INTRODUCTION:

The manufacture of products of requisite attribute and quality consistently at the lowest possible cost is the prime objective of any pharmaceutical plant. 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. 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, labelling 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. [1][2]

The word validation simply means assessment of validity or action of proving effectiveness. Validation is a team effort where it involves people from various disciplines of the plant. The development of a drug product is a lengthy process involving drug discovery, laboratory testing, animal studies, clinical trials and regulatory registration.[4] Process controls include raw materials inspection, inprocess 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. 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.[3]

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 (Agalloco 1995). 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. 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.[5]

Need of Pharmaceutical Validation:

Validation is an integral part of quality assurance; it involves the systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. A validated process is one which has been demonstrated to provide a high degree of assurance that uniform batches will be produced that meet the required specifications and has therefore been formally approved. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control. [6]

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;

1. Analytical

2. Instrument Calibration

3. Process Utility services

4. Raw materials

5. Packaging materials

6. Equipment

7. Facilities

8. Manufacturing operations

9. Product Design

10. Cleaning

11. Operators

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.[7]

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. The VMP should be a summary document, which is brief, concise and clear. The VMP should contain data on at least the following:

1. Validation policy.

2. Organizational structure of validation activities.

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

4. Documentation format: The format to beØ used for protocols and reports.

5. Planning and scheduling.

6. Change control.

7. Reference to existing document

8. In case of large projects, it may be necessary to create separate validation master plans.[8]

Validation Set Up:

To establish the desired attributes. These attributes include physical as well as chemical characteristics. In the case of parenterals, these desirable attributes should include stability, absence of pyrogens, and freedom from visible particles. Acceptance specifications for the product should be established in order to attain uniformity and consistently the desired product attributes, and the specifications should be derived from testing and challenge of the system on sound statistical basis during the initial development and production phases and continuing through subsequent routine production. The process and equipment should be selected to achieve the product specification. For example; design engineers; production and quality assurance people may all be involved. The process should be defined with a great deal of specificity and each step of the process should be challenged to determine its adequacy. These aspects are important in order to assure products of uniform quality, purity and performance.[9]

Four major advantages of Validation:

1. Assurance of quality

2. Process optimization

3. Reduction of quality costs

4. Safety

Assurance of quality:

Validation is an extension of the concepts of quality assurance since close control of the process is necessary to assure product quality and it is not possible to control a process properly without thorough knowledge of the capabilities of that process without validated and controlled processes, it is impossible to produce quality products consistently. End product testing, in the absence of validation, gives little assurance of quality for variety reasons, among which are

1. Very limited sample size.

2. The limited number of tests performed on an a sample. For example, it is impractical to test for all potential impurities or contaminants.

3. The limited sensitivity of the test

Process Optimization:

The optimization of a process for maximum efficiency, while maintaining quality standards, is a consequence of validation. Literal meaning of word to optimize is “To make as effective, perfect or useful as possible”. The optimization of the facility, equipment, systems, and processes results in a product that meets quality requirements at the lowest cost.[10]

Reduction of Quality Costs:

Quality costs are divided in to four categories.

They are:

1. Preventive costs.

2. Appraisal costs.

3. Internal failure costs.

4. External failure costs.

e.g.: of internal failure costs. Any validated and controlled process will result in fewer internal failures like

1. Fewer rejects

2. Reworks

3. Re-tests

4. Re-inspection

Process validation makes it possible to do the job right the first time. Also, a scientifically studied and controlled process makes it unlikely that defective products will be dispatched to market thus no recalls or market complaints.[11]

Safety:

Validation can also result in increased operation safety. e.g.: gauges used on equipment that designed to operate at certain temperature and pressures must be reliable i.e. they must be calibrated.

Types/ Methods of Validation:

Prospective Validation:

It is defined as the established documented evidence that a system does what it purports to do based on a pre planned protocol. This validation usually carried out prior to distribution either of a new product or a product made under a revised manufacturing process. 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.

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.[12]

Concurrent Validation:

It is similar to prospective, except the operating firm will sell the product during the qualification runs, to the public at its market price, and also similar to retrospective validation. This validation involves in-process monitoring of critical processing steps and product testing. This helps to generate and documented evidence to show that the production process is in a state of control. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts. The decision to carry out concurrent validation must be justified, documented and approved by authorized personnel. Documentation requirements for concurrent validation are the same as specified for prospective validation.

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 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. Retrospective validation is only acceptable for well established processes and will be inappropriate 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.[13]

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. 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:

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

2. Changes in the source of active raw material manufacturer.

3. Changes in packaging material (primary container/closure system)

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

5. Changes in the equipment (e.g., addition of automatic detection system).

6. 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.

