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R O C E S S

TECHNICAL

Suite Changeover
Involving Diverse Hosts
in Multiproduct Facilities
Kristin S. Murray, Debra K.S. Anderson, and Heidi M. Reichert

iotechnology manufacturing
space is precious and
expensive. As successful
biotechnological products
continue to proliferate,
commercial biopharmaceutical
manufacturers must be able to
establish and maintain facilities that
can nimbly respond to changes in
drug-substance production plans.
For well over 10 years, the concept
of multiproduct facilities has been
mainstream for minimizing the
cost, risk, and time associated with
bringing new products to market.
Factors including the overall cost
of manufacturing facilities, contract
manufacturing opportunities,
pipeline development needs, and
periodic limitations in capacity have
all required manufacturers to be
efficient with manufacturing suite
changeover procedures. Companies
must either use disposables in lieu
PRODUCT FOCUS: PRODUCTS OF
FERMENTATION AND CELL CULTURE

PROCESS FOCUS: MANUFACTURING


WHO SHOULD READ: QA,
REGULATORY AFFAIRS, MANUFACTURING,
CLEANING AND VALIDATION ENGINEERS

KEYWORDS: MANUFACTURING
SUITE CHANGEOVER, CAMPAIGN
MANUFACTURING, HOST CELL, RISK
MANAGEMENT/ASSESSMENT, CHO,
E. COLI
LEVEL: BASIC
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DUNCAN WALKER (WWW.ISTOCKPHOTO.COM)

of shared equipment or develop


cleaning validation and verification
approaches that effectively and
efficiently change over both
equipment and facilities.
Regulatory agencies provide
general guidance to industry
regarding operation and compliance
requirements for multiproduct
facilities. Guidances focus on the
principles required for changeover,
including segregation of dedicated
and nondedicated equipment,
cleaning validation and verification
for shared product contact
equipment, and prevention of
cross-contamination between
manufacturing processes. Regardless
of the scope of a changeover, a
manufacturing area must be cleared
and cleaned of the prior product to
minimize risk of cross-contamination
or carryover.

REGULATORY REQUIREMENTS FOR


MULTIPRODUCT FACILITIES
Regulations regarding the
registration and maintenance of
multiproduct facilities vary among
the global regulatory agencies. The
US Food and Drug Administration
(FDA) demands a very stringent
process to convert facilities from
single- to multiple-product
status. The agency also requires
notification when new products
are introduced into a previously
approved multiproduct facility
(1). Most other regulatory bodies
view multiproduct activities (new
products, changeover) simply
as processes driven by Good
Manufacturing Practices (GMP)
(2, 3). No formal submission of a
product license application is needed
if a manufacturer can ensure no
impact to the licensed products
manufactured in the same facility.

Instead, the scientific justifications


for changeover procedures such as
cleaning validation and verification,
multiproduct equipment use, and
cross-contamination minimization
procedures are reviewed during
routine GMP inspections.
Regardless of the applicable
regulatory process or requirements,
manufacturers are responsible for
identifying and mitigating potential
risks to product quality, process,
personnel, and facility when either
converting a single-product facility
to multiproduct or introducing a
new product into an established
multiproduct facility. Furthermore,
manufacturers are wise to use
effective risk-management processes
that concurrently mitigate critical
business risks associated with, or
independent of regulatory concerns.
Given these considerations, risk
management should be well
ingrained in routine manufacturing
operations and be a fundamental
influence when facilities develop
standard operating procedures
(SOPs).
Risk management is a process
of well-defined steps, which when
taken in sequence support better
decision making by providing
greater insight into potential
hazards associated with a process.
Common tools include fault-tree
analysis (FTA), hazard analysis and
critical control point (HACCP)
methods, and failure mode and
effect analysis (FMEA) (46).
Various industries have used the
above-mentioned risk-management
tools for years to analyze product
or process risk, including the use
of HACCP by the diagnostic and
food industries (4) and the use of
FMEA by the device industry (7).
An ICH (International Conference
on Harmonisation of Technical
Requirements for the Registration
of Products for Humaan Use)
expert working group is developing
a draft guidance on quality risk
management (Q9) (8), which
was released for comment in late
2004. Implementing quality risk
management is the fundamental
consideration in manufacturingsuite changeover procedures,

