INTRODUCTION:

The prime objective of any pharmaceutical plant is to manufacture products of requisite attribute and quality consistently, at the lowest possible cost. Although validation studies have been conducted in the pharmaceutical industry for a long time, there is an ever increasing interest in validation owing to their industry’s greater emphasis in recent years on quality assurance program and is fundamental to an efficient production operation. ¹

Pharmaceutical Process Validation is the most important and recognized parameters of cGMPs. The requirements of process validation appear of the quality system (QS) regulation. The goal of a quality system is to consistently produce products that are fit for their intended use. Process validation is a key element in assuring that these principles and goals are met. The process validation is standardization of the validation documents that must be submitted with the submission file for marketing authorization. ²

Validation is a concept that has evolved in united states in 1978.The concept of validation has expanded through the years to embrace a wide range of activities from analytical methods used for the quality control of drug substances and drug products to computerized systems for clinical trials, labeling or process control, Validation is founded on, but not prescribed by regulatory requirements and is best viewed as an important and integral part of cGMP. ³

This principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished product inspection or testing each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications. ⁴

The development of a drug product is a lengthy process involving drug discovery, laboratory testing, animal studies, clinical trials and regulatory registration. Process controls include raw materials inspection, in process controls and targets for final product. The purpose is to monitor the online and off-line performance of the manufacturing process and then validate it. Even after the manufacturing process is validated, current good manufacturing practice also requires that a well-written procedure for process controls is established to monitor its performance .⁵

Validation mainly based on, FDA regulations describing current good manufacturing practice (cGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211. The cGMP regulations require that manufacturing processes be designed and controlled to assure that in process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. Process validation is required, in both general and specific terms, by the cGMP regulations in parts 210 and 211. ⁶

History of Validation:

The concept of validation was first proposed by two FDA officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals. It was proposed in direct response to several problems in the sterility of large volume parenteral market. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated process of pharmaceutical. ⁷

In 1976 the FDA proposed a whole set of current GMP regulations which were revised several times. In several major countries GMP regulations are considered official law and noncompliance is prosecutable. Additional compliance policies, guides and guidelines are not legally binding. However the pharmaceutical industry follows them as a part of good management and business practice .⁸

U.S.F.D.A. was the pioneer in advocating the concept of process validation, but till 29th September 1978 the definition of process validation did not appear in any part of literature of U.S.F.D.A. No cGMP regulations talked anything about process validation .⁹

Process Validation Definition:

Process validation is establishing documented evidence which provides a high degree of assurance that a specified process will consistently produce a product meeting its pre-determined specifications and quality characteristics. ¹⁰

Process Validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. ¹⁰

The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to expected result. ¹¹

A validation manufacturing process is one which has been proved to do what it purports or is 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 the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, system, building, personnel), but it also includes the control on the entire process for repeated batches or runs. ¹²

Process Validation is the means of ensuring and providing documentary evidence that processes within their specified design parameters are capable of repeatedly and reliably producing a finished product of the required quality. ¹³

Action to verify that any process, procedure, activity, material, system or equipment used in manufacturer or control can, will, and does achieve the desired and intended results. ¹⁴

Importance of Validation:

Various importance of validation in pharmaceutical industries are^15-17:

· Assurance of quality.

· Time bound.

· Process optimization.

· Reduction of quality cost.

· Nominal mix-ups and bottle necks.

· Minimal batch failures, improved efficiently and productivity.

· Reduction in rejections.

· Increased output.

· Avoidance of capital expenditures.

· Fewer complaints about process related failures.

· Reduced testing in process and in finished goods.

· More rapid and reliable start-up of new equipments.

· Easier scale-up form development work.

· Easier maintenance of equipment.

· Improved employee awareness of processes.

· More rapid automation.

· Government regulation (Compliance with validation requirements is necessary for obtaining approval to manufacture and to introduce new products).

· To reduce barch to batch variations.

· To achieve reproducible products of same quality, purity and strength.

· To assure safety and efficacy and to minimize hazardous effects

· To reduce the chance of product recall from market.

· To save the cost that arises because of lengthy investigation procedures in case of product variations.

