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FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products

[7/7/2021] The FDA advises drug manufacturers of non-sterile, water-based drug products that Burkholderia cepacia complex (BCC or B. cepacia) continues to pose a risk of contamination.[1], [2], [3]  BCC is a group of gram-negative bacteria comprising more than 20 species that has been linked to multiple instances of opportunistic infections.[4] For example, Paroex® Chlorhexidine was recalled in 2020 due to objectionable microbial contamination including the BCC species B. lata. Inadequate design, control, or maintenance of pharmaceutical water systems have led to contamination with BCC and other water-borne opportunistic pathogens. 

Patients exposed to BCC contamination may be at an increased risk for illness or infection, especially patients with compromised immune systems or who are otherwise susceptible to infection.[5]  In 2016, severe BCC infections occurred when contaminated docusate oral solution was used in intubated children and other compromised patients. Repeated recalls of contaminated antiseptics, such as povidone iodine, benzalkonium chloride, and chlorhexidine gluconate, have occurred in the U.S. and overseas. These drugs may be used in hospitals when caring for patients who are often particularly vulnerable due to their medical conditions.[6], [7], [8]    

It is essential that manufacturing facilities, equipment, and processes are designed to prevent contamination and strict sanitary standards are continually followed. There is a long history of product recalls due to BCC contamination traced back to deviations from current good manufacturing practice (CGMP) requirements.

In light of these BCC contamination incidents, the FDA is reminding drug manufacturers to:

  • Establish procedures that are designed to prevent objectionable microbiological contamination of non-sterile drug products by assuring appropriate material quality, equipment and facilities, process design, maintenance and cleaning, production and storage time limitations, and monitoring of environmental conditions (21 CFR 211.113(a)).[9]
  • Design, control and maintain a suitable water system, and ensure it does not provide conditions that support biofilm formation. Routine monitoring of microbial counts and identity of microflora in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in manufacturing operations. 
  • Ensure vigilant production management and quality unit oversight to proactively detect hazards that may impact manufacturing, including quality and safety of raw materials, intermediates, and finished drug products. This includes ensuring that distribution and piping systems used for water and drug manufacturing remain sanitary and suitable for their intended use. (21 CFR 211.42, 21 CFR 211.100, 21 CFR 211.22)
  • Establish scientifically sound and appropriate specifications and test procedures to assure that drug components (e.g., water and inactive ingredients) and finished drug products conform to appropriate microbial quality specifications (21 CFR 211.84, 21 CFR 211.160(b)). This includes testing of raw materials and the finished product batch (21 CFR 211.165(b)) prior to disposition to ensure they are free of microbial contamination that is objectionable in view of the intended use of the drug.
  • Ensure that test methods are appropriately validated to ensure they are accurate, sensitive, specific and reproducible (21 CFR 211.165 21 CFR 211.194). Also, when USP methods are part of the microbial release testing regimen, verify these methods for their suitability under conditions of use.
  • 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, or to minimize bioburden in each batch (21 CFR 211.110).
  • Investigate any failure to meet specifications or quality standards, including other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy (21 CFR 211.192), and implement appropriate corrective and follow-up actions to prevent recurrence.

BCC Growth and Contamination

BCC can survive or multiply in a variety of non-sterile drugs formulated with water because it is resistant to certain preservatives and antimicrobial agents.[10], [11] In most cases, the contaminated drugs contained preservatives or had intrinsic antimicrobial properties. However, BCC persisted and even multiplied in these drug products. Preservatives cannot compensate for insanitary or substandard manufacturing practices. Additionally, when an operation fails to meet CGMP standards, the level of microbiological contamination introduced during the course of batch production is unpredictable, and test results can vary widely. Because of the uneven distribution of microbial contamination across a batch, testing of a limited sample may not readily detect unsafe batches. The nature of contamination and risk posed by contaminated drugs underscore the importance of designing manufacturing operations to prevent contamination of drugs with objectionable microorganisms, including BCC. 

Testing and Quality Risk Management

The USP published a compendial test for BCC that became official on December 1, 2019, titled 〈60〉 Microbiological Examination of Non-Sterile Products—Tests for Burkholderia Cepacia Complex. FDA recommends that manufacturers use the method described in this USP chapter to test drug products for the presence of BCC after appropriate method verification. If a manufacturer chooses to develop an alternative in-house method, the alternative method or procedure must be fully validated and should produce equivalent or superior results to the compendial method.  

Microbial risk assessment should use International Conference on Harmonization (ICH) Q9 principles to inform pre-market and post-market decisions related to design, control and maintenance. Effective quality risk management is customer-centered and includes understanding the clinical profiles of patients that may receive any drug(s) formulated with water. Accordingly, manufacturers should leverage both clinical and quality assurance subject matter expertise to understand the full spectrum of patients who can use their drugs, with special attention to the severity of impact on those patients who may be particularly susceptible to opportunistic pathogens. Notably, while less common, drugs with substantial microbial contamination have also caused infections in healthy individuals.

Similarly, while drugs with higher water content are of most concern, deficient manufacturing or product integrity can lead to the introduction and survival of objectionable microbiological contamination in drugs with lower water activity.[12]

In accord with CGMP, microbes should be identified and evaluated to determine if they are objectionable in view of the intended use of a product. A pattern of BCC contamination in equipment or raw materials may be an indication of biofilm or other unaddressed contamination sources. This underscores the importance of vigilance in a manufacturer’s production and quality assurance activities to prevent contamination hazards, detect emerging problems, and act in a timely manner to prevent consumer exposure to unsafe drugs.

Reporting Adverse Event and Quality Problems

Adverse events or quality problems experienced with the use of any drug, including 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:


[4]Jin et al. Genome-based classification of Burkholderia cepacia complex provides new insight into its taxonomic status, Biology Direct (2020) 15:6, https://doi.org/10.1186/s13062-020-0258-5

[5]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.

[7]Dos Santos Saalfeld, S. M., Shinohara, D. R., Dos Anjos Szczerepa, M. M., Martinez, H. V., Vieira de Campos, E., Mitsugui, C. S., Rodrigo Oliveira, A., Cristina Granzotto, A., Alexandra Nishiyama, S.,  Tognim, M. C. (2020). Consecutive outbreaks of BURKHOLDERIA CEPACIA complex caused by INTRINSICALLY Contaminated Chlorhexidine mouthwashes. American Journal of Infection Control, 48(11), 1348-1353. doi:10.1016/j.ajic.2020.04.025

[8]Ko, S., An, H., Bang, J. and Park, S. (2015). An outbreak of Burkholderia cepacia complex pseudobacteremia associated with intrinsically contaminated commercial 0.5% chlorhexidine solution. American Journal of Infection Control, 43(3), pp.266-268

[9]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.

[10]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. 


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