The 503b Outsourcing Facility Compliance Dilemma

April 5, 2016 by Ben Frey, Principal Compliance Consultant

On the Blog: Principal Compliance Consultant Ben Frey discusses GMP compliance, FDA guidelines, and 503b outsourcing facilities.

At the time of this writing, there were 59 registered 503b outsourcing facilities posted on the FDA’s website.

All firms that had been inspected were issued FDA inspectional observations in the form of FDA-483, and in some cases were issued Warning Letters or other form of injunction. The question that comes to mind is why are 100% of all outsourcing compounding facilities failing to meet the expectations of GMP compliance?

To understand the dilemma facing outsourcing compounding facilities and FDA regulators, we need to look at the amendments to the Food Drug and Cosmetic Act (FD&C Act) that were passed in November 2013 under the title of the Drug Quality and Security Act (DQSA).  This act provides compounding pharmacies the ability to register as an outsourcing facility and compound sterile products in large quantities without the requirement of prescriptions.  As such, the outsourcing facility is required to manufacture, package, hold, distribute and test their compounded products within compliance of GMP requirements per 21 CFR part 211.  Per the FD&C Act, failure to comply with GMP requirements renders the compounded product as “adulterated” and unsuitable for use and distribution regardless of the product’s conformance to release specifications.

The dilemma comes from the fact that the GMP requirements in 21 CFR 211 were established for the manufacture of drugs and finished pharmaceutical products that have been approved through the drug application process.  As a consequence, the GMP requirements for drugs are significantly more stringent than the standards that were in place prior to DQSA (USP <797> for compounding sterile products).

While recognizing the notable distinctions between aseptically manufactured drug products and compounded pharmaceutical preparations, FDA has developed industry guidance to convey minimal expectations for GMP compliance.  Currently, this Guidance to Industry is in draft form and does not carry legally enforceable provisions; therefore, FDA has gone on record that it intends to use enforcement discretion as the guidance remains in draft.

How do 503b outsourcing facilities resolve this dilemma (meeting drug GMP compliance through draft, non-enforceable FDA guidance and a policy of enforcement discretion)?  One solution is to understand all of the risks associated with sterile compounding bulk products.  This assessment of risk would obviously start with potential impact of manufacturing, holding, testing and distribution processes to the safety, quality, purity and efficacy of products.  Processes and systems that pose the greatest risk to patient safety will require the highest level of control and oversight.  Examples of high risk processes / systems include:

  • Sterility Assurance
  • Process Controls – Material / component management, control of critical processing parameters, batch documentation and release, etc.
  • Laboratory Testing
  • Labeling
  • Deviation / Adverse Event / CAPA Management

While it is the responsibility of the outsourcing compounding facility to comply with GMP requirements, as they are applicable to pharmaceutical compounding, it is recognized that the guidance available for compliance is somewhat nebulous.  Therefore, it is up to the 503b outsourcing facility to develop controls and systems based on the level of potential risk to patient safety.  Watch for future blogs that will focus on some of these high risk processes / systems and recommendations for mitigation of the risk.

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