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Microbial experts should employ proactive practices on the manufacturing floor, rather than relying on testing.
The presence of microorganisms in pharmaceutical products is a potential hazard to patient safety and product quality. Consequently, there are regulatory expectations that microbial populations be appropriately controlled. A publication cited numerous recalls triggered by the actual or suspected presence of microorganisms (1). Clearly, industry faces a continuing problem in preparing products assuring microbial quality on a consistent basis. In sterile products, this expectation is an absolute; for non-sterile products, however, there is some flexibility, although depending upon the route of administration, absence of a particular microbial species is sometimes required. An inherent complication exists with these prohibitions: how is microbial absence in a pharmaceutical product, whether partial or total, to be established? Since the inception of microbial limits, the pharmaceutical industry has relied on sampling of products followed by microbiological analysis as described in the pharmacopeia. It should be obvious that sampling and analysis has not achieved the desired results; emphasizing testing is not an effective microbial control mechanism to ensure the desired level of microbial control (2–5). This publication outlines practices for control of microbial populations that shift the modality from reactive to proactive.
The most basic expectations for microorganisms in pharmaceutical products relate to “… appropriate standards of identity, strength, quality, and purity.…” (6). The last of these (purity) addresses concerns for the presence of contaminants that might be harmful to the patient. Microorganisms undoubtedly fall into that category where their presence would cause infection or illness. FDA current good manufacturing practice (CGMP) regulations include specific, albeit general expectations for microbial control in 21 Code of Federal Regulations (CFR) 211.113 (7):
“211.113 Control of microbiological contamination.
“(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
“(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.”
These subparagraphs mandate the use of procedural measures to provide microbial control of manufacturing processes to maintain the desired microbial state.
The regulations are supported by pharmacopeial references for sterile and non-sterile products. United States Pharmacopeia (USP) chapter <71> Sterility Tests includes the following acceptance criteria: “Incubate portions of the media for 14 days. No growth of microorganisms occurs” (2). An informational USP chapter <1111> Bioburden Control of Nonsterile Drug Substances and Products includes multiple statements of the phrase “absence of …” linked to individual microbial species that vary with the route of administration (5). The results of these tests are presumed definitive proof that a particular lot meets the specified criteria. The test results are used to accept some batches while rejecting others. Environmental monitoring (air, surface, and personnel) along with aseptic process simulations are utilized with sterile products to further assess the effectiveness of operational controls. Raw materials API sampling along with limited environmental assessments are employed with non-sterile processes to assess their microbial content. Utilities, primarily purified water and water for injection, are monitored for microorganisms on a continuing basis. It might seem to some that this compilation of test results assures patient protection from microbial contamination is afforded. The Jimenez study suggests otherwise (1). No amount of sampling and testing can do that because testing is not control. More importantly, it is evident that adequate microbial controls are not sufficiently effective because contamination is recovered all too frequently.
The largest shift in microbial control strategy may have occurred in the mid-1970s when validation was introduced as the means for resolution of sterility failures undetected by end-product sterility tests (8). The independent assessment of process robustness provided by sterilization validation vastly increased the confidence in the sterility of materials. Validation has evolved to the point where most of the world’s large-volume parenteral (LVP) products are parametrically released without sterility testing. Validation forces a rigor in process/product development and execution that has increased the reliability of processes used for sterile and non-sterile products.
A Parenteral Drug Association survey on environmental monitoring for non-sterile products revealed that industry practices varied widely (9). The United States Pharmacopeial Convention began the development of an informational chapter in its 2005–2010 cycle, and it declared that monitoring was not an effective means to establish microbial control for these products (10). The USP <1115> chapter included the following statement:
“A critical consideration in ensuring product quality is to prevent conditions within the manufacturing facility or manufacturing process that favor the proliferation or ingress of microorganisms. Microbial growth in excipients, components, and drug substances is a concern because it creates the possibility that viable microbial content could reach unacceptable levels.” (10).
The emphasis placed on prevention points the way forward, but perhaps lacks clarity on the direction to be followed. A more recent USP chapter on sterility assurance outlines the recommended actions more explicitly:
“Sterility cannot be demonstrated without the destructive testing of every sterile unit. In a real sense, microbiological safety is achieved through the implementation of interrelated controls that in combination provide confidence that the items are suitable for use as labeled. It is the controls that provide the desired assurance from microbiological risk rather than the results of any in-process or finished goods testing.” (11).
