you should be
aware, at all times, of the current state of your
operations.
Kepner and Tregoe,
The Rational Manager, 19653
A systematic approach to cGMP corrective
action includes those activities, required in both
regulations and the basic logic of manufacturing,
Systematic Corrective Action
Regulations/
Standards
Regulations guide
production planning.
Plan specifies ex-
Plan pected performance.
Report identifies
performance
problems.
Follow-up resolves
Execute
root cause of
problems.
2929
 Michael Clark & Wade Speir & David Sandahl
that an organization uses to plan, execute, report,
and follow-up on production. The system ensures
that deviations are identified and resolved so that
output standards are met (or preferably,
exceeded). These systems can be paper-based or
embedded in software applications. In either
case, they must provide a clear picture of the cur-
rent state of your operations.
Regulations/Standards
The first step in cGMP compliance based on
systematic corrective action is establishing the
production standards and FDA regulations (often
supplemented by ISO and Baldrige criteria) that
are the foundation for compliance. These define
what should occur. The critical objective is defin-
ing the regulations and standards in terms that
will be meaningful in the manufacturing environ-
ment. It is important to note that unless these
standards are understood and supported in the
organization, they are of little utility.
Figure 2
Corrective Action Systems Requirements
System Attributes
Realistic Performance Standards?
Accurate Reporting of Actual Performance?
Effective Corrective Action System?
Systematic corrective action depends, by definition, on both realistic standards and accurate actuals.
Copyright Kepner-Tregoe, Inc. reproduced by permission.
Plan
Plan is the step in which the sequencing and
scheduling of work is specified based on the regu-
lations and standards, including estimates of sup-
plies, material, and other required resources over
time. The plan must identify when, how, and who
will be involved in achieving performance require-
ments. The critical objective is providing realistic,
quantitative performance standards that can be
tracked over time. Together, the regulations/stan-
dards and the plan provide the benchmark against
which manufacturing performance is measured.
Execute
Execute is the step in which planned operations
occur to produce the required outputs according to
established regulations and standards. Meeting the
30 Special Edition: Corrective and Preventive Action
formal plan should be simple, but the caprice of
real world manufacturing can cause a variety of
deviations from the plan.
Report
Report is the step in which planned performance
is compared with actual performance. Effective
reporting precisely specifies the nature of deviations,
including their identity, location, timing, and magni-
tude. In addition, information about distinctions be-
tween successful and unsuccessful production opera-
tions must be effectively documented. The critical
objective of the report step is identifying, on a short
interval basis, all meaningful deviations between
planned and actual performance.
Many corrective action systems lose their business
value through weak reporting. Often, they focus on
extraneous information that is believed to be desirable
to meet FDA, and perhaps ISO, requirements. Figure 2
demonstrates accurate reporting is an essential logical
requirement of an effective corrective action system.
Yes/No Yes/No Yes/No Yes/No
No No Yes Yes
No Yes No Yes
No No No Yes
Follow-up
Follow-up involves resolving the deviations
between Plan and Execute identified in the Report
step. An effective approach to follow-up should con-
tinuously improve execution, as well as provide more
accurate input to better plans. Critical objectives of
the follow-up step include prioritization of deviations
for corrective action, a disciplined process for investi-
gating root cause, improving operations, and mini-
mizing the risks associated with change.
Successful follow-up requires a level of discipline
seen in few organizations. Complex management
systems, sometimes belabored by the perceived
conflict between compliance and efficiency, often
work against, rather than for, effective follow-up.
We believe effective follow up should center on
focused application of corrective action, as illus-
trated in Figure 3.

Figure 3
Systematic Model Embeds Corrective Action Logic in Follow-Up
Decision Potential
Analysis Problem Analysis
FOLLOW-UP
Problem Situation
Analysis Appraisal
Copyright Kepner-Tregoe, Inc. reproduced by permission.
Many electronic systems are designed to man-
age the information flow around the plan, execute,
and report cycle. Some dedicated systems have
been developed primarily to track each relevant
document to meet FDA requirements. However,
few systems we have seen make the vital leap
between managing compliance documentation and
improving business performance.
Ensuring Effective Corrective Action
To ensure the effective resolution of issues, sev-
eral steps are required. These include:4
Situation Appraisal: identifying and
prioritizing issues.
Problem Analysis: finding the root
cause of deviations.
Decision Analysis: selecting the best
solution for the deviation.
Potential Problem Analysis: avoiding
risks inherent in the solution.
Situation Appraisal: Bringing order and clarity
to a complex environment, setting priorities, and
planning actions to resolve each concern. This is
especially important at the operations management
level in identifying high priority and costly issues
that require action. Effectively prioritizing resource
utilization is one of the most important elements in
a well functioning corrective action system.
Problem Analysis: Investigating the cause or
causes of failure. When something goes wrong, the
question is, why? Problem analysis provides a
powerful logic for understanding the root cause of
Special Edition: Corrective and Preventive Action
Michael Clark & Wade Speir & David Sandahl
Regulations/
Plan
Standards
OPERATIONS
SYSTEM
Report
Execute
performance deviations. Corrective action that
drives business value rests upon a foundation
comprised of an effective, systematic logic for find-
ing root cause.
Decision Analysis: Making choices between
alternative corrective actions. Decision analysis is
concerned with selecting the action that best
meets agreed performance objectives, while man-
aging the risks attendant to any change.
Alternative actions may be known, or a new solu-
tion must sometimes be created. Senior manage-
ment is often involved in sanctioning the actions
that are adopted.
Potential Problem Analysis: Anticipating risks
that may arise from implementing a corrective action
and planning appropriate action before they become
reality. Preventive and contingent actions are estab-
lished to minimize risks, while promoting and capi-
talizing actions are established to extend benefits.
Forward-looking organizations can often avoid most
significant manufacturing deviations through disci-
plined use of potential problem analysis.
Information Technology/Process Thinking
We referred earlier to the sweep of progress
that can be characterized as the ongoing quest for
productivity: more output for less input. In our time,
there is no doubt that we have caught up in at
least two revolutionary streams of progress.
Information Technology has been a rising force
since the end of World War II. Relentless improve-
ments in hardware and software have driven costs
so low that every conceivable sort of business data
is now gathered, stored, calculated, and distributed
31
 Michael Clark & Wade Speir & David Sandahl

within and between entities of all kinds. If it can be Paradigm Two position.
counted, it is probably in a computer, and is as We believe that FDA cGMP regulations and
likely to be in a report somewhere. resource-efficient production are fundamentally
The IT revolution is a key enabler of the second compatible. Systematic corrective action, building
revolutionary stream of our day, Process Thinking. upon the revolutions of information technology and
Very suddenly, the business management hierar- process thinking, can quickly build manufacturing
chies derived from 18th Century military organiza- efficiency that goes beyond compliance.
tions are being replaced by organizations based on
Process Thinking. Whereas command and control Case Study Example
systems were once viewed as the key to efficiency,
it has become clear that mastery of process is the The following is a case study example of a devi-
only certain way to continuously increase the ratio ation that an effective corrective action system
of output to inputs. would address.
Oddly, the IT revolution is rather pointless with- Following a new product (TM tablets) launch, a
out Process Thinking. With more and more data lit- manufacturer received reports of customer com-
erally at their fingertips, many managers are plaints about bad tablets. Consumers provided the
awash in useless analyses and unread reports. information that the tablets didnt look right, and
Our ability to produce volumes of data has complaints were beginning to accumulate from
increased exponentially with the IT revolution. several countries in which the manufacturer did
What about our ability to make effective use of that business.
data? Add regulatory pressures to this mix and it is Following the chain of logic and data, the manu-
easy to see how organizations become FDA facturer quickly assembled the standards and plan
obsessed rather than business results focused. for production, production reports, and a compila-
Process Thinking, like any logic, makes sense tion of consumer complaints. It was clear that this
out of otherwise incoherent data. Process Thinking was a high priority concern, and a corrective action
enables us to know where to look, what to look for, team was charged with finding the root cause of
what to gather, what to exclude, and, most impor- the deviation.
tant, what to do. Process thinking must be built into Using problem analysis, the team summarized
business systems as suggested within the follow- the data as shown in Figure 4.
up step of the Corrective Action model outlined
previously. Effective process thinking allows organi-
zations to have real-time information about their Figure 4
production and quality environments and, there- TM Tablets Out of Round/Appear
fore, true control over their business systems.
Finally, it must be acknowledged that business Old and Worn
results are ultimately driven by the most powerful Is Is Not
resource available to any organization: its people.5 What TM tablets Vials, cartons
How do people act within an environment of TM tablets in 50-tablet vial TM tablets in
effective corrective action and compliance? What Out of round 12-tablet vial
(appear old and worn) Broken,
specific methods do they employ as they perform
contaminated
daily to produce the organizations business
Where Canada, Peru Switzerland
results? What do they think about when produc- All parts of tablet Specific pattern
tion deviations occur? What avenues can they
When Two weeks ago Before two weeks
take to set clear priorities, find root cause, select Continuously Sporadically,
effective solutions, and manage the risks of Consumers and retailers periodically QA,
implementation? plant inventory,
These questions are easily answered within a special testing
systematic corrective action program that is Extent Almost 25% of 50- <25%
grounded in process thinking and linked to busi- tablet stock in Peru >25%
ness processes. They must be answered to move and Canada
70% of tablets in vial >70%
organizations from a compliance first, Paradigm
All vials in carton <70%
One existence and toward a results focused or Increasing Steady, decreasing
Copyright Kepner-Tregoe, Inc. reproduced by permission.
32 Special Edition: Corrective and Preventive Action
 Michael Clark & Wade Speir & David Sandahl

A number of hypotheses had been generated
about the cause of this problem, some based on
fact, others on rumor. Senior management consid-
ered recertification of several vial and carton ven-
dors, and discussed with operations management
a thorough overhaul of the manufacturing lines.
The corrective action team tested each hypothe-
sis, using the facts they had gathered, and the
results are summarized in Figure 5.
Figure 5
application of Process Thinking to the existing data
prevented adoption of much more expensive alter-
native courses of action. A tightening of standards
and improved operations reporting gave manufac-
turing management the necessary tools to prevent
recurrence of the problem, improving both produc-
tivity and customer satisfaction. The analysis was
added to the database for the operation. And, of
course, the well-documented approach satisfied
the regulatory requirement for systematic root
cause analysis.

The Corrective Action Team

Gathered Results
Possible Cause Does Not Explains
Hypotheses Explain Only if References
Vendor A 50-tablet Why not 1. Porter, M. E. and van der Linde, C., Green and
Competitive: Ending the Stalemate, Harvard Business
vial does not protect Switzerland?
Review, September-October 1995.
product during 2. Heilbroner, R. and Thurow, L., Economics Explained
shipping (Where Markets Fail, pages 189-94), Simon &
Vendor B 50-tablet Why not Schuster, New York, New York, 1994.
vial does not protect Switzerland? 3. Kepner, C. H. and Tregoe, B. B., The Rational
product during Why not seen Manager: A Systematic Approach to Problem Solving
shipping in special ship- and Decision Making, Kepner-Tregoe, Inc., Princeton,
New Jersey, 1965.
ping test? 4. A good summary of these techniques can be found in
New carton does Why not seen Shipping is Spitzer and Evans, Heads You Win, pages 241-82,
not protect 50-tablet in special ship- different to Simon & Schuster, New, York, New York, 1997.
vial during shipping ping test? Canada and Peru 5. A compelling discussion of the difficulties encountered
in implementing IT systems can be found in Markus
Cotton is stuffed too Why not Shipping is and Benjamin, The Magic Bullet Theory of IT Enabled
tightly in 50-tablet Switzerland? different to Transformation, Sloan Management Review, Winter
vial and does not Canada and 1997.
protect product Peru
Increased Why not tablets
production in 12-tablet
rate weakens vials? Why not
tablets Switzerland?
Why not June
and July?
Copyright Kepner-Tregoe, Inc. reproduced by permission.

Based upon their analysis, the corrective action

team concluded that the most probable cause was
cotton being stuffed too tightly in the 50-tablet vial,
offering too little protection in shipping.
To test their conclusion, the team suggested
three simple tests to confirm the true cause:

Determine the actual method of shipping

Run vibration tests with plant stock
Repack cotton

These simple tests enabled the manufacturer to

make a small change in packing procedure that
eliminated the deviation. The rigorous and timely

Special Edition: Corrective and Preventive Action 33

Implementing Corrective Action:
An Escalation Approach to
Compliance and Business Value
O
ur research indicates
In the following that the primary reason
for failure in many cor-
pages, we detail rective action systems is the
absence of a disciplined escala-
the logical tion process, guiding corrective
action from problem recognition,
and practical resolution, and reporting to per-
manent improvements in proce-
requirements dures. While investigation of
for effective nonconforming product is a
known requirement of the cGMP
implementation of environment, implementation,
like God, is in the details. In the
corrective action. following pages, we detail the
logical and practical require-
ments for effective implementa-
tion of corrective action.
Unfortunately, many quality
systems are awash with investi-
gation documentation that offers
no clear path to process im-
by provement and, thus, no added
Michael Clark value to the business. Filing doc-
Consultant uments becomes the primary
Kepner-Tregoe driver of activities, consuming
and hours of meeting time, but pro-
Wade Speir ducing little progress toward
Consultant finding the cause of manufactur-
Kepner-Tregoe ing deviations. Absent appropri-
and ate logic and activity, documen-
David Sandahl tation cannot, by itself, produce
Partner effective corrective action.
Kepner-Tregoe We believe that the intent of
34 Special Edition: Corrective and Preventive Action
cGMP regulations can best be
achieved by the adoption of a
disciplined escalation protocol,
much like those employed by
help desk providers.1 The data
and logic requirements of this
approach are described below in
detail, but first we must establish
some basic assumptions.
Assumptions
The manufacturing organiza-
tion must have a clear, well-com-
municated strategic direction. This
strategy must drive specific, vali-
dated, measurable performance
standards for manufacturing. The
management and control system
must be capable of identifying, at
short intervals, performance devi-
ations against these standards.
Unfortunately, rather than
actively managing traditional
manufacturing performance fac-
tors such as throughput, quality,
timeliness, and cost, many
cGMP manufacturing planning
and control systems seem to be
driven by the requirement to
generate documentation.
Standards are often unclear, and
the strategy of the organization
may not be well articulated.

The Logic of Deviation Escalation
In production environments, the logic of the
deviation control procedure is likely to break down
at several links in the chain.
Figure 1
The Deviation Escalation Procedure
What Does Your System Do When the Answer is No?
Recognize a Yes Find True
Problem? Cause?
No
A deviation is not yet
recognized due to
unclear standards or
poor measurement
Copyright Kepner-Tregoe, Inc. reproduced by permission.
The reality of manufacturing is that few individu-
als can do everything that they should to implement
effective corrective action. Examine some of the
limitations many individuals in manufacturing face.
Recognize a Problem
The operator does not know whether his or her
products or processes have deviated from fuzzy or
nonexistent performance standards. This can be
due to unclear standards or inadequate measure-
ment technology.
Find True Cause
The operator notices a deviation and initiates a fix
that quickly brings the process back into operation or
reports a problem that can be handed off to mainte-
nance for quick resolution. Problem solved. But
maybe not. This conclusion presumes a few things:
The operator is fully aware of the process
performance requirements;
This particular occurrence is not part of a
Michael Clark & Wade Speir & David Sandahl
wider performance trend outside the scope of
experience or knowledge of the operator;
The fix does not require any deviation from
already established Standard Operating
Procedures (SOPs);
Yes Select a Yes Implement?
Fix?
No No No
Is there a defined escalation process to
handle the issue?
All performance deviations and their fixes should be
documented to detect process-wide trends. An organi-
zations management system would capture these
deviations for further treatment as a trend if appropri-
ate. Issues where an on-the-spot operator fix is imple-
mented are most often not documented, making time
interval trend analysis impossible or useless.
Select a Fix
The operator is successful in finding cause, but
implementing corrective action requires additional
expertise or authority. It may require the expertise
of the engineering staff or equipment manufactur-
ers for added insights.
Implement the Solution
Making any change to a cGMP manufacturing
process should be undertaken with care. Few oper-
ators have such sufficient scope of independent
action, even when addressing manufacturing prob-
lems. Significant project planning and risk assess-
ment efforts must be undertaken.
Special Edition: Corrective and Preventive Action 35
 Michael Clark & Wade Speir & David Sandahl
The Corrective Action Deviation
Escalation System
Recognizing, Resolving, and Reporting
Deviations.
An effective system of corrective action is a
process for escalating reported deviations to the
appropriate level for resolution, yet the lack of a
clear process for raising and prioritizing issues
hamstrings many corrective action systems. While
considerable documentation is generated within
cGMP environments, documentation cannot over-
come the weaknesses illustrated above.
Given that people in organizations will tend to
orient their behavior on the job toward what they
understand is right, it is important to guide
behavior within a corrective action process
designed to continuously improve the enterprise.
Following our lead assumption that the strategic
direction of the organization is well defined and
clear, implementing effective corrective action
requires the following:
Clear Performance Criteria for Business
Processes. Included business processes are pre-
ceded by inputs and create outputs that advance
the organization toward its production or strategic
targets. Without valid process performance stan-
dards, corrective action cannot exist.
Management Control Systems that Identify
and Record Deviations. Information regarding pro-
cess performance is captured on a short-
interval basis along the dimensions of quality, cost,
timeliness, throughput, etc. The metrics must be
meaningful to operators overseeing the process and
linked to strategic measures of success. Deviations
are readily visible to operators.
Prioritization and Assignment Process
that Initiates and Escalates Action. Once devi-
ations from standard are reported, they must be
prioritized across the entire manufacturing sys-
tem in terms of their current impact on opera-
tions, the safety exposures they present, and
their potential future impact on operations. The
deviations are then divided into: (a) those that
can be corrected immediately at the operator or
maintenance level and (b) those that require sig-
nificant resources and thinking to resolve. The
latter often require adjustment to SOPs and fixes
that must be implemented across several pro-
cesses. In all cases, a monitoring plan is estab-
36 Special Edition: Corrective and Preventive Action
lished to confirm root cause.
Project Management and Follow-up
System that Manages Issues. Corrective actions
that require significant resources, process
changes, or substantial technical expertise must
be managed through a project plan. The project
plan must be formulated systematically, specifying
a projects objectives, resource requirements,
schedule, risks, and opportunities. It is essential
that all projects be formulated using the same pro-
cess so that the projects can be tracked and prior-
itized relative to one another and the organiza-
tions strategic goals.
Documentation of Follow-up, Process
Change Control, and Monitoring. Each project
or operator/maintenance lead corrective action is
reconciled against the reporting system to en-
sure resolution. All meetings are either geared
toward project-based or operator/maintenance-
based corrective actions. When escalated and
resolved systematically, results can be more eas-
ily documented and explained to regulators.
The Elements of the Corrective
Action Deviation System
Each of these elements of the corrective action
deviation system is reviewed in detail below.
1. Clear Performance Criteria
for Business Processes
The processes that make up a system are defined
by the strategic goals of the organization. Figure 2
illustrates some of the concepts that provide the foun-
dation of an effective corrective action system.
A validated performance standard and monitor-
ing actual performance experienced accompanies
each process diagrammed in Figure 2. Each seg-
ment of the process will have expected or desired
outputs. The desired performance or performance
standard should be based on the following:
What customers expect or require in terms of
performance;
What management expects or requires; and
What the next process step or other interre-
lated processes need from this segment of the
process as input for effective performance.
As with customer requirements, the desired
performance should be quantifiable and usually
will fall into the following categories: accuracy,

