1. INTRODUCTION:

The validation is one of the concept that has been running continuously with some advancement since its first appearance in the united states in 1978. The concept of the validation has expanded through the years to control and monitor a wide ranges of activities from the analytical method to process methods, that are used for the quality control of the drug substances and drug product to computerized systems for clinical trials (Gaurav Khurana et al, 2013).

It gives the ideas about the understanding of the following conditions is exist i.e. quality, safety and efficacy. Quality of a product cannot be adequately assured only by in process and finished product inspection or testing. Each and every step of a manufacturing process should be control to assure that the finished product meets all the quality attributes or characteristics including specifications (Pankaj Verma et al, 2012).

Therefore, validation has become one of the most important elements of quality assurance that associated with a particular process. The process differs so firstly, therefore there is no any universal approach for the validation and regulatory bodies such like FDA, EC. They are the agencies who has developed general non mandatory guidelines. As per the European Community, for medicinal products, the validation is “Action of proving”, in accordance with the principles of GMP that any procedures, process, requirement, material, activity or system, which actually leads to expected results (Gaurav Khurana et al, 2013).

The development and formulation of a drug product is a lengthy process because of the involvement of the several steps that includes drug discovery, laboratory testing, solubility testing, incompatibility studies, animal studies, clinical trials and regulatory registration. So, process controls that include raw materials inspection, in process controls and targets for final product are the major part of validation process. Even after the validation of manufacturing process, the cGMP practice is also required, that is a well written procedure which is required for the process controls (Pankaj Verma et al, 2012).

1.1. General concept:

Assurance of product quality can be possible by carefully study about the several factors that includes selection of quality parts and materials, sufficient product, process design, control of the process, and finally the end product testing. Because of the more complexity of the medical products now a days, we cannot assure the product quality by routine end product testing only (Gaurav Khurana et al, 2013).

1.2. USFDA Definition:

As per the USFDA, the Process validation is an authorized documented evidence that provide a high degree of assurance that a specified process will consistently give a product meeting, as its predetermined specifications and quality characteristics (Gaurav Khurana et al, 2013).

2. Advantages of Validation:

The validation process is a regulatory requirement to assure the safety of product, Adequate validation is beneficial to the manufacturer, because of the several advantages that includes, (N K Jain et al)

1. Reduces the risk of regulatory non compliance

2. Reduce the time to market a new produc

3. Reduces the chances of product recall from the market

4. Eliminates the scrap and reduces the defect cost

5. Make the process better understandable

6. Reduces the risk of preventing problems and assure the smooth running of the process.

3. Why validation?

Validation is a regulatory requirement because of the several reason. It is required in every process in the global health care industry for pharmaceuticals, biologics, and medical devices. So now a days the validation and the validation like activities are found in no of industry like banking, software, nuclear power, microelectronics etc. Among others that include the health care product production. As pharmaceutical industry uses the expensive materials, sophisticated facilities, and equipment’s, highly qualified personnel. So, details study and control of the manufacturing process is necessary, for reducing of the product cost, product recall from the market, reworks, and also to improve the productivity (Subhrajit Mantry et al, 2014).

3.1. Essentials of validation:

Pharmaceutical validation is essential for several reason that includes (Subhrajit Mantry et al,2014),

1. To reduces the batch to batch variations.

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

3. To assure the safety and efficacy and to minimize the hazardous effects.

4. To reduces the chances of product recall from the market.

5. To save the cost arises because of the lengthy investigational process of the product.

6. To decrease the risk of defect cost.

7. To decreases the risk of regulatory non compliances.

8. A fully validated process may require less in process controls and end product testing. (Elsie Jatto et al, 2002)

3.2. Condition required for Validation:

The validation should be considered in the following situations (Subhrajit Mantry et al, 2014),

1. Totally new process

2. New equipment

3. Process and the equipment which has been changed for the suitability purposes.

4. Process where the end product test is poor and an unsatisfactory indication of the product quality.

3.3. Needs of Validation:

The pharmaceutical validation is an integral part not only in the field of Quality assurance but also in the field of Pharmaceutics. It involves the systemic study of systems, facilities and also the process. Its aim is to determined that they are performing their intended functions adequately and consistently or not as that of specified. Simply the validated process is one which can give a high degree of assurance about the production of the uniform batches and that batches are meeting their requirements specifications. Validation in itself cannot improve but confirm that the process has been developed and are under control (Pankaj Verma et al, 2012).

