FDA Proposes Flexible Oversight for Quality Systems

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Pharmaceutical Technology, Pharmaceutical Technology-10-02-2008, Volume 32, Issue 10

Manufacturers seek real-world benefits from investment in QbD and risk-management strategies. This article contains bonus online-exclusive material.

The promise of the US Food and Drug Administration's quality-by-design (QbD) initiative is that manufacturers that demonstrate extensive process understanding and control will enjoy a flexible regulatory approach, as well as increased assurance that their products are safe, effective, and of high quality. For the past decade, FDA has been striving to modernize good manufacturing practices (GMPs), improve its pharmaceutical inspectorate's abilities, and promote quality manufacturing on a global basis.

Jill Wechsler

Recent crises involving adulterated and contaminated drugs and pharmaceutical ingredients have raised the profile of FDA's ongoing campaign. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), has championed these initiatives for years, and they remain top priorities for her.

Woodcock and leaders of CDER's Office of Pharmaceutical Science (OPS) are counting on industry to implement sophisticated quality testing and production methods to help monitor thousands of products that are quickly shipped around the world. A series of standards developed by the International Conference on Harmonization (ICH) describes how, on a global basis, process understanding and control should be based on sound science and quality risk management.

Manufacturers, for their part, have been hearing speeches about QbD and design space for nearly a decade. Now they are looking for evidence that investment in quality systems and processes will improve the efficiency of the application-review and approval process, ease the burden of plant inspections, and rationalize the postapproval drug-monitoring system.

FDA officials seek to meet such expectations through pilot programs and new policies that link QbD approaches to flexible regulation and real-world management of product risks. QbD is not just a "buzzword," commented Moheb Nasr, director of OPS's Office of New Drug Quality Assessment (ONDQA) and a member of Pharmaceutical Technology's Editorial Advisory Board, at the Drug Information Association annual meeting in June 2008.

In Washington This Month

Nasr believes that quality risk management has become sufficiently accepted around the world to define a systematic approach to pharmaceutical development and manufacturing. QbD can provide cost savings and improved systems for manufacturers, as well as efficient regulatory oversight by FDA and other authorities, Nasr said at the Pharmaceutical Technology "Quality and Process Excellence" conference in July 2008. QbD helps manufacturers overcome real-world challenges by supporting a formalized approach to quality risk management that improves product design, increases process understanding, encourages continual improvement, and better uses modern manufacturing and analytical technologies. By adopting modern manufacturing methods to ensure quality, manufacturers also can enhance efficiency and reduce costs.

Offering leeway

Flexible regulatory oversight is an added benefit for companies that adopt QbD approaches. Nasr explained that by establishing a design space based on pro-duct characteristics and performance, a manufacturer may gain leeway to reduce end-product release testing and to make process improvements without further regulatory review.


Another potential reward for manufacturers that use QbD is relaxed requirements governing postapproval manufacturing changes. FDA has developed a guidance to spell out opportunities for reduced oversight of certain low-risk chemistry, manufacturing, and controls (CMC) changes. The agency's plan outlines more than 40 categories of changes that could be downgraded to allow manufacturers to report such actions in annual reports instead of filing changes-being-effected supplemental applications. Many of the reductions essentially involve administrative changes that do not need extensive CMC review, Nasr explained. Simplified reporting may apply to changes involving the following elements:

  • Components and composition (e.g., formulation changes that do not alter drug release, the elimination of an overage, or a switch to a new nonfunctional coating material previously approved by FDA for other products).

  • Manufacturing processes (e.g., installing new equipment of similar design to equipment being replaced or adding a duplicative process as part of scale-up without changing parameters).

  • Site changes for test laboratories or the packaging of oral solids. A move to a new facility for producing active pharmaceutical ingredients (APIs) could be simplified if the facility is already approved for another product that is administered by the same route and made by the same company. Most site changes affecting biotechnology products would still require notification and FDA review.

  • Specifications related to an additional in-process test or to tightening existing acceptance criteria.

  • Container-closure systems (e.g., changes for nonsterile drug substances or a switch to a new glass supplier for the same product type).

  • Stability protocols (e.g., to reduce testing frequency or shorten the expiry date, provided that stability is maintained).

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.

A draft guidance for implementing the PMP proposal is being developed by a steering committee that Nasr chairs. The group includes officials from OPS, CDER's compliance office, and FDA's Office of Regulatory Affairs, which oversees drug-manufacturing plant inspections. The guidance is expected to discuss quality-control strategies and risk assessment for drug substances and products and outline how a PMP should describe proposed changes to risk assessment, design-space issues, and continuous-improvement proposals.

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.

