FDA boosts cGMP initiative for risk-based manufacturing

By Mark A. DeSorbo

ROCKVILLE, Md.—A final guidance on the use of electronic records and signatures as well as four draft documents on aseptic processing, resolving disputes over scientific and technical issues, protocols and process analytical technology are the latest accomplishments in the Food and Drug Administration's initiative, Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century: A Risk Based Approach.

At an early September press conference, the FDA also announced that it has formed the Pharmaceutical Inspectorate (PI), which will consist of highly trained FDA who will devote most of their time to conducting human drug manufacturing quality inspections at the majority of prescription and other complex or high-risk pharmaceutical operations.

In addition to collaborating with academia, industry and other government agencies to promote innovative approaches to drug development and regulations, the FDA has also announced that it is seeking to improve international standards for drugs through efforts at supporting global harmonization and collaboration with its public health counterparts in other nations.

In particular, several scientific workshops are planned overseas later this year and early next year to educate, discuss and identify new scientific approaches to achieve several goals in the FDA's quest to revamp regulations for pharmaceutical manufacturing and product quality.

“This cGMP initiative for risk-based manufacturing is a major part of the FDA's recently announced strategic action plan,” FDA Commissioner Mark B. McClellan told reporters. “We think the opportunity for improving pharmaceutical manufacturing—to improve efficiency, to improve safety—are substantial by relying on some new techniques, new management techniques, new medical technologies and production technologies that have been developed in recent years since the last time…good manufacturing practices were fundamentally updated, which was about a quarter of a century ago.”

Perhaps the two most important documents to affect cleanrooms and contamination control technology are the guidance on electronic records (CFR 21 Part 11), and the draft on aseptic processing.

Joe Famulare, director of the Division of Manufacturing and Product at the Center for Drug Evaluation and Research (CDER), says the purpose of the Part 11 guidance remains the same—to allow for innovation and the widest use of technology that is consistent with the FDA's public health mission.

The FDA, he explains, continues to re-examine Part 11, saying that the agency anticipates initiating rulemaking to change Part 11 as a result of that re-examination.

The guidance indicates that FDA officials will narrowly interpret the scope of Part 11, and while the re-examination is underway, the agency intends to exercise enforcement discretion with respect to certain requirements.

That is, the agency does not intend to take action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of Part 11 as explained in this guidance. But records must still be maintained or submitted in accordance with the underlying predicate rules, and the agency can take regulatory action for noncompliance.

“We wanted to be consistent with the cGMP initiative and address all parts of regulated industry because Part 11 is not only for drugs, but also for [medical] devices and all parts of FDA regulated industries,” Famulare says. “There have been difficulties with interpretation in the past, and we hope to clarify some of those difficult areas. Two major themes that remain are the narrow scope of Part 11 records and Part 11 signatures, and the areas of enforcement discretion, which is specifically detailed in the guidance.”

Along with a collective effort of FDA offices, Famulare adds that in finalizing the document, officials had the benefit of 61 responses and more than 389 comments from the industry.

Famulare, along with Robert Sausville, branch chief for Biological Drug and Device Compliance, say the aseptic processing guidance will look at numerous areas of the manufacturing process, including the critical role of personnel, isolator and blow fill seal technology, the early upstream processing stem for biologics, as well as the importance of automation, design and control.

“We know that the science of aseptic processing has evolved since the issuance of the 1987 guidance, and with the finalization, we hope to replace it with this more up to date guidance,” Famulare adds.

Sausville adds that the document is also more “user-friendly” now that a table of contents, more headings and subheadings have been added.

We have also added a number of definitions and some new topics,” he says. “We have also harmonized the environmental monitoring expectations with the European Union, and we have also updated sterilization and filtration sections.”

Highly-trained FDA members will now conduct drug manufacturing quality inspections at complex or high-risk pharmaceutical operations.
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