Viewed in this manner, the means to establish microbial control must be derived from the facility, equipment, and utility system design and the operational practices for materials, components, personnel, etc. The appropriate elements are embodied in global CGMP regulations (12). The suggested means to assure control is to place increased emphasis on the design and practice elements that potentially impact microbial contamination, which requires expanded participation of microbiological experts in all aspects of production. Effective microbial control can never be realized solely by sampling and analysis. Increased sampling of products, environments, or personnel will not improve product quality. Enlisting the firm’s microbiological expertise in proactive measures such as vendor audits, facility and equipment design reviews, and facility walk-throughs can provide meaningful improvements in performance. Microbial assessment in this fashion must be recognized as an ongoing process entailing continual diligence by qualified personnel. Best practices go well beyond those listed below and would include:
These practices should be extended to API, raw material, and component suppliers to better assure the microbial quality of all items which become a part of the finished product.
Although it is the process elements that provide the true means for microbial control, there needs to be continued assessment of their effectiveness through sampling and testing of environments, utilities (water and air), equipment (post-cleaning), materials (excipients, active pharmaceutical chemicals, in-process and finished goods), and personnel (primarily for sterile products). Reliance on these without fully addressing the other relevant activities is not adequate to secure microbial control. Absence in end-product testing does not mean absence; it means not detected. Although current compendial requirements suggest otherwise, expecting absence of any microbial strain in a non-sterile product is nonsensical (5). Absent a sterilization process, there are no means to assure absence (13). Absence of microorganisms in sterile products is the goal, and operational practices can come close to realizing that, but nevertheless cannot deliver the absolute state of “sterility”. Regardless of the type of product/process used, testing is not control. That lesson was learned in the mid-1970s in the United States and United Kingdom when contaminated units of terminally sterilized products were administered to patients; sterility testing in this example was inadequate to assure patient safety (8). The means to patient safety is the implementation and maintenance of process controls. Microbial monitoring of all kinds is little more than an inadequate alarm system. It will continue to be used, because even an ineffective alarm is better than no alarm at all. Its lack of utility as the primary means of assuring microbial control, however, must be accepted.
Improvements in microbial control for microbial products aren’t realized by increased sampling and analysis, but rather through the implementation of effective process controls across the manufacturing operations. Sampling and testing play a role in assessing whether implemented controls are effective, but do not provide any means of control. To assure effective microbial control, a comprehensive program of effective control actions is essential. Individuals with a background in microbiology bring direct understanding of the potential contamination risks and can be especially effective in assessing and improving the performance of the control measures. Their education and insight should be applied where it can be most impactful. As the means to assure that products are devoid of potential microbial contaminants are never absolute, regardless of the product type, control provided is best asserted on the factory floor rather than in the laboratory. Trained microbiologists should make daily reviews of operations, including behind-the-scenes areas such as warehouses, equipment storage, utility, and other environments where microbial presence and proliferation can result in the undesirable ingress of microorganisms into pharmaceutical products. They have the expertise to identify the contamination risks and offer constructive solutions to improve microbial control. It is time for them to leave the laboratory and get out on the factory floor to identify situations that lead to microbial contamination and offer appropriate corrective measures.
1. L. Jimenez, Am. Pharma. Rev., 22 (6) 48-73 (2019).
2. USP, USP General Chapter <71>, “Sterility Tests,” USP 37-NF 32 (2014).
3. USP, USP General Chapter <61> “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests,” USP 37-NF 32 (2008).
4. USP, USP General Chapter < 62> “Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms,” USP 34-NF32 (2008).
5. USP, USP General Chapter <1111> “Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use,” USP 34-NF 32 (2009).
6. FDA, 21 CFR 211.160 (b) (2008).
7. FDA, 21 CFR 211.113 (2008).
8. K. Chapman, Pharm. Tech., 15 (10) 82-96 (1991).
9. PDA, Survey on Environmental Monitoring of Non-sterile Oral Solid Pharmaceutical (Tablet/Capsule) Manufacturing and Storage Areas (2006).
10. USP, USP General Chapter <1115> “Bioburden Control of Nonsterile Drug Substances and Products,” USP 38-NF 33 (2015).
11. USP, USP General Chapter <1211> “Sterility Assurance,” USP 41-NF 36 (2019).
12. EMA, EudraLex Volume 4, Good Manufacturing Practice (GMP) Guidelines (2020).
13. J. Agalloco, Pharmaceutical Technology Bioprocessing and Sterile Manufacturing eBook s31-s35 (May 2016).
James Agalloco is is president of Agalloco & Associates.
Vol. 45, No. 9
When referring to this article, please cite it as J. Agalloco, “Moving Out of the Lab to Optimize Microbial Control,” Pharmaceutical Technology, 45 (9) 2021.