Process control is a prerequisite to the reproducibility of any industrial manufacture of bioproducts according to specifications. Accurate process design and description of process limitations are a must. The limits are defined on the basis of critical data collected at all stages: from initial development to large-scale production. This guarantees that the manufactured bioproduct will meet all its specifications.
Control of impurities is an important aspect. However, there are certain impurities that may not require testing of the drug substance or the drug product, given that the manufacturer demonstrates efficient control or removal to acceptable levels in line with specifications. EMEA's guidelines also take into consideration the fact that only limited data may be available at the time of submission, and may in some cases allow such data to be supplemented after marketing authorization, in accordance with regional regulations.
Process control aims to guarantee consistency of the production process. There are two aspects to process control: defining action limits and acceptance criteria. Firstly, process control is achieved through in-process tests at certain critical steps (or less critical ones) in order to make decisions based on action limits (e.g. investigate or take certain action). Action limits are to be set by the manufacturer on the basis of data gathered during development and validation runs and are subject to further refinement after product approval. Secondly, in-house testing generates data that are compared against relevant acceptance criteria. For bioproducts, for instance, acceptance criteria need to be defined for in-process testing for adventitious agents at the end of cell culture. In some cases in-house tests may offer sufficient evidence of proper adherence to specifications so as not to require testing of the drug substance or the drug product, as mentioned above.
Control must also be done for the quality of the raw materials and excipients according to relevant standards. For example, if the bioproduct is intended for human use (e.g. drug substance or drug product), the raw biomaterials or reagents need to be tested for the presence/absence of potentially harmful endogenous or adventitious agents. If some steps of the manufacture include monoclonal antibodies (e.g. affinity chromatography), measures need to be taken to guarantee that the quality and safety of the product are not compromised by any related impurities or potential contaminants. The quality of the excipients and the container/closure systems is defined in pharmacopoeias. For non-pharmacopoeial excipients, appropriate acceptance criteria should be established.
Pharmacopoeial specifications refer to certain analytical procedures and acceptance criteria, which are applied for evaluation of a drug substance or drug product. Examples of pharmacopoeial specifications for bioproducts include tests for sterility, endotoxins, microbial limits, volume in container, uniformity of dosage units, particulate matter etc. The pharmacopoeial methods and acceptance criteria define guidance values for harmonization so that the analytical procedures and acceptance criteria are identical or methodologically equivalent.
Release limits or shelf-life limits may be established where justified, e.g. potency and degradation products. The release limits are tighter the shelf-life limits of the drug substance or drug product.
Appropriate statistical analysis of quantitative results is required, when necessary. The choice and rationale of statistical methods should be justified and described in sufficient detail to allow independent calculation.