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Pharma Times - Vol. 44 - No.

11 - November 2012 17
Qualifcation of Equipment A Risk-Based Approach
S. M. Mudda*
Executive Director Technical & Operations,
Micro Labs limited, Bangalore & Director of ISPE India Affliate
*Email Id: smm@microlabs.in
Why Qualifcation?
The principle responsibility of a pharmaceutical manufacturer
is to manufacture medicines of the highest quality that are safe
and effective.
The quality of the product is achieved through:
A well-designed product
Qualified facility and equipment
Current Good Manufacturing Practices
Qualified and trained personnel
While the quality is achieved through 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 manufacturers quality assurance
systems and it is no surprise that GMP codes of all the leading
regulatory agencies of the world include this activity.
Regulatory Requirements:
GMP regulations of all the leading regulatory agencies require
that the equipment used for Manufacturing, Testing or holding
and critical systems should be qualified prior to use as described
WHO TRS 937, Annex 4, Appendix 6, Qualification of Systems
and Equipment.
The c ont i nued s ui t abl e
perf ormance of equi pment
is important to ensure batch-
to-batch consistency. Critical
equipment should therefore, be
Cr i t i cal Qual i t y i mpact i ng
systems such as Water System,
Air Handling System should be
Qual i f i c at i on s houl d be
compl et ed bef or e pr ocess
validation is performed. The
process of qualification should
be logical, systematic process
and should start from design phase of the premises, utilities
and equipment.
EU Guideline, Annex 15 Qualifcation and Validation
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.
Evidences should be demonstrated to support the validation
and to verify the operating parameters and limits for the critical
variables of the operating equipment.
Accordingly, each drug product manufacturer should identify the
validation requirements needed to prove control of the critical
aspects of the product and process.
In accordance with these regulations, every manufacturer
has to qualify equipment used for manufacturing and testing to
demonstrate that it serves its intended purpose.
Additionally, the calibration, cleaning, preventative maintenance,
operating procedures and operator training procedures and records
should be documented.
It is important to note that selection and qualifcation of the
equipment plays a signifcant role in ensuring consistency in the
quality of the product
In the next few paragraphs I intend to give a brief step-wise
overview of the qualification process and then focus on the current
issues before the industry.
Qualifcation Process:
The journey of equipment qualification starts from the User
Requirement Specifications (URS) which are discussed with
the vendor and based on the agreement signed. The URS shall
include identified Critical to Quality Attributes and relevant Critical
Process Parameters which in general consists of Process/ Product
Requirements, Operational Requirements, GMP/GLP Requirements,
Safety Requirements, Documentation Requirements, Discussion/
Review/Comments etc.
Design qualifcation: While designing a specific system or
equipment the user requirements should be considered. Based
on URS, the equipment design is discussed and equipment design
qualification is undertaken.
Installation qualifcation: After the design Qualification, the
Factory Acceptance Testing (FAT) is undertaken followed by SAT
(Site Acceptance Testing) after approval of the FAT. Once the
equipment meets the SAT requirements, the systems and equipment
should be correctly installed in accordance with an installation plan
and installation qualification protocol. Installation qualification should
include identification and verification of all system elements, parts,
services, controls, gauges and other components.
Operational qualifcation: Systems and equipment should
operate correctly and their operation should be verified in
accordance with an operational qualification protocol. Critical
Pharma Times - Vol. 44 - No. 11 - November 2012 18
operating parameters should be identified. Studies on the critical
variables should include conditions encompassing upper and lower
operating limits and circumstances (also referred to as worst case
conditions). Operational qualification should include verification of
operation of all system elements, parts, services, controls, gauges
and other components.
Training of operators for the systems and equipment should
be provided, and training records shall be maintained. Systems
and equipment should be released for routine use after completion
of operational qualification, provided that all calibration, cleaning,
maintenance, training and related tests and results were found to
be acceptable.
Performance qualifcation: Systems and equipment should
consistently perform in accordance with design specifications. The
performance should be verified in accordance with a performance
qualification protocol. The equipment is performing as per its
intended use shall be demonstrated at this stage.
