MICROBIOLOGY CONFERENCE ANS BIOBURDEN WORKSHOP PROVIDE FOOD FOR THOUHT
This year the European Microbiology Conference of the ECA Academy took place high above Prague - in in the 24th floor of the Corinthia Hotel. But the participants only had a short time to enjoy the fantastic view over the city before the moderator of the pre-conference workshop Bioburden demanded their full attention. Dr. Marcel Goverde of MPG Consulting gave the first thought-provoking impulses on this diversified area. What is bioburden and what is its definition? Which regulations exist? The best definition can be found in EudraLex which not only lists the levels but also describes the microorganisms and differentiates between bioburden and contamination. This was followed by a short summary of important regulations and bioburden levels.
Dr. Radhakrishna S. Tirumalai, USP Convention, talked about USP <1115> in the first of six official workshop lectures. The USP chapter presented at this Conference will enter into force in December 2014 and is supposed to close the regulatory gap existing in the standards on microbiological control of non-sterile pharmaceutical production areas. The scope of effective microbiologial controls is not only a structured risk analysis of the processes; it should be taken into consideration especially the patient risk and the resulting benefit.
Picking up this lecture, the moderator Dr. Goverde pesented the implementation of Chapter <1115> for a production line that had been chosen as a pilot because of its microbiological problems. He used a case study to illustrate the approach to the FMEA carried out including the evaluation schemes on quantification and priorisation of the microbiological contamination risk. He put special emphasis on the integrated assessment of the efficiency of the proposed CAPAs and promised a major simplification of the following process assessments due to the generic FMEA carried out.
Dr. Sven Deutschmann, Roche Diagnostics, talked about the challenge to harmonise the historically evolved control differences at Roche/Genentech in such a way that the FDA expectations were met. His focus was on sampling, limit definition and deviation management. The lecture was so well received that discussions started already when Mr. Deutschmann still talked. Since time was amply scheduled the discussion could take place to the satisfaction of the participants.
In the afternoon, Dr. Jörg Degen, BSL, started the second part of the workshop with his lecture on bioburden tests of combined products. The individual bioburden control programme has to be adapted using neutralising agents, and a validation of the functionality has to be carried out. Next, Dr Degen presented the problems using case studies - flexibility is the key here. Concerning validation, which is important for the extraction efficiency and the neutralisation function he rightly said: "This is microbiology so you can't expect the same results every time."
Alexandra Stärk, Novartis Pharma AG followed with the presentation of bioburden in sterile companies. Just as the previous speakers she informed the audience about the regulatory background first. Apart from giving impulses on general methods, test frequency and the training of delegated samplers she especially addressed one of FDA's favourite topics: sample hold time. Because of the many different products which make an individual validation impossible the sample hold times were adapted to the water samples. Alexandra Stärk not only presented the choice of the defined requirements but also the method used which allowed for trending despite low bioburden results.
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At the end of this one-day workshops Dr. Marja Claassen- Willemse, MSD Oss, explained the non-sterile bioburden control strategy using the NuvaRing. She emphasized bioburden control not only during commercial production but also during product development. Control measures concern the controlled manufacturing environment as well as the release test of the components, active ingredients and the final product and in-process controls. In addition to the microbial enumeration test (TAMC and TYMC) the absence of five specified microorganisms is tested. Finally, she presented the use of RMM and promised further data. The lectures compensated the participants for the bad weather.
At the first day of the actual European Microbiology Conference bad weather and rain clouded the view from the conference hall - this gave the participants the opportunity to concentrate completely on the topics presented. After a shortened welcoming of the newcomers the Chairman of ECA's RMM Working Group and moderator of the conference Dr. Sven Deutschmann opened the Conference and quickly led up to the first speaker of the day.
Dr. Rajesh K. Gupta, Biologics Quality & Regulatory Consultants, showed his expertise in the area of the validation of microbiological methods with regulatory approval. Freely adopting the motto "Producing microbiological quality instead of testing for it afterwards", he showed possibilities for a microbiological quality assurance which uses different strategies such as validation, monitoring and verification in an overlapping way. He stressed the fact that understanding the backgrounds, regular communication with the regulatory authorities as well as using strong modern technologies is important for successful microbiological methods.
Barbara Gerten from Merck Millipore built bridges between food, water and pharmaceutical industry with her presentation. In a refreshing lecture she talked about revised ISO methods for the detection of gram-negative bacteria. After explaining the methods for the detection of enterobacteriaceae, Cronobacter sakazakii, Salmonella and Escherichia coli she showed which points are worked on in order to improve the pre-enrichment especially of gram-negative bacteria. The publication is expected for 2015/2016.
The following lecture by Dr. Tim Sandle, Bio Products Laboratory, was about the Human Microbiome Project and the implementation of the clean room microbiology. The HMP in which 300 test subjects participated could detect connections between microcoenosis and illnesses by means of the metagenome. Dr. Sandle explained that variants could be recognised between parts of the body and individuals. Changes over time could be recognised as well. Because of the HMP results cultivation methods, efficiency of disinfection and gowning instructions should be reconsidered in the clean room microbiology. With regard to the cultivation methods the motto should be "Take care of the challenging ones".
