Regulatory and compendial considerations
Unless there is appropriate justification, the maximum acceptable deviation in the active-ingredient content of the finished product shall not exceed ± 5% at the time of manufacture.Within the pharmacopoeias, there is generally no allowance for an appropriate justification, and in general, regulators ignore this caveat. It is clear that the pharmaceutical industry lags behind many other areas of manufacturing with respect to its approaches to quality and risk management.
During the past 10 years, however, there have been global regulatory changes toward risk-based and lifecycle approaches to cGMPs and regulatory issues relating to chemistry, manufacturing, and controls led particularly by FDA. In 2004, FDA proposed that there should be science-based regulation of product quality stating (2):
As pharmaceutical manufacturing evolves from an art to a science and engineering based activity, application of this enhanced science and engineering knowledge in regulatory decision-making, establishment of specifications, and evaluation of manufacturing processes should improve the efficiency and effectiveness of both manufacturing and regulatory decision-making.
As a consequence, FDA developed process analytical technology (PAT) guidance (3). It stated that "product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance" (3). It further asserted "the advantage of using these PAT principles and tools during development is to create opportunities to improve the mechanistic basis for establishing regulatory specifications" (3). FDA emphasized that one goal of the PAT guidance was to tailor the agency's usual regulatory scrutiny to meet the needs of PAT-based innovations that improve the scientific basis for establishing regulatory specifications.
FDA's process validation guidance, first published in 1987, required major changes to take into account the new risk-based approaches, and FDA subsequently revised and finalized process validation guidance in 2011 (4). The core principle was maintained that if a process were adequately controlled, the product would consistently meet its predetermined quality attributes. The biggest change was a move from a fixed number of batches constituting validation to placing the emphasis on process design and understanding by the generation of a design space. Within this design space, adjustment of parameters would not constitute a change. Hence, for robust processes, the traditional fixed limit is replaced by a proven acceptable range.
Out-of-specification (OOS) results have always been and continue to be a major regulatory concern. FDA took eight years to finalize its guidance on this topic (5) following the 1993 ruling, regarding OOS results, by Judge Wolin in the United States of America v. Barr Laboratories (6). The arguments regarding the "isolation" of outliers from the specification continues to be contentious not only in the US but in the EU as well. The application of scientifically sound statistical methodologies in conjunction with root-cause investigations is acceptable to the authorities provided that their use and application are predetermined and proceduralized. If the regulators wish to move the industry to risk-based process validation, the industry will require that regulators also move toward risk-based specifications, but this topic has not been adequately addressed.