Process Validation Article 1

Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Kashyap et al
www.pharmasm.com IC Value 4.01 351

PHARMA SCIENCE MONITOR
AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

PROCESS VALIDATION: ACTION OF PROVING EFFECTIVENESS
Kashyap Ankita*
1
, Rana AC
2
, Singh Gurpreet
1

1
Department of Pharmaceutics, Rayat Institute of Pharmacy, RailMajra S.B.S Nagar,Punjab, India
2
Department of Pharmacology,Rayat Institute of Pharmacy, Rail Majra S.B.S Nagar, Punjab, India
ABSTRACT
The most discussed and important subject of pharmaceutical industry is none other than
validation. Validation is a tool of quality assurance which provides confirmation of the
quality in equivalent systems, in process, software and testing methods. Validation of
individual steps of the manufacturing process is called process validation. A properly
designed system will provide a high degree of assurance that every step, process change
has been properly evaluated before its implementation. Three consecutive batches are
taken up for process validation.
Keywords: Process Validation, FDA, Validation Protocol, Qualification.
INTRODUCTION
Process Validation is defined as the collection and evaluation of data, from the process
design stage through commercial production, which establishes scientific evidence that a
process is capable of consistently delivering quality products. Validation was earlier
defined as a documented procedure for obtaining, recording and interpreting data
required to show that a process will consistently comply with predetermined standards.
The word validation simply means, assessment of validity or action of proving
effectiveness.
[1]
According to European community for medicinal products, validation is
action of proving, in accordance with the principles of GMP that any procedures,
process, requirement, material, activity or system actually leads to expected results. Ted
Byers and Bud Loftus were the first FDA officials to propose the concept of validation in
the mid 1970s. FDA has the authority and responsibility to inspect and evaluate process
validation performed by manufacturers.
[2]
The CGMP regulations for validating
pharmaceutical (drug) manufacturing require that drug products be produced with a high
degree of assurance of meeting all the attributes they are intended to possess (21 CFR
211.100(a) and 211.110(a)).
[3]
USFDA defined process validation as establishing
documented evidence which provides high degree of assurance that a specific process
will consistently produce a product meeting its pre determined specifications and quality
characteristics.
[4]


Thus validation is a scientific study of process:
1) To inspect that the process is consistently doing what it is supposed to do (i.e that the
process is under control).
2) To demonstrate the process variables acceptable limits for these variables and to set up
appropriate in process controls.
RESPONSIBILITIES OF VARIOUS PHARMACEUTIACAL DEPARTMENTS
WHEN CARRYING OUT PROCESS VALIDATION.
Quality Assurance
a) Review of Equipment qualification, facility qualification and utility validations
reports.
b) QA is responsible for: Review of Equipment qualification, facility qualification and
utility validations reports.
c) cGMP compliance during manufacturing process, review and evaluation of the
data/results generated during validation.
d) Preparation, training and approval of protocol, review of the data compiled, review of
deviations (if any), monitoring the process as per the process parameters and for
withdrawal of validation samples in co-ordination with Production.
e) Preparation of Process validation summary report, its review and approval.
Production
It is responsible for:
a) Training of personnel for unit operation.
b) Executing the batches as per the Batch production record and execution of Process
Validation Protocol.
c) Compilation of data related to manufacturing area and furnishing the same for review.
Review of protocol and summary report.
Quality Control
QC is responsible for:
a) Raw material and packing material analysis
b) In process and finished product samples analysis as per the sampling plan.
c) Collection and review of in process test data and Finished Product analysis data.
d) Submission of data /results to QA for review and evaluation


e) Analysis of in process samples and compilation of data.
Engineering.
It is responsible for:
a)Qualification and calibration of all the processing equipment/instrument before the start
of Process validation batches.
b) To maintain the system to provide required environmental conditions and other
utilities for manufacturing of the batches.
TYPES OF PROCESS VALIDATION
Depending on when it is performed in relation to production, validation can be
prospective, concurrent, retrospective or revalidation (repeated validation).
Prospective Validation
[5,6]
Prospective validation is carried out during the development stage by means of a risk
analysis of the production process, which is broken down into individual steps: these are
then evaluated on the basis of past experience to determine whether they might lead to
critical situations.

