Pharmaceutical manufacture: new standards and best practice

There has been increased regulatory focus on data integrity recently and, as Andrew Hopkins reminded delegates, data provides the foundation for people’s trust in medicines. Hopkins, a Senior GMP Inspector with the UK Medicines and Healthcare Products Regulatory Agency (MHRA), explained that Quantitative Risk Management is based on accurate feedback and the consequences of not getting it right can cause patient harm or product shortages and create a considerable financial cost for the companies concerned.

Hopkins gave a regulator’s perspective on data integrity, defining it as ‘the extent to which all data are complete, consistent and accurate throughout the data lifecycle – covering everything from initial generation and recording through processing (including transformation or migration), use, retention, archiving and retrieval’.

He highlighted some of the issues that can lead to data problems, such as:

• Poor design of data recording systems – i.e. systems built without consulting those who do the job. For example, this can result in not keeping batch records in a suitable place, which means operators may not bother to fetch them or will choose to fill in data later from memory.
• Poor knowledge and understanding – where the recorders do not understand why accurate recording is important.
• Operators not wanting to be the bearer of bad news nor create more work, if results are ‘out of spec’ – so they ‘tidy up’ results and make them look better.

The solution was, Hopkins suggested, ‘to design paper and electronic systems that reduce the opportunities for falsification’. Such systems need to provide data that is ‘attributable, legible and permanent, contemporaneous, original and accurate,’ he said.

Just because you don’t find an organism through your current EM systems doesn’t mean they are not there

Hopkins looked specifically at data integrity in environmental monitoring (EM). ‘Just because you don’t find an organism through your current EM systems doesn’t mean they are not there,’ he warned, adding that common mistakes are made in deciding where to put settle plates or where to take swabs: ‘All microbial monitoring must be based on the risk assessment,’ he said, ‘and if you are not putting samplers in the right place your EM is not telling you what you need to know.’

He added: ‘To have a sound EM programme, you need to have knowledge of the process risks, so it is imperative to get out of the lab and into the facility to understand what is going on.’

Always use smoke studies to inform your micro-monitoring, he suggested, as laminar air flows (LAF) will affect the air flow in front of cabinets and benches. Also, in Grade A/B facilities where there are fridges, incubators and microscopes, do not just monitor the obvious: sample the rack on the microscope or the back of the fridge where the dust is collecting. ‘You need to really think out of the box and not just do what you have always done,’ he emphasised.

You need to build your EM so that the data you are getting is true and integral

A particular bugbear that he frequently observes on inspections is that, although the work is done at the front of cabinets, settle plates are placed at the back so that the EM monitoring does not compromise the process. ‘You need to build your EM so that the data you are getting is true and integral. Put settle plates at the front and if you can’t do that, then do some swabbing afterwards,’ he advised.

He went on to look at wider data integrity issues in microbiology, such as insufficient training: ‘Those doing the recording are not always experienced microbiologists,’ he said, ‘but it is often assumed that by giving them a book of instructions, anyone can do it.’

He also questioned the security of data once recorded: ‘Data usually sits on a desk until somebody sends it to the server; often, at this point, anyone can go into the system and change the data,’ he warned.

Many companies as yet do not have a data integrity policy. Such companies, he suggested, should first read the guidance and then:

1. Introduce a data integrity policy
2. Instill the correct culture to enable operators to say when things go wrong
3. Understand your processes and weaknesses and mitigate where possible
4. Tailor the Pharmaceutical Quality System to suit – i.e. have the right key performance indicators, make sure people are recording deviations correctly, and build it into your self-inspection.

Operating in an ageing facility

Microbiologist and consultant Phil Greaves of Biotiq looked at the particular microbiological issues of operating in an ageing facility. A quick poll of conference delegates showed that many worked in facilities dating from the 1960/70s, some were in pre-war (WW2) buildings, while others worked in old, historic buildings.

Typical of ageing facilities are failures of structure as well as the decreasing reliability of equipment due to electrical and mechanical components wearing out. There can also be issues with technology obsolescence, where components become difficult to replace. ‘Ageing facilities rarely offer up just one problem and, as dealing with any one ageing issue can be challenging, dealing with several at once can be terminal,’ said Greaves. He also reminded delegates that business continuity is an important consideration when selecting suppliers in the pharmaceutical sector.

Ageing issues often manifest themselves as microbiological events. Issues to look out for include:

• Degradation of construction joints that could lead to air leaks affecting high pressure areas via a venturi effect
• Wear on variable air volume boxes that could affect the control of air supply into cleanrooms
• Voids or spaces in old buildings that contain large amounts of dust and latent fungal spores, which could lead to significant contamination risk during repair or modification.

He went on to look at managing the risks of ageing infrastructure and suggested: Be realistic but innovative about how far production capacity can be increased in old facilities. Introduce a detailed and more frequent programme of inspection of cleanroom walls, floors, ceilings for damage or cracks. Increase the EM programme for early detection of rising trends and include unclassified areas of the facility where people and materials flow. Increase planned and preventative maintenance for equipment, as the requirements will differ for 10-year old equipment compared with one-year old. And finally, introduce a rolling programme of technology updates – looking three years ahead to prevent all occurring at once.

