Technical Review Article | Open Access | Published 11th October 2024
Major outcomes of the common A3P/ECA/PHSS/AFI/BPOG Survey on current industry practices for the inclusion of Local Isolates in the GPT & on-going discussions on the relevance of that expectation.
Isabelle HOENEN | EJPPS | 293 (2024)
A key current expectation for the sterile medicinal products manufacturers is to document and implement an efficient overall contamination control strategy including metrics that provide evidence of an appropriate performance[1]. The microbial test methods validation and microbiological monitoring program are obviously key elements of that strategy as they must contribute to demonstrate the expected performance of the combined effect of the design and qualification of a facility and associated installations/equipment, of all operational activities including the sanitization, of the aseptic process validation and of the operators training, qualification, and behaviours in clean classified areas.
1. INTRODUCTION AND PROBLEM STATEMENT
The microbiological environmental monitoring program must include for any culture media the verification of their ability to support growth of a wide range of micro-organisms and an adequate identification strategy must be applied for the microflora recovered in clean classified areas[2]. Growth promotion property must also be established for media used for aseptic process simulation and sterility testing[1, 2, 3]. Indeed, if the media used do not support the growth of the micro-organisms that are present, the false negative results obtained will make undetectable the potential issues and/or product contamination. Furthermore, the knowledge of the usual local flora is critical for experienced microbiologists, as it provides them key data to evaluate the effectiveness of the cleaning and sanitization program, to adjust as necessary the overall contamination control strategy or to determine the source of an atypical contamination and finally to implement the appropriate remediation and improvement plans.
The inclusion of local flora isolates in addition to the pharmacopeial referenced collections strains to challenge the microbiological media growth properties and microbiological methods, becomes more and more a topic of great debate… and controverse… between microbiology experts[4, 5, 6, 7, 8, 9, 10, 11, 24, 28] and there is clearly no consensus on the scientific rationale behind this expectation that, yet is of almost systematic verification during regulatory inspections, has led to observations and has conducted a large majority of companies to finally include local isolates in their GPT pool, generally based on … poor documented rationales.
Current EU GMP Annex1 Manufacture of Sterile Medicinal Products[1] includes the following definition for “local isolates: Suitably representative microorganisms of the site that are frequently recovered through environmental monitoring within the classified zone/areas especially grade A and B areas, personnel monitoring or positive sterility test results.”
In the literature different terms for “local isolate” can be found e.g: “local environmental (EM) microflora“, “wild type microorganisms” “normal flora“, “local flora”, “environmental isolates“, “fastidious microorganisms”, “house isolates”, “plant isolates” etc…in the present article, the author will use the term “local isolates”.
The definition of Growth Promotion Test (GPT) is provided by the USP:
– in Chap <1116>[2]
“Procedure that references Growth Promotion Test of Aerobes, Anaerobes and Fungi in Sterility Tests USP <71> to demonstrate that the media used in the microbiological environmental monitoring program, or in the media-fill runs, are capable of supporting growth of indicator microorganisms and of environmental isolates from samples obtained through the monitoring program or their corresponding ATCC strains”.
– in Chap <1117,1>[29]
“A test intended to confirm the ability of a nutrient medium to support growth of a predetermined type and number of microorganisms.”
Helpful summaries of key guidance, pharmacopoeia and regulation documents asking for the inclusion of “facility isolates or stressed microorganisms” in the microbial test panel, with the precision of which of them do formally expect (or just suggest) local isolates in addition to the pharmacopeial referenced strains, can be found in Table 1 of ref[5], Table 1 of ref[6] and Tables 1 & 2 of ref[9].
These tables, so as the long list of regulatory texts and guidance’s examined for the purpose of the present article[1, 2, 3, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 29], underline the jungle of existing unclear requirements and it is indeed difficult to understand for which test this inclusion is just “recommended” or is really “mandatory“.
In general, there is a large consensus among microbiologists on the fact that the pharmacopeial referenced strains used for the compendial tests were selected especially based on their representativity of most local flora isolates[10, 11]. These compendial strains, with a long history of use and prepared following strict national culture collections criteria, ensure standardization between media manufacturers and laboratory users[24].
The addition of “normal flora organisms” for media growth promotion tests can be found in the FDA Guidance to Inspections of Microbiological Pharmaceutical Quality Control Laboratories since 1993. Conversely, there is no more any recommendation to use local isolates for either method suitability or growth promotion testing in the 2020 Second edition of the FDA Pharmaceutical Microbiology Manual[11].