Where possible critical situations are identified, the risk is evaluated, the potential causes
are investigated and assessed for probability and extent, the trial plans are drawn up, and
the priorities set. The trials are then performed and evaluated, and an overall assessment
is made. If, at the end, the results are acceptable, the process is satisfactory.
Unsatisfactory processes must be modified and improved until a validation exercise
proves them to be satisfactory. This form of validation is essential in order to limit the
risk of errors occurring on the production scale, e.g. in the preparation of injectable
products.
Concurrent Validation
[5,6]
Concurrent validation is carried out during normal production. This method is effective
only if the development stage has resulted in a proper understanding of the fundamentals
of the process. The first three production-scale batches must be monitored as
comprehensively as possible. The nature and specifications of subsequent in-process and
final tests are based on the evaluation of the results of such monitoring.
[1]
This careful
monitoring of the first three production batches is sometimes regarded as prospective


validation.Concurrent validation together with a trend analysis including stability should
be carried out to an appropriate extent throughout the life of the product.
Retrospective Validation
[5,6]
Retrospective validation involves the examination of past experience of production on the
assumption that composition, procedures, and equipment remain unchanged; such
experience and the results of in-process and final control tests are then evaluated.
Recorded difficulties and failures in production are analysed to determine the limits of
process parameters. A trend analysis may be conducted to determine the extent to which
the process parameters are within the permissible range. Retrospective validation is
obviously not a quality assurance measure in itself, and should never be applied to new
processes or products. It may be considered in special circumstances only, e.g. when
validation requirements are first introduced in a company. Retrospective validation may
then be useful in establishing the priorities for the validation programme. If the results of
a retrospective validation are positive, this indicates that the process is not in need of
immediate attention and may be validated in accordance with the normal schedule. For
tablets which have been compressed under individual pressure-sensitive cells, and with
qualified equipment, retrospective validation is the most comprehensive test of the
overall manufacturing process of this dosage form. On the other hand, it should not be
applied in the manufacture of sterile products.
Revalidation
[5,6]
Revalidation is needed to ensure that changes in the process and/or in the process
environment, whether intentional or unintentional, do not adversely affect process
characteristics and product quality.Revalidation may be divided into two broad
categories:
Revalidation after any change having a bearing on product quality.
Periodic revalidation carried out at scheduled intervals.
Facility Validation
[7]
It should include planning, documentation, construction and testing to design
specifications and cGMP requirements.
Services Validation
[7]
This involves qualification activities like


a) Environmental control system e.g. HVAC and AHU.
b) Water Storage and Distribution System.
c) Compressed Air System.
d) Steam Distribution System,etc
Analytical Method Validation
[7]
It involves evaluation of product quality attributes through testing to demonstrate
reliability is being maintained throughout the life cycle and that the precision, accuracy,
specificity, LOD, LOQ, linearity, selectivity have not been compromised.
Cleaning Validation
[7]
It involves high degree of cleaning procedure to give assurance that the cleaning process
results in equipment/area having product contamination below the acceptable level.
Computer Validation
[7]
It involves validating the software used for automation or testing purposes.
Equipment Validation
[7]
It involves qualifying the design, installation, operation, instrumentation, control system
and performance of the equipment.
KEY ELEMENTS REQUIRED FOR A SUCCESSFUL VALIDATION
8
The essential tools or elements required for conducting successful validations are as
follows:
1) Understanding: The single and the most important of all is the requirement of good
understanding of what validation is. This understanding goes beyond the basic definition
of validation, beyond the concept of requiring a minimum of three runs. This
understanding must be anchored by sufficient years of practical experience and
knowledge. It will permit sound and logical decisions even under most intense situations.
2) Experience: Solid validation experience along with resources are needed to attain
success in validation program by a firm.
3) Communication: Communication is the best method of environment understanding.
Communication is essential for any activity that requires more than one resource to
complete. This point is understandable considering that conducting effective validation
involves multi-departments as mentioned earlier in the role of various departments.


4) Co-operation and Focus: Commendable co-operation and focused effort amongst
departments like Quality control, Quality assurance, project engineering, process
engineering, project management, facilities, accounting, regulatory etc is must.
5) Resources: Resources means personnel who will plan and execute equipment on
which validations will be performed on materials with which to conduct validations.
Laboratory that will perform necessary analysis should provide necessary funding for the
validations allocate sufficient time to perform validations. Validation can often begin but
cannot be completed if any one of these resources is missing.
6) Budget: Successful validation should not be limited by a budget assembled by
personnel who have no appreciation for what is required to successful complete
validation. Further, it is important to understand that validations costly.
7) Plan: The various departments involved need a perfect plan in order to get good team
synergy.
8) Training: It is essential that lead validation resource for a given validation project
initiate, facilitate, co-ordinate and/or communication the need for resource training as
required by validation event.
9) Standard Operating Procedures (SOPs): SOPs capture activities that routinely occur
within a firm. Departments charged with abiding by or following these SOPs must first
be trained against SOPs.
10) QC Laboratory Support: The testing is handled by the QC group. QC is expected to
produce results in timely manner. So often the wait for the receipt of analytical results
cases the entire validation project to come to halt. Thus validations are based on results
obtained.
PPQ OR VALIDATION PROTOCOL
[8,9]
A written protocol is the one that specifies the manufacturing conditions, controls,
testing, and expected outcomes is essential for process validation. Apart from this, the
protocol should give details of critical steps of the manufacturing process that should be
measured, the allowable range of variability and the manner in which the system will be
tested.
[8]
A validation protocol provides a synopsis of what is hoped to be accomplished listing the
selected process and control parameters, number of batches to be included in the study


specifying how the data once assembled should be treated for relevance. The date of
approval by the validation team should also be noted.
[9]

