PHARMACEUTICAL
VALIDATION
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VALIDATION
The U.S FDA defines Process Validation as, “It is an
establishing documented evidence which provides a
high degree of assurance that a specific process will
consistently produce a product meeting its predetermined
specifications
and
quality
characteristics.”
validation is documented act of proving that any
procedure , process, equipment, material, activity or
system actually leads to the expected result.
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NEED FOR
VALIDATION
Validation is required to meet the following requirementsAssurance of consistency of process
Government regulation
Process optimization
Economic considerations and cost reduction
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Scope of validation
Analytical test methods
Instrument calibration
Process utility services
Raw materials
Packaging materials
Equipments
Facilities
Manufacturing operations
Product design
Cleaning
Operators
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Importance of validation
Reduction of quality cost
quality cost consists of
a. Preventive cost – cost incurred in order to prevent
failures or to reduce the appraisal cost e. g. Quality
planning, training, SOPs, calibration, sanitation
b. Appraisal cost- are costs incurred for inspection, testing,
and quality evaluation
E. g. Testing of raw materials, in process materials, and
finished products.
1.
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Internal failure cost – costs associated with a non
conforming materials- materials that does not meet
quality standards required. – still in the possession of
company.
e.g. – rejects, reworks, retests, wastages, substandard
materials.
a. External failure cost - Cost associated with a non
conformance conditions after the product has left the
company’s ownership.
e.g. recalls, complaints, returns due to quality related
problems.
a.
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2.Proces optimization
Useful to make process effective, efficient, perfect, useful as
possible at the minimum cost.
Trained, qualified people are a key element in process and
have greatest impact on improving efficiency and
productivity.
3.Assurance of quality
It is an extension of quality assurance, since close control of
the process is necessary to assure the product quality.
Without validated and controlled processes, it is impossible
to produce quality product consistently.
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4. Safety
Validation can result in increased safety.
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Advantages of Validation
Reduces the risk of regulatory non compliance
May result in reducing time to market for new
products
Reduces the chances of product recall from the
market
Eliminate the scrap and reduces defect cost
Make process better understood
May require less in process control and end product
testing
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Limitations
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Validation means synonymously we think it as “perfect”
but it is wrong.
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If something is perfect means no scope for improvement.
But in practical nothing is perfect.
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Nothing is perfect and validation is just close adaptation
to existing environment but environment continuously
changes so this adaptation means validation also changes.
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Validation also has practical limit and related cost.
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STAGES OF VALIDATION
Validation is preceded by a pre-approval inspection program. During
the pre-approval inspection the FDA accepts the process
validation protocol based on the company’s commitment to
successfully complete three production-size validation batches
prior to product launch. In some cases a prevalidation (process
demonstration qualification) production-size batch is completed
before the entire formal three-batch program is carried out.
Following the approval of the validation protocol by the FDA, the
actual process validation is carried out.
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The stages of validation can be summarized as follows1.
Stage I: Product design and development including
the preliminary step of Preformulation studies.
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Stage II: Preparation of clinical and biobatches
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Stage III: Process scale-up and evaluation
4.
Stage IV: Formal process validation
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STAGES OF VALIDATION
Preformulation studies:
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Preformulation studies must be included as a preliminary
step in the product and process development stage. The
important preformulation studies to be carried on for
Active Pharmaceutical Ingredients i.e. API’s are as followsColor, odor, taste, solubility
Particle morphology ( DSC, TGA, X-ray diffraction)
Particle size distribution and surface area
Crystal and bulk density, compaction index
Angle of repose and flowability index
Spectrophotometry
Water content, LOD, moisture uptake
Microbial limits and heavy metals
HPLC assay and impurity profile
STAGES OF VALIDATION
Stage I: Product design and DevelopmentFollowing successful preformulation studies, the API is
transferred to the formulations laboratory for preliminary
product design and development studies.
In most cases the drug is mixed with the suitable diluent,
binder and glidant combination and filled in a suitable two
piece opaque hard gelatin capsules for preliminary
actability and phase I clinical studies.
