PHARMACEUTICAL VALIDATION

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VALIDATION

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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 pre-determined 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.

NEED FOR VALIDATION

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Validation is required to meet the following requirements-Assurance of consistency of processGovernment regulationProcess optimizationEconomic considerations and cost reduction

Scope of validation

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Analytical test methods Instrument calibration Process utility services Raw materials Packaging materials Equipments Facilities Manufacturing operations Product design Cleaning Operators

Importance of validation

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1. Reduction of quality costquality 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.

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a. 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.

b. 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.

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2.Proces optimizationUseful 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 qualityIt 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. SafetyValidation can result in increased safety.

Advantages of Validation

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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

Limitations

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Validation means synonymously we think it as

“perfect” but it is wrong.

If something is perfect means no scope for

improvement. But in practical nothing is perfect.

Nothing is perfect and validation is just close

adaptation to existing environment but environment

continuously changes so this adaptation means

validation also changes.

Validation also has practical limit and related cost.

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. 11

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The stages of validation can be summarized

as follows-

1. Stage I: Product design and development

including the preliminary step of

Preformulation studies.

2. Stage II: Preparation of clinical and

biobatches

3. Stage III: Process scale-up and evaluation

4. Stage IV: Formal process validation

STAGES OF VALIDATION

Preformulation studies: 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 follows-

Color, 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

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STAGES OF VALIDATION

Stage I: Product design and Development-

Following 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. 14

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This is followed by prototype tablet dosage form studies including the following-

Direct compression versus wet granulationMaximization of chemical and physical

stabilityMinimization of product and process costsProduct characterizationProduct selection and product design

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.16

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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 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.18

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

Process validation options

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The guidelines on general principles of process validation mention four options:

Experimental ApproachProspective validationConcurrent validation

Analysis of historical dataRetrospective validation

RevalidationPeriodic RevalidationRevalidation after change

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.

Prospective validationProspective validation must include the following:-

1. Short description of the process.2. Summary of the critical processing steps to be

investigated3. List of the equipments to be used along with their

calibration status4. Finished product specifications for release5. List of analytical methods6. Proposed in-process controls with acceptance criteria7. Additional testing to be carried out8. Sampling plan9. Methods for recording and evaluating results10.Functions and responsibilities11.Proposed time-table

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Concurrent validationIn 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 validation25

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.26

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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.

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.28

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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

sizeSequential batches that fail to meet the

product in process specifications.

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

Performance specifications

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EQUIPMENT VALIDATIONUser 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 VALIDATIONDesign 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.32

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. 34

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 COMMITTEEThe 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 program-

1. Quality control- Chemical testing, Microbiology and Quality assurance

2. Production3. Engineering4. Product development( Research and

development)

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VALIDATION MASTER PLANAll 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:-

a) Validation policyb) Organizational structure of validation

activitiesc) Summary of facilities, systems, equipments

and processes to be validatedd) Documentation format: the format to be used

for protocols and reportse) Planning and schedulingf) Change controlg) 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 personnel3. Identification and description of the sterilizer and its

process controls 4. Identification of standard operating procedures for the

process equipment 5. Description of and/or SOP for instrument calibration

procedures6. 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 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 Title Prepared by Checked by Approved by Date of preparation Valid upto Test/ Operating Procedures

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