Cleaning and disinfection failures

In the past few years, the number of observations from regulators relating to cleaning and disinfection have risen. A review of 2013 FDA observations, for example, showed 25% were related to cleaning and disinfection (see panel). With this in mind, Rachael Blount, Global Validation Manager, Team Leader for Ecolab, looked at regulatory requirements and expectations for cleaning and disinfection, based on the EU GMP and US Food and Drug Administration (FDA) Code of Federal Regulations (CFR) guidelines.

Useful documents included:

• Pharmaceutical Inspection Convention PIC/S PI 007-6 Validation of Aseptic Processes
• USP <1072> Antiseptics and Disinfectants
• PDA Technical Report No. 70 – a new document that is particularly useful for validation programmes.

Blount also provided many observations of best practice along with examples of non-compliance and audit failures.

Cleaning and disinfection is often under-valued in terms of contamination control, she said, most probably because it is carried out by contractors out of normal work hours and thus goes unseen. ‘When not regularly observed, cleaning practices could be completely unrelated to what is in the standard operating procedures (SOPs),’ she warned, recommending that microbiologists actually go out and watch how people go about cleaning.

When not regularly observed, cleaning practices could be completely unrelated to what is in the standard operating procedures

She reviewed what the guidance says about personnel and training and emphasised the need to ensure that every person assigned to a task firstly understands why they are undergoing the training. Training topics should include: aseptic technique, cleanroom behaviour, microbiology, hygiene, gowning, patient safety, and hazards posed by non-sterile drug products.

EU GMP guidance makes it clear that such training applies to technical and maintenance personnel and contract cleaners, she said.

Other advice was that the training should be recorded and should contain a practical component (e.g. performance of techniques, including visualisation of risks), not just reading the SOPs.

Documentation and records is a frequent area for inspector observations, she said, highlighting that FDA Aseptic Processing guidance says: ‘Disinfection procedures should be described in sufficient detail (e.g. preparation, work sequences and contact time) to enable reproducibility.’ Despite this, contact times are often missing. She also advised: ‘Keep instructions concise and in one document’ and, for audit purposes, ‘have a schedule, so that inspectors can see at a glance when the cleaning was done.’

Documents should include:

1. Who is responsible for the activities
2. A schedule of cleaning/disinfection
3. Descriptions of materials approved for use
4. Details of techniques to be used
5. Instructions for cleaning and storage of equipment used
6. Instructions for preparation and disposal of disinfectant solutions.

In addition, she suggested, consider how the document will be used in practice; make it clear and concise, using pictures and tables, and include a rationale of why.

Oliver Chancel, a Sterility Assurance Expert and formerly Head of Performance and Pharmaceutical Support for Merial, Toulouse, France, provided 10 case studies that provided lessons on sterility assurance, all based on observations from 2014 (although some observations had cropped up repeatedly over the years).

The first case study involved manual membrane valves where a small red ring, known as the travel stop, is not properly set. As a consequence, when the handle is tightened the valve looks closed, but the mechanism is not actually closed and will lead to contamination issues, he said.

Case study 2 involved blocked autoclave drains. In a case at Devenport Hospital in the UK in the 1970s in which five people died, the autoclave cycle was designed to last 30min at 115°C but a small piece of glass stopped condensates leaving the drain, thus the actual sterilisation temperature of vials at the bottom of the autoclave was only 47°C. Chancel noted that while this happened 40 years ago, similar observations were still being made: ‘Daily observation of common things such as drains is important and someone needs to do it,’ he said.

Case study 3 was about cooling and the fact that steam occupies 2,000 times more volume than liquid water. Thus, when it condenses it may result in negative pressure and risk recontamination of equipment. ‘Bad cooling practices after steaming will cause contamination and an expensive non-vacuum proof tank may implode,’ he said.

Case study 4 concerned rinsing after Cleaning in Place, which is often overlooked, he said. The presence of any stagnant water remaining will increase the risk of microbial contamination on water/air interfaces. ‘Dilute cleaning residue is an excellent medium for microbes, therefore good (sloping) design of equipment is a prerequisite and both draining and drying after rinsing are essential.

Case study 5 covered temperature probes: the site where a probe is inserted into a tube is difficult to clean and sterilise if the probe is perpendicular to the tube. Therefore, it is better to locate the probe inside the shoulder of a tube to reduce the deadleg and then enhance the cleaning and sterilisation process.

Case study 6 discussed some common water bacteria that can enter a viable but not cultural (VBNC) state. Chancel said, they cannot divide any more and therefore are less likely to be detectable on standard growth media or may need longer incubation. ‘Just three days on rich Trypticase Soya Agar plates is not the best incubation practice for samples of pharmaceutical waters,’ he said.

Biofilms can grow inside the tubes of disinfectant containers, leading – absurdly – to the contamination of cleanrooms during disinfection

Case study 7 covered inappropriate gowning and aseptic practices, which are still often observed, he said, while case study 8 looked at inappropriate consumables. Disinfectant containers made of plastic and with a tube that is non-sterilisable pose a common risk, he said. Biofilms can grow inside the tubes, leading – absurdly – to the contamination of cleanrooms during disinfection. Use of non-adapted/non-sterilisable disinfection tools and non-sterile water are ideal conditions for biofilm formation, fragments of which will then be scattered around the cleanroom during disinfection.

The final case study involved the use of isokinetic probes – an observation Chancel saw three times in 2014. Two different isokinetic probes were observed for the same particle counter, but one of the two was not isokinetic as its diameter was not adapted to the flow rate of the pump. To be isokinetic and for the air speed at the inlet of the probe to be around 0