The following points would give an insight to the basic elements of a protocol:
[9]
The manufacturing conditions, including operating parameters, processing limits, and
component (raw material) inputs.
The data to be collected and when and how it will be evaluated.
Tests to be performed (in-process, release, characterization) and acceptance criteria for
each significant processing step.
The sampling plan, including sampling points, number of samples, and the frequency of
sampling for each unit operation and attribute. The number of samples should be
adequate to provide sufficient statistical confidence of quality both within a batch and
between batches. The confidence level selected can be based on risk analysis as it relates
to the particular attribute under examination. Sampling during this stage should be more
extensive than is typical during routine production.
Criteria and process performance indicators that allow for a science- and risk-based
decision about the ability of the process to consistently produce quality products. The
criteria should include:
A description of the statistical methods to be used in analysing all collected data (e.g.,
statistical metrics defining both intra-batch and inter-batch variability).
Provision for addressing deviations from expected conditions and handling of
nonconforming data. Data should not be excluded from further consideration in terms of
PPQ without a documented, science-based justification.
Design of facilities and the qualification of utilities and equipment, personnel training
and qualification, and verification of material sources (components and
container/closures), if not previously accomplished.
Status of the validation of analytical methods used in measuring the process, in-process
materials, and the product.
Review and approval of the protocol by appropriate departments and the quality unit.
KEY FEATURES
[10]
1) Equipment and Process


a) Equipment and Process: Installation Qualification (Document qualification,
Installation Qualification, Operational Qualification, Process Qualification)
b) Process: Process Qualification
c) Product: Product Qualification
2) System to ensure timely revalidation
3) Documentation
1) Equipment and Process :Equipment and Process should be designed and/or selected
so that product specification are consistently achieved. This should be done with
participation of all appropriate groups that are concerned with assuring a quality product.
Example: Engineering design, Production operations and Quality personnel.
a) Equipment:
Design Qualification: User requirements should be considered when deciding on the
specific design of a system or equipment. A suitable supplier should be selected for the
appropriate system or equipment (approved vendor) .
Installation Qualification: The study establishes confidence that the process equipment
and ancillary systems are capable of consistently operating with in the established limits
and tolerances. The phase of validation includes:
1)Examination of equipment design
2)Determinations of calibrations
3)Adjustment requirements
4)Maintenance
5)Identifying critical equipment features that could affect the process and product.
Operational Qualification: Systems and equipment should operate correctly and their
operation should be verified in accordance with an operational qualification
protocol.Crucial operating parameters should be identified. It should include verification
of all operation of all system elements, parts, services, controls and other components.
b) Process
Performance Qualification: The purpose of Performance Qualification is to provide
rigorous testing to demonstrate the effectiveness and reproducibility of the process.
understand what is required. Parts of the process which may vary so as to affect important
product quality should be challenged.


c) Product
Performance Qualification: Product Process Qualification activities apply only to
medical devices.
2) System to ensure timely revalidation
There should be a QA System in place which requires re-validation whenever there are
challenges in packing, formulation, equipment or process which could impact on product
effective characteristics and whenever there are changes in product characteristics.
The QA procedures should establish the circumstances under which re-validation is
required. The extent of re-validation will depend upon the nature of changes and how
they impact upon different aspects of production that had been previously validated.
c) Documentation
Documentation at each stage of the process validation lifecycle is essential for effective
communication in complex, lengthy, and multidisciplinary projects. Documentation is
important so that knowledge gained about a product and process is accessible and
comprehensible to others involved in each stage of the lifecycle. Information
transparency and accessibility are fundamental tenets of the scientific method. They are
also essential to enabling organizational units responsible and accountable for the process
to make informed, science-based decisions that ultimately support the release of a
product to commerce.
The degree and type of documentation required by CGMP vary during the validation
lifecycle. Documentation requirements are greatest during Stage 2, process qualification,
and Stage 3, continued process verification. Studies during these stages must conform to
CGMPs and must be approved by the quality unit in accordance with the regulations.
Viral and impurity clearance studies, even when performed at small scale, also require
quality unit oversight.
CGMP documents for commercial manufacturing (i.e., the initial commercial master
batch production and control record and supporting procedures are key outputs of Stage
1, process design. We recommend that firms diagram the process flow for the full-scale
process. Process flow diagrams should describe each unit operation, its placement in the
overall process, monitoring and control points, and the component, as well as other
processing material inputs (e.g., processing aids) and expected outputs (i.e., in-process