completeness, timeliness, quantity, cost, and
dimension.
Actual performance should reflect clear, short
interval information on desired performance. It is
critical that the assessment of actual performance
be based on actual data and not gut feeling or opin-
ions about the performance.
The first element in an effective corrective
action system requires that clear and relevant per-
formance standards be established for each pro-
cess within the system based on optimum perfor-
mance under known process parameters.
AmBio Pharmaceutical Case Study
This case study illustrates several unproduc-
tive approaches found in a cGMP manufacturing
environment and eventual resolution using a
systematic approach for corrective action
directed through a disciplined escalation proce-
dure.
Special Edition: Corrective and Preventive Action
Michael Clark & Wade Speir & David Sandahl
AmBio is a pharmaceutical product that is for-
mulated from recombinant materials, filled as a liq-
uid, freeze dried into a wafer-like cake, and recon-
stituted with a unique diluent prior to patient injec-
tion. The purpose of the freeze-drying step is to
increase the product shelf life. Product with excess
moisture will yield erroneous results, and the mois-
ture will cause visible and physical product degra-
dation in a short period of time. After freeze drying,
moisture concentration is measured using a gas
chromatograph and a method called headspace
analysis. This analysis measures the moisture in
the air above the cake under the theory that an
equilibrium moisture concentration will be reached
between the cake and the surrounding air.
After reviewing the corrective actions for the
moisture content issue over the past few years, it
was obvious that moisture content was not being
controlled in a purposeful and predictable man-
ner. It seemed that different levels of moisture
concentration could be observed by altering the
37
 Michael Clark & Wade Speir & David Sandahl
process run speeds or altering other key set
points during the manufacturing process. The
relationship between optimum process perfor-
mance and set points was not clearly known and
was, in reality, dictated by operator experience.
In most cases, this was enough to maintain the
system within quality control standards. Lately,
with increased volume requirements and the
introduction of other product types into the sys-
tem, the problem was occurring more often. For
this organization to meet its production and qual-
ity goals, true corrective action needed to be
implemented.
The manufacturing staff at a pharmaceutical
manufacturer has just received notification from
the Quality Assurance chemistry lab that two
batches of AmBio had again failed for high mois-
ture content. Since AmBio was in high demand
and batches that fail for high moisture would have
to be scrapped, the identification of a root cause
was a high priority.
However, AmBio was already the subject of
high priority manufacturing quality issues, includ-
ing discoloration. A request from Marketing to
adjust volume targets upward contributed to the
urgency of the situation. The manufacturing staff
had already documented interim actions imple-
mented by the operators to ameliorate the mois-
ture problem and some of the other production
deviations.
2. Management Control Systems that
Identify and Record Deviations
A system is a set of dynamically linked pro-
cesses. Several processes are often required to
produce a single product. The task of a manage-
ment control system is to act as the dashboard for
the manufacturing environment. What is monitored
depends on the performance standards estab-
lished for each process and the information that
management requires to operate the business with
minimal deviations.
The indicators of performance should be along
the dimensions of time, cost, and quality. The inter-
val and extent of control should be set to quickly
identify and record deviations and causes, whether
proximate or root, for later appraisal and resolution.
Process performance information should be shared
widely across the organization so that operators
understand the things that matter most quality,
timeliness, and cost.
38 Special Edition: Corrective and Preventive Action
Although the first batch of AmBio to fail QA test-
ing was AB 76, review of historical data showed a
drastic shift in moisture concentration from lot AB 73
to lot AB 74. Further review of historical data
showed a similar shift in February of the prior year
and out-of-specification results were recorded in
May, June, July, and August 1997. Operator-initiated
corrective action was implemented based on the the-
ory of seasonality. This possible-cause theory sug-
gests that higher temperature and humidity levels
associated with spring and summer explains the out-
of-specification results. The operators, relying on
their experience, made the appropriate adjustments
in process operation. One of the measures taken
involved slowing the rate of production a slight per-
centage. In fact, the condition wasnt viewed as an
operational deviation at the time since operator
actions seemed to bring the process back into speci-
fication. This system is rather sensitive and involves
some complex science and sometimes doesnt react
well to the constant push (of production).
In retrospect, the firm learned that the actions
implemented by the operators didnt seem to sup-
port the data. The February batch failures were
ignored. In addition, temperature and humidity
charts were available for each manufacturing room
for three months prior to the incident and the
months over which failing product were produced.
There was no trend in the temperature or humidity
data to support seasonality as a root cause. Of
course, this data wasnt readily available to the
operators for their review. The operators reduced
the production rate and did the best they could to
keep the process balanced in terms of moisture
content, volume requirements, and the other qual-
ity metrics associated with the process.
A closer examination of the reporting systems
around AmBio revealed a major flaw that pre-
vented deviations from being highlighted through-
out the organization and escalated to the appro-
priate level of resolution. Performance of the
AmBio production processes along certain quality
dimensions was being summarized on a monthly
and sometimes weekly basis. Because of this
summarization, problems were reported in very
broad terms such as volume shortage or quality
problems. The recording systems were not spe-
cific enough to allow effective action to be taken
or to detect where the system was in jeopardy
against key performance criteria. This type of
reporting is compounded by the fact that people
tend to speak in broad generalities for simplicity.

The control systems were adjusted across all
AmBio processes to capture and report deviations
on an hourly basis. The specificity of reporting
migrated from volume shortage at the monthly
level to AmBio product stability problems at the
weekly level. Finally, at the hourly level, problems
were tracked as follows: AmBio lyophilized vials
moisture concentration exceeds process control
limits (0.05%), and AmBio batch 53 has discol-
oration.
3. Prioritization and Assignment Process
that Initiates and Escalates Action
There can be little doubt that an investigation
should be initiated when disease or a health haz-
ard is likely to be created. But cGMP control sys-
tems must also proactively identify and prioritize
manufacturing deviations if they are to contribute to
sound business operations.
Once deviations are identified by management
control systems, they can then be prioritized and
assigned for resolution. This system should encom-
pass deviations such as health hazards defined in
regulations and opportunities for manufacturing
process improvements. Prioritization, based on the
impact of those deviations, should consider how
performance affects any of the following:
The ultimate end customer;
The next customer in the process flow;
Internal customers who receive any output
from the area of discrepancy;
The business results for the company includ-
ing regulatory exposures; and
The consequences to the people doing the
work in the process.
Prioritization metrics can also be established in
terms of traditional manufacturing measurements,
such as downtime, process capacity, work-in-
process inventory levels, etc.
Some deviations can be temporarily con-
tained through adaptive actions. CAUTION:
Containment actions tend to reduce the priority
given to certain deviations, allowing containment
actions to become permanent fixes. Costs to
maintain containment actions must also be con-
sidered when assessing the impact of a devia-
tion.
Once prioritized, the organization can then
direct assignment of the deviation to the proper
Special Edition: Corrective and Preventive Action
Michael Clark & Wade Speir & David Sandahl
level for resolution. Deviations can be character-
ized in two ways to facilitate effective escalation:
Technical: Those deviations that can be cor-
rected at the operator or maintenance level
through either containment actions or corrective
actions not requiring any process and SOP
changes;
Organizational: Those deviations that are
beyond the abilities of operators and maintenance
staff to correct and have been occurring over long
time frames. Correction of these issues generally
requires alterations of SOPs and may also
include adjustment of performance standards.
Such issues are best tackled off-line by a small
group of individuals charged specifically with res-
olution of this deviation. The suggested corrective
actions are also reviewed by regulatory personnel
and appropriate documentation created and
maintained.
Rarely will the stone be thrown that corrects all
of the problems in a system at one time. Yet, this is
how the search for root cause is often undertaken:
trying to find the big fix that will instantly raise the
system to a superior level of performance. True
process improvement requires corrective action
implementation one deviation at a time. Once devi-
ation C (high moisture content) is corrected, then
the overall system results improve. Eliminate devia-
tion B (discoloration) and the system has raised
its performance yet again.
The corrective action system should prioritize
the deviations that exist within the system and
direct resources toward their resolution accord-
ingly. All too often, teams involved in process
improvement projects jump to revising the pro-
cess before they have defined the scope of the
project. This can spell disaster. It is essential
that the scope of the project be clearly thought
out and that top management and the process
team are in agreement on the scope of the
effort.
Due to the recurrent history of the AmBio
moisture content deviation, the problem was
reclassified and escalated above the operator
level alone. A team was formulated consisting of
operators, quality assurance engineers, R&D per-
sonnel, and regulatory representatives. The pur-
pose of the team was to collect data regarding
the history of the problem and to eventually iden-
tify root cause with a recommendation made to a
39
 Michael Clark & Wade Speir & David Sandahl
management committee regarding potential
actions. The team used problem analysis 2 to
organize their efforts and guide the team through
the process of finding root cause. See Appendix
for the root cause analysis and resolution of the
AmBio Case Study.
4. Project Management and Follow-up
System that Manages Issues.
The corrective action team should plan their
efforts using a systematic process of project man-
agement. It is essential that every project be
planned and managed consistently. As these pro-
jects often draw on the same resources, priorities
must be set. It is highly unlikely that every
improvement project will be implemented. Lacking
clear prioritization by management, critical
resources in the organization are often overloaded
with improvement projects, sharply reducing the
likelihood that any one project will actually be
completed.4
Before presenting improvement plans to man-
agement, the team must develop an implementa-
tion plan using a consistent project planning tech-
nique. At a minimum, the implementation plan
should include:
Project objectives.
Work breakdown structure.
Resource requirements.
Responsibility assignments.
Risk analysis.
Again, the most critical part of the implementa-
tion plan is clear project objectives. Establishing
project objectives means determining the objec-
tives expected outcomes and constraints for the
project. The project objectives assure clarity of
purpose.
Consider key criteria for success of the pro-
ject in areas such as business and financial
needs, technology, organization, marketing, and
other areas that affect your organization. Con-
sider the key constraints that could affect project
success such as legal requirements, environ-
mental requirements, financial limitations, orga-
nization policies, and other external or internal
factors that impact your organization. Manage-
ment should, on a periodic basis review each
project plan against objectives and risks.
40 Special Edition: Corrective and Preventive Action
5. Documentation of Follow-up, Process
Change Control, and Monitoring.
Based on a thorough understanding of the
strategic direction for the organization and disci-
plined analysis of the deviation, the process team
should revise and document the new process
using approved change control procedures. The
new process should be flowcharted with major
changes and improvement actions highlighted.
Each strategic system requirement should be
reviewed against the new process to assess
whether the new process will in fact better meet
these system requirements. Once the team has
agreed on the new process, its resource require-
ments should be determined and compared to the
old process. Resource requirements should
include the following:
Skills and knowledge needed by the people
performing the key tasks in the process.
Number of people needed to staff the process.
Equipment, systems, and facilities needed.
In order to determine if the process improve-
ments are effective, specific, quantifiable measures
should be established. The measurements should
relate to both the effectiveness and the efficiency
of the new and improved process.
After the process improvements are imple-
mented, the management control system contin-
ues to verify that requirements are being met. It is
important to standardize the process improve-
ments so that higher levels of performance are
made permanent.
After all process improvements have been
made and standardized for the highest priority pro-
ject, the priority for project execution is updated,
and the cycle begins again on the next most criti-
cal deviation.
Conclusion
We have proposed a corrective action process
for deviation escalation and management which
enables businesses to recognize a problem, find
true cause, and select and implement solutions.
The system ensures that strategically driven per-
formance criteria are defined and measured by a
management control system that prioritizes imme-
diate fixes and longer-term projects and provides
 Michael Clark & Wade Speir & David Sandahl

for ongoing documentation monitoring.
Such a system enables businesses to use their
quality systems to move beyond compliance to cre-
ate business value through continuous improve-
ment to production processes.
Simon & Schuster, New York, New York, 1997.
3. See above Spitzer and Evans.
4. An explanation of Kepner-Tregoes Project Portfolio
Prioritization and Management approach can be found
in Preventing Project Proliferation, a white paper
available from the authors.

References
1. A useful description of the help desk escalation
approach used by Sun Microsystems in Europe can be
found in Computer, Heal Thyself, by Andrew Taylor in
the March 1998 issue of Customer Service Support
magazine.
2. Problem Analysis is a systematic process based on
research into critical thinking skills for finding the root
cause of a deviation and developed by Kepner-Tregoe,
Inc. A good summary of this technique can be found in
Spitzer and Evans, Heads You Win, pages 241 282,

AmBio Pharmaceutical Case Study Resolution

Appendix
The following pages demonstrate a specification or description of the teams efforts using the Problem Analysis process.
Problem Statement: AmBio lyophilized vials moisture concentration exceeds process
control limits.
Is Is Not
What AB 20 ml vials AB 5 ml vials
What object? AB batches 66, 68, 69 (> .47%) AB batches 63 or earlier
AB batches 64, 65 (High > .35%) Other products, controls

High moisture %

What deviation? Accelerated stability

Performance, SD, discoloration
Where Chemistry lab Not tested anywhere else
Where geographically? Gas chromatograph NA No other instrument

Mutual diluted sample

When
When first? 4/28/98 9/25/97 4/25/98
(2/13/97 8/21/97) (12/11/96 2/4/97)

When since? All samples since None since, partial

When in the life cycle?

Post-freeze drying NA
Extent AB 66 = 25/80, 79/80 All
How many objects? AB 68 = 33/80
AB 69 = 46/80

What is the size? .47% moisture

How many deviations? All vials in each batch

What is the truth? Constant Increasing, decreasing

Copyright Kepner-Tregoe, Inc. reproduced by permission.

Special Edition: Corrective and Preventive Action 41

 Michael Clark & Wade Speir & David Sandahl

Appendix (continued)
AmBio Problem Analysis: Possible Cause Development and Evaluation Table
Distinctions Changes Possible Cause Does not explain Explains only if
What 20 ml vial & stopper vs.
5 ml vial & stopper

<surface area/volume vs.

>surface area/volume

>volume/dry time vs. Product fill volume Other products Other products
<volume/dry time error (too high) cycle have
excess capability
3 day lyo cycle vs. Inefficient drying Other products
1-2 day lyo cycle Performance OK Only inefficient
No alarms w/RTF
-45c freezing point vs.
-30 to -40c freezing point Freezing too high Performance OK
All
Head space analysis vs. thermocouples
Direct moisture analysis out of calibration

Measured on gas chromatograph

vs. Omni, visual

Chemistry lab vs.

Manufacturing lab
Where
When Equipment calibration 4/26/98 Calibration error Manual sample Error is in
1/31/97 out of specification measurement or
calculation not
Warmer, more humid Seasonal Humidity in room Average test result dispensing error
weather compromised product 2/4/97
patterns integrity Unknown
No discoloration
Performance OK
Accelerated Stability
OK
Extent
Copyright Kepner-Tregoe, Inc. reproduced by permission.
Once the moisture issue was escalated above ately.
the operator level, in depth analysis was con- To rule out room humidity as a possible cause,
ducted. The AmBio Problem Analysis: Possible a statistically significant sample of vials was drawn
Cause Development and Evaluation Table shows from the three failed lots and submerged in water.
how various possible causes were ruled out For humidity to compromise the product integrity,
because they could not explain the information moisture must be able to enter the vials. After
gathered in the IS/IS NOT specification table. being submerged for five minutes, there was no
For example, the ever-popular seasonality expla- sign of moisture inside the vials. These examina-
nation, whereby higher temperature and humid- tions could only be conducted after the deviation
ity levels associated with spring and summer are was escalated above the operator level. The
used to explain a variety of product failures, was Implementation Plan developed by the team sug-
disproved because there was no discoloration, gested that management make available lab time
and performance and accelerated stability tests to conduct various confirmatory tests.
passed. To rule out lyophilizer issues around The most likely cause was determined to be
freezing temperatures, all thermocouples were some type of calibration error due to the fact that
recalibrated and found to be operating appropri- the product performance and appearance were

42 Special Edition: Corrective and Preventive Action

 Michael Clark & Wade Speir & David Sandahl

normal. However, this did not explain the fact that deviation associated with discoloration, which later
the manual sample was also out-of-specification proved to have a different cause. Only through visi-
and the one sample, tested on 2/4/97, was in line ble escalation were the priority conflicts able to be
with average moisture concentration. resolved and the proper resources directed toward
Testing the hypothesis that some type of cali- resolution. The team members indicated that their
bration error was made during standard preventive natural inclination as a company is always to jump
maintenance involved two distinct tests. First, to into action. That is what they get paid for... react
prove that the instrument itself was functioning dif- and fix. What the escalation system has taught
ferently after the preventative maintenance, sam- them is that sometimes you need to start slower to
ples from two batches that previously yielded .23% go faster. The escalation process allowed us to
and .25% were retained. concentrate on the task at hand. It removed many
Moisture concentrations were retested and of the distractions and took the heat off of the
found to be > .47%. In addition, moisture analysis front-line guys. We knew that if we reported and
was performed on varying sample volumes ranging followed the process that focused action would be
from .2 to 1.0 ml drawn from the same production the result. It really helps when youre not operating
lot. The resulting moisture values ranged from 0.00 in a vacuum.
to 0.50%. A properly functioning instrument system
would yield equivalent results regardless of sample
volume. These results pointed to the integrator por-
tion of the system. The exact root cause was deter-
mined to be a high integrator default setting that
heightens instrument sensitivity and affects the lin-
ear range.
The operators initially involved in this analysis
did not have the authority or expertise to make
adjustments to the integrator portion of this sys-
tem. Additionally, many of the operators and
research staff were engaged in solving another

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Special Edition: Corrective and Preventive Action 4343