The FDA Guidance for Industry for Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice since September 2004[3] says “The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates. Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge“.
The USP <1117> Microbiological Best Laboratory Practices does precise that micro-organisms used to challenge the growth promotion properties of media “may include representative environmental isolates (but these latter isolates are not to be construed as compendial requirements)“.
Even the recent revision of the EU GMP Annex1[1] which includes following expectations:
– point 10.9 “Media used for product testing should be quality control tested according to the related Pharmacopoeia before use. Media used for environmental monitoring and APS should be tested for growth promotion before use, using a scientifically justified and designated group of reference micro-organisms and including suitably representative local isolates“.
– APS section, point 9.45 ii. “On completion of incubation […] samples of the filled units should undergo positive control by inoculation with a suitable range of reference organisms and suitably representative local isolates“.
Is somehow unclear because the term “suitably representative” can lead to subjectivity and latitude of interpretation: does it mean “predominant”, “normal”,… ? In addition, these expectations don’t contribute to clarify how the selection of these “suitably representative” isolates must be performed.
Nevertheless, this text includes a definition for “local isolates” in the glossary which confirms that the focus must be on the flora recovered from the environmental monitoring in the aseptic areas (Grade A & B and associated operators) and from the positive sterility tests.
The USP <1231> Water for Pharmaceutical Purpose[21] recommends including “additional organisms” when representing those “considered objectionable and/or typically isolated from the water system (house isolates)”.
At point 8.5.4 the importance of a solid identification strategy is underlined such as to have the best knowledge possible of the “normal flora” of the systems” and be able to detect new species independently of the action or alert levels defined.
More importantly, this informational chapter reminds the key general controversial elements about the so called “wild type” of the local isolates[4, 5, 6, 7, 8, 9, 10, 11, 24] that are valid for all environments (not only for water systems): the difficulty to culture and to ensure good laboratory storage conditions for these “stressed” strains usually only exposed to low nutrients environments, their ability to adapt to their surrounding environment and mutate, and so to become non representative of the source environment. The local isolates strains growth and stability are by nature unpredictable….
“Water system isolates may be incorporated into a company culture collection for use in tests such as antimicrobial effectiveness tests, microbial method validation/suitability testing, and media growth promotion test. The decision to use water isolates in these studies should be risked based because many such isolates may not growth well on high nutrient media required. And because once adapted to laboratory media, they may not perform like their wild type progenitors”.
In addition, another universal controversial element is the fact that the traditional monitoring methods based on culture media have limited capability to capture transient contaminations, characteristic of most micro-organisms in these hostile environments where they can’t survive without resistance systems as the one developed by the spore formers[24]. So, the absolute representativity of the local isolates recovered by these methods in a system or an environment is by nature also questionable.
This complexity linked to the numerous unclear expectations and/ or recommendations associated to the recent experts challenges about the absence of clear scientific added value for the systematic use of additional local isolates to the GPT challenge pool, has conducted the A3P, with the active collaboration of the ECA, PHSS, AFI and the BPOG, to launch in 2022 a survey to collect current industry interpretations, practices, rationales, difficulties, and challenges.
The present article has the objective to present the major outcomes of this survey, to assess the rationales and the difficulties linked to the implemented strategies at industry level and finally to provide a view on on-going discussions on that topic and potential enhancements/ solutions for a well-balanced strategy based on some experts’ inputs.
2. PRESENTATION OF THE SURVEY RESULTS
The survey sent out by following industry associations (A3P, ECA, AFI, PHSS, BPOG) in 2022 included 26 questions with the objective to capture whenever possible the rationale for each one. The survey was answered by 97 participants.
3. HIGH LEVEL SUMMARY AND ASSESSMENT OF THE RESULTS
80% of the 97 participants include local flora strains in addition to the compendial strains in the GPT pool. Among them 66% use a unique set of local strains recovered in their production areas for all GPT tests; some of them include in addition a waterborne microorganism based on process, product or design specificities.
Very different rationales are used to support their strategies: a majority use the top 3 to the top 5 of the micro-organisms predominantly recovered (30% of the participants include 2 local strains in their GPT pool, 18% have 3, 9% have 5 and 7% only 1), sometimes one of each category of the compendial strains, more rarely the category of the greatest risk for the product or a combination of one human origin strain + one representative of airborne microorganism + one waterborne microorganism.
