FDA is fast-tracking a set of changes to 21 CFR Part 211 targeting control of raw materials, excipients and components used in pharmaceutical manufacturing. Also being completed are changes impacting management responsibilities, self-inspections, defect investigations, change control, training documentation, and use of purified water in manufacturing.
A GMP guidance detailing expectations for quality agreements is in the works as well, and the regulations may be further upgraded to support the guidance in this area.
Recent contamination and adulteration events in the US and around the world, including the tragic heparin and diethylene glycol contaminations (IPQ May/June 2008 and Nov./Dec. 2008), have prompted FDA to “fast-track” changes to the regulations governing supply chain and ingredient control.
Announcing the forthcoming GMP proposals at a Global Outsourcing Conference at Xavier University on June 14, Center for Drug Evaluation and Research (CDER) Office of Compliance Team Leader Brian Hasselbalch stressed that these adulteration issues “represent credible threats to our marketplace” and that “raw material controls have to be improved.”
Hasselbalch explained that once the agency has completed the drafting process, the proposed regs will follow FDA’s standard review and comment process, with either three or six months to provide comments.
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Hasselbalch, who leads ORA’s Guidance and Policy Team, explained that the changes will primarily involve 21 CFR 211 sections 80 – 96. They will require drug producers to know who the original manufacturer is for all excipients and active ingredients, and any subsequent repackers and relabelers – “that you know who they are, who handles [the material] in the supply chain,” similarly to the EMA proposed pedigree, Hasselbalch said.
The US effort to strengthen its supply chain rules parallels a similar move underway in the EU which was also discussed at the Xavier Conference (see “In the News” June 16 companion story).
In addition there will be an expectation for manufacturers to audit their suppliers, although FDA is still working through the details of those requirements.
“We will not demand that you individually audit,” the compliance official commented. “We acknowledge and recognize a surrogate or a third party audit arrangement. It may be more efficient and more effective, quite honestly.” A third party audit, he said, would have to be performed by “a credible auditing arm [with] certain characteristics that assure the integrity and the quality of the audits.”
The new regs will also require tamper-evident packaging or other security features applied by the original manufacturer or by a subsequent repacker, and use of only components “recognized as safe for their intended use.” Hasselbalch cited BSE materials as an example, and said that the regulation will reference CFR section 300.100 on banned components as well as the inactive ingredient list.
The last proposal in this set of changes will require manufacturers to notify FDA of any lots of components or excipients with “serious defects.” The idea is that FDA can then notify other users of the material and allow them to more quickly recover the material from the market. Hasselbalch noted that “you might not see it for whatever reason, but if somebody else does you will learn about it and that will be to your benefit.”
The second set of changes being made to the regulations represents phase two of an effort FDA has been working on for several years to enhance existing regulations and propose additions. The first phase was finalized last year (IPQ Jul./Aug. 2008, pp. 33 – 40).
The phase two changes include: • establishment of management responsibilities • requirements for self-inspection, change control, and documentation of training and its effectiveness • enhancing existing regulations regarding defect and problem response • requirements for purified and potable water, and • withdrawal of the expiration dating exemption for over-the-counter (OTC) products.
The regulation will contain more detail about corporate responsibility and executive responsibility/accountability, consistent with current guidance such as ICH Q10. The pattern for the GMP development would thus reflect that projected in the quality agreement case – “a guidance first to get you used to it, then the regulation,” Hasselbalch noted.
The FDA official said that most companies already have a self-audit program, and the agency believes it should be required. He assured the audience that FDA’s policy of not looking at the self-inspection reports except in highly unusual circumstances will not change.
Explicit requirements will be added for change control systems, including the requirement for firms to have a change control procedure.
Regarding GMP training, the new regulations will require that the training be performed and documented. It is a “little known fact,” that the regulations do not require this training, Hasselbalch noted, calling it an “oversight.” In addition, some measure of training effectiveness will be required, though how that will be done will not be specified, he explained, adding that FDA will be “open-ended and open-minded.”
FDA will also be enhancing two particular regulations: 211.192 and 211.180(e). The changes, Hasselbalch explained, will “clarify more about what a defect investigation should do and the nature of the follow-up,” including more deliberate analysis, documentation, and timeliness. “We are not going to set timeframes on it – we do not like to do that – but we are going to insist that it be more timely,” he emphasized.
Section 211.180(e) requires an annual review, and FDA wants to specify that this assessment process be more frequent. The review is the “key feedback mechanism in the regulations, to teach you what you did not know about your process and product quality,” Hasselbalch commented.
In the proposed regulation, purified water will become the de facto quality of water for drug manufacturing, and explicit instructions for testing of potable water will also be included.
The last proposed change will be to withdraw the expiration dating exemption for OTC drugs. Currently if the OTC drug is stable for at least three years and there is no daily dose limitation, (e.g., sun screens), there is no requirement for expiration date labeling. Under the new regulations, an expiry date will be required. The reasoning behind this stipulation will be included in the preamble, Hasselbalch commented.
Also in the works at FDA is a GMP guidance that will provide the elements FDA expects to see in a quality agreement, which may be called a “technical agreement” or simply a “contract.” The guidance will explain the expectation that the agreement be in writing and specify clearly what each party commits to do.
Other expectations discussed in the guidance will include: • identification of the contract site address, building, and equipment/line, and services/materials to be provided • description of the drug, its intended use, and all specifications • provision for periodic audits to CGMP and contract specifics • a commitment to share regulatory inspection findings • procedures for change control related to new equipment, facility modifications, change in key personnel, change in SOPs and test methods, and • full disclosure of all errors, deviations, changes, OOS results, and investigations, as well as adverse events that did or might impact the drug.
Hasselbalch also noted that FDA is beginning work on Phase 3 regulation changes, which may include quality agreement requirements to support the guidance and “factors that disfavor quality.”