7. Changes in the plant/facility.[2][5]

Importance of Validation

1. Assurance of quality

2. Time bound

3. Process optimisation

4. Reduction of quality cost.

5. Nominal mix-ups, and bottle necks

6. Minimal batch failures, improved efficiently and productivity.

7. Reduction in rejections.

8. Increased output.

9. Avoidance of capital expenditures

10. Fewer complaints about process related failures.

11. Reduced testing in process and in finished goods.

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

13. Easier scale-up form development work.

14. Easier maintenance of equipment.

15. Improved employee awareness of processes.

16. More rapid automation.

17. Government regulation (Compliance with validation requirements is necessary for obtaining approval to manufacture and to introduce new products)[7][9]

Basic Concept of Process Validation:

Pharmaceutical Process Validation is the most important and recognized parameters of cGMPs. The requirement of process validation appears 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 goal are met. The process validation is standardization of the validation documents that must be submitted with the submission file for marketing authorization. The process validation is intended to assist manufacturers in understanding quality management system (QMS) requirements concerning process validation and has general applicability to manufacturing process. According to FDA

Assurance of product quality is derived from careful and systemic attention to a number of importance factors, including: selection of quality process through in-process and end product testing.[9][11]

The basic principle for Validation may be stated as follows:

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. IQ considerations are:

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

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

3. Calibration, preventative maintenance, cleaning schedules.

4. Safety features.

5. Supplier documentation, prints, drawings and manuals.

6. Software documented.

7. Spare parts list.

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

Operational Qualification (OQ)

Establishing by objective evidence process control limits and action levels which result in product that all predetermined requirements. OQ considerations include:

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

2. Software parameters.

3. Raw material specifications

4. Process operating procedures.

5. Material handling requirements.

6. Process change control.

7. Training.

8. 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.

PQ considerations include:

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

2. Acceptability of the product.

3. Assurance of process capability as established in OQ.

4. Process repeatability, long term process stability

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.[10][13]

The Regulatory Basis for Process Validation:

The concept of process validation from its beginnings in the early 1970s through the regulatory aspects associated with current good manufacturing practice (cGMP) regulations and the application thereof to various analytical, quality assurance, pilot plant, production, and sterile product and solid dosage forms considerations. In the early 1990s, the concept of preapproval inspection (PAI) was born and had as one of its basic tenets the assurance that approved validation protocols and schedules were being generated and that comprehensive development, scale-up, and bio batch and commercial batch validation data were required in order to achieve a successful regulatory PAI audit.

There are several important reasons for validating a product and/or process. First, manufacturers are required by law to conform to cGMP regulations. Second, good business dictates that a manufacturer avoids the possibility of rejected or recalled batches. Third, validation helps to ensure product uniformity, reproducibility, and quality. Although the original focus of validation was directed towards prescription drugs, the FDA Modernization Act of 1997 expanded the agency’s authority to inspect establishments manufacturing over-the-counter (OTC) drugs to ensure compliance with cGMP.

Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The cGMP regulations for finished pharmaceuticals, 21 CFR 210 and 211, were promulgated to enforce the requirements of the act. FDA has the authority and responsibility to inspect and evaluate process validation performed by manufacturers. The cGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)).

Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The ultimate legal authority is Section 501(a) (2) (B) of the FD and C Act, which states that a drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or were not operated or administrated in conformity with cGMP. Assurance must be given that the drug would meet the requirements of the act as to safety and would have the identity and strength and meet the quality and purity characteristics that it purported or was represented to possess. That section of the act sets the premise for process validation requirements for both finished pharmaceuticals and active pharmaceutical ingredients, because active pharmaceutical ingredients are also deemed to be drugs under the act. The cGMP regulations for finished pharmaceuticals, 21 CFR 210 and 211, were promulgated to enforce the requirements of the act. Although these regulations do not include a definition for process validation, the requirement is implicit in the language of 21 CFR 211.100, which states: “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 possess.”[5][9][13]

Phases in Process Validation:

The activities relating to validation studies may be classified into three:

Phase 1: Pre-Validation Qualification Phase:

This phase 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.[5][9][11]

Validation Protocol:

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

1. Objectives, scope of coverage of the validation study.

2. Validation team membership, their qualifications and responsibilities.

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

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

5. A list of all equipment to be used; their normal and worst case operating parameters. Outcome of IQ, OQ for critical equipment.