 (CAPA)
Corrective and
Preventative Actions
A Medical Device Case Study
T
he goal of any product
...all can benefit design and/or production
process is to produce
from an evaluation product that meets some stated
requirement(s), i.e., design out-
of what works put = design input. Three key
activities ensure this: product
or doesnt design with design control, pro-
with others. cess validation and/or verifica-
tion, and corrective action activi-
ties. This article focuses on the
third, corrective and preventive
actions (CAPA).
What the FDA Requires
The FDAs Quality System
Regulation, 21 CFR Part 820,
Subpart J Corrective and
Preventative Action, Section
820.100, states, in part, that:
(a) Each manufacturer shall
establish and maintain proce-
dures for implementing correc-
tive and preventive action. The
procedures shall include:
(1) Analyzing processes,
by work operations, concessions,
John E. Lincoln quality audit reports, quality
Principal records, service records, com-
John E. Lincoln and Associates plaints, returned product, and
44 Special Edition: Corrective and Preventive Action
other sources of quality data to
identify existing and potential
causes of nonconforming prod-
uct, or other quality problems.
Appropriate statistical methodol-
ogy shall be employed where
necessary to detect recurring
quality problems;
(2) Investigating the cause of
nonconformities relating to prod-
uct, processes, and the quality
system;
(3) Identifying the action(s)
needed to correct and prevent
recurrence of nonconforming
product and other quality prob-
lems;
(4) Verifying or validating the
correcting and preventive action
to ensure that such action is
effective and does not adversely
affect the finished device;
(5) Implementing and record-
ing changes in methods and
procedures needed to correct
and prevent identified quality
problems;
(6) Ensuring that information
related to quality problems or
nonconforming product is dis-
seminated to those directly
responsible for assuring the
John E. Lincoln
quality of such product or the prevention of such
problems; and
(7) Submitting relevant information on identified
quality problems, as well as corrective and preven-
tive action, for management review.
(b) All activities required under this section, and
their results, shall be documented.
The FDAs new Quality System Inspection
Technique (QSIT), in its QSIT Inspection
Handbook, October 1998 Draft, lists CAPA as one
of the seven systems areas for compliance review,
with CAPA also one of the top four primary indica-
tors of compliance with the Quality System
Regulation. Under the section devoted to CAPA,
its Purpose/Importance is stated:
The purpose of the corrective and preventive
action subsystem is to collect information, analyze
information, identify and investigate product and
quality problems, and take appropriate and effec-
tive corrective and/or preventive action to prevent
their recurrence. Communicating corrective and
preventive action activities to responsible people,
providing relevant information for management
review, and documenting these activities are
essential in dealing effectively with product and
quality problems, preventing their recurrence, and
preventing or minimizing device failures.
One of the most important quality system ele-
ments is the corrective and preventive action sub-
system. It goes on to state that corrective action is
two-fold: 1) Correct the existing product noncon-
formity or quality problems, and 2) Prevent the
recurrence of the problem.
Implementation or Refinement
Of course, none of this is new, except the CAPA
acronym and its focus as part of the new top-down
inspection strategy of the FDAs QSIT, harmonized
somewhat with the European communitys ISO 9001
inspection strategy. Whether one is a new company
involved in implementation or an established com-
pany reviewing existing systems for compliance, and
perhaps upgrading the management reporting activ-
ity, all can benefit from an evaluation of what works
or doesnt with others. In either case, such a system
must incorporate the following:
A determination of the key indicators of qual-
ity for each device
Methods of accurately measuring/quantifying
each of the key indicators repeatedly and
their recording/documenting
Development of accept/reject, pass/fail crite-
ria for each
Reporting/trending of data
Reacting to negative trends, out-of-limit/specifi-
cation conditions, repetitive complaints/rejects
Determination of key inputs (possible sources
of variation) for each indicator
Locating root cause(s) of reject(s), i.e., which
of the key inputs is responsible, starting with
the most serious and/or costly
Eliminating root cause(s)
Verification/validation, control, and continuous
monitoring of change(s)
Starting over with the next most serious
and/or costly variance, which has now been
elevated to first place
Implementation at a Start-up
Medical Device Manufacturer
This company manufactured several versions of
balloon inflation devices used in angiograms and in
the widening of partially blocked arteries. A non-
conforming material system (incoming, production,
final, and post-sterilization QC), and a complaint
system (which captured all expressions of cus-
tomer dissatisfaction, including returns, sales, and
service) had been put in place using manual forms
and logs. The logs provided the sequential num-
bers that were assigned each form when issued,
and the logs had provision for a brief, one- to four-
word description of the complaint or non-confor-
mance, from which trend data could be quickly
extracted. The nonconformances and complaints
were then summarized from the log data and
trended monthly (see Figures 1 and 3). Senior
management was on distribution for the monthly
reports, which were also discussed at weekly man-
agement production meetings, in which the
Director of QS/RA participated, and at monthly
company-wide employee meetings, conducted by
the QS Director.
SPC (Statistical Process Control)
and Six Sigma
Early on, SPC was brought into use, both with
control charts (see Figure 2), as well as the later
additions of Alert and Action limits to the
Special Edition: Corrective and Preventive Action 45
 John E. Lincoln

Figure 1
Nonconforming Materials Report (NCMR)
For Month of September
Date: ___________________________
Nonconformances
Labeling Incorrect Dirty Damaged Seals / Missing Other Other
Confign W/N Oper Packg Docn Comment
01. Kits 1 3 1 Line Clear
02. Devices 1 1 1 Test Data
03. Drapes 1 2
04. IQA+ 2 6
Note: The above lists the number of NCMRs issued for the month, and the category of nonconformance for
which each was issued. It does not list the actual number of units nonconforming in each lot that was
NCMRd.
Writing of NCMRs for missing COC discontinued on February 6th; COC requests still given purchasing.
Incorrect Configuring includes wrong box quantity per catalog or other documentation.
Seal/Packaging includes dirt/particulate in seals, wrinkled or incomplete seals, wrong boxes used, Sorex
water- or freight-damaged boxes, etc.

spreadsheets discussed above, below the Totals
line and generated by spreadsheet macros. Alert
limits were set at 1.9 sigma (actually s, sample
standard deviation, using n-1 in the macros), and
action limits at 3.0 sigma, with required action
defined/mandated by standard operating procedure
(SOP). Such Alert and Action signals required an
immediate response, documented. The general
trends were monitored (see Figures 2 and Figure
4) and reacted to as indicated by the trend(s). A
six sigma program was instituted, with non-con-
formances tracked by defects per million (defects
in PPM, defined by us as defects found/total
inspected x 1M). Obviously, negative trends got the
initial attention, but positive trends were also evalu-
ated to locate common denominators which could
then be institutionalized.
Our goal in each instance was to first develop
and maintain a statistically stable system. A sta-
ble system is predicable. It is achieved by the sys-
tematic removal of special (unusual, unanticipated)
causes of trouble/variation best detected by statis-
tical methods.
Having achieved this, the next step wasnt a
step, but continuous improvement Deming/Shew-
hearts Plan-Do-Check-Act, with the goal of 3.4
defects per million (six sigma; allowing for a mean
shift of 1.5 sigma) and even zero defects in some
processes. While there was no program to reach
such goals at an arbitrary end of the program date,
the goal was continuous improvement for the life of
the process or product, constantly driving down the
defect-per-million rate. The responsibility for
improvement of a stable system rested squarely
with management, because the elimination of com-
mon causes (the systems noise) requires invest-
ment in training, part modifications, new equip-
ment, or other resources beyond the capability of
the line employee/operator to effect.
Weekly Meetings
The weekly production management meetings
were attended by the vice president of operations,
the director of QS/RA, together with department
managers, including sales, engineering, manufactur-
ing, purchasing/materials management, and cus-
tomer service, all of whom were made aware of the
key quality problems and took part in brainstorming
their impact and possible solutions. Each specific
product family problem(s) was usually discussed
when that particular product family was under dis-
cussion, e.g., due for production, or if there was a
sales demo problem or new field complaint. A third
forum was during the weekly PIT (Productivity
Improvement Team) meetings, in which production
personnel shared as a self-directed work team,
with the director of QS/RA, manufacturing manage-
ment, and engineering also in attendance. They
shared a similar charter to address and correct the

46 Special Edition: Corrective and Preventive Action

John E. Lincoln

Figure 2
NCMR Monthly Report
For September

30

27

24

21
NCMRs Issued

18

15

12

6 KITS
3 DEVICES
DRAPES
0 IQA
LABEL CONFIG. DIRT OPER PACKG DOCN OTHER

NCMR Yearly Report

For 199__

39
36
33
30
No COCs:
27 Particulate
NCMRs Issued

24
21
18
15
12
9
KITS
6 DEVICES
3 DRAPES
0 JAN FEB MAR APR MAY JUN JUL AUG SEPT OCT NOV DEC IQA

Discontinued Reporting No COCs: 2/6/9__

Special Edition: Corrective and Preventive Action 47

 John E. Lincoln

Figure 3
Product Complaint Analysis
Date: ___________________________
YTD: 199__ Complaints
Wrong Improper Damaged Missing *Customer Monthly
Confign Labeling W/N Work Particulate Parts Service Totals
JAN 1 2 1 4
FEB 6 1 5 5 17
MAR 1 2 2 3 8
APR 2 5 3 10
MAY 4 1 2 1 8
JUN 1 7 1 4 13
JUL 2 3 2 2 9
AUG 2 1 4 1 8
SEP 9 1 1 11
OCT 0
NOV 0
DEC 0
TOTALS 18 3 38 8 1 20 88
Customer Service:
1) Did not want; 2) Later delivery; 3) Expired product; 4) No reason given; 5) Would not accept COD;
6) Wrong item, etc.

problems, ranked according to priority (Pareto Incoming material/components, in-house/manufac-

charted). So, although senior management having
CAPA responsibility (tho not using this term at
that time) was defined as residing with the Director
of QS/RA, the Director had the active support and
participation of top management and line employ-
ees. At all of these meetings, not only were those
problems addressed/corrected, but potential for
recurrent problems was evaluated, and preventa-
tive action taken where it was felt advisable. Sadly,
at some companies reviewed by this author, this
participative and proactive approach to CAPA is
still not the case.
Reporting Systems
Failed field units were brought into the plant on
an RGA (Returned Goods Authorization) number,
previously assigned by customer service, and
cross-referenced to the original complaint number
(issued by QS/RA), received and sterilized (EtO),
then routed to engineering or QAE for evaluation.
turing, and final acceptance failures/rejects were
recorded on a NCMR (Nonconforming Materials
Report), tracked by a sequential numbering sys-
tem (the log system mentioned above), and also
routed to Engineering/QAE for evaluation. This
was a small $5-10M/yr volume company, with
approximately 30 employees. Engineering con-
sisted of three persons, handling R&D, Man-
ufacturing and sterilization engineering, and QS
consisted of three individuals, the director, a docu-
ment control specialist, and a sterilization/QC
technician. As a result, QAE functions were han-
dled by the director of QS/RA, who had that back-
ground.
Results of the evaluation/failure investigation
were written up as part of the complaint form or
the NCMR, with attached documentation or lab
book references, as appropriate. Both groups of
documents were reviewed and incorporated into
separate reports with trend graphs each month
(Figures 1-4), primarily consisting of computer

48 Special Edition: Corrective and Preventive Action

John E. Lincoln

Figure 4
Complaints 199__
By Type of Complaint

7
Total Complaints Received

3
SERVICE
2 LABELING
W/N WORK
1 PARTICULATE
PARTS
0 JAN FEB MAR APR MAY JUN JUL AUG SEPT OCT NOV DEC CONFIGURATION

MONTH

Complaints 199__
By Product Lines

Wrong Configuration;
Damaged/Inoperable
10

8
Total Complaints Received

2
DEVICE
1 DRAPES
KITS/PACKS
0 JAN FEB MAR APR MAY JUN JUL AUG SEPT OCT NOV DEC
MONTH

Special Edition: Corrective and Preventive Action 49


spreadsheets with graphics (QuattroPro or
Excel). The NCMR report also included a list of
rejects per vendor on incoming receipts.
Trending
Monthly trends started pointing toward device
operational problems. Further review of the sup-
porting documentation identified recurring leak
problems with some of the inflation devices (think
syringe). This was viewed as potentially serious
(could contribute to an air embolism in a patient if
a balloon catheters balloon, manufactured/sup-
plied by other device companies, should burst in
use) and a source of the most frequent and angry
customer complaints (understandably so).
Immediate corrective and preventive action was ini-
tiated.
Test Methodology
As a result of these leak problems cropping up
in-house with some destructive sample testing,
and the corroborating complaints from the field,
various types of leak tests were evaluated and
results correlated to each other. The company had
an automated leak tester, which was available in
production. This was dedicated to their most com-
plex inflation syringe, and a test procedure was
developed, acceptable values established, and x-
bar and R (average and range) control charts pre-
pared for key values (see Figure 5). This testing
was performed initially by an engineer.
For the less sophisticated syringes, both those
produced on the companys own tooling, and those
vendor-supplied, several simpler test methods
were evaluated:
Purchase of another mechanized tester;
Manual pressure decay testing, using tubing
and a calibrated pressure gauge which was
developed in house, and requiring the opera-
tor to hook the end of the tubing to the luer
fitting of the syringe, apply pressure to a
stated level, and timed for any decay/leak;
and
A syringe plunger seal integrity test, where
the plunger was seated, the tip dead-ended,
and the plunger then pulled back, held for a
timed period, and allowed to return and set-
tle. Any difference in the starting point and
end point of the plunger, displacement in ccs,
50 Special Edition: Corrective and Preventive Action
John E. Lincoln
read from the syringes scale (previously
tested for accuracy), was then noted on a
control chart.
After much testing, the third method above was
selected, due to its accuracy being on par with the
other two, its simplicity, speed and ease of opera-
tion for the production operators who would be per-
forming it. Further tests showed the area of the
plunger tip/seal and syringe barrel interface most
prone to leakage, and the SOP then defined how
far the plunger was to be pulled back to ensure this
most trouble-prone area was included in the test.
Since a failure could be the result of an
improper test procedure, a failure had to be
retested prior to recording. And failed units were
set aside for review by QAE/Engineering for analy-
sis of the exact cause of failure (e.g., barrel out of
round or scored, plunger tip problems/damage/de-
formation, tolerance build-ups, particulate, or).
This leak test procedure was then verified by
repeated testing of known good product and vari-
ous quantified control failures, all documented in
lab books.
Production personnel were trained, and the sys-
tem was implemented in production, to be per-
formed by the production personnel involved in
syringe assembly. Sufficient data was gathered on
initial production samples so a manual control
chart could be developed by the QS department,
with the grand average (x-double bar, average of
the averages), and the three sample standard devi-
ation upper (UCL) and lower control (LCL, or zero
on the range chart) limits (see Figure 6).
In production, exceeding the upper control limit
or falling into a pattern not to be expected ran-
domly (defined by SOP, with sample illustrations)
resulted in an immediate line shut down, analysis,
and problem solving by Production, QAE and/or
Engineering. A temporary 100% leak testing for
that lot and the next several lots, depending on the
nature of the problem found, was then instituted,
as defined by SOP. Control charting was retained
during the 100% testing.
The completed charts for each production lot
were reviewed and signed off by the operator(s),
and the original became part of the Device History
Record for each lot. The control charts also
became part of the documents listed for review on
the final QA release checklist for each lot.
Each DHR was reviewed and signed off by QS
as a requirement for release.
 51
Figure 5
X & R Quality Control Chart for Subgroup Size of 5
Corporate Quality Systems Engineering

Special Edition: Corrective and Preventive Action

Inspector: Lot:
Product: Filter Process: Pressure Decal Test Machine: Pressure Tester Date:
Characteristic: Leaks Dimension and Tolerance: 0 - 1.0 H20 / 30 Secs. Unit of Measurement: Inches of H20
Sample Measurement (X) Results
Date
SUM AVG RANGE
12-1

9-10

12-1

Time
end
10-

1-2
2-2
7-8
8-9

10-

1-2
2-3
3-4
11

11

1 2 3 4 5 (X) (X) (R)

Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 0.0 0.0 0.0 0.0 0.0 0 0 0
2 0.0 0.4 0.2 0.2 0.0 .8 .16 .4
6 E-1.0 Ranges

3 0.4 1.0 0.2 0.4 0.8 2.8 .56 .8

.9 4 1.0 1.0 1.0 0.0 0.0 3.0 .6 1.0
5 0.0 0.0 0.0 0.0 0.0 0 0 0
8E-1.0

.8
.7 6 0.0 0.0 0.0 0.0 0.4 .4 .08 .4
.6 7 0.0 0.0 0.0 0.0 0.0 0 0 0
X .5 8 0.0 0.0 0.0 0.0 0.0 0 0 0
UCL .4 9 0.0 0.0 0.0 0.0 0.0 0 0 0
.3 10 0.0 0.0 0.0 0.0 0.0 0 0 0
X .2 11 0.0 0.0 0.2 0.0 0.0 .2 .04 .2
.1 12 0.0 0.0 0.0 0.0 0.0 0 0 0
LCL 0 13 end
14
15
16
Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 17
18
19
1.2 20
(1.1) 21
1.0 22
UCL (.9) 23
R .8 24
(.7) 25
.6 26
R (.5) 27
.4
28
John E. Lincoln

(.3)
.2 29
30
(.1)
LCL 0 Totals 1.44 2.8

Grand Average (x) & (R) .12 .23
Note: For coded data show coding basis below:
N/A
 52
Figure 6
X & R Quality Control Chart for Subgroup Size of 5
Corporate Quality Systems Engineering
Catalog Number: Inspector: Lot:
Product: Syringe Process: Assembly Machine: N/A Date:
Characteristic: Seal Test Dimension and Tolerance: 0.0 CC +.135 -0.0 Unit of Measurement: CC Displacement/5 Sec.
Sample Measurement (X) Results
Date
Time SUM AVG RANGE

8:50-9:50
9:50-10:50
10:50-11:50
12:50-1:50
1:50-2:50
1 2 3 4 5 (X) (X) (R)
Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 0 .1 0 .2 0 .3 .06 .2
2 0 0 0 0 0 0 .0 .0
.40
3 0 0 0 0 .2 .2 .04 .2
.35 4 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0
.3 6 .1 0 0 0 .1 .2 .04 .1
X .25 7
8
.20 9
10

Special Edition: Corrective and Preventive Action

.15 11
UCL .10 12
13
X .05 14
15
0 16
Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 17
18
.35 19
20
.30 21
UCL .25 22
23
R .20 24
25
.15 26
R .10 27
28
.05 29
30
0 Totals 0.14 0.5
Grand Average (x) & (n) .02 .08
Note: For coded data show coding basis below:
John E. Lincoln
John E. Lincoln
Process Inputs and CAPA
Review of the process inputs drove continuous
improvement projects, generally centered around
the rubber plunger seal and barrel ID. Since a
component and batch lot numbering system were
in-place, evaluation of raw material lot numbers,
vendors, and materials showed certain specific lots
of molded barrels and/or rubber plunger tips were
the most trouble prone. The worst lots were
scrapped, other lots were used with 100% leak
testing, after worst-case samples had been leak
tested after sterilization, but the majority of the lots
revealed no problems, and five sample per hour
control chart testing proved sufficient. The molding
cycle was reviewed and changes made, and tool-
ing refinements, specifically, a follow-on project
then addressed the mold tool core pin and molding
cycle (core dwell and cooling cycles specifically) to
eliminate the syringe ID variance, and some older
lots of plunger tips were scrapped. The tip ven-
dor/molder, also evaluated, then changed their
material composition to increase resiliency and
decrease memory/hysteresis. The data generated
allowed factual discussions with vendors (as
opposed to he said, she said allegations) for res-
olution at their end (or a change in vendor).
Changes were controlled through document control
and both verified (first article inspection to print,
functional tested, et al) and validated, all docu-
mented and approved.
With the other product family, which used a
pressure transducer for continuous inflation pres-
sure readings, the problem centered about the
bonded interface between the plastic barrel body
and the metal-encased, paralyne-coated trans-
ducer. Corrective action here centered first on the
elimination of the paralyne coating to allow for a
better bond, which brought the tracked failure rate
down. Further corrective action resulted in the
location, validation, and replacement of the metal-
cased transducer with a plastic-encased trans-
ducer having the same plastic composition as the
barrel. This left the interface bonding operation
itself, with few failures, as the only remaining
source of leaks. This was changed to a UV cure
epoxy operation.
As a result of these corrective and preventative
action programs, both product lines had their
defect rates pushed down to almost zero, with only
an occasional spike, never out of the statistically-
expected range. The control charts averages and
limits were recalculated to reflect the tighter toler-
ances now routinely achieved.
At this point, my involvement with the company
ceased.
In Summary
The FDA has increasingly recognized the impor-
tance of relying on statistical and other elements
(listed above) of process control, rather than, or as
an adjunct to, inspection to assure adherence to
specification, even to the point of changing their
emphasis (more an evolving) in their compliance
inspections, from details to systems and root
causes, starting in 1990 with their emphasis on
pre-production quality control, to 1996s Quality
System Regulation, with its emphasis on design
control (820.30) and statistical methods (820.250),
to their latest pilot inspectional strategies with
emphasis on reviewing a companys key or critical
operations, mentioned earlier, including CAPA.
CAPA is here to stay for the medical device
manufacturer (as it is for any global company).
Rather than view it as a necessary regulatory evil,
forward-looking companies have come to see its
value and contribution to the bottom line.
Reduction in scrap, and/or rework has a direct
effect on profits.
As production personnel become more conver-
sant and comfortable with the methodology, the
non-value added activity of inspecting quality in
(which doesnt!) can largely give way to controls
that are automated, mechanized, and/or are opera-
tor-dependent rather than inspector-driven. This
provides almost immediate feedback to the one
closest to the process, thereby reducing the pro-
duction of nonconforming product once a shift in
the process has been detected. The same data,
when collected/distributed and trended, provides
hard data for company corrective and preventative
action (CAPA) initiatives. All this, while still meeting
FDA and/or international regulatory requirements.
Can anything be better?
Special Edition: Corrective and Preventive Action 53
 John E. Lincoln

