INTRODUCTION:

The prime objective of any pharmaceutical plant is to manufacture products of maximum efficacy but along with this the next main objective is quality product which needs to be monitored at every stage of development of product life cycle, at the lowest possible cost. Since validation studies have been conducted by pharmaceutical industry for a last few year, there is 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 come through the years for activities of 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.^1,2

The word validation simply means assessment of validity or action of proving effectiveness. Validation is a collaborative effort with people from all disciplines in the factory. This principle includes the understanding that performance, safety, and the conditions under which performance is created or built into the product. Control every step of the manufacturing process, from processing and inspection or testing of the finished product only, to ensure that the final product meets all quality specifications, including specifications, without quality assurance. The development of pharmaceuticals is a long process that includes drug discovery, clinical trials, animal studies, clinical trials and regulatory registration. Process control includes raw material analysis, process control, and final product planning.³ The goal is to monitor and then complete the online and offline performance of the production process. Even after the manufacturing process has been approved, now good manufacturing must establish a quality control system to monitor its performance.

Validation is 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.^4,5

NEED FOR VALIDATION:

It might not be feasible to use equipment not knowing if it'll produce the merchandise we would like, not to employ people with no assurance that they can do or fail to implement process checks or examinations to ensure that the product meets specifications. The pharmaceutical industry uses expensive materials, sophisticated facilities and equipment, and highly qualified personnel. The efficient use of those resources is important for the continued success of the industry. The value of product failure rejects reworks, recalls, and complaints are sufficient a part of the total production cost. Detailed study and control of the manufacturing process batch validation is important if failure cost is to be reduced and productivity is improved. There are three reasons by the pharmaceutical industry is concerned that their processes perform consistently expected that is, that are validated.

HISTORY OF PROCESS VALIDATION:

The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in 1979 in the USA, to improve the quality of pharmaceuticals. It was proposed in direct response to several problems in the sterility of the large volume parenteral market.

1978: GMP includes validation.

1987: First validation guidelines (Equipment IQ).

2000: New Approaches/Documentary presentation.

2008: New Process validation Draft guidelines.

(Equipment and analytical validation)

2011: New Process validation guidelines issued.⁶

Phases of Validation⁷:

The activities relating to validation studies are classified into three phases:

1. Phase 1 Pre-Validation Phase or the Qualification Phase:

Qualification involves the process related to product development and research development. it also includes commercial batches and technology transfer batches. Technology transfer to commercial batch production is also under the qualification phase. Stability studies along with storage and handling of IPQC and finished drug product. The qualification phase is further divided into:

· Equipment Qualification

· Installation Qualification

· Master Formula Record

· Operational Qualification and

· Process Capability.

2. Phase 2 Process Validation Phase (Process Qualification Phase):

Designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the “worst case” conditions.

3. Phase 3 Validation Maintenance Phase :

Validation consists of information-related procedures, including verification of reports. The production process does not contain changes, deviations, malfunctions, or modifications, and all operational procedures are followed along with the change management process. At this stage, the verification team also ensures that there are no changes/differences that would lead to compliance and reuse.

OBJECTIVES OF PROCESS VALIDATION⁸:

· The manufacturing process, in addition to each equipment, must be validated.

· The goal is to create a strong manufacturing process that consistently produces a drug product with less variation that adheres to quality criteria of purity, identity, and potency.

· A validation plan for the manufacturing process should be formed and executed by engineers to satisfy guidelines. The validation plan usually involves just a PQ section.

· If major changes occur after the initial validation will result in the need for subsequent revalidation like equipment validation.

· In the end, process validation will ensure a robust product that is highly reproducible over time.

Importance of Validation⁹

· Assurance of quality.

· Time bound.

· Process optimization.

· Reduction of quality cost.

· Reduction in rejections.

· Increased output.

· Avoiding capital expenditures

· Fewer complaints about process-related failures.

· Reduced testing in process and finished goods.

· Improved employee awareness of processes.

Responsibilities to Perform Process Validation Fluently:

Department	Responsibility
Manager production	Responsible for manufacturing of batches and review of protocol and report
Manager QC	Responsible for analysis of samples collected
Executive QC	Responsible for samples collection and submission to QC
Manager Maintenance	Providing utilities and engineering support
Executive Production	Responsible for preparation of protocol and manufacturing of validation batches
Manager QA	Responsible for protocol authorization and preparation of summary report

Types of Process Validation:

