Inside Washington: FDA Revises Inspections and Compliance Policies for Drugs and Biologics

One goal of FDA's initiative to overhaul how it ensures high-quality pharmaceutical production is to apply more oversight and stricter rules to higher-risk products and processes (Inside Washington, October 2003). This approach involves revising field inspection programs and policies to use the agency's limited resources more effectively, particularly as FDA increasingly deals with more complex and diverse manufacturing operations. FDA officials are looking to link inspection priorities to risk factors: new proposals may omit preapproval inspections (PAIs) for low-risk products and select inspection sites based on manufacturing complexity and company compliance history.

These policies are being applied to traditional drugs now, with a plan to phase in changes for biotech therapeutics transferred from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER). FDA is continuing current oversight programs for biologics, with CDER staff now conducting PAIs and Team Biologics continuing to handle GMP audits (see "Assessing Team Biologics" sidebar). Meanwhile, certain CBER compliance practices are influencing new proposals for overseeing traditional drugs.

Adding Expertise

One innovation announced in September is to create a pharmaceutical inspectorate (PI). Similar to Team Biologics, PI will raise the expertise of field officers who inspect drug production facilities (GMP implementation documents available at

www.fda.gov/ cder/gmp/index.htm

). FDA's Office of Regional Affairs (ORA), which oversees the agency's field force, plans to train some 50 investigators to form the PI over the next four years. A memorandum of understanding between ORA and CDER describes how PI members will be selected, trained, and assigned, noting that PI members will focus on facilities that use more complex production technologies. Unlike Team Biologics, these individuals will still be based in FDA district offices and will not travel the country.

Consolidation Update

FDA also plans to include more review specialists in plant inspections to better coordinate application reviews with GMP inspections. CBER scientists and reviewers have regularly participated in preapproval and GMP inspections for biotech products. Now this approach is being extended to drugs. Specialists - from FDA centers or its other offices - will likely play a larger role in conducting high-risk inspections, resolving technical issues, reviewing draft warning letters, and developing approaches for regulating and encouraging new manufacturing technologies.

Flexibility on PAIs

In adopting a risk-based approach to compliance, FDA announced in September that it no longer will mandate PAIs for certain low-risk drugs, including some narrow therapeutic index drugs on FDA's list of the top 200 prescribed drugs. The agency still can conduct PAIs for these products, but district field office managers will gain more flexibility in deciding whether inspections are needed.

Assessing Team Biologics

For biologics, CDER will continue the CBER practice of assigning staff to conduct PAIs, but compliance officials believe that current policy provides flexibility to omit a PAI for a less complex biotech product when warranted.

The new policy is expected to reduce the number of PAIs overall (particularly for generic drugs and postapproval changes) and to allow inspectors to focus on more high-risk products and processes. PAIs still will be conducted regularly for new molecular entities, priority applications, treatment INDs, manufacturers' first applications, companies experiencing GMP problems, and various problem situations.

Resolving Disputes

Because scientific and technical manufacturing disagreements arise during GMP inspections, FDA launched a program for drugs and biotech products to resolve these issues efficiently, hoping to remove roadblocks to manufacturers adopting new technologies. A draft guidance issued in September describes a formal dispute resolution program. As a first step, FDA urges manufacturers to clarify disputes with the plant inspection team during the inspection process. Such discussions may occur as issues emerge or after the inspection when investigators usually discuss their observations with company management.

Pharmaceutical Inspectorate FAQs

If the disagreement is not resolved and FDA issues a form 483 citation, a manufacturer can request the new, two-tiered dispute resolution process. The first tier involves referring the scientific or technical issue to the appropriate ORA district office within 10 days of the inspection's completion. If ORA disagrees with the manufacturer, it will write up a review of the issue, usually consulting with the center staffs involved.

If a manufacturer disputes ORA's position, it can move to tier two and appeal the issue to an FDA dispute resolution panel. The panel of FDA officials will review the case and issue a report.

FDA anticipates the program will address broad scientific issues, such as the adequacy of a manufacturer's process control design or the appropriateness of a particular lot testing or sampling scheme. FDA will launch a 12-month pilot in January and aims to refine the proposal and issue final guidance by January 2005.

Shift to CDER

With the oversight of biologics moved to CDER, the center's Office of Compliance (OC) is monitoring the manufacturing quality of biotech therapeutics. The 208 staffers transferred from CBER to CDER include several compliance officers who joined the new Therapeutic Facilities Review Branch in OC's Division of Manufacturing and Product Quality (see "Consolidation Update" sidebar). This division, headed by Joe Famulare, is responsible for overseeing foreign and domestic drug inspections, drug recalls, and GMP policy development, particularly as it relates to electronic records and electronic signatures. OC's Division of New Drugs and Labeling Compliance monitors labeling requirements, including oversight of Internet claims and health fraud.

As part of a reorganization last January, the OC formed a Division of Compliance Risk Management and Surveillance to help implement new risk management initiatives. Among other responsibilities, this division will monitor reports of drug quality problems and other data to focus GMP inspections on facilities that make higher risk products. OC director David Horowitz plans to target more inspections this year at new establishments and plants that make prescription drugs and sterile products. For the future, FDA is developing more advanced risk-based models to select sites for inspection based on the complexity of manufacturing process, product type, and compliance history. The aim is to focus additional surveillance where quality problems could have a serious impact on patients. Horowitz says that over time, the model for prioritizing sites for inspection will also include the biotech products for which CDER has recently been assigned responsibility. BPI