Validation requirements


Validation requirements of who gmp guidelines: Qualifying existing equipment and planning for validation

VALIDATION is, perhaps, one of the least understood aspects of WHO GMP but is fundamental to the production of quality pharmaceuticals.

There must be two big questions queuing up :

What is meant by validation? And, the next, bigger question,
Why to do it?

Why to do it?


The main advantages to be obtained from validation are assurance of quality and process optimization, both resulting in a reduction of total costs.

There is a more compelling reason:

Validation of pharmaceutical processes is a Regulatory Requirement under all regulatory guidelines .
Also, the emphasis placed on validation by the international regulatory agencies is high…. For instance, the USFDA treats products made using a non – validated process as adulterated.
§ 210.1 Status of current good manufacturing practice regulations.

Let us look at what the who gmp demands! who gmp requirements

26.1. Validation studies shall be an essential part of Good Manufacturing Practices and shall be conducted as per the pre-defined protocols. These shall include validation of processing, testing and cleaning procedures.

26.3. Processes and procedures shall be established on the basis of validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Critical processes shall be validated, prospectively or retrospectively.

26.4. When any new Master Formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified shall be demonstrated to yield a product consistently of the required quality.

26.5. Significant changes to the manufacturing process, including any change in equipment or materials that may affect product quality and/or the reproducibility of the process, shall be validated.

So let us provide Validation the attention it demands and deserves.

Let us start from the basics. These are the three basic principles of Quality Assurance:

Quality, safety and effectiveness must be designed and built into the product.

Quality cannot be inspected or tested into the finished product.and

Each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications, i.e. the process is in a state of control.

Validation of processes and systems is fundamental to achieving these goals.

But what is exactly meant by validation?

The US FDA defines process validation as:

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 attributes.

But this not the only definition of Validation.

There are a number of definitions of validation – all of which say the same thing in different ways.

For example,…..

The abridged WHO definition of the validation of manufacturing processes is:

“Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result”.

Their expanded definition is:

“The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensure that the manufacturing processes – including equipment, buildings, personnel and materials – are capable of achieving the intended results on a consistent and continuous basis”.

So, in short, Validation is the establishment of documented evidence that a system does what it is supposed to do.

There are three key points to be noted from these definitions:

1. The evidence must be documented i.e. the results of the validation must be recorded.

2. Validation applies to several aspects of manufacturing, including e.g. process development, materials, personnel and equipment and

3. It should demonstrate that the system does what is expected of it.

Validation is, therefore, always carried out against a set of criteria that are defined in advance.

These criteria are detailed in pre-defined protocol documents.

A successful Qualification / Validation exercise is one in which all the claims (Acceptance Criteria) in the individual protocols were fulfilled completely.

So now that we have defined Validation, let us proceed to the next term- Qualification!

Many a people confuse the two terms and use one for the other.

Qualification or validation?

The “system” is the complete set of equipment needed to carry out a specific process.

A system must be qualified to operate in a validated process. Qualification is part of validation.

You qualify a system e.g. autoclave, freeze dryer, Homogeniser, CIP system, clean room and water treatment. and

You validate a process e.g. sterilisation, freeze drying, mixing, cleaning, filling.

There are different stages of qualification.

Design qualification (DQ)
Installation qualification (IQ )
Operational qualification (OQ)
Performance qualification (PQ

These stages are generally applied to projects such as premises, equipment and supporting systems such as water supply systems, Heating, Ventilation and Air Conditioning (HVAC) and other systems.

Design qualification (DQ) is the process of completing and documenting design reviews to illustrate that all quality aspects have been fully considered at the design stage. The purpose is to ensure that all the requirements for the final systems have been clearly defined at the start. In other words, has it been designed and selected correctly?

Installation qualification (IQ) is the process of checking the installation, to ensure that the components meet the approved specification and are installed correctly, and to see how that information is recorded. The purpose is to ensure that all aspects (static attributes) of the facility or equipment are installed correctly and comply with the original design. In other words, has it been built or installed correctly?

Operational qualification (OQ) is the process of testing to ensure that the individual and combined systems function to meet agreed performance criteria and to check how the result of testing is recorded. The purpose is to ensure that all the dynamic attributes comply with the original design. In other words, does it work correctly?