Scope of Validation:

Pharmaceutical Validation is a vast area of work and it practically covers every aspect of pharmaceutical processing activities, hence defining the Scope of Validation becomes a really difficult task. However, a systematic look at the pharmaceutical operations will point out at least the following areas for pharmaceutical validation. ¹⁸

· Analytical

· Instrument Calibration

· Process Utility services

· Raw materials

· Packaging materials

· Equipment

· Facilities

· Manufacturing operations

· Product Design

· Cleaning

· Operator

Planning For Validation:

All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents. ¹⁹

· The VMP should be a summary document, which is brief, concise and clear.

· The VMP should contain data on at least the following:

o Validation policy.

o Organizational structure of validation activities.

o Summary of facilities, systems, equipment and processes to be validated.

o Documentation format: The format to be used for protocols and reports.

o Planning and scheduling.

o Change control.

o Reference to existing document.

o In case of large projects, it may be necessary to create separate validation master plans.

Departments Responsible For Validation:

The major departments those are responsible for validation are²⁰:

· Site validation committee: Develop site master validation plan.

· Manufacturing department: Prepares the batches as though their routine production batches. To assist in collection of data.

· Quality assurance: Ensure compliance and that documentation, procedures are in place. Approves protocols and reports. Review of validation documents. To approve the process.

· Quality controls: Perform testing contracts validation testing and reviews protocol and report as needed.

· Research and development: Deals with product design.

· Engineering department: Installation, quality and certify plant, facilities, equipment and support systems.

Validation Team and Its Responsibilities:

A multidisciplinary team is primarily responsible for conducting and supervising validation studies. Personnel qualified by training and experience in a relevant discipline may conduct such studies. Various responsibilities of validation team are: ¹⁷

· Creates updates and reviews/approves individual project validation plans and validation deliverables.

· Ensures validation compliance with the company validation master plan and project validation plan.

· Coordinates, implements, verify elements of VMP.

· Consults, evaluates and approves changes.

· Reviews and approves IQ/OQ/PQ procedures and plans.

· Reviews test results and makes recommendations regarding release.

· Assess risks and develops contingency plan.

Reason for Process Validation:

The possible reason of performing process validation may include²¹:

· New product or existing products as per SUPAC changes.

· Change in site of manufacturing.

· Change in batch size.

· Change in equipment.

· Change in process existing products.

· Change in composition or components.

· Change in the critical control parameters.

· Change in vendor of API or critical excipient.

· Change in specification on input material.

· Abnormal trends in quality parameters of product through review during Annual Product Review (APR).

· Trend of Out of Specification (OOS) or Out of Trend (OOT) in consecutive batches.

Basic Concept of Process Validation ^{3, 8, 17}

· Calibration, verification and maintenance of process equipment.

· Prequalification or revalidation.

· Establishing specifications and performance characteristics.

· Selection of methods, process and equipment to ensure the product meets specifications.

· Qualification or validation of process and equipment.

· Testing the final product, using validated analytical methods, in order to meet specifications.

· Challenging, auditing, monitoring or sampling the recognised critical key steps of the process.

Phases in Process Validation:

The activities relating to validation studies may be classified into three phases as ^22-23:

Phase1: Pre-Validation or Qualification Phase:

This phase is 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 and storage, and handling of in-process and finished dosage forms, equipment qualification, installation qualification master production document, operational qualification and process capacity.

Phase 2: Process Validation Phase:

It is designed to verify that all established limits of the critical process parameter are valid and that satisfactory. Products can be produced even under the worst conditions.

Phase 3: Validation Maintenance Phase:

It requires frequent review of all process related documents, including validation of audit reports, to assure that there have been no changes, deviations failures and modifications to the production process and that all standard operating procedures (SOPs), including change control procedures, have been followed. At this stage, the validation team comprising of individuals representing all major departments also assures that there have been no changes/deviations that should have resulted in requalification and revalidation. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications. It is assumed that throughout manufacturing and control, operations are conducted in accordance with the principle of good manufacturing practice (GMP) both in general and in specific reference to sterile product manufacture.

Types/Methods of Validation:

Different types of pharmaceutical process validation includes^24-26:

Prospective Validation:

It is defined as the established documented evidence that a system does what it purports to do based on a preplanned protocol. This validation usually carried out prior to distribution either of a new product or a product made under a revised manufacturing process. This validation usually done during the product development stage. Performed on at least three successive production-sizes (Consecutive batches).

In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase, the production process should be categorized into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiment should be designed to determine the 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 specifications and environmental conditions have been determined.

Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally 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 equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation.