3.3.1. Assurance of quality:

A process is well understood and in a state of control and confident, but after that also without validation, the quality of the product cannot be assured.

3.3.2. Cost reduction:

As each and every step in the validation is monitored continuously and constantly, there is reduces in the rework and rejects and also reduction of the recall from the market, which leads to an effective cost reduction.

3.3.3. Govt regulation:

Validation has been considered as an integral part of the GMPs (Good Manufacturing Practices) So worldwide compliance with the validation requirements is necessary for obtain an approval to manufacture and to introduce new products. (Khushboo D Singh et al, 2014)

3.4. Importance of validation:

In a single word, it is very difficult to explain about the importance of pharmaceutical validation, because it has several importance. So below are some of the point from which we can understand the importance of pharmaceutical validation (Khushboo D Singh et al, 2014)

1. Assuarance of quality

2. Time bound

3. Process optimization

4. Reduction of quality cost

5. Minimal batch failures

6. Improve productivity

7. Reductions in rejections

8. Increased output

9. Avoidance of capital expenditure

10. Reduction in the complaint regarding the process failures

11. More rapid and reliable startup of new equipment’s

12. Easier scale up from the developmental work

13. Reduce the product recall from the market

14. Easier maintenance of the equipment’s

15. Govt regulations (i.e. compliance with the validation requirements) is necessary for obtaining

An approval to manufacture and to introduce a new product. (Subhrajit Mantry et al, 2014)

4. Types of validation:

As we know that the pharmaceutical validation is an integral part now a days, so it has been classified as several ways, but below mentioned four are important validation process, but among these process validations is most important and that I have explained fully (Pankaj Verma et al,2012 and Subhrajit Mantry et al, 2014),

1. Process validation

2. Analytical validation

3. Cleaning validation

4. Computerised validation

4.1. Process validation:

4.1.1. Introduction:

The quality system regulation defines the process validation as an establishing documented evidence, which provide a high degree of assurance that a process will consistently give a product or product meeting its predetermined specifications.

4.1.2. Advantages:

1. Expanded real time monitoring and adjustment of process.

2. Enhanced data and evaluation capabilities and increased confidence about process reproducibility and product quality.

3. Improved ability to set target parameters and control limits for routine production, correlating with the validation results.

4. Enhanced reporting capability.

4.1.3. Basic principle:

1. It Demonstrate that controlling, monitoring, and measuring equipment’s and instrumentation are capable of operating within the parameters that are prescribed for the process equipment’s.

2. Revalidation, installation qualification.

3. For ensure about the product meeting specification, choice of methods, process and equipment.

4.1.4. Types of process validation:

The process validation has again classified as four types,

1. Prospective validation

2. Concurrent validation

3. Retrospective validation

4. Revalidation

4.1.4.1. Prospective validation:

It is conducted for the product that are made under modified production process, where the modification is significant and may affect the product characters. It is preplanned scientific approach. It includes the initial stages of validation. It includes the design about the in-process test sampling plans, design if the batch records, defining the raw materials specifications. Here the validation protocol is executed before the process to be start for commercial use. If there will be three consecutive batches runs within the agreements parameter by giving product of the desired quality, then it can be considered for an acceptable. It is performed for a new product.

4.1.4.2. Concurrent validation:

It is a validation process where current production batches are used to monitor. Here current batches are to be studies. It gives limited assurance regarding the consistency of quality from batch to batch, but it may be the practical approach under certain conditions.

Example:

1. A previous validation process is being transferred to a third-party contract manufacturer or to another site.

2. The product with a different strength of a previously validated product with the same amount of API (Active Pharmaceutical Ingredients) and inactive ingredients.

4.1.4.3. Retrospective validation:

It is conducted for a product which are already being marketed. It may also be used for older product which are not validated by the fabricator, at the time when that was first marketed.

Example:

1. Batches manufacture for a defined period.

2. Number of batches released per year.

3. Batch size, strength, manufacturing year, period.

4. Packaging documents.

5. Data for stability testing for several batches are essential element of retrospective validation.

4.1.4.4. Revalidation:

It is required when there is a change in any of the critical process parameters. It may include the primary packaging components, raw materials fabricator major. If the equipment or premises fail to meet the product and process specification in batches, may also need revalidation.

