Many factors are typically considered in setting quality specifications for pharmaceutical drug substances and drug products. The extent of development and commercial-scale manufacturing experience plays a key role in decisions about how acceptance limits are established. As part of the regulatory dossier, it is important that the sponsor provide key information that justifies the tests, analytical methods used, and acceptance criteria applied for quality assessment of a given drug substance or drug product. Appropriate justification data and scientific background can be critical to successful regulatory approval of the proposed specifications. Although prescriptive guidance on how to set specifications is not universally possible nor practical, greater clarity is desirable regarding what body of data and scientific information provides acceptable justification for a given specification and what general approaches are suitable for evaluating these data.

The contents of such a justification may encompass relevant development data, pharmacopeial standards, International Conference on Harmonization (ICH) requirements, batch data for materials used in toxicology and clinical studies, stability information, and data from validation and commercial batches. In some cases (e.g., content uniformity) there are accepted standard criteria articulated in either pharmacopeias or regulatory guidances. In other cases, such as impurities, there is an expectation that the limits are derived in some manner from the development experience.

In considering what development batch data to include, the first clinical batch and beyond are the critical ones, with greater emphasis placed on data for drug-substance batches made by the same synthetic route as that registered in the application. In the case of a drug product, the development batches that represent the same formulation and composition as that being registered are emphasized. Process experience at various scales of operation and the depth of process understanding also should be clearly communicated in the regulatory filing. In deciding what attributes require a specification, it can be just as important to justify which attributes do not require regulatory specifications as it is for those that do and which are deemed important in controlling quality, safety, and efficacy of pharmaceutical products.

One of the most difficult challenges in establishing and subsequently justifying specifications is achieving the appropriate balance among all factors, including patient safety and efficacy, scientific data, analytical variability, process knowledge and capability, regulatory requirements, and business issues. There is clear agreement that the safety and efficacy of a drug to the patient are the primary considerations, but beyond these absolute requirements there is less guidance on how to weigh the other aspects in establishing that a drug is fit for use. The greater the extent of the scientific data and understanding available for a quality attribute, the more prominent scientific considerations become in justifying the specification for that attribute.

When only limited manufacturing data are available at the time of filing, a key question is how to position the acceptance criterion for the attribute under consideration with respect to safety results (including acceptable exposure limits), efficacy, and the demonstrated process capability. It is very common that the limit established solely on safety considerations would be considered too loose by regulators while that based on a regulator's perception of process capability would be considered overly restrictive by a sponsor. A regulator's assessment of process capability is based on limited information available at the time of filing and very likely does not reflect the actual process capability. (Throughout the remainder of this article process capability will be used to represent the zone described by both the variability and the position of the mean of the process, both at development or commercial scale. There is no generally accepted definition for this term in the context of pharmaceutical specifications, leading to widely varying interpretations of this concept, particularly between industry and regulators.)