Several comments were made regarding to the slow growing and the low adaptability of stressed organisms among the local isolates strains and that this requires sometimes to exceed the incubation duration expected by the pharmacopeia for the GPT.
77 % prepare and preserve these strains in house. 43 % have defined a process for removing a local strain from the GPT pool; among them 65 % apply the rule of no recoveries of that strain observed during a certain period.
82 % of the respondents have an annual frequency for the reevaluation of the local strains to include in the GPT pool (mainly done during EMPQE or annual microflora assessment).
29 % of the respondents declare having faced issues/failures with their local flora during GPT. Issues can be observed for a large variety of genus and species, among the listed ones: Staphylococcus epidermidis, Methylobacterium species, Micrococcus luteus, Ralstonia picketti). The root causes were mainly linked to microbiology laboratory practices issues (size or homogeneity of inoculum, concentration of the inoculum, inoculation preparation issues, subculture issues, contamination of the inoculum, …) or linked directly to the strains sensibilities or maintenance of the cultures (no growth observed after the 3 days, loss of viability after storage, stress that led to death of the microorganism, very low growth, …) .
During the GPT failures investigations, 46% of the participants answered that their laboratory practice is to repeat the testing with the use of triplicates. 36% use a collection strain of the same microorganisms in case of recovery difficulty.
When they introduce a new container closure system, 55% of the respondents assess the impact on GPT during an APS; among them 40% would challenge this as part of the first APS performed after the introduction of the primary product component, 28% would run a specific APS before introduction of a new primary product component in routine and 32% would manage this via a laboratory study. In some cases, the decision to run 1 to 3 APS exercises is based on a formal risk assessment.
These survey results show that:
– the participants encounter similar challenges with local isolates: slow growing local isolates, viable but non culturable isolates, inoculum preparation issues (non-homogeneous preparations, micro-organisms that form clusters, highly sensitive strains to small amounts of process related residuals substances or to the amount of oxygen or soluble gazes -situations observed on incubated APS units-, lack of stability of the strains, etc…). They also struggle with the conservation, expiry date management and with the workload associated with all the tests using these local isolates strains.
– in general, the strategies in place are not based on scientific data or strong rationales… which leads to the conclusion that the inclusion of local isolates in the GPT challenge pool is mainly driven by a compliance or regulatory inspections risk reduction management decision and not sufficiently based on a scientific approach.
4. CURRENT ONGOING DISCUSSIONS AND EXPERTS’ INSIGHTS
Salaman BYRON, in his article[24] “Facts about Environmental Isolates and Growth Promotion Test” in the American Pharmaceutical Review, summarized in the table below the main PROs and CONS linked to the inclusion of Local isolates strains in the microbiological media GPT challenge pool.
Note : EI is the acronym for Environmental Isolates
For him, “despite the facts discussed, the analysis of EI in GPT is still the best information available to evaluate the effectiveness of microbial contamination controls. Implementing standard operating procedures and grappling with the practicalities of EI selection and culture maintenance that will sustain the cultural characteristics of such wild-type isolates around some degree of regulatory uncertainty is what is required.” […] “the utilization of EI is considered a good practice to challenge the robustness of microbial methods.”
In the context of lack of guidance or published rationales for the local isolates’ selection process, Robert WESTNEY suggests following possible enhancements[25]:
– in any case ensure to have a procedure that explains the selection process to avoid inspection observations and ensure also that the site microbiologists understand the intended use of a firm’s media.
– assess the need to include or not “atypical”, “unusual”, “emergent” micro-organisms recovered during trends or non-conform monitoring results, not only the “normal” microflora.
– to overcome the challenges linked the preparation, homogeneity, and stability of microbial suspensions concentration (inoculate concentration of less than 100 CFU expected), studies to ascertain the stability or growth ability may help to anticipate any change in concentration during storage and to define an expiry date for the standardized suspension. Another solution may be represented by using ready-to-use preparations of customers in house isolates.
