BioPharm

18 BioPharm International eBook March 2018 www.biopharminternational.com Outsourcing Resources Quality Agreements Manufacture, processing, packing, or holding of a drug product is defined as "includ[ing] packaging and labeling operations, testing, and quality control of drug products" (2). In 2012, the Food and Dr ug A d m i n i s t r a t i o n S a f e t y a n d Innovation Act (FDASIA) amended Section 501 of the FD&C Act, clar- ifying that CGMP "includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and estab- lishing the safety of raw materials, materials used in the manufactur- ing of drugs, and finished drug products." This amendment clari- fied the link between a firm's qual- it y ma nagement ac t iv it ies a nd CGMP. CGMP regulations require that the quality unit's procedures and responsibilities are in writing, and that they are followed (3). The CGMP regulations recognize that many owners use contract facil- ities, such as production facilities, testing laboratories, packagers, and labelers, to perform manufactur- ing activities. FDA regards contract facilities as extensions of the owner. Contract facilities are responsible for ensuring CGMP compliance with the manufacturing activities they perform for the owner. While FDA's regulations do not require quality agreements, they do require that firms put their quality unit proce- dures and responsibilities in writing and follow them. The regulations make clear that the owner's qual- ity unit is responsible for the drug products it manufactures, and such responsibility includes the approval or rejection of products manufac- tured, processed, packed, or held under contract by another company. WHAT DOES FDA DO WITH A FIRM'S QUALITY AGREEMENT? When owners work with contract facilities, one way to ensure that both entities are CGMP-compliant is via quality agreements. "Quality agree- ments should clearly describe the materials or services to be provided, quality specifications, and commu- nication mechanisms between the owner and the contract facility," the guidance says (1). During an inspec- tion, FDA may review and collect copies of quality agreements as a way of verifying compliance with FDA's regulations. Quality agreements, however, are not the only mecha- nism for ensuring that owners and contract facilities comply with CGMP. What is important is that the respec- tive parties' quality unit responsibili- ties and procedures are in writing and are followed. As noted earlier, FDA regards contract facilities as extensions of the drug owner. Owners' quality units retain legal responsibility for approving or rejecting drugs man- ufactured by the contract facilities, including final release of drugs. That is to say, CGMP responsibili- ties cannot be contracted away with quality agreements. As FDA has made clear in numerous warn- ing letters, owners are responsi- ble for the quality of drugs they produce, regardless of the agree- ments in place with contract facili- ties (4). Similarly, contract facilities are responsible for the drugs they produce and activities they per- form, regardless of the agreements in place with the product owner or application sponsor. If a party performs manufacturing activities, it is responsible for complying with CGMP, and no written instrument between the parties can remove or shift this obligation. It is important to note that, while FDA may uncover issues at a contract facility that extend to the owner, and vice versa, FDA sends warn- ing letters only to facilities it has inspected. However, FDA may add the owner or contract facility as a CC line in a warning letter. In addition, findings at one facility may trigger an FDA inspection at another facility. MISTAKES THAT A GOOD QUALITY AGREEMENT COULD PREVENT S i n c e f i n a l i z i n g t h e g u i d - ance document, FDA's Office of Manufacturing Quality (OMQ )— w it h i n t h e C e nt e r f o r D r u g Evaluation and Research's Office of Compliance—has issued at least a dozen warning letters that point out problems stemming from failure to fully comply with CGMP require- ments and failure to communicate roles and responsibilities in contract manufacturing relationships (4). The following examples illus- trate the range of problems FDA sees when: • The owner and contract facility failed to follow their qualit y agreement • Owners failed to ensure contract facilities were CGMP-compliant • Firms failed to communicate issues or changes • Fir ms at tempted to cont rac t away responsibility. Many of these examples also illustrate how poor practices can put patients at risk due to the fail- ure of the parties to ensure product safety and quality. In some of these cases, FDA sent warning letters to the contract facility with a courtesy copy to the owner. In other cases, both the owner and the contract facility received warning letters. WHEN THE OWNER FALLS SHORT In a recent case, FDA investigators found that a drug manufacturer failed to validate its manufacturing processes and to test components used in drug manufacturing. In response to the FDA 483 observa- tions, the company claimed that it was not a manufacturing facility. It said that it "is a private label dis- tributor, which has no manufactur-

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