Every manufacturer has to qualify equipment used for
manufacturing and testing to demonstrate that it serves its
intended purpose.
Re-qualifcation: Re-qualification of systems and equipment
should be done in accordance with a defined schedule.
Calibration: The test equipments which are equipped with test
instruments and are used for the control, weighing, measuring,
monitoring and are critical for assuring the quality of drug
substances and drug products should be calibrated according to
written procedures and the established schedule.
Preventive Maintenance and Cleaning: There should be
a preventive maintenance program for all equipments. Similarly,
cleaning of equipments is of utmost importance in the prevention
of batch to batch and product to product contamination.
Periodic Review of Validation/ Qualifcation Status: All the
qualified equipments should be periodically evaluated to verify that
they are still operating in a valid manner. There should be an annual
review and conclusion should be drawn whether equipment stands
in validated state or not.
Change Control: Any changes in the equipment which can
have impact on the product quality should be addressed through
the change control system depending upon the nature of impact
of the change on the product quality. The extent of requalification
after the change should be justified based on a risk-assessment
of the change.
Current Status of GMP Compliance:
A review of the deficiencies related to qualification cited by all
major regulatory agencies such as UK MHRA, WHO and US FDA
reveals that there is a substantial scope for improvement by the
industry on this front. Some of the examples of the deficiencies
mentioned below will certainly draw our attention to this fact.
A Major source of GMP defciencies:
Acceptance Criteria: The IQ/OQ for the Drum Hoop Mixer
did not contain sufficient details with regard to the acceptance
criteria or how the protocols were enacted. A discrepancy was
identified but no explanation or impact was documented.
Measurement Range: The blister packing machine range of
temperatures mentioned on the batch documents for forming
and sealing had not actually been validated. Furthermore, the
speed of the machine had not been specified.
List of Qualifed Equipment: There was no list of equipment to
aid in assessing the need for periodic evaluation of its validation
Validation Protocol: There was no pre-authorized validation
protocol for the process.
Validation Report: No report had been written for the validation
of the product. There was no conclusion stating that the
validation had been successful.
Qualification Protocol: The complexity and criticality of
equipment and systems are often not taken into account when
designing qualification protocols.
Qualifcation Protocol: No rationale was documented for the
decision not to take all temperature data points into account
when averaging the results, and only hourly results were taken
and averaged.
Qualifcation Protocol: No rationale was documented in the
qualification protocol for running the dryer under pressurized
conditions and for only 6 hours, given that the routine drying
processes were performed under full vacuum and for significantly
longer periods of time (16 hours).
Issues Before The Industry:
Traditional Approach to Qualifcation:
Historically, the pharmaceutical industry has been using standard
equipment for manufacturing and testing of pharmaceuticals as
opposed to custom-built equipment that is designed keeping the
requirements of the product in mind. We therefore see standard
equipment like, Rapid Mixer Granulator, Fluid Bed Dryers, Rotary
Compression machines, Automatic capsule fillers of standard make
being used in the industry. Over a period of years, addition of new
parts for new functionality has been seen in limited processes, either
for automated online monitoring of the process or occasionally
for controlling the process to ensure that it runs within the pre-
determined limits.
Nonetheless, not appreciating the real intent behind the GMP
and regulatory expectations related to qualification activity, users
are currently spending significant human efforts and financial
resources in commissioning and qualification activities. These
activities appear to be performed merely for compliance purposes
since quite often it involves a mere repetition of verification already
performed by the manufacturer.
As stated earlier, since the same standard equipment is
employed by different manufacturers for variable formulations
of different requirements, the standard bookish approach for
qualification makes the whole exercise inefficient since difference in
the product and the process require different validation approaches
including the level of documentation.
