Anda di halaman 1dari 25

ejbps, 2015, Volume 2, Issue 3, 830-854. Review Article SJIF Impact Factor 2.

062

European Journal of Biomedical ISSN 2349-8870


Venugopal. European Journal of Biomedical and Pharmaceutical Sciences
Volume: 2
AND Issue: 3
Pharmaceutical sciences 830-854
http://www.ejbps.com Year: 2015

A SYSTEMATIC APPROACH TO EQUIPMENT QUALIFICATION

Dr.S.Venugopal*

Head-QA & RA Chromo Laboratories India Private Limited, Pashamylaram, Telangana,


India.
Article Received on 17/04/2015 Article Revised on 10/05/2015 Article Accepted on 31/05/2015

*Correspondence for Equipment qualification


Author Equipment qualification is a key element in the pharmaceutical quality
Dr. S.Venugopal system. In recent times Regulatory agencies are more focusing on
Head-QA & RA Chromo
qualification of equipment. During the investigation of process
Laboratories India Private
deviations and complaints, equipment is a key element to consider. For
Limited, Pashamylaram,
Telangana, India. example “6M methodology” men, machine, method, material, mother
nature and measurements. Machine is the most key element in
investigations because with out equipment manufacturing and testing isnot possible.
Qualification of the equipment starts from design of the equipment based on the user
requirement specification and functional requirement specification. Equipment qualification
is carried out in various steps as mentioned below.

Types of qualifications
• Design qualification
• Installation qualification
• Operational qualification
• Performance qualification
• Maintenance qualification
• Safety qualification
• Verification qualification
• Re-qualification

www.ejbps.com 830
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

EQUIPMENT
QUALIFICATION

Some important definitions to remember

Worst Case
A condition or set of conditions encompassing upper and lower processing limits and
circumstances, within standard operating procedures, which pose the greatest chance of
product or process failure when compared to ideal conditions. Such conditions do not
necessarily induce product or process failure.

Change Control
A formal system of reviewing and documenting proposed or actual change that might affect
the validated status of a system, equipment or process followed by action to ensure ongoing
validated state.

Qualification
Action of proving any equipment works correctly and leads to the expected results.

Design qualification (DQ)


The documented verification that the proposed design of the equipment and system is suitable
for the intended purpose.

Installation Qualification (IQ)


The documented verification that the equipment and system as installed or modified, comply
with the approved design and the manufacturer‟s recommendations.

www.ejbps.com 831
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Operational Qualification (OQ)


The documented verification that the equipment and system, as installed or modified, perform
as intended throughout the anticipated operating ranges.

Performance Qualification (PQ)


The documented verification that the equipment and system, as connected together, can
perform effectively and reproducibly, based on the approved process method and product
specification.

Verification Qualification (VQ)


The documented verification that the equipment and system, as connected together, still in
the state of art and actually leads to the expected results and user requirements.

Safety Qualification (SQ)


The documented verification that the equipment and system as installed or modified, comply
with the safety requirements of process, facility and personnel.

Maintenance Qualification (MQ)


The documented verification that the proposed maintenance program of the equipment and
system is suitable for the intended purpose.

Re-Qualification (RQ)
The documented verification that the systems, as connected together, are still performing
satisfactorily. Re-qualification is required as an outcome of relocation, major modification
and due to ageing.

Quality Risk Assessment


A systematic process for the assessment, control, communication and review of risks to the
quality of the drug (medicinal) product across the product lifecycle.

Standard Operating Procedure (SOP)


Written and approved description of essential steps, their sequence, responsibilities and
precautionary measures necessary to assure that operations can be accomplished routinely
and in a standardized manner.

www.ejbps.com 832
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Why Qualification?
The prime responsibility of the pharmaceutical manufacturer is to manufacture the products
of the highest quality that are safe and effective. In general the consistent quality of the
product is achieved through:
 A well designed product
 Qualified facility and equipment
 Current good manufacturing practices
 Qualified and trained personnel
 Good engineering practices

While the quality is achieved though all the above factors. It is important to note that
selection and qualification of the equipment plays a significant role in ensuring consistency in
the quality of the product. Consequently, qualification of equipment has become an essential
part of a pharmaceutical manufacturer‟s quality assurance systems and it is no surprise that
GMP codes of all the leading regulatory agencies of the world include this activity.

