Introduction
Pharmaceutical products are required to provide a therapeutic response in patients, with a minimum of adverse side effects. They must also be safe for patients to take. Ensuring quality and safety requires that they be free of microorganisms that could harm patients or affect product quality.
Editor’s Note: The presence of microbial contaminants poses a serious threat to raw material, drug substance, and drug product quality and patient safety. Bioburden levels must be strictly controlled in order to prevent serious product quality problems and adverse patient reactions.
FDA has spelled out requirements in its CGMP code (1) and in more recent risk-based guidance documents (2). The United States Pharmacopeia (USP) set standards with USP Chapters <62>, Microbiological Examination of Non-Sterile Products and <1111> Microbiological Examination of Non-Sterile Products Acceptance Criteria (3,4).
However, subsequent USP guidance (USP <1115>) focused less on in-process and post-production microbial testing and more on facility, equipment, and process design and operation. In this article, two members of USP’s expert committee on microbiology , suggest ways in which USP <62> and <1111> might be improved, to more closely reflect today’s manufacturing realities and subsequent guidance. Before making formal suggestions for change, they are seeking industry opinion. Please contact them to discuss these issues, share your thoughts, or for more information.
FDA’s CGMPs specifically requires that written procedures be established and followed to prevent “objectionable micro-organisms” from affecting patient safety and drug substance and product quality (5), The agency also expects that appropriate tests be run on each individual lot of product, as well as on containers and closures, to check for potential microbial contamination (6).
Considered properly, the regulations expect procedures and testing to be designed so that they minimize any adverse consequences associated with the potential presence of ‘objectionable’ microorganisms. They do not and should not mandate the absence of all such microorganisms because that would be impossible to achieve for a non-sterile product (7).
Sampling and analysis cannot ensure the absence of objectionable microorganisms. Quite simply, nothing can, and the means to provide patient safety lies in other aspects of manufacturing a non-sterile drug product (e.g., facility, equipment, and process design and operation), along with expert assessment of the potential impact of microbiological contaminants, as advanced by USP’s Chapter <1115> (Bioburden Control of Nonsterile Drug Substances and Products) (8).
History
USP first included recommendations on microbial control for non-sterile products in chapter <62>, first published in USP 29 (5) in 2003 (9). However, the expectations outlined in that chapter had previously been revised and harmonized with requirements from other global pharmacopeia (10,11). The results were USP Chapters <62> and <1111>, published in 2006, and effective 2009, which broadened CGMP expectations by requiring the use of microbial tests designed to ensure the absence of various ‘objectionable’ strains in non-sterile dosage forms and APIs.
These standards place undue emphasis on the testing of finished materials, diverting attention from the means (i.e., the equipment, systems, and facility design and operational practices) required to protect products and patients from microbial contamination. They also formalized expectations that specific strains of microorganisms be considered for each type of drug administration, which implied that other microbes were of less or no concern.
In 2006, USP addressed some of these shortcomings by developing a draft informational chapter on environmental monitoring for non-sterile manufacturing, which endeavored to shift the focus from product testing to facility, system, and equipment design and operation, which, collectively, provide the foundation for microbial contamination prevention and control.
The result was USP <1115> Bioburden Control of Non-sterile Drug Substances and Products, which was finalized in 2015 andoutlines the concepts and principles necessary to protect products from adventitious microorganisms (12).
This informational chapter helps clarify how the regulatory expectations (stated in 21 US Code of Federal Regulations (CFR) 211.113 a) are to be realized. While microbial sampling and testing play an important role in microbial control, the chapter suggests, they cannot assure the quality of the materials being produced, whether they are APIs. raw materials, or finished pharmaceuticals.
More recently, USP revised the content of USP <1211> Sterility Assurance following the principles outlined in <1115>. During the development of this chapter, the limitations of microbial testing as evidence of microbial control were discussed. It was generally acknowledged that testing, and particularly sterility testing, was an ancillary component of microbial control. Consequently, the microbial prohibitions outlined in <1111> are even less useful because sterilization is not used to prepare non-sterile products, so they can never be rendered completely free of microbial contamination.
Recommended revisions
The authors recommend that USP <62> and <1111> be revised to achieve the following goals:
- Increase awareness that microbial control for non-sterile products is not absolute and must be provided operationally (i.e., mandating the absence of any microorganisms is an unrealistic expectation).
- Replace the emphasis on ‘absence’ expected in these chapters with a fuller understanding that microbial control is actually provided by design of process and facility, along with personnel practices and procedures other than microbial sampling and testing.
- Broaden the scope of concern for microbial control to include other microorganisms, rather than limiting it to the specified species identified in these chapters.This is problematic because the use of specified species to aid in in microbial control is not well understood, except by academically trained microbiologists.
- Shift the emphasis on microbial control for non-sterile products from a laboratory (testing) focus to a manufacturing control focus.