1. Prospective Validation:

Prospective validation is usually carried out when always need a new formula, process, and/or feature accredited before regular Production begins. It is also usually functional when there is enough historical information unavailable or inadequate and in-process and final product testing is insufficient to ensure a high degree of confidence for product quality. In prospective validation, validation is the protocol the process is run before it is placed for commercial use. During product development phase, the manufacturing process should be classified into individual measures. Every step should be evaluated based on experience or theory consideration to determine critical parameters that can affect the quality of the finished product. Every experiment should have a plan and full documentation in the authorized protocol. All equipment, production environment, and there should be analytical testing methods full recognition has been given. Only master batch documents can be prepared after the critical parameters of the process are identified and machine settings, components there is specifications and environmental conditions have been determined. A series of chess using this defined procedure should be produced. In theory, numbers processes are carried out and observations are made should be sufficient to allow a normal range of to establish to provide diversity and trends adequate data for evaluation. Three it is generally considered acceptable finally with continuous bash chess/run agreed parameters, giving the desired product quality forms the right belief process. Recognition During the process of chess there should be extensive sampling and testing prepared and on production, at different stages extensive documentation should. In detail should also be tested on the final product in its package. Following the conclusion of the review, recommendations should be made on the extent of monitoring and restrictions required for regularity in the process product. This should be included in batch production and packaging records or proper S.O.P. limits frequency and actions will be taken in case of limitation exceeded should be specified.¹⁰

2. Concurrent Validation:

It is the same as the future, except for active parenting the firm will sell the product during the qualification run people at its market price. This belief the process of critical processing involves observation measures and product testing. This helps generate documentation to show evidence that the product the process are under control.¹¹

3. Retrospective Validation:

Retrospective validation is the validity of the process accumulated historical production, testing, control, and other information for the product already production and distribution. This kind of belief can use historical data and information batch records, product log books, lots found records, control charts, test and inspection results, lack of customer complaints or grievances, failure reports, service reports, and audit reports. Next, available large historical data may provide more confidence and a better picture than information probably out of a few tests’ recognition. This kind of belief is only acceptable in well-established processes of critical quality there are features and complex process parameters to identify and document. Plus, it's worth it because the specificity and control of the process should be identified and documentation, and there should not be excessive process/product failure except for/partner error equipment failure is not related to equipment suitability.¹²

4. Revalidation:

Revalidation is the repetition of the validation process or a selected part of it. It's either performed periodically to determine the method or to incorporate changes within the procedure. Documentation requirements are going to be equivalent to the initial validation of the method. Revalidation becomes necessary in certain situations.¹³

Regulatory Basis for Process Validation:

Once the concept of having the capacity to foresee and prepare execution to fulfill client prerequisites advanced, FDA administrative authorities built up that there was a lawful premise for requiring approval. The final word for a lawful specialist is Area 501 (a)(2)(B) of the FDandC Act, which states that a sedate is regarded to be debased if the strategies utilized in, or the offices or controls utilized for, its fabricate, handling, pressing, or holding do not accommodate to or weren't worked or managed in similarity with cGMP. Affirmation must tend that the sedate would meet the needs of the act as to security and would have the character and quality and meet the standard and virtue characteristics that it implied or was spoken to have. That area of the act sets the introduction for handling approval necessities for both wrapped-up pharmaceuticals and dynamic pharmaceutical fixings since dynamic pharmaceutical fixings too are considered to be medicate beneath the act. The cGMP directions for wrapped-up pharmaceuticals, 21CFR 210 and 211, were declared to implement the prerequisites of the act. Even though these controls don't incorporate a definition for preparing approval, the necessity is inalienable in the dialect of 21 CFR211.100, which states: “There should be composed methods for generation and process control planned to guarantee that the sedate items have the character, quality, quality, and immaculateness they indicate or are spoken to have.¹⁴

Process validation will be performed in the following steps:

1. Dispensing:

The aim of our test program is essentially to check the feasibility of the required process thus enabling us to provide a process guarantee for each application—the customer benefits by receiving a proof of process before investing in the production equipment. Our dispensing laboratory is equipped with state-of-the-art dispensing equipment integrated into our standard table-top robotic systems. The dispensing equipment available is suitable for mono- or two-component viscous material.

Equipment available in our dispensing laboratory:

· Ceramic volumetric piston pumps – different sizes

· Precision volumetric, positive cavity pumps – different flow rates

· Cartridge dispensers – different sizes

· Jet dispensing devices

· Multiple-axis robotic cells for applications simulation – different sizes

· Certified precision balance

· Ovens and UV curing devices

· Activation and precision surface cleaning by means of atmospheric plasma technology and many others

The tests can be useful to:

· Simulate production working conditions

· Analyze test data as a support in selecting equipment

· Ensure that the equipment complies with the customer specifications and is suitable to guarantee the required performances

· Research new equipment designs

· Visualize, for example using a diagram, the behavior of the equipment in a specific process situation

· Improve the efficiency of the existing processes¹⁵

2. Equipment Qualification:

Calibration is the process of comparing a known device ("standard" device) with an unknown device (target device). During calibration, the offset between the two devices is measured and the target device (if possible) is set back to tolerance. Calibration fil es usually contain "look" and "left" data. When a micropipette is determined to be out of calibration, it is usually sent to the manufacturer for recalibration.