It is therefore, imperative that the qualification study is designed
taking into account the critical process parameters, identification
of potential failures of the process control parameters leading to a
defective product, including these parameters in the Qualification
Study and based on the outcome of the study designing appropriate
in-process controls for monitoring the quality during manufacturing
Absence of this approach obviously has lead to a number
of deficiencies that are cited by all the leading global regulatory
agencies as stated in the preceding paragraph.
Pharma Times - Vol. 44 - No. 11 - November 2012 19
Inadequate URS:
URS is the starting point of the qualification process that helps
build an equipment of good design. The experience has shown that
inadequately defined URS has been the fundamental weakness in
the equipment qualification process.
Very often, the user of the equipment converts the standard
technical specifcation of the supplier into his URS.
Contrary to stating the requirements of design of the equipment
clearly based on the product and process needs, very often the user
of the equipment converts the standard technical specification of
the supplier into his URS.
Such is the lack of knowledge of this important quality impacting
activity that the investigations done to identify the cause of a
quality complaint of the product rarely point out the lack of good
design and good qualification as the root cause thus, allowing the
complaints to recur.
Thus, we have a situation of having perfectly qualifed equipment
that is not able to produce a product of desired quality standards
Thus, we have a situation of having perfectly qualified equipment
that is not able to produce a product of desired quality standards
Poorly Designed Qualifcation Protocols:
Another commonly seen weakness is the inability to write a
good protocol for qualification of the equipment. Although the
protocol approval team is drawn from cross- functional members
representing production, Engineering and Quality Assurance,
often writing of the protocol is considered as a responsibility of
the engineering function alone. This disconnect between the
process development, production and QA with the engineering
team has lead to serious gaps in the qualification studies leading
to inadequate qualification of the equipment and consequently
earning critical GMP deficiencies.
In a case of Performance Qualification (PQ) Study of a blender,
the number of samples to be drawn, the sampling locations and
the acceptance criterion for content uniformity were substantially
different in the PQ Protocol from the Process Validation Protocol
of the product that was used for qualifying the same equipment.
The investigations revealed that both the protocols were written
at different times and were signed by different individuals without
consulting each other. Worst still, the study was concluded
as satisfactory despite differences in parameters stated in the
protocols since QA certified the PQ of the equipment without
referring to the Process Validation Report and the corresponding
Batch Record.
Another weakness is poor facility of language that leads to
badly written protocols and equally poorly written reports that clearly
indicates that the entire study is carried out without getting into the
depth of the subject.
Example - Case Study:
An automatic labeling system consisting of three key
components, a labeling head, a conveyor for product transport, and
an integrated control system each of which, in turn, having their
own sub-components was used for labeling bottles on an integrated
bottle packing line. Additionally, an Optical Character Reader was
integrated with the machine to ensure the presence of label and
also to confirm that the overprinted variable matter is readable and
correct. Bottles with defective labels were in turn rejected by a
Rejection System using a pneumatically operated pusher arm that
worked at a required pressure level.
The machine was qualified, set for use and was running
satisfactorily until a market complaint of bottles with missing print
and defective printing came as a surprise.
A detailed root cause investigation was carried out on various
aspects such as operations, handling of rejects, operation of the
equipment etc. Finally, through a risk assessment carried out, the
functioning of the rejection system came into light. It was revealed
that defective packs were detected at the detection station but
were not rejected by the pusher arm of the rejection system. The
probable reason was exceptional pressure drop of the pusher arm
that stopped the arm movement which could happen as a result of
a power failure or power fluctuations.
Following CAPAs were initiated:
a) UPS back-up to the system.
b) Installation of pressure gauge to measure the pressure
required for operating the pusher arm for rejecting the defective
c) Installation of pressure switch which stops the machine while
running, if the pressure of the pusher arm drops.
For implementing the identified CAPAs the operating SOP of
the labeling machine and the batch records were revised to include
instructions for setting, challenging and monitoring the pusher arm
pressure that was adequate for proper functioning of the rejection
The case study presented above confirms the points raised in
the preceding paras.
It was a case of inadequate URS that did not identify the quality
impacting nature of the rejection mechanism and therefore did
not capture it as a parameter for qualification in the protocol.