Equipment Qualification Process


User Requirements Specification (URS)
Provides a clear and precise definition of what the user wants the system to do. It defines the
functions to be carried out, the data on which the system will operate and the operating
environment. The URS defines also any non-functional requirements, constraints such as
time, costs and what deliverables are to be supplied. The emphasis should be on the required
functions and not the method of implementing those functions.

Equipment qualification is a major challenge in GMP compliance environment. A very well


designed qualification program needs to be employed to meet the regulatory requirements.
The qualification program begins with design qualification and it is never ending process as
the equipment requires regular maintenance and re-qualification whenever relocation,
replacement, modification, breakdown rectification, addition or deletion of accessoreis is
performed.
Design qualification: Design qualification shall be prepared by considering the all user
requirements, functional requirements given by the project management team or process
engineering team and safety requirements given by safety team. In case of proprietary
equipment design qualification may not be required as the manufacturer will cover the entire
user requirements. A proprietary design or technique is one that is owned by a company. It

www.ejbps.com 833
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

also implies that the company has not divulge specifications that would allow other
companies to duplicate the product Proprietary is the opposite of open. Design qualification is
combination of user requirement specification, design specification, functional requirement
specification and safety requirements (considered as safety qualification). User requirement
specification shall be prepared by the user as a basis for designing any equipment or system
to be produced from an external agency. URS shall be prepared in consultation with
project/engineering technical team and external agencies like consultants.

User requirements specifications are typical constitutes of the following but not limited to;
• Material of construction
• Process and product requirements. (Capacity, product nature, properties, measuring and
monitoring devices like temperature indicator, temperature sensor, load cell, online pH
meter or any other requirement related to product or process)
• Operational requirements (working temperature, pressure, vacuum, pH, utilities,
quantities, minimum and maximum volumes)
• GMP requirements (MOC, Environment, Requirement to avoid contamination and cross
contamination, clean in place or clean out of place)
• Safety requirements (Process/Equipment/Personnel/specific safety requirements)
• Documentation requirements (User manuals, qualification documents, test certificates,
calibration certificates etc.,)

Based on the URS engineering team shall prepare a design specification. The design
specification is translation of the URS in to technical terms as an inter phase between URS
and FRS. Project engineering team shall prepare the FRS based on the design specification.
FRS shall be reviewed by technical team for completeness.

FRS shall have following details but not limited to.


• Micro details of the equipment or system
• Piping and instrumentation diagrams
• Schematic drawings
• Dimensions of the equipments and its parts

Installation qualification: Installation qualification shall be carried out by verification


against the design qualification. In case of the equipment design needs to be confirmed before
shipment to the site for installation, factory acceptance test (FAT) shall be carried out.

www.ejbps.com 834
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Request for FAT shall be mentioned in the functional requirement specification. FAT shall be
carried out by the engineering team at the manufacturer site and check the equipment against
the specified design. Few organizations terming the FAT as SAT (site acceptance test). In
general equipment qualification shall be carried out by using the check list.

The protocol/check list shall include the verification of all the equipment components,
ancillaries receipt and installation with the following.
• Equipment name, model number, equipment identification number.
• List of services to be connected and acceptance criteria.
• Equipment installation location, date of installation, signature of the person carried out
installation.
• Confirmation of maintenance manual, if any.
• Spare parts list, if any.
• Material of Construction of the equipment, if any.
• Details of lubricants used, if any.
• Verification of the services.
• Safety features.
• Drawings/ Manuals.
• Instruments to be connected.
• As built inspection report (if any)

The installation qualification protocol shall include but not limited to the verification of the
equipment details with the following.
• Description of the equipment
• Identification of the system/equipment
• Identification and inspection of the major components/accessories
• Classification, Identification & verification of process control instruments
• Identification and inspection of the contact surfaces
• Identification and inspection of the documents
• Identification and inspection of utilities
• Identification of instruments, indicators, sensors/review
• Acceptance criteria
• Deficiency and corrective action report
• Summary and evaluation of results
• Approvals

www.ejbps.com 835
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

In deviations from the specified design or acceptance criteria shall be documented and
justified in the installation qualification report.

Operational qualification: Operational qualification phase of qualification program, it is


intended to check whether the equipment is operating as per the equipment specifications and
whether this is meeting the functional/user/design requirements. The OQ study shall be
carried out by using the equipment qualification check points.

The operational qualification documentation shall include.


