Process Validation

Bijoylakshmi Shaw

Student

Bengal School of Technology
   (A college of Pharmacy)





                                        Process Validation 

1.   Introduction:

Validation is the most recognized and important parameter of GMPs. Process Validation of a process will ensure production of drug of reproducible quality. In pharmaceutical industry, process validation performs to build the quality into the product; it’s proven to be an important tool for quality management of pharmaceuticals. It involves the systemic 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. The requirement of process validation appears of the quality system 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. It is intended to assist manufactures in understanding management system requirements concerning process validation and has general applicability to manufacturing process. So, 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.

2. 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 pharmaceutical. 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 29^th 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. 

3. Process Validation Definition:

Validation can be defined as a procedure that demonstrates that a process under standard conditions in capable of consistently producing a product that meets the established product specification. K.G Chapman calls process validation as “organized documented common sense ’’. Validation means demonstration, by provision of objective evidence that consistently meets its predetermined requirements. It is, therefore, an element of the quality assurance program associated with a particular product or process.

                       The U.S. Food and Drug Administration(FDA) has proposed guidelines with the following definition  for process validation :- “ process validation is establishing documented evidence which provide a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage form) will consistently produce a product meeting its pre-determined  specifications and quality characteristics’’.

4. 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 cycle of the product and process. The activities relating to validation studies may be classified into three stages:-

Stage 1: process Design

Stage 2: process Qualification

Stage 3: Continued Process Verification

                             Fig. 1: Approaches to process validation

4.1 Stage 1:-

Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale up activities.

                         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,  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.

4.2       4.2          Stage 2:-

Pro 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 complaint procedures must be followed in this stage and successful completion of this stage is necessary before commercial distribution of a product. There are two aspects of process qualification:

a) Design of facilities and Qualification of Equipment and Utilities.

Ø  Proper design of manufacturing facility is desired under than 21 CFR parts 211, subpart C, of the cGMP regulation on buildings and facilities.

Ø  Activities performed to assure proper facility design and that the equipment and utilities are suitable for their intended use and perform properly. 

b) Process Performance Qualification Criteria and process performance indicators that allow for a science and risk based decision about the ability Of the process to consistently produce quality product.

Ø Part of the planning for stage 2 involves defining performance criteria and deciding what data to collect when, how much data, and appropriate analysis of the data.

Ø Likely consist of planned comparisons and evaluations of some combination of process measures as well as in-process and trial product attributes.

Ø Manufacturer must scientifically determine suitable criteria and justify it.

Ø Objective measures, where possible.

Ø May be possible to leverage earlier study data if relevant to the commercial scale.

4.3 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  and deviation, failures, modification 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.  

         Fig. 2: Three model of process validation according to FDA                          Guidance for Industry- Process validation 

5. Need of Validation:

Quality is always an imperative prerequisite when we consider any product. 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. It becomes primes 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 cannot be adequately controlled solely by pharmacopoeia analysis of the final product.

·        Validation gives confident over the product manufacturing process.

·       It’s give assurance to the product quality as per customer requirements.

·        To obtain consistent reliable and accurate data.

·        Act as a proof in decision making.

·       Validation mandatory as per regulatory requirements.                     If we are not going for validation then following problems can be occur.

6. Types of Process Validation:

The guidelines on general principles of process validation mention four types of validation:-

A.     Prospective Validation

B.       Concurrent Validation

C.      Retrospective Validation

D.     Revalidation

Fig. 3: Types of Process Validation

6.1  

 6.1 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 is conducted prior to the distribution of new product. This validation usually carried out prior to distribution either of a new product or product made under a revised manufacturing process. Performed on at three successive consecutive batches. 

                  ·         A description of the process / experiments

·        Details of the equipment / facilities to be used

·        The variables to be monitored

·        The samples to be taken where, when, how and how many

·        The product performance characteristics / attributes to be monitored, together with the test

                     

 6.2 Concurrent Validation:

        It is establishment of documented evidence of what a system does or what it purports to do information generated during implemented of the system.

                  ·        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.

It is important in this case 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 the validation team.

6.1          6.3   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.

                    ·        Batches manufactured for a defined period

·        Number of lots released per year.

·        Batch

Size/strength/manufacture/year/period.

·        Master manufacturing/packaging documents.

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

  6.4 Revalidation:

       Revalidation provides the evidence that changes in a process and 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.   

  

                     ·        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).                         

7. Pre-requisites of validation:

Qualification is pre-requisite of validation. Qualification includes the following:-  

                                      Design qualification

     Installation qualification

     Operational qualification        

   Performance qualification

        

                          Fig. 4: Pre-requisites of validation

8. Validation Master Plan (VMP):

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 schedules.

                          All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in validation master plan.

                         It should comprise prospective, concurrent and retrospective validation as well as revalidation.

                         The validation master plan should be a summary document and should therefore be brief, concise and clear.

                         SOP’s and validation protocols and reports. 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.

9. Validation protocol:

After performing VMP, the next step is to prepare validation protocol. Detailed protocol for performing validations is essential to ensure that the process is adequately validated. There are the following contents in a validation protocol:-

·        Purpose & scope of validation.

·  Responsibilities and functioning of persons/ organizational units involved in the validation.

·        Type of validation to be conducted.

·        Number of process validation runs.

·        Quality of materials used in the process.

·        Description of the process (e.g. unit operation, flow diagram).

·    All major equipment to be used, their types/ design and their installation and operational qualification (IQ/OQ).

·        Critical process parameters and operating ranges.

10. Importance of process validation:

Effective process validation contributes significantly to assuring drug quality, the basic principle of quality assurance is that a drug should be produced that is fit for its intended use. 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 have as their goal and the production of articles that are fit for their intended use.

·        Improve the use of technology.

·        Improve the business benefits.

·        Improve operational efficiency.

·        Improve compliance with regulations.

·        Reduce the risk of failure.

·        Reduce the cost.

·        Process optimization.

·        Increased customer satisfaction.

·        It gives assurance of quality and safety.

·        It assures the smooth running of the process.

11. 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. Pharmaceutical process validation is the most important and recognized parameters of cGMP. The process validation is intended to assist manufactures in understanding quality management system (QMS) requirements concerning process validation and has general applicability to manufacturing process. Validation has been proven assurance for the process efficiency and sturdiness and it is the full-fledged quality attributing tool for the pharmaceutical industries. It also renders reduction in the cost linked with process monitoring, sampling and testing.  Finally it can be concluded that process validation is a key element in the quality assurance of pharmaceutical product.

                 

            

12. References:

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

2.      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.

3.      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.

4.      Sharma PP; Validation in Pharmaceutical Industry.6^th Edition, Vandana Publication, New Delhi, 2008; 91-115.

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

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

7.      Kumar NL, Moorthy DG, Kumar SR; An Overview of Pharmaceutical Validation: Quality Assurance view point. 2011; 1 (4): 1003-1014.

8.      Patel RC, Bhuva CK; Pharmaceutical Process Validation: Pharmatutor, ART-1053 .