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FDA finalizes quality guidelines for contract manufacturers

The Food and Drug Administration has finalized guidelines, three-and-a-half years in the making, suggesting what should go into quality agreements between pharmaceutical companies and outsourced contract manufacturers.

The agency's recommendations come at a time when fully two-thirds of pharmaceutical manufacturing is outsourced, putting significant demand on contract manufacturing organizations (CMOs), according to a recent report from Industry Standard Research.

The FDA's new guidance on quality contract drug manufacturing arrangements, released Nov. 22, includes clarification of issues contained in its draft guidance from May 2013. For example, regulators say guidance is limited to the complex process of commercial contract drug manufacturing, and, while perhaps useful for, is not intended for clinical drug research, development or distribution.

In its 16-page document, FDA also explains that Current Good Manufacturing Practice (CGMP) requirements apply to all contract facilities, including analytical testing labs.

In general, the agency's guidance contains clarifications, not surprises, and basically underscores the need for quality drug manufacturing practices, said Manuel Aragon, president of CTMA Inc., an Irvine, Calif.-based pharma technical services firm.

"None of [the FDA's guidelines] really looked outlandish," Aragon told BioPharma Dive. "They looked like standard procedures that any facility should be adhering to" in order to comply with good manufacturing practices and prevent adulterated drug products.

In its finalized document, FDA recommends that owners and contract facilities implement written quality agreements delineating manufacturing activities to facilitate compliance with CGMP. The agency suggests that quality contracts between companies and CMOs include the purpose and scope of contract manufacturing services to be provided; provisions on how to resolve disputes and how to change manufacturing processes, and contract revision policies.

From a CPMG perspective, regulators said the quality agreement's most critical elements involve manufacturing activities, which should include details on each party's responsibilities and address such matters as how owners can evaluate and audit contract facilities. Also, the FDA suggests the agreement should define owner/contract facility expectations for reviewing and approving documents, including standard operating procedures, manufacturing records, specifications and lab records.

Good outsourced pharmaceutical manufacturing "culture is pretty strong here [in the U.S.]. I've been in the business since 1992 and it was pretty strong then," and has continued to be strong as production has become increasingly high tech, Aragon said. It is a bigger problem with contract manufacturing outside of the U.S., he added, noting examples of production processes going awry can be found in FDA warning letters.

FDA, for example, issued a warning letter Nov. 16 to India-based Wockhardt Ltd., citing practices that failed to conform to CGMP during October 2015 inspections of CP Pharmaceuticals, the firm's drug manufacturing facility in the UK. Among other problems, the firm "failed to follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile," the FDA said. The agency suggested that the company hire an aseptic processing consultant.

So far this year, CDER's Office of Manufacturing Quality has issued 36 warning letters, up from 20 warning letters in the year prior. 

FDA illustrates owner, facility duties

In its guidance, FDA offers two hypothetical scenarios illustrating how owners and contract facilities are both responsible for good manufacturing practices.

In the first case, the FDA, while inspecting a contract facility that manufactures an injectable drug product for an owner, finds significant objectionable conditions. Most relate to deficient maintenance of facilities and product manufacturing equipment: equipment is broken, pipes are tarnished and seals are leaking. Also, the facility's design fails to adequately prevent contamination. Under the quality agreement, the owner is responsible for upgrades and maintenance of facilities and equipment used to manufacture its product. But the owner has failed to provide upgrades and perform maintenance, and the contract facility continues to manufacture the product under non-CGMP conditions with risk of contamination.

In the second case, the contract facility is manufacturing the owner's FDA-approved prescription drug product. During inspection, FDA sees that the facility’s batch records don't accurately reflect the manufacturing process because the records fail to document the addition of reclaimed powder. Although batch records are inaccurate, and therefore not compliant with CGMP, the facility claims that its records comply with the expectations contained in the quality agreement with the owner.

In both cases, FDA's guidance says that the owners and contract facilities alike appear to be in violation of CGMP requirements since a quality agreement cannot exempt them from statutory or regulatory responsibilities. In the first case, the contract facility violates CGMP by continuing to manufacture on faulty equipment, even though the quality agreement says the owner is responsible for its maintenance and upkeep. In the second case, the contract facility violates CGMP by using a batch record that does not accurately reflect the manufacturing process, even though the record complies with the quality agreement.

As for the owners in both examples, FDA says they remain responsible for ensuring that products are made in compliance with CGMP even when quality agreements assign certain manufacturing activities to contract facilities. If FDA were to find such problems at the contract facility, regulators "might determine that it is appropriate to inspect the owner," the guidance says, and owners also could be in violation of CGMP because of their failure to oversee contract facilities' manufacturing activities.

In other words, Aragon said, "The parent company is always responsible for doing lot-release and end-use release of the product. The company and CMO are both responsible if it's produced in a non-CGMP manner. FDA is just putting out [that] there's no way of getting out of responsibility."

To sum it up, Aragon said he doesn't "believe any of this is onerous. It does cost money for companies to adhere to [good manufacturing practices]," but automation and real-time access to data end up saving money. "The challenge comes in integration from various vendors...but that doesn't mean you can't have a cohesive [drug manufacturing] system that's easy to use," he said.

Filed Under: Regulatory / Compliance Manufacturing
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