As the development of a new drug product progresses, the batch sizes manufactured generally increase. The early First Time in Man (FTIM) clinical trials commonly involve dosing to a small number of subjects, with the majority of the manufactured product often being required for stability studies and analytical testing. As one proceeds from formulation design to Phase I clinical trials and subsequently through to Phase II & III, batch sizes generally increase. Following a successful clinical trial outcome, resulting in the granting of a marketing authorization, the batch sizes manufactured may be further increased to cover the market demands.
Current International Conference on Harmonization (ICH) guidelines state that data from stability studies should be provided on at least three primary batches of the drug product (1). The primary batches should be of the same formulation and packaged in the same container-closure system as proposed for the marketed formulation. The manufacturing process used for these primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. Two of the three batches should be at least pilot-scale batches and the third one can be smaller, if justified. Where possible, batches of the drug product should be manufactured by using different batches of the drug substance. Typical batch sizes used throughout development as defined in the European Medicines Agency's (EMA) guidance for Process Validation are laboratory-scale, pilot, and production-scale batches (2).
Laboratory-scale batches. These are produced at the research and early development laboratory stage. They may be of very small size (e.g., 100–1000 times less than production scale). Laboratory-scale batches may be used to support formulation and packaging development, early clinical and/or preclinical stages. Laboratory-scale batches can also be analyzed to assist in the evaluation and definition of critical quality attributes (CQAs). A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates, and drug product.Pilot-scale batches. These may be used in the process-development or optimization stage. They may be used to support preclinical and mid- to later-stage clinical evaluation and also to support formal stability studies. If supporting formal registration, a pilot-batch size should correspond to at least 10% of the production-scale batch. For oral solid-dosage forms, this size should generally be 10% of production scale or 100,000 units, whichever is greater. The choice of pilot scale is often difficult for the project team as members must balance parameters such as anticipated product volumes, anticipated site of production, equipment constraints at that site, and regulatory expectations. With the increasing trend toward developing orphan drugs, the authors believe that the regulatory expectation of pilot-scale batches of 100,000 units is not always valid and should be discussed with the relevant regulatory authority.
Production-scale batches. These batches are of the size that will be produced during the routine manufacturing and marketing of the product. Data on production-scale batches may not always be available prior to granting marketing authorization.