Additional revisions to <1111> would reinforce its message that microbial control of non-sterile products is provided by appropriate process/facility design and operational practices.
Specific Recommendations
The authors suggest that the wording of the opening paragraph of USP <62> be changed to the following:
The tests described hereafter will allow determination of the absence of, or limited occurrence of, specified microorganisms in those monograph products where their presence is specifically considered potentially detrimental to patient health that may be detected under the conditions described.
The tests are designed primarily to determine whether a substance or preparation complies with an established monograph specification for microbiological quality. When used for such purposes, follow the instructions given below, including the number of samples to be taken, and interpret the results as stated below. If a product monograph does not indicate a requirement, or there is no monograph for the product, this test is NOT required.
Alternative microbiological procedures, including automated methods, may be used, provided that their equivalence to the Pharmacopeial method has been demonstrated.
They also suggest revising USP <1111> to remove the specific mention of individual microbial strains, as seen in Colum 4 (enumerating “Specified Microorganism(s)” in Table I.
In addition, they suggest incorporating the following passages into the Chapter text:
The presence of high concentrations of microorganisms in nonsterile preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient. Manufacturers have therefore to ensure a low bioburden of finished dosage forms by implementing current guidelines on Good Manufacturing Practice during the manufacture, storage, and distribution of pharmaceutical preparations.
Microbial examination of nonsterile products is performed according to the methods given in the texts on Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests <61> and Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms <62>.
Acceptance criteria for nonsterile pharmaceutical products based upon the total aerobic microbial count (TAMC) and the total combined yeasts and molds count (TYMC) are given in Tables 1 and 2. Acceptance criteria are based on individual results or on the average of replicate counts when replicate counts are performed (e.g., direct plating methods).
When an acceptance criterion for microbiological quality is prescribed, it is interpreted as follows:
— 101 cfu: maximum acceptable count = 20;
— 102 cfu: maximum acceptable count = 200;
— 103 cfu: maximum acceptable count = 2000; and so forth.
If it has been shown that none of the prescribed tests will allow valid enumeration of microorganisms at the level prescribed, a validated method with a limit of detection as close as possible to the indicated acceptance criterion is used.
For each of the dosage forms listed in Table I, recovery of isolates should be followed by an assessment for their relevant pathogenicity or significance for concern in the respective administered dosage form.Significance relates to ensuring patient safety and the maintenance of product quality and efficacy. The significance of microorganisms recovered should be evaluated in terms of the following:
- Use of the product, since hazard varies according to the route of administration (e.g., whether via eye, nose, or respiratory tract).
- Nature of the product. Questions would include: Does the product support growth? Does it have adequate antimicrobial preservation?
- Method of application.
- Intended recipient, since risk may differ for different patient populations (e.g., neonates vs. infants, adults, and the debilitated.
- Use of immunosuppressive agents and corticosteroids.
- Presence of disease, wounds, and organ damage.
Where warranted, a risk-based assessment of relevant factors should be conducted by personnel with specialized training in microbiology and in the interpretation of microbiological data. For raw materials, the assessment takes account of the processing to which the product is subjected, the current technology of testing, and the availability of materials of the desired quality.
In short, these are relatively limited revisions, but could have important implications for industry and make these important USP chapters more useful and reflective of industry practice.
References
1. US Code of Federal Regulations, 21 CFR 211,113a), 1978.
2. US Code of Federal Regulations 21 CFR 211.84(d)(6), 1978.
3. J. Agalloco, Bioprocessing and Sterile Manufacturing, a Pharmaceutical Technology eBook, pp 31-35 (2016).
4. USP, Chapter <62> Microbial Examination of Nonsterile Products: Tests for Specified Miocroorganisms, Sixth Interim Revision Announcement (USP, 2016).
5. USP, Pharmacopeial Forum 25 (2), pp 7774-7785, (USP, March – April 1999).
6. USP, Pharmacopeial Forum 27 (2), pp 2313–2325 (USP, March – April 2001).
7. K. Ginsbury, “Proposed USP Chapter on Nonsterile Bioburden Long Overdue, But Clarification Still Needed,” Pharmacopeial Forum, August 22, 2014(PDA, 2014)
8. USP, Chapter <38> (USP, 2015).
9. USP, Chapter <41> 2nd supplement, (USP, 2018).
10. USP, Chapter <62> (USP, 2009).
11. S. Sutton, PharmTech 30 (12) (2006).
12. S. Sutton, PharmTech Sterile Manufacturing Supplement, 2009.
About the Authors
James Agalloco, is principal of Agalloco & Associates, jagalloco@aol.com; (908) 874-7558*
and Donald Singer is senior microbiology technical consultant, North America, Ecolab Life Sciences.
* to whom all correspondence should be addressed.
