Third Time’s the Charm – FDA Publishes Final Guidance on Insanitary Conditions

December 4, 2020

By Phil Crooker, VP – Technical, Regulatory & Access, Parexel

On November 9, 2020 the U.S. Food and Drug Administration (FDA) announced the availability of a final guidance for industry entitled ‘‘Insanitary Conditions at Compounding Facilities.’’ You can find a copy of the final guidance and the Federal Register notice here - https://www.fda.gov/regulatory-information/search-fda-guidance-documents/insanitary-conditions-compounding-facilities-guidance-industry?utm_medium=email&utm_source=govdelivery.

In the Federal Register notice, FDA reiterated that drug products compounded under insanitary conditions could become contaminated and cause serious adverse events, including death, in patients. FDA published this guidance to help compounding facilities and State regulatory agencies understand some examples of what FDA considers to be insanitary conditions that could cause a drug to become contaminated or rendered injurious to health. These examples are intended to help compounding facilities take action to prevent the occurrence of these and other insanitary conditions, as well as to implement appropriate corrective actions when such conditions already exist.

This is the third version of the guidance that has been published. Here is a brief history of how FDA reached the point of being able to publish a final guidance after extensive efforts to collect comments from the public and revise the guidance.

  • In the Federal Register of August 4, 2016 (81 FR 51449), FDA announced the availability of a draft guidance for industry entitled, ‘‘Insanitary Conditions at Compounding Facilities.’’ The draft guidance provided examples of insanitary conditions that the Agency has observed at compounding facilities it has inspected and considers to be insanitary conditions. The draft guidance also described corrective actions that compounding facilities should take when they identify such conditions and the regulatory actions FDA may take in response to identified insanitary conditions.
  • FDA received comments on the draft guidance including feedback from various stakeholders (e.g., physicians, pharmacies), particularly concerning the implications of the policies described in the draft guidance for physicians who prepare drugs in their offices. In the Federal Register of September 26, 2018 (83 FR 48632) FDA published a revised draft guidance to address the stakeholders’ feedback and to provide further clarification on the insanitary conditions described in the guidance, as well as the actions FDA intends to take with respect to insanitary conditions. FDA issued the revised draft guidance to enable the public to further review and comment before finalization of FDA’s policies concerning insanitary conditions.

Similar to the response after the original draft guidance was published, FDA received comments on the revised draft guidance from various stakeholders (e.g., physicians, pharmacies, outsourcing facilities). Several comments concerned the implications of the policies described in the revised draft guidance for physicians who compound or repackage drug products or mix, dilute, or repackage FDA-licensed biological products in their offices.

In response to these comments, FDA made additional changes to the revised draft guidance. These include:

  • Adding a footnote to state that ‘‘processing of beta-lactams’’ does not refer to mixing, reconstituting, or other such acts that are performed in accordance with the directions contained in FDA-approved labeling.
  • Adding a footnote to reflect that the FDA does not generally object to rapid movement, temporary blocking or disruption of first air in the ISO 5 area when necessary for the safe handling of radiopharmaceuticals to minimize radiation exposure.
  • Revising the language in a footnote to state that FDA generally does not intend to take action under section 501(a)(2)(A) of the FD&C Act against a physician who is compounding a drug product, repackaging an FDA-approved drug product, or who is mixing, diluting, or repackaging an FDA-licensed biological product, provided that it occurs in the physician’s office for in-office administration to the physician’s patients.
  • Adding recommendations encouraging compounders to use risk evaluation strategies and risk management tools to develop appropriate controls necessary to prevent the occurrence of insanitary conditions at their facilities.

Most of the case law determining the scope and definition of insanitary conditions resulted from FDA enforcement actions involving foods. See United States of America v. Nova Scotia Food Products Corp. 568 F.2d 240 (1977). In that case, the defendants contended that the prohibition against insanitary conditions includes only conditions in the plant itself. The defendant distinguished between these insanitary conditions and conditions of sterilization required to destroy micro-organisms, which they contended are not insanitary conditions. The court recognized that there is a plausible argument that can be made that the references in the law are to insanitary conditions in the plant itself, such as the presence of rodents or insects. But the court also stated that when dealing with the public health, the language of the law should not be read too restrictively, but rather as consistent with its overriding purpose to protect the public health. The court also agreed with the trial court’s decision that the manner of processing can give rise to the survival, with attendant toxic effects on humans, of micro-organisms which would not have survived under stricter sanitary conditions. In that sense, the food does not have to be actually contaminated during processing and packing but simply that it may have been rendered injurious to health by inadequate sanitary conditions of prevention.

The clear message from that case is that FDA enjoys wide discretion to define the scope of insanitary conditions that includes the condition of the manufacturing facility as well as processing and operating conditions and examples of both are found in the final guidance.

A final word of caution - regulated industry should realize that although the final guidance was written with compounding pharmacies in mind as the primary audience, commercial manufacturers are also at risk of having insanitary conditions violations included as part of FDA regulatory and enforcement actions. For such an example, see the Warning Letter sent to BioDiagnostic International in July, 2018 here - https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/biodiagnostic-international-554322-07122018.

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