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Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
DEPARTMENT OF PHARMACY,
KATHMANDU UNIVERSITY, DHULIKHEL,
KAVRE, NEPAL
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PROCESS VALIDATION
Submitted to:
JAYABIR KARMACHARYA
Department of Pharmacy
Kathmandu University
Kavre, Nepal
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
AN APPROACH TO,
PROCESS VALIDATION
SUBMITTED FOR INTERNAL EVALUATION FOR
THE DEGREE IN MASTER IN PHARMACY
BY
BIBEK SINGH MAHAT, M. PHARM STUDENT,
1ST YEAR, 1ST SEMESTER, BATCH OF 2009
SUBMITTED TO:
JAYABIR KARMACHARYA
DEPARTMENT OF PHARMACY
SCHOOL OF SCIENCE
KATHMANDU UNIVERSITY
DHULIKHEL, NEPAL
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
TABLE OF CONTENTS:
1. VALIDATION……………………………………………………………………3
2. PROTOCOLS……………………………………………………………………5
4. QUALIFICATIONS…………………………………………………………….6
6. PROCESS VALIDATION……………………………………………………..9
6.4. Revalidation…………………………………………………………14
8. REFERENCES…………………………………………………………………16
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
1. VALIDATION
“Validation is a key element of the quality assurance system in a pharmaceutical company”
For a long time, our understanding of pharmaceutical quality was such that one relied solely on
the control of raw materials and final products. The intermediate process was guaranteed by
established experience and the professional honesty of longtime employees. Today, our
understanding is almost the reverse. Well-tested raw materials from qualified suppliers are used
in a process that must be so well controlled that, theoretically, absolutely nothing can result other
than a product that conforms to the specifications. In contrast, the place of manufacture and staff
carrying out production are interchangeable, as long as they are qualified.
The new approach is conclusive, reasonable, sensible, since if a serious defect is identified at the
final product quality control, irreparable damage has already occurred. For drug products,
reprocessing is prohibited in most cases or is only possible with a great deal of additional
expenditure. Since modern drug substances and innovative preparations are also becoming ever
more expensive, it is, therefore, necessary to avoid the final product being rejected using
preventive measures, such as validation. Therefore, to guarantee a reproducible quality,
processes must be validated. 4
Definitions:-
“The establishing of documented evidence which provides a high degree of assurance that a
planned process will consistently perform according to the intended specified outcomes”.
(WHO guide to GMP requirements , part-2 ,validation, Geneva 1997)
"Action of proving, in accordance with the principles of Good Manufacturing Practice, that
any procedure, process, equipment, material, activity or system actually leads to the expected
results.” (EU GMP Guideline)
a) Quality, safety and efficacy must be designed and built into the product.
b) Quality cannot be inspected or tested into the product.
c) Each critical step of the manufacturing process must be validated. Other steps in the
process must be under control to maximize the probability that the finished product
consistently and predictably meets all quality and design specifications.
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
Validation of processes and systems is fundamental to achieving these goals. It is by design and
validation that a manufacturer can establish confidence that the manufactured products will
consistently meet their product specifications. Documentation associated with validation
includes3:-
Validation studies verify the system under test under the extremes expected during the process to
prove that the system remains in control. Once the system or process has been validated, it is
expected that it remains in control, provided no changes are made. In the event that
modifications are made, or problems occur, or equipment is replaced or relocated, revalidation is
performed. Critical equipment and processes are routinely revalidated at appropriate intervals to
demonstrate that the process remains in control. The validity of systems / equipment / tests/
processes can be established by prospective, concurrent or retrospective studies. 1
Validation protocols have not been compiled or are not being followed
Information about the equipment used, the critical process parameters, sampling data,
number of validation batches or acceptance criteria is missing from the validation
documentation
Changes to validated processes are not being addressed
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
2. PROTOCOLS
A protocol is a written set of instructions broader in scope than a Standard Operating Procedure
(SOP). SOPs are the detailed written instructions for procedures routinely performed in the
course of any of the activities associated with pharmaceutical manufacturing.
A protocol describes the details of a comprehensive planned study to investigate the consistent
operation of new system / equipment, a new procedure, or the acceptability of a new process
before it is implemented. Protocols include significant background information, explain the
rationale for and the objective of the study, give a full description of the procedures to be
followed, set out the parameters to be measured, describe how the results will be analyzed, and
provide pre-determined acceptance criteria for making conclusions. 1
Validation studies, stability studies, and clinical studies are examples of written protocols for
pharmaceutical manufacturers. Validation protocols are important in ensuring that documented
evidence is taken which demonstrates that an equipment item, a system, a process or a method
consistently performs at a specified level.
