Process validation: An evidence of quality production

Process validation is a documental evidence that a specific process will consistently produce a product that meets its predetermined specification and quality characteristics, says Prof. (Dr) Biswanath S A

Therapeutic agents are administered to prevent and cure ailments in suitable pharmaceutical dosage forms which primarily comprise tablets, capsules, liquid preparations intended for oral administration, ointment, paste, cream for topical application and injectables for parenteral administration.

The design and development of a dosage form initiates in a small batch scale in a research and development section. However, the design in a small scale can’t simply be amplified to achieve production size batch. Because the amount of material is less in quantity and the equipment used are simple and robust than those used in production scale. Hence, a well-designed pharma industry should have an R&D section from where the developed formula and process pass through pilot batch to production scale batch.

The transfer of technology from laboratory stage to production stage follows the following sequence: Preformulation studies with active drug substance and excipients, development of prototype formula with laboratory equipment, preparation of scale up batches with pilot laboratory equipment for stability testing and possible chemical study, scale up with production size equipment and evaluation, protocol-driven validation studies in production equipment.

Although it is of utmost importance to ensure required qualities of the finished products, these parameters alone may not be sufficient to demonstrate that the process is valid and the manufacturer has full control over the manufacturing process. It also may be necessary to conduct additional tests depending upon the manufacturing process and complexity of the products.

Since the finished products are generated by passing through a number of steps and stages, each of the steps of each of these stages must be defined and the defined parameters must be adhered to. Process validation is an act to establish through documental evidence, a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specification and quality characteristics.

During the development stages, sufficient information regarding the behaviour and the physical and chemical properties of active medicaments, key excipients and the manufacturing process should be collected. The generated information should then be used to identify and evaluate the critical pharmaceutical process parameters. These parameters are then examined and controlled to ensure batch-to-batch reproducibility.

It may also be necessary to challenge the process by making intentional changes to define limits of tolerance. When a particular method of manufacture, based on the consideration of physical and chemical properties of the active ingredients, excipients, formulation and impact of processing on product quality and stability, has been defined and justified, the manufacturing process is said to be fully described.

The process must provide sufficient proof of the feasibility at a production scale batch to ensure consistent approved quality of the product. The data generated by process validation can be used to replace routine verification of certain list on batch-to-batch basis and can be justified for exclusion of the tests on the finished products.

The validation data derived from small laboratory batches help in evaluating and defining the critical product performance characteristics and this enables the choice of appropriate manufacturing process.

The validation data derived from pilot batches can be used to support final stability studies and to support preclinical and clinical evaluation. Data of pilot scale batches gives an indication of production-scale products. The manufacturing process can further be developed and optimised using the data of pilot scale batches. These data assures that the product and the process will be feasible on an industrial scale.

Sometimes non-standard methods may be necessary to manufacture products. In such case, data on three consecutive batches at production scale level must be provided. During scale-up from laboratory scale through pilot scale to production scale, repetition of lengthy and costly tests may be avoided if sufficient information is gathered during properly designed development and process optimization studies. Such information may be used to justify that scale up could be achieved without a consequent loss of quality. If a change in batch size is required, it should be ascertained that such changes in batch size would not change the characteristics of the final products.

However, significant changes, whether introduced intentionally or unintentionally, to processes or new equipment, which are likely to impact on product quality, revalidation is required. Revalidation study should be conducted under following conditions: change in critical component, change in equipment, significant change in processing conditions, change in facility or plant, significant change in batch size and if sequential batches fail to meet the specifications.

The author is Head, Department of Pharmaceutical Technology, Jadavpur University, Kolkata. E-mail: biswanathsa2003@yahoo.com