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F.M. Gryna, Jr., McGraw-Hill 3rd Edition, 1993.
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8. Understanding Industrial Designed Experiments, S.R. Auditing In-Plant Training
Schmidt, Ph.D., and R.G. Launsby, M.S., Air Academy
Press, 1994. Autoclave Labeling
Bulk Pharmaceuticals Laboratory Compliance
Calibration Lyophilization
GXP Training Out-of-Specification Issues
GXPs Packaging Validation
Change Control Pre-Approval Inspections
Chromatography PLC Validation
Cleaning Validation Process Validation
Complaint Handling Project Management
Computer Validation Protocol Templates
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Cost of Validation Revalidation
Design Control SOPs
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54 Special Edition: Corrective and Preventive Action

Implementing Corrective Actions
For FDA Observations
D
uring the fourth GMP by
This article covers: the Sea Conference, an
Facilities, interactive session ad-
dressed a critical subject faced
Equipment, by Industry, i.e., How to Re-
spond to FDA Objectionable
Standard Observations commonly known
as an FD-483. Moderated by Mr.
Operating Joe Phillips, Deputy Director,
FDA, Central Region, Phila-
Procedures (SOPs), delphia, the discussion was cen-
tered on both specific citations
Process Validation, as well as underlying systemic
issues. However, there is a big-
Water Systems, ger issue underlying this pro-
Media Fills, cess and that is how does a
company approach such a situa-
Change Controls, tion? This article is an attempt to
make some sense out of this
Cleaning process and to provide a few
simple, logical steps that should
Validation, be followed whenever an FDA
investigator makes an observa-
Stability, tion about a given practice in a
manufacturing company during
Environmental an inspection. A review of proce-
Monitoring, and dural issues is followed by a dis-
cussion of actual FDA observa-
Out-of-Specification tions during inspection of various
manufacturing sites and how to
(OOS) issues. correct those, addressing both
possible deficiencies at hand
and any quality/compliance sys-
tems-related issues.
Most all pharmaceutical,
by biotechnology and medical
Shahid T. Dara device manufacturers have
President experienced the unpleasant task
Compliance Consulting Inc. of responding to FDA investiga-
Special Edition: Corrective and Preventive Action
tor observations commonly re-
ferred to as FD-483 citations.
Immediate reaction of manage-
ment is usually to fix all the ap-
parent problems associated with
a given citation, without even
considering the validity of the
observation. The fact is that an
observation during an FDA in-
spection is the investigators
interpretation of how the com-
panys processes and proce-
dures meet or fail to meet the
respective cGMP regulations
and not necessarily the final
Agency position on the said sub-
ject. That is why many experts
believe only minor and simple
procedural issues should be
addressed while an FDA site
inspection is in progress. A hasty
reaction while correcting an ob-
servation might cause more
harm than benefit. An organiza-
tion should be prepared to face
this eventuality and should have
procedures in place to address
this subject. This procedure
could be an extension of the
Standard Operating Procedure
(SOP) on how to coordinate an
FDA inspection and how to re-
spond to a FD-483.
FDA inspection usually ends
with an exit meeting between
FDA and company management,
where the investigators observa-
tions are explained. From the
manufacturers side, key man-
55

agers from regulatory affairs, quality assurance,
and production should attend this meeting along
with a representative of senior management. The
company should listen to the investigators remarks
without making any definite responses or commit-
ments to any of the observations, as one needs to
be very careful in responding to these observations.
At the same time, the companys management
must convey their understanding of the seriousness
of the situation and reflect commitment to further
evaluate all the observations and take appropriate
corrective actions, both to fix the observed prob-
lem and any underlying systemic problems, where
applicable. Once the FDA has issued a formal list
of observations or FD-483, management should
meet to review the issues in detail. The regulatory
affairs department should lead such a meeting, as
they are the ones responsible for sending a re-
sponse to FDA within a certain period of time, usu-
ally 30 days from issuance of a FD-483. The re-
view process should include all the key players
within an organization, i.e., quality assurance, pro-
duction, analytical laboratories, validation, engi-
neering, and maintenance and should define the
following:
Current state of cGMP or Quality System
Regulation (QSR) compliance in light of FDA
observations
Impact on the business, both short and long
term
Review prior FDA inspections and FD-483s to
determine if all the corrective actions commit-
ted to were in fact implemented.
Any repeat observations (a definite sign of
trouble)
Define the corrective actions needed obser-
vation specific and systems-related
Resource requirements and their availability
within the organization personnel as well as
financial
Implementation of corrective actions and
timelines
Assignment of responsibilities and account-
ability
Initial response to FDA and follow-up commu-
nications
Internal follow-up to assure implementation of
corrective actions committed to and all asso-
ciated activities, i.e., additional validation
activities, documentation revisions, employee
training issues, etc.
56 Special Edition: Corrective and Preventive Action
Shahid T. Dara
This way, one can manage any compliance
situation in a realistic fashion, without over com-
mitting the organization to what it is unable to
deliver. Where the observations are extensive
and corrective actions are complex, it may be
valuable to develop a comprehensive company
wide corrective action plan. The plan should
include appropriate timelines (Gantt charts). This
plan would then be submitted to the FDA with a
proposal that the company would report pro-
gress against the plan to the Agency at agreed
upon time intervals. FDA would review all the
corrective actions taken by the company in re-
sponse to the previous inspectional observations
in a follow-up inspection and this could happen
within six to 12 months of initial inspection or
even earlier. It is therefore prudent that the man-
ufacturer should communicate with the local dis-
trict office as to the progress of the corrective
action plan and such communication could in-
clude any setbacks or missed timelines due to
unavoidable circumstances and how such inci-
dents are being addressed. This unpleasant task
has definite benefits as it makes the organiza-
tion aware of its deficiencies in the compliance
arena and defines what it would take to maintain
an acceptable level of cGMP or QSR compli-
ance.
Here is a list of actual FDA observations,
made during inspection of various manufactur-
ers. Let us assume that each set of observations
is for a different company to better understand
the issues at hand and also to provide an
acceptable corrective action plan for each. Also,
one should assume that the systems discussed
under each set of observations were the only
ones reviewed by the Investigator and are so
titled. The Agencys view is that the company
management must not only address the specific
observations, but should also review the overall
quality/compliance programs in place to assure
that any underlying systemic issues are also
resolved. Therefore, the company concerned
should review all related systems, equipment,
and products while responding to an FD-483
citation, because that has been a leading defi-
ciency in such responses. Therefore, the discus-
sion following each group of FDA observations
attempts to address the possible corrective
actions for specific issues as well as system-
related problems and strategies for addressing
these observations.
Shahid T. Dara
COMPANY ONE:
FD-483 Observations Issued to Company One:
1.0 FACILITY/EQUIPMENT ISSUES:
Regarding aseptic and critical operations
1.1 Autoclave used to sterilize vial stoppers and fill-
ing equipment is not validated in that no tem-
perature distribution/heat penetration studies
have been performed and no load configura-
tions have been defined.
In addition, the autoclave vent filter is not tested
for integrity upon installation or replacement.
Thermocouples have never been calibrated
and the clean steam supplying the autoclave
is not monitored.
CORRECTIVE ACTIONS:
The autoclave must be requalified with special
emphasis on heat penetration and heat distribution
studies for both empty and full chambers.
All possible load configurations should be de-
fined, diagrammed, and qualified as part of the re-
qualification of the autoclave.
The autoclave vent filter has to be tested for
integrity at the time of installation and replacement.
The replacement frequency could be determined
during the re-qualification of the autoclave based
on the filter manufacturer recommendations. A def-
inite replacement schedule should be then estab-
lished based on qualification data and usage his-
tory of the filter concerned.
All thermocouples must be calibrated before use
and a schedule should be determined for periodic
re-calibration as part of the overall critical instrument
calibration program. Only calibrated thermocouples
should be used both in qualification studies as well
as during the routine operation of the autoclave.
The clean steam source should be reviewed to
assure that it is capable of consistently producing
steam of desired quality, i.e., to determine if the
steam generation system has been qualified and is
operating within a state of control. A protocol needs
to be developed to monitor the quality of incoming
clean steam to the autoclave, detailing the sampling
points, testing regimen, and acceptance criteria.
This information would become part of the auto-
clave qualification data as supporting information.
1.2 The performance of the de-pyrogenation
ovens has not been demonstrated in that
no temperature distribution studies have
been performed.
Special Edition: Corrective and Preventive Action
CORRECTIVE ACTIONS:
The de-pyrogenation oven must be re-qualified
with special emphasis on temperature distribution
studies, to determine potential cold and hot spots
within the oven.
1.3 The HEPA filters in the Class 100 and sur-
rounding Class 10,000 areas have not
been tested for integrity.
CORRECTIVE ACTIONS:
High Efficiency Particulate Air (HEPA) filters
have to be tested for integrity at the time of instal-
lation and periodically thereafter based on the
manufacturer recommendations and usage history.
Depending on the classification of the cleanroom
area, a HEPA filter integrity testing program could
be developed to address this issue as the require-
ments are much more stringent for a Class 100
area versus a Class 10,000 area.
1.4 The filling machine hopper is located out-
side of the Class 100 curtained area in the
syringe filling room. Sterile siliconized stop-
pers are placed inside an unsterilized hop-
per in a Class 10,000 environment during
the filling operation.
CORRECTIVE ACTIONS:
The filling line should be reconfigured and the
hopper of the filling machine must be brought
inside the Class 100 curtained area.
The hopper storing the sterile siliconized stop-
pers must also be relocated to the Class 100 area
and be pre-sterilized prior to its use.
Both these changes would necessitate that the
filling line be considered for re-qualification as these
moves could impact the airflow pattern within the
curtained area. Also, this line configuration would be
different from the one that was initially qualified via
media fills (assuming these were done).
1.5 Laminarity of the air supplying the cur-
tained Class 100 vial and syringe filling
areas is not assured in that the velocity of
the air has not been tested and smoke
studies have not been performed.
CORRECTIVE ACTIONS:
Air supply to the sterile core should be defined
as to the velocity of the air, number of air changes
per hour, as well as the air flow patterns. Smoke
57

tests must be performed to assure that there is no
turbulence and airflow is in the laminar pattern,
both in static and operational conditions. The test
should be videotaped and would become part of
the sterile filling operations validation records.
1.6 The filling machine operators are not moni-
tored either during or after the filling operation.
CORRECTIVE ACTIONS:
The operators must be monitored for microbial
quality as part of the overall environmental moni-
toring program. The number and frequency of sam-
pling could be defined as part of the overall re-
qualification of the aseptic filling process.
System Issues:
The concerned company has some major com-
pliance issues and if these citations are any indica-
tion, the quality/compliance systems are severely
deficient. The management should either perform
an in-depth review and analysis of current quality,
compliance, and validation practices, or hire an
independent consultant to perform an audit and
make appropriate recommendations. Specifically
the following systems should be reviewed in detail
and upgraded accordingly to meet the regulatory
requirements and industry standards:
Facilities/Utility systems qualification
Equipment qualification
Process validation
Calibration program
Preventive maintenance program
Material and personnel flow
Aseptic manufacturing/Filling lines layout
Environmental monitoring/Control program
Employee training program
SOPs and other critical documentation
Along with the system issues, the company will
also have to address the compliance issues
related to the product that has already been pro-
duced under existing (potentially violative) condi-
tions and is either in the distribution channels or
sitting in the warehouse. This applies to the in-pro-
cess materials as well and the organization must
make a decision as to their disposition.
COMPANY TWO:
FD-483 Observations Issued to Company Two:
2.0 QUALITY UNIT:
58 Special Edition: Corrective and Preventive Action
Shahid T. Dara
2.1 Quality unit has failed to assure the accu-
racy, completeness, and timeliness of vali-
dation reports, manufacturing documents
and analytical reports.
CORRECTIVE ACTIONS:
All reviewers within the quality unit should be
retrained on how to review each type of document
to assure compliance with cGMPs, with emphasis
on accuracy, completeness, and documentation
completed within a prescribed time period. Such
documentation completion and review time limits
could be established as part of the SOPs govern-
ing each type of quality/compliance document. To
further assure that the quality unit reviewers are
indeed performing their job, there should be peri-
odic double checks of approved documents.
2.2 Production areas have procedural notes
Post-its taped on walls and equipment,
which contain certain information and
instructions not contained in SOPs and
Batch Records.
CORRECTIVE ACTIONS:
Post-it notes must never be allowed to docu-
ment any critical product/process-related informa-
tion. The master batch records and SOPs should
be compared against the information on these
Post-it notes to see if this information is of any criti-
cal value. Also, it should be determined if the man-
ufacturing process was still within its validated
parameters or not. Meanwhile, all master batch
records and associated SOPs have to be reviewed
to assure compliance with the approved applica-
tion. The employees must be trained to emphasize
the use of actual documents for reference pur-
poses and use of Post-it notes and other scratch
paper should be forbidden.
2.3 Production maintains an unofficial DIARY
which refers to a bulk (active ingredient
powder) as powder wet, described as wet
and lumpy. Since this information is not
part of the official Batch Record it was not
reviewed by the Quality Unit prior to
release of (finished product).
CORRECTIVE ACTIONS:
Use of all unofficial documents to record any
product-related information must be barred. The
said diary and information contained in it should be
Shahid T. Dara
investigated to determine if the APIs wet and lumpy
characteristic has any adverse effect on the fin-
ished drug product. Also, the specifications for the
said API and its reserve samples should be re-
viewed to determine if this material is hygroscopic
and if this impacts its purity and assay value. The
official batch record has to be reviewed to see if a
revision is necessary to add this information to
complete the document. Regulatory affairs must get
involved to assure that the integrity of the approved
applications is maintained unless supplements
need to be filed to update the information.
2.4 The Quality Unit was not aware that pres-
sure readings across critical rooms were
not being recorded.
The Quality Unit was not aware the Post
Use filter integrity testing was not being
documented for portable tank vent filters.
CORRECTIVE ACTIONS:
An SOP and a log would be established to
record the pressure readings across critical rooms
and the data would be reviewed by Quality
Assurance (QA) periodically. The concerned
employees should be trained accordingly.
The SOP on filter integrity testing needs to be
reviewed and revised to assure that post use filter
integrity test data is recorded in an appropriate
form and periodically reviewed by the Quality Unit
(QU).
2.5 A sticky note, attached to the official lab
report, both dated 8/1/99, contained OOS
test results for (potency testing). The values
for this testing were not included on the
final lab report.
CORRECTIVE ACTIONS:
The Out-of-Specification (OOS) SOP should be
reviewed and revised if needed. The said incident
must be investigated to determine why this critical
data was recorded on a sticky note and not reported
in the final lab report. The product involved should
be placed on hold pending completion of this inves-
tigation and a detailed review of the batch history to
determine if the product meets all its specifications.
The analytical laboratory personnel should be
retrained on handling OOS data.
2.6 Work to replace a valve on the WFI system
was completed on 12/12/98. The documen-
Special Edition: Corrective and Preventive Action
tation of the repair and re-certification of
the system was dated 5/10/99. The system
was used beginning 12/13/98.
CORRECTIVE ACTIONS:
This incident would be investigated to determine
why it took such an inordinate length of time for the
documentation and re-certification to be com-
pleted. The current change control system has to
be reviewed and revised, if necessary, to assure
that any qualified/validated system that undergoes
major repairs or parts change is placed on hold
until all required testing and documentation is com-
pleted, reviewed, and approved by the QU.
2.7 The validation report (lyophilization of prod-
uct) did not address the failure of shelf tem-
peratures to meet specifications (-2 to -8 C)
during the cycle.
CORRECTIVE ACTIONS:
Since the process validation run did not meet its
specifications, it must be considered for revalida-
tion. Also, any deviations and failures to meet pre-
determined specifications during a validation run
must be documented, investigated, and justified as
to their cause and impact on the overall qualified
status of a system or process.
System Issues:
This particular organization has not defined the
role of the QU within its operations, resulting in a
non-functional quality system. Management must
define the quality goals for the company and then
develop a quality system and implement it. Specif-
ically, the following areas need immediate atten-
tion:
Documentation management system
Documentation review process
Employee training
Internal audit program
SOPs
Change control system
Validation program
COMPANY THREE:
FD-483 Observations Issued to Company Three:
3.0 PROCESS VALIDATION
3.1 Not all manufacturing processes are vali-
dated.
59

CORRECTIVE ACTIONS:
Manufacturing processes for all products need
to be evaluated as to their validation status and
appropriate action should be initiated. The com-
pany must perform a comprehensive and in-depth
assessment/audit of all manufacturing processes
to determine which processes need validation
based on FDA and Industry guidelines. This evalu-
ation could include a Good Automated Practice
(GAP) analysis to determine specifically which pro-
cesses require validation and which previously vali-
dated processes do not meet regulatory and indus-
try requirements.
3.2 Regarding (product # 1) manufacturing:
3.2a Sterile media fills have not been performed
for the bulk filling operations. These bottles
are labeled sterile.
CORRECTIVE ACTIONS:
An assessment must be made to determine if
the bulk product vials have to be sterile to deter-
mine whether there is a need to perform media fills
to qualify the bulk filling operations. Otherwise, the
label could be revised to delete the word sterile.
3.2b Aseptic technique of the filling operators
has not been evaluated.
CORRECTIVE ACTIONS:
Aseptic techniques of the filling room operators
need to be reviewed and a validation protocol should
be developed to evaluate their proficiency to assure
that the operators are indeed performing their tasks in
accordance with accepted aseptic processing stan-
dards. This study would also help determine a base-
line and could serve as a reference point for future
periodic evaluations of operator aseptic technique.
3.3 Regarding (product # 2) manufacturing:
3.3a Although process validation reports state
that (product # 2) purity level decreases
and the impurity carryover increases after
40 column reuses using a total protein load
of 120 mg (equivalent to 120 g full scale),
no protein load or column reuses have
been established in routine manufacturing.
For example, the (type) column has been
used in manufacturing in 54 cycles and
protein loads ranged from 49 to 148 g.
Since August 1998, three lots have failed
purity and have been reprocessed.
60 Special Edition: Corrective and Preventive Action
Shahid T. Dara
CORRECTIVE ACTIONS:
The manufacturing process must be revalidated
to establish the maximum protein load and number
of reuses for the column. Also, the historical data
for this product should be reviewed to determine
the average batch size as well as the optimum and
worst-case operational conditions.
3.3b In 1994 the fermentation operation was
scaled up (approximately doubled).
Although the harvest volume remained
constant following dia-filtration, the amount
of protein doubled prior to the (____) pre-
cipitation. There was no evaluation of the
effect of this modification on purity levels.
CORRECTIVE ACTIONS:
The process has to be reviewed in detail to
determine the impact of this change. If necessary,
the fermentation operation should be revalidated to
assure the desired purity levels for the product.
3.3c Scaled-down column validation supporting
the (____) column reuse is incomplete in
that the DNA impurity level was not moni-
tored during the study and the product # 2
purity level ranged from 76-86% based on
HPLC analysis which may not be represen-
tative of the process. The specification for
the product # 2 is greater than 90%.
CORRECTIVE ACTIONS:
The process must be revalidated to define the
Deoxyribonucleic Acid (DNA) impurity levels as well
as to optimize the purification process to consistently
produce a product that meets its specifications.
3.3d There is no periodic monitoring following
the cleaning operation for (____) column
demonstrating that the resin is consistently
cleaned (no carryover) throughout the life
span of the column.
CORRECTIVE ACTIONS:
The column rinse samples has to be tested for
any carryover residuals, both product and deter-
gent-specific. The cleaning validation for the col-
umn should be reviewed to see if a supplemental
revalidation is required to assure that the column
resin is consistently cleaned.
3.4 Regarding (product # 3) manufacturing:
Shahid T. Dara
3.4a There are no in-process or lot release test
specifications, or process validation studies
demonstrating the purification operation
consistently remove some process-related
impurities. For example: {Chemical # 1} is
used to purify (product # 3) from endotox-
ins in the large and small-scale purification
operations followed by {process step} used
to remove residual {Chemical # 1}.
{Chemical # 1} levels in the sterile filled
final batch concentrate ranged from <0.006
to 0.4 g in 3 batches analyzed.
CORRECTIVE ACTIONS:
The in-process and finished product specifica-
tions must be established based on the develop-
ment data for the purity and impurities profile. The
manufacturing process should be validated to
assure that the purification operations are consis-
tently capable of removing all the processing
chemicals from the end product. Also, these stud-
ies should be used to establish an acceptable
residual level for these chemicals.
3.4b Not all in-process dating is supported by val-
idation studies. For example, (product # 3
precipitate) can be stored on the __ filters
for up to 60 days. There are no studies eval-
uating product quality for this hold period.
CORRECTIVE ACTIONS:
Process time limits must be established for each
critical phase of the operation in accordance with
cGMP requirements and this could be accomplished
during revalidation of the manufacturing process.
System Issues:
Essentially this company has not performed
process validation in-depth. The following systems
need to be in place in order to address all the
specifics and underlying cGMP issues presented in
these observations:
Master validation program
Documentation-product specifications, in-pro-
cess, and finished product
Process time limits
Cleaning validation program
Employee training
COMPANY FOUR:
FD-483 Observations Issued to Company Four:
Special Edition: Corrective and Preventive Action
4.0 WATER SYSTEM
4.1 During 1998 and 1999, water test failures
have occurred, including TOC, LAL and
microbial testing.
4.2 There is no data to support the method and
frequency of sanitization of the cold WFI
system, nor is there assurance the water
meets its quality specifications, in that:
4.2a The system is sanitized on a monthly basis
by bringing the water up to more than 80C
and circulating it for 2 hours. There is no
data supporting the length of time, nor fre-
quency of these flushes.
4.2b The system was sanitized on 5/22/99.
Action limits, (including yeast and gram
negative organisms) were exceeded on
5/24/99; 5/28/99; 6/1/99 and 6/2/99.
4.2c Actions for investigations into high micro-
bial counts, including molds, consists of
additional sampling and do not include
increasing sampling frequency, increasing
sampling locations, and changes in the
sanitization schedule.
CORRECTIVE ACTIONS:
The said failures must be investigated to assure
that appropriate action is taken in the future, if
water samples fail to meet their specifications. The
water system has to be requalified to determine
the frequency and method of sanitization for the
system, as current practice is apparently not sani-
tizing the water purification system. As part of the
re-qualification effort, the design and installation of
the purification system should also be investigated
to see if it is a rugged enough system, able to with-
stand operational stresses encountered during rou-
tine operation. At the same time, the sampling/test-
ing procedures and sampling techniques need to
be reviewed to determine if poor sampling tech-
nique is the reason for these failures. Also, the
SOP addressing the investigation of high microbial
counts in water samples should be reviewed and
revised to assure that appropriate and timely cor-
rective actions are in place to assure the quality of
water produced. The organization must also review
the drug products manufactured with suspect qual-
ity water to determine if there is any risk to public
61

