A Brief Review on Pharmaceutical Validation
Darshan A. Salade*, Kishor S. Arote*, P. H. Patil, Vikas V. Patil, Amol R. Pawar
*Corresponding Author E-mail: kishorarote770@gmail.com
ABSTRACT:
Validation is the procedure which authorizing documentary evidence that proves the following process will consistently produce the product which leads to the expected result. According to GMP validation studies are important part of GMP these are required to be done as per predefined protocols, the minimum that should be validated include process, testing and cleaning as a result such control procedure stablish to monitor the output and validation of manufacturing processes that may be responsible for variability of drug product. Validation is the one of the important part in achieving and maintaining the quality of the final product. The validation study provides the accuracy, sensitivity, specificity and reproducibility of the test methods employed by the firms, shall be established and documented. Process validation is the process for improving the safety and quality of the dosage form which is manufactured in the pharmaceutical industry. Process validation is an integral part of quality assurance as per cGMP. Validation and quality assurance will go hand in hand, ensuring the thorough quality for product. Process validation plays a key role in the pharmaceutical manufacturing process as it delivers a high degree of assurance and evidence that the process, which is being carried out gives out the uniform results, that is, it means the required specifications, which has been performed accurately. The purpose of this review is to present an introduction and general review on validation in pharmaceutical industry.
KEYWORDS: Validation, Pharmaceutical Industry, Quality Assurance, GMP, Consistent.
INTRODUCTION:
The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals. The prime focus of validation is on ensuring if the quality is built into the system at every step, and not just tested for at the end.1 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.2,3
The key purpose of all pharmaceutical industries is to discover quality products consistently, at the lowest possible cost. Validation plays a very significant role in quality assurance and productivity improvement. Process validation establishes the flexibility and constraints in the manufacturing process controls in the attainment of desirable attributes in the drug product while preventing undesirable properties.4,5
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 211.6,7
Validation has become one of the Pharmaceutical industry’s most familiar and discussed subjects. Its critical success factor in product support and ongoing commercialization. Quality is always an authoritative requirement when we consider any product. Therefore, the drugs must be manufactured to the highest quality levels. Finished product testing by itself does not assurance the quality of the product. A process validation procedure is required as specified by the current good manufacturing practices Regulations for Finished pharmaceuticals and is therefore applicable to manufacturing of drugs.8
Why Validation Is Required:
The pharmaceutical industry uses expensive material, sophisticated facilities and equipment and highly qualified personals. It would not be feasible to use equipment not knowing if it will produce the product we want, not to employ the people with no assurance that they can do or fail to implement process checks or examination to assure that product meet specification. Detailed study and control of the manufacturing process batch validation is necessary if failure cost is to be reduced and productivity is improved. Validation is helps in assurance of quality and reduction of cost. The validation helps in reducing the reject, reworks, recalls and complaints about the product.9
For existence of Safety, Quality, Efficacy1 in product. A validated process gives High degree of pledge for uniformity. Process validation does not improve anything related to quality of the product, but control and maintain the measures to fulfil requirements consistently through adequate validations.10
Types of validation:
Fig.1-Types of validation
Process validation:
USFDA defined process validation as “establishing documented evidence which provides high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.” Process validation provides the flexibility and constraints in the production process controls in the achievement of desirable qualities in the drug product while preventing undesirable attributes.11,12
Types of Process Validation:
A) Prospective process validation:
It is defined as the established documented evidence that a system does what it implications 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 batches.13
The objective of the prospective validation is to prove or demonstrate that the process will work in accordance with validation protocol prepared for the pilot production trials. Prospective validation should normally be completed prior to the distribution and sale of the medicinal product. 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 broken down 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 experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol.14,15
Prospective process validation is executed after the completion of the R and D trial in order to produce the product for the commercial purpose. This is one of the crucial part of the process validation as most validation efforts depends on the prospective experimentation so that data that support the validation could be generated. This type of validation is generally connected with the introduction of new drug product into the market and involves the studies of all their manufacturing processes.16
Prospective validation should include the following
1. Short description of the process
