Quality Issues for Multiregional Clinical-Trial Materials - Pharmaceutical Technology

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Quality Issues for Multiregional Clinical-Trial Materials
The authors examine risk management relating to the quality issues of clinical-trial materials and discuss areas that would benefit from additional consideration and harmonization.


Pharmaceutical Technology
Volume 35, Issue 10, pp. 124-132

Specifications . Formal specifications are required for the release of clinical-drug products and related materials, yet the complete relevant knowledge for establishing meaningful specifications will not exist in the early-development stages, including information needed for selecting tests and the associated acceptance criteria. Some examples include tests for metal catalysts used early in an API synthesis, requirements for residual solvents, and dissolution requirements for solid oral formulations.

Shelf-life and stability . Establishing an initial shelf-life for clinical supply requires extrapolation from a previous representative batch based primarily on limited accelerated testing. Adhering strictly to the ICH stability expectations for establishing and extending shelf-life would be a serious impediment to product development. Again, little guidance exists concerning a practical approach to establishing the initial shelf-life of a prototype product that is likely to undergo significant refinements before a mature product design is achieved. Although most regulators expect concurrent stability studies to be conducted on representative samples of the clinical-trial material, this testing is of limited value with respect to ensuring the quality of the batch and frequently is of little value to the developer.

Starting materials and description of the API synthesis . A commercial API synthesis is, in part, defined by the regulatory approval of designated starting materials. This designation has significant implications because it provides a detailed disclosure of the synthesis process and defines where cGMPs apply. Agreement on starting materials typically occurs before the manufacture of registration batches and is based on a detailed understanding of the factors that influence API quality, in particular the impurity profile.

At the early stages in process development of an API synthesis, there is no regulatory approved starting material designation, and there is a limited amount of information regarding the source or even the absolute identity of impurities appearing or potentially present in the final API. In addition, the route of synthesis is changing and evolving as the requirements shift from laboratory-scale quantities to a commercially viable synthesis. The net result is vague regulatory expectations regarding the level of detail and the extent of disclosure of the chemical steps leading to the final API. As a result, there are often additional requests by regulatory authorities that result in further expenditure of resources by the applicant and regulatory authority or potential delays of clinical trials.

Potential impurities . Although the concept of an actual impurity is reasonably well-defined in ICH Q3A (R2) Impurities in New Drug Substances, the concept of what constitutes a potential impurity is not (6). Decisions on designation of potential impurities, including degradation products, drive many activities and issues for the API and drug product. These decisions include the development of analytical procedures, the designation of API starting materials, the development of the API synthesis, the description of the synthesis, formulation development, and the design of stability protocols. Additionally, any process designating potential impurities must consider the level of concern. Recent emphasis on genotoxic impurities complicates the issue because one must consider whether a particular compound is potentially genotoxic and whether it is present at levels of concern, which are typically in the parts-per-million range. Industry and regulators can improve the efficiency of the pharmaceutical-development process by considering these issues and establishing related best practices to the benefit of the industry and patients.

The concept of "representative"

A key concept of the pharmaceutical industry for introducing change is an assumption that some entity is representative of future materials produced by a proposed process. For example, the registration of a commercial product includes some number of so-called registration batches of API and drug product that are intended to be equivalent in quality and representative of the future quality of the commercial product. An application for a change to an approved commercial process typically includes a collection of analytical results from the product considered to be representative of future production, together with appropriate statistical comparison to the existing product. The term representative does not equate with identical. For example, registration batches may be produced at pilot scale rather than at full production scale and still are considered to be representative of the commercial-scale process. For late-stage and commercial scenarios, ICH Q1A (R2) Stability Testing of New Drug Substances defines what can be considered representative (7).

During all phases of development, this same strategy of using representative materials to justify change, justify reduced stability studies and establish initial shelf-life or extend shelf-life is frequently used and can be a valid and efficient development tool. As change is inherent in development, the ability to use representative materials to initially predict future performance is essential. The same criteria that define representative for a commercial process, however, are not transferable to early development. Again, the lack of regulatory guidance or established industrywide best practices relevant to development leads to unpredictable or uneven acceptance of the use of representative materials by regulatory authorities. There is a clear benefit to develop such best practices and/or regulatory guidance that defines the concept of representative by stage of development.


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