Thursday, September 23, 2010

Validation - The Essential Quality Assurance Tool For Pharma Industries

Validation - The Essential Quality Assurance Tool For Pharma Industries

Prof.S. Saraf

K. Dashora, D. Singh, Swarnlata Saraf and S. Saraf *.
Institute of Pharmacy, Pt.RavishankarShuklaUniversity, Raipur 492 010.
*Author for correspondence (e-mail:

Quality is always an imperative prerequisite when we consider any product. It becomes prime when it relates to life saving products like pharmaceuticals. Although it is mandatory from the government and regulatory bodies but it is also a fact that quality of a pharmaceutical product can not be adequately controlled solely by pharmacopoeial analysis of the final product. Today quality has to be built in to the product right from its inception and rigorous international environmental, safety and regulatory standards need to be followed. Validation had proven to be an important tool for quality management of pharmaceuticals. According to ISO 9000:2000

Validation is defined as "Confirmation, through the provision of objective evidence, that the requirements for a specific intended use or application have been fulfilled". In contrast with Verification, Validation rather focuses on the question whether a system can perform its desired functions. This review is an attempt to prove the it as essential tool for quality management in pharmaceutical industry.


Validation is a concept that has been evolving continuously since its first formal appearance in United States in 1978. The concept of validation has expanded through the years to encompass a wide range of activities from analytical methods used for the quality control of drug substances and products to computerized system for clinical trial, labeling or process control.1

Validation is the overall expression for a sequence of activities in order to demonstrate and document that a specific product can be reliably manufactured by the designed processes, usually, depending on the complexity of today’s pharmaceutical products, the manufacturer must ensure; "that products will be consistently of a quality appropriate to their intended use”. 2

To achieve this with confidence, only in process control and finished product testing alone are not sufficient to assure product quality; but all factors including the services which could affect product quality must be correctly designed, demonstrated to work effectively. Consistently and their performance is also regularly conformed so that consistent quality product is obtained. For example, no sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are infect sterile .

In recent year many manufacture houses have attempted to define their philosophy and strategy for self inspecting their plants for manufacturing ,processing and packing ,including holding of drugs .As much these manufacturers are interpreting the GMP guidelines as evaluated by Food and drug Authority and the schedule M after due modification in 1988.3

A philosophy of performing systematic inspection has worked and may be termed “Drug in- process inspection and validation”. The compliance to their working rules defines a validated manufacturing process as “one has been proven to do what it purport or it represented to do. The proof of validation is obtained through the collection and evaluation of data, preferably beginning from the process development phase and continuing through in to the product phase. Validation necessarily includes process qualification such as materials, equipment, system, building and personnel, but it also includes the control of the entire process for repeated batches or runs.

The word “validation” simply means assessment of validity or action of proving effectiveness. According to European community for medicinal products, validation is action of proving in accordance with the principals of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.

Validation is a proof that a process works and this must be done using scientific and statically principles. This is done to establish process capability and to confirm product acceptability.4 Validation determined process variables and the acceptable limits for these variables and accordingly sets up appropriate in process controls, which specifies alert and action levels.5


Conducting process validation is not only a regulatory requirement, but also makes a great deal of sense from engineering as well as a business point of view .It is evident that pharmaceutical companies that are well versed in conducting process validation have a competitive advantage over those who are not6. Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practices regulations for finished pharmaceuticals, 21 CFR parts 210 and 2117,8 . A requirement for process validation is set forth in general terms in sections 211.100 written procedures; deviations–which states, in parts; “there shall be written procedures for production and process control designed to assure that the drug products have the identity , strength, quality, and purity they purport or are represented to posses”. Several sections of cGMP regulations states, validation requirement in more specific terms. Excerpts from some of the sections are:-section 211,100, sampling and testing of in –process materials and drug products.

a ) “------------- Control procedures shall be established to monitor the output and validate the performance of those manufacturing process that may be responsible for causing variability in the characteristics of in process material and drug products.”

Section 211, 113, control of microbiological contamination

b) “------------- Appropriate written procedures, design to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”

The requirement of process validation is implicit in the language of schedule M, Good manufacturing practices regulation which states “To achieve the objective, each licensee shall evolve methodology and procedure which should be documented and kept for reference and inspection”.

Process validation is required by the medical device GMP regulation,21 CFR part 820.Section 820.5 requires every finished device manufacturer to states: “……………….. Prepared and implement a quality assurance program that is appropriate to the specific device manufactured……………….”

