The FDA advises drug manufacturers of non-sterile, water-based drug products that Burkholderia cepacia complex (BCC) continues to pose a risk of hazardous contamination. BCC is a group of gram-negative bacteria comprising more than 20 species that has been linked to multiple instances of opportunistic infections.1 Deficient manufacturing practices, particularly in the design, control, and maintenance of water systems, have led to contamination with BCC and other water-borne opportunistic pathogens.
Patients exposed to BCC contamination may be at increased risk for illness, especially patients with compromised immune systems or who are otherwise susceptible to infection.
In 2016, severe BCC infections occurred when contaminated docusate oral solution was used for children requiring mechanical ventilation and for other immunocompromised or susceptible patients.2,3 The distribution of this contaminated product ultimately led to criminal charges and conviction.4 In addition, repeated recalls of contaminated antiseptics, such as povidone iodine, benzalkonium chloride, and chlorhexidine gluconate, have occurred in the United States and overseas. These marketed defects are notable because these drugs are often used in hospitals when treating patients who are particularly vulnerable due to their medical conditions. 3,5-9
There is a long history of both over-the-counter (OTC) and prescription drug recalls due to BCC contamination traced back to deviations from current good manufacturing practice (CGMP) requirements. Recalls date back to at least the 1980s and early 1990s, when multiple povidone-iodine contamination events occurred, and FDA published a letter to industry warning of these hazards.10-12 In recent years, recalls have included products such as topical antiseptics,13,14 topical pain relievers,15 a cherry-flavored suspending base,16 and an oral antiseptic rinse.17
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 ensuring appropriate material quality, equipment and facilities, process design, maintenance and cleaning, production and storage time limitations, and monitoring of environmental conditions (e.g., 21 CFR 211.113(a)).18
- Design, control, and maintain a robust water system, and ensure the water system 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 (e.g., 21 CFR 211.63, 21 CFR 211.65, 21 CFR 211.67, 21 CFR 211.84, 21 CFR 211.113(a)).
- Ensure vigilant production management and quality unit oversight to proactively detect hazards that could affect 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 (e.g., 21 CFR 211.22, 21 CFR 211.42, 21 CFR 211.100).
- Establish scientifically sound and appropriate specifications and test procedures to ensure that drug components (e.g., water and inactive ingredients), in-process materials, and finished drug products conform to appropriate microbial quality specifications (e.g., 21 CFR 211.84, 21 CFR 211.160(b)). This includes testing of components and the finished product batch (e.g., 21 CFR 211.165(b)) before 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 developed, and appropriately validated, to ensure they are accurate, sensitive, specific, and reproducible (e.g., 21 CFR 211.165, 21 CFR 211.194). Also, when USP methods are a 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., when significant phases begin or end or after a lengthy storage). Valid in-process specifications are essential for early detection of process control problems and to ensure that the drug product will meet its final specifications for either absence of microbial contamination, where appropriate, or bioburden limits (e.g., 21 CFR 211.110(a)(6)).
- 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 (e.g., 21 CFR 211.192), and implement appropriate corrective actions and preventive actions (CAPA).
BCC Growth and Contamination
BCC can survive or multiply in a variety of non-sterile drugs formulated with water because the bacteria are resistant to certain preservatives and antimicrobial agents.10 13 19 In most cases, the contaminated drugs contained preservatives or had intrinsic antimicrobial properties. However, BCC persisted and even multiplied in these drug products. As a result, microbial growth emerged later in the product’s shelf-life even though the batch met microbiological specifications at the time of initial release testing.14
Preservatives in drug formulations cannot compensate for insanitary or substandard manufacturing practices. Additionally, when an operation fails to meet CGMP requirements, the level of microbiological contamination introduced during the course of batch production is unpredictable, and test results from separate samples taken from a batch can vary widely. Because of this uneven distribution of microbial contamination across a batch, relying on quality control sample testing may not detect unsafe batches. The nature of contamination, and risk posed by contaminated drugs, underscore the importance of the CGMP requirement to design operations to prevent contamination with microorganisms such as BCC that are objectionable in view of the intended use of a drug (21 CFR 211.113(a)).
Testing and Quality Risk Management
The USP published a compendial test for BCC species on December 1, 2019: Chapter <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 organisms 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 results that are equivalent or superior to the compendial method (21 CFR 211.194(a)(2), 21 CFR 211.110(a)(6), USP <1223>).
Microbial risk assessment should use International Conference on Harmonization (ICH) Q9 principles when making premarket and postmarket decisions related to design, control, and maintenance. Effective quality risk management is customer centered and includes an understanding of the clinical profiles of patients who may receive any drugs 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 patients who may be particularly susceptible to opportunistic pathogens. Notably, although less common, non-sterile dosage forms with substantial microbial contamination have also caused infections in healthy individuals.
Although 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.20
Microbes should be identified and evaluated to determine whether they are objectionable in view of the intended use of a product. It is essential that scientifically sound and appropriate microbial identification methods are established and followed (21 CFR 211.160). A pattern of objectionable contamination in equipment or materials (e.g., raw materials, in-process) 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.
Draft Guidance Issued
It is essential that manufacturing facilities, equipment, and processes are designed to prevent contamination and that operations continually adhere to strict sanitary standards. Accordingly, in 2021, FDA published the draft guidance document Microbiological Quality Considerations in Non-Sterile Drug Manufacturing to assist manufacturers of active ingredients and finished dosage forms with establishing and meeting appropriate quality standards in accord with CGMP requirements.
