Professional Documents
Culture Documents
062
Dr.S.Venugopal*
Types of qualifications
• Design qualification
• Installation qualification
• Operational qualification
• Performance qualification
• Maintenance qualification
• Safety qualification
• Verification qualification
• Re-qualification
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EQUIPMENT
QUALIFICATION
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.
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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.
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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.
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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.
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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
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In deviations from the specified design or acceptance criteria shall be documented and
justified in the installation qualification report.
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.
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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.
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
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in manufacturing industry. Good automation practices (GAP) is in use by most of the leading
pharmaceutical companies as part of the safety qualification program.
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
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Scope
Responsibilities
System description/history
Design verification
Installation verification
Operational and performance verification
Record of tests performed
Conclusion
Post approval
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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.
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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.
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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?
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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.
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.
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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
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.
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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
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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
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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‟.
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