Planning for changes

Manufacturers that anticipate specific postapproval manufacturing changes may benefit further by spelling out such activities in a CMC postapproval management plan (PMP) that FDA is developing. CDER officials previously talked about negotiating CMC regulatory agreements with companies to establish plans for reduced oversight of postapproval changes. But the agency's current thinking is that manufacturers should develop and propose a regulatory framework for managing and implementing postapproval changes specific to each product. The agency then would review and approve such plans as part of the application review process.

A company's plan would reflect its understanding of its process and product and provide a risk-based scientific foundation for managing change. Manufacturers would submit their plans as part of a new drug application (NDA) or supplement. The information would be included in Module 1 of the common technical document if that format is used. FDA would then assess the PMP and refer to it in a resulting approval letter. Although the earlier idea of a regulatory agreement raised legal questions, FDA officials believe that the agency's current statute provides sufficient room to permit the PMP program.

The goal is for manufacturers to gain regulatory relief in the form of fewer or milder plant inspections, as well as fewer postapproval supplements, if they adopt a quality- and risk-based production system. However, reduced prior approval of manufacturing changes would increase reliance on field inspectors to ensure that a change complies with GMPs. Thus the new policy could actually expand the need for plant audits. Whether PMPs lead to less-frequent inspections depends largely on the nature of the change, Nasr explained. Just how field and review activities will mesh to provide efficient and appropriate regulatory oversight remains to be seen.

Building on a pilot program

Lead candidates for testing the PMP approach include manufacturers that have participated in ONDQA's CMC pilot program, which has provided a customized review and assessment of a dozen NDAs and supplements that incorporate QbD approaches. FDA initiated this program in 2005 to examine how manufacturers apply design space and control strategies to actual manufacturing situations. ONDQA has reviewed and approved eight applications under the pilot; three were still under review as of July, and one more application remained to be submitted.

For Nasr and his staff, the pilot applications have provided real examples of how design space and process knowledge can be captured at an operational level and relate to normal operating ranges, equipment, and scale. Nasr reported at the Pharmaceutical Technology conference that the pilot applications have presented evidence of increased upstream testing of critical quality attributes, of on line use of near-infrared spectroscopy for blend uniformity; of on-line analyzers for intermediates; and of in-process testing for tablet disintegration, identification, and dose uniformity.

Companies have not used a standard approach to establishing a control strategy, Nasr said. Some manufacturers controlled excipient properties beyond compendial standards, and some used in-process controls and process analytical technology (PAT) to gain better assurance of quality. Traditional specifications were retained in some cases and dropped in others, based on a thorough process understanding.

The pilot applications uncovered confusion about the role of analytical methods in a quality control system. If the basic premise of QbD is that quality cannot be tested in or inspected in but must be designed into the manufacturing process, Nasr said, that raises questions about the role of analytical methods in monitoring product quality and demonstrating process understanding. QbD does not necessarily mean less analytical testing, he added; rather, it means the right analysis at the right time, based on science and risk level.