US FDA offers guidance on complicated process of contract drug manufacturing
This article was originally published in SRA
The US Food and Drug Administration is inviting feedback on a draft guideline that explains how written quality agreements can be used for establishing responsibilities of all parties involved in contract manufacturing of drugs subject to current good manufacturing practice (cGMP) requirements1.
Although written quality agreements are not explicitly required under existing cGMP regulations for human drugs, the FDA believes that such written agreements can be used as a tool to delineate responsibilities and assure the quality, safety and effectiveness of drug products. Specifically, the guideline explains how concerned parties can draw on quality management principles to carry out the complicated process of contract drug manufacturing by defining, establishing and documenting the responsibilities of all those involved in drug manufacturing, testing, or other support operations.
Stakeholders have until 29 July to submit comments on the draft guideline, which applies to the commercial manufacturing of active pharmaceutical ingredients (APIs or drug substances, or their intermediates), finished drug products, combination products and biological drug products.
Industry organizations, such as the International Pharmaceutical Excipients Council (IPEC) and the Active Pharmaceutical Ingredients Committee (APIC) of the European Chemical Industry Council have previously issued their own guidance documents on this topic. However, lawyer Joseph W Cormier of Hyman, Phelps & McNamara notes that the FDA's draft guidance is somewhat different in how it presents these concepts3. "Whether and to what extent the Draft Guidance changes or merely reinforces industry practice is yet to be seen," he says.
The guideline clarifies that, in all cases, the owner of the drug (ie the party that introduces a drug into interstate commerce) is responsible for assuring that the drug product is neither adulterated nor misbranded as a result of any of the actions of the contracted facilities.
Some of the manufacturing operations that contracted facilities perform for owners include, but are not limited to:
- formulation;
- fill and finish;
- chemical synthesis;
- cell culture and fermentation, including biological products;
- analytical testing and other laboratory services; and
- packaging and labeling.
For their part, all contracted facilities must assure compliance with applicable cGMP requirements for all manufacturing, testing or other support operations performed to make a drug for the owner, the guideline states.
In general, a quality agreement should clarify which of the cGMP activities are to be carried out by each party as per the applicable regulations. The FDA recommends that quality agreements should be separate documents, or at least be severable, from commercial contracts such as master services agreements, supply agreements, etc. Also, the agency recommends that representatives from each party's quality unit and other relevant stakeholders should actively participate in the drafting of the quality agreements. While the FDA does not routinely request or review business documents or business agreements on inspection, it routinely requests and reviews evidence of quality agreements (or the lack of quality agreements), the guideline says.
The draft document elaborates on the elements of a quality agreement and refers to hypothetical scenarios to illustrate some common problems in contracted manufacturing arrangements; the scenarios also demonstrate the FDA's thinking on how the problems could be resolved.
References
1. Federal Register, 28 May 2013, 78(102), 31943-31944, www.gpo.gov/fdsys/pkg/FR-2013-05-28/pdf/2013-12539.pdf
2. Contract Manufacturing Arrangements for Drugs: Quality Agreements, 28 May 2013, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf
3. FDA Law Blog, FDA Issues Guidance regarding Contract Manufacturing Quality Agreements, 9 June 2013, www.fdalawblog.net/fda_law_blog_hyman_phelps/2013/06/fda-issues-guidance-regarding-contract-manufacturing-quality-agreements.html