This two-day event is held every November by Pharmig — a professional, not-for-profit organisation for those who work in, or alongside, microbiology departments within pharmaceutical, cosmetics or healthcare sectors. To celebrate 25 years of this annual event, the organisers decided to reflect back and to look at how microbiology methods have changed in the last 25 years, as well as looking ahead to future developments. This report provides highlights of the first day’s presentations and gives a brief outline of the second day’s programme.
To start the first morning David Begg, ex-medicines inspector and microbiologist, Sharon Johnson, looked at how microbiology has changed. Johnson commented on how much is now different in the world 30 years later, in regards to the speed and immediacy in which information is now available with the internet and new technology, in fact leading to an information overload. And although the same things are being tested in a microbiology lab there are more tests that can now be conducted, leading to a lot of data, which is not always processed in the best possible way.
Johnson commented on how pre-prepared media, disposable and pre-sterile consumables and increased automation has led to some companies believing less-qualified microbiologists are sufficient in the lab, while increased outsourcing and cross-functional team members means the required microbiological understanding is not as readily available.
With more standards, requirements and more complex techniques around, it is in depth microbiological expertise that is valuable and necessary, believes Johnson. She warned that a loss of microbiological understanding must be prevented and companies must engage more with the regulators to solve some of the problems being faced.
David Begg called for a sharp focus on the importance of pharmaceutical microbiology, reminding the audience of events such as the contaminated IV fluids that killed five people at the Devonport Hospital in 1971. He also praised Pharmig for filling a unique role, unfettered by commercial considerations, enabling an open arena to discuss microbiology.
Begg urged microbiologists to not lose sight of the identity, core beliefs and values of Pharmig, and the role of microbiology in pharma.
Rapid Microbiological Methods
Andrew Hopkins, Expert GMDP Inspector for the UK Medicines and Healthcare Regulatory Agency (MHRA), discussed the use of rapid microbiological methods (RMM) from the point of view of the MHRA, responding on behalf of regulators, he indicated what labs should look out for. Hopkins said that less than 50% of labs are using RMM and companies are not moving forward as fast as they could. He detailed RMM issues from a regulatory perspective and he challenged some current perceptions of the new methods such as the belief that regulators are not pro RMM and the new technology is too intimidating for companies to invest in. To counter these points he quoted the regulatory audit and Red Tape Challenge issued by the MHRA in March 2012: “Through the MHRA, we will work with industry and other international regulators to develop actions, which will create a more enabling regulatory environment for the adoption of innovative manufacturing technology.”
Hopkins evaluated traditional environmental monitoring (EM) and pointed out that only a small fraction of the air and surfaces that influence the product can be tested. He said the techniques have low recovery efficiency and how only a limited range of organisms can be isolated. He explained that while a positive isolate is a significant event, a negative result may be misleading — the absence of contamination in a sterility test does not prove the product is sterile, rather demonstrates that the contaminant was not found. “It is therefore important to carefully design validation protocols,” he said, urging microbiologists to recognise the inadequacies of current methodologies.
Hopkins turned the question of why should companies invest in RMM on its head, asking: “Why wouldn’t you?” Gently reminding the audience that the Marketing Authorisation Holder has a regulatory obligation to keep up with new technology and MHRA directives.
He encouraged companies that are thinking about new lab designs and equipment to reach out to the MHRA and have design conversations at the start, not the end, of the process. “Always talk to regulators, there is a perception that they are not approachable” he said, “but the regulatory bodies want the best outcome for patients and the MHRA is eager to support innovation”.
He discussed the MHRA Innovation Office, which was set up in 2012 and designed specifically in response to calls from academia, government and industry to have access to free and expert regulatory information, advice and guidance to help develop innovative medicines, medical devices or novel manufacturing processes. Hopkins concluded with the caveat that although RMM offers a new tool in the tool box to be utilised, it does not necessarily replace existing tools, again stressing the importance of validating testing protocols.
Open discussion sessions followed the opening talks, where delegates had the opportunity to attend informal discussion sessions allowing an exchange of ideas, outside of the ‘lecture-led’ presentations. Topics included: cleaning & disinfectants, endotoxins, rapid methods, environmental monitoring, data integrity and a microbiology general Q&A surgery.