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. Detailed testing should also be done on the final product in its package.

Upon completion of the review, recommendations should be made on the extent of monitoring and the in process controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures.

Limits, frequencies and action to be taken in the event of the limits being exceeded should be specified.

Prospective validation should include, but not be limited to the following:

· Short description of the process.

· Summary of the critical processing steps to be investigated.

· List of the equipment/facilities to be used (including measuring, monitoring/recording equipment) together with its calibration status.

· Finished product specifications for release.

· List of analytical methods, as appropriate.

· Proposed in-process controls with acceptance criteria.

· Additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate.

· Sampling plan.

· Methods for recording and evaluating results.

· Functions and responsibilities.

· Proposed timetable.

Batches made for process validation should be the same size as the intended Industrial scale batches. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise and the marketing authorization.

Concurrent Validation:

A process where current production batches are used to monitor processing parameters. It gives of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch. After three initial commercial batches are taken and the process is handed over to the manufacturing facilities, batch after batch and studied if any deviation is observed or required. This time the in-process quality control parameter are also decided and monitored which finally becomes the I.P.Q.C. test for regular production.

Normally three batches are recorded fully on part of initial concurrent validation programmer. If initial development batches and the commercial production batches use same type of equipment then revalidation of the whole process during commercial manufacturing may not be required I.P.Q.C. tests should be carried out for every batch to see that the process is moving forward in the expected direction.

Concurrent Validation may be the practical approach under certain circumstances. Examples of these may be when:

· A previous validated process is being transferred to a third party contract manufacturer or to another site.

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

· The numbers of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control.

· The numbers of batches produced are limited.

· Process with low production volume per batch and market demand.

· Process of manufacturing urgently needed drug due to shortage or absence of supply.

· In all above cases concurrent validation is valid, provided following conditions are appropriately.

· Pre-approved protocol for concurrent validation with rational.

· A deviation shall be raised with justification and shall be approved by plant head /head process owner/Head-QMS.

· Product behaviour and history shall be reviewed based on developmental/scale up /test batches. A detailed procedure shall be planned for handling of the marketed product if any adverse reactions observed in concurrent validation process.

· Concurrent validation batches shall be compiled in report and shall be approved all key disciplines.

Retrospective Validation:

It is defined as the established documented evidence that a system does what it purports to do on the review and analysis of historical data and information. This is achieved by the review of the historical manufacturing testing data to prove that the process has always remained in control. This type of validation of a process for a product already in distribution and is based on extensive data accumulated over several lots over time.

Retrospective validation is only acceptable for well established processes and will be in appropriate where there have been recent changes in the composition of the product, operating procedures or equipment. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.

The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance logbooks, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results.

Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet the specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to access process consistency, but fewer batches may be examined if justified.

Some of the essential elements for Retrospective Validation are:

· Batches manufactured for a defined period (minimum of 10 last consecutive batches).

· Number of lots released per year.

· Batch size/strength/manufacturer/year/period.

· Master manufacturing/packaging documents.

· Current specifications for active materials/finished products.

· List of process deviations, corrective actions and changes to manufacturing documents.

· Data for stability testing for several batches

Revalidation:

Re-validation provides the evidence that changes in a process and/or the process environment that are introduced do not adversely affect process characteristics and product quality. Revalidation required when there is change in any of the critical process parameters, formulations, primary packaging components, raw material fabricator, major equipment or premises. Failure to meet product and process specifications in batches would also require process revalidation. Documentation requirements will be the same as for the initial validation of the process.

Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.

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

· Changes in raw materials (physical properties such as density, viscosity, particle size distribution and moisture etc that may affect the process or product).

· Changes in the source of active raw material manufacturer.

· Changes in packaging material (primary container/closure system)

· Changes in the process (e.g., mixing time, drying temperatures and batch size)

· Changes in the equipment (e.g., addition of automatic detection system). Changes of equipment which involve the replacement of equipment on a “like for like” basis would not normally require revalidation except that this new equipment must be qualified.

· Changes in the plant/facility.

· Variations revealed by trend analysis.

A decision not to perform revalidation studies must be fully justified and documented.

Principle for validation:

The basic principle for validation may be stated as follows^27-30:

Design qualification (DQ):

The first element of validation of new facilities, systems or equipment could be design qualification (DQ). The compliance of the design with GMP should be demonstrated and documented. It is a documented verification of the design of equipments and manufacturing facilities. DQ considerations are:

· Good manufacturing practices and regulatory requirements.

