Industry meetings conducted by the IVT Network have recently included a “Senior Level Think Tank” session on the respective topic for the meeting. These sessions have become a major feature at IVT conferences. They are frequently requested and well-attended by conference participants. Attendees generally have a sound technical background and several years of experience in the designated topic. Participants are sent a series of questions in advance of the meeting. They are asked to submit responses for eventual use at the session. When participants are convened at the IVT meeting, the session is facilitated to ensure most if not all of the questions and topics raised are discussed.
Microbiology Think Tank, Philadelphia, August 2014
An IVT Microbiology Week think tank was held in Philadelphia, PA, USA in August 2014. Participants were asked to submit responses to the following questions in preparation for the session:
- What do you consider the most challenging task currently on your “to do” list?
- What area of microbiology is your greatest concern?
- Any fears or concerns regarding complying with regulations?
- What microbiology-related trends have you seen at your site?
- What is frustrating, inefficient, or ineffective in your risk management approach?
Session participants had a combined work experience running into well over 100 years -- a perfect environment for benchmarking and knowledge-sharing. Participants worked in sterile and aseptic products manufacture, non-sterile dosage forms, cosmetics, contract testing and environmental monitoring support (water, HVAC). Specific experience levels ranged from a microbiologist with 28 years clinical experience to a participant working for a cleanroom vendor with an excellent “hands-on” understanding of cleanroom clothing, cleaning processes, and microbes.
Some of the most notable outcomes from the session are listed below. Note the diversity of topics addressed.
Costs of not being Proactive
One participant explained how companies spend a fortune on environmental monitoring and testing, but do not invest in simple and relatively inexpensive measures such as mops, wipes and sanitizers which can prevent build-up of rust and particulates. This topic has recently been much publicized in recalls and regulatory actions. Others agreed that industry spends far too much on testing, and does not devote resources to preventing contamination episodes.
One of the ideas raised during the session was to calculate the cost of each contamination episode – not merely in terms of the material / product that is lost, but with a cost of non-quality. The following were suggestions of non-quality costs for consideration:
- Time, translated to dollars based on salaries of employees at all levels, who are involved in the episode including investigations, placing material on hold, performing additional cleaning cycles etc.
- Downtime of capital expenditure equipment and facilities during investigation
- Salaries paid to operators and managers who cannot manufacture product during the investigation.
- Additional media fills and other validations to re-qualify the area
- Additional cleaning and disinfection cycles
- Lost sales because of delays in batch release
- Stock out – because valuable warehouse space is held for the quarantined stock and so there is no room for saleable goods
- Unsold material held during the investigation
- Cost of additional environmental monitoring tests and contamination identification
- Write-up time for the investigation
- Review time of management
- Cost of implementation of corrective actions.
It was proposed that participants send in their ideas for factors to be considered in developing a cost of quality model for these types of episodes – and once that is available it can be shared. Once these types of calculations become standard, it will be relatively easy to use management review meetings to obtain resources for planned upgrades to facility and equipment.
Various aspects of the general topic of personnel were discussed. Ongoing replacement / attrition rate of personnel and resources invested in bringing newbies up to competency is a major problem. It was proposed that a cost of quality model be developed which would be persuasive in convincing management to move from temporary workforce in critical jobs even in peaks, to permanent employees. A discussion was held on means for really confirming personnel competency after training on the job and it was concluded that this has to be by watching them doing it while following the written, approved instructions. Proficiency testing and work sheets vs uncontrolled “work aids” were addressed. There was pretty much a consensus that in a GMP environment, only controlled versions of approved instructions could be used if they were to remain up to date and reflect standard practice.
Other personnel-related concerns raised included:
- Staying in front of the ever changing opinions of regulatory bodies – every year they have a new hot topic
- Microbiologists should be involved in setting (microbiological) specifications and in CMC review of those sections related to contamination control, cleanrooms and microbiology
The broad and general topic of cost effectiveness was discussed. Highlights included:
- How to engage management’s attention to quality in cosmetics manufacture, when regulators sometimes take the view “well you haven’t killed anyone so it’s ok.” One suggestion was to use product liability and the threat of ambulance chasing lawyers and their frivolous law suitsat management review meetings to bring management on board regarding the need to be proactive in preventing contamination episodes. A cost of quality model could also be developed for this application
- Implementing rapid microbiology methods and how to validate these methods
- Quality control release testing
- Balancing getting most information from an environmental monitoring program without going nuts – we need to not do too much work. Jeanne Moldenhauer says: “Meaningful, manageable and defendable.” A formal risk assessment is essential and an EU written requirement in Annex 1 to the GMPs.
An intense discussion took place regarding how much of our resources should be diverted to identifying organisms and maintaining libraries. In any case, if strains (maybe damaged) which are recovered are cultured, they rapidly become lab strains rather than wild types. It is of questionable value to hold them for much more than one year, but certainly they should be directly frozen once isolated and without passaging. MALDI-TOF was discussed as a really low cost (after capital expenditure) and rapid, identification method with the proviso that for sterility testing and possibly media fills, it may not have regulatory acceptance. It certainly seems to be a very useful methodology for companies with large numbers of environmental monitoring isolates to identify.
- What is of most value is to trace back where we found an isolate and use this information to think about how it got there, why it stayed there, and how we can prevent it in the future -- In particular, to check that our disinfectants are broad spectrum and capable of eliminating this particular strain.
- To identify one morphologically distinct colony of each type isolated on a plate to build up a database of flora we find. This particularly applies in the less clean areas where companies often tend to identify only “above alert level” – whereas that can leave them with missing information.
- Whatever identification methods are used, classic colony morphology should always be step one and gram staining and biochemical tests can and often should also be used.
- Participants were adamant that an experienced microbiologist must review and analyze data. Also microbiologists must impart their understanding of the analyzed data as concise and precise information to management in order that it be applied as knowledge and acted on for facility and equipment upgrade; replacement of “shedders” – operators whose environmental monitoring results show repeatedly high counts and proactive additional cleaning / disinfection cycles when production volumes increase.
- If you find Salmonella in the cleanroom, you should be worried unless you are using eggs.
The major issue discussed with respect to audit trends was related to pressure differentials (if required or not) and separation of clean and “dirty” areas in the microbiology laboratory. See references below. Whereas these measures were not common five years ago, it seems that increasingly this separation is standard and it does seem to be the prudent course of action if false positive results are to be avoided.
Participants summarized by sharing what they perceived as the benefits of the three-hour session. The only missing piece from their insights is the psychological aspect of sharing your burning issues. This was very much felt in the class room and discussed by attendees.
Participants found the think tank beneficial and even therapeutic. It was great to benchmark and hear that others had similar problems. Under “what did you learn”, attendees wrote:
- I enjoyed the session greatly and learned much from the participants.
- Microbiology is broad and the application varies greatly from cosmetics, food, sterile, non-sterile and you tend to stay in your own world.
- Interesting to hear how others handle similar situations in different industries.
- I’m right and my management needs encouragement and educating – reinforced the numbers thing (cost of quality).
- Good to find out what other microbiologists are concerned about.
- Same as others – wild crazy world that keeps me in business.
- Need to stay current and join more committees like PDA.
- Deal with same things – upper management making changes that cost money but are necessary for compliance – how do you approach that? GMPs are not a quality system.
- Testing is still the primary goal as opposed to prevention.
- One can and always learns from others.
- We do too much with isolates.”
- Lean labs are a pain.
- We should stay in touch!
WHO Technical Report Series, No. 961, Annex 2. WHO Good Practices for Pharmaceutical Microbiological Laboratories, 2011
USP <1117> Microbiological Best Laboratory Practices