Thus, the optimum pressure required for operation of the pusher
arm was neither defined nor qualified.
Since the failure of the operation of the pusher arm was not
anticipated, no suggestion was made in the URS to provide
for a system for dealing with such eventuality that was later
implemented as a CAPA in the form of a pressure switch that
would stop the equipment should the pressure drop below the
required pressure.
Delink between Qualifcation Report and Batch Record:
The outcome of the qualification study should result in defining
the critical process control parameters along with the operating
range that can serve as monitoring tool during manufacturing
process and will result in consistent delivery of quality product. The
inability of capturing these parameters from the qualification report
into the batch manufacturing instructions takes away the benefit
the extensive qualification study.
It is the responsibility of QA to ensure that the SOPs for
Operation of the equipment capture the machine setting parameters,
verification of these parameters by challenging them during the
machine setting and thereafter including them as in-process controls
and in-process challenges in the SOPs and in the Bach Records.
Risk-Based Approach to Qualifcation:
The qualification as practiced today appears to be performed
from a lack of understanding of the GMPs related to equipment
suitability leading to huge effort and documentation without
Pharma Times - Vol. 44 - No. 11 - November 2012 20
corresponding benefit to the industry. Adoption of risk-based
approach will ensure that a balance between the levels of efforts put
in the qualification of equipment and benefit to the product quality
is achieved. Thus, Risk-based qualification can improve quality and
reduce validation efforts.
International Society of Pharmaceutical Engineers (ISPE) is
actively engaged in encouraging this approach and has come out
with excellent guidelines towards this end.
The ISPE White Paper Risk Based Qualification for the 21

Century published in March 2005 propagates 10 Principles for
Risk-Based Qualification that emphasizes focus on critical aspects
for qualification while leaving out the others.
ICH Q9, Quality Risk Management (QRM) provides a systematic
process for the assessment, control, communication and review of
risks to the quality of the drug product across the product life cycle
that can be applied to the qualification study. ICH Q9 Annexure-II
provides the potential application of QRM.
The guideline expects to determine the scope and extent of
qualification studies by applying the risk management principles
and tools.
Ten Principles for Risk-Based Qualifcation
The application of QRM to equipment qualification is explained
along side the ICH/QRM model below.
Application of Quality Risk Management for Equipment
The Key focus in the risk assessment phase is active
engagement of the user with the supplier of the equipment that
should lead to identification of Critical to Quality components and
systems as described below. The supplier can provide a large
number of support activities and services during the life cycle of
a product under all the different perspectives offering a significant
contribution in the risk management process.
Specifcation Phase: At the Specification Phase the user can
communicate potential risks and the relevant impact to the supplier
on Quality of the Product, Safety of the operator & the Business.
This phase involves the risk identification and risk analysis.
Design and Manufacture Phase: During Design and
Manufacture Phase the Supplier shall identify critical parts and
communicate these to users to evaluate the risks and provide
additional controls and counter measure wherever necessary and
finally accept the system design. This phase involves the evaluation
of and control of the risk.
It should be noted that while the technical part of the risk analysis
can be performed by the supplier, its a responsibility of the user to
evaluate the risks, to provide any required additional controls and
finally to accept the residual risks.
The IQ, OQ and PQ activities should be limited to systems and
components with Direct Impact on the product quality. All the rest of
the system may be simply commissioned and managed according
to Good Engineering Practices (GEP). As stated above the
identification of critical parts is an outcome of the risk analysis.
The Way Forward:
The initiative of Risk-based Qualification was taken forward
by the industry and ISPE under the advise of US FDA. On the
publication of the White paper, ISPE worked with pharmaceutical
companies and consulting companies to create an American Society
of Testing and Measurement (ASTM) standard. The teams goal
was to integrate risk-based methodology conforming to the ICH
Q8, Pharmaceutical Quality Systems and ICH Q9, Quality Risk
Management standards. A new voluntary consensus standard,
ASTM E 2500, Standard Guide for the Specification, Design, and
Verification of Pharmaceutical and Biopharmaceutical Manufacturing
Systems and Equipment was approved in June, 2007.