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This is followed by prototype tablet dosage form
studies including the following Direct compression versus wet granulation
 Maximization of chemical and physical stability
 Minimization of product and process costs
 Product characterization
 Product selection and product design
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STAGES OF VALIDATION
Stage II Preparation of clinical and biobatches-
This represents the process development stage after
the drug has been determined to be physically and
chemically stable based upon accelerated, elevated
temperature testing.
It includes scaling up of the product and the process
to 10x pilot laboratory size batches.
According to the FDA, the minimum requirement for
a biobatch is 100,000 units.
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The scope of the stage II process development is as
follows Process
optimization
 Determination
of critical processes and critical
process variables
 Maintenance
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of product stability
STAGES OF VALIDATION
Stage III: Process scale up and evaluation
This includes the scaling up of the process to the magnitude of
100x.
This is the full scale production batch also called as pilot batch.
This is carried on for further process optimization and to
evaluate the critical process parameters.
Many companies directly proceed to the three batch formal
validation without stage III prevalidation work.
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STAGES OF VALIDATION
Stage IV: Formal process validation
The formal validation is carried out in accordance with the
protocol approved during the pre-approval inspection.
The primary objective is to establish process reproducibility
and consistency.
Whenever possible the formal validation should continue
through packaging and labeling operations so that the stability of
the product can be established and documented in the primary
container-closure system.
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TYPES OF VALIDATION
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Process Validation
Equipment Validation
Cleaning Validation
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Process validation options
The guidelines on general principles of process
validation mention four options:
Experimental Approach
Prospective validation
Concurrent validation
Analysis of historical data
Retrospective validation
Revalidation
Periodic Revalidation
Revalidation after change
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Prospective validation
This is carried out prior to the distribution of a new
product or an existing product made under a revised
manufacturing process where such revisions are likely to
affect the quality of the product.
This approach is a critical step analysis in which unit
operations are challenged to determine those critical
process variable that may affect the overall process
performance. This is done by using either ‘worst case
analysis’ or by ‘fractional-factorial design.’
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It is generally considered acceptable that three
batches within the finally agreed parameters would
constitute a validation of the process.
Batches made for the validation must be the same
size as the intended industrial scale batches.
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Prospective validation
Prospective validation must include the following:1. Short description of the process.
2. Summary of the critical processing steps to be investigated
3. List of the equipments to be used along with their
calibration status
4. Finished product specifications for release
5. List of analytical methods
6. Proposed in-process controls with acceptance criteria
7. Additional testing to be carried out
8. Sampling plan
9. Methods for recording and evaluating results
10.Functions and responsibilities
11.Proposed time-table
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Concurrent validation
In exceptional circumstances it may be acceptable not to
complete a validation program before routine production
starts.
The decision to carry out concurrent validation must be
justified, documented
and
approved
by
authorized
personnel.
Documentation requirements for concurrent validation are
the same as specified for prospective validation
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Retrospective validation
Retrospective validation is acceptable only for well established
processes and will be inappropriate for processes where
there have been recent changes in the product, operating
procedures or equipment.
Retrospective validation is based on historical data which has
its source in batch processing and packaging records, process
control records, maintenance log books finished product data
etc.
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Batches selected for the validation must be representative
of all the batches made during the review period,
including the batches that failed to meet the product
specifications
For retrospective validation generally the data from ten
to thirty batches is examined to assess process
consistency but fewer batches may be examined if
justified.
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Revalidation
Facilities, systems, equipment and processes including
cleaning must be evaluated periodically to confirm that they
remain valid.
Where significant change has been made in the process
and/or in the process environment, a review with evidence
that the facilities, systems, equipment and processes meet
the prescribed requirements fulfils the need for revalidation.
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The following conditions require revalidation Change in a critical component-active pharmaceutical
ingredient, key excipient or primary packaging.
 Change or replacement in a critical piece of
equipment.
 Significant changes in processing conditions.
 Change in facility and/or the plant.
 Significant increase or decrease in batch size
 Sequential batches that fail to meet the product in
process specifications.
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EQUIPMENT VALIDATION
Qualification is simple words is nothing but the validation of
individuals components or elements of a process.
Qualification of any element of the pharmaceutical process is
typically made up of the following components User
requirement specifications
 Design
specifications
 Installation
specifications
 Operation
specifications
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specifications
EQUIPMENT VALIDATION
User requirement specifications- (URS)
This includes a list of qualitative and quantitative expectations
that a user expects from a particular equipment.