Section 820.3 states: “………………….All activities necessary to verify confidence in the quality of the process used to manufacture a finished device…………”

A generally stated requirement for process validation is contained in section 820.100, states:

“Written manufacturing specification and processing procedure shall be established, implemented, and controlled to assure that device conforms to its original design or any approved changes in that design”. Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specification.

Section 820.100(a) (1), states: “Control measures shall be established to assure that the designed basis for device, components and packaging is correctly translated in to approved specification” 9.

{mospagebreak title=Importance and Scope Of Validation}


The most compelling reasons to optimize and validate pharmaceutical productions and supporting processes are quality assurance and cost reduction .the basic principles of quality assurance has as their goal and the production of articles that are fit for there intended use.10 These principles are Quality, safety, and effectiveness must be designed and built in to the product, quality cannot be inspected or tested in the finished products and each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specification. The relationship of quality assurance and process validation goes well beyond the responsibility of any quality assurance functions, nevertheless it is fair to say that process validation is a quality assurance tool because it is establishes a quality standard for the specific process.

Quality control is the part of GMP, it is concerned with the sampling specification, testing and with organization documentation and release procedures.11,12 Where as assurance of quality is derived from careful attention to a number of factors including selection of quality materials, equipments, adequate product, process design ,selection of approved vendors, proper GMP inspections , employee training ,technical audit, critical evaluation of market complaints, in-process control of processes, and end product testing.13-20

Process validation should result in fewer product recalls and trouble shooting .process consistently under control requires less process support, will have less down time, fewer batch failures , and may operate more efficiently with greater output .In addition timely and appropriate validation improves quality assurance ,reduces cost by process optimization ,enables more effective and rapid trouble shooting ,shortens lead time leading to low inventories ,empowers all employees to control their processes and to improve them ,enables better system control ,maintains, and improves a high degree of assurance that specific process will consistently produce a product meetings its predetermined specifications and quality characteristics 21,22.


Following are the area were validation can be implied : Analytical test methods, Instrument calibration, Process utility services, Raw materials, Packaging materials, Facilities, Manufacturing, Product design, Cleaning and Operators. 23-26


The activities relating to validation studies are classified into three phases.

Phase 1:

Pre-validation phase or the qualification phase ,which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage form, equipment qualification ,installation qualification, master production documents, operational qualification, process capability.

Phase 2:

Process validation phase (process qualification phase) designed to verify that all established of the critical process parameters are valid and that satisfactory products can be produced even under the worst case conditions.

Phase 3:

Validation maintenance phase requiring frequent review of all process related documents ,including validation audit report to assure that there have been no changes ,deviations, failures modification to production process, and that all SOP’s have been followed including change control procedures. At this stage the validation team also assures that there have been no changes /deviations that should have resulted in requalification and revalidation.


It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (prospective validation). Where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes which have been in use for some time without any significant changes may also b validated according to an approved protocol (retrospective validation) 27,28.

Prospective validation:

In prospective validation, the validation protocol is executed before the process is put in to commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical consideration to determine the critical parameters that may affect the quality of finished product. A series of experiment should be design to determine criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol.

All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specification and environment conditions have been determined. By using this defined process a series of batches should be produced. In theory, the number of the process runs carried out and observations made should be sufficient to allow the normal extent variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs with in the final agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate these data.

Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipments and facilities dedicated of commercial production, operating range of critical process, and a thorough analysis of the process data in case of requalification and revalidation 29,30.

During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detail testing should also be done on the final product in its package.

Upon completion of the review, recommendation should be made on the extent of monitoring and the in-process control necessary for routine production. These should be incorporated into the batch manufacturing record and packaging record or appropriate standard operating procedures. Limits, frequencies and action to be taken in the even to the limits being exceeded should be specified.

Concurrent validation:

In using this approach there is the always the risk of having to modify process parameters or specifications over a period of time .this situation often leads to question regarding disposition of the batches that had already been released for the sale, subsequently known to have undesired quality characteristics.

Concurrent validation may be the practical approach under some circumstance. Example:

· When a previously validated process is being transferred to a third party contract manufacturer or to another manufacturing unit.

· Where the product is different strength of a previously validated product with the same ratio of active/inactive ingredients.

· When the number of lots evaluated under the retrospective validation were not sufficient to obtain a high degree assurance demonstrating that the process is fully under control.

· When the number of batches produced are limited.