ASTM E2500 is a Risk-based and Science-based approach to the
specifcation, design, and verifcation of manufacturing systems
and equipment that have the potential to affect product quality
and patient safety.
ASTM E2500 is a Risk-based and Science-based approach to
the specification, design, and verification of manufacturing systems
and equipment that have the potential to affect product quality and
patient safety.
The overall objective is to provide manufacturing capability to
support defined and controlled processes that can consistently
produce product meeting defined quality requirements.
The guiding principle of the ASTM E2500 is to design the
equipment by adopting the risk-based approach and manufacture the
equipment by following the Quality Systems and Good Engineering
Practices (GEP). The guideline strongly recommends, leveraging
the information generated during the FAT SAT and commissioning
stages to reduce the extent of IQ and OQ activities. In other words
the ASTM guideline recommends verification of the data generated
during the FAT, SAT and commissioning phase in lieu of IQ and
OQ activities and go straight for PQ. The term verification is used
to describe both commissioning and qualification.
There is a similarity between GEP and GMP. In both cases,
Quality should be achieved by design, and not just tested at the
end of the process. Embedding quality into an equipment design is
mostly a suppliers responsibility in a cooperative and trustworthy
relationship with the user.
Pharma Times - Vol. 44 - No. 11 - November 2012 21
ASTM Process Flow:

Pharma Times - Vol. 44 - No. 11 - November 2012 22
# Verifcation as Qualifcation:
Benefts of ASTM E2500-07
A recent case study on equipment selection, design and
qualification using this approach demonstrated that a substantial
amount of time and cost could be saved. The approach encouraged
involvement of validation engineers from the URS stage. All
functions were involved in performing risk assessment, identifying
the individual user requirement, specifying the testing/verification
requirements, assessment of the Site Acceptance / Factory
Acceptance and application of increased knowledge of the QA.
The application of this approach resulted in reducing a huge
amount of time. The time required for vendor documentation was
limited to six weeks. The information generated during the FAT/
SAT was leveraged thereby reducing the IQ stage to 10 days from
1-2 months and OQ stage to 3 days from 2- 3 months.
The equipment delivery to qualification and commercial use
was completed within a period of less than 3 months.
The information generated during the FAT/ SAT was leveraged
thereby reducing the IQ stage to 10 days from 1-2 months and
OQ stage to 3 days from 2- 3 months.
Benefts of Risk-Based Approach
It appears that regulators also will start accepting this
approach very soon. In 2006, a new facility to manufacture two
new products during facility and equipment qualification used
risk assessments, commissioning, and process qualification
approach to confirm the equipment was suitable for its intended
use. The QA was involved in the risk assessments, approved
the overall project quality plan, and conducted post-approval of
the process qualification protocols. There was no installation
qualification/operational qualification per se performed. The
inspectors inquired about this, and observed a much smaller
volume of paperwork associated with this phase of the project.
The approach used was explained to the inspectors, and the
facility passed its inspection.
The risk-based qualification will be immensely beneficial to the
industry since it demonstrably reduces the cost and time required for
qualification. It is also good to see that even regulators are willing
to encourage this initiative.
However, it has to be understood that the success of this
approach is dependent on the equipment manufacturer following
his quality system and GEPs. Since the commissioning data
is leveraged for qualification the standards for quality of this
documentation should be established.
The industry leaders, QA professionals and engineers have to
understand this concept and use it judiciously to ensure that the
risk assessment is based on good science and supported by Good
Engineering Practices.
1. EU GMP Guideline, Annexure 15
2. Pharmaceutical Inspection Convention /Scheme (PIC/S)
3. WHO TRS 937, Annexure-4
4. ICH Q8 Pharmaceutical Development
5. ICH Q9 Quality Risk Management
6. ISPE White Paper Risk Based Qualification for the 21
7. ASTM E 2500 (2007), 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
Indian Pharmaceutical
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