Good Manufacturing Practices: FDA’s 21st Century Quality Initiative Turns From Concept To Implementation

The pharmaceutical industry is welcoming FDA's move toward greater flexibility in quality control inspections and manufacturing changes for firms with good quality systems but seeks more concrete information on how flexibility will be achieved in practice.

Marking the two-year anniversary of its "GMPs for the 21st Century Initiative" in September, FDA released several draft guidances and white papers on a more modernized approach to good manufacturing practices.

The bundle of documents signaled a turning point in the initiative - from assessment and policy design to actual implementation. Now industry wants the next step in industry/FDA collaboration to focus on how flexibility within the process will be acheived.

The 21st Century Initiative documents address a broad range of topics, including innovation and continuous quality improvement, risk-based inspections, warning letter assessment, international harmonization, aseptic processing, and combination products.

Comments on one draft guidance - addressing quality systems - focus on the desire for specific information on converting good quality systems into regulatory flexibility.

The quality systems draft guidance is intended to "serve as a bridge between the 1978 GMP regulations" and more contemporary approaches which stress "quality management, quality assurance, and the use of risk management tools."

In separate December comments on the quality systems draft, for example, several industry groups endorsed what it is a key principle underpinning the entire initiative - that "modern quality systems, when coupled with manufacturing process and product knowledge, can handle many types of changes to facilities, equipment, and processes without the need for a regulatory submission."

Industry groups also lauded FDA's affirmation that "an effective quality system, by lowering the risk of manufacturing problems, may result in shorter and fewer FDA inspections."

Such praise was followed, however, by requests to better clarify FDA's willingness for "regulatory flexibility."

The European Federation of Pharmaceutical Industry Associations commented, for example, that "further clarity will need to be developed on the mechanisms as to how industry and FDA will work together to define and apply 'regulatory flexibility' for filings and inspections where a company meets the criteria for good process knowledge and good quality systems."

The pharmaceutical association PDA likewise found the quality systems guidance "clear" as to the "overall benefit realized by a firm which develops and implements quality systems consistent with the principles stated" but "unclear" as to the specific "mechanisms by which a firm can implement changes without the need for regulatory submissions."

The Pharmaceutical Research and Manufacturers of America also praised FDA's willingness to allow manufacturers to implement changes without submitting regulatory paperwork as a "major step forward."

However, PhRMA asked for further direction on when such flexibility would be allowed, in order to prevent potential compliance problems and misinterpretations.

Abbott Labs went a step further and recommended that FDA hold workshops to outline how the agency will implement the quality systems guidance.

The risk-management approach outlined in the guidance aims to give companies more flexibility to identify and focus resources on areas of greatest potential weakness.

Nonetheless, as the concept becomes practice, industry groups also have reservations that the quality initiative might in fact provide a cloak for FDA to expand its regulatory and enforcement reach.

Citing the guidance's expectations for management and the quality planning process as examples, EFPIA cautioned: "Care needs to be taken that this guidance does not raise the expectations of inspectors or lead to the citation of deviations related to this guidance as opposed to deviations related to compliance with the cGMP regulations."

One outstanding issue is how FDA's enforcement programs will incorporate approaches that are more oriented to risk management rather than a prescriptive set of rules.

"The concept of risk management/assessment is key to the agency's approach and to a robust quality system," PhRMA asserted in comments to FDA. However, the quality systems draft guidance "is very brief on details and direction for risk management."

The developments in FDA's 21st Century initiative and the breadth and depth of the related guidances will significantly affect the review of chemistry, manufacturing and control information in marketing applications as well as the GMP inspection process.

FDA has unveiled an ambitious blueprint for a new "quality assessment system" to replace its current "CMC review" approach.

The system is intended to streamline the regulatory process to encourage continuous improvement and quality innovation via a focus on manufacturing science rather than chemistry. FDA has outlined a restructuring of its CMC review divisions to accommodate the revamped system.

The agency has also adopted a number of GMP strategies to reduce generic drug approval times and address workload issues.

The generic drug initiatives include early review of dissolution methodologies and eliminating re-reviews of active ingredient drug master files. The U.S. Pharmacopeia also is working to clarify regulatory standards for generic products.

For biopharmaceuticals, assessing product comparability is the focus of several regulatory initiatives both in the U.S. and overseas, with broad implications for improving processes and assuring the quality of products.

Emerging regulatory guidances address the complexity of assessing biopharmaceutical manufacturing changes and the links between the process, product structure/function and safety/efficacy.

The International Conference on Harmonization in November completed a harmonized comparability guideline on assessing intra-product manufacturing changes. FDA and the EU are working separately on interpreting the issues for "follow-on" biologics.

Contributed by "The Gold Sheet," a pharmaceutical and biotechnology quality control publication. To learn more, call 800-332-2181or visit www.thegoldsheet.com