3. Verification:

It is simply the process of "verifying" that a device is within tolerance (within an acceptable range). Verification usually results in "as found" data. If the device is not within tolerance, it is sent for recalibration.

4. Environmental Monitoring:

Environmental monitoring is an essential requirement in the pharmaceutical industry. Results that the manufacturer obtains from environmental monitoring must be reproducible and ensure that the aseptic environment is under control. Today, more than ever, environmental data is scrutinized during FDA CGMP and preapproval NDA inspections and this trend will likely continue. Environmental test methods that have been in existence for years are accepted throughout the industry, but the user must bear the responsibility of proving that the methods yield reproducible results. New test methodologies must be validated to be as good as or better than the methods they are replacing. Currently, environmental result alert/action levels in existing facilities should be based on industry guidelines and facility performance validation. The pharmaceutical manufacturer must demonstrate that the levels that have been established for the facility have a statistical basis related to the historical performance of the facility. As time goes on, environmental levels may be readjusted to coincide with the operational performance levels of the facility.¹⁶

Study of CPP Parameter:

A Critical Process Parameter (CPP) is a term used in pharmaceutical production for process variables that have an impact on a critical quality attribute (CQA) and, therefore, should be monitored or controlled to ensure the drug product obtains the desired quality. Physical and chemical CPPs are commonly monitored using in-line/on-line process sensors or at-line process analyzers. CPPs are covered extensively in FDA guidance, especially the Process Analytical Technologies framework, and the European Medicines Agency’s ICH Q8 (R2). Reliable monitoring of CPPs provides the foundation for process knowledge, process control, quality control, and control strategies. They also play a pivotal role in risk assessment, risk analysis, and quality risk management, all of which foster a spirit of quality by design. CPPs are essential as process engineers optimize the entire process by which raw materials are converted to desired outputs. Often this involves defining a design space and leveraging design of experiments (DoE) studies. The goal is process validation that ensures the safety and efficacy of the pharmaceutical products.

Sampling during production:

The sampling plan and procedure must be defined in the validation protocol and training provided to relevant staff before the validation activity begins. Samples are representative of the entire batch. So it should be uniform and should be taken correctly from the right places. Sampling plans must be developed to take into account the specific characteristics being measured and the risks associated with accepting defective lots. Sampling plans and methods should be predetermined and documented in the protocol. Colleagues involved should be trained. Sampling procedures documented in the protocol should provide sampling locations, sample size, and sampling frequency, and should also include required tests or evaluations. Samples must be representative of the population and the sampling plan must be designed to determine any segregation during blending, transportation or handling and any variability or other factors that may affect product consistency. The need to demonstrate homogeneity of intermediates should be considered on a case-by-case basis depending on how the intermediate is used in the subsequent process. In general, the study of intermediate homogeneity is less important than that of the final product, especially if the intermediate will be further processed in the next or final stages of the process. If the homogeneity of the intermediate is important to the quality of the final product prepared from it, the homogeneity performance of the intermediate mixture should be considered.¹⁷

Models of Process Validation:

Fig. 1 Three model of process validation according to FDA Guidance for Industry

Decision of Process Validation:

Following model can be used for conformation of process validation

CONCLUSION:

Pharmaceutical process validation is the most important and well-known parameter for in- process materials and final products. The product must be designed to be robust enough to withstand the variability of the manufacturing process, and the manufacturing process must be capable and stable enough to ensure the good and safe performance of the product consistently. Process validation includes a set of activities that occur throughout the product and process life cycle. Validation has proven to ensure the efficiency and robustness of the process, making it a complete quality assignment tool for the pharmaceutical industry and for the production of a wide variety of dosage forms and solutions. Validation is the most common term in the field of drug development, manufacturing, and specification of the final product. It also reduces costs associated with process monitoring, sampling, and testing. Above all, consistency and reliability of valid processes to produce quality products are of great importance to the industry—the importance of verifying the quality assurance process. Validation is an extension of the concept of quality assurance because to ensure product quality, strict process control is required, so final product testing without validation provides little quality assurance for various reasons and a very limited sample size. A limited number of tests have been performed on the samples.

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Received on 26.07.2023 Modified on 13.11.2023

Asian J. Pharm. Ana. 2024; 14(1):33-38.

DOI: 10.52711/2231-5675.2024.00007