[5/22/2017] The FDA advises drug manufacturers of non-sterile, water-based drug products that there have been recent product recalls due to Burkholderia cepacia complex (BCC or B. cepacia) contamination.(1, 2, 3) BCC and other water-borne opportunistic pathogens are among the contaminants that can be found in pharmaceutical water systems.
BCC can survive or multiply in a variety of non-sterile and water-based products because it is resistant to certain preservatives and antimicrobial agents.(4, 5) Detecting BCC bacteria is also a challenge and requires validated testing methods that take into consideration the unique characteristics of different BCC strains.
People exposed to BCC are at an increased risk for illness or infection, especially patients with compromised immune systems.(3, 6)
Specifically, the FDA is reminding drug manufacturers to:
- Establish procedures designed to prevent objectionable microorganism contamination of non-sterile drug products, such as procedures to assure adequate quality of incoming materials, sanitary design, maintenance and cleaning of equipment, production and storage time limitations, and monitoring of environmental conditions (21 CFR 211.113(a)).7
- Use scientifically sound and appropriate acceptance criteria (e.g., USP Chapter <1111> Microbiological Examination of Non-sterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use)8 and test procedures (e.g., USP <61>/<62> Microbiological Examination of Non-sterile Products: Microbial Enumeration Tests and Tests for Specified Microorganisms, respectively) to assure that drug product components (including pharmaceutical water) and finished drug products conform to appropriate quality standards (21 CFR 211.160(b)).
- Provide appropriate drug product specifications (tests, methods, and acceptance criteria) in applications submitted to the FDA (21 CFR 314.50(d)(1) for new drug applications, or 21 CFR 314.94(a)(9) for abbreviated new drug applications). As appropriate, additional laboratory tests may be needed to determine whether products are suitable for release.
- Ensure that the methods used to test finished drug products prior to release for distribution are appropriately validated, accurate, sensitive, specific and reproducible (21 CFR 211.165).
- Test in-process materials during the production process (e.g., at commencement or completion of significant phases, or after storage for long periods), using valid in-process specifications to assure, among other things, that the drug product will meet its final specification, including criteria for absence of microbial contamination, where appropriate (21 CFR 211.110).
- Investigate any failure to meet specifications, including other batches of the same drug product and other drug products that may have been associated with the specific failure or disrepancy(21 CFR 211.192), and implement appropriate corrective and follow-up actions to prevent recurrence.
Adverse events or quality problems experienced with the use of a non-sterile water-based drug product should be reported to FDA’s MedWatch Adverse Event Reporting program. Adverse events may be reported in the following ways:
- Complete and submit the report online at www.fda.gov/medwatch/report.htm; or
- Download and complete the form, then submit it via fax at 1-800-FDA-0178.
- FDA Updates on Multistate Outbreak of Burkholderia cepacia Infections
- Sage Products Issues Voluntary Nationwide Recall of Comfort Shield Barrier Cream Cloths Due to Microbial Contamination
- PharmaTech LLC Issues Voluntary Nationwide Recall Due to Potential Risk of Product Contamination
- Torbeck L, D. Raccasi, D.E. Guilfoyle, R.L. Friedman, D. Hussong. 2011. Burkholderia cepacia: This Decision is Overdue. PDA J. Pharm. Sci. Tech., 65(5): 535-43. https://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM275569.pdf
- Hutchinson, J., W. Runge, M. Mulvey, G. Norris, M. Yettman, N. Valkova, R. Villemur, and F. Lapine. 2004. Burkholderia cepacia infections associated with intrinsically contaminated ultrasound Gel: The role of microbial degradation of parabens. Infec. Cont. Hosp. Epid., 25: 291-296.
- As noted in the preamble to the 1978 CGMP final rule, parts 210/211, “Microorganisms could be objectionable by virtue of their total numbers or their detrimental effect on the product or by their potential for causing illness in the persons ingesting them. A definition of the term is not practical in the regulations, however, because the objectionable nature of a microorganism may develop only in relation to the unique circumstances of a particular formulation, a particular ingredient, a particular method of manufacture, or the conditions found at a particular firm.” 43 FR 45053.
- Guidance for Industry: Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073423.pdf