• Calibration procedure including limits
• Reference to the manual/national/compendia standards
• Procedure for operation and maintenance of the equipment.
• Operational parameters
• Acceptance criteria as per manual and PO specifications.
• Operational runs across the entire operating range, operational dates, and signature (s) of
the person who operated the equipment.
• Safety features.
• Operation results
• Conclusions
• Training records (if applicable)

Empty consecutive runs of the equipment shall be carried out to verify the operational
performance of the equipment within the specified ranges mentioned in the design
qualification. These are called as simulation cycles. If the equipment operates within the
specified operational parameters and tolerances, then the equipment shall be operationally
qualified.

Operational qualification shall include the following but not limited.


• Critical instrument calibration
• Test functions
• Safety features
• Verification of standard operating procedures
• Simulation cycles
• Change tests
• Operation results

www.ejbps.com 836
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

• Deficiency and corrective action report.


• Summary and evaluation of results
• Operational runs, operational dates, signatures of the execution team

The results/outcome of the qualification study shall be recorded in the operational


qualification report. After carrying out the operational qualification, the equipment shall be
handed over to user. User shall plan for usage of the equipment with product and verify the
performance of the equipment. Any deviations from the specified design or acceptance
criteria shall be documented and justified in the operational qualification report.

Performance qualification: On completion of the installation and operational qualification,


three consecutive batches of intended product will be executed and the results obtained are
subjected to the product acceptance criteria. Three batches should be of same size and all the
raw materials involved in the particular batches should be from approved vendors. If any one
of the batch is not meeting the specification, consider the next batch for the qualification with
appropriate justification for the failure. All the deviations observed during the course of
performance qualification shall be noticed and appropriate corrective and preventive actions
shall be made. All the actions made shall be recorded in the summary of performance
qualification report. An acceptance criterion is usually based on operational parameters
selected for the performance verification of the equipment. The selected parameter should
indicate the performance of the equipment. Few examples are depicted below.

For a centrifuge performance verification the following should be verified.


• Loss on drying of the wet material after fixed spinning time.
• Consistency of the wet weight after fixed spinning time
• Consistency of the mother liquor volume after fixed spinning time.
• Consistency of the purity characteristics after fixed spinning time.
For a reactor performance verification the following should be verified.
• Consistency of critical process parameters.
• Consistency of heating and cooling operations.
• Consistency of the distillation time using a fixed temperature range.
• Consistency of the purity characteristics and yield of the product
For drier performance verification the following should be verified.
• Consistency of drying time and yield.
• Consistency of the material water content or loss on drying.

www.ejbps.com 837
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

• Consistency of heating and cooling operations.


• Consistency of the purity characteristics and yield of the product

The above parameters may be selected for the performance verification of the equipment and
the results of minimum three consecutive runs shall be verified for consistency. For each
product/process the performance of the product shall be verified. As an alternative approach
process validation can be used as a tool for the demonstration of the performance of the
equipment. Sometimes the performance qualification of the equipment shall be carried out
using retrospective review of the available data.

Maintenance qualification: Once the equipment installation, operational and performance


qualification is completed the equipment shall be used for routine usage. It is essential to
have a maintenance qualification program in order to ensure the consistent performance of
the equipment. It is a documented verification that the proposed maintenance program of the
equipment and system is suitable for the intended purpose. Maintenance qualification should
include the preventive maintenance of the equipment as per the manufacturer
recommendations.

The qualification may include the following.


• SOP for preventive maintenance.
• Periodical checks to be carried out at different frequencies.
• Essential spare parts to be maintained.
• Replacement frequency and procedure of moving parts.

A proper maintenance qualification of the equipment is to avoid the break downs of the
equipments. This will help to reduce the frequent break downs and also to reduce the
downtime of the equipment. Nowadays industries are facing major problem in procuring the
spare parts for equipments and instruments. So it is essential to maintain the minimum
inventory of the essential spare parts. A well documented maintenance qualification program
will increase the life time of the equipment.

Safety qualification: Safety is required everywhere, every time, for everything and
everyone. Safety qualification is a documented verification that the equipment and system as
installed or modified, comply with the safety requirements of process, facility and personnel.
So for pharmaceutical industry, safety is integral part and equipment safety is most essential

www.ejbps.com 838
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

in manufacturing industry. Good automation practices (GAP) is in use by most of the leading
pharmaceutical companies as part of the safety qualification program.

Few examples are depicted below.


• Installation of solenoid control valve to achieve the desired temperature.
• Installation of safety valves for the vessels and utility connections.
• Installation of online measuring and monitoring devices to monitor and control the
process parameters.
The following points to be considered as part of the safety qualification.
• Safety devices to be installed to control the unit operations.
• Safety procedures to be followed with respect to equipment in extreme/emergency
conditions.
• Safety considerations to install, operate and maintain the equipment.
• Online measuring devices to be installed to avoid the accidents and incidents.