With a recent focus in the media on data integrity this topic is worthy of further note. The workshop on data integrity, led by representatives from Lonza, was an opportunity for individuals to ask questions and voice problems they have come across in their own labs.
The issue of human reliability was discussed extensively and how to reduce inconsistent data. Is there a need for more second checking in microbiology departments to meet data integrity requirements? Furthermore, is it feasible to suggest that all the work of a trained microbiologist should be checked by another microbiologist? Although some labs prioritise this, others do not have the manpower nor budget. Is it possible that the second microbiologist would simply agree with the first’s findings and what is a statistically significant margin of error? It was concluded that the latter depends on what is being counted. If micro-biologists are expecting to see 0–2 colonies, being out by even one colony is significant. It is also important to look at the chain of custody, has the same individual reported the data throughout the process and do they have a vested interest in the result?
One delegate also shared their company’s experience of finding a problem in data integrity and presenting it to a regulatory body for advice and help. They said it was the right decision and would encourage other companies with validity or integrity problems to seek advice, believing that regulatory agencies want to see proactiveness, in problem solving.
Regulatory updates
Andrew Hopkins then returned to the stage to provide an overview on recent regulatory updates and the implications of Brexit, relevant to the microbiology industry. In particular, he covered Annex 1 and discussed the implications of the recent coordination between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).
Hopkins began by introducing the proposed coordination between the FDA and EMA, which have decided to mutually recognise each other’s good manufacturing practice (GMP) inspections of pharmaceutical facilities. This mutual recognition, applied from 1 November 2017, means the MHRA and EU authorities will not be automatically required to inspect facilities in the US and vice versa. Hopkins confirmed that blood, plasma and tissue inspections are outside the scope of this agreement. He directed those seeking further information to the Q&A issued by the EMA.1
Hopkins considered what this will mean for the UK MAH/Importer: He said the agreement is in place but will be finalised in two years time, when all EU countries are included in the scope. Testing for the next two years is still required on importation of product from the US. ‘For Cause’ inspections (to investigate a specific problem that has come to the FDA’s attention) can still occur. He added EU/UK inspections by EU Competent Authority inspectors will be based on EU GMP but that sites should still address US GMP and CFR requirements as the USA FDA reserve the right to inspect. He emphasised that not all products are currently covered, currently eight EU countries have been approved, the remainder will be assessed 15 July 2019, with the assessment via the Joint Audit Programme (JAP) process; its aim is to verify implementation of EU legislation on GMP national law. On ways in which Brexit might affect microbiologists, Hopkins said: “While negotiations continue, the UK is still a member of the EU and MHRA still has a full and active role.” On behalf of the MHRA, Hopkins read a prepared statement and as the agency does not know, which way Brexit negotiations will go, it has different plans according to various possible scenarios.
GMP update
Annex 1, first issued in 1972, has seen small but numerous changes in the past. In 2012, there was a proposal to revise it fully and that proposal was re-issued in 2014, triggering the update process. The key reasons for the update, according to Hopkins, was the need to ‘tidy it up’, the requirement to introduce principles of quality risk management and to reinforce the need of manufactures to keep up with current technologies (single-use and closed loop systems and other technologies in processing and testing).
At the time of going to press Annex 1, was currently under consideration by the European Commission, with no timeline confirmed. The new drafted document takes into account advances in the application of process analytical technology (PAT), quality by design (QbD) and quality risk (QRM) principles.
Water intended for use in the manufacture of parenteral drugs, known as water for injection (WFI), where the solvent is water, is defined by the US Pharmacopoeia (USP) as highly purified water containing less than 10 cfu/100 ml of aerobic bacteria. A two part Q&A WFI document, containing seven questions, was published in August 2017 to support the change in European Pharmacopoeia Monograph 0169 and gives guidance on extra GMP considerations and biofilms (not just water systems). Hopkins highlighted the importance of considering the membrane design and maintenance of the reverse osmosis (RO) system and to sample based on a worst case scenario.
To conclude his talk, Hopkins said an updated advanced therapy medicinal product (ATMP) for GMP guideline was published 22 November 2017 and he offered a reminder that both the MHRA and EMA have published data integrity guidelines in the past two years.
