Burkholderia cepacia - FDA Advice on Contamination Risk

On 22 May, the FDA advised drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products. The publication was based on recent product recalls due to Burkholderia cepacia complex (BCC or B. cepacia) contaminations. Non-sterile aqueous drug products and parts of water systems may potentially be contaminated with organisms in the Burkholderia cepacia complex (BCC).  BCC strains have a well-documented ability to ferment a wide variety of substrates and are known to proliferate in the presence of many traditional preservative systems. Thus, despite the presence of otherwise adequate preservative systems, BCC strains can survive and even proliferate in product during storage. 

The recent recalls and the fact, that an exposure to BCC can increase the risk of illness or infection now induced the FDA to remind drug manufacturers of non sterile products to establish suitable methods to prevent objectionable microorganisms contamination considering the requirements of the 21CFR 211 "CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS"  and  21CFR 314 "APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG" .

The requirements have been described several times in FDA's Microbiology/Virology Reviews and in presentations from FDA representatives - e.g. at the European Microbiology Conference in May 2017 as follows:

  • "Identify potential sources for introduction of BCC during the manufacturing process and describe the steps to minimize the risk of BCC organisms in the final drug product. We recommend that potential sources are examined and sampled as process controls. These may include raw materials and the manufacturing environment. A risk assessment for this species in the product and raw materials is recommended to develop sampling procedures and acceptance criteria. 
  • Provide test methods and acceptance criteria to demonstrate the drug product is free of BCC. Your test method should be validated and a discussion of those methods should be provided. Test method validation should address multiple strains of the species and cells should be acclimated to the conditions in the manufacturing environment (e.g., temperature) before testing.
  • As there are currently no compendial methods for detection of BCC, we have provided suggestions for a potential validation approach and some points to consider when designing your validation studies. However, any validated method capable of detecting BCC organisms would be adequate. It is currently sufficient to precondition representative strain(s) of BCC in water and/or your drug product without preservatives to demonstrate that your proposed method is capable of detecting small numbers of BCC. 
  • Your submission should describe the preconditioning step (time, temperature, and solution(s) used), the total number of inoculated organisms, and the detailed test method to include growth medium and incubation conditions. It is essential that sufficient preconditioning of the organisms occurs during these method validation studies to insure that the proposed recovery methods are adequate to recover organisms potentially present in the environment." 

Furthermore, it is of importance, that any kind of adverse events or contaminations are immediately reported to the responsible FDA office. Concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specification established for it in the application it should be reported with 21 CFR:NDA  Field Alert Report and/or reported to FDA’s MedWatch Adverse Event Reporting .

More details can be found at "FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products"

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