health or if there is a need for additional testing or
long term monitoring for these batches, like addi-
tional stability testing, etc.
System Issues:
The critical issue here is inadequate qualifica-
tion of water purification system and a lack of in-
depth investigation into microbial quality failure of
water samples. This organization needs to review
its current utility systems qualification practices as
well as quality failure investigation procedures and
follow-up corrective actions.
Utility systems qualification
Water sampling/Inspection techniques and
employee training
Quality failure investigation
COMPANY FIVE:
FD-483 Observations Issued to Company Five:
5.0 MEDIA FILLS
5.1 Regarding media fills:
5.1a Not all lyophilizer and chamber loading
activities that occur during routine produc-
tion are simulated during the media fills. For
example: medium filled vials are stoppered
immediately following the last tray loading
into the chamber prior to lyophilization simu-
lations; no worst case number of trays are
loaded in the lyophilizer during the media fill.
CORRECTIVE ACTIONS:
Media fills must be repeated, simulating all rou-
tine production activities, including worst-case sce-
narios for filling time, and minimum and maximum
number of trays for each load.
5.1b Sterile challenge media fill containers
found to have growth and a container
defect, are culled out following incubation
and are excluded.
CORRECTIVE ACTIONS:
This practice must be discontinued; however, a
container defect can be a cause for the false posi-
tives and could compromise the overall results of
the media fill. This could be controlled by using
more stringent acceptance criteria for the incoming
containers, which would reduce the probability of
using a defective container in a media fill run.
62 Special Edition: Corrective and Preventive Action
Shahid T. Dara
5.1c For the media fills that are carried out upon
the conclusion of a routine production run
of a product with anti-microbial activity, the
removal of residual anti-microbial activity
with the specified volume of medium ini-
tially pushed through the filling lines has
not been validated.
CORRECTIVE ACTIONS:
Media fill runs must be performed following the
production run of a product with anti-microbial
activity and the validation protocol should be
revised to require flushing the line with an ade-
quate amount of growth media to remove any
residual anti-microbial activity. The amount needed
to flush out the residual anti-microbial activity
should be determined based on a series of tests
as part of the qualification studies.
5.1d Specified incubation temperature range of
30-35C is not supported by data.
CORRECTIVE ACTIONS:
The incubation temperatures for the media filled
containers must be in accordance with United
States Pharmacopoeia (USP) requirements, i.e.,
20-25C for one week and 30-35C for the second
week to assure that both aerobic and anaerobic
microbes could be detected, if present.
5.1e Not all media fills exceeding the specified
action level are followed by at least three
consecutive successful media fills after an
investigation and corrective action.
CORRECTIVE ACTIONS:
There must be three consecutive successful
media fills to validate an aseptic filling operation, if
there is a failure during a media fill run, it would
invalidate the entire run, whether it is the first or
the third media fill that fails.
5.1f No assurance that all media filled units in-
volved in aseptic process validation runs
are evaluated for growth following incuba-
tion. There is no reconciliation of filled ver-
sus evaluated units.
CORRECTIVE ACTIONS:
The media fill batches must be treated like a
production batch and there should be an inven-
tory reconciliation performed for the number of
Shahid T. Dara
containers issued, filled, and incubated while
calculating contamination rate.
System Issues:
Here again, the company has some fundamen-
tal systems deficiencies, including:
Validation protocols preparation, review and
approval process
Process mapping to define all critical aspects
of a manufacturing process
Revalidation criteria and practices
Change control procedures
Development of acceptance criteria for valida-
tion studies
These systems should be reviewed to define
the deficiencies, if any, and should be corrected
according to industry guidelines to meet FDA
expectations.
COMPANY SIX:
FD-483 Observations Issued to Company Six:
6.0 VALIDATION AND CHANGE CONTROL
SOP ### Deviation Reporting allows un-vali-
dated processing or testing changes to be imple-
mented during production or testing. For example:
6.1a Deviation # 1234, dated 11/25/98, allowed
a change to the procedure for washing the
C4 column.
6.1b Deviation # 2345, dated 1/29/99, allowed a
change in the flow rate across the C4 column.
6.1c Deviation # 3456, dated 2/15/99, allowed a
change in the number of uses of the C4
column.
6.1d Deviation # 4567, dated 4/24/98, allowed a
change in the method for (finished product)
assay.
There is no report documenting why these pre-
viously validated procedures in processing/testing
required a change, and the impact, if any, of that
change.
CORRECTIVE ACTIONS:
All these deviations must be fully investigated
and the impact of each deviation on the validated
Special Edition: Corrective and Preventive Action
status of the process and testing method has to be
evaluated. A determination should be made as to
the impact on the quality of the final product. The
underlying cause of these citations is a lack of an
effective change control program that would have
forced the organization to review each and every
critical change in an otherwise validated process or
test method, and for its impact on the overall qual-
ity and compliance status of a given product.
System Issues:
The company needs an effective change control
system, along with a detailed quality failure investi-
gation procedure to address all these issues.
COMPANY SEVEN:
FD-483 Observations Issued to Company
Seven:
7.0 CLEANING VALIDATION (multi-use facility,
shared equipment)
Regarding cleaning of the multi-product equipment:
7.1 Changeover procedures to preclude contami-
nation or cross contamination can not be
assured in that the cleaning procedures for
removal of products, buffers or cleaning
agents have not been validated. For example;
7.1a The validation study for (product # 1) had
not been completed prior to the introduc-
tion of (product # 2) campaign in the manu-
facturing facility. The protocol was written
and approved two years ago.
7.1b No cleaning validation studies were per-
formed which demonstrate removal of
(product # 1) prior to the introduction of
(product # 2) campaign, even though prod-
uct changeover sampling was performed.
7.2 Validation studies did not address product
recovery from swab and equipment.
7.3 The final rinse water is not routinely or
periodically monitored after the cleaning
procedure for product and buffer tanks, fer-
mentors and centrifuges, though these ves-
sels are used to manufacture and/or store
multiple products.
7.4 The {assay type} results used to assess
63

residual protein in multi-product equipment
is biased in that a positive assay result may
not be used to determine the amount of
residual protein that remains after cleaning.
(Single positive result may be discarded
and reported as negative results.)
CORRECTIVE ACTIONS:
Cleaning validation must be performed for each
drug product as part of the development cycle. In this
case, the cleaning validation program is non-existent
and the organization needs to develop a comprehen-
sive program to address FDA concerns, as current
procedures and practices do not assure that the
potential for cross-contamination between products
and cleaning agents is minimized. Cleaning validation
must be completed for each product before introduc-
ing the next product into the same equipment. The
protocol must stipulate the timelines for completion of
each phase of the cleaning validation. The design of
experiment would include valid recovery methods for
the residues, both the drug product as well as the
cleaning agents. The study should also establish the
criteria for testing frequency, test methods, and
acceptance specifications for the final rinse water
samples. Analytical test methods used to determine
the residual proteins must be validated as well and no
positive results should be discarded without due
investigation. For routine production, the final rinse
sample should be tested for the residual product as
well as any buffers and cleaning agents, before
releasing the equipment for use in the manufacture of
any other product.
For the products that have been manufactured
without any cleaning validation, using the same
equipment, the manufacturer must perform a de-
tailed review of each product to assure that these
met all their specifications. As an additional mea-
sure, the reserve samples could be tested for any
potential cross-contaminants or selected batches of
such products could be placed on concurrent stabil-
ity testing.
System Issues:
Here again the quality system elements are not
in place that would ensure that the products
involved are manufactured in a compliant environ-
ment, meeting their desired quality attributes. At a
minimum, the company needs to establish the fol-
lowing systems:
Equipment cleaning validation program
64 Special Edition: Corrective and Preventive Action
Shahid T. Dara
Analytical test method validation program
Equipment cleaning and usage criteria
COMPANY EIGHT:
FD-483 Observations Issued to Company Eight:
8.0 STABILITY
8.1 (Finished Product), lot # 1234, was tested
for stability at 3 months in November 1998.
On 11/10/98, triplicate results for assay
were 24.6; 25.6; 24.4 unit per ml (spec =
27 unit/ml; SD <3.7). According to the labo-
ratory investigation, the test met validity
requirements and the SD was less than 1.
The lot was formulated with a 15% overage
to a potency of 34.5 units/ml.
According to the lab investigation three more
replicates were tested in order to establish the
validity of the first test. There is no documentation
that the first test was invalid. On 11/12/98 the tripli-
cate assay results were 30.9; 32.5; 31.9. These
results were then averaged with the first result.
(Avg. = 28.3, SD = 3.8). This result was invalidated.
A third assay was performed on 11/24/98 with
results; 29.5; 28.1; 26.3 and the average of 28.2
was reported. The protocol authorizing re-testing
was signed on 12/4/98.
On 2/10/99, the same lot was tested for stability
at six months with the assay results of; 27.2; 25.8;
26.1 units/ml (avg. = 26.4, SD = 1). The test met
validity requirements. The lot was re-tested on
2/12/99 with the results: 29.9; 29.4; 30.8 units/ml.
(Average of all six results = 28.2, SD = 2.11). The
average of the six results was reported.
8.2 There is no justification for testing 3 addi-
tional replicates, nor does the investigation
reference the 3-month results. Action to be
taken, such as adding additional testing
points is not addressed.
In addition, the investigation does not reference
accelerated stability studies, which indicate the
product may not be stable.
8.3 CBER was not notified of these results in
accordance with Error and Accident reporting.
CORRECTIVE ACTIONS:
The entire episode of stability testing for this par-
ticular lot from the three-month point onwards must
Shahid T. Dara
be investigated thoroughly to determine the cause
for all the replicate testing at the three-month test
point as well as at the six-month test point. The
major issue is that valid test results were discarded
without any justification and the protocol that author-
ized retesting at the three-month test point was
signed off after the fact. It appears that the company
is attempting to prove that the product is not degrad-
ing as fast as the initial three-month test point data
indicated, considering the lot was formulated with
15% overage. Aside from the fact that this particular
product is not stable as formulated, the company has
violated the cGMP requirement regarding analytical
test data integrity and record-keeping. The company
also violated the requirement for reporting such inci-
dents within 72 hours to the Center for Biologics
Evaluation and Research (CBER) as required by the
regulations. This particular lot should be considered
for recall, while other lots of the same product must
be reviewed in-depth to determine if it is an isolated
incident or the product needs to be reformulated.
This investigation should be expanded into products
similar to the one in question, same Active
Pharmaceutical Ingredient (API) or similar formula-
tion/packaging configuration. The company needs to
address procedural issues as well regarding report-
ing of product-related quality incidents/failures to the
Agency. As part of the stability-monitoring program,
the company should also have procedures in place
for review of the stability data at each test point, both
for ambient and accelerated conditions, and how to
handle any adverse situations.
System Issues:
Laboratory controls are the main issue here and
how to handle the raw data within the testing lab.
This particular company should perform a compre-
hensive review of its analytical laboratory policies
and procedures, with special emphasis on criteria
for re-testing of stability samples, if the initial results
are too low or too high but are still within the speci-
fications. This situation is different from a typical
OOS data investigation and handling. Here the
company is attempting to assure that the product in
question will meet its shelf life or expiration date.
COMPANY NINE:
FD-483 Observations Issued to Company Nine:
9.0 ENVIRONMENTAL MONITORING
Environmental monitoring activities were found
deficient as follows:
Special Edition: Corrective and Preventive Action
a. Operators who perform aseptic connections
are not required to submit touch plate sam-
ples after these activities.
b. Filling room operators are required to sub-
mit only one set of personnel monitoring
samples per day, even though they may
enter and exit aseptic filling areas multiple
times for rest and lunch breaks.
c. Monitoring for non-viable particulate is lim-
ited to 2-one minute samples collected at
two locations, while viable sampling is lim-
ited to 1-20 minute sample at one location.
These sampling times are not representa-
tive of the total time required to aseptically
fill products (4-7 hours).
d. Environmental sampling is performed
weekly for class 10,000 compounding areas
and is not performed on a per batch basis.
CORRECTIVE ACTIONS:
Environmental monitoring is performed to as-
sure that the manufacturing facilitys microbial and
particulate environment is within control and will
not compromise the sterility of the final drug prod-
uct produced. The schedule for environmental
monitoring must be based on the facility qualifica-
tion and aseptic process validation studies to de-
fine the sampling frequency and the specific sites
for viable and non-viable particulate counts. In this
particular case, the company needs to review the
existing aseptic operation validation data (equip-
ment qualification and media fill runs) to see if the
current environmental monitoring/sampling prac-
tices are based on these studies. Otherwise, the
system must be revised to make the following
changes:
Operators performing aseptic connections
must be required to submit touch plate sam-
ples before and after these activities.
Filling room operators must be sampled
according to the same plan used during the
media fills validation. If there is any inconsis-
tency, the sampling frequency should be at
least at the beginning, middle, and end of a
filling run. Each time an operator leaves or re-
enters the aseptic core, he or she must be
sampled for potential bio-contaminants.
The sampling frequency and locations for both
viable and non-viable particulate must reflect
the manufacturing/filling line configuration as
well as the length of the filling operation.
65
 Shahid T. Dara

For the Class 10,000 compounding area, the CORRECTIVE ACTIONS:

environmental monitoring must be at least on
a daily basis for the data to be of any value. If
more than one batch is manufactured on a
given day, then the area has to be sampled
as many times as well.
System Issues:
The organization has failed to develop a com-
prehensive environmental monitoring program for
its aseptic processing operations, which would most
probably invalidate any processes that might have
been considered validated otherwise. The company
must review its operating practices and develop a
program that would assure that the manufacturing
environment is maintained within a state of control
and this would include both the particulate and
microbial quality of the environment.
OOS is the hot subject with FDA since the Barr
decision. The Agency issued guidelines on how to
handle OOS data in 1998. Companies are
expected to have a formal OOS data investigation
procedure in place, requiring an in-depth inquiry
into any OOS situation. No data must be discarded
or voided without a complete investigation into its
possible cause. This company should implement a
comprehensive OOS data-handling program and
train all its concerned employees on proper investi-
gation into such an incident. The investigation
should start with the analyst performing the test so
that no erroneous causes are assigned to a given
incident of OOS results. Good science coupled
with good documentation practices can help
resolve this tricky situation and can also prove an
excellent training tool for the employees.

COMPANY TEN: System Issue:

FD-483 Observations Issued to Company Ten:
10.0 OOS Investigation
Out of specification results may be voided when
a single retest gives acceptable results. The OOS 1
results are not invalidated but attributed to unknown
analyst error, undocumented instrument error or
unassignable cause. Although there is no docu-
mentation to support the firms opinion that the
errors occurred, the OOS data may be discarded
and the results voided.
A lack of an effective change control system is
leading to these observations.
The above discussion of FDA observations dur-
ing inspections of manufacturing operations is still
an indication that Industry has come a long way in
the cGMP compliance arena, but it has a longer
way to go before achieving that imaginary total
compliance or control status.

10.1 On 3/28/98, (finished product- suspension),

lot # 1234, failed to meet its 6 month stabil-
ity specification of >667 u/ml. (Result = 579
u/ml). Re-measurement results were 593
u/ml. One re-test (844 u/ml) and a re-sam-
ple (841 u/ml) were completed. The average
of 843 u/ml is reported. The cause of the
low result is suspected to be failure to thor-
oughly knead the sample. The analytical
method does not include a kneading step.

10.2 On 8/1/98, (finished product-solution), lot #

2345, failed assay during validation of the
product. The assay was on a duplicate
sample from the beginning of filling. The
OOS was attributed to an unknown analyst
error, perhaps using an incorrect pipette
during the analysis. Five re-tests were con-
ducted and the average result reported.

