GMPs for Small-Molecule Drugs in Early Development (Part I)

The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) is an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals through scientifically driven best practices and standards. The consortium seeks to contribute to the improvement of the safety and efficacy of pharmaceuticals for patient benefit. The consortium was formed in early 2010 with the goal of collectively addressing the scientific, technical, and regulatory challenges facing the development of both small- and large-molecule derived medicines. The advancement of global, science-based and scientifically driven standards and regulations is a key enabler towards achieving this goal.

Current industry practice and CMC standards

An overarching driver during all phases of drug development is assuring product quality to minimize risk to patient safety during clinical assessment. During the late stage of development, Chemistry, Manufacturing, and Control (CMC) efforts focus primarily on the establishment of processes and controls that have been demonstrated to continually meet the target product profile for the new drug, thereby underwriting its continued safety, efficacy, and quality throughout the commercial lifecycle. This development knowledge is summarized in the documentation assembled to support the commercial license.

A large body of guidance and recommendations exist to clarify the associated regulatory requirements at the time of submitting the commercial marketing application. For example, International Conference on Harmonization (ICH) consensus guidelines and extensive regional regulatory guidance all provide clear expectations, in particular, on how the critical attributes of the commercial product should be identified, understood, and controlled (1). Similarly, FDA guidance on the CMC requirements to support Phase 2b/3 clinical studies, which aim to demonstrate the long-term safety and efficacy of the new drug in the targeted patient population, provides clarity on these late phase expectations (2). ICH guidance on the application of GMP for APIs provides clarity on specific information required for the manufacture of new drug substance for investigational clinical use, which may be applied to earlier clinical phases (3).

From an industry perspective, it is common to consider the "early" phase of development as covering Phase 1 and 2a clinical studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing change into synthetic processes, dosage forms, and the corresponding analytical methods and specifications. For example, simple clinical formulations may be employed during Phase 1/2a that are not intended for the commercial dosage form, but instead are utilized primarily to demonstrate safety and initial proof of concept in the clinic. In addition, these early-stage fit-for-purpose formulations may provide valuable information relating the physico-chemical properties of the drug substance to in vivo pharmacokinetic performance, which in many instances is used to design formulations for late-phase clinical studies and commercial use. Likewise, some information generated from scale-up and characterization of the drug substance can contribute to the overall drug substance knowledge base. This formation and collection of knowledge is consistent with the concepts of the quality by design (QbD).

Developing an understanding of the scope and extent of CMC information required and how GMP is applied during this early stage of development continues to be discussed across the industry. Consulting available guidance is the first step towards this understanding. Activities carried out in support of early development are clearly not in the scope of the ICH guidance, as clarified in the preamble introducing these documents. A rare exception of current regulatory guidance that clarifies compliance expectations during the early phases of development is the FDA guidance on defining GMP requirements for manufacturing and testing of materials intended for early clinical use (4). Some insight on CMC activities associated with the early phase of product development can also be gleaned from historical guidance on the content of regulatory documents for Phase 1 clinical studies (5). Because many aspects of the Phase 2a clinical studies that follow on from a successful Phase 1 program are similar in their scope and expectations, the opportunity exists to formally make this comparison and clarify whether these approaches and expectations can be aligned across early phase studies. The authors strongly believe that additional clarity regarding best practices related to the application of GMPs in early development would greatly assist worldwide regulatory agencies in adapting consistent expectations for the content of original INDs and other early regulatory documents.

The case for consistent early phase development approaches

It is clear that the CMC information generated to support early phase clinical studies should demonstrate that suitable manufacturing and product controls are in place to minimize the risk to patients and assure the quality and stability of the products used. The limitations of the available guidance, coupled with the high likelihood of change described above, results in pharmaceutical companies adopting a variety of approaches based on their interpretation of their internal technical, quality, and process risk assessments. These actions result in pharmaceutical companies providing varying amounts of detail in the subsequent regulatory documents that support early clinical assessment. The processes and procedures adopted may vary in their scope, and content of supporting documentation for either internal or externalized activities. Because products and processes are less well understood in the early phases of development, activities should focus on accumulating the appropriate knowledge to adequately ensure patient safety. Focusing on this area should ensure that beneficial therapies reach the clinic in an optimum timescale with minimal safety concerns. However, the adoption of unnecessarily conservative approaches may lengthen the timeline to clinical assessment or present a barrier to efficient development or innovation. In summary, an exploration of the development and application of consistent phase-based approaches to early drug development would be beneficial to both industry and regulatory stakeholders.