Verification qualification: It is a documented verification that the equipment and system, as


connected together, still in the state of art and actually leads to the expected results and user
requirements. This can be done by monitoring and reviewing of break downs and periodical
product quality reviews. Few companies will use the approach of the annual product quality
review. They review the preventive maintenance program results, break downs and products
quality as part of the annual product quality review and they will verify the performance of
the equipment. Few companies will verify the equipment performance with trend analysis
and statistical evaluation of the product quality attributes. A statistical approach like 3 sigma,
6 sigma, process capability index shall be used as a tool to verify the performance. In case of
old equipments, which are in use and being used with qualifications performed at the level of
minimum basic requirements those equipments shall be verified under Verification
Qualification.

Verification qualification is based on retrospective review of the available data related to the
design, operation, performance, maintenance and changes made thereafter till date.

The following section shall be included but not necessarily be limited to:
 Pre-approval
 Objective

www.ejbps.com 839
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

 Scope
 Responsibilities
 System description/history
 Design verification
 Installation verification
 Operational and performance verification
 Record of tests performed
 Conclusion
 Post approval

Re-qualification: Although equipment is periodically maintained with maintenance


qualification program, a re-qualification is required to avoid the equipment break downs
during the operation.

Re-qualification shall be done in the following cases.


• After rectification of major break down
• Addition, deletion and modification to the equipment.
• Periodical re-qualification.
• Relocation of the equipment.
During the re-qualification the following activities shall be performed.
• Documenting the equipment and its accessories as installed.
• Operational qualification with the use of simulation cycles.
• Performance qualification with product.

Top ten observations with respect to equipment:


i. Manufacturer recommends performing the maintenance of the equipment once in a
month but firm has the written procedure with the frequency of the once in six months.
ii. The design pressure of the equipment is up to 5 Kg/cm2 only but firm require the
equipment with pressure of 7 Kg/cm2 and the equipment is in use. Qualification of the
equipment is in question.
iii. Calibration of measuring and monitoring devices installed with the equipment was not
carried to cover the usage range.
iv. Equipment performance is not verified with product to show the suitability of the
equipment.

www.ejbps.com 840
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

v. Equipment stirrable volume is reduced to decrease the stirrable volume but re-
qualification is not carried out.
vi. Simulation cycles are used to verify the performance of the equipment. The performance
of the equipment is not demonstrated with the product.
vii. Periodical re-qualification or performance verification of the equipment is not carried out
to confirm the suitability of the equipment.
viii. Reactor agitator is modified to meet the process requirement, but the equipment is not re-
qualified before use.
ix. Variable frequency drive is installed with the equipment to change the revolutions per
minute of the equipment, but during the qualification program the VFD is not evaluated
for its qualification or suitability.
x. Vial filling machine qualification does not include the test of vial challenge.

General deficiencies observed during the equipment qualification:


• Equipment drawing was not matching with equipment installed.
• Training to the operators was not available to operate the equipment. Documented
training program is not available.
• P&ID is not available as part of the equipment qualification program.
• There is no raw data is available for the equipment qualification.
• Equipment manufacturer recommendations are not considered during the preparation of
equipment operation and preventive maintenance procedures.
• Equipment operational qualification does not cover the entire equipment usage range.
• Equipment qualification does not address the all utilities connected to the equipment.
Example: Firm using hot oil as a utility for rotary cone vacuum drier but this utility is not
covered during the equipment qualification. Re-qualification is not carried out.
• Equipment consists of load cell to measure the mass but the details were not documented
in the qualification program.
• Filters are used in the supply air system of equipment, but its maintenance (cleaning,
replacement and verification) is not described in the qualification document.
• Qualification of the equipment is carried out by the firm internal maintenance team, but
the team is not qualified to conduct the qualification program.

www.ejbps.com 841
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Quality Risk Assessment


Quality risk assessment is required alongside change control in order to assess the possible
impact of the change so that action can be taken to reduce or eliminate risk. This must include
all risks to patients, environment and laboratory systems. The assessment may be used to
determine the extent of validation required. Consideration should be given to Annex 20 of the
EU GMP9. Quality risk assessments begin with a well-defined problem description or risk
question. When the risk in question is well defined, the types of information needed to
address the risk question will be more readily identifiable.