66 Special Edition: Corrective and Preventive Action

 Non-Conformance,
The Corrective and Preventive
Action (CAPA) Initiator
T
here must always be a
Non-conformance well defined and docu-
mented reason to initiate
is a key concept a corrective or preventive action,
and that reason is termed non-
for quality systems conformance. Non-conformance
that is frequently is a key concept for quality sys-
tems that is frequently overlooked
overlooked as as companies focus on correc-
tive and preventive action sys-
companies focus tems. In May, 2001, FDA repre-
sentative Lillian Gill presented
on corrective and data that identified non-conform-
ing products, acceptance activi-
preventive ties, and Corrective and Preven-
tive Action (CAPA) as the top
action systems. three most frequently observed
citations on Form FD-483 re-
ports for medical device compa-
nies during 2000.1 Acceptance
activities relate to determining
conformance or non-confor-
mance, so the remaining top two
issues are directly attributable to
non-conformance processing.
While consulting with medical
device companies over the past
ten years, the author has found
the primary problem with non-
conformance is conceptual. Vary-
ing and conflicting definitions of
non-conformances, defects, and
complaints lead to inconsistent
by methods of identification and
David A. Manalan subsequent reaction. Beyond de-
President finition problems, companies
INQC Consulting also fail to understand the scope
Special Edition: Corrective and Preventive Action
of non-conformance. Figure 1
illustrates the limited view of
scope and definition of non-
conformance held by many
companies.
FDA-regulated companies
must first meet the specific re-
quirements of the Agency, that
are legally enforceable through
the Food, Drug, and Cosmetic
Act. This law specifically pro-
hibits products that are adulter-
ated or misbranded. Thus, the
FDAs Warning Letters to a com-
pany regarding quality systems
could conceivably include the
following:
The above-stated inspec-
tion revealed that these de-
vices are adulterated within
the meaning of Section 501(h)
of the Act, in that the methods
used in, or the facilities or con-
trols used for manufacturing,
packing, storage, or installation
are not in conformance with
the Quality System Regulation
(QSReg) for medical devices,
as specified in Title 21, Code
of Federal Regulations (CFR),
Part 820, .
Notice that products become
adulterated because the quality
system is not in conformance
with FDA requirements. Thus, all
67
 David A. Manalan

Figure 1
Traditional Non-Conforming Product View
Information Non-Conformance
Incoming, Non-Conforming
and Decision Activities: Per 21
In-Process,
CFR Parts 820-
Final Product Acceptance Subpart I
Activities
Identification
Documentation
Conforms Evaluation
(And Investigation)
Segregation
Disposition

Corrective and
Preventive Action

products manufactured by the company are non-
conforming products because they do not meet the
specification of the Act which prohibits adulterated
products. FDAs system-based assessment of med-
ical device manufacturers, the Quality System In-
spection Technique (QSIT) further reinforces this
concept.
Within the QSReg 21 CFR 820, FDA defines
nonconformity as the non-fulfillment of a specified
requirement.2 However, FDA inspectors and other
capable auditors would consider the lack of objec-
tive evidence that a specified requirement was met
would constitute nonconformity. Simply put, if con-
formance cannot be demonstrated, then the item or
system is non-conforming. Thus, a non-conformance
includes failure to have a specified requirement,
failure to assess whether the requirement was ful-
filled, and/or failure to meet the requirement.
ISO-9000: 20003 differentiates nonconformity
from defect and suggests that the term defect
should be used with care due to product liability
issues. In the preamble to the QSReg (comment
30),4 FDA takes a different view of these terms.
FDA emphasizes that a nonconformity may not
always be as severe as a product defect or failure,
but a product defect or failure will typically consti-
tute a non-conformity. In this view, defects are a
subset of nonconformity. FDA also defines the term
complaint as an allegation that distributed product
is defective, making complaints a subset of defects.
This article adopts the FDA view that non-confor-
mance is the predominant characteristic which initi-
ates CAPA.5 CAPA also dictates the need for ana-
lyzing processes, work operations, audit reports,
complaints, and other sources of quality data to
identify causes of non-conforming product. Thus,
CAPA requires an expanded search for non-confor-
mance.
Determination of whether conformance or non-
conformance exists requires specifications, a means
of assessing conformance to specifications, and the
actual assessment and records. Determination of
whether a non-conformance requires CAPA is a
separate and subsequent activity. Non-conformance
can be categorized as:
Expected
Unexpected
Possible
Expected non-conformance would usually relate
to acceptance activities, where a sample of prod-
uct is allowed to have some level of defect and still
be acceptable. Unexpected non-conformance in-
cludes product that is rejected, defective items re-
turned from users, and some types of audit find-
ings related to a product. Possible non-confor-
mance encompasses quality system audit findings
and Form FD-483 observations.
Along with three categories of non-conformance
are three sources of specifications.
Societal
Customer/User
Manufacturer
Societal specifications, defined by FDA, are
based in law, focus on ensuring the safety and
effectiveness of medical devices by compliance
with all relevant regulations. FDA specifications or

68 Special Edition: Corrective and Preventive Action

David A. Manalan

requirements include pre-market, manufacturing,
and regular inspection activities. The companys
pre-market approval or pre-market notification in-
cludes specifications, from the manufacturer, which
become legally enforceable by the FDA. Manufact-
uring activities, including design controls when ap-
plicable, must comply with the QSReg for all pro-
ducts. Finally, if deficiencies are noted during an in-
spection, the Form FD-483 and Warning Letter, if
issued, provide additional specifications for action.
Customer/User specifications focus on user ex-
pectations, needs, and intended uses. Customer/user
specifications require that the device must perform
as expected by the customer or user. It is impor-
tant to document these expectations, not simply to
rely upon the stated intended use by the manufac-
turer. Labeling, installation, and training are impor-
tant parts of these specifications. Design controls
are the manufacturers primary method for defining
these specifications.
Manufacturer specifications are designed to
serve as surrogates to ensure that medical devices
meet FDA and customer-user specifications. Man-
ufacturers usually develop the most comprehensive
and well documented specifications to ensure that
medical devices meet customer/user and FDA re-
quirements. There are component specifications,
supplier specifications, process specifications, per-
sonnel specifications, and others related to the
production and installation of products. All of these
specifications must be listed or referenced in the
Device Master Record (DMR), and conformance to
these specifications is maintained in the Device
History Record (DHR) or the Quality System
Record (QSR).
With three types of non-conformance, and three
sources of specifications, Figure 2 describes how
the various specific items of non-conformance can
be organized. Because FDA expects all medical
devices and related records to meet requirements,
there are no entries for Anticipated NC in the
FDA column.
Non-conformance, regardless of category, has
basic requirements. The manufacturer must estab-
lish procedures to control non-conforming product.
These procedures must describe identification,
documentation, evaluation, segregation (isolation),
and disposition per 21CFR 820, Subpart I.2 The
evaluation of non-conforming product must include
a determination of the need for an investigation,
documentation of this determination, and any fur-
ther actions. At this point, a decision on whether or
not to initiate a CAPA is made.
For anticipated non-conformance, such as one
reject in a sample size of 32, when the remaining
samples meet the established Acceptable Quality
Limit (AQL), the key procedures covering accep-
tance activity for that product should be followed. If
they specify how rejected samples are processed,
what is done with rejected samples, how the identi-
fication of the product is done, how the product is
controlled before acceptance, and what occurs
when the product is not acceptable, then there is
no need for a separate procedure for this type of
non-conformance. Records of these activities sat-
isfy the requirement for additional documentation. If
a customer requires service or repair, and the ser-
vice or repair was anticipated, then the service or
repair procedure and associated records meet the
non-conforming product requirement.
Unanticipated non-conformance requires a gen-
eral procedure that could include complaints as well
as manufacturing non-conformance. This procedure
should be expansive enough to include the possible

Figure 2
Categories of Non-Conformance and Source of Specifications
Anticipated Unanticipated Possible
Non-Conformance Non-Conformance Non-Conformance
FDA Form FD-483 items related to FDA Warning Letter regarding
specific products or processes QSReg deficiencies
Customer Service or maintenance Complaint regarding specific Customer audit findings on
request product lot Medical Device product quality concerns
Update/Upgrade requests Regulations (MDR) for product
Manufacturer Regular service end-of-life Frequent, unexpected repair Uncalibrated measuring devices,
repair non-conforming samples non-conforming lots, missing quality systems findings in
from acceptance lots records, process out-of-proven internal audits, use differing
range, product specific internal from intended use
audit deficiencies

Special Edition: Corrective and Preventive Action 69

 David A. Manalan

Figure 3
Comprehensive Non-Conforming Product View
Information
Incoming, Non-Conformance
and Decision
In-Process, Activities
Acceptance
Final Product Identification
Activities
Alleged Defects Documentation
Trend Data Evaluation
Service Report Non-Conforming (And Investigation)
Procedures Segregation
and Instructions Audit Findings
FD-483 Disposition
Conforms
Action
External Needed
Communication Corrective and
? Yes Preventive Action

No

non-conformance issues as well. A key element in established, while ensuring that all relevant FDA
the non-conformance procedure is the determination and ISO quality system requirements are met.
of whether CAPA should be initiated based on the Summary reports on non-conformance can be pre-
evaluation of the non-conformance and its possible sented for management review, and the non-con-
effect on safety and effectiveness. It must include the formance trends can be used in preparing quality
notification of person(s) or organizations responsible plans with measurable objectives.
for the non-conformance , as well as recording the
results for trending and training purposes.
Possible non-conformance is always the result
of an evaluation of non-conformance. When a non- References
conformance item is found in a lot, the possible 1. Gill, L. Regulatory Compliance: A Quality Perspective.
non-conformance of the remainder of the lot must AQC Proceedings. May 2001.
be considered. An audit may find a device that is 2. FDA. Medical Devices; Current Good Manufacturing
Practice (CGMP) Final Rule; Quality System
out-of-calibration, which requires an evaluation of Regulation 61FR52601. October 7, 1996.
the impact on all products measured with it to de- 21CFR820.3(q) Nonconformity means the nonfulfill-
termine whether non-conformance has occurred. ment of a specified requirement.
An FDA inspection may conclude that validation 3. ISO 9000 Quality management systems-Fundamentals
documentation of a process is inadequate, and and vocabulary. P. 8., 2.6.2.
4. FDA. Medical Devices; Current Good Manufacturing
thus all products made with that process must be Practice (CGMP) Final Rule; Quality System
viewed as possibly non-conforming. None of these Regulation. 61FR52601 (30). October 7, 1996.
situations are associated with the potentially non- 5. 21CFR820.100 Corrective and Preventive Action.
conforming product in preventive action. Preventive
action prevents defects, while all of the examples
given here relate to product that already exists, so
any non-conformance has already occurred.
Figure 3 provides a visual summary of this arti-
cle. In the comprehensive system, all information
sources feed an information and decision activity,
which not only centralizes all non-conformance
activities, but also ensures that a decision is made
on whether or not to initiate a CAPA based on con-
forming and non-conforming product results.
Expanding the scope of non-conformance allows a
simpler and more effective quality system to be

70 Special Edition: Corrective and Preventive Action

 Corrective and Preventive
Action: Planning to Achieve
Sustainable GMP Compliance
S
uccessful implementation
This article of Corrective And Preven-
tive Action (CAPA) is
provides important highly dependent upon the effec-
tiveness of the planning that goes
and practical into it. The temptation is to just
insights on how to do it. However, this often-admired
attitude is rewarded by false
have the right starts, incompleteness, and ulti-
mate delays in implementation. In
perspective, the many circumstances, CAPA is in
response to Food & Drug Admini-
right strategy, plan, stration (FDA) enforcement activ-
ity, so getting it right and getting it
and tools for done on time is crucial.
This article provides impor-
developing an tant and practical insights on
how to have the right perspec-
effective CAPA tive, the right strategy, plan, and
[Corrective And tools for developing an effective
CAPA plan. Indeed, if you have
Preventative paid for the ground once; you
cannot afford to pay for it over
Plan] plan. and over again.
The Right Perspective
Corrective and preventive
action is a major focus of the
FDA during inspections. It should
be no surprise that a firm can
have a problem in this area from
time to time. In fact, Good Man-
ufacturing Practice (GMP) recog-
by nize this, and have provided sec-
John E. Snyder tions of the regulation that deal
President with complaints, deviations, and
John Snyder & Company, Inc. investigations. However, the intent
Special Edition: Corrective and Preventive Action
of these regulations is not just to
catalog problems. The purpose is
to have a way to surface issues,
and have them come to the at-
tention of the right personnel in
the organization to permanently
address them.
Whether the issues surface by
means of your own systems,
such as internal auditing, cus-
tomer complaint investigations,
manufacturing deviation investi-
gations, or through the FDA, by
means of an FD-483 or Warning
Letter, there are four (4) consider-
ations to remember as you make
plans to correct the problems:
Determine the Root Cause of
the Presenting Problem
When an incident occurs, or
you observe an unfavorable
trend, investigate it immediately.
How to conduct an effective in-
vestigation is beyond the scope
of this article. However, suffice it
to say that you must have a thor-
ough understanding of the cir-
cumstances surrounding the pre-
senting problem. This requires a
thoughtful analysis to discover
the root cause. Without this, the
effectiveness of any prescribed
CAPA is only a guess. If you do
not investigate the root cause,
you have no reason to be sur-
prised when the problem pops
up again.
71
John E. Snyder

There once was a firm that had a nagging recur- lems from happening over and over again.
rence of microbial failures in one of their intermedi- An investigator observed a note in a batch
ates. The susceptibility of the intermediate to micro- record that a deviation was required to permit the
bial contamination was well known, and the firm use of a piece of equipment, although the calibra-
continually retrained its operators (the ubiquitous tion check was overdue by a month. The investiga-
corrective action) on the
approved cleaning procedures.
However, it was not until a sig- However, when quality system
nificant number of batches were
rejected, along with a growing
procedures are not designed properly,
customer backorder, that an or when they are not continuously
investigative team of engineers
and quality professionals were improved by our experiences, we can
deployed to look deeper into the
problem. It was discovered that
expect no more than to react to
a dead leg in the process piping incidents as the recur.
was seeding the batch with the
persistent microorganism. When
this root cause was finally identified, and the dead tor asked to review the justification for the devia-
leg was removed, the problem did not recur. tion, which simply stated no product impact OK
per Quality Assurance (QA). A further inquiry into
Determine The Extent of the Problem the frequency of such a deviation revealed that it
The present problem is simply what received your was not only a common practice, but that a stan-
attention. The problem may be representative of oth- dard form with this preprinted justification had
ers just like it waiting in the wings. The issue may been developed to handle these routine deviations.
have been first observed in one system, building, Looking deeper into the matter not only revealed
batch, line, or shift. However, the problem may be that the system was deficient, but that there was
operating undetected in other places, and could be no one truly responsible for managing the system,
causing a secondary problematic effect downstream. schedule, or delinquency reports.
A firm was cited by the FDA for failure to main-
tain purity of the product due to paint chips noticed Prevent Recurrence at a Corporate Level
in a mixing bowl. The firm identified the paint chip Theoretically, one of the advantages of large,
as having flaked off the mixing equipment. The firm multi-site corporations is the ability to leverage tech-
dutifully blasted down the metal, and polished it to nology and expertise. There is a tremendous oppor-
the original surface to correct the problem. How- tunity to discover internal best practices, and deploy
ever, the manager could not get the funds approved them globally for the greater good of the corpora-
to remedy two other mixers in the same condition. tion. The same applies to GMP quality systems and
As one could have predicted with almost certainty, experiences gained from internal audits and regula-
the problem recurred in another area. FDA noted it tory inspections. There should be a mindset of giv-
again on a subsequent inspection as failure to cor- ing a heads up to counterparts in other parts of the
rect the problem, which invited a Warning Letter. organization. Even better, is to have a corporate
system, and an environment that provides an
Prevent Recurrence at a System Level action-oriented system and forum to encourage
Preventive action requires asking, What system sharing of meaningful information for continuous
failed? We understand that in a GMP environment, improvement on a global scale. The highest level of
written procedures direct our work and are an inte- the organization must set such expectations, and
gral part of our training system. However, when create a culture of openness for this to succeed.
quality system procedures are not designed prop- There was a firm that had multiple sites where it
erly, or when they are not continuously improved manufactured its drug products. The firm was sur-
by our experiences, we can expect no more than prised to be party to a consent decree of perma-
to react to incidents as they recur. A system-level nent injunction for one of its sites following what it
view seeks to leverage learning and prevent prob- had considered to be a minor FD-483 for computer

72 Special Edition: Corrective and Preventive Action


system validation. There were no previous Warning
Letters issued at the site. What the firm failed to
realize was that other FD-483s had been written
many times over the previous years for the same
issue at other sites.
It is important to understand that FDA views a
specific site as part of a whole. When the FDA calls
a problem to the attention of a company a second
time, it is considered a repeat observation, whether
the observation is made at two different sites, or
two different countries. FDA, or any other regulatory
body, will conclude that there is a corporate prob-
lem, not just a local problem. In such cases, the
Archimedes Principle will likely be applied, and a
larger FDA enforcement lever will be selected to
force corporate movement to finally resolve the sys-
temic problem.
Those levers, which include seizures, injunc-
tions, and prosecution, have tremendous business,
financial, and personal consequences.
The Right Strategy
There is much to consider when deciding upon
a strategic approach to CAPA planning. There is no
one size fits all. Circumstances vary and so must
the strategy. However, there are a number of ques-
tions to consider when formulating an appropriate
strategy for a given situation. For example:
How Will Executive Management Lead?
The question is how, not if executive man-
agement will lead the effort. Effective CAPA pro-
grams rarely focus on a small, single departmental
activity. The magnitude of the business risk and the
degree of cross-functional (if not global) collabora-
tion and effort required mandates that the top
executive take the lead. While other functional
leaders may be tasked with managing the details,
the importance of the President and CEO commis-
sioning the process and providing ongoing visible
support is vital. There is too much at stake for
him/her personally and for the firm, not to be
involved. The question becomes a matter of deter-
mining the practical ways to exhibit the kind of
leadership and support that rallies, unites, and
engenders cooperation within the organization as
quickly as possible.
It was reported that a CEO received a Warning
Letter for GMP violations at one of his manufactur-
ing plants. The CEO responded to the FDA request-
ing that in the future to please refer all matters of
Special Edition: Corrective and Preventive Action
John E. Snyder
this type directly to the quality department. Such a
detachment failed to recognize both the serious-
ness of the matter and his personal responsibility.
Consider requesting the following tangible sup-
port from the President and CEO:
Conduct a round of employee meetings at
each site to explain the regulatory situation in
a forthright and balanced way. Use the meet-
ing to explain how the company is managing
the effort, and that s/he is expecting teamwork
on this business challenge priority. Keep the
meeting realistic and positive, without mini-
mization and happy speak.
Receive progress reports as a standing agenda
item at executive management meetings. Set
the tone for openness. Require objective mea-
sures in terms of milestones and target dates in
sufficient detail in order to obtain an accurate
picture of the progress being made.
Show interest by being available to resolve
issues and to appropriate funds in a timely man-
ner. It cannot be business as usual. The clock
is ticking. Streamlined mechanisms must be put
in place for executives to support the effort.
Otherwise, the normal issue elevation and deci-
sion-making processes will devour the timelines.
When the urgent situation passes and CAPA is
implemented, the President and CEO should
ask what will be done differently in the future
in order not to pay for this ground again?
How Extensive are the Problems?
Most likely, a major campaign for CAPA was
mounted as the result of a regulatory enforcement
action. If so, the FDA has given some very specific
feedback in the form of an FD-483 or Warning Letter,
or possibly they delineated requirements within a
consent decree. The FDA will assuredly state in boil-
erplate language that theirs is not an all-inclusive list
of violations. They will also remind you that it is not
their responsibility to inspect your firm into compli-
ance. It is your responsibility to know the require-
ments, and to comply with all the regulations. The list
of violations is not a to do list. The job is not done
when every item has been checked off. The question
to be asked internally is, Do we really know for our-
selves where we stand?
When asked whether the issues communicated
by the FDA reflected their own internal findings
from audits or quality performance metrics, a com-
73
 John E. Snyder
pany official indicated that he did not normally con-
cern himself with such level of detail. Upon review,
it was discovered that many of the issues were
known by internal means. Moreover, it was discov-
ered that there was no forum for management to
review to audit findings or to support CAPA. This
underscores the importance of knowing for yourself
where you truly stand, and not to allow a good or
bad FDA inspection to be an absolute GMP com-
pliance barometer.
Consider the following when determining the
scope of the plan:
Conduct an independent quality system
assessment. An assessment is different than
an audit. An assessment is an in-depth collab-
orative review of all the elements of a GMP
quality system by subject matter experts and
system owners. Combine this information with
your own internal audit findings, quality data
and metrics, and then prioritize remediation
targets by means of a rational decision-making
process that weighs various risk factors.
Include other sites, domestic and international,
in the assessment. This is especially important
if there have been FD-483s or Warning Letters
issued to multiple sites. Use this as an oppor-
tunity to reexamine the overall corporate qual-
ity system: the architecture, policies, proce-
dures, and work instructions.
Develop an integrated CAPA plan. Leverage
the strengths of your company and spread out
the work. Welcome the thinking that would per-
mit one site to benefit from the experiences of
another. There may be no other choice when
widespread progress must be quickly made.
What is the Enforcement
Acceleration Rate?
The first source to identify a potential problem
should be your own findings through internal audits
and interpretation of quality metrics and trends,
assuming they are effectively designed and imple-
mented. The best possible position to be in is to
proactively respond to your own internal signals.
When combined with ongoing surveillance of in-
dustry practice and FDA initiatives and guidance,
these early detection systems can put you in an
advantageous position. However, once FDA in-
spections reveal violative conditions and when offi-
cial action is indicated, the clock starts counting
74 Special Edition: Corrective and Preventive Action
down. Unfortunately, when a firm is dealing with a
second or third FD-483 or Warning Letter, the en-
forcement momentum can be formidable to push
back. Where a firm sits on this momentum contin-
uum will affect the planning strategy, and dictate
the required energy to push forward.
A firm with extensive nationwide operations re-
ceived Warning Letters at various sites for similar
issues. The firm later came under a consent decree
of permanent injunction. Time passed while the firm
was implementing its corrective action plan. In the
interim, the FDA conducted a short inspection at a
facility that had not been recently inspected. The
inspection netted an FD-483 with a half dozen brief
observations, which seem relatively light as char-
acterized by the firms executive. What the firm
failed to realize was that the FDA was documenting
as little as was necessary to establish that the
same violative conditions still existed within the
firm. Shortly thereafter, the CEO received a letter
from the FDA to cease operations at the facility, per
the provisions of the decree. The firm had no other
choice than to stop operations at the site and focus
on an accelerated, corporate-wide remediation pro-
gram.
Keep these points in mind as you consider how
best to plan when involved in an intensifying situation:
The FDA may not always follow progressive
stages of enforcement. A Warning Letter may be
received with no previous FD-483. An in-
junction may follow an FD-483. The next FDA
move depends upon many factors. In this
sense, each communication from the FDA must
be handled with a sense of urgency, but not
hastily and thoughtlessly. A companys response
to an FD-483 or Warning Letter is strategic and
critical. Responses can precipitate further
enforcement action, or mitigate the situation.
Certainly, if there is a second FD-483 any-
where in the firm, not to mention a Warning
Letter, you are already in the crosshairs. Time
is running out on being well into a comprehen-
sive, global quality system assessment and
CAPA plan.
Regardless of the situation, maintaining open
lines of communication with the District Office
of the FDA, and other related FDA centers and
offices is crucial. Share your plan with the
FDA, as well as verifiable deliverables and tar-
get dates. It is far better to share changes in
the plan (such as slipped target dates) with