Consider the example of a domestic water purifier. The URS
for it will include the following elements Name- Domestic water purifier.
 Objective- To improve the quality of water for domestic potable
water needs.
 Sizing- Amount of water required daily for drinking
 Method of water purification- Boiling, UV, Reverse Osmosis.
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EQUIPMENT VALIDATION
Design Qualification-(DQ)
This indicates the process of verifying and documenting that the
design of an equipment incorporates features that are in line with
the requirement of the process and the URS.
Design specification can also take the form of functional design
specification as in the case of more advances and critical industrial
equipments e.g. Industrial Autoclave.
The compliance of the design with the cGMP must be
demonstrated and documented.
E.g. In case of the water purifier the brochure specifies that the
design of the equipment consists of A charcoal filter
 A particulate filter
 A quartz tube
 A device to monitor the intensity.
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EQUIPMENT VALIDATION
Installation Qualification-(IQ)
This includes the procedures and documentation to show that
all important aspects of the installation of facility support system
meet the design specifications and that the vendor’s
recommendations regarding the installation have been
considered to ensure that the equipment operates consistently
and within established limits and tolerances.
E.g. In a water purifier the installation validation includes
assurance that The equipment is mounted correctly
 The water pressure is adequate
 The drain is connected/accessible to the sink
 The electricity is of correct amperage
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EQUIPMENT VALIDATION
Operation qualification- (OQ)
It is the done following the IQ and it is meant to show that the
facility , support system or the equipment perform as intended
throughout all anticipated operating ranges under a suitable load
and in accordance with the design specifications.
For e.g. When the water purifier is turned on, it should deliver
water. When the switch is turned off , it should stop delivering the
water. When the water supply is cut off, the error light should
glow and if the UV lamp is disconnected the alarm is activated.
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EQUIPMENT VALIDATION
Performance qualification:This consists of actual demonstrations during the course of the
validation program which show that the equipment performs
according to a predefined protocol and achieves process
reproducibility and product acceptability.
E.g.: For a water purifier Performance Qualification will include
the following Checking the visual clarity of the water.
 Checking that the taste of the water obtained is acceptable.
 Checking the microbiological quality of the water.
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THE VALIDATION COMMITTEE
1.
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The composition of the validation committee will depend
upon the component of the process being studied and
technical disciplines available.
In most companies the validation or Chemistry,
Manufacturing and Control (CMC) committee is
responsible for establishing and operating the complete
validation program for the specific manufacturing site.
In some companies the program is led by a validation
manager whereas in others, quality assurance personnel
have taken on expanded responsibilities in this regard.
Normally the following disciplines are involved in the
plant validation programQuality control- Chemical testing, Microbiology and
Quality assurance
Production
Engineering
Product development( Research and development)
VALIDATION MASTER PLAN
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f)
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g)
All validation activities must be planned. The key elements
of a validation program 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.
The VMP should contain the following data:Validation policy
Organizational structure of validation activities
Summary of facilities, systems, equipments and processes
to be validated
Documentation format: the format to be used for
protocols and reports
Planning and scheduling
Change control
Reference to existing documents.
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VALIDATION PROTOCOL
For E.g.: A Steam sterilization protocol should include the following items:
1.
An introduction defining the objectives of the validation study.
2.
Responsibilities of validation personnel and operating department
personnel
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Identification and description of the sterilizer and its process controls
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Identification of standard operating procedures for the process
equipment
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Description of and/or SOP for instrument calibration procedures
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Identification of calibration procedures for temperature monitoring
equipment (thermocouples, data loggers etc)
7.
A description of following studies to be conducted- Bioburden
determination, microbiological challenge, integrity testing of vent filter
membranes, container mapping studies, loaded chamber heat
penetration etc.
8.
Process parameter acceptance criteria
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VALIDATION REPORT
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Title
Objective of the study
Refer to the protocol
Details of the material
Equipments
Programs and cycles used
Details of Procedures and test methods
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Standard Operating Procedure
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Title
Prepared by
Checked by
Approved by
Date of preparation
Valid upto
Test/ Operating Procedures
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