As an aid to clearly defining the risk(s) for risk assessment purposes, three fundamental
questions are often helpful.
1. What might go wrong?
2. What is the likelihood (probability) it will go wrong?
3. What are the consequences (severity) of its going wrong?

Risk is the combination of likelihood and consequence of a hazard being realized. Risk
assessment can be complex and requires input from persons who both understand risk
assessment and the processes and systems being assessed.

There are four basic steps in a risk assessment


Step 1 – Risk Identification – Identify the hazards - (what might go wrong?)
Step 2 – Risk Analysis – Evaluate the risks (how bad? how often?) and decide on the
precautions (is there a need for further action?)
Step 3 – Record your findings and any proposed risk control or risk reduction (action to
mitigate against the risk).
Step 4 – Review assessments and update as necessary.
On overview of Risk assessment process.

www.ejbps.com 842
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Risk identification is a systematic use of information to identify hazards referring to the risk
question or problem description. Information can include historical data, theoretical analysis,
informed opinions, and the concerns of stakeholders. Risk identification addresses the “What
might go wrong?” question, including identifying the possible consequences. This provides
the basis for further steps in the quality risk management process.

Risk analysis is the estimation of the risk associated with the identified hazards. It is the
qualitative or quantitative process of linking the likelihood of occurrence and severity of
harms. In some risk management tools, the ability to detect the harm (detectability) is also a
factor in the estimation of risk.

Risk Control includes decision making to reduce and/or accept risks. The purpose of risk
control is to reduce the risk to an acceptable level. The amount of effort used for risk control
should be proportional to the significance of the risk. Decision makers might use different
processes, including benefit-cost analysis, for understanding the optimal level of risk control.
Risk control might focus on the following questions.
a. is the risk above an acceptable level?
b. what can be done to reduce or eliminate risks?
c. what is the appropriate balance among benefits, risks and resources?

www.ejbps.com 843
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

d. are new risks introduced as a result of the identified risks being controlled?

Risk reduction focuses on processes for mitigation or avoidance of quality risk when it
exceeds a specified (acceptable) level. Risk reduction might include actions taken to mitigate
the severity and probability of harm. Processes that improve the detectability of hazards and
quality risks might also be used as part of a risk control strategy.

Review: the implementation of risk reduction measures can introduce new risks into the
system or increase the significance of other existing risks. Hence, it might be appropriate to
revisit the risk assessment to identify and evaluate any possible change in risk after
implementing a risk reduction process.

Risk assessment is a system of various group activities provide through documentation of


potential modes of Product and / or Process and its effects on Product Performance. It also
evaluate and documents potential modes of failure of Product / Process. Actions are the
identified, which could eliminate or reduce the potential failures.

FMEA (failure mode effects analysis) is one of the best tool in conducting the risk
assessment. Although many tools are available for risk assessment, FMEA gives the
quantitative determination of the risk to the patient. All the risks involved in the
manufacturing of the drug substance/drug product will ultimately shows the impact on the
patient. Every risk is directly or indirectly will impact the patient. Equipment is the key
element in the manufacturing of medicinal products hence a risk assessment needs to be
employed for the equipment qualification program in order to determine the level of
qualification required for equipment. All the equipments involved in the manufacturing may
not be required the completed qualification program. Only equipments which will directly
have the impact on the quality of the product requires complete qualification program. To
assess this requirement the below mentioned process may be useful and can be easily
implemented.
 FMEA technique involves calculation of RPN (risk probability number) which is derived
from severity, occurrence and detection.
 Impact/Severity of Failures or Consequences (Severity-S): Impact or Severity of the
Failure or Consequences on the equipment, Instrument and product quality.
 Causes of Failure (Occurrence-O): Cause of failure is determined. The probability of the
occurrence of cause is evaluated.

www.ejbps.com 844
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

 Detection of Failure (Detection-D) and Control Measures of Failure: The probability of


detection of a failure is determined. If the Function / Item Fails, proposed corrective
action or control measure taken to be evaluated for the Detection of Failure.

The Study of the Risk involved in operation of the Equipment / Utilities is done for all the
Critical functions. Each factor is being measured by giving 5-different ratings as below:
• Risk Priority Number (RPN) = S x O x D
• Note: S - Severity, O - Occurrences, D – Non Detection

Severity Occurrences Non-Detection


Measures
Rating Rating Rating
Very High 5 5 5
High 4 4 4
Moderate 3 3 3
Low 2 2 2
None 1 1 1

The above factors are applied on Function / Item of the Equipment / Utility for Impact / Risk
Assessment and rated accordingly and finally for each function Risk Priority Number (RPN)
is drawn by the Formula: (S x O x D = RPN). The RPN results for all functions / items will
be fitted to the ranges / limits and then the Qualification requirements will be based on the
RPN categories.

