For companies that compound human drugs in accordance with section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (i.e., human drug compounders that are not registered with FDA as outsourcing facilities under section 503B), effective 1 August 2016, “FDA investigators will make a preliminary assessment of whether such entities are compounding their human drugs in accordance with certain conditions of section 503A before closing the inspection.”
The change comes as FDA says that “in the substantial majority of cases, inspected human drug compounders not registered as outsourcing facilities were compounding at least some of their drugs not in accordance with section 503A, subjecting their drugs to CGMP requirements.”
The agency also clarifies that since the 2012 fungal meningitis outbreak, when contaminated injectables compounded at a New England pharmacy resulted in over 60 deaths and 750 cases of infection, FDA has investigated numerous serious adverse events, including infections and deaths, associated with poor quality (e.g., contaminated or superpotent) sterile and non-sterile compounded drugs, and many compounders have recalled drug products and temporarily or permanently ceased sterile operations as a result of FDA’s inspections.
The inspection changes follow the release of new draft FDA guidance describing how the agency will restrict the compounding of drugs that are essentially copies of commercially available or approved drugs.
Future Inspections
Moving forward, if an FDA investigator issues a Form 483 (which can precede the issuance of a warning letter), or a list of inspectional observations to the firm, the investigator will not include observations that represent deviations solely from FDA’s current good manufacturing practice (CGMP) requirements “unless it appears, based on the investigator’s preliminary assessment, that the firm compounds drugs that do not qualify for the exemptions under section 503A.”
Section 503A details the required conditions that must be met for a drug compounded by a licensed pharmacist in a state-licensed pharmacy or federal facility, or by a licensed physician, to qualify for exemptions from provisions of the FD&C Act.
FDA notes that because a Form 483 does not represent a final agency determination on a manufacturer’s compliance, FDA investigators identified deviations from drug production practices on such forms that could lead to quality problems without regard to whether the observations were linked to CGMP deficiencies or other deficiencies.
“After the inspection, when determining whether to pursue regulatory action, such as a warning letter, FDA has considered a number of factors, including evidence concerning compliance with the conditions of section 503A,” the agency said in a notice. “When FDA has issued a warning letter, FDA has only cited compounders that were not registered as outsourcing facilities for violations of CGMP requirements when the agency had evidence that at least some of their drugs were not compounded in accordance with the conditions of section 503A.”
FDA also says it has received input from stakeholders that they would like inspectional evidence regarding section 503A to be reviewed earlier, prior to closing an inspection, and to be taken into consideration in decisions about what to include in a Form 483.
“In response to stakeholder input, and as noted above, FDA investigators now will make a preliminary assessment regarding the firm’s compliance with certain conditions of section 503A before closing an inspection, and if a Form FDA-483 is issued to the firm it will not include observations that represent deviations only from CGMP requirements unless the investigator’s preliminary assessment is that the firm compounds drugs that do not qualify for the exemptions under section 503A,” FDA said.
After its inspection, FDA will conduct a review of the evidence to evaluate whether the firm compounds all of its drugs in accordance with certain conditions of section 503A and other applicable provisions of federal law.
“When FDA’s more thorough postinspection review differs from the FDA investigators’ preliminary assessment and reveals that a facility fails to produce drugs in accordance with the conditions of section 503A, FDA intends to consider citing CGMP violations in any regulatory action it decides to pursue,” the notice reads. “Importantly, although drug products compounded in accordance with the conditions of section 503A are exempt from certain requirements in the FD&C Act, as described above, they remain subject to all other provisions of the FD&C Act that apply to conventional drug manufacturers, including, but not limited to, the prohibition on preparing, packing, or holding drugs under insanitary conditions.”
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