Example:

1. Change in raw materials, physical properties (density, viscosity, particle size).

2. Changes in the sources of API manufacturer.

3. Change in the packaging materials.

4. Changes in the process (Example: Mixing time, drying, temperature, speed etc.).

5. Changes in the equipment.

6. Changes in the plant or facilities.

5. Major Phases of Validation:

The activities that are involved in the study of the validation are classified into three phases. (Elsie Jatto et al, 2002)

5.1. Phase 1: Pre validation qualification phase:

This phase involves the all of the activities which are related to the research and development of the product. As it is the before step of the validation process, it also involves the formulation of the pilot batch studies, scale up studies and the transfer of that technology to the commercial scale batches, improvement in the stability conditions and the storage, and handling of the in process and finished dosage forms, the qualification that includes the equipment qualification, installation qualification, operational qualification, master formula record or master production document, and process capacity.

5.2. Phase 2: Process validation phase:

This phase is also called as current validation phase. This phase is specially designed to verify of all of the established limits of the critical process parameter that the parameter is valid and are able to produce satisfied product even under the worst conditions.

5.3. Phase 3: Validation maintenance phase:

In this phase frequently review of all the process related documents is required. The documents include validation of audit reports. It is performed to assure that there have been no changes, deviations, failures and modifications to the production process of the product and also that all standard operating procedure (SOPs) that including the change control procedures, have been followed. Here all the individuals who are represented from other department are also assure that there have been no changes, deviation that should have resulted in requalification and revalidation. A carefully designing and validating of the system and process controls can assure a high degree of confident about the production of the same quality of all the lots or batches with meeting of their intended specifications. The validation step that are recommended by the GMPs are as follows,

1. All of the data that are generated during the duration of studies should be formally reviewed and certified as evaluated against pre-determined criteria.

2. As a pre requisite, all of the studies should be conducted in a details study, pre authorized protocol or the series of protocols, which in turn is subject to formal, change control procedures.

3. Both of the personnel who are conducting the study and who are those running the process being studies should be appropriately trained and qualified and should be suitable and competent to perform the task that are assigned to them.

4. Availability of the suitable facilities, equipment’s, instruments and methodology is necessary.

5. Suitable clean room facilities should be available in both of the local and background environment. There should be assurance that the clean room environment as specified is secured through the initial qualification and subsequently through the implementation of a programme of re testing in process equipment should be properly installed, qualified and maintained.

6. The process should be revalidated at intervals.

Protocol should be specified in the following ways:

1. There should be already a definition of the purpose, objective and the scope of the study.

2. There should be Installation and qualification requirement for new equipment’s.

3. Any upgradation requirement for an existing equipment with a justification for the changes and also for the qualification requirements.

4. Requirement of the calibration of the test equipment’s.

5. Reference to any of the relevant standard operating procedure.

6. Requirement for the current format of the report on the study.

7. Acceptance criteria against which the success (or otherwise) of the study is to be evaluated.

8. The personnel responsible for evaluating and certifying the acceptability of each stage in the study and for the final evaluation and certification of the process as a whole, as measured against the pre-defined criteria.

All personnel who are involved in the studies should be properly trained and qualified because the quality of the end product is dependent on them. All the information or data that are generated as a result of the study protocol should be evaluated by the trained and qualified individual. The judgement should be against protocol criteria as the product meeting or failing the requirements. There should be availability of the written evidence that supporting the evaluation and conclusion. If such an evaluation report show that the protocol criteria have not been meeting, then the study will be considered as having a failed to express the acceptability and the reasons should be investigated and documented. Any of the failure to follow the procedure as allowed in the protocol must be considered as potentially compromising the validity of the study itself and requires critical evaluation of all the impact on the study. Finally, the certification of the validation study should determine the pre-determined acceptance criteria that should be against which of the success or failure which was evaluated.

6. CONCLUSIONS:

From the above review study, it was concluded that the validation is a concept that has been growing continuously since its first appearance in the united states in the year 1978.It gives the ideas about the understanding of the existence of the condition like accuracy, safety and efficacy of the product. It is a regulatory requirement to assure the safety of the product. Validation on itself cannot improve but confirm that the process has been developed and are under control. As it is an integral part now a days, it can be classified as various ways, but among other the process validation is an important one and that I have explained in this study.

7. REFERENCES:

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Received on 01.06.2020 Revised on 25.06.2020

Asian J. Pharm. Res. 2020; 10(4):307-311.

DOI: 10.5958/2231-5691.2020.00052.0