Worst case RPN: On the basis of Severity rating 5 (Very High), Occurrence rating 2 (Low)
and Non Detection rating 2(Low), the worst-case RPN is calculated.
i.e., RPN = S x O x D = 5 X 2 X 2 = 20.

RPN Categories
• If RPN results are within 1-19 points, Functions will be verified through the operational
qualification.
• If RPN results are 20 and above points, the consistency of quality will be verified through
the Performance qualification.
Based on the results obtained from the study of Risk Analysis i.e., the RPN Factor results,
the Qualification requirements of each Function / Item of the Equipment / shall be
mentioned in the risk assessment report.

www.ejbps.com 845
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Example-1: Risk assessment of Purified water system


S. Item / Severity of Failure or Cause of Failure or Detection of Control
S O D RPN
No. Function Consequences (S) Occurrence (O) Failure (D) Measures
Feed pump • No water supply to • Monitoring as
from sump to over head tank • Any mechanical • By visual per SOP
1 1 2 1 2
Over head • Insufficient water /Electrical problem • Over flow • Preventive
tank pumping to overhead tank Maintenance
• Monitoring as
• Any mechanical
NaoCl dosing • Microbial growth • Free chlorine per SOP
2 /Electrical problem 5 2 1 10
pump development testing • Preventive
• Improper dosing
Maintenance
• Monitoring as
• Filter media per SOP
Dual Media • Turbidity increases
3 • Improper back wash • Testing • Preventive 4 2 2 16
Filter • TSS will increase
Maintenance
• Sanitization
• Monitoring as
• Resin problem per SOP
4 Softener • Hard ness will fail • Improper • Testing • Preventive 3 2 2 12
Regeneration Maintenance
• Regeneration
• Monitoring as
• Integrity per SOP
5 UF system • Microbial growth • Improper • Testing • Preventive 4 1 2 8
sanitization Maintenance
• Sanitization
• Does not remove TDS • Monitoring as
& other ions • Improper cleaning • Conductivity per SOP
6 RO system • Microbial growth of membranes sensor • Preventive 5 2 1 10
development • Testing Maintenance
• Conductivity will fail • Sanitization

www.ejbps.com 846
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

S. Item / Severity of Failure or Cause of Failure or Detection of Control


S O D RPN
No. Function Consequences (S) Occurrence (O) Failure (D) Measures
• Monitoring as
• Any • Conductivity per SOP
• Conductivity will fail
7 EDI mechanical/Electrical & pH sensor • Preventive 5 2 1 10
• PH will fail
failure • Testing Maintenance
• Sanitization
• Monitoring as
• Due to stagnation per SOP
• If Loop line is not • UV chamber
PW storage • Microbial growth • Testing
8 running • Preventive 5 2 1 10
tank development • Flow meter
• Low velocity of Maintenance
water in loop • Sanitization
• Flow meter
• Monitoring as
per SOP
• In adequate water
• Testing • Preventive
• Microbial growth flow
Distribution • Flow meter Maintenance
9 development • Pipe line 5 2 1 10
system • Boroscopy • Sanitization
• Conductivity fail construction /welding
test • Flow meter
surfaces
• Boroscopy
testing
• Due to stagnation
• Improper cleaning
of sump • Monitoring as
• Improper dosing by per SOP
• Microbial load
10 Chlorination dosing pump or failure • Testing • Preventive 5 2 2 20
development
of dosing pump Maintenance
• In adequate • Sanitization
Concentration of
NaoCl
11 Dechlorinatio • Softener Resin damage • Improper dosing of • Testing • Monitoring as 5 2 2 20

www.ejbps.com 847
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

S. Item / Severity of Failure or Cause of Failure or Detection of Control


S O D RPN
No. Function Consequences (S) Occurrence (O) Failure (D) Measures
n • RO membranes damage SMBS by dosing per SOP
pump or failure of • Preventive
dosing pump Maintenance
• In adequate
Concentration of
SMBS
• Load on RO membranes • Monitoring as
Hardness • Membranes life will per SOP
12 • Softener failure • Testing 5 2 2 20
removal decrease • Preventive
• Scale formation Maintenance
• Monitoring as
Microbial • Integrity of filter per SOP
• Contamination of water
13 reduction by • Improper • Testing • Preventive 5 2 3 30
and system
Ultra filtration sanitization Maintenance
• Sanitization
Removal of • Monitoring as
ions, • TDS will increase • Membranes problem per SOP
5
14 Microbes and • Conductivity fails • Improper cleaning • Testing • Preventive 2 3 30
TOC by RO • TOC fails of membranes Maintenance
system • Sanitization
• Monitoring as
per SOP
Final Removal • Conductivity fails • Any mechanical/
15 • Testing • Preventive 5 3 2 30
ions by EDI • TOC fails Electrical problem
Maintenance
• Sanitization

www.ejbps.com 848
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Example-2: Risk assessment of Air handling unit