Jim Polarine, STERIS Corporation, took up the subject and shared his enthusiasm for microorganisms with the participants by talking about case studies from the area of the contamination with spores in the environmental monitoring. There were examples for contaminations stemming from the human flora but also for contaminations with spores of moulds which he highlighted particularly. They are often transferred by objects brought into the clean room zones. Here the wheels of transport carriages and sliding doors should also be inspected. Apart from several proposals concerning prevention Jim Polarine reminded the participants to bear in mind that the cultivation time is of great importance especially in the case of contaminations with spores and that cleaning alone and disinfection aren't sufficient. In that case sporicidal disinfectants are needed.
After the rich lunch buffet Gilberto Dalmaso, Particle Measuring Systems, presented the Biolaz. This realtime air monitoring system allows a continuous microbiological control which needs no consumables and can help to keep the maintenance costs low. Furthermore, the system which enables a riskfree qualification path by integration with the traditional monitoring system is validated according to USP and EP requirements.
The Conference proceeded in real time with a lecture by Jörg Dressler, PMT, on real time detection of bioburden in process and injection water. The water quality which is essential especially in the pharmaceutical industry is regulated by the pharmacopoeias. Autofluorescence gives the possibility to move from a lengthy process of testing with transport, processing and cultivation of samples to real time testing. A wavelength of 405 nm which uses the fluorescence of NADH and riboflavin has been found to be perfect. It still has to be found an appropriate standard for the unavoidable verification of the method. According to Mr Dressler it would be recommendable to use the socalled bioball.
At the end of the first conference day Dr. Timo Krebsbach, laboratory L+S, devoted his statements to the transfer of microbiological methods, of the related know-how and of all important documents such as plans and reports. The key for a successful transfer of methods lies within the attentive passing on of the know-how, this means test procedures, validation documents as well as information on possible faults have to be passed on. The question on the establishment of the test is the central issue. In spite of the methods which usually are determined by the pharmacopoeias a product specific validation is necessary that can be carried out parallel to the testing. In the case of critical product tests an experimental test of the method is provided for.
In time for the social event the weather was fine again. The planned bus tour in and around Prague culminated in a short detour to the cloister Strahov. There we were offered a great view over Prague, illuminated by the setting sun. Afterwards, we went to the restaurant Žofín Garden on an island in the Vlatava, also known as Moldavia. At medium- sized tables there was a lot of hilarious talk and discussion during a menu with three courses that united the modern and the traditional Czech cuisine.
Mary-Anne Weatherhead, Pfizer Ltd. was the first with her cheerful lecture on the cooperation between microbiologists and QPs. At the beginning of her career she had herself worked as a microbiologist and she enlightened the participants on the fact that QPs have to ensure that the patient is always in the focus of QPs. Therefore, safety, quality, efficiency and compliance with the regulations are of key importance. As a little didactical highlight she presented her helpers: little microbes made of plush which the participants liked a lot. With the help of the little microbes she illustrated the importance of microbiological basis training for the employees. When she was asked if she uses RMM she answered enthusiastically that a fast method could save batches even before one could see that there was a problem at all using traditional methods.
In his second lecture Dr. Krebsbach talked about the microbiological container closure integrity test - CCit which is required by FDA but without a predefined method. For an appropriate test a small well-growing bacterium, a sufficient number of batches and a suitable positive control are needed. The laboratory L+S was able to reach a detection limit of up to 10 μm with Brevundimonas diminuta. Jelena Novaković Jovanović, Galenika A.D., presented theoretical and practical points of view on the topic suitability test. It serves for demonstrating that all anti-microbial characteristics of the product have been neutralised. she asked to consider that the planning of tests has a decisive influence on the time and the financial burden and that even products without anti-microbial substances may have a growth-retarding effect because of the influence of the pH value.
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Afterwards, Anja Friedrich, BSL, talked about her experiences with bioindicators. By definition they are of bacterial origin and are used as instruments for the development, establishment, and validation as well as for routine controls in sterilisation processes. Thereby, the test results can be used to identify levels of safety and guarantee for the sterilisation.
Dr. Dietmar Mayer, IDT Biologika, presented possibilities and restrictions of the application of molecular biological methods for the control for foreign matters. With the alternative mycoplasma test technologies that are now accepted by the authorities, a door opens to the combination of traditional culture methods with molecular selection methods. With unspecified next generation sequences non growable microorganisms can also be demonstrated. But it has to be taken into consideration that the benefit of microbiological methods is restricted without especially pure reagents.
In his second lecture Dr. Gupta talked about the environmental monitoring (EM) during sterile production. After a short introduction why the microbiological security of medicinal products is so important the resulting difference between sterile and non-sterile production was emphasised. Since sterility tests do not secure the absolute absence of growable microorganisms it is important to develop quality during production by staff training, process design, validation and controls of the components, the facilities and the environment. The EM should be adapted from case to case.
Announced as "Last but really not least", Oliver Gordon, Novartis Pharma, talked about a comparative study of different incubation conditions for the microbiological environmental monitoring that resulted from heterogeneous specifications of incubation temperature and time in the guidelines. Critically eying the studies he explained the procedure of these tests carried out in situ as well as in vitro. Finally, he explained that a 2-plate-strategy for the microbial numeration test and for mould is effective but that is associated with a higher risk of contamination during the taking of samples. And according to him it is no problem to detect fewer moulds if the limits are based on a trending of historical data.
Summarising, the Conference and the workshop offered a comprehensive update on the actual topics in the microbiological quality control and offered many examples for a feasible implementation in the daily laboratory praxis.
Author:
Nadja Wenter
... is with Novartis Pharma Stein. There she is in charge for the area of microbiological quality assurance of a new production site for the non-sterile production of medicinal products.