It is important in these cases however, that the system and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by validation team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considerable acceptable that a minimum of three consecutive batches within the finally agreed parameters giving the product the desired quality would constitute a proper validation of the process.

Retrospective validation:

In many establishments, processes that are stable and in routine use have not under gone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated.

The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation.

Retrospective validation is only acceptable for well established detailed process and will be inappropriate where there have been recent changes in the formation of the product, operating procedures, equipments and facility.

The source of data for retrospective validation should include amongst others, batch documents, process control charts ,maintenance log book, process capability studies, finished product test results, including trend analysis, and stability results.

For the purpose of retrospective validation studies, it is considered acceptable that data for a minimum ten consecutive batches produced be utilized. When the less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospective that the process is fully in control .In such cases the study should be supplemented with concurrent or prospective validation.

Some of the essential elements for retrospective validation are:

  • Batches manufactured for a defined period (minimum of last ten consecutive batches)
  • Number of lots released per year.
  • Batch size /strength /manufacturer /year /period.
  • Master manufacturing/packaging documents.
  • Current specification for active materials/finished products.
  • List of process deviation, corrective actions and changes to manufacturing documents.
  • Data for stability testing for several batches.
  • Trend analysis including those for quality related complaints.

Process Revalidation

Revalidation provides the evidence that change in a process and /or the process environments that are introduced do not adversely affect the process characteristics and product quality. Documentation requirement will be the same as for the initial validation of the process.

Revalidation becomes necessary in certain situations .Some of the changes that require revalidation are as follows.

  • Changes in raw materials properties such as density, viscosity, particle size distribution, moisture, etc. that may affect the process of product.
  • Changes in the sources of active raw material manufacturer.
  • Changes in packing material (primary container/closure system).
  • Changes in the process (such as mixing time, drying temperature, and batch size).
  • Changes in the equipment (e.g. addition of automatic detection system).Changes of equipment which involves the replacement of equipment on a “like for like ’’basis would not requires are validation except that this new equipment must be qualified.
  • Changes in the plant /facility.


All changes must be formally requested documented and accepted by the validation team .The likely impact/risk of the change on the product must assess and the need for the extent of revalidation should be determined .

Commitment of the company to control all change to premises, supporting utilities, system, materials, equipment and process used in the fabrication/packaging of pharmaceutical dosage forms essential to ensure a continued validation status of the system concerned.

The change control system should ensure that all notified or requested changes are satisfactory investigated, documented and authorized. Products made by process subjected to changes should not be released for sale without full awareness and consideration of the changes by the validation team. The team should decide if a. revalidation must be conducted prior to implementation of the proposed change.


The FDA’s guideline defines validation as:

“Establishing documented evidence, which provide a high degree of assurance that a specific process will consistently produce a product meeting with its pre-determined specifications and quality characteristics”.

The development of validation documentation is an essential part of any successful validation programmed or study. The documentation should be concise, unambiguous, detailed, and thorough31,32.

Table 1: Components of a good validation document.

Good validation documentation

A written historical perspective of what was manufactured, filled, cleaned, packaged, how it was done, and which controls were in place.

A way to minimize mistakes and variables.

Provide evidence that “something happened” how, when, and by whom.

Everything you wanted to know but were afraid to ask, written history of product, its components, equipment, and its process before product introduction to market.

Compliance to GMP requirement and ensure reproducibility

Validation takes place within following areas: New : Formula/product, process, procedures, manufacturing, packaging, Changes in : Processing procedures, manufacturing, packaging, cleaning, equipment, computer system and infrastructure and Failures : Revalidation.Within these area, the validation documentation requirements will depend on complexity of the process, project scope, GMP risk (it increases with the complexity of the system), and GAP analysis (define the strategies for achieving goals, identify the weakness).

Key Validation Documents

· Validation master plan (VMP).

·Validation protocols: Installation qualification (IQ), Operational qualification (OQ), Performance qualification (PQ), Computer systems, Facility/utility/equipment qualification protocols, process, packaging, and cleaning.

· Standard operating procedures.

·Optimization batch guidelines.

· Validation reports.

· Change control system 31,33,34.

Importance of the VMP:

The VMP describes clearly and concisely the company’s philosophy, expectations and approach to be followed. It identifies the systems and controls to be validated and the level of testing required. It covers all aspects of the project as equipment qualification, training, maintenance, and change control. It should be developed in the early stages of a project and allow a logical progression from plan to validation schedule. The VMP can also assist in monitoring and tracking the progress of the project by performing periodic audit reviews v/s the approved version of the VMP 31.