Severity of
S. Item / Cause of Failure Detection of
Failure or Control Measures S O D RPN
No. Function or Occurrence (O) Failure (D)
Consequences (S)
• Damage to
ON/OFF • Operational SOP
• AHU does not switch • ON/OFF
1 (Touch • Preventive 1 1 1 1
start • Circuit / indicator
panel) Maintenance
Electrical problem
• Cleaning of pre filter
• Damage to filter or replacement of pre
• Inadequate
• Choke filter
Differential
• MOC of filter • Magnehelic • Preventive
pressure
• Return air gauge Maintenance
Pre filter & Inadequate air
2 damper position • MOC certificates • Daily monitoring of 4 3 1 12
fine filters velocity
disturbed • Display provided Differential pressure
• Contamination
• Choking of in the room • Measurement of air
• Choking of
return filter velocity at HEPA filter
HEPA filter
• Monitoring of Particle
count contamination
Cooling coil • In adequate
& Temperatures and
• Any mechanical / • Monitoring as per
3 Condenser Relative Humidity • Display unit 5 3 1 15
Electrical problem SOP
(DX coil • Testing will be
unit improper
• LAF does not
• Any mechanical /
start • Daily monitoring of
Electrical problem
• Inadequate air • Magnehelic Differential pressure
• Sound and
4 Blower velocity gauge • RPM of the motor 4 2 2 16
vibration will
• Inadequate • Measurement of air
increase
Differential velocity at HEPA filter
pressure

www.ejbps.com 849
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Severity of
S. Item / Cause of Failure Detection of
Failure or Control Measures S O D RPN
No. Function or Occurrence (O) Failure (D)
Consequences (S)
• Replacement of
• Inadequate
HEPA filter
Differential
• Preventive
pressure • Damage to filter
Maintenance
• Inadequate air • Choke
• Integrity/Leakage • Daily monitoring of
5 HEPA filter velocity • Improper 5 1 3 15
test Differential pressure
• Particle installation /
• Measurement of air
Contamination Integrity
velocity at HEPA filter
• No uniformity of
• Monitoring of Particle
airflow
count contamination
• Shredding of
MOC of
6 • Contamination particles • MOC certificate • PO verification 5 2 1 10
filters
• Damage
• Contamination • Choking/Damage
• Operational SOP
• Inadequate of filters
• Calibration of
Differential • Failure of
7 Air velocity • None Magnehelic Gauge 5 2 5 50
pressure Magnehelic gauge
• Preventive
• Cross • Motor/Blower
Maintenance/Monitoring
contamination problem
• Choking/Damage • Daily monitoring of
• Inadequate air of filters Differential pressure
Pressure velocity • Failure of Calibration of
8 • Display unit 5 3 2 30
Differential • Cross Magnehelic gauge Magnehelic Gauge
Contamination • Motor/Blower • Preventive
problem Maintenance
• Inadequate air
HEPA Filter • Improper • Preventive
9 velocity • None 5 2 5 50
Integrity installation Maintenance/Monitoring
• Contamination
10 Airflow • Cross • Damage/Choking • None • Preventive 5 2 5 50

www.ejbps.com 850
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

Severity of
S. Item / Cause of Failure Detection of
Failure or Control Measures S O D RPN
No. Function or Occurrence (O) Failure (D)
Consequences (S)
direction Contamination of filters Maintenance/Monitoring
• Inadequate air
velocities
• Inadequate
differential
pressure
• Inadequate
Temperature testing • Daily monitoring
• Cooling coil
11 and Relative • Not complies • Display unit • Preventive 5 4 1 20
• Condenser unit
Humidity with the Maintenance
requirement
• Damage/Choking
of filters • Preventive
• Inadequate air Maintenance/Monitoring
Clean air
12 • Contamination velocities • None • Periodic monitoring of 5 2 5 50
supply
• Inadequate particle count
differential contamination
pressure
• Inadequate light
• Any Electrical • Preventive
13 Lighting for performing the • By Visual 5 3 2 30
problem or burnt Maintenance
activities
• Any mechanical
• Uncomfortable • Preventive
14 Sound problem to • By hearing 5 2 3 30
working Maintenance
motor/blower

www.ejbps.com 851
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

RESULTS AND CONCLUSIONS


Based on above RPN results, Items and functions having the RPN above 20 will be verified
for performance and other parameters shall be verified through operational qualification. This
system is required to monitor/qualify as per the VMP guidelines.