Bringing in biologics

The success of the CMC pilot for conventional drugs has prompted CDER to launch a similar initiative for biotechnology submissions. FDA announced the program in July 2008, calling for manufacturers to voluntarily submit CMC information in an Expanded Change Protocol (ECP) that describes the implementation of QbD and risk-management approaches for large molecules. OPS's Office of Biotechnology Products (OBP) is managing the pilot, which accepts original NDAs and biologic license applications as well as supplements.

The stated aims of the OBP pilot are to define clinically relevant attributes for complex products and link these approaches to the manufacturing process. Although many QbD principles apply equally to small molecules and to biologics, assessing relevant attributes is "a much greater challenge for complex pharmaceuticals," states FDA (1). Manufacturers have used comparability protocols to describe the specific tests and acceptance criteria that can ensure that a single manufacturing change will not produce negative effects. ECPs will describe QbD approaches and critical quality attributes as applied more broadly to multiple unit operations. As with drugs, QbD approaches for biologics aim to reduce process variability and to produce consistent therapies that meet quality attributes related to the product's efficacy and safety. This task is more difficult for biotechnology products because they are hard to characterize, and their manufacturing processes are more complex and variable.

Through the OBP pilot, FDA hopes to learn more about ways to link product performance characteristics and quality attributes to clinically relevant measures. The program is limited to 10 supplements and five original applications, preferably products that have been overseen by OBP through the product-development and testing process and that have benefited from early discussions between the manufacturer and FDA reviewers about development issues. Several manufacturers have indicated interest in participating and may submit applications and supplements for pilot review during the next two years.

That information should help the regulators implement a QbD, risk-based approach for complex products and to develop guidance for industry. As with the CMC pilot for drugs, manufacturers that adopt quality and risk-based approaches may gain leeway to make manufacturing-process changes without submitting postapproval manufacturing supplements.

Modifying early studies

Another FDA effort to establish appropriate oversight of drug manufacturing and quality-control methods involves modifying certain requirements for producing test therapies used in Phase I clinical trials. As part of its campaign to encourage innovative drug development, FDA proposed a new policy two years ago to exempt investigational drugs for early studies from certain GMP regulations. The agency withdrew that proposal, however, in the face of objections that the change could jeopardize the health and safety of participants in clinical trials. Since then, FDA has reviewed those comments and devised a new, more clearly articulated final rule.

The new policy, which took effect in September 2008, explains more clearly that FDA is modifying only manufacturing requirements that are not relevant for producing materials for early clinical trials (2). The agency has not changed policies designed to ensure drug quality during studies of large numbers of patients or during commercial production. Instead, the rule drops the requirement of a fully validated manufacturing process (including rotation of stock for drug-product containers) for products made for use in Phase I trials and the requirement for separate packaging and production areas.

The main beneficiaries of the policy are expected to be research laboratories and clinics that conduct investigatorinitiated studies. Some biotechnology companies might find the new policy helpful in producing small quantities of costly therapies because the rule applies to vaccines, recombinant biopharmaceuticals, in vivo diagnostics, blood products, and gene therapies.

But most drug and biotechnology manufacturers that enter Phase I studies with the expectation of moving on to Phase II and III trials are expected to meet GMP standards even when producing initial clinical supplies. Pharmaceutical companies want to ensure that all procedures are in place for future scale-up to larger trials—where test products must meet GMP requirements —and for eventual commercial production. Moreover, study sponsors want to avoid questions about the validity of data from a Phase I study that result from complaints that the test drug was not produced by a well-controlled, reproducible process.

In general, FDA leaves it to manufacturers to determine whether it makes sense in their particular case to produce Phase I drugs without fully complying with Part 211 regulations. Even manufacturers that decide to drop certain irrelevant manufacturing procedures are still responsible for ensuring the quality and safety of their investigational drugs. And FDA emphasizes that it always retains the right to halt a clinical trial if it finds that a test drug fails to meet quality standards.

To avoid such problems, FDA also issued a companion guidance with recommendations for establishing appropriate quality-control procedures for meeting GMP requirements for clinical supplies. The guidance emphasizes that manufacturers of test products should have well-defined written procedures, an adequately controlled manufacturing system, and accurate records from product testing and manufacture. Anyone producing even small quantities of a drug should conduct a comprehensive and systematic evaluation of the manufacturing setting (i.e., equipment, process, personnel, and materials) to identify and eliminate potential hazards. Small-scale operations may do this efficiently by using disposable equipment and prepackaged materials that reduce the chances of contamination. Using contract or shared manufacturing facilities and testing laboratories also may be helpful.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com


1 FDA, "Submission of Quality Information for Biotechnology Products in the Office of Biotechnology Products; Notice of Pilot Program," Fed. Regist. 73 (128), 37973 (July 2, 2008).

2. FDA, "Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials," Fed. Regist. 73 (136), 40453–40462 (July 15, 2008).