Overhauling Compliance and GMPs

The US Food and Drug Administration (FDA) is moving boldly and aggressively to update and revise systems to ensure manufacturer compliance with good manufacturing practices (GMPs). By announcing progress on its initiative to improve regulation of pharmaceutical manufacturing in February, the agency put on hold its controversial electronic record keeping policy and shifted oversight of warning letters from the field to FDA centres. Agency officials also rolled out significant changes in plant inspection policies, a new process for making post-approval manufacturing changes and other actions designed to encourage modernization of production systems. These initiatives are part of FDA's broader initiative to develop a "risk-based approach" to GMP regulation of pharmaceuticals, which was launched last August (2002).

Working together

The GMP overhaul is headed by Center for Drug Evaluation and Research (CDER) director, Janet Woodcock, but also applies to biological and veterinary drugs. As described in a 6 month 'progress report' (www.fda.gov/cder/gmp/index.htm), the initiative involves dozens of staffers in FDA centres, district offices under the Office of Regulatory Affairs (ORA) and the commissioner's office who are developing a broad range of policies. Another update is expected in 6 months as FDA gains input from industry and other parties (see sidebar "Working together").

Reinventing inspections

A major thrust of the programme is to make the GMP inspection process more efficient. FDA acknowledges that limited resources prevent it from inspecting every pharmaceutical manufacturing plant, warehouse and packaging facility every 2 years, as required by statute. The agency consequently seeks to target inspections to higher-risk facilities and to streamline the inspection process itself. Last year, CDER fully implemented a systems-based inspection programme for drugs that focusses inspections on key aspects of a manufacturing process, instead of covering the entire plant.

The current initiative continues this approach by identifying those higher-risk facilities that should be at the top of the inspection priority list. These include:

• sterile drug manufacturing operations

• prescription drug manufacturers (excluding medical gas repackagers)

• new registrants not previously inspected.

The agency aims to inspect those higher-risk facilities every 2 years, while visiting the thousands of medical gas repackagers much less often. The next step is to develop a "more complex" risk-based model for prioritizing sites for inspection. This will consider additional risk factors such as extent of patient exposure, type of formulation and GMP compliance record of the company. FDA aims to concentrate its resources on those facilities where non-compliance is most likely to yield the greatest adverse public health consequences, explained David Horowitz, director of CDER's Office of Compliance. His office was reorganized recently to create a Division of Compliance Risk Management and Surveillance that will identify more high-risk facilities requiring more frequent inspection and relate risk data to oversight activities.

In addition to refining inspection priorities, FDA is making significant changes in who conducts inspections, evaluates GMP violations and determines appropriate enforcement action. These important initiatives will:

Establish a pharmaceutical inspectorate. Similar to the Team Biologics programme for biotech products, FDA plans to form teams of specially trained inspec-tors to visit pharmaceutical manufacturing facilities. Instead of a central cadre that inspects plants across the country, as with Team Biologics, there will be multiple pharmaceutical inspection teams in ORA district offices that will conduct preapproval as well as GMP inspections. FDA hopes to enroll 15–25 drug inspectors in the programme by June.

Add product specialists to inspection teams. CDER specialists will be more available to participate in field inspections when needed. This is likely to occur for manufacturers using unique delivery technologies such as a new patch; a special process analytical technology (PAT) inspection group will review facilities implementing new production systems. It remains to be seen if increased use of specialists slows down inspections, delays approvals or is too costly, as some fear. If so, FDA may look at ways for specialists to advise inspectors without actually participating in site visits.

Reduce disputes involving inspection deficiencies. FDA is encouraging manufacturers to discuss with investigators any observations listed on a 483 inspection report that a company feels are unjustified scientifically. The aim is to resolve issues early, where possible, and avoid listing incorrect observations. FDA will also test whether allowing a 48 hour delay in issuing a 483 could resolve scientific and technical issues that arise late in inspections and thus reduce citations and warning letters. The agency plans a 12 month pilot to determine whether such a delay allows inspectors to consult with FDA experts. The agency hopes that this approach will encourage the use of new technologies, instead of the "don't use" approach adopted by firms to avoid technical disputes with field inspectors.