2. summary of the critical processing steps to be investigated
3. List of the equipment’s to be used along with their calibration status
4. Finished product specifications for release
5. List of analytical methods
6. Proposed in-process controls with acceptance criteria
7. Additional testing to be carried out
8. Sampling plan
9. Methods for recording and evaluating results
10. Functions and responsibilities.17
B) Concurrent Process Validation:
The concurrent process validation establishes documented evidence that the process is in a state of control during the actual execution of the process. The in-process testing and/or monitoring of critical operations during the manufacture of each production batch is done for concurrent process validation.18
It is 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.17
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 number 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 number of batches produced are limited.19
C) Retrospective Process validation:
It is defined as established documented evidence that a system does what it purports to do on the review and analysis of historical information. This is achieved through the review of the historical manufacturing testing data to prove that the process has always remained in control. (20) It is conducted for a product already being marketed, and is based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which is now to be validated to confirm to the requirements of division 2, Part C of the Regulation to be Food and Drugs Act. Retrospective Validation is only acceptable for well-established detailed processes and will be Inappropriate where there have recent changes in the formulation of the products, operating procedures, equipment and facility.21,22
The retrospective process validation should contain the following
· 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
· Trend analyses including those for quality related complaint23
D) Revalidation:
Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricator, major equipment or premises. Failure to meet product and process specifications in batches would also require process re- validation. 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.24,25
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)26
Stages of Process Validation:
Process Validation is explained as the group and assessment of data, from the process design stage and between commercial production, which gives scientific confirmation that a process is capable of continually delivering quality product. Process Validation require a sequence of activities taking place over the lifecycle of the product and process. The venture relating to validation studies may be categorized into three stages:8
Fig. 2 – Stages of process validation
Stage 1 – Process Design:
This stage is to design a process suitable for routine commercial manufacturing based on knowledge gained through development and scale-up activities that can consistently deliver a product that meets its quality attributes. This stage provides a key input to the studies that are carried without the application of good manufacturing practices, during the product development studies which ultimately helps in the various design stages such as anticipated dosage form, manufacturing route.27
Stage 2 – Process Qualification:
During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. It confirm that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under “worst case” conditions.28
Process qualification has two stages. They are:
1. Design of the facility and qualification of the equipment and utilities
2. Process performance qualification (PPQ), in this stage CGMP-compliant procedures must be followed.
3) Stage 3 – Continued process validation:
All the continual data assembled to sustain the quality of product are evaluated in the third stage. The goal of the third validation stage is ongoing assurance is gained that the process remains in a state of control during routine commercial manufacturing.21
Phases of process validation:
1) Phase 1:
Phase 1 is also called as Pre-validation Qualification Phase. 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 and storage and handling of in-process and finished dosage forms, equipment qualification, installation qualification, master production document, operational qualification and process capacity.29
2) Phase 2:
Phase 2 is also called as 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.30
3) Phase 3:
Phase 3 is also called as 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.31
Equipment validation:
Equipment validation is established documented set up that proves any equipment works correctly and leads to accepted and accurate results. The process of equipment validation is based on the principle that equipment must be designed, constructed, maintained, and adapted to perform the operations which are to be carried out.32
Types of Equipment Validation:
A) Design Qualification:
“It is a documented verification that the proposed design is suitable for intended purpose.” The design qualification outline the key features of the system designed to address the user requirements, regulatory compliance and selection rationale of a particular supplier.33
Important DQ consideration include:
1. GMP‟s and regulatory requirements.
2. Performance criteria.
3. Facility air flow, movement flow and pressure regimens.
4. Reliability and efficiency.
5. Commissioning requirements
6. Construct ability and installation of equipment.34
B) Installation Qualification:
It is a documented verification that all the aspects of a facility, utility or equipment that can affect product quality adhere to approved specifications and are correctly installed. Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances food and drug administration (FDA).35
Important IQ consideration include:
