FDA Warning Letter relating to the Use of an alternative microbiological Method

On July 17, the US Food & Drug Administration (FDA) published a Warning Letter to Sage Products Inc. A drug manufacturing facility inspection showed significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals.

The warning letter refers to the following three issues:

  • Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).
  • Your firm failed to establish scientifically sound and appropriate sampling plans and test procedures designed to assure that in-process materials and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
  • Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunction or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

Very interesting is that for the testing of some oral care products Sage used a non-adequate method for the microbiological screening of the products manufactured in their own site as well as for the screening of products made by a contract manufacturing organisation. The warning letter stated that they tried to validate this method, but were not able to demonstrate that it could reliably and repeatedly determine whether objectionable microorganisms were present in their drugs.

Therefore, they had tested by a growth based compendial method, because this method (a modified USP microbiological limits method) provides additional information about the type and number of microorganisms. The result was an exceedingly high microbial count of over 57,000 CFU/ml, and also identified Burkholderia cepacia, an objectionable microorganism, in this product lot.

The FDA summarized the deficiencies in the method validation as follows:

  • It specifies a xxx dilution factor. USP <62> requires a 1:10 dilution factor. Your dilution factor is xxx times greater than the USP method and provides insufficient detectability to rule out the presence of objectionable microorganisms and unacceptable total counts.
  • It does not account for the enrichment step called for in USP <62>.
  • It does not include the scraping step during sample preparation, which your submitted laboratory data indicates is required to validate organism recovery.
  • It lacks evidence that small numbers of various microorganisms, including those that are injured and stressed, can be reliably recovered. Specifically, sample effect (defined by your firm as the inhibitory effect of a sample on the growth of various microorganisms) data for B. cepacia was collected using a fresh-grown culture, not a stressed organism.
  • Microbial recovery results for each challenge organism are not fully described. The identity of recovered growth from organism challenge studies was not always verified.
  • It does not establish potential sample interference factors (e.g., enhancing or quenching) for each product formulation

All details can be found in the FDA Warning Letter to Sage Products. Following, Stryker Corporation announced that the company has informed the U.S. Food and Drug Administration (FDA) of a voluntary product recall involving specific lots of Oral Care products sold through the company's Sage Products business unit.

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