the FDA than for FDA to discover this them-
selves upon re-inspection. However, it is far
better to build confidence and credibility, by
keeping commitments through effective plan-
ning and execution.
How Should the Process be Managed?
With the President and CEO clearly in com-
mand and aligning the organization with this prior-
ity, someone must clearly be designated as his/her
manager of the CAPA process. Most likely this will
be the head of the QA function,
but perhaps not. If you use the
analogy of a new business
acquisition, or new product
Consultants should never be
launch, or any other enterprise required to sustain a system.
imperative, you will understand
the need to have a driver who
has a proven record for getting things done. It is
equally important for the driver to have a direct
reporting relationship to the President and CEO.
A President was stunned to find out that com-
mitments made to the FDA in his companys re-
sponse to a Warning Letter could not be verified in
all cases upon re-inspection. No red flags stood
out in his mind that had suggested a failure to fol-
low through. His investigation revealed that the cor-
rective action plan required the purchase of a
piece of equipment that was clearly critical to suc-
cessful implementation. He discovered that one of
his VPs would not approve the purchase requisi-
tion at the time it was needed to meet the commit-
ment date, but opted to approve the requisition the
following quarter due to budget variance consider-
ations. The VP had failed to realize the longer-term
consequences of his action. No one seemed to
want to go around him to the President. Not only
was there lost time, but there was lost credibility
with the FDA. The VP was rewarded for making
the quarter.
Consider these points when establishing a
structure to manage the process:
The process manager (driver) should act on
behalf of the President and CEO, and must
have direct access to the top executive to pro-
vide status reports, a picture of reality, and to
request specific support as needed.
The process manager should work in the con-
text of a cross-functional senior management
steering team, the purpose of which is to gen-
Special Edition: Corrective and Preventive Action
John E. Snyder
erally manage corrective action project teams,
integrate cross-functional activities and re-
sources, and remove the obstacles. The steer-
ing team must quickly resolve issues that could
affect the timeline of the deliverables, and most
of all is a champion of the project teams.
The steering team must avoid putting adminis-
trative burdens on the teams doing the work,
but rather protect them from distractions. The
busy-ness of administration should not be
confused with real progress toward verifiable
results.
The steering team members should go to the
standing project team meetings to obtain infor-
mation, rather than create additional meetings
to receive team reports. If the steering team
members are getting their progress reports at
the same time and by the same means as the
President and CEO, then they may not be
adding real value, and should be dissolved or
reconstituted.
How Should Consultants be Used?
Value-added and results-oriented consultants
should be considered as additional resources.
Carefully selected consultants can bring a wealth
of experience and expertise to the process. De-
termining the right consultants, at the right time,
and for the right purpose is important to the suc-
cess of the project. Simply inserting consultants
into a situation can be a big mistake, particularly in
the absence of an overarching strategy, or laying a
solid foundation for the work they are retained to
do. Consultants are never a substitute for the com-
pany infrastructure that is necessary to sustain
regulatory compliance in the long run.
A firm had received several FD-483s and War-
ning Letters over several years at one of its manu-
facturing locations. During this time, the firm had
used the services of no less than a half-dozen con-
sulting firms directed toward its problems. Yet there
seemed to be little progress in terms of sustained
compliance. It was later recognized that the consul-
tants had been used to fix specific problems, rather
75
 John E. Snyder
than to help management survey the overall situa-
tion and recommend systemic and integrated solu-
tions. The work of the consultants had reflected the
narrow view of CAPA by the management. The firm
later retained consultants having both technical and
strategic capabilities with measurable success.
Consider these suggestions on how best to
incorporate consultants into the plan:
Use a consultant when an objective perspec-
tive is needed. This includes quality system
assessments, and verification or certification
that remediated systems are indeed in place,
in use, and effective.
You may benefit from a senior consultant with
significant experience dealing with FDA
enforcement activity to help develop a strategy
and assist with developing communications to
the FDA and District meeting preparation.
A senior consultant may serve well as a general
contractor to help identify and manage the
other specialists needed to support the effort.
She/he would be a valued executive team mem-
ber working closely with the process manager.
Use consultants when you are missing or un-
certain of your own internal expertise. Subject-
matter experts can help to develop quality sys-
tems, or perform work where knowledge in
specific science or experience is necessary.
Involve consultants where you lack the critical
mass needed to accelerate the process. They
should not, however, become default employ-
ees. Consultants should never be required to
sustain a system.
Consider how best to use differences in experi-
ence and expertise between FDA and industry
consultants; the former having policy and in-
spection experience, and the latter having sys-
tem design and implementation experience.
Should a Professional Project
Manager be Used?
The skills of a professional project manager are
very useful, if not a necessity to support CAPA
work. A project manager works together with the
President and CEO, process manager, and steer-
ing team to ensure that the correct assumptions
and strategy are reflected in a workable plan. The
project manager and subject matter experts may
collaborate to help project teams map out a pro-
cess flow diagram of the current as is and re-
76 Special Edition: Corrective and Preventive Action
designed to be systems, around which new pro-
cedures will be established. The project manager is
equipped to help teams to evaluate their work into
manageable pieces to give the project structure,
deliverables, and accountability.
A plan in the hands of the project manager is
neutral and apolitical. She/he stands back and
looks at the plan objectively to determine if the plan
gets you where you want to go, on time, with the
going-in assumptions. If the plan falls short, the
assumptions and tasks may need to be challenged.
The work may need to be approached in a different
way to accomplish the same goal. In which case,
the plan becomes the focus of scenario playing and
modifications, not personalities.
A VP of a firm felt it was his prerogative to dic-
tate to his site directors that they fix its compliance
problems by a certain date, by a certain means, or
else. He viewed his just go do it approach as quite
appropriate, given their regulatory situation, his
position of authority, and what his directors were
paid to do. The VP defined the goal, assigned the
teams, and established the way the work was to be
conducted, including the assumptions and budget.
He laid out the assignments in a lengthy memoran-
dum that his directors received by mail drop along
with the edict to do it. This approach was destined
for trouble from the start. It failed to establish a
working plan, or integrate with other site priorities,
thereby causing confusion and mixed messages.
The breakdown of the actual tasks, functional inter-
dependencies, and analysis of resources needs to
accomplish the work were not conducted. The
result was a demoralized staff and calls to
recruiters.
Here are skills that you should expect from a
professional project manager to help in the CAPA
planning process:
Project managers can facilitate project teams
meetings to breakdown the work into deliver-
able pieces.
Project managers work with teams to docu-
ment responsibility, and identify the resources
and costs. This brings accountability to the
process.
As the plans emerge from the many project
teams, the project manager identifies the interde-
pendencies, and demonstrates where resources
can be leveraged across projects. S/he may chal-
lenge the pathway of the activities to find where
tasks can be parallel, rather than serial.

Project managers track progress of project
teams by providing management and other
interested parties with updates with varying
levels of detail.
The Right Plan
A variety of images come to mind when you think
of the word plan. They may range from a simple
checklist for the days activities to complex computer
models and charts that bring together the diverse
materials and trades to build a skyscraper. It is in-
conceivable not to have a plan that guides the
CAPA process. Without a plan, you are left to your
best intentions to meander, realizing only when time
has run out that the mission was not accomplished.
You stand there mystified, wondering what was
missing in those status reports that should have
been your first clue that things were really not going
as well as you thought.
The complexity of the circumstances usually
dictates the level of detail there should be in a
plan. However, there are certain steps that need to
be considered in any CAPA plan to ensure sustain-
ability of a system into the future. These steps help
to address the common failures of CAPA imple-
mentation. These are:
Failure to Analyze
Failure to Agree
Failure to Communicate
Failure to Execute
The following describes twenty (20) major tasks
that a project team needs to consider when devel-
oping a project plan. These tasks are divided
among four (4) major phases or milestones: prepa-
ration, design, implementation, and verification.
Taken collectively, these tasks address common
failures.
Preparation Phase
Form and Train Project Teams
Identify the right combination of skills and experi-
ence to tackle the problem and provide training sup-
port to achieve a stated goal. Each member must
understand his or her specific role on the team.
Training must include the context the team plays in
the overall compliance strategy. Training needs to
include problem analysis, and other tools of quality
and project management, as necessary. The order of
Special Edition: Corrective and Preventive Action
John E. Snyder
priority of the project must be clear and made practi-
cal in terms that are relevant to the team members.
Research/Analyze Issues and Develop an As
Is Process Flow Diagram
Begin with library work and basic study of the
problem. This includes determining the nature and
extent of the problem, and identifying the underly-
ing causes of the system failure. Develop an As Is
process flow diagram of the existing system to cre-
ate a common understanding of the system among
team members, as well as serve as the focal point
for improvement discussions. Based on the analy-
sis, determine the root cause of the failure. This is
essential to have any basis of confidence in the
corrective action. Identify the primary and contribut-
ing causes through frank discussions. In some
instances, an underlying cause may be the busi-
ness culture, and management must be prepared
to accept all objective and sincere efforts to identify
such causes. However, root causes must be
derived by careful observation and analysis.
Develop Project Scope, Alternatives, Assump-
tions, Obstacles, and Costs
Specifically identify the activities that are inside,
as well as outside, the scope of the project in order
to avoid any misunderstanding. Explain the thought
process used for determining the specific direction
the team takes to help others outside the team
understand. However, any specific approach taken
to resolve a problem has its assumptions, real and
potential obstacles, and cost. Identify these early in
the planning phase to ensure that all required ap-
provals are secured in advance. Shortcuts in this
step leads to misunderstandings, eleventh-hour
objections, and irrecoverable delays.
Develop Communication Plan
Develop a written communication plan to keep a
wide array of personnel informed whom are essen-
tial to move the new system off the page of a pro-
cedure and into behavioral changes. A communi-
cation plan identifies personnel, type and fre-
quency of communication, and should include all
relevant groups, such as corporate, division (inter
and intra), as well as affected site personnel. Com-
municate with consultants and other subject-matter
experts to obtain their input upfront when their ex-
perience can be most beneficial to the project.
Maintain close communication with those whose
signatures are required for approval of new policies
77
 John E. Snyder
and procedures. Failure to communicate with all
who have a say is a leading cause of the failure
to implement a newly designed system.
Milestone Status Review Preparation and
Presentation
Conduct a major project review upon completion
of steps one through four. This review will likely in-
clude executives, steering committee, project man-
ager, and relevant consultants. Key participants are
those who are responsible for approving new policies
and procedures. It is useful for other sites and divi-
sions to participate in the review as a means to trans-
fer learning. At this point, the project team shares its
findings from the analysis phase, and presents a
high-level review of how the team arrived at its deci-
sions and alternatives. It is time to put the assump-
tions, obstacles, and estimated costs on the table.
Feedback to the project team at this point is essential
to avoid lost time. The output from this review must be
clear support for the general direction the project
team takes, or sufficient feedback that enables the
team to make necessary adjustments.
Design Phase
Develop a To Be Process Flow Diagram
Use a To Be process flow diagram as the pri-
mary design tool to develop the new system. Use
information gathered and analyzed in the previous
phase, as well as related audit and inspection ob-
servations as inputs to the new design. Editing an
old procedure or purchasing a commercially avail-
able SOP template is often mistaken for CAPA.
Without a disciplined and business process ap-
proach to remediation, the results over time invari-
ably become a collection of patchwork procedures
that are inefficient and often work against other busi-
ness processes. It is far more helpful in the long run
for a cross-functional team to take this opportunity, not
only to remediate a system for compliance pur-
poses, but for business efficiency as well.
Review Existing Policies and Procedures
Review all the policies and procedures in the qual-
ity system that relate to the system being redesigned.
Rarely can one make a change to one system with-
out affecting others. Ensure that all the related poli-
cies and procedures are consistent with the new sys-
tem being designed. Review definitions, responsibili-
ties, references, as well as details that must be con-
sistent and harmonized. All these sources and levels
78 Special Edition: Corrective and Preventive Action
of documents must be considered as part of the en-
tire body of material that must be reviewed as part of
the redesign effort. This avoids the common problem
of creating a fractured quality system in which com-
plying with one procedure causes one not to com-
ply with another; a no win situation.
Develop New Policies, Procedures, and
Architecture
Develop new policies and procedures based on
the To Be process flow diagram. Consider if there
should be an umbrella procedure that generally
describes the overall system and refers to the vari-
ous related, but distinct operating procedures. Con-
sider whether the exceedingly detailed and job spe-
cific operations should be in separate departmental
work instructions. All of these levels of procedures
should be viewed as a balanced outline that has a
proper weight and parallelism with its constituent
parts. A balanced, architectural approach to a col-
lection of procedures within a system provides an
orderliness that is easier to train, understand, follow,
and easier to explain during a regulatory inspection.
Writing a new procedure in a vacuum as a quick fix
is usually a mistake. While it may seem quick and
easy, the lack of a consideration of the interdepen-
dencies of systems and procedures will likely sur-
face as non-conformances in other areas.
Establish Performance Metrics for the System
Establish metrics for the system being designed
and build the metrics, reports, and frequency into the
system procedures. The metrics should provide two
kinds of information: how well the system is doing
and what the system is detecting. For example, a
planned versus actual internal audit schedule table
would be a measure of how the system is operating,
and a bar chart of type of nonconformance by work
center would measure what the system is detecting.
Integrate these metrics, as appropriate, with the
Annual Product Review (APR) and management
review systems. These metrics, otherwise known as
quality data and trends in regulatory terms provide
a significant means to proactively prevent potential
quality problems and to sustain the quality system.
Confirm Design with Subject Matter Experts
Confirm the design of the new system with your
consultant or other subject matter experts to ensure
that the system, as described by policies and proce-
dures, addresses the issues. By this point in the pro-
ject, the team will have expended more than half its