The draft guidance is intended to assist manufacturers in assuring microbiological quality of their non-sterile drugs. The recommendations apply to solid non-sterile dosage forms, as well as semisolid and liquid non-sterile dosage forms (e.g., topically applied creams, lotions, solutions, and swabs, and oral solutions and suspensions). These recommendations will also assist manufacturers in complying with the CGMP requirements for finished pharmaceuticals and components (e.g., active pharmaceutical ingredients).
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:
- 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.
1 Jin, Y, J Zhou, J Zhou, M Hu, Q Zhang, N Kong, H Ren, L Liang, and J Yue, 2020, Genome-Based Classification of Burkholderia cepacia Complex Provides New Insight Into Its Taxonomic Status, Biology Direct 15:6, https://doi.org/10.1186/s13062-020-0258-5.
2 FDA Updates on 2017 Burkholderia cepacia Contamination: FDA Lab Findings Again Link Rugby Diocto Oral Liquid Docusate Sodium to B. cepacia Infections, 2017, https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-2017-burkholderia-cepacia-contamination.
3 Glowicz, J, M Crist, C Gould, H Moulton-Meissner, J Noble-Wang, JB de Man, A Perry, Z Miller, WC Yang, S Langille, J Ross, BJ Garcia, J Kim, E Epson, S Black, M Pacillo, JJ LiPuma, R Fagan, 2018, A Multistate Investigation of Health Care–Associated Burkholderia cepacia Complex Infections Related to Liquid Docusate Sodium Contamination, January–October 2016, Am J Infect Control 46:649-655, https://doi.org/10.1016/j.ajic.2017.11.018.
4 FDA Press Release, 2022, South Florida Federal Judge Orders Prison Time for Former Pharmatech CEO; FDA Company Announcement, 2020, Rugby Laboratories Issues Voluntary Nationwide Recall of Diocto Liquid and Diocto Syrup Manufactured By PharmaTech, LLC Due to Possible Product Contamination.
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, Infect Control Hosp Epidemiol, 25:291–296, https://doi.org/10.1086/502394.
6 FDA Letter to Health Care Providers, 2021, Stop Using All Eco-Med Ultrasound Gels and Lotions Due to Risk of Bacterial Contamination – Letter to Health Care Providers.
7 CDC, 2022, Outbreak of Burkholderia stabilis Infections Associated With Contaminated Nonsterile, Multiuse Ultrasound Gel—10 States, May–September 2021, MMWR, 71(48):1517–1521, http://dx.doi.org/10.15585/mmwr.mm7148a3.
8 Dos Santos Saalfeld, SM, DR Shinohara, MM Dos Anjos Szczerepa, HV Martinez, E Vieira de Campos, CS Mitsugui, A Rodrigo Oliveira, A Cristina Granzotto, S Alexandra Nishiyama, and MC Tognim, 2020, Consecutive Outbreaks of Burkholderia cepacia Complex Caused by Intrinsically Contaminated Chlorhexidine Mouthwashes. Am J Infect Control, 48(11):1348–1353, https://doi.org/10.1016/j.ajic.2020.04.025.
9 Ko, S, H An, J Bang, and S Park, 2015, An Outbreak of Burkholderia cepacia Complex Pseudobacteremia Associated With Intrinsically Contaminated Commercial 0.5% Chlorhexidine Solution, Am J Infect Control, 43(3):266–268, https://doi.org/10.1016/j.ajic.2014.11.010.
10 CDC, 1989, Contaminated Povidone-Iodine Solution—Texas, MMWR, 38(8):133–134.
11 Anderson, RL, RW Vess, JH Carr, WW Bond, AL Panlilio, and MS Favero, 1991, Investigations of Intrinsic Pseudomonas cepacia Contamination in Commercially Manufactured Povidone-Iodine, Infect Control Hosp Epidemiol, 12(5):297-302, https://pubmed.ncbi.nlm.nih.gov/1865100/.
12 Anderson, RL, RW Vess, AL Panlilio, and MS Favero, 1990, Prolonged Survival of Pseudomonas cepacia in Commercially Manufactured Povidone-Iodine, Appl Environ Microbiol, 56(11):3598-600, https://doi.org/10.1128/aem.56.11.3598-3600.1990.
13 FDA Company Announcement, 2021, Durisan Hand Sanitizer Recall Due To Microbial Contamination.
14 FDA Warning Letter, 2021, Spartan Chemical Company, Inc.
15 National Drug Codes List, 2021, FDA Recalls NDC 76305-301 China-gel Topical Pain Reliever Menthol And Camphor (Synthetic) Cream Topical; FDA Company Announcement, 2020, MPM Medical LLC Issues Voluntary Nationwide Recall of Regenecare HA Hydrogel Due to Burkholderia cepacia Contamination.
16 FDA Company Announcement, 2022, Fagron Inc. Issues Voluntary Nationwide Recall of SyrSpend SF Cherry Due to Microbial Contamination.
18 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.”
19 Torbeck, L, D Raccasi, DE Guilfoyle, RL Friedman, and D Hussong, 2011, Burkholderia cepacia: This Decision is Overdue, PDA J Pharm Sci Tech, 65(5):535–43, https://doi.org/10.5731/pdajpst.2011.00793.
20 FDA Alert, 2018, FDA alerts consumers of a nationwide voluntary recall of topical drug products made by Industria Farmacéutica Andrómaco due to contamination: FDA lab confirmed high levels of microbial contamination in company’s Pasta De Lassar Andromaco diaper rash treatment.