6. Requirements for calibration of all measuring devices.

7. Critical process parameters and their respective tolerances.

8. 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.

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

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

11. Training requirements for the processing operators.

12. Validated test methods to be used in in process testing and for the finished product. Specifications for raw and packaging materials and test methods.

13. Forms and charts to be used for documenting results.

14. Format for presentation of results, documenting conclusions and for approval of study results.[1][3][5]

Validation Master Plan:

The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as revalidation.

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. The format and content should include:

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

2. Organizational structure: personnel responsibilities.

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

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

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

6. Re-validation activities, actual status and Key acceptance criteria.

7. Documentation format.

8. Reference to the required SOP’s.

9. Time plans of each validation project and sub-project.[9][11][13]

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

1. To ensure that a valid formulation isdesignated.

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

3. To assist the design of the validation protocol.

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

To work with production and engineering to develop and carry out the qualification program for production equipment and facilities/process systems.

To develop validated analytical methods to allow:

1. The stability program to be carried out.

2. The testing of raw materials and finished product

3. The development of release specifications for the raw materials and finished product.

4. The testing of processed material at a certain specified stages.

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.[1][8][9]

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). The report should include at least the following:

1. Title and objective of study.

2. Reference to protocol.

3. Details of material

4. Equipment

5. Programmes and cycles used.

6. Details of procedures and test methods.

7. Results (compared with acceptance criteria).

8. Recommendations on the limit and criteria to be applied on future basis.[2][4][9]

CONCLUSION:

Validation is the most widely used word in the areas of drug development, manufacturing and specification of finished products. The consistency and reliability of a validated process to produce a quality product is the very important for an industry. Validation has been proven assurance for the process efficiency and sturdiness and it is the full fledged quality attributing tool for the pharmaceutical industries Pharmaceutical Process Validation is the most important and recognized parameters of cGMP. The process validation is intended to assist manufacturers in understanding quality management system (QMS) requirements concerning process validation and has general applicability to manufacturing process. Validation is the commonest word in the areas of drug development, manufacturing and specification of finished products. It also renders reduction in the cost linked with process monitoring, sampling and testing. Apart from all the consistency and reliability of a validated process to produce a quality product is the very important for an industry.

REFERENCES:

1. Sharma A, Saini S; Process Validation of Solid Dosage Form: A Review. International Journal of Research in Pharmacy and Science, 2013; 3 (2): 12- 30.

2. Kaur H, Singh G, Seth N; Pharmaceutical Process Validation: A Review. 2013; 3 (4): 189-194.

3. Thaduvai R, Rao BS, Jeybaskaran M; Process Validation of Pantoprazole 40 mg Tablets: The Pharma Innovation. 2012; 1 (5): 50-52.

4. Kavita, Khurana G, Chaudhary S; Process Validation of Solid Dosage Form: A Review. Pharma Science Monitor, An International Journal of Pharmaceutical Sciences, September 2013; 4 (4): 390- 391.

5. Chapman K. G: A History of Validation in the United States, Part I, Pharma Technology. November 1991; 39-98.

6. Nash R. A., Wachter A. H: In Pharmaceutical Process Validation. Third Edition; Revised and Expanded, Marcel Dekker Inc., New York, 1993.

7. Potdar MA; Pharmaceutical Quality Assurance. 2nd Edition, Nirali Prakashan, 2009: 8.6-8.20.

8. WHO Expert Committee on Specifications for Pharmaceutical Preparations. WHO technical report, series no. 863 – 34th report, Annex 6 – GMP: Guidelines on the Validation of Manufacturing Processes: 4-7.

9. ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients: 33.

10. Potdar MA; Current Good Manufacturing Practices for Pharmaceuticals. 2nd Edition, Pharma Med Press Publication, Delhi, December 2007: 8.2-8.3.

11. Validation of Solid Dosage Forms the FDA view, 1989; 15(6-7): 1119-1133.

12. Guidelines for Process Validation of Pharmaceutical Dosage Forms. Saudi Food and Drug Authority, Kingdom of Saudi Arabia, 2010; 9-15.

13. Guidance for Industry: Process Validation: General Principles and Practices. U.S. Department of Health and Human Services, Food and Drug Administration, Centre for Drug Evaluation and Research (CDER), Centre for Biologics Evaluation and Research (CBER), Centre for Veterinary Medicine (CVM), January 2011.

Received on 27.05.2016 Accepted on 30.06.2016

Asian J. Pharm. Tech. 2016; 6 (3): 169-176.

DOI: 10.5958/2231-5713.2016.00024.6