1. Installation conditions (wiring, utilities, and functionality)
2. Calibration, Preventive maintenance, cleaning schedules.
3. Safety features.
4. Supplier documentation, prints, drawings and manuals.
5. Software documentation
6. Spare parts list.34
C) Operational Qualification:
It is a documented verification that all aspects of a facility, utility or equipment that can affect product quality operate to intend throughout all anticipated ranges. During OQ, critical operating parameters for the equipment and systems should be identified and studies are carried out for critical variables. Studies includes condition or a set of conditions including both upper and lower operating limits referred to as “worst case” conditions.36
OQ considerations include:
1. Process control limits (time, temperature, pressure, line speed, and setup conditions).
2. Software parameters.
3. Raw material specification.
4. Process operating procedures
5. Material handling requirements.
6. Process change control
7. Training
8. Short term stability and capability of the process34
D) Performance Qualification:
It is a documented verification that all aspects of a facility, utility or equipment perform as intended in meeting predetermined acceptance criteria. PQ is establishing confidence that the process is effective and reproducible, establishing confidence that a process in accordance with the design qualifications.37
PQ consideration 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.34
Re-Qualification:
It means ensuring that the equipment is in the state of control after any changes or certain time period and periodic assessment of the equipment within defined intervals is called re-qualification. This should be done with proper review and documentation has to be done. The review should summarize the need for re-qualification. The Preventive Maintenance Program and Documentation system is required to handle small alterations with no direct effect on final or in-process product quality.38
Validation life cycle:
Validation is a continuing and evolving process. The validation process which extends from very basic to very broad theoretical and methodical investigation of how the system and processes perform. Its scope encompasses documentation revision control, training and maintenance of the system and process. Evidence of validation should be seen at the corporate level and be reflected in the management structure. Validation is a method for building and maintaining quality.39
Fig. 3 – Validation life cycle
1. Consistent through output.
2. Reduction in rejections and reworks.
3. Reduction in utility cost.
4. Avoidance of capital expenditures.
5. Fewer complaints about process related failure.
6. Reduced testing process and finished goods.
7. More rapid and accurate investigations into process deviation.
8. More rapid and reliable start-up of new equipment.
9. Easier scale-up from development work.
10. Easier maintenance of equipment.
11. Improve employee awareness of processes.
12. More rapid automation.40
Disadvantages of validation:
1. Validation is time consuming process.
2. The process for manufacture is often complex and costly.
3. Validation also has practical limit and related cost.
Application of validation41
Reduction of quality cost:
Through correct validation, cost of the following procedures can be improved.
a) Preventive costs can incurred in order to prevent failure and reduce appraisal costs.
b) Appraisal costs of inspection, testing and quality evaluation.
c) Internal failure costs
Process Optimization:
The development of the facility, equipment system, closures etc. results in a product that encounter quality necessities at the lesser costs. Trained and qualified personnel’s are the key elements in the process optimization that results in upgrading efficiency and productivity.
Assurance of quality:
Validation and the process control are one of the important protocols of GMPs. Without validation and controlled process, it is impossible to attain quality products. Hence validation is a key element in assuring the quality of the product.
Safety:
Validation can also result in increased worker safety. Properly standardized, validated instruments and devices are used to reduce accidents and results in safety. Validation can also result in the increase in operation safety. e.g. instruments used on equipment that intended to operate at certain temperature and pressures must be dependable i.e. They need to be calibrated.
Better consumer quality:
Through proper validation, market recall is evaded which results in better consumer care and quality of the product. Quality costs are divided in to four categories.
They are:
1. Preventive costs.
2. Appraisal costs.
3. Internal failure costs.
4. External failure costs
CONCLUSION:
This review gives an idea about the validation in pharmaceutical industry. Validation is an essential component of GMP. Validation helps assure product will meet standard quality, safety, efficacy, purity, effectiveness according to GMP. Validation is commonly used in drug development, manufacturing and specification of final product. Validation is helps in eliminating the chances of batch failure as the product are manufactured under optimizing each manufacturing stage. Validation helps in reduce the cost of quality which gives the best quality of product. Validation includes a sequence of activities taking place in the lifecycle of product and process. Finely the pharmaceutical validation helps to provide a positive assurance of batch consistency and integrity of final product which is manufactured under rules and regulations of GMP.
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Received on 02.05.2022 Modified on 18.05.2022
Accepted on 30.05.2022 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Ana. 2022; 12(3):211-217.
DOI: 10.52711/2231-5675.2022.00035