FDA is also adding extra wording to the 483 report to clarify that cited deficiencies are only "inspectional observations" and do not represent final agency determination of company compliance with GMP regulations. The aim is to help manufacturers and others understand that these observations are just "one piece" of the overall compliance process, explained ORA chief, John Taylor.

Shift control of warning letters to centres. A major change is to return final review and authority to issue manufacturing warning letters to CDER, CBER (Center for Biologics Evaluation and Research) and CVM (Center for Veterinary Medicine). A decade ago, FDA transferred warning letter oversight from the centres to the field to speed up and gain more uniformity in the compliance process. This latest change again seeks to reduce inconsistencies in warning letters, now citing those that arise from differing approaches among ORA district offices. FDA's chief counsel will continue to have final clearance on warning letters, which aims to centralize agency authority and add weight to final letters.

In CDER, Horowitz's compliance office will conduct a "triage" on warning letters proposed by district offices. Letters citing obvious violations may be sent out immediately, whereas others that raise technical issues may be further reviewed by a cross-agency group, explained Woodcock.

Establish a formal dispute resolution system. FDA plans to create a process for resolving those disputes arising from GMP inspections that cannot be resolved informally during or immediately following an inspection, as described above. A manufacturer may first request a formal review of a 483 citation by the district office, in consultation with the appropriate centre. If the company disagrees with decisions at that level, it can appeal to a dispute resolution panel in the office of the commissioner. FDA is developing criteria for determining when an issue involves scientific and technique issues suitable for dispute resolution; how and when a firm may seek such reviews; how FDA will resolve internal disagreements arising from such deliberations; and methods for disseminating information on resolved disputes.

The overall aim of these new policies is to prevent a delay in approval of new products because of technical disagreements that arise during inspections. FDA also hopes to avoid issuing invalid 483 observations and warning letters that lead to contracted disputes. In addition, the agency wants to avoid pressuring a manufacturer to make what it considers unnecessary changes in production processes merely to gain agency approval.

Encouraging innovative changes

FDA officials believe that streamlining the inspection process and reducing needless disputes will encourage manufacturers to implement new production technologies designed to reduce manufacturing errors and promote quality production. FDA launched the PAT initiative 2 years ago, which promotes the use of new process monitoring and control technologies to improve manufacturing efficiency.

A working group is developing a draft guidance on regulatory processes for applying PAT and the agency has formed a PAT review-inspection team to facilitate oversight of such innovations.

The GMP initiative seeks to spur further use of new manufacturing technologies by making it easier for firms to implement post-approval manufacturing changes. FDA issued a draft guidance in February that clarifies how firms can develop comparability protocols (CPs), which can reduce the need for prior approval of changes in production systems from agencies.

Manufacturers have always been able to develop protocols for making certain routine CMC (chemistry, manufacturing and controls) changes, such as revisions in packaging or expiration dates. During the past decade, CDER has developed the SUPAC (scale-up and post-approval changes) programme, which simplifies regulation of specified post-approval changes in manufacturing processes and systems for certain dosage forms. To facilitate changes for more complex drugs made from biotechnology that do not lend themselves to the SUPAC model, FDA has issued guidances on how biotech companies can establish comparability protocols to gain more predictability for contemplated post-approval changes.

This new initiative clarifies how the CP approach may be used by manufacturers of conventional drugs, including animal drugs and generic products. The draft guidance spells out the basic elements of a CP, including acceptance criteria and tests and analytical procedures to be used to document that certain changes do not adversely affect product quality. A CP would consist of a detailed plan for documenting such comparability and may be submitted as part of a new drug application or after initial product approval. It allows FDA to designate a reduced reporting category for a subsequent manufacturing change (that is, a changes-being-effected supplement instead of prior approval).