The Master Validation Plan should also indicate why and when revalidations will be performed,
either after changes or relocation of equipment or systems; changes to processes or equipment
used for processing; or for changes in assay methods or in equipment used in tests. 1
The order in which each part of the facility is validated must be addressed in the Master
Validation Plan. For example the water system should be validated before validating a piece of
equipment that uses this water system.
The DQ, IQ, OQ and PQ must be performed in order: the master validation plan should indicate
how to deal with any deviations from these qualifications, and state the time interval permitted
between each validation. 1
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
4. QUALIFICATIONS
i) Design qualification (DQ)
The first element of the validation of new facilities, systems or equipment could be design
qualification (DQ).The compliance of the design with GMP should be demonstrated and
documented.
This document should be written for the critical processing equipment and systems that are used
within the facility, e.g. an HVAC system, an autoclave or a pH meter. The IQ should list all the
identification information, the location, utility requirements and any safety features of the
equipment.
The IQ protocol prepared for each piece of equipment or system lists the name, description,
model and identification numbers, the location, utility requirements, connections, and any safety
features of the system/equipment which needs to be documented.
It should verify that the item matches the purchase specifications, and that all drawings, manuals,
spare parts list, vendor address and contact number, and other pertinent documentation are
available. 1
Installation qualification (IQ) should be performed on new or modified facilities, systems and
equipment. IQ should include, but not be limited to the following:- 2
This document outlines the information required to provide evidence that all the components of a
system or of a piece of equipment operate as specified. This involves testing of all normal
operation controls; all alarm points, all switches and displays, interacting controls, and any other
indications of operations and functions. The OQ document should provide a listing of SOPs (or
reference to specific manual instructions) for operation, maintenance and calibration;
information on the training of operators; and instructions for any static or dynamic tests to show
that the equipment operates as expected under normal conditions. Specifications and acceptance
criteria must be defined for all the operations. The OQ document should include information on
equipment or system calibration, pre-operational activities, routine operations and their
acceptance criteria. 1
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
Operational qualification (OQ) should follow Installation qualification. OQ should include, but
not be limited to the following: 2
a) Tests that have been developed from knowledge of processes, systems and equipment;
b) Tests to include a condition or a set of conditions encompassing upper and lower operating
limits, sometimes referred to as “worst case” conditions.
c) The completion of a successful Operational qualification should allow the finalization of
calibration, operating and cleaning procedures, operator training and preventative
maintenance requirements. It should permit a formal "release" of the facilities, systems and
equipment.
This part of the validation for systems and equipment is performed after both Installation and
Operational Qualifications have been completed, reviewed and approved. The PQ document
describes the procedure or procedures for demonstrating that a system or piece of equipment can
consistently perform and meet required specifications under routine operation and, where
appropriate, under worst case situations.
The PQ should include a description of the preliminary procedures required, the detailed
performance test(s) to be done, and the acceptance criteria for each test. The PQ also requires
that other supporting equipment used during the qualification have been validated. 1
Evidence should be available to support and verify the operating parameters and limits for the
critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative
maintenance, operating procedures and operator training procedures and records should be
documented.
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
ii) DOCUMENTATION:- 2
a) A written protocol should be established that specifies how qualification and validation will
be conducted.
b) The protocol should be reviewed and approved.
c) The protocol should specify critical steps and acceptance criteria.
d) 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.
e) Any changes to the plan as defined in the protocol should be documented with appropriate
justification.
f) After completion of a satisfactory qualification, a formal release for the next step in
qualification and validation should be made as a written authorization.
a) The effect of the change on the specific system /process under consideration as well as the
wider implication for other systems and processes of the facility.
b) Re-validation of the system/process or other systems may be necessary depending on the
significance of the change.
c) No changes should be made for any validated, approved equipment /systems /tests /
processes without formal review and approval via the change control procedure.
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
6. PROCESS VALIDATION
Process validation is a fundamental component of the quality assurance system of
pharmaceutical manufacturers. It should verify that the procedures and processes used in drug
product manufacturing are appropriate to their purposes and guarantee that the manufactured
drug product is of the required quality. Process validation is, thus, a basic factor for drug product
safety. 5
A process is a series of interrelated functions and activities using a variety of specified actions
and equipment which is designed to produce a defined result. To validate the reproducibility and
consistency of a process, the full defined process is carried out using validated equipment, under
the established procedure usually at least 3 times The process must successfully and consistently
meet all acceptance criteria each time to be considered a validated process. In many cases, "worst
case" conditions are used for the validation to ensure that the process is acceptable in the extreme
case. Sometimes worst case conditions for systems can only really be tested over time and hence
must be evaluated using a rigorous long term monitoring program. 1
Each of these categories may apply to several distinct processes in the manufacturing facility.
