Adapting to new standards and technology

The 24th Annual Pharmig Conference, held in Nottingham in November, discussed recent changes in regulatory guidance that reflect new risk management approaches, how best to incorporate new technologies, or are the of result lessons learnt from recent microbial contamination incidents. Susan Birks reports

The scope and impact of Annex 1 changes were outlined for microbiologists at Pharmig's 24th Annual Conference in November

Pharmaceutical regulation has undergone considerable change over the past few years and this is set against a backdrop of rapid economic, technological and social change that pharmaceutical businesses face.

The microbiologist has an unenviable task of managing some of the consequences of such rapid change and being up to date with best practice is key. To address this need, Andrew Hopkins, GMDP Inspector for the UK Medicines and Healthcare Regulatory Agency (MHRA), gave an update on Annex 1 and looked at common inspection deficiencies for sterile manufacture.

Annex 1, first issued in 1972, has seen numerous small changes in the past but in 2012, there was a proposal to revise it fully and that proposal was re-issued in 2014, triggering the update process.

This was mainly the job of a joint working group (WG) of the Pharmaceutical Inspection Co-operation Scheme (PICS) and European Medicines Agency (EMA). The result is likely to reach public consultation by early 2017.

Key reasons for the update were to introduce the principles of Quality Risk Management. Furthermore, many new technologies have been introduced (single-use and closed loop systems and other technologies in processing and testing) and the Annex reinforces the need for manufacturers to keep up with current technologies.

Another reason for the update was to iron out some ambiguities and hangovers from previous versions. While the title has not changed, the Annex has some new sections and changes to others (see Table 1).

Table 1:



Sections listed in the new Annex 1
1. Scope – gives additional areas (other than sterile medicinal products) where the general principles of the annex can be applied.
2. Principles – general principles as applied to the manufacture of medicinal products.
3. Pharmaceutical Quality Systems (PQS) – highlights specific requirements of PQS when applied to sterile medicinal products.
4. Personnel – gives guidance on the requirements for specific training, knowledge and skills, and on the qualification of personnel.
5. Premises – general guidance regarding the specific needs for premises design and on the qualification of premises, including use of barrier technology.
6. Equipment – guidance on the design and operation of equipment.
7. Utilities – guidance on special requirements of utilities such as water, air and vacuum.
8. Production and specific technologies – discusses approaches for aseptic and terminal sterilisation processes. It covers lyophilisation and BlowFillSeal where specific requirements may be required.
9. Viable and non-viable environmental and process monitoring – this section differs from section 5 in that the guidance applies to ongoing routine monitoring, e.g. setting of alert limits and reviewing trend data. The section also gives guidance on requirements of aseptic process simulation.
11. Glossary – an explanation of specific terminology
Information courtesy of A. Hopkins

In particular the section on Equipment has been updated, re-enforcing the need to keep the operators away from the product using current technology.

Elsewhere, Cleanroom qualification (ISO 14644) is now separated from monitoring and the 5.0µm particle size figure has been removed, as it is no longer relevant.

The Annex includes guidance on utilities and general services such as compressed air and says that Water For Injection can now be produced by Reverse Osmosis but adds that checks must be made for biofilms.

Section 9 deals with Production and Specific technologies such as Blow Fill Seal (BFS), as well as Pre-use Post Sterilisation Integrity Testing (PUPSIT) and Container Closure Integrity (CCI).

In section 10, the different aspects of non-viable and viable environmental and process monitoring have been put together. The section reinforces the development of EM by risk assessment and involves the setting of limits and the evaluation of trend data. It also covers rapid microbial methods.

Hopkins looked at some possible contentious issues, in the new Annex 1, e.g., where the value 5.0µm was removed from cleanroom “Qualification” but kept for “Routine Monitoring”. He also looked at the section on Container Closure Integrity, which is causing a lot of discussion.

This section says: “Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. glass or plastic ampoules should be subject to 100% integrity testing. Samples of other containers should be checked for integrity according to appropriate procedures.”

This has been taken by some to mean a sample from every batch , said Hopkins, but the MHRA’s current stance is that they expect periodic (approx. yearly) CCI of non fused containers.

Hopkins noted other GMP updates that may impact sterile manufacture and that are relevant to microbiology procedures.

For example, those in Chapter 5, sections 5.10, 5.20 and 5.21 and Annex 15 section 9.2. and 9.3. Some non-GMP updates that he said are worth noting include: ISO 14644 Part 1 (Cleanroom Qualification) where there are a number of changes including, classification nomenclature, sample number.

There is also a WFI Monograph update scheduled for 2017, he said, as well as a GMP document for Advanced Therapy Medicinal Products (ATMPs) that is being prepared.

