FDA Drug Evaluation Office to Change Method of Good Manufacturing Practices Inspections
From FDA Enforcement Manual, Thompson Publishing Group
Borrowed Idea
GMP Inspections
Fewer Preapproval Inspections
Taking its cue from the Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER) currently is revising its inspectional program to provide for a systems-based approach that would facilitate shorter, more consistent good manufacturing practice (GMP) inspections, according to an agency official.
Because the new program would allow the FDA to inspect drug manufacturers more frequentlyand thus give the agency a more accurate assessment of the current compliance status of a firm—CDER also is revising its preapproval inspection (PAI) program to give District Offices the authority to waive some currently required PAIs for firms in good compliance standing, according to Joseph Famulare, director of CDER's Division of Manufacturing and Product Quality.
The Center plans to transfer the resources it saves from conducting fewer PAIs to its postmarket inspection program, which would further facilitate more frequent GMP inspections, Famulare noted.
Speaking at a June 6 Food and Drug Law Institute conference in Washington, DC, Famulare said that the revisions to the GMP program would enable CDER to better assess the compliance status of manufacturers as a whole, rather than their compliance status for a particular product or class of products, as often occurs under the current GMP compliance program guide.
Borrowed Idea (Back to Top)
By adopting a systems-based approach to drug GMP inspections, CDER is borrowing an idea first developed by CDRH in its quality systems regulation for medical devices, Famulare acknowledged. However, unlike CDRH, CDER does not plan to revise its GMP regulation to account explicitly for quality systems. Instead, CDER has taken the position that the current drug GMP regulation already comprises six major systems.
Like the device quality system inspection technique (QSIT), the revised drug CPG will provide for a "top-down" inspection, where FDA investigators first will examine a firm's procedures for systems and processes, before delving further into records of complaints, noncomformities, and corrective and preventive actions.
By replacing its traditional "bottom-up" inspection with QSIT, CDRH has reduced significantly the amount of time it spends on an average device GMP inspection, a result CDER hopes to duplicate when it switches to a top-down approach to drug inspections.
GMP Inspections (Back to Top)
CDER plans to organize the revised GMP CPG into six major systems already imbedded in the drug GMP regulation, as follows:
- quality control system;
- manufacturing resources control system;
- materials control system;
- production control system;
- packaging and labeling control system; and
- laboratory control system.
The revised CPG will permit both comprehensive GMP inspections and abbreviated GMP inspections. A firm would receive a comprehensive inspection if it has not been inspected within the last two years or if it is a "for cause" inspection, Famulare said.
The document would allow District Offices to determine which systems to inspect for both a comprehensive and abbreviated inspection. For example, in the most recent version of the revision, the FDA would inspect the quality control system plus one other major system when conducting an abbreviated inspection. For comprehensive inspections, the most current revision provides that an FDA investigator would inspect "four or five" of the systems, Famulare said.
The revisions should enable FDA investigators to draft shorter, more organized lists of inspectional observations (FDA Form 483s), with observations grouped by system rather than product class, Famulare said. Consequently, District and Center compliance officers could more accurately determine whether a 483 observation is an isolated deviation, or a system-wide deficiency that requires further regulatory action, Famulare noted.
CDER and the FDA's Drug Field Committee currently are discussing the proposed revisions and the agency should issue a final CPG "very shortly," Famulare predicted. Drug companies will have an opportunity to comment on the revised CPG when it is published in the Federal Register, but because the FDA considers the document to be a Level 2 guidance, the agency may implement the program immediately upon issuance.
Fewer Preapproval Inspections (Back to Top)
In conjunction with its efforts to revise the GMP CPG, CDER also is working to revise the PAI CPG to allow for more flexibility in that program (CPG 7346.832). The current PAI program—developed in the wake of the generic drug scandal of the late 1980s—mandates that the agency conduct PAIs as a condition of approval for certain types of high-risk drugs, including drugs that: are on the "Top-200 List" of most widely prescribed drugs; have a narrow therapeutic range; are new chemical entities; or are the first generic or new dosage form in their class.
Under the revisions being discussed, CDER would convert some of the mandatory PAI categories to "potential inspection categories," allowing District Offices to determine whether an inspection is warranted based on the compliance history of the firm, Famulare said. For example, the revised CPG likely would eliminate mandatory PAIs for drugs with narrow therapeutic ranges and for drugs in the bottom half of the Top-200 List, he indicated.
CDER should complete its revisions to the PAI CPG by the end of the year, according to Famulare.
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