CPs may describe one or multiple CMC changes and will be more or less difficult to compile depending on the complexity of a product and ability to characterize it. Those drugs that are robust, fairly safe and sensitive to analytical procedures may be more suitable for this approach. FDA discourages using CPs for significant changes in product specifications, formulation, type of delivery system, source materials, or in moves to a new site or facility that require a new GMP inspection. Protocols may be most useful in changing to equipment with a different operating principle, as could occur in implementing PAT.

Manufacturers will have to decide individually whether it makes sense to document the analysis and testing needed to file a CP. A firm may find it valuable to gain FDA agreement on a strategy for implementing manufacturing changes that it knows it wants to make. Biotech manufacturers have generally found comparability protocols too complex and detailed to tackle before market approval, but FDA anticipates broader use of this approach for small molecules, commented Ajaz Hussain of CDER, who heads up this project. Manufacturers have until 20 April to submit comments to FDA on the proposal.

Starting over on Part 11

One of the most significant announcements in the February GMP progress report was that FDA has launched a broad re-examination of its regulation for electronic record keeping and submissions, and will not enforce previously announced policies in this area for now. FDA issued a new draft guidance to explain its intent to narrow its approach for implementing Part 11 and to be lenient about requiring compliance with recent guidances. The agency acknowledged that this effort "may lead to revisions to clarify its scope and requirements" of Part 11 - for all FDA-regulated products, including medical devices and foods in addition to drugs.

In effect, it's back to the drawing board to develop a new policy for requiring validation and documentation of electronic records keeping systems. FDA has spent years deliberating this programme, which led to the publication of regulations for implementing Part 11 in 1997. Unfortunately, that policy generated voluminous objections from manufacturers for being too vague, too complex and too costly to implement. The agency tried to clarify its approach in several draft guidances and numerous presentations, but recent efforts to enforce Part 11 rules during GMP inspections raised further outcries.

When FDA launched its GMP overhaul initiative last August (2002), it signalled that a major change was under way by shifting responsibility for implementing Part 11 from ORA back to CDER. The agency then withdrew a draft guidance on electronic copies of records on 4 February 2003, to halt further industry review of the policy. As part of its GMP progress report a few weeks later, FDA issued its new draft guidance, which withdrew an internal compliance policy guide plus other draft guidances on validation, glossary of terms, time stamps and maintenance of electronic records.

Most important for manufacturers is the promise that field investigators will exercise "enforcement discretion" for regulating Part 11 while agency officials re-evaluate the rule. FDA "will not normally take regulatory action to enforce compliance with the validation, audit trail, record retention and record copying requirements of Part 11," the draft guidance states. The agency says it will continue to enforce electronic signature policies that apply to legacy systems, as well as predicate rules that require records to be maintained and submitted in a secure and reliable manner. FDA recommends that manufacturers maintain audit trails or other security measures to ensure the reliability of records and also validate computer systems that could affect product quality, safety and record integrity. Manufacturers should also supply copies of electronic records as required by predicate rules and protect electronic records so that they can be retrieved if needed.

Agency officials explain that they will seek a more narrow approach to Part 11 to clarify that the policy does not apply to every use of a computer or information system by a manufacturer. For example, Part 11 would apply to records maintained by a company in electronic format, but not to a computer that generates paper printouts of electronic records and other "merely incidental" uses of computers.

FDA plans to quickly publish a final guidance to clarify its policy review process. A key challenge for the agency is to determine whether it needs to revise the basic regulation or can accomplish its objectives through new guidances.

In addition to finalizing the two new draft guidances and implementing new inspection procedures, FDA officials plan to move forward with efforts to increase the quality of its own regulatory processes. FDA is commissioning an outside study of effective business practices and policies that could apply to internal review operations. The agency also seeks to harmonize its GMP policies with international standards through continued discussion with regulatory authorities and manufacturers in the International Conference on Harmonization (ICH). Agency officials will explore related topics for harmonization with colleagues at an ICH July (2003) meeting in Brussels.