Working Group activities

To address the opportunities identified, the IQ Working Group utilized the experience and knowledge of IQ member companies to produce an aligned and more detailed position on best practices in the application of GMPs in early development. The Working Group has examined the CMC aspects associated with early stages of pharmaceutical development, and agreed on the establishment of best practices and provision of additional clarity would be of benefit focusing on activities in the following areas, which are described in more detail in the sections below: analytical method validation practices, specifications, drug-product manufacturing, and stability.

The goal was to compare how phase-appropriate approaches to GMPs are being used in the early phase of development across the consortium. In this way, clarity on how GMP is being applied to this phase of development can be provided, based on interpretation of the limited CMC guidance available and best practice shared. Allied to this was establishing the baseline requirements, detailed work packages and summary information required to produce effective and approvable regulatory documentation in support of early phase clinical studies.

In each area, Working Groups members explored approaches taken by their own organizations allowing areas of commonality and diversity to be highlighted. Based on this detailed review common approaches and best practices were shared. Where possible, risk-based approaches are advocated, taking into account the complexity of the investigational formulation and its manufacturing process. This information is summarized in four companion papers, which will be published in subsequent issues of Pharmaceutical Technology to exemplify the best approaches taken by IQ member companies represented on this Working Group. The following paragraphs summarize some of the key questions and issues in each area, which will be expanded on in more detail in the forthcoming articles.

Analytical method validation. The analytical methods used to control investigational clinical products are based on good science and are demonstrated to be fit for their intended purpose. A life-cycle approach to the method development process, which is iterative in nature as the necessary controls align with the evolution of the manufacturing process and expanding product knowledge space, is advocated. Demonstrating that the method is suitable for its intended purpose via validation or qualification experiments will be explored and the relative merits of each approach discussed. Specific recommendations for the extent of validation (i.e., criteria studied) for different types of methods and analytes will be made. The Working Group will also propose minimum documentation requirements for early development including the scope and role of procedures, protocols, development reports, the recording of experiments, and appropriate Quality oversight.

Specifications. The development of appropriate control strategies during early development will focus on how phase appropriate specifications might be established during early GMP clinical studies. For example, during the early phase of development, generic approaches to setting certain specification test methods and acceptance criteria may be appropriate. The evolution of acceptance criteria during the early phase of development, as product and process knowledge increases and emphasis shifts from purely safety to safety and efficacy will be explored. The ongoing activity of the control and qualification of impurities from drug substance to finished product will be examined and each contributory element will be discussed in detail. A comparison of internal controls and the specification that will be filed, including any release and stability aspects to support clinical evaluation will be made. The appropriate application of generic or compendial acceptance criteria will also be considered.

Drug-product manufacturing. During the early phase of development, the manufacture and delivery of suitable investigational clinical products into the clinic for proof of concept and preliminary safety assessment requires facilities, manufacturing equipment, manufacturing processes and manufacturing records that are appropriate for this purpose. Suitable controls that protect operator and patient safety mitigate the potential for cross-contamination and associated documentation that provides sufficient detail to ensure quality and facilitate replication of future batches must be in place. Investigational products are fit-for-purpose and may range from predispensed aliquots of the active ingredient (e.g., drug in capsule, drug in bottle) through to prototype formulations designed to evaluate enabling delivery technology (e.g., for poorly soluble compounds or modified release). Their requirements in terms of functionality and in process controls will be different from the more complex later phase or commercial presentations.

The Working Group will explore the level of in-house and regulatory documentation for the key operations associated with the manufacture and supply of investigational clinical drug products. Detailed recommendations, encompassing the agreed upon best practice, will be provided.

Stability. Information to ensure the proposed storage conditions and the time period over which acceptable quality is maintained is required to support early phase clinical studies from a technical and quality perspective. The potential for limited drug substance and/or product availability during the early stages of development means that the maximum amount of information needs to be leveraged from a limited amount of study material. With this in mind, stability strategies to efficiently assign scientifically sound retest/use periods in early development will be considered. The role of predictive modeling, forced degradation, and accelerated stability data will be considered. In terms of early phase regulatory filings, the concept of representative batch data, concurrent stability and differentiating the major/minor process or formulation changes that trigger additional stability studies will also be discussed.