Performance qualification (PQ), also called process qualification, is the process of testing to ensure that the individual and combined systems function to meet agreed performance criteria on a consistent basis and to check how the result of testing is recorded. The purpose is to ensure that the criteria specified can be achieved on a reliable basis over a period of time. In other words, does it produce the product correctly?

Priorities for Process Validation

Type of process Requirement

– Every new process before approval for routine manufacture

Sterile products :All processes affecting the sterility, and manufacturing environment including sterilization stage

Non-sterile Low dose tablets and capsules: mixing and granulation; content uniformity (and other parameters)

Other tablets and capsules: uniformity of mass (and other parameters)

There are different types of documents related to validation:

Master plans,
Reports and

Each manufacturer should have a validation master plan (VMP).

The validation master plan should typically include at least the following sections:
Approval page and table of contents.
Introduction and objectives.
Facility and process description.
Personnel, planning and scheduling.
Responsibilities of committee members.
Process control aspects.
Equipment, apparatus, processes and systems to be validated.
Acceptance criteria.
Documentation e.g. validation protocols and reports.
Training requirements.

The Validation protocols (VP) are essentially question papers and model answer papers.

Q It is a detailed document relating to a specific part of the validation process e.g. the OQ for a manufacturing vessel.
Q It outlines the tests that are to be carried out, the acceptance criteria and the information that must be recorded.
Q It also defines the approval process for the validation.
Q The protocol should clearly describe the procedure to be followed for performing validation.
Q It should include at least the objectives of the validation and qualification study, the site of the study, the responsible personnel, a description of the equipment to be used (including calibration before and after validation), SOPs to be followed (e.g. the operation and cleaning of the equipment) and the standards and criteria for the relevant products and processes.
Q The type of validation and time/frequency should also be stated.
Q The processes and/or parameters to be validated (e.g. mixing times, drying temperatures, particle size, drying times, physical characteristics, content uniformity, etc.) should be clearly identified.

You will recall the definition of Validation:
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 attributes.

Validation Reports (VR) are obviously a compilation of all the answers to the tests.

The results obtained during the performance of the validation, must be recorded.
The validation report reflects the final test results and other documents such as instrument calibration certificates.
It is on the basis of this report that the decision is taken on whether a particular process is judged to be validated.
During the inspection, you must assess whether there is a written report reflecting the results after completion of the validation.
The results should have been evaluated, analyzed and compared with acceptance criteria by the responsible personnel.
All results should meet the criteria of acceptance and satisfy the stated objective. If necessary, further studies should have been performed.
If the results were found to be acceptable, the report should been approved and authorized (signed and dated).
The report should include the title and objective of the study, and refer to the protocol, details of material, equipment, programs and cycles used, together with details of procedures and test methods.
It should provide a comparison of the results with the acceptance criteria.

In addition, it should include recommendations on the limits and criteria to be applied to all future production batches.
It is common practice in many companies for the protocol and the report to be combined into a single set of documents.
The protocol is approved as a form on which the test results are recorded as they become available.
This reduces the amount of paperwork that needs to be stored and makes an overall assessment of the validation results easier to carry out.

Standard Operating Procedures (SOPs) are approved written procedures describing operations, testing, sampling, interpretation of results and corrective actions that relate to the operations that are taking place in a controlled environment.
Documentation Requirements for compliance with who gmp guidelines
DOCUMENTATION is CRITICAL area reflecting SYSTEMS of the COMPANY that are followed and hence effective DOCUMENTATION proves VARIOUS CERTIFICATIONS.



To define Location & surrounding a detailed Site Master File (SMF) should be prepared which should define location of the factory with details such as adjacent factories / area on all the four poles viz. North, South, East and West, connectivity to nearest major city, address & communication facility.

The SMF should also contain information on Building and Premises with details such as plot area and built-up area, orderly & logical placement of equipment and systems to avoid mix-up, contamination & cross contamination, civil design of the factory, cleaning & painting frequency.

To define Water system a Water system manual is advisable which should define equipments, schematic of water system depicting user points & purposes, sampling points & testing frequencies, water system validation policy.

Standard Operating Procedure (SOP) for disposal of Waste should define types of effluents generated, Precautions & segregation.

In the Warehousing Area SOP’s should be available for environmental monitoring, Receipt, warehousing and dispensing of materials (RM/PM/Engg. Spares), Sampling & precautions to avoid mix-up, contamination & cross contamination, Reject material handling, Rodent control.