regardless of the type of changeover


(e.g., mammalian to mammalian
cells, or mammalian to Escherichia
coli cells), to predict risk factors to
product quality.
RISK MANAGEMENT
IN SUITE CHANGEOVERS
In manufacturing-suite host-cell
changeovers, the three main
elements of formal risk assessment
are examination of the risks
associated, consideration of the
changeover process activities and
their scientific justifications, and
conclusions about the safety and
efficacy of subsequent products.
Historically changeover
procedure decision-making processes
have been captured only by
executable documents: the standard
operating procedures, protocols,
master plans, and so on. Using a
formal risk-assessment process takes
the process a step further, allowing
a manufacturer to standardize and
formally document its decisionmaking process. This strengthens
the defense of decisions made by
thoroughly accounting for what
was considered, detailing how it
was considered, and stating the
logical conclusions. The systematic
discipline of a formal risk assessment
also can uncover issues that may be
missed in a more intuitive,
less-formal process.
Carryover Hazards: Critical
to changeover operations is
proactive identification of
potential hazards associated with
carryover between manufacturing
processes. In biopharmaceutical
changeovers, potential carryover
hazards include product- and
process-related impurities such as
deoxyribonucleic acid (DNA), hostcell proteins (HCP), growth media,
fermentation broth, buffering
solutions, and adventitious agents.
These hazards are standard in the
biopharmaceutical industry and are
not limited to host-cell changeovers.
Assessing the Tools: Once specific
process hazards are identified, the
respective controls must be assessed.
This requires understanding the
manufacturing and changeover
processes to determine how the

hazards can exist and where


mitigations can prevent, reduce,
remove, or detect those hazards.
Risk-assessment tools can then
be used to determine and rate
the residual effectiveness of those
mitigations. Areas of highest risk
can be identified, and additional
procedures and/or controls can
be implemented if necessary. The
resulting risk-assessment package
can then be used to demonstrate
the effectiveness of (and defend
the rationale for) the changeover.
SUITE CHANGEOVER INCLUDING
A HOST-CELL CHANGE
One Wyeth facility conducts
campaign manufacturing, in which
a suite may periodically be used
to produce multiple products.
The facility has accumulated
extensive experience in both
changeover procedures and process
understanding. Established
procedures ensure manufacture of
only one product within a suite at
any time. Between campaigns, a
suite product changeover provides
a high level of assurance that crosscontamination of one product
or process component into the
next does not occur. Validated
procedures for manufacturing
suite changeover, based on
guidance from regulatory agencies,
typically outline the following:
identifying shared equipment
between manufacturing processes
removing all unnecessary
dedicated equipment, supplies,
raw materials, and so on, from the
manufacturing suite
isolating remaining dedicated
equipment that cannot be removed
cleaning the facility and any
nondedicated equipment remaining
in the manufacturing suite
changing out any facility or
equipment components for which
replacement is economical and
preferred over cleaning verification
(e.g., gaskets, hoses, and probes)
confirming the effectiveness
of cleaning product-contact
equipment, with appropriate
analytical testing
verifying completion of all
changeover activities through a

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Figure 1: Manufacturing flow diagram

Table 1: Host-cell changeover contaminants for consideration


Host-Cell
Changeover Direction

Contaminants for
Consideration

CHO cell culture to


E. coli fermentation

Virus, adventitious
agents (e.g.,
mycoplasma), CHO
HCP

Virus/adventitious agent: Potential for a viral

E. coli fermentation to
CHO cell culture

Phage, endotoxin,
E. coli HCP

CHO HCP: Potential for CHO HCP to be

quality assurance inspection and


by verification in a changeover
protocol.
Typically before a manufacturingsuite changeover, subject-matter
experts evaluate the affected
manufacturing processes
for potential process-stream
components of concern that may
carry over from the exiting to the
entering product. Results of their
evaluations form the basis of the
changeover plans, procedures, and
protocols. Although there is a slight
general risk of carryover from a
facility or environment in areas with
open process operations, the highest
risk for potential carryover between
manufacturing processes is posed by
the nondedicated product-contact
equipment. For changeover of
manufacturing suites from CHO cell
culture to E. coli fermentation, the
only nondedicated product contact
equipment were the fermentor/
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Special Considerations
or other adventitious-agent contamination
during CHO cell culture manufacturing;
these agents are generally not a concern
for E. coli fermentation processes

carried over into the E. coli process.