Contents of typical VMP:

Following are the contents of VMP : Introduction, Purpose, Scope, Overview /Description of system to be validated, Responsibilities, Validation methodology, Acceptance criteria, Validation report, Change control, Validation project milestone, Deliverables.

Benefits of VMP:

A VMP is created when the project is complex, include high risk ,and when more extensive and thoroughly verification and system review are required. If study is simple involving only one validation study /variables, a validation protocols may be used instead. The benefits of VMP includes, i) It provides the total pictures of the project. ii) It is a management tool for tracking progress. iii) Assignment of responsibility, which promote team work. iv) It identifies acceptance criteria before the start of validation.

The Validation protocol for process, packaging, and cleaning:

The Validation protocol for process, packaging, and cleaning studies is a written plan stating how validation will be conducted including purpose, scope overview/description of system to be validated, responsibilities, validation methodology, acceptance criteria, validation report, change control, required SOPs and decision points on what constitutes acceptable test results.

Format for validation protocol:

·Cover page (approvals)

·Scope of project (which process being validated)

·Objectives /backgrounds


· Installation qualification (IQ), Operational qualification (OQ), Performance qualification (PQ)

· Role and responsibilities.

· SOP’s requirement.

· Process monitoring.

· Sampling and testing.

· Process monitoring.

· Acceptance criteria /test methods.

· Deliverables.

· Documentation requirement

· Additional information-

§ A flow chart of the process

§ Sampling methods to be used

§ In process samples to be collected and details of collection

§ Testing to be conducted on samples collected

§ Sample size ,type of container, and swab techniques

§ Tools and precautions 31,33.

Equipment /Facility /Utility qualification protocols:

The qualification protocols are a very important document of the protocol process. The complexity of the equipment, facility, utility systems, involved and their relationship to the quality of the product dictate the scope ,details, and contents of the qualification protocol. The major component of the qualification protocols are 1,35.

  • Installation qualification (IQ):

Document that the equipment is properly installed according to the manufacturer and purchaser’s specifications. It covers equipment /system descriptions, which includes principle of operation, design requirements, equipment specifications piping, instruments diagrams, facility functional specifications, equipment utility requirements, and equipment safety features.

  • Operational qualification (OQ):

Document that the equipment operates within established limits and tolerances. It covers equipment operation procedures established and challenged equipment control functions, calibration requirements and schedules established, and maintenance requirements.

  • Performance qualification (PQ):

Document, which the equipment can operate reliably as intended for the process under routine, minimum, and maximum operating ranges.

  • Facility /Utility qualification: 31

It involves installation, operation and performance qualification of the building and the equipment. It covers -

  • Plant layout /construction. it includes material flow ,air locks, structure and finishing ,fire safety /alarm system ,manufacturing rooms ,and ware house.
  • Utilities and services. . it includes potable water, cooling water, drainage, plant system, purified water system, compressed air , heating ventilation air conditioning (HVAC) systems.


· Purpose.

· Scope.

· Equipment description includes master list of equipment requiring installation qualification/operational qualification.

· Role and responsibilities.

· Definitions.

· Qualification criteria for IQ methodology/execution, OQ methodology/execution, PQ methodology.

· Deviation reports.

· Acceptance criteria.

· SOP requirements.

· Executive summary report.

· Change control.

· Deliverables.

· Attachments: Raw data sheets, test results, preventive maintenance schedules, test incidence reports, and equipment calibration certifications.

Validation reports:

It summarizes the results, disposition, conclusions, and recommendations of the validation study relative to the protocol / VMP. The main components of the report are as follows 31:

· Cover page.

· Over view.

· Product name.

· Description of the process being validated.

· Location.

· Number of batches being validated.

· Validation study plan.

· Scope.

· Results.

· Discussion.

· Recommendations.

· Conclusion.

· Change control.


The quality assurance of pharmaceutical product involves a number of factors. The complexity of modern day medical products requires more than the routine end product testing, as the end product testing is not sufficient to assure quality of finished product.

The review highlights various aspects on process elements, regulatory requirements, and validation documentation that are considered by regulatory agencies. The particular requirement of process validation will vary according to the nature of the pharmaceutical product and type of process. The broad concepts stated in this review have general applicability and provide an acceptable framework for building a comprehensive approach for the validation.


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