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:
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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.
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