Phage: Potential for phage contamination
of the E. coli cells during manufacturing;
phage is generally not a concern for CHO
cell-culture processes.
Endotoxin: E. coli cells produce very high
levels of endotoxin during manufacturing
E. coli HCP: Little potential for E. coli HCP
to be carried over into the CHO processes

bioreactor and the cleavage reactor/


harvest vessel, as shown in Figure 1.
The flow diagram (Figure 1)
indicates manufacturing steps
for an E. coli manufacturing
process and the corresponding
steps for a mammalian CHO-cell
manufacturing process. In this
instance, the nondedicated product
contact equipment is limited to two
unit operations within the upstream
steps in the manufacturing process.
For any manufacturing-suite
changeover, the main concern
is that a component, whether
inherent or introduced into the
previous manufacturing process,
will be carried into the subsequent
manufacturing process through the
use of nondedicated product contact
equipment. Such components
include raw materials, product,
product-related impurities, and
adventitious agents. Each specific
manufacturing process is designed

to reduce or remove process- or


product-related impurities particular
to that process and host-cell type
to an acceptable level. When the
manufacturing suite changeover
involves a host-cell change,
additional contaminants should be
considered because the downstream
procedures may not have been
designed to remove contaminants
specific to that host type. In the
case outlined in Table 1, the E. coli
manufacturing process had not been
designed or validated for reduction
or removal of viruses.
During formal risk assessment
associated with a manufacturing
suite changeover, any inherent
component or potentially
introduced contaminant that could
carry over into the subsequent
manufacturing process needs to be
evaluated. That evaluation assesses
whether cleaning procedures and
cleaning verification methods
(e.g., analytical methods), as
well as any additional mitigation
methods performed before, during,
or after a manufacturing suite
changeover will reduce or remove
the potential hazard. Use of this
formal, documented process has
two positive outcomes: It justifies
decisions made by the subjectmatter experts, and it documents
the assessment of the mitigation and
detection methods to ensure that no
failure modes were missed during
the suite changeover.
FORMAL RISK ASSESSMENT
The risk-management process
provides a disciplined environment
for assessing what could go wrong
(hazards), determining which
hazards have the greatest impact on
the process or product (severity),
and implementing strategies to deal
with identified hazards (mitigation).
The process flow diagram
in Figure 2 illustrates key steps
in managing a formal risk
assessment for a manufacturing
suite changeover. It describes key
outputs, documented evidence
of these outputs, and overall
process outcomes.
As Figure 2 shows, the four
key stages of risk management are

project definition and initiation,


process and risk component
understanding, risk analysis, and
the overall risk assessment
conclusion (5). Below, we
describe the application and key
lessons learned for each stage
during execution of the formal
risk assessment at Wyeth for a
manufacturing suite changeover.
Stage 1 Defining and Initiating
Your Project, Educating Your Team:

The scope of the risk assessment


was defined, and the team members
were identified. Key considerations
included developing the underlying
purpose, goals, and scope of
the analyses and recruiting and
developing members of the riskassessment core team. These
fundamental steps at this stage
ultimately drive a successful
risk-assessment:
understanding the scope of the
risk assessment and therefore asking
the appropriate questions
investing sufficient time to
understand the process under
evaluation
providing time for the riskassessment team to become oriented
and knowledgeable about their tasks.
Defining the Scope: A changeover
process is an integrated transition
between the end of a previous
manufacturing process and the start
up of a subsequent one. Team focus
is required to define what does
and does not fall within the scope
of the assessment. The scope is
limited to issues that could lead to
the carryover of a hazard from one
process into a subsequent one or to
issues surrounding the inability to
detect a hazard that is inadvertently
carried over. It does not include
general failures of either processes
or failures in their equipment.
In this case, once the scope was
detailed, it was recognized that
the process under evaluation went
beyond general manufacturingsuite changeover activities and
included parts of the manufacturing
cleaning and startup processes
that could affect carryover. The
multidisciplinary risk-assessment
team comprised subject-matter
experts in changeover, cleaning,
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Figure 2: Risk-assessment process map

and validation processes who would


support process understanding and
risk analysis.
Stage 2 Understanding
Process and Risk Components:

Key aspects of process and riskcomponent understanding include


identifying the types, sources, and
interrelationships of changeover
hazards; understanding all of
the processes supporting suite
changeover (including procedures
in place before and after changeover
that help mitigate carryover
contamination); and identifying all
respective mitigation and detection
methods and any manufacturing

or changeover process controls in


place before, during, and after suite
changeover to prevent, reduce,
remove, or detect the hazards.
Using process maps (PMs), the
risk assessment team compiled all
available information to illustrate
the overall changeover process. PMs
included related activities required
for concluding manufacture of
the first product and beginning
manufacture of the next one.
Evaluation of the processes
demonstrated that controls and
procedures were also in place before
and after a suite changeover to
help mitigate the overall risk of

Table 2: Analytical methods


Assay

Contaminants Identified

Examples

Total organic carbon (rinse


water and equipment surface
swabs)

Organic chemicals,
biological components (raw
materials, process-related
components, adventitious
agents, product and HCP

Organic buffers, proteins,


lipids, detergents,
carbohydrates, nucleic acids

Conductivity (rinse water)

Inorganic chemicals

Salts, buffers, inorganic


polymers, acids and bases

Visual (surface inspection)

General

Dried materials

Product-specific assays
(immuno-based assays)

Product, product-related
impurities, and HCP

HCP, product

carryover between the processes.