For Production Area general SOP’s advisable are for Man & material flow, Environmental monitoring & controls.

For Ancillary Areas SOP’s for Personnel Hygiene Instructions, Cleaning & Disinfection of areas, Transfer of spares to production are essential.

Department manual for Quality Control Area should be prepared which should define Separate areas viz. physico-chemical, microbiological, instrumentation areas, Separate Air Handling Units for microbiological area.

Department manual for Administration Dept. should define Recruitment policy considering qualification & experience, No. of persons adequacy to workload, Written duties of technical staff, Training policy. The manual should also define Pre and ongoing Medical Examination Policy, Illness reporting system, Control on transfers of eatables, Gowning policy.

The Department manual for Production should be prepared and should contain details such as Control of critical manufacturing steps by approved staff, Maintenance schedule of AHU for β Lactam Areas, Department cleaning schedule, Environmental control, In-process, reprocessing, reject material handling, Printing & overprinting controls.

The department should have SOP’s for Status labeling, Line clearance sanitation in the manufacturing premises.

In the Stores SOP’s for Inventory management of Raw Materials, Receipt, storage & issue of materials, Labeling policy – Under Test, approved, rejected, sampled should be available.

The Department Manual for Production should define following for Production equipment Non reactive contact parts, Grade of lubricants used and different Log books available.

The Department Manual for QA should define Authorised persons list for document approval, Documentation change control.

The Department Manual of Stores should also include Labeling policy, Receipt, storage & issue, Rejected material handling
Receipt Records.

The Department Manual for Quality Assurance should be prepared with details such as GMP / GLP Practices, Controls on starting materials, intermediates & bulk products, Calibration and Validation policies.

The manual should also contain details on Internal Audit Team, Audit procedure, Frequency.

The Quality Control Department should have SOP’s for Sampling, Inspecting & testing of RM, PM, Intermediate & bulk finished products, Product Complaint handling, Stability Study, Instrument Calibration, Testing method validation.

The QC department should also have detailed Specifications for Raw Materials , Packing Materials and Finished Product.

Detailed Master Formula Records for each product & batch size should be available.

Authorised packaging instructions for each product, pack size &type should include Product Name, Dosage form, strength & composition, Pack size of final container in number / doses, weight / volume, List of PM including quantities, size, & type, code / ref. no. relating to PM specifications required for standard batch size, Specimens of PM.

The Batch Packaging Records should be available for each batch.

Based on master formula Batch Processing Records should be available for each product.

SOPs shall be available for Receipt of Materials, Sampling, Batch Numbering, Testing, Records of Analysis.

Reprocessing should be done as per SOP & Validation should be done. There should be Authorised SOP & records. Investigation &corrective action should be carried out. Stability evaluation should be made for the batch under question.

Validation of Processing, testing and cleaning procedures should be done. Reports summarising results & conclusions should be made available. Periodic revalidation should be done. Critical processes should be either prospectively or retrospectively validated. Significant changes in process, equipment or materials affecting product quality and / or process reproducibility should also be validated.

Recall system should be defined for timely information of stockists, wholesalers, suppliers, retailers using print or electronic media. Recall operations should be capable of being initiated promptly. Distribution records should be readily available to recall team. Recall record shall include reconciliation, Recall effectiveness should be evaluated from time to time.

Product Complaint should be carefully reviewed & recorded, Investigated / evaluated, Investigation record & remedial action should be recorded. Serious adverse reactions should be informed to licensing authority. SOP describing action to be taken, recall to be made for defective product.
Succinct Site Master File document containing specific & factual good manufacturing practice in pharmaceutical manufacturing-GMP at the premises should be available with details on factory and the quality systems that are followed.

Keep reading this blog for cGMP and WHO GMP requirements SOP Pharmaceutical Validations Master Manufacturing documents sample Change control procedure and format water purification system and its validations cleaning validations ,personnel hygiene and guidelines for gmp microbiological procedure SOPS and manufacturing procedures for pharmaceutical dosage forms Master validation plan sample copy and for your WHO GMP requirementsgood manufacturing practice guide for pharmaceuticals manufacturing
Quality assuarance guide for pharmaceuticals manufacturing
Q.A guide for pharma
Pharmaceuticals manufacturing guide
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