total effort. Ideally, the team has availed itself of ex-
pertise all along the way. Regardless, this is a good
checkpoint to consciously affirm that the newly de-
signed system completely addresses the issues. It
may be useful to revisit the regulatory inspection
feedback, internal audits, the team analysis, and root
cause determination to serve as a reminder of the
issues that prompted the project in the first place.
Milestone: Status Review Preparation and
Presentation
Conduct a major project review upon completion
of steps six through ten. This is the second major pro-
ject review, and should include the same participants
as before. Key participants continue to be those who
are responsible for approving new policies and proce-
dures. It is useful for other sites and divisions to par-
ticipate in the review as a means to transfer learning.
At this point, the project team shares its work in the
form of new draft policies, procedures, and local work
instructions. The team uses the To Be process flow
diagram to present an overview of the new system.
By this point in the plan, there should be no serious
objections regarding the fundamental direction the
project team has taken. This should have occurred
during the first review meeting, and/or resolved with
the communication plan. The output from this review
must be clear support to approve procedures, and to
proceed with the implementation phase.
Implementation Phase
Obtain Approvals of New Procedures
Those who are responsible for approving new poli-
cies and procedures will have participated in the two
major project review meetings. Additionally, the com-
munication plan will have addressed the need for
early and frequent discussions with these signatories.
There should be no reason that an approver should
dissent or raise a significant issue at this point. Such
issues had opportunities to be raised and resolved at
project review meetings and ongoing communication.
The approvers should be familiar with the documents
to the extent that approval signatures should be able
to be obtained within a fraction of one day.
Develop An Implementation Plan
Develop an implementation plan that specifies
the requirements for new policies and procedures
to be put into effect. This plan must address valida-
tion, regulatory, training, and logistical issues.
Significant implementation issues must be antici-
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John E. Snyder
pated in advance and integrated into the project
timeline. This is not the time to discover that a new
piece of equipment with a six month lead-time
must be purchased to implement the new system.
Process Through Change Control and
Document Control Systems
Policies and procedures are controlled docu-
ments of the quality system. New or revised poli-
cies and procedures represent a change to the
present system, and therefore, must be reviewed
with respect to such aspects as the state of valida-
tion and regulatory notification. The process must
ensure that a state of control is maintained, and
the change is permitted within technical and regu-
latory boundaries. The document control process
ensures that only approved and the most recent
revisions of procedures are in the workplace.
Conduct General Awareness and Specific Job
Training
Determine who is to be trained, who will conduct
the training, the appropriate method of training, and
how competency will be assessed and documented.
Training must be consistent with policies and proce-
dures that define the training management system.
Avoid a read and sign approach to training. The new
procedures are part of a system redesign that were
likely the result of a negative regulatory inspection.
This is the point where the best intentions fail due to
inadequate training. This is an opportunity to explain
the importance of the system, and how it relates to the
quality of your products in an industry with high public
trust. Emphasize the importance of following proce-
dures and good documentation practice in a regulated
environment. Use this training time to explain that the
new system is part of an overall strategy to ensure
efficient business practice, regulatory compliance, and
a secure future. Many an opportunity is lost when
training is viewed in an apathetic manner.
Milestone: Perform an Internal Audit to Confirm
The New System is In Place and In Use
Conduct an internal audit of the new system after
it has been in place for a reasonable period of time
to assess the effectiveness of implementation. Up to
this point, all the parts of the plan have been
directed toward putting a new system in place. An
audit of the system must be constructed at this point
to determine if the system is in place, in use, and
effective. In place is determined by the presence of
the new procedures and examination of training
79
 John E. Snyder
records for relevant personnel. In use is deter-
mined by the examination of historical documenta-
tion relevant to the new system. Effective is deter-
mined by the elimination of the original noncompli-
ant state in the long run as revealed by performance
metrics. Effective may also be assessed in terms of
the efficiency gains with the new system.
Verification Phase
Assemble The Verification Document
Gather and organize all documentation (poli-
cies, procedures, and records) that establish evi-
dence that the new system is appropriately de-
signed (system architecture and performance met-
rics), addresses the compliance issues (specifically
and systemically), has been implemented (con-
trolled change, trained, and issued), and is being
followed (control records and audit).
Conduct The Internal Review and Approvals of
The Verification Document
Structure the verification document to provide for
steering committee review and approval, with final
review by the head of QA. This final internal review
affirms to the steering committee and executives
that documented evidence exists that a new system
that corrects the issue and prevents its recurrence
is in place and in use. The review also familiarizes
key personnel with the very documentation that
they may be called upon to use to defend the sys-
tem during a regulatory inspection.
Defend the Verification Document with Third-
Party Reviewers
Submit the verification document to third-party
verifiers (consultants/subject-matter experts) for
review. Formally present, discuss, and defend the
document with third-party verifiers and appropriate
company personnel. It is useful for other sites and
divisions to participate in the review and defense
meetings as a means to transfer learning. Follow-
up any outstanding issues that may have surfaced
during the internal and third-party review of the
system. Additional evidentiary documents that may
have been generated as a result of follow up activ-
ity to the review must also be included in a revision
of the verification document.
Milestone: File Project Documents and Schedule
Internal Audit
File key documents, including the verification
80 Special Edition: Corrective and Preventive Action
document, associated with the project, in the tech-
nical library or appropriate archive. These docu-
ments will be crucial resources during a regulatory
inspection, as well as for future-related projects.
The Right Tools
A formal process must be used to report on the
progress of CAPA. Informal methods or no news is
good news are inappropriate for projects that
manage product quality and compliance enforce-
ment risks. As stated earlier, repeat regulatory
inspection observations invite enforcement conse-
quences. Therefore, a formal project tracking sys-
tem is necessary to measure progress of project
teams. Unfortunately, many tracking systems are
cumbersome, and fail to offer management an
accurate view of real progress through real tasks
that offer real solutions. Without such a system,
management may be both unaware of what is truly
necessary or when to intervene with support.
Figure 1 can be utilized by CAPA project teams
to guide them through the CAPA process. Its pur-
pose is to help teams to incorporate the twenty
critical steps toward sustainable compliance. It can
also be used as a simple and effective way to track
the progress of a team, or multiple teams.
This document can be updated weekly, and
used by project leaders and steering committee
member sponsors as a management tool. It is not
meant to displace other conventional project man-
agement tools, but rather to supplement them.
Assuming that end dates are based upon a regu-
latory or business imperative, every effort must be
made to hit the target dates for each step. A culture
of effectively hitting the dates must be engendered.
Problems that could potentially impact the timeline
need to be surfaced and addressed right away. It is
the responsibility of the steering team to help the
project teams by running interference and collabo-
rating with cross-functional management. Issues that
are beyond the capability or authority of the project
team may need to be elevated. Indecision and unre-
solved issues will unforgivingly devour the timeline.
Conclusion
The CAPA terms, and concepts of preparation,
design, implementation, and verification are clearly
found within cGMPs. This article makes the case for
taking a strategic approach to the planning that must
go into CAPA. Whether regulatory compliance prob-
 John E. Snyder

Figure 1
Four Phases and Twenty Tasks for an Effective Corrective and
Preventive Action Plan for Sustainable Compliance
Phase Step Start Date End Date
Number Team Tasks Plan Actual Plan Actual
1 Form and Train Team
2 Research/Analyze Issues and Develop an
Preparation

As Is Process Flow Diagram

3 Develop Project Scope, Alternatives,
Assumptions, Obstacles, and Costs
4 Develop a Communication Plan
5 Phase Review Preparation and Presentation
6 Develop a To Be Process Flow Diagram
7 Review Existing Policies and Procedures
Design

8 Develop New Policies, Procedures, and Architecture

9 Confirm Design with Subject Matter Experts
10 Phase Review Preparation and Presentation
11 Obtain Approvals of New Procedures
Implementation

12 Develop Implementation Plan

13 Process Through Change Control and Document
Control System
14 Conduct General Awareness and Specific Job Training
15 Phase Review of Internal Audit that System is in
Place and in Use
16 Assemble Verification Document
17 Conduct Internal Review and Approvals of
Verification

Verification Document
18 Issue and Review Verification Document
with Third-Party Reviewers
19 Follow-up on Outstanding Issues Identified
20 Conclusion/File Project Documents
and Schedule Internal Audit

lems are identified internally or through regulatory

inspections, strategically approaching the problems Article Acronym Listing
is essential. Unfortunately, problems often are inade-
quately resolved because they do not take into con- CAPA: Corrective And Preventive Action
sideration the broader context of enforcement FDA: Food & Drug Administration
action or success factors that must be built into the GMP: Good Manufacturing Practice
plan. The planning approach described in this arti- QA: Quality Assurance
cle guides the user to take into account many APR: Annual Product Review
aspects that must be addressed to ensure success-
ful CAPA, and to avoid paying for the same ground
over and over again.

Special Edition: Corrective and Preventive Action 81

 Be SMART With Your Corrective
and Preventative Actions (CAPA)
W
e are presented with
Compliance can problems that we ana-
lyze and solve on a
only be achieved daily basis. Some of these prob-
lems are very minor, and take
when the only a moment to determine a
solution. However, others are
corrective action more complex, and might involve
is in place, several individuals or teams, as
well as span across many pro-
and is acting cesses. With all problems, we
want to avoid the mistakes that
synergistically led to them. Therefore, we try to
find a systematic way to ensure
with all quality we avoid previous mistakes in
the future. Corrective actions are
systems. the systematic solutions to prob-
lems that, once implemented, will
prevent the reoccurrence of mis-
takes.
To better define a corrective
action, it is helpful to know what it
is not. A corrective action is not a
fix. A fix is a solution that restores
a system to its original state.
While a fix may make a system
run again, or make a piece of
equipment operational, it does
not analyze the deviation, look for
the root cause, and implement
changes to avoid repeated fail-
ures in the future. In addition, a
corrective action is not a single
solution implemented to bring
the system into compliance.
Compliance can only be achieved
when the corrective action is in
place, and is acting synergisti-
by cally with all quality systems. Fin-
Larry Nold ally, a corrective action is not pre-
Production Manager ventive action. Although most, if
Bayer Corporation not all, of the same concepts dis-
82 Special Edition: Corrective and Preventive Action
cussed below apply to preventive
actions, corrective actions are im-
plemented to correct problems
that have occurred, while a pre-
ventive action corrects problems
that will, or may occur.
Once a deviation is discover-
ed, it must be documented and
investigated. It is beyond the
scope of this article to give an in-
depth discussion into the investi-
gation of deviations, although any
investigation must be thorough
and documented. Generally, the
deviation owner will investigate
with review and approval by the
quality group. However, this
guideline may not always be fol-
lowed. In some instances, the
quality group may independently
investigate and report their find-
ings. In these instances, the in-
vestigation still must be reviewed
by an unbiased second party for
completeness and accuracy.
Regardless of who investi-
gates, a report must be written
and approved. An investigational
report into a deviation needs to
include at a minimum:
Cause
Product impact
Corrective action
The Code of Federal Regula-
tions (CFR) Part 211.192 states:
All drug product production
and control records, including
those for packaging and label-
ing, shall be reviewed and
Larry Nold
approved by the quality control unit to determine
compliance with all established, approved written
procedures before a batch is released or dis-
tributed. Any unexplained discrepancy, (including
a percentage of theoretical yield exceeding the
maximum or minimum percentages established in
master production and control records) or the fail-
ure of a batch or any of its components to meet
any of its specifications shall be thoroughly inves-
tigated, whether or not the batch has already
been distributed. A written record of the investiga-
tion shall be made and shall include the conclu-
sions and follow-up.1
It is important to keep in mind that the report is
being written, not just to release product for sale, or
to justify a previously distributed product, but to assure
all stakeholders, including Quality Assurance (QA),
regulatory agencies, and especially the patient, that
the deviation did not affect the safety, identity,
strength, purity, or quality of the product.
The U.S. District Court supported the guidelines
set forth in the CFR for investigations and correc-
tive actions in the now industry famous case of the
U.S versus Barr Laboratories.2 Judge Alfred M.
Wolin wrote the following opinion for the courts with
respect to investigations and corrective actions:
Extending beyond the laboratory and often
labeled formal investigation, these inquiries
should follow the outline the government provided
with companies paying particular attention to any
necessary corrective action, whether reprimand-
ing, retraining, or firing employees, remixing
batches, or adjusting processes. Thus, in the fail-
ure report firms must: State the reason for the
investigation; provide a summation of the process
sequences that may have caused the problem;
outline the corrective actions necessary to save the
batch and prevent a similar occurrence; list other
batches and products possibly affect, the results
of their investigations and any required corrective
action; and finally preserve the comments and the
signatures of all production and quality control per-
sonnel who conducted the investigation and
approved any reprocessed material after addi-
tional testing.
While a court with New Jersey jurisdiction ren-
dered the opinion, it is the precedent and case law
by which the Food and Drug Administration (FDA)
bases its stance, and the standard Industry has
adopted. The FDA expects corrective action, which is
the follow-up, required in the CFR, and the court has
reinforced this expectation by specifically stating that
corrective actions are required for investigations.
SMART Corrective Actions
A corrective action must rectify the root cause
of a deficiency to prevent a reoccurrence of the
problem. If after the corrective action is imple-
mented and the problem persists, then either the
root cause was not corrected, or the actual root
cause was not identified. Identification of a root
cause to a problem can be difficult. All the data
may not be present to identify a root cause. The
root cause may be masked by other symptoms not
related to the problem, or there may be many prob-
lems acting synergistically to appear as one prob-
lem. If the corrective actions are not effective, then
the investigation was not complete in that it did not
find a root cause, and the investigation must be
either continued or reopened. Corrective actions
that work are SMART: Specific, Measurable, At-
tainable, Realistic, and Timely (SMART). A correc-
tive action must contain all five attributes if it is to
be effective. If any corrective action is missing any
one of the attributes, its chances for long lasting
success will be truly diminished.
First, ensure your corrective action is Specific.
Too broad or narrow of a corrective action could
hamper or hinder the outcome. For example, a
water inlet valves diaphragm is being harmed
because the water valve is too close to the clean
steam generator to which it feeds. In order to cor-
rect the problem and other potential problems re-
lated to it on site, you could:
Move the valve further upstream, and replace
the diaphragm with a more heat resistant one.
Survey all valves on-site for a suitable loca-
tion, and implement a program that will
change out all diaphragm valves with heat
resistant ones.
Move the valve, and/or replace the diaphragm,
while ensuring that other water inlet valves to
clean steam generators either have the cor-
rect diaphragm, or are in a suitable location.
Clearly, option number one will solve the prob-
lem with the diaphragm valve, however, the solution
is confined to only that system. Thus, option one is
too narrow. Option two is too broad. There is no
Special Edition: Corrective and Preventive Action 83

need to implement a site wide program for a prob-
lem with one valve in this case. There are always
limited resources to draw from, so you want to en-
sure your corrective action will be efficient without
sacrificing quality. Option three would be the best
choice in this instance. It corrects the specific prob-
lem, yet audits similar and identical systems to
avoid the same mistake.
Next, any corrective action that is developed
must be Measurable. A corrective action that states:
Enhance effectiveness across all quality systems
is meaningless. One general guideline to use when
writing and implementing corrective actions is to
use the 3 Ws:
Whom
What
When
Ensure all parties involved with the who state-
ments are in agreement with the corrective action.
To encompass the what part of the corrective
action, whenever possible, include specific num-
bers for what is to be done. For example, a correc-
tive action that states: Replace all diaphragm
valves on the clean steam generator may appear
straightforward, but there is plenty of room for mis-
takes. One interpretation may be to replace only
the steam diaphragm valves, since the corrective
action deals with the clean steam generator.
Another interpretation may be to replace the water
valves, as well as the clean steam valves. How-
ever, a correction action that states, replace dia-
phragm valves X1, X2, and X3, leaves little room
for miscommunication. Finally, a well-written cor-
rective action will contain a due date to measure
whether it was completed on time. Once again,
ensure all parties involved are in agreement with
the due date.
In numerous instances, corrective actions that
are considered good ideas end in failure because
the resources were not available to implement
them. Therefore, the goal of the corrective action is
not Attained. To ensure that corrective actions are
attained, all resources to complete the corrective
action must be available. Resource allocation must
be considered when writing a corrective action.
This includes, but is not limited to, personnel, time,
and material.
Other times, corrective actions may not be con-
sidered good ideas because they are not realistic.
Earlier in this paper, an example was given related
84 Special Edition: Corrective and Preventive Action
Larry Nold
to changing all valve diaphragms at a manufacturing
site. Although the idea may have merit because
there may be a better diaphragm, it may not be real-
istic from a logistical standpoint, or from a cost/ben-
efit analysis. A balance needs to be struck between
correcting the problem, and how the problem is cor-
rected. In the example, a compromise was reached
to replace the diaphragm that needed to be replaced
with a similar situated diaphragm. This is a correc-
tive action that can be implemented for a definite
benefit, at a reasonable cost.
Although the last attribute of a good corrective
action is Timeliness, it is no less important than
the preceding ones. The four other attributes of a
corrective action, specific, measurable, attainable,
and realistic are worthless if the corrective action is
not completed in a timely manner. In most cases,
an appropriate time span for the corrective action
to be implemented is before the equipment or sys-
tem is used again. In the situation where training is
involved, then the individuals must be retrained
before the task is started. Timeliness must start
with the investigation. Recently, numerous compa-
nies have been cited by regulatory agencies for the
timeliness of their investigations, and consequently,
their correction to the problems were not timely. In
fact, failure investigations were the leading topic for
Warning Letters issued in 2001.3 Moreover, if a
timely investigation is not conducted, then the firm
is in some way indicating that the problem and cor-
rective action is not of immediate concern, when in
fact, just the opposite could be true.
Corrective actions can vary over a wide spec-
trum, and their implementations generally fall into
three categories. The first category, which is usu-
ally the weakest, is training. Training may be appro-
priate for the short-term, but there is no guarantee
that the training will be effective, or that the knowl-
edge base will be passed on when new personnel
arrive. The second level is to have the corrective
action written into a Standard Operating Procedure
(SOP). While this approach is much better than
simple training, since the corrective action has
been proceduralized, you are still relying on a per-
sons memory to ensure the corrective action
occurs. The third category is written confirmation
that a procedure defined by a corrective action has
been completed. This third tier of corrective action
implementation can manifest itself in several differ-
ent forms ranging from revalidation protocols, to
change control documents, to Batch Production
Records (BPRs), or checklists.
Larry Nold

Finally, corrective actions should be tracked and Figure 1

monitored by one group, usually the Quality Unit
(QU). Periodic reports should be issued, summariz- Corrective Action Flowchart
ing the status of the corrective actions. Metrics
should be tracked and reported for various cycle Discrepancy
times. These cycle times can include the amount of
time that has elapsed since the corrective action
was opened to when the work has been completed Investigation
for the corrective action, however, work completed
should not be considered completion of the correc-
tive action, since it still needs to be verified. Write SMART
Another cycle time to monitor is work completion to Corrective Action
verification. Verification is signed off by the QU that
the corrective action is complete. Verification can be
done in numerous ways. For example, the QU may
need to verify training was completed, a document All Involved No
with a revision has become affected, physical in- Parties Agree
spection of a system, or monitoring an operation to
ensure a corrective action was incorporated. With Yes Track Corrective
verification completed, the last step for the QU is to Action
sign-off the corrective action complete, and thus the
metric of open to close can be tracked for all cor- Change Control No
rective actions.

Conclusion Yes
Change Control
Once done, corrective actions are usually thought Documents
of as completed, and not to be looked at again un-
less the same problem occurs. However, looking at
the flowchart in Figure 1, there are definite feed- Implement
back loops in the workflow of corrective actions. Corrective Action
The QU with operations should review corrective
actions on a regular basis. A full review should be
done with the Annual Product Review (APR). During
No Corrective
the APR, corrective actions should be reviewed for
Action Effective
overall impact. One or two corrective actions, by
themselves, may not have any effect on the prod-
uct, but a few actions, functioning synergistically,
may cause a shift, and could go undetected, un- Review of All
less viewed as a whole. In addition, corrective Corrective Actions
actions should be reviewed to determine the overall
effect on systems or groups. Reviewing corrective
actions will also indicate if any system or equipment
is failing, or having problems at an unusual rate. As Yes Undesirable No
part of the APR, a summary report should be writ- Synergistic
Effect
ten for corrective actions, describing the reviews
discussed above, as well as the metrics listed
above.
At times, employees see corrective actions as blems from reoccurring are easy to explain, and
mandated, burdensome, requirements that must thus it is easy to obtain the necessary buy in from
be completed to allow them to continue their work. employees. Writing SMART corrective actions,
However, good corrective actions that prevent pro- ensuring that corrective actions are properly proce-

Special Edition: Corrective and Preventive Action 85

 Larry Nold

duralized, periodically reviewed, and obtaining em-

ployee buy in ensures a properly functioning cor-
rective action program. When a corrective action
program is effective, problems are systematically The Ultimate
investigated and solved; therefore allowing the
business to move forward, secure in the knowledge
it will not have to revisit old problems. Resource
Glossary of Computerized
References System and Software
1. FDA. Code of Federal Regulations, Food and Drugs.
Current Good Manufacturing Practice for Finished
Development Terminology
Pharmaceuticals. Title 21, Part 211 (U.S. Printing
Office, Washington, DC). (April). 1999. This document serves
2. United States vs. Barr Laboratories, Inc. 92-1744. NJ,
812 F. Supp. (1993) P. 458.
as a glossary of terminol- UM
AN
SERVICE
S
U

SA
&
F HEALTH
3. Inspection Results for 2001 Not Many Surprises. ogy applicable to soft-

TO
Warning Letters Citations and Form 483 Observations ware development and

EN
M
RT
DEPA

Fairly Similar. BioQuality. Vol. 7, No. 1 (January). 2002. computerized systems in

P. 7. Glossary of
FDA-regulated indus- Computeri
zed System
tries. It will facilitate and
Software D
consistency in describ- evelop
Terminolog ment
ing the requirements of y

the law and regulations Reference
ma
investigator terial for
Article Acronym Listing applicable to such s
FDA/Indus and other
try personn
el
products and systems.
APR: Annual Product Review The organization of
BPR: Batch Production Record this document is alphabetical.
CAPA: Corrective And Preventative Action Acronyms are grouped at the beginning of each alpha-
CFR: Code of Federal Regulations betical section, and are followed by words, terms, and
FDA: Food and Drug Administration phrases. Acronyms are expanded at the beginning of
QA: Quality Assurance each alphabetical section and defined with the full
QU: Quality Unit term or phrase. The terms are defined, as much as pos-
SMART: Specific, Measurable, Attainable, sible, using available standards. Over 850 terms,
Realistic, and Timely phrases, and acronyms are included in this document.
SOP: Standard Operating Procedure
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86 Special Edition: Corrective and Preventive Action