Understanding the relationship
between all those controls and
procedures provided further
confidence in the effectiveness of
the overall changeover process.
The controls and procedures
included
a well-characterized master and
working cell bank
characterized raw materials
with appropriate specifications
SOPs surrounding all methods,
operations, and monitoring of the
manufacturing process and areas
comprehensive validation
programs for equipment and
processes, including cleaning
and steaming
validated in-process and
release-testing methods and
corresponding specifications
the appropriate end-ofproduction testing methods
to ensure the integrity of the
manufactured product.
At the outset, team members
were eager to choose tool(s) for
the overall risk-assessment process
before thoroughly discussing
and collectively understanding
the changeover processes under
evaluation. However, by investing
some effort toward understanding
process and risk-components, the
team realized that it could apply
many commonly available riskassessment tools. Ultimately, a
complete understanding of the
process drove selection of tools that
would demonstrate the effectiveness
of the processes and controls in
place during a manufacturing-suite
changeover. The team used risk
assessment tools to serve the overall
assessment rather than using those
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tools to drive the assessment itself.


Stage 3 Risk Analysis: The
purpose of this stage was to
bring together information from
the process and risk component
understanding stage, evaluate it,
and determine any residual risk.
Key aspects of the risk analysis
stage included
understanding how cross
contamination might occur
understanding analytical
method-acceptance criteria and how
it affects the carryover potential of a
given contaminant
understanding the severity
of impact on the subsequent
manufacturing process if a
contaminant was carried over using
calculations of residual materials
identifying and including
the capability of all processes and
controls before, during, and after
the suite changeover
defining the ratings for risk
elements
applying the risk ratings to the
compiled contaminant evaluation
and determining overall residual risk
of carryover between manufacturing
processes
evaluating and understanding
the residual risk, determining
whether it was acceptable, and
reducing it if appropriate.
During this stage, the riskassessment team first used a topdown fault-tree analysis to examine
sources of general contamination to
the manufacturing suite, including
environment, process, raw materials,
equipment, and personnel. The FTA
graphically illustrated the logical
structure of the initiating events that
could lead to contamination, and
the measures in place to mitigate

them. The team then moved


forward with a modified HACCP
bottom-up analysis to examine
underlying risks associated with
specific carryover contaminant types
and associated cleaning validation,
verification, mitigations, and
detection methods. Conducting
a bottom-up analysis early in the
process enabled the team to identify
areas requiring the most research.
The FTA reinforced that one
of the most critical aspects of a
successful changeover is a valid and
robust cleaning program in which
removal of potential contaminants
can be verified through analytical
testing. The modified HACCP
included rating the analytical
methodology used during
cleaning validation. That involved
understanding the advantages and
limitations of the various analytical
methods available, verification
that a particular analytical
method could detect the hazard
in question, and the anticipated
condition of any residual hazard
on the manufacturing equipment
after cleaning. This was key to
determining whether the analytical
methods used were appropriate
for detecting any residual materials
remaining after equipment cleaning.
In particular, the project team
evaluated the advantages and
limitations behind rinse-water
conductivity, immuno-based product
specific assays, visual inspection
of manufacturing equipment to
verify cleaning, and the use of total
organic carbon (TOC) gathered
from rinse water or equipment
surface swabs. This evaluation
considered the state of possible
residual material after exposure to
harsh cleaning conditions, including
exposure to heat and pH extremes
for various amounts of time, and the
analytical methods ability to detect
the soil. Table 2 summarizes the
analytical methods considered.
The most formidable limitation
to the product-specific immunobased method is that cleaning
methods incorporating heat and
pH extremes have been shown
to denature protein products,
thus eliminating the possibility of

