Innovation and improvement
The ability to innovate and improve is crucial, not only to ensure the most up-to-date technologies are used to ensure patient
safety, but also to improve efficiency and eliminate waste. There have been a number of recent examples of incidents where
contamination of drugs has resulted in serious patient harm (e.g., heparin, melamine). These incidents have led to the development
and introduction of modern analytical technologies (e.g., nuclear magnetic resonance [NMR]) to help mitigate risks of future
occurrences. The pharmaceutical industry has not been quick to adopt new measurement technologies for a variety of reasons
such as the significant costs, potential regulatory risk, and resources associated with changing the registered details globally.
At the PDA workshop, an example was shown that illustrated the significant cost that a pharmaceutical manufacturer may be
faced with attempting to introduce improvements to analytical methodology when products are registered in many global markets.
Reducing the barriers to innovation and improvement through better regulation has been a focus of governments through programs
such as the UKs Better Regulation of Medicines Initiative (BROMI) or the Executive Order 13563—Improving Regulation and Regulatory
Review in the US.
There are examples from the pharmaceutical industry where flexibility to use any appropriate method is allowed (e.g., FDA's
melamine guidance) (15) which states "alternative method or methods can also be qualified for use in screening components
for the presence of melamine" and defines the performance required as, "The test method used should be suitable for detecting
melamine contamination in at-risk components down to at least 2.5 parts per million (ppm)," or FDA'S Heparin Guidance (16)
that again allows alternative methods to be used. Recent proposed changes to the FDA guidance on sterility testing are "intended
to provide manufacturers of biological products greater flexibility and to encourage use of the most appropriate and state-of-the-art
test methods for assuring the safety of biological products" (17).
The concepts of comparability protocols/postapproval change management protocols introduced in October 2012 in the US and
in Europe may provide a mechanism of facilitating easier postapproval changes. Again, as previously stated, from an industry
perspective it is crucial that there be alignment in thinking in this area.
Global alignment of stakeholders
As highlighted already, it is key for an industry that manufactures and markets globally to have a regulatory framework that
also operates globally (aligned and harmonized). In the field of analytical science, the regulatory framework is defined by
a number of stakeholders—the regulatory authorities, the pharmacopeias, and other standard setting bodies such as ISO and
ASTM, which may be recognized by the regulatory authorities. With the changes associated with the introduction of QbD, it
is important that the thinking and concepts are aligned across these different bodies. The development and publication of
ICH Q8, 9, 10, and 11 have played a significant role in motivating alignment among the ICH regions; however, not all the thinking
in this area is integrated. It is, however, recognized that the European Pharmacopoeia has already been offering flexibility
including the use of alternative approaches for a number of years, which is expressed in particular in the Ph.Eur. (General Notices section 1.1). Moreover, the European Pharmacopoeia has been playing a leading role in developing thinking
on the implications of large sample sizes (9). The USP has been promoting the concept of performance-based monographs and
has issued examples of these in a new USP Medicines Compendium as well as a general chapter on how to define performance requirements
for methods. USP has also recently established an expert panel that is looking to revise its guidance on method validation
and verification. ASTM has been developing guidance on how PAT methods should be validated, while the EMA has issued new draft
guidance on use of NIR (18). FDA is promoting thinking on the use of confidence intervals for batch release decisions with
reference to ASTM guidance on this topic (19).
Ensuring global alignment is an extremely difficult goal; however, from an industry perspective it is the key barrier to innovation
and effective implementation of QbD. To advance these concepts, more must be done in this area. It is encouraging to see
that pharmacopoeia authorities have agreed to discuss global good pharmacopoeial practices under the auspices of the World
Health Organization (WHO).