Guideline requirements for equipment qualification


ICH-Q7: GMP for Active Pharmaceutical Ingredients
12.30. Before starting process validation activities, appropriate qualification of critical
equipment and ancillary systems should be completed. Qualification is usually carried out by
conducting the following activities, individually or combined.

EU GMP: Annex 15 Qualification and Validation


 This Annex describes the principles of qualification and validation which are applicable
to the manufacture of medicinal products. It is a requirement of GMP that manufacturers
identify what validation work is needed to prove control of the critical aspects of their
particular operations. Significant changes to the facilities, the equipment and the
processes, which may affect the quality of the product, should be validated. A risk
assessment approach should be used to determine the scope and extent of validation.
 All validation activities should be planned. The key elements of a validation programme
should be clearly defined and documented in a validation master plan (VMP) or
equivalent documents.
 The VMP should be a summary document which is brief, concise and clear.
 A written protocol should be established that specifies how qualification and validation
will be conducted. The protocol should be reviewed and approved. The protocol should
specify critical steps and acceptance criteria.
 A report that cross-references the qualification and/or validation protocol should be
prepared, summarizing the results obtained, commenting on any deviations observed, and
drawing the necessary conclusions, including recommending changes necessary to correct
deficiencies. Any changes to the plan as defined in the protocol should be documented
with appropriate justification.
 After completion of a satisfactory qualification, a formal release for the next step in
qualification and validation should be made as a written authorization.

www.ejbps.com 852
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

WHO GMP: WHO TRS 937 Annex 4, Appendix 6, Qualification of Systems and
Equipments
 The continued suitable performance of equipment is important to ensure batch-batch
consistency. Critical equipment should therefore, be qualified.
 Critical Quality impacting systems such as Water System Air Handling systems should be
qualified.
 Qualification should be completed before process validation is performed. The process of
qualification should be logical, systematic process and should start from design phase of
the premises, utilities and equipment.

CONCLUSION
Qualification is an essential vital element of the pharmaceutical quality system.
Manufacturing is mainly depends on the performance of the equipment. Consistent
performance of the equipment is only possible when the equipment is properly qualified,
verified and maintained. A well designed qualification program assures the consistence
performance of the equipment, saves valuable time and cost. The success of the equipment
qualification is mainly depends on the good engineering practices followed in the
organization in combination with a risk based systematic approach described in this article.
Qualification is a never ending process so it is a cyclic process. Appropriate documentation
of the qualification program is very important as lack of the documented evidence does not
give any meaning to qualification. The pharmaceutical manufacturers, engineers, quality
assurance team have to understand the concepts described in this article and use it
appropriately to ensure that the risk based qualification is based on good science and
supported by good engineering practices and good manufacturing practices.

REFERENCES
1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. ICH
Harmonized Tripartite Guideline., 2000; (Q7a).
2. I.S.P.E. Pharmaceutical Engineering Guide for New and Renovated Facilities, Vol. 5
Commissioning and Qualification, March 2001
3. PIC/S Recommendations on “Validation Plan, Installation and Operational Qualification,
Non-Sterile Process Validation, Cleaning Validation”, August 2001.
4. EC Guide to GMP, Annex 15 „Qualification and Validation‟.

www.ejbps.com 853
Venugopal. European Journal of Biomedical and Pharmaceutical Sciences

5. S.M.Mudda, Qualification of Equipment- A Risk based approach, Pharma Times Vol.44,


No.11, November-2012.
6. ISPE White Paper – Risk Based Qualification for the 21st century (2005).
7. ASTM E 2500 (2700), Standard Guide for the Specification, Design and Verification of
Pharmaceutical and Biopharmaceutical Manufacturing Systems.
8. Risk based equipment qualification: A user/supplier cooperative approach, GAMP Italia
Equipment Validation Work Group, Pharmaceutical Engineering, Volume 27, No.3 May-
June 2007.

www.ejbps.com 854