· Performance criteria.

· Reliability and efficiency.

· Maintenance and access to critical equipment and instrumentation.

· Safety and environment impact.

· Facility air flow, movement flow and pressure engines.

Installation Qualification (IQ):

Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendation of the supplier of the equipment are suitably considered. Installation qualification should be performed on new or modified facilities, systems and equipment.

IQ considerations are:

· Equipment design features (i.e. material of construction clean ability, etc.)

· Installation conditions (wiring, utility, functionality, etc.)

· Calibration, preventative maintenance, cleaning schedules.

· Safety features.

· Supplier documentation, prints, drawings and manuals.

· Software documented.

· Spare parts list.

· Environmental conditions (such as clean room requirements, temperature, and humidity).

· Description of equipment.

· Facility functional specifications.

· Principle of operation.

Operational Qualification (OQ):

Establishing by objective evidence process control limits and action levels which result in product that all predetermined requirements. Conduct of an Operational qualification (OQ) should follow an authorized protocol. The critical operating parameters for the equipment and systems should be identified at the O.Q stage. The plans for the O.Q should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Operation qualification (OQ) should follow Installation qualification.

OQ considerations are:

· Process control limits (time, temperature, pressure, line speed, setup conditions, etc.)

· Software parameters.

· Raw material specifications

· Process operating procedures.

· Material handling requirements.

· Process change control.

· Training.

· Equipment control function.

· Short term stability and capability of the process, (latitude studies or control charts).

· Potential failure modes, action levels and worst-case conditions.

· The use of statistically valid techniques such as screening experiments to optimize the process can be used during this phase.

Performance Qualification (PQ):

Establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements. Performance qualification (PQ) should follow successful completion of installation qualification and operational qualification.

PQ considerations include:

· Actual product and process parameters and procedures established in OQ.

· Acceptability of the product.

· Assurance of process capability as established in OQ.

· Process repeatability, long term process stability.

· Tests to include a condition or set of conditions encompassing upper and lower operating limits.

Re – Qualification:

Modification to, or relocation of equipment should follow satisfactory review and authorization of the documented change proposal through the change control procedure. This formal review should include consideration of re qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventive maintenance program.

Stages of Process Validation:

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 product. Process Validation involves a series of activities taking place over the lifecycle of the product and process. The activities relating to validation studies may be classified into three stages^31-32: (Figure-1)

Stage 1 – Process Design:

“Focusing exclusively on qualification efforts without also understanding the manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. It 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 forms, equipment qualification, installation qualification, master production documents, operational qualification, process capability. Also this is the stage in which the establishment of a strategy for process control is taking place using accumulation knowledge and understanding of the process. ”

Stage 2 – Process Qualification:

During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. It confirms that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under “worst case” conditions. GMP compliant procedures must be followed in this stage and successful completion of this stage is necessary before commercial distribution of a product.

Stage 3 – Continued Process Verification:

Ongoing assurance is gained during routine production that the process remains in a state of control. The validation maintenance stage requires frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including change control procedures. A successful validation program depends on the knowledge and understanding and the approach to control manufacturing processes. These include the source of variation, the limitation of the detection of the variation, and the attributes susceptible of the variation.

Strategy for Validation:

The validity of a specific method should be demonstrated in laboratory experiments using samples or standards that are similar to the unknown samples analyzed in the routine. The preparation and execution should follow a validation protocol preferably written in a step-by step instruction format as follows ^{4, 33}:

· Develop a validation protocol or operating procedure for the validation.

· Define the application purpose and scope of the method.

· Define the performance parameters and acceptance criteria

· Define validation experiments.

· Verify relevant performance characteristics of the equipment.

· Select quality materials, e.g., standards and reagents.

· Perform pre-validation experiments.

· Adjust method parameters and/or acceptance criteria, if necessary.

· Perform full internal (and external) validation experiments.

· Develop SOPs for executing the method routinely.

· Define criteria for revalidation.

· Define type and frequency of system suitability tests and/or analytical quality control (AQC) checks for the routine.

· Document validation experiments and results in the validation report.

Validation Protocol:

Detailed protocols for performing validations are essential to ensure that the process is adequately validated. Process validation protocols should include the following elements³⁴:

· Objectives, scope of coverage of the validation study.