detecting product-specific activity


in that method. Unlike specific
immuno-based methods (e.g.,
enzyme-linked immunosorbent assay
[ELISA]), TOC and conductivity
sensitivities and detection are not
compromised by exposure of protein
to the harsh pH and temperature
conditions during equipmentcleaning procedures. TOC and
conductivity analysis also enable
detection of many other process soils
and potential contaminants present
in equipment. Therefore, TOC,
conductivity, and visual inspection
were determined to be the most
appropriate methods for productchangeover cleaning verification.
They provided a robust detection
method for both residual organic
and inorganic matter, enabling
detection of a wide range of potential
process components both inherent
to the process (raw materials and
process-related) as well as potential
contaminants to the process
(adventitious agents, phage, virus).
Once analysis of all compiled
information was complete, a
series of objective rankings were
required for the various components
encompassing the overall
residual risk rating (an objective
combination of risk assessments
from the various components of a
changeover process). It describes the
remaining risk of carryover into the
subsequent manufacturing process
after protective measures have been
taken. That includes the likelihood
of hazard existing in the previous
manufacturing process, the strength
of the mitigation procedure, and the
quality of the detection method.
For risk ratings to be useful, they
must be objective and have enough
relative value to differentiate one
rating from another. Whether high
or low, 15, red or green, ratings
definitions must be comprehensive
and precise to allow distinctions to
be made between them. The riskassessment team initially struggled
with establishing those rankings,
attempting to apply quantitative
methods exclusively rather than
considering qualitative measures.
For example, at first the team
averaged numerical ratings to get
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a mitigation strength score for


a given hazard. The quantitative
approach skewed the overall
risk rating to indicate a lower
effectiveness for a particular hazard
than the actual data supported.
The key to rating risks was
to keep the rankings simple and
straightforward while remembering
that they still need to be specific
enough to yield a sensible and
acceptable risk-distribution profile
across the changeover process.
The definitions of categories are
crucial to determining a consensus
on how much risk is actually present
in a process.
Stage 4 Conclusion from Risk
Assessment: The overall conclusion

from our risk assessment process


was that the underlying risk
of contamination from one
manufacturing campaign into the
next was very low. The mitigation
and detection capabilities in place
before, during, and after the
manufacturing suite changeover
were extremely effective in reducing
the risk of impact to the safety or
efficacy of the subsequent process
or product.
PROCESS KNOWLEDGE IS KEY
Elements for success in this risk
assessment process included
a well defined scope
a multidisciplinary team with
expertise in the content of the risk
assessment scope and comfortable
enough to work together within
that context
good understanding of process
and risk elements
ratings that are well defined,
adequately differentiated, and
meaningful for the scope
focus on the goal of the
assessment so that the tools serve
the assessment and not visa versa.
In this instance, current Good
Manufacturing Practice (cGMP),
commercial operations, and
manufacturing processes using
either CHO cell culture or E. coli
fermentation are in place and have
been licensed, with the appropriate
procedures and controls to assure
safe and consistent product
manufacture. The suite changeover

bridging these two manufacturing


processes demanded in-depth
understanding of process and risk
components to determine whether
the proper mitigations and controls
were in place to mediate any
potential carryover between the
processes. Understanding how a
complex process can fail allows for
activation of proper mitigation and
detection systems.
The overriding key to successful
risk management is proactive use
of a risk assessment process to
demonstrate that mitigations,
controls, and analytical methods
in place before, during, and after
a manufacturing suite changeover
are sufficient to reduce the risk
of carryover between processes,
regardless of host-cell type.
Another important factor is the
understanding that procedures
for host-cell changeover may not
be appreciably more extensive
than those used for same hostcell changeover. In our industry,
we continue to envision that with
more changeovers involving diverse
host-cell types, the systematic
application of quality management
policies, procedures, and practices
to the task of assessing, controlling,
and communicating risk will lead
to a reduced reporting category
with the FDA as well as increased
harmonization in regulatory
approaches throughout the world.
ACKNOWLEDGMENTS
The authors thank Dr. Alfredo Canhoto,
Stephen Reich, and Craig Meinhardt for their
support during the risk assessment process
and manuscript preparation, Dr. Victor
Van Cleave for his critical review of this
manuscript, and Kathleen Reckendorf
for proofreading and editing support.

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Corresponding author Kristin S. Murray


is senior regulatory coordinator at
Wyeth BioPharma, One Burtt Road,
Andover, MA 01810, 978-247-4543,
fax 978-247-4708, kmurray@wyeth.
com; Debra K.S. Anderson was formerly
with KMI/Parexel Waltham, MA; and
Heidi M. Reichert is an associate
director at Wyeth BioPharma.

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