For instance, cleaning process can be the cleaning of glassware, the cleaning of the facility
(floors and walls), equipment cleaning such as Clean-in-Place (CIP), or Clean-out-of-Place
(COP), cleaning of garments, etc. Sterilization can be the Sterilize-in-Place (SIP) process,
glassware sterilization, filter sterilization, steam sterilization, dry heat sterilization, etc.
Each process to be validated must be a specific process clearly described in a Master Formula or
in an SOP. All the equipment, the processing parameters, and the specifications at each step must
be detailed. Complete descriptions of the identity, code numbers, construction, operating
capacity, and actual operating ranges must be defined for the equipment. The processing
parameters for all steps must be sufficiently detailed to permit complete reproducibility of the
process each time it is performed: time periods, pH, volumes, temperatures, measurements,
specifications, acceptable ranges, etc. The controls and tests and their specifications must be
defined. The purity profiles for production processes must be defined for each step. To be
considered validated, the process must consistently meet all specifications at all steps throughout
the procedure at least three times consecutively. 1
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
It is very important that the specifications for a process undergoing validation be pre-determined.
It is also important that for all critical processing parameters for which specifications have been
set, there must be equipment to measure all of those parameters during the validation study.
Process Validation studies examine a process under normal operating conditions to prove that the
process is in control. Once the process has been validated, it is expected that it remains in
control, provided no changes are made. In the event that modifications to the process are made,
or problems occur, or equipment or systems involved in the process are changed, a re-validation
of the process would be required. 1
Very often validation studies require that more measurements are made than are required for the
routine process. The validation must prove the consistency of the process and therefore must
assess the efficiency and effectiveness of each step to produce its intended outcome. 1
General Considerations:-
a) Process validation should normally be completed prior to the distribution and sale of the
medicinal product (prospective validation). In exceptional circumstances, where this is not
possible, it may be necessary to validate processes during routine production (concurrent
validation). Processes in use for some time should also be validated (retrospective
validation).
b) Facilities, systems and equipment to be used should have been qualified and analytical
testing methods should be validated. Staff taking part in the validation work should have
been appropriately trained.
c) Facilities, systems, equipment and processes should be periodically evaluated to verify that
they are still operating in a valid manner.
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
2) Using this defined process (including specified components) a series of batches of the final
product may be produced under routine conditions. In theory the number of process runs
carried out and observations made should be sufficient to allow the normal extent of variation
and trends to be established and to provide sufficient data for evaluation. It is generally
considered acceptable that three consecutive batches/runs within the finally agreed
parameters would constitute a validation of the process. 2
3) Batches made for process validation should be the same size as the intended industrial scale
batches. 2
4) If it is intended that validation batches be sold or supplied, the conditions under which they
are produced should comply fully with the requirements of Good Manufacturing Practice,
including the satisfactory outcome of the validation exercise, and with the marketing
authorization. 2
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
6.4. REVALIDATION:-
Facilities, systems, equipment and processes, including cleaning, should be periodically
evaluated to confirm that they remain valid. Where no significant changes have been made to the
validated status, a review with evidence that facilities, systems, equipment and processes meet
the prescribed requirements fulfils the need for revalidation.1
Pilot-scale* is an intermediate scale which is sometimes used to determine the validity of new or
modified processes before full-scale operations are attempted. For both lab-scale and pilot scale
validation studies to be acceptable as proof of the validity of the full scale process, it must be
demonstrated that the scale-down has been calculated for all critical parameters of the process:
times, temperatures, amounts, column sizes, flow rates, pressures, etc.
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
Validation studies to be conducted on the production scale batches. It should contain the
following information:-
i. Summary
ii. Introduction
iii. Batches used for validation
iv. Manufacturing equipment
v. Critical process steps and parameters
vi. Acceptance criteria
vii. Sampling plan
viii. Tabulation of the test results
ix. Batch Analysis
x. Evaluation of data, and where applicable, including statistical process control
analysis
xi. Evaluation of data including comparison against acceptance criteria
xii. Discussion on deviations and out of specification results
xiii. Conclusion and recommendations
1, 2, 3
REFER ANNEX -1:- FORMAT OF PROCESS VALIDATION PROTOCOL
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An Approach to Process Validation
Bibek Singh Mahat, M. Pharmacy, 1st Year, 1st Sem. Roll No. 7
8. REFERENCES:-
5. GMP Manual , Good Manufacturing Practice and Implementation, Anita Mass, Barbara
Peither , Thomas Peither , Mass and Peither GMP Publication, Germany , 2006
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