Conducting clinical trials is an integral part in developing new, safe, and efficacious pharmaceutical products. Exposing
study volunteers to an experimental drug, particularly in the early stages of development, is challenging because of the limited
information on the functional performance of the drug candidate. Regulatory guidances and formal control and approval procedures
are in place to reduce risks and safety threats to study volunteers. This article discusses the management of risks in pharmaceutical
quality of clinical-trial supplies, particularly the challenges that occur for early-stage clinical trial materials for which
knowledge of the drug compound is limited. The basic dilemma that seems difficult to fully circumvent is that one is gaining
knowledge about the importance of quality attributes through the development process, yet the application of GMPs is predicated
on that knowledge. The authors examine this dilemma and resolution in several areas: step-wise modifications of test products,
the concept of "representative," genotoxic impurities, specifications and acceptance criteria, and stability studies.
Basic dilemma
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The principles that ensure that modern pharmaceutical products are produced to be safe and efficacious are codified in cGMPs.
In the US, these requirements are set forth in the Federal Food, Drug, and Cosmetic Act, specifically in Section 21 of the Code of Federal Regulations (CFR) Parts 210 and 211 (1–3). In Europe, cGMPs are specified in Eudralex Volume 4, and similar standards exist in most countries
(4). In large part, existing regulations do not distinguish between clinical supplies and approved commercial products. One
notable, but limited exception, is FDA's approach to certain Phase I clinical supplies.
In 2008, FDA finalized a rule exempting certain Phase I clinical supplies from Section 21 CFR Part 211 and simultaneously issued a guidance describing cGMP expectations for these clinical drug products (5). Although
the guidance relaxes some expectations for clinical supplies compared with those for approved commercial products, the guidance
requires most of the quality systems and components described in Section 21 CFR Part 211, including those for validated test procedures, specifications with acceptance criteria, and stability studies conducted
on representative samples of the clinical supplies.
This situation creates a dilemma for industry and regulators: one is still gaining knowledge about quality attributes during
development, but application of cGMPs is based on the knowledge that is being acquired. More uncertainty about what is important
to quality exists in early development compared with later in development as a product design matures and moves to commercial
approval. This knowledge gap means that it is impossible to implement the same level of cGMPs at Phase Ia as compared with
a commercial drug product.
Although authorities generally do not expect the same level of cGMPs throughout development, there is little specific regulatory
guidance on expectations for early development or for the various stages of development. As a result, International Conference
on Harmonization (ICH) guidances on quality and other guidelines that are designed for commercial products are applied unevenly
and unpredictably to early-development clinical trial materials because the consideration of quality varies from reviewer
to reviewer and company to company. This inconsistency affects issues relating to specifications, shelf-life and stability,
starting materials and the description of an API synthesis, and potential impurities.