During the 2021 PDA/FDA on-line Joint Regulatory conference[11], Dennis GUILFOYLE (former FDA inspector involved in the redaction of key guidance related to Microbiological Methods) and Tony CUNDELL (Consulting Microbiologist, former member of the 2020-2025 USP Microbiology Committee of Experts, active PDA Member) presented scientific data that support the fact:
that USP QC collection strains are very representative of the most common environmental isolates recovered environmental isolates and identified from pharmaceutical environmental monitoring.
that domestication of such “wild type strains” may significantly alter the characteristics (phenotype and genotype) of the stored microorganisms
For them “the use of environmental isolates are not necessary as supplement QC microbes for Media Growth Promotion and Suitability testing for the Microbiological Examination of non-sterile products and for sterility testing”.
The benefits they see for using environmental isolates are in the case of Antimicrobial Effectiveness testing, Disinfection Efficacy studies, EM media and new microbiological method validation.
For the present article, Tony CUNDELL, has accepted to provide some additional inputs:
-“In general, the QC organisms for method suitability and growth promotion testing are specified in the compendial chapters and if you use them you have met the minimum requirements of the official test. The required organisms are broadly representative. Adding S. epidermidis when you use S. aureus is not necessary.
– Routine growth promotion testing of general microbiological culture media based on the very low probability of poor performance is not a value-added activity. Our clinical colleagues stopped doing this years ago.
– Dennis GUILFOYLE and I presented the argument that the use of environmental isolates had become a compliance issue that was not justified by science at the 2021 FDA-PDA Conference and the argument was accepted by FDA attendees such as Rick Friedman. FDA investigators will be instructed to not require environmental isolates. – Unfortunately, the media used for EM and water monitoring and their growth promotion test organisms are not definitively defined in compendial test methods. The selection of promotion tests for R2A agar that are derived from <61> are inappropriate as are the Ph. Eur. incubation conditions
– Most QC microbiology labs do a poor job maintaining culture libraries.
– There is a strong move from traditional culture-based methods to bio-fluorescent particle monitoring”.
… And he warned about the risk linked to surveys results which “may often reinforce bad practices”.
Arjan LANGEN, Global Sterility Assurance Director & Global Auditing Leader at GE Healthcare, active ECA member has also provided comments and recommendations:
– “Based on the feedback given by the participants, my main conclusion is that there is no common industry standard for the use of local strains from the GPT panel: participants give many different answers with respect to the selection, preparation, removal, and the number of local strains used in the GPT.
– It’s quite surprising that still 20 % of the participants are not using local strains in their GPT at all. These companies are probably not inspected by the FDA as the Aseptic Processing guide includes already a consideration to use house isolates in the GPT since 2004.[…] The use of local GPT strains can be considered to be an FDA requirement. But as the revised Annex1, now containing a requirement to include ‘suitably representative local isolates’ in the GPT, it can be concluded that the use of local isolates in the GPT will formally be a requirement for many countries in the world.
– Another interesting outcome is the fact that most sites don’t use a line specific panel of local strains for the GPT. As a result, it poses a risk that a line specific contaminant (for instance related to the use of line specific materials) is not proven to be detected in the Aseptic Process Simulation of that specific line. My strong recommendation is to at least consider using line specific panels, unless evidence is gained that the local strains are not specifically related to a line.
– Finally, I see it as a potential concern that 23% of the participants is using an external vendor for delivering the local strains. Local strains are generally required to be included in the growth promotion test because these strains could be stressed or damages and therefore their growth might not be detected using the standard media and standard incubation times and temperatures. If strains are re-cultured at the vendor and the number of passages will increase, there is a risk that the growth properties of local strains will improve and the added value of using local strains in the GPT would be questionable.
As a conclusion and based on the participants feedback, it seems important that a common industry standard is developed for the use of local strains in the growth promotion test.
Many companies are still using the traditional growth-based detection methods to assess the potential contamination risk of our sterile products. And we do know that these methods have their limitations, based on the media we use and the incubation time and conditions. We should make sure that the growth promotion test is performed adequately, and the use of local strains will improve the test if these strains are adequately selected and prepared.
A detailed industry standard on how to select, culture and use the local strains in the GPT would be very helpful in improving the quality of the growth promotion test, the detectability of our culture media and – in the end – the safety of our sterile products.”
Lucia CERESA, Consultant, former Charles River R&D technology and market development manager, active PDA member & PDA Italian Chapter Steering Committee Member, has accepted to answer the following questions for the purpose of the present article:
Q: When it is relevant to include local isolates in addition to the pharmacopeial strains?
