For the past year, FDA officials have been developing new policies and programs to update and revise methods for manufacturing drugs and biologics. Last month, commissioner Mark McClellan unveiled several key proposals that further implement FDA’s two-year "Pharmaceutical CGMPs for the 21st Century" initiative that was launched last August. The initiative’s aim is to spur industry adoption of innovative manufacturing technologies and to relate agency oversight of pharmaceutical quality to product and process risks.

FDA issued a number of guidance documents last February addressing good manufacturing practices (GMPs) and setting the stage for the recent announcements. The new policies aim to clarify policies for implementing Part 11 electronic records and electronic signatures, managing post-approval changes, and ensuring the quality of sterile drugs produced by aseptic processing. Another draft guidance encourages manufacturers to adopt innovative drug production technologies, and a similar proposal for biotech manufacturing is in the works.

FDA also is making changes in its plant inspection program. It is establishing a special cadre of highly trained field staff to inspect pharmaceutical facilities; revising its pre-approval inspection program to focus on more high-risk products and processes; and establishing a program for discussing and resolving scientific and technical disputes related to GMP issues.

In response, FDA withdrew several earlier guidances on specific Part 11 components in February and announced its intent to adopt a more relaxed enforcement posture for this complex policy. Now FDA is starting over with Part 11 by launching a formal rulemaking process to revise the policy — an initiative that will take several years to accomplish. The main task is to revise the preamble to the rule, clarifying its scope and intent, explains Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER).

While the Part 11 rewrite proceeds, the agency issued a final guidance for manufacturers to follow in the meantime. The guidance clarifies points raised in the hundreds of comments filed by regulated parties, and it reiterates FDA's intention to not enforce requirements for validating computerized systems, maintaining computer-generated, time-stamped audit trails, and ensuring future access to records and copies of them. FDA also will use discretion in calling for legacy systems (those operational before Aug. 20, 1997) to meet Part 11 requirements. Manufacturers must continue to maintain and submit electronic information that meets requirements set by FDA predicate rules calling for controls on electronic record systems, written policies, and system checks to ensure record and data integrity. Additional guidance may be issued on specific issues.

Extending Comparability Protocols Another FDA priority is to encourage industry to develop and file more comparability protocols (CPs) to manage manufacturing changes and simplify the agency's post-approval regulatory process. This approach could reduce the considerable resources FDA devotes to reviewing thousands of manufacturing supplements. It also may make it unnecessary for manufacturers to obtain prior FDA approval before making more routine changes in equipment, procedures, and ingredients.

In February, FDA issued a draft guidance on developing CPs for small-molecule drugs for humans and animals, including well-characterized synthetic peptides. That guidance describes the chemistry, manufacturing, and controls (CMC) information needed to create a protocol able to reduce the reporting category level for a post-approval manufacturing change.

Last month FDA continued this initiative by issuing a similar draft guidance on developing CPs for large molecules, including more complex peptides. The new guidance describes situations where a CP might be useful (such as changes in equipment size, raw materials, and production steps); when it would be inappropriate (for example, changes requiring new clinical data, product formulation, or delivery system type); how it should be submitted to FDA; and what data should be included. The guidance notes that a move to a new facility may be difficult to address in a CP because it could involve changes difficult to identify in advance.

FDA will evaluate comments on this proposal and the earlier draft guidance with an eye to issuing final versions in 2004. The agency also plans to evaluate the number and types of manufacturing supplements submitted each year to identify further opportunities for coordinating review and inspection activities and managing manufacturing changes without prior FDA review or approval.