The role of the pharmaceutical quality system in early development is of paramount importance. FDA, EMA, and Japanese regulations require a pharmaceutical quality system be in place prior to the manufacturing of GMP materials. Quality management is overseen by a "Quality Unit" that qualifies and oversees activities in the areas of GMP Materials, Facilities and Equipment, Production, Laboratory Controls, and Packaging/Labeling. The size and complexity of the Quality Unit overseeing GMP manufacturing, and its associated procedures, may vary based on a manufacturers' size and stage of drug development, but the basic aspect of a quality system must be in place. In early development, the manufacturing process is not yet fully defined and the analytical methods are not yet fully validated. Therefore, the quality system implemented during early phase should take into account the likely process changes, in-process adjustments, specification changes, scope of the stability studies, and the continuous development of the analytical methods as intrinsic to the work being performed prior to the determination of the final process and validation of the analytical methods during later stages of development.

With these issues in mind, the IQ Consortium has assembled a multidisciplinary team called the GMPs in Early Development Working Group to explore and define common industry approaches and practices when applying GMPs in early development. The aim of this initiative is to develop a set of recommendations, which can identify opportunities to improve lead time to first-in-human studies and reduce development costs while maintaining the required standards of product quality and patient safety. The Working Group has developed a series of opportunity statements that challenge whether the industry in general is taking full advantage of the flexibility provided in current regulations and guidance during the early phases of drug development. The focus of this Working Group can be summarized into the following opportunity statements:

• Each pharmaceutical company interprets existing GMP guidance according to its own culture and risk assessment practices. Debates between internal company stakeholders often result in conservative "one-size fits all" interpretations across the development continuum that can draw resources away from focusing on the truly critical-to-quality attributes of the drug development and manufacturing processes.

• Feedback from a 2007 Pharmaceutical Research and Manufacturers of America (PhRMA) effort called the R&D GMP Initiative Team indicated that the biggest roadblock to achieving greater flexibility in Early Development was described as "ourselves"; for example, a reluctance from individual organizations to maximize the flexibility offered by current guidance (6).

• A common approach to GMP expectations for early development would be beneficial to build alignment with internal industry stakeholders and across international regulatory agencies. For example, alignment on the content of original investigational new drug applications (INDs) and other early regulatory documents would be beneficial to industry and regulatory bodies alike.

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.

Initially, the scope of this study has been restricted to oral dosage forms of small-molecule drugs, with a focus on the ICH regions, but there is a long- term goal for wider harmonization and international applicability. As described above, the early phase of development is interpreted as applying up to Phase 2a, where the emphasis is on safety aspects in small clinical studies of short duration where robust patient monitoring is utilized. Preclinical studies performed under good laboratory practice (GLP) are not in the current scope, however, certain activities that take place in this phase are discussed where there is significant overlap or natural continuity.

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.

Summary

It is hoped that the output from activities of the IQ Consortium GMPs in Early Development Working Group will provide useful material to support further debate, both internally and within the public forum. The goal is to promote clarity and consensus within the pharmaceutical industry and to establish a more detailed approached to applying GMP in the early phases of development that are aligned across both industry and regulatory agencies. To build on this initiative and encourage further dialogue, the IQ consortium is planning a workshop during 2013 to encourage alignment towards this common approach. It is recognized that these articles are intended to be thought-provoking and individual companies may decide to take a different path to CMC product development than the concepts recommended in the papers.

About the Authors

Amnon Eylath is in Quality at ARIAD Pharmaceuticals, Cambridge, MA; Brent Kleintop and Tony Mazzeo are in Analytical and Bioanalytical Development at Bristol-Myers Squibb, New Brunswick, NJ; James S. McElvain is in Analytical and QC at Kythera Biopharmaceuticals, Calabasas, CA; Andy Rignall is in Analytical Sciences at AstraZeneca R&D, Macclesfield, UK; and John Skoug* is in Formulation Sciences at Abbott Laboratories, Abbott Park, IL.

*To whom all correspondence should be addressed.

References

1. ICH website, See "Quality Guidance Documents," www.ich.org.
2. FDA, Draft Guidance for Industry: INDs for Phase 2 and 3 Studies of Drugs, Including Specified and Therapeutic Biotechnology-Derived Products (Rockville, MD, February 1999).
3. ICH, Q7 G ood Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Nov. 2000).
4. FDA, Guidance for Industry: cGMP for Phase 1 Investigational Drugs (Rockville, MD, July 2008).
5. FDA, Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies, including Well-Characterized, Therapeutic, Biotechnology-Derived products (Rockville, MD, Nov. 1995).
6. J. McElvain et al., "Phase Appropriate GMP Expectations During Clinical Development: An Industry Perspective," presentation at the PDA/FDA Joint Regulatory Conference (Washington, DC, Sept. 2007).