A: “For the Validation study for an alternative method I always suggest adding to the required strain, local isolates because closely related to the potential risk. Also to perform suitability testing before doing any LOD (Limit-of-detection) study to verify any potential reduction of grow that need to be investigated”.
Q: What would you recommend as a balanced strategy for the selection of the local isolates to include in the GPT test pool?
A: “I think that the knowledge of the local flora is extremely important to understand better the potential risk for contamination. I also think it is a good idea to trend the predominant; the most usual but also the most critical or the one never found before. From a critical analysis of the trend it is possible then to choose the top 5.”
Q: Would you recommend one unique set of local isolates for all media & uses? or different? Why?
A: There should be a consolidate set BUT must be confirmed over the time, this is the reason for trending analysis: to investigate any change and compare the changes over the years.
Q: Any warning point or recommendation during discussion with regulatory inspectors? during technical investigation? for the QC lab practices?
A: “Inspectors appreciate a rationale for decision based on risk analysis and assessment with knowledge of the flora present in the facility and most related to critical operation and operators.”
Di MORRIS, Compliance Advisor, PNR Pharma, Former Medicines Inspector UK Dpt of Health, co-Deputy Chair of the PHSS is not surprised with the difficulties encountered by the participants of the survey in the recovering some local organisms, as they can’t growth on the usual rich growth media under typical incubation conditions and/or in the GPT delays. In addition, for her the concentration of an inoculum of 40-100 CFU where the objective is to recover a very low number of challenged organisms is not meaningful for the facility flora. For growth promotion tests she would more advocate for the use of “stressed ATCC strains” (following potentially methods such as the ones indicated in the ISO/CD 11133: 2014 Microbiology of food, animal feed and water -Preparation, production, storage and performance testing of culture media and reagents -) to better represent the stressed organisms that we are trying to recover. Finally, her recommendation is that “Companies should be using predominant and difficult to eradicate local isolates in their studies as they would in disinfectant efficacy work”.
T. BONNEVAY, Global Microbiology Analytical Expert, Sanofi Pasteur, EDQM Microbiological Methods Expert, A3P Board Member
Thierry Bonnevay adds that at QC Microbiological laboratory level, “it is of particular importance to have an adequate technical experience for the microbial library management: banking, maintenance, control and characterization of these environmental strains and a continuous training of the technicians in this particular field of competency”.
For him, “the concentration of the inoculum of these additional challenge test microorganisms is also key: <100 CFU, of course… but > 25 CFU because with a lower spike than 25, there can be too much variability in the recovery”. In addition, “the technique of inoculation and spreading on a plate in case of solid media requires a lot of reproducibility and experience (for example Gram-negative bacteria such as Pseudomonas do not like to be spread with rakes at all).”
5. CONCLUSION
The survey results and the experts’ inputs confirm the lack of clear regulatory expectations and the absence of consensus among the experts’ microbiologists.
The need of a specific and applicative guidance for the industry and regulators, providing:
– science-based elements for the selection of the local flora strains to include in the GPT pool in addition to the compendial strains with the relevance to include them (or not) for culture media GPT, APS units GPT after incubation, microbial methods validation/ suitability tests, sterility tests, disinfectants validation studies, alternative microbiological methods validation, …
– key elements for the QC Laboratories to ensure the safe selection and inoculum preparation of the local strains, the stability and storage of these local isolates strains cultures and to develop a well-balanced strategy considering costs/complexity, is obvious and critical to ensure the robustness of the strategy defined and applied on a plant.
In the meanwhile, the strategy for the selection and inclusion on the local isolates strains in the GPT challenge pool will continue to depend greatly on the plant microbiologist’s expertise and manufacturing environment knowledge … and its acceptance by the regulatory inspectors will vary depending on their overall industrial microbiology knowledge and experience.
This article underlines one more time the limitations of the traditional culture-based methods. These limitations are more and more recognized and the guidance for the validation and use of alternative methods[9, 25, 26, 27] may help to strengthen the knowledge of the microflora really present at the manufacturing plants.
“The views and opinions of the author expressed herein do not necessarily state or reflect those of Eli Lilly company.” A special Thanks to the Associations that have contributed to this common survey and to the experts for their precious inputs and kind participation.