· Validation team membership, their qualifications and responsibilities.

· Type of validation: prospective, concurrent, retrospective, re-validation.

· Number and selection of batches to be on the validation study.

· A list of all equipment to be used; their normal and worst case operating parameters.

· Outcome of IQ, OQ for critical equipment.

· Requirements for calibration of all measuring devices.

· Critical process parameters and their respective tolerances.

· Process variables and attributes with probable risk and prevention shall be captured.

· Description of the processing steps: copy of the master documents for the product.

· Sampling points, stages of sampling, methods of sampling, sampling plans.

· Statistical tools to be used in the analysis of data.

· Training requirements for the processing operators.

· Validated test methods to be used in process testing and for the finished product.

· Specifications for raw and packaging materials and test methods.

· Forms and charts to be used for documenting results.

· Format for presentation of results, documenting conclusions and for approval of study results.

Validation Master plan:

Validation Master Plan is an internally approved document that describes in clear and concise wording about the general expectations, intensions, methods and approach to be used during the entire validation effort .The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The validation master plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, sop’s and validation protocols and reports. ³⁵

The size of validation master plan can not defined but it should not be just 4/5 pages, at the same time it cannot be 400/500 pages The acid tests of the validation master plan is that it spells out all the planned activities with a time frame and clear cut responsibilities assigned for various people. The F.D.A inspectors do demand a copy of the validation master plan to see. Then idea of this document is to show the F.D.A inspectors that the company has a highly organized approach to the validation programme. The format and content should include:

· Introduction: validation policy, scope, location and schedule.

· Organizational structure: personnel responsibilities.

· Plant/process/product description: rational for inclusions or exclusions and extent of validation.

· Specific process considerations that are critical and those requiring extra attention.

· List of products/ processes/ systems to be validated, summarized in a matrix format, validation approach.

· Re-validation activities, actual status and

· Key acceptance criteria.

· Documentation format.

· Reference to the required SOP’s.

· Time plans of each validation project and sub-project.

Points to be considered In Validation Master plan:

Mr. Lou Angelucci has very clearly defined what point should be considered in developing a validation master plan. He says in developing your master plan following questions must be addressed as:

· What are the scope and boundaries of the validation efforts?

· How many systems you are validating? Is it just one building or more than one?

· What is the scope of activity?

· Are the buildings fed by different utilities?

· Who will participate in the development of the master plan?

· Have you defined the validation approach?

· How long do you expect it to take?

· Are the acceptance criteria outlined?

· When you talk about your process, what specifics can you identify? Are these USP methods that you are identifying?

· Who will actually execute the protocol? Will they be from the validation group or engineering or combination group?

· Who will sign it? The master plan is basically an approved document with signatures of approval. It is not just something that quality assurance, the validation department or engineering puts together. It is a group activity.

Conclusively it can be said that a validation master plan should be a reflecting mirror of your good intentions in the area of your planned work on validation. It should be reviewed and revised at a definite time frequency preferable once in a year.

Validation Report:

A written report should be available after completion of the validation. If found acceptable, it should be approved and authorized (signed and dated). It should derive conclusions regarding the validation status of the process and necessary recommendations for routine process. Validation report shall be prepared to assess the adherence to the protocol after execution of batches. Data can be collected in predesigned format during execution. The actual yield obtained at different stages shall be checked against the formulation order of the validation batch processing records.³⁶

The report should include at least the following:

· Title and objective of study.

· Reference to protocol.

· Details of material.

· Equipment.

· Programmes and cycles used.

· Details of procedures and test methods.

· Results (compared with acceptance criteria).

· Recommendations on the limit and criteria to be applied on future basis.

Expert Evaluation:

This is an evaluation of the entire study against the protocol requirements as outlined above. It should be prepared and the conclusion drawn at each stage stated. The final conclusions should reflect whether the protocol requirements were met. The evaluation should include an assessment of the planned calibration and maintenance programmes for the equipment and instrumentation to maintain the validated conditions. In addition, all process monitoring and control procedures required to routinely ensure that the validated conditions are maintained should be reported. The evaluation should be signed by authorized officers of the organization who were members of the team establishing the protocol and who have appropriate expertise in the area assigned to them. Overall approval of the study should be authorized by the head of the validation team and the head of the quality control department.³⁷

Process Validation and Quality Assurance:

The relationship of quality assurance and process validation goes well beyond the responsibility of any quality assurance (QA) function. Nevertheless, it is a fair to say that process validation is a QA tool, because it establishes a quality standard for the specific process. Quality assurance in pharmaceutical companies embodies the effort to assure that products have the strength, purity, safety and efficacy represented in the company’s new drug application (NDA) filings.