Hopkins finished by highlighting some common causes of deficiencies which he said related mainly to poorly designed facilities and processes, poorly controlled monitoring regimes and poor investigations and risk assessments.

Common deficiencies relating to Environmental Monitoring (EM) included poorly designed EM strategies, results not being reported in a timely manner or not reacted to and their impact not properly assessed. In particular, investigations and trending was poor and formulaic, he said, rather than using common sense.

In most of these cases, good knowledge and understanding of the process was lacking or was applied by the wrong people.

He expressed concerns about the growing loss of microbiology skills: Education has become less hands on, automation is increasingly being introduced, meanwhile industry does not always recognise where the expertise is required, he said.

Data integrity

Julie Roberts of J. Roberts Associates returned this year to give more insight on the regulatory inspectors’ expectations regarding data integrity.

This has been a topic of discussion before now but the inspection authorities have started to review the extent to which all data are complete, consistent and accurate throughout the data lifecycle during their visits, she said.

She mentioned that the MHRA, FDA, PIC/S and EMA had all produced guidance on this issue and said the key issues to consider are: how to manage the data, retrieve it, review it, and how will you access it in five years time? She also pointed out that data integrity also applies to meta data.

“Without meta data, the data has no meaning. It often tells the story of what happens, so it needs to be managed too,” she said.

Whereas in the past a printout of the raw data was sufficient, now it is the electronic data when it was created that is important, not the printout, she advised.

Thus, traceability of each step – who logged on when, who reviews the raw data and what are the audit trails? are all key factors to consider.

She compared the situation of the (usually) lone microbiologists to that of those working in Chemistry QC, where often there are two people looking and reviewing the data; a first technician reads the pH and a second checks and signs it, or where the chromatogram plate is read and photographed or the gel plate is retained.

There is relatively little second checking in Microbiology at the moment, she commented, yet chemists have been doing it for many years.

She considered similar means of verifying and retaining raw data in microbiology. She also talked about process mapping to check if processes are managed in a consistent way and not subject to bias, as well as the need to understand the process and to know how secure is the data is at each step.

Also important is whether the reviewers are evaluating data in context: “Do they understand what meta data is relevant to the review process and has that data formally been defined?”, she commented.

Look at the chain of custody, she advised: “Has the same person put the data down throughout the process and do they have a vested interest in the result?”

Changing to these new ways of working may require a lot of extra effort, but she suggested that any resource assigned to ensuring the integrity of data should be commensurate with the importance that data has in terms of product quality.

She then talked about the new capabilities of inspectors, who have now been trained to interrogate the “back-end” of systems to see if any deletions have been made. In addition, “they will empty incubators and count plates to see how they relate to trends last year!”, she warned.

Is there a need for more second checking in microbiology departments to meet data integrity requirements?



The next speaker was from the US. Tony Cundell (Microbiological Consulting LLC) is a microbiologist of long repute, a member of the US Pharmacopeia Microbiology Committee of experts, and co-editor of the book Water activity Applications in the Pharmaceutical Industry. Cundell recently received the 2016 PDA Martin van Trieste Pharmaceutical Science Award for outstanding contributions to the advancement of pharmaceutical science.

He looked at microbiological monitoring and regulation from a US viewpoint, focussing particularly on sterile compounding. He gave an interesting overview of the New England Compounding Centre fungal meningitis outbreak in 2012 that killed 64 people and infected 753 others in multiple US states. This catastrophe subsequently led to the revision of USP<797>.

Areas that Cundell covered included: microbial risk analysis of compounded sterile preparations (CSP); facility design; control and monitoring practices; sterility and bacterial endotoxins testing of CSP and opportunities for the application of alternative sterility tests.

He went on to look at the risks for CSP and microbial and endotoxin contamination, listing the most likely causes from personnel and the compounding environment, compounding operations and the sterilisation processes.

He also looked at the microorganisms most frequently associated with US CSP infection outbreaks, such as gram-negative, oxidase positive bacteria, Serratia mercescens, Burkholderia cepacia and Pseudomonas fluorescens.

He discussed current methods of release testing which involve sterility tests and bacteria endotoxin essays and their limitations. For example, many materials have a short shelf life and will be administered before completion of the compendial sterility test. Not all microorganisms grow under culture, and confirmation of the test – via turbidity – is subjectively assessed and won’t necessarily pick up low levels of contamination, he commented.

He explained that USP<797> allows for alternative micro methods to be used for preparations whose “use time” is less than the 14 days incubation using the compendial tests. While the opportunity is there to use alternative methods, their validation can be a challenge, said Cundell.

He listed some of the alternative technologies for rapid sterility tests and went through each of them briefly. He finished by noting the huge healthcare contribution that CSP makes but added that microbial contamination risks are higher than those within pharmaceutical manufacturing.