References
01. Current EU GMP Annex 1 Manufacture of Sterile Medicinal Products
02. Current USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments
03. FDA Guidance for Sterile Drug Products produced by Aseptic Techniques (2004) – Current GMP
04. Westney, R (2021) The use of In-house Microbial Isolates in Media Growth Promotion Testing: Challenges and Solutions, American Pharmaceutical Review The Use of In-House Microbial Isolates in Media Growth Promotion Testing: Challenges and Solutions | American Pharmaceutical Review – The Review of American Pharmaceutical Business & Technology
05. Booth, C (2019) Environmental Isolates: What’s the proper use of in-house isolates?, Pharmaceutical On-line Environmental Isolates What’s The Proper Use Of In-House Cultures (pharmaceuticalonline.com)
06. Booth, C (2019) How to establish Growth Promotion Tests for Pharmaceutical Culture Media, Pharmaceutical On-line How To Establish Growth Promotion Tests For Pharmaceutical Culture Media (pharmaceuticalonline.com)
07. Sandle, T (2018) Microbiological Culture Media: A Complete Guide for Pharmaceutical and Healthcare Manufacturers, Chapter 9 The use of environmental isolates in Pharmaceutical Microbiology, DHI/PDA, Bethesda, MD, USA pp. 219-239
08. Cundell, T; Tidswell, E; Massaro C (2021): Live, stressed and dead micro-organisms – their role in Microbial Test Method Validation, American Pharmaceutical Review Live, Stressed, and Dead Microorganisms – Their Role in Microbial Test Method Validation | American Pharmaceutical Review – The Review of American Pharmaceutical Business & Technology
09. Guilfoyle, D and Cundell T (2022): Do Plant Isolates have a role in Method Suitability and Growth Promotion Testing in the Microbiology Laboratory? Is it a Matter of Science versus Compliance?, PDA Journal of Pharmaceutical Science and Technology, 76, pp. 444-460
10. Guilfoyle, D and Cundell T (2021): Do Environmental Isolates (EI) have a role in Method Suitability and Growth Promotion (GP) Testing in the Microbiology Laboratory?, Joint PDA/FDA Regulatory Conference 27-29 Sept 2021
11. FDA Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories, 1993
12. Second edition of the FDA Pharmaceutical Microbiology Manual (PMM) 2020, Chap Sterility Test
13. USP <71>, EP 2.6.1, JP 4.06 Sterility Tests, Table 1. Strains of the test Micro-organisms suitable for use in the Growth Promotion T and the Method Suitability Test
14. USP <71>, EP 2.6.1, JP 4.06 Sterility Tests, Table 1. Strains of the test Micro-organisms suitable for use in the Growth Promotion T and the Method Suitability Test
15. USP <61>, EP 2.6.12, Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests
16. FDA CBER 21 CFR 610.12 Sterility Test, 2019
17. PIC/S PI 012-3 Recommendation on Sterility Test
18. TGA guidelines for sterility testing of therapeutic goods, 2006, Chapter Methodology
19. USP <51> Antimicrobial Effectiveness Testing
20. USP <1117> Microbiological Best Laboratory Practices
21. USP <1231> Water for Pharmaceutical Purpose
22. PDA TR1 Aseptic Processing rev 2023, Topic 1. Growth Promotion testing of Environmental Monitoring Media
23. PDA TR22 Process Simulation for Aseptically Filled Products (rev 2011)
24. Salaman-Byron (2019) Facts about Environmental Isolates and Growth Promotion Test, American Pharmaceutical Review Facts about Environmental Isolates and Growth Promotion Test | American Pharmaceutical Review – The Review of American Pharmaceutical Business & Technology
25. USP <1223> Validation of alternative microbiological methods
26. EP 5.1.6 Alternative Methods for Control of Microbiological Quality
27. PDA TR33 Evaluation, Validation and Implementation of Alternative and Rapid Microbiological Methods
28.Sandle T (2020), Why it’s time to strengthen and widen the microbial test panel, European Journal of Parenteral and Pharmaceutical Sciences, Vol. 25, Issue 4
29. USP 1117,1 Microbiological Chapters – Glossary
“The views and opinions of the author expressed herein do not necessarily state or reflect those of Eli Lilly company.” A special Thanks to the Associations that have contributed to this common survey and to the experts for their precious inputs and kind participation.
Author Information
Corresponding Author: Isabelle HOENEN
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