materials and finished product). It is also useful to generate and preserve process flow
diagrams of the various scales as the process design progresses to facilitate comparison
and decision making about their comparability.
VALIDATION: THE STRATIGEM
1) The first and foremost requirement is preparing a validation protocol. This would
include the procedure for operating validation.
2) The next comes the purpose of application and scope of the method, defining the
specified requirements and objectives.
3) This step contains the performance parameters along with the acceptance criteria. It
should be noted that each stage should begin when the previous is over.
4) The validation experiments should be defined.
5) The equipment to be used for the purpose should possess the desired performance
characteristics because the drug has to be manufactured in the equipment itself.
6) The raw materials to be used should meet the required standards that is the active drug
substance and excipients should be of good quality.
7) Pre-validation programs should be performed.
8) This step is critical as the critical process variables should be set within their upper and
lower critical limits during process operation. This would help in giving good outputs.
The underlying meaning is that adjusting method parameters (acceptance criteria) is
necessary.
9) SOPs or Standard operating procedures are must for executing the method in routine.
10) The basis for re-validation are meant to be explained.
11)The type and frequency of system suitability tests and/or analytical quality control
(AQC) should be routinely checked. If the requirements of the validation protocol are not
met with respect to process input and output, the process should be subjected to re-
validation following an insight or analysis of data. This should further be followed by a
co-ordinated formal discussion by the validation team.
12) Lastly the results are to be tabulated in the validation report.
VALIDATION SUMMARY REPORTS
Validation Summary Reports provide an overview of the entire validation project.
Once the summary report is signed, the validation project is considered to be complete.


When regulatory auditors review validation projects, they typically begin by reviewing
the summary report. The document should also contain a formal release statement to
allow the system to be used for regulated work.The validation summary report should
include:
A description of the validation project
All test cases performed, including if those test cases passed without issue
All deviations reported, including how those deviations were resolved
Reference to protocol
The details of material and equipment used
Evaluation, including comparison with the acceptance criteria and
recommendations (including frequency of revalidation/requalification)
Certification (approval)
If applicable, preparation of an abbreviated version of the validation report for
external use, for example by the regulatory authority
The validation protocol and report may also include copies of the product stability
report or a summary of it, validation documentation on cleaning, and analytical
methods.
[11,12]

CONCLUSION
The validation summary report brings together all of the documentation collected
throughout the whole of the life cycle. It gives a recommendation for management
approval when the system is validated. The validation report should document detailed
results of the validation effort, including test results. Whenever possible, test results
should be expressed in quantified terms rather than stated as pass/fail. The report
should be reviewed and approved by designated management.
13
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Italy, 1989, Vol. 15, No. 6-7: 1047-1058.
2. www.wikipedia.org/wiki/Validation (drug manufacture) , Dated: 20/09/2011.
3. www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM255585.
4. Herbert LA, Leon L, Joseph SB: Pharmaceutical Dosage Forms Tablets, 2
nd
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New York, Marcel Dekker, Inc: 417-447.


5. Good manufacturing practices for pharmaceutical products: In: WHO Expert
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nd
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World Health Organization, 1992:14-79 (WHO Technical Report Series, No.
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6. Validation of analytical procedures used in the examination of pharmaceutical
materials: In: WHO Expert Committee on Specifications for Pharmaceutical
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th
report, Geneva,
World Health Organization, 2003, 113-139 (WHO Technical Report Series, No.
908).
8. Neal C: Prerequisites for successful validation, J Validation Technique, 2003, 9:
240-244.
9. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM070336.
10. A WHO guide to good manufacturing practice (GMP) requirements: Part 2,
Validation, Geneva, Global Programme for Vaccines and Immunization:Vacccine
Supply and Quality: Global Training Network, WHO 1997, 139-165.
11. FDA 483, Warning letter, Abraxis Bioscience, Inc, 11777 San Vincente Blvd,
Suite 550, Los angeles, CA 90049, 18/12/2006.
12. FDA 483, Warning letter, Sanofi Pasteur, Inc Discovery DriveSwiftwater,
Pennsylvania 18370, 20/06/2006.
13. www.google.co.in/url, pharmaceutical validation report, pharmaceutical
manufacturing.wordpress.com.

For Correspondence:
Kashyap Ankita
Email: [email protected]

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Vol - 4, Issue - 3, Supl - 1 Apr-Jul 2013 ISSN: 0976-7908 Kashyap et al

www.pharmasm.com IC Value 4.01 351

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