However, with proper facilities, compounding operations and good aseptic techniques, these risks can be mitigated, he said.

Rapid Methods

Using rapid methods Paul Newby, SM Manager, Glaxo-SmithKline (GSK) then looked at the use of Rapid Microbiological Methods (RMM), giving the background to RMM implementation and application within GSK.

He also looked at candidate technologies and validation considerations and discussed some of the issues and challenges.

Newby has experience in this field since Veramyst, dispatched in the Summer of 2006, was the first new GSK submission (NDA & MAA) to include RMM. In this instance the product is a non-sterile, preserved aqueous nasal spray and the RMM system used is based on ATP bioluminescence.

Newby said that the submissions were based directly on experience gained from Phase 1 activities and were built on the foundation of EP 5.1.6, USP<1223> and PDA TR 33. He went on to look in more detail at the use of water activity (Aw) in microbial risk analysis, explaining that microbial metabolism and growth is impacted under dry conditions.

Most pathogens require above 0.90Aw to proliferate and generally at below 0.6Aw there is no microbial proliferation.

Therefore water activity is a good parameter to control and monitor the potential for microbial proliferation.

Dr Kevin Wright, Principal Scientist Microbiology Capability Organisation, Procter & Gamble (UK) then considered the transfer of microbiological methods between labs.

As more pharmaceutical companies operate in a global world with multiple facilities, outsourcing is an increasing trend.

Ensuring that microbiological methods between labs and different suppliers on different continents are carried out to the same protocols is key and he highlighted some of the issues to watch out for.

Managing pseudomonas

Bharat Patel, Consultant Medical Microbiologist with Public Health England (PHE), gave a practical insight into Pseudomonas and the importance of managing water supplies.

The insight he gave had been gained following the devastating incident where, over the course of two months, 25 babies in Neonatal Intensive Care Units in Northern Ireland were affected by Pseudomonas.

There were five deaths and, as a result, a wide-ranging independent review was undertaken. Pseudomonas was found to be present in new taps installed in the facilities.

The investigation increased the understanding of the link between Pseudomonas and water and has contributed to new national guidance which he outlined. Biodurden control for non-steriles.

Tony Cundell returned on the second day to give his second paper, this time on bioburden control in the manufacture of non-sterile drug products.

In this talk, he covered critical quality attributes of non-sterile products: microbial count, absence of specified microorganisms, and objectionable microorganisms.

He looked at risk hierarchy by dosage form, the role of formulation and product attributes and of facility design and unit processing steps.

Lastly, he went on to look at risk mitigation steps and at further case histories of microbial contamination.

Laura Guardi, Senior QA Auditor, AstraZeneca, provided a practical approach to validation in disinfectants. Her main message was the importance of using a matrix approach to cater for different facility surfaces and organisms.

She looked at the selection of test methods and common pitfalls and gave examples of Warning Letters. She finished by looking at how to prepare the validation package for inspection.

Anna Lovatt, Microbiology Manager Oral Health, GSK, looked at what to consider when choosing a rapid microbial identification system.

She gave a brief summary of the different identification systems available and many of the key considerations in choosing the right system.

Each system has benefits and disadvantages so it is important to ensure the system chosen is appropriate for the facility in question and the product type.

The importance of understanding your facility’s requirements and developing a User Requirement Specification (URS) were other key considerations.

Using HACCP

Edel Fitzmaurice, MD of Fitzmaurice Scientific, looked at the use of HACCP as a tool for reducing microbiological contamination.

Widely used in the food manufacturing, HACCP is slowly gaining acceptance in the pharma sector.

She provided the key points of HACCP and looked at how it could be used as a risk analysis and risk reduction tool.

She explained how to identify key sampling and test plans and discussed VACCP (Vulnerable Assessment and Critical Control Points) and TACCP (Threat Assessment Critical Control Points).

The event closed with Pete Gough, Executive Director, NSF Health Sciences, Pharma Biotech, discussing the potential impact of Brexit on the pharma sectors.

For example, will the UK remain or leave the European Economic Area? If the answer is yes, failure to secure a good trade deal could result in higher costs and a reduction in the availability of medicine, Gough warned.

He put forward different models that the UK could adopt, such as the Swiss, Turkish, Canadian or Singaporean models of trade with the EU.

He looked at possible implications such as whether we would see UK GMP diverging from EU GMP, and would the European Medicines Agency (EMA), currently based in London, look to move?

According to Gough, the MHRA provides around 40% of the EMA’s scientific expertise and conducts 25% of its inspections, so the EU pharma sector could feel some short term impact.

This two-day meeting provided much practical insight on why it is necessary to keep up to date with regulatory guidance and technological change, and how to incorporate change into working practices. For information on future Pharmig events visit www.pharmig.org.uk

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