Manufacturers object to provisions in FDA’s microbiological quality guidance

Regulatory NewsRegulatory News | 10 January 2022 |  By 

An industry trade group and pharmaceutical manufacturers are calling for revisions to the US Food and Drug Administration’s (FDA) draft guidance on microbiological quality considerations for non-sterile drugs (NSDs), which they say proposes onerous new microbiological testing requirements.
The 24-page draft guidance was released for comment in September 2021 and is designed to help manufacturers control microbiological contamination of their non-sterile drugs and stems from FDA’s concerns over a high number of adverse events and recalls associated with contaminated products, including Burkholderia cepacia complex (BCC) in non-sterile water-based drug products.
The major sticking point in the guidance for industry is a recommendation for drugmakers to periodically identify microorganisms in their manufacturing facilities, which Pfizer commented would be a “significant new requirement” that is not necessary for NSDs and which would be unsustainable for manufacturers. (RELATED: FDA addresses microbial contamination in non-sterile drugs, Regulatory Focus 29 September 2021)
The comment period on the guidance closed at the end of December.
The guidance covers product development considerations, risk assessments and good manufacturing practice (GMP) requirements that are relevant to establishing microbiological control in manufacturing operations for NSDs.
AAM: Not practical to test every microorganism
In its comments to FDA, the Association for Accessible Medicines (AAM) took issue with a provision calling for manufacturers to test potential objectionable organisms for each nonsterile product.
The guidance states that, “The need for additional controls of objectionable microorganisms should be determined for each product. For example, the presence of BCC in aqueous non-sterile drug products may lead to both drug product degradation and patient infection.”
AAM writes that, “It is not practical for the pharmaceutical industry to test for every potential, objectionable organism in a non-sterile drug product” and suggests that FDA recommend use of “indicator organisms” instead. The presence of indicator organisms in products “signals potential sterility issues.” Such testing principles are commonly applied to foods and beverages, the group writes.
Pfizer objects to periodic identification of microorganisms
Pfizer objected to a provision in the guidance that calls for manufacturers to “periodically identify” microorganisms present in the manufacturing facility. The company said doing so would require periodic environmental monitoring (EM), which the company said is typically performed “with low frequency if at all” for NSDs.
The requirement for manufacturers to periodically identify microorganisms present in the manufacturing facility is a significant new requirement," Pfizer said. "Introducing the requirement for periodical identification (ID) means periodical environmental monitoring (EM) is inherently also required ... it is not clear how these IDs can add value: in other words, ensuring that a manufacturing environment is free from specific organisms with a reasonable confidence would require a high number of samples and IDs which may be not sustainable for NSD manufacturers and not commensurate with the risk.”
Cipla: Testing goes against ICH Q7
Cipla said the guideline is not aligned with the International Council on Harmonization’s (ICH) Q7 guideline on active pharmaceutical ingredients (APIs) in calling for microbiological testing of components such as APIs and excipients, which is not specified in the Q7 guidance.
The guideline said, “It is important to provide for appropriate microbiological control of the components (e.g., excipients and APIs) if non-sterile drug products, even if the components possess a low water activity.”
Perrigo objects to addition of BCC test
Perrigo objected to a provision calling for testing products for the presence of Burkholderia cepacia and reporting these results in a changes-being-effected (CBE)-0 filing.
“The addition of a BCC test through a CBE-0 process requires resource time and added costs that can be lessened through an Annual Reportable filing,” writes Perrigo. “The manufacturer is not relaxing microbiological control nor removing a test through the addition of a BCC test, therefore not impacting the safety, quality, identity, purity, and efficacy of the non-sterile drug.”
PDA offers mixed assessment
The Parenteral Drug Association (PDA) provided some general comments on the guidance. The group said the draft has “good points about manufacturing process controls and testing with references to compendia and [good manufacturing practices] GMPs.”
Yet the guidance “reads very erratically, with too many instances and footnotes that have additional text that really should be in the main reading flow, instead of asking a reader to go back and forth between text and footnote.”
PDA also recommended that FDA provide more examples or case studies showing where risk assessments “supported the presence of low-level bioburden as non-objectionable.”


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