FDA addresses microbial contamination in non-sterile drugs

Regulatory NewsRegulatory News | 29 September 2021 |  By 

The US Food and Drug Administration (FDA) on Wednesday issued a draft guidance to help manufacturers control microbiological contamination of their non-sterile drugs (NSDs). The guidance stems from FDA’s concerns over a high number of adverse events and recalls associated with contaminated products.
The agency reports receiving 197 adverse event reports from microbiological or fungal contamination of non-sterile products between 2014 and 2017. Of these, 32 were deemed serious events. These events are underreported, so the actual number may be “significantly higher,” said FDA. During the same period, 50 recalls were associated with contaminated NSDs. Of the recalls a “wide range” of objectionable organisms were found in aqueous and non-aqueous NSDs.
The draft guidance covers product development considerations, risk assessments, and good manufacturing practice (GMP) requirements that are relevant to establishing “microbiological control” in a manufacturing operation for an NSD.
The guidance covers solid non-sterile dosage forms. Additional dosage forms included in the guidance include semi-solid forms; liquid non-sterile dosage forms including topically applied creams, lotions and swabs; and oral solutions and suspensions. It also applies to prescription or non-prescription drugs and covers approved new drug applications (NDA) or abbreviated new drug applications (ANDAs) as well as over-the-counter monograph drugs.
The guidance also focuses on adverse events and recalls of drug products stemming from Burkholderia cepacia complex (BCC) contamination in non-sterile dosage forms, and describes prevention and testing for BCC in aqueous dosage forms of NSDs.
FDA today announced a Class I recall of Eco-Med Pharmaceuticals’ ultrasound gels and lotions. The US Centers for Disease Control and Prevention (CDC) have identified at least 66 cases of BCC infection, including 60 bloodstream infections, associated with Eco-Med’s ultrasound products, according to FDA’s announcement.
In another recent case of BCC contamination, FDA issued a July warning letter to Sanit Technologies, or Dursan, for problems related to contamination of hand sanitizers. 
Use risk assessments
Manufacturers should identify product-specific characteristics and manufacturing process elements that would make their products more susceptible to bioburden or objectionable microorganisms, according to the draft guidance. More stringent controls should be in place for liquid products since they have a higher potential for microbial growth than solids, though non-sterile liquid drug products that have a non-aqueous base may potentially pose lower risk of microbial proliferation
The US Pharmacopeia (USP), though “not exhaustive,” is a good resource for microbiological test methods and acceptance criteria for non-sterile drugs, though FDA points out in the guidance that firms must be aware that USP’s list of objectionable microorganisms is not comprehensive.
 “Solid dosage forms with a water activity that will not support vegetative microbial growth are excellent candidates for reduced microbial testing for product release and stability,” FDA advised manufacturers in the guidance.
FDA refers manufacturers to the International Council on Harmonization’s Q6A guideline on Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, which specifies conditions for which “periodic or skip testing” may be performed for solid oral dosage forms.
Risk-based impact assessments should address product-specific elements such as dosage form, water activity, proposed use, packaging, and others. Manufacturers should also take into account manufacturing elements such as process steps, equipment cleaning processes, environmental controls, and specific manufacturing steps such as filtration that might reduce bioburden.
A risk-based impact assessment also needs to include consideration of components, the water system, environment, equipment and cleaning agents, and personnel, among other considerations.
Assess containers
Manufacturers should ensure that containers provide adequate protection from water, microbial ingress, or other sources of microbial contamination.
They should also consider that single-dose containers may be better than multiple dose containers for preventing such contamination. The guidance states that “for certain dosage forms, a single-dose container/closure might provide superior safety with respect to preventing extrinsic microbial ingress into the finished product.”
Manufacturers should also be aware that certain manufacturing steps, such as those that are aqueous-based “may create conditions in which microorganisms can proliferate, particularly during extended in-process holding periods” and have a greater impact on prompting bioburden.
The agency advises against “extended holding” of aqueous in-process materials, such as coatings, suspensions, or liquid mixtures prior to adding a preservative.
Use USP test methods
FDA advises manufacturers to use USP’s Total Aerobic Microbial Counts (TAMC) test or the Total Combined Yeast and Mold Count (TYMC) test to assess the microbiological quality of finished solid dosage forms. Other tests are permitted, including rapid microbiological methods, but manufacturers must demonstrate their suitability and equivalence to the compendial methods.
FDA does not expect application holders of approved drug products to amend their product specification if they are inconsistent with the recommendations in the guidance. However, if a new supplemental application proposes to add a new manufacturing process or to relax certain process parameters, FDA “may request that application holders update the microbiological testing information in the product specification during assessment and before approval” and file a supplement.
The guidance includes a table specifying when certain changes in microbiological testing necessitates the filing of an annual report, a changes being effected (CBE) supplement or a prior approval supplement (PAS).
The deadline for comment is 30 December.
FDA draft guidance


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