Equipment sanitisation validation
Neil Lewis, Global Household Care Microbiology, Procter & Gamble (P&G), introduced an alternative approach to defining and validating heat sanitisation and took delegates through a case study of effective sanitisation, carried out by P&G.
It is difficult to prove effective sanitisation of equipment because positive verification is rare and arduous to prove due to the inherent contamination risks. Lewis’ case study presented an alternative methodology, which simplified and optimised the sanitisation process. He advocated that the approach was a means of reducing costs, offering sustainable processes and microbiological control, and providing documented proof of efficacy. Currently sanitisation with steam is common and is a proven and effective technology, with a well established validation process. However, it is expensive, time-consuming and has safety risks, said Lewis. Among the negatives he listed were: it is a negative test with no measurement of reduction, there is a potential issue with swab recovery, it has questionable robustness and limited optimisation opportunity.
Currently industry standards vary considerably for how long and at what temperature sanitisation should be conducted. Therefore P&G trialled an experimental validation approach with research organisation Campden BRI, with the aim of determining what exposure time it takes to kill organisms at a given temperature, testing four different surfaces with five representative organisms.
Lewis took the delegates through the methodology, demonstrating how science could be used to establish a process and provide a rationale. He concluded that the data generated in the investigation allowed for optimisation of the process and design, which led to cost and capacity benefits and reduced risk in the sanitisation process.
Preventing human error
Les Meader, MD of Omnia CS and Foresight Innovations, gave a presentation on “Understanding Human Error: Our Role as Ambassadors for Future Human Error Prevention”. In his presentation he defined human error and examined the role that the brain plays in processing information. He mapped how the human brain’s key systems contribute to six error types, then discussed key strategies in preventing human error in the workplace.
He encouraged people to proactively identify the conditions leading to human error in the workplace. An understanding of human brain function can then be applied to prevent human errors in the workplace. He encouraged the use of all available tools to prevent human error in and urged attendees to become ambassadors for human error prevention.
Burkholderia multivorans
The second day, of the two-day event saw the presentation of an industry case study: a microbial investigation of contamination by Burkholderia multivorans ‘the perfect storm’ presented by Geert Verdonk, Director Global Center of Expertise Microbiology, Merck.
Continuing with the Burkholderia theme Dr John Metcalfe, Master Microbiology Reviewer, CDER, FDA, presented “A CDER perspective on Burkholderia Cepacia in complex and Aqueous Non-sterile Drugs”. Using the case study of Burkholderia cepacia complex contamination of a non-sterile nasal spray: he looked how to decide when a recall is warranted.
Thermostable adenylate kinase
Mark Sutton, Scientific Leader for Healthcare Biotechnology, Public Health England, tackled the development of thermostable adenylate kinase (tAK) indicators for decontamination process monitoring in pharmaceuticals. He gave an in depth look at the development of tAK indicators as a rapid read-out surrogate marker for assessing decontamination process efficacy and how to demonstrate a correlation between tAK indicator inactivation and BI kill in gaseous decontamination systems. Finally he built a case to support the implementation of tAK indicators in pharmaceuticals.
In one of two talks, Dr Edward Tidswell, Executive Director, Microbiology Quality Assurance, Merck & Co, discussed changes to the USP around sterility testing and parametric release. His second presentation entitled “10 Years On and Where We Need to Go in Microbiological QRM”, was delivered alongside Kevin O’Donnell, Market Compliance Manager, HPRA. They discussed the challenges most commonly faced and how these difficulties evolve. They took a look at risk-based concepts in standards, guidance, regulations and technical papers. And considered the past, present and future for microbiologists.
They then looked at common deficiencies in risk assessments and the tools used to address them and hypothesised about whether it is possible to change the paradigm of aseptic manufacturing risk assessment and what this would involve.
Willy Verstaete, LabMET, University of Ghent, Belgium, concluded the conference with a presentation on innovative eco-microbiology, looking at whether it has the potential to meet the needs of the next decade.
This two-day conference offered valuable and practical insight on why it is necessary to keep up to date with regulatory guidance, and gave professionals the forum to discuss their ideas and demonstrated how to incorporate change into working practice. For information on future Pharmig events visit www.pharmig.org.uk
References
- http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2017/10/WC500237908.pdf