Although quality assurance is usually designated as a departmental function, it must also be an integral part of an organization’s activities. When process validation becomes a general objective of the technical and operational groups within an organization, it becomes the driving force for quality standards in development work, engineering activities, quality assurance, and production. ³⁸

The quality assurance associated with the pharmaceutical development effort includes the following general functions:

· To ensure that a valid formulation is designated.

· To qualify the process that will be scaled up to production-size batches.

· To assist the design of the validation protocol.

· To manufacture the bio batches for the clinical program, which will become the object of the FDA’s preapproval clearance.

Quality assurance is the effort taken to ensure compliance with government regulations for the systems, facilities, and personnel involved with manufacturing products. QA audits will be quite varied in scope to achieve this assurance. These responsibilities include batch record reviews, critiques of product design, process validation activity, and, possibly, audits of other departments operations.

Relationship between development studies and process validation data:

It is expected that during development stage, the manufacturer of the product should gain sufficient information about the behaviour and physical and chemical properties of the drug substance, the composition of the product in term of active ingredient(s) and key excipients and the manufacturing processes to clearly define the critical steps in the manufacturing process. Critical parameters of the product should be identified at an early stage; for example the dissolution rate of an active substance and the effect of the presence, type and amount of lubricant.

Information generated during the development stage should thus be used to identify and evaluate the critical pharmaceutical process parameters, which may need to be examined and possibly controlled in order to ensure batch-to-batch reproducibility. In order to define these critical parameters it may be necessary to challenge the process by making deliberate changes to demonstrate robustness of the process and define the limits of tolerance.¹⁷

Relationship between method of manufactures and process validation data:

Having defined and justified a particular method of manufacture based on a consideration of the physical and chemical properties of the active ingredient, the key excipients, the choice of formulation and impact of processing on the product quality and stability, the manufacturer should progress to fully describe the manufacturing process. Such a description should address also the need and value of in-process controls and the manufacturer’s approach to process optimization. The evaluation of the process should provide adequate proof of the feasibility of the process at the production scale thereby ensuring the consistent quality of the product in line with the approved specification. ¹⁷

Relationship between process validation and specification of the finished product:

The ICH guideline Q6A specification for new drug substances and products permits skip lot testing, i.e., replacement of routine verification of certain tests on a batch by batch basis. In addition, data generated through process evaluation or validation can be used to justify why certain test need not be conducted routinely on the finished product at release. ¹⁷

Process validation within the quality management system:

Process validation is part of the integrated requirements of a quality management system. It is conducted in the context of a system including design and development control, quality assurance, process control, and corrective and preventive action. The product should be design robustly enough to withstand variations in the manufacturing process and the manufacturing process should be capable and stable to assure continued safe products that perform adequately. Corrective actions often identify inadequate processes/process validations. Each corrective action applied to a manufacturing process should include the consideration for conducting process validation/ revalidation. ³⁹

Documentation:

A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria. A report that cross-references the qualification and/or validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification.

After completion of a satisfactory qualification, a format release for the next step in qualification and validation should be made as a written authorization. The degree and type of documentation required by cGMP is greatest during process qualification, and continued process verification. Studies during these stages must conform to cGMPs and must be approved by the quality unit in accordance with the regulations (21 CFR 211.22 and 211.100). ⁴⁰

CONCLUSION:

Pharmaceutical Process Validation is the most important and recognized parameters of cGMP. Validation is the most widely used word in the areas of drug development, manufacturing and specification of finished products. The cGMP regulation require that manufacturing processes be designed and controlled to assure that in-process materials and finished product meet predetermined quality requirements and do so consistently and reliably. The product should be designed robustly enough to withstand variations in the manufacturing process and the manufacturing process should be capable and stable to assure continued safe products that perform adequately. Process validation involves a series of activities taking place over the lifecycle of the product and process.

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Received on 28.07.2014 Modified on 12.08.2014

Research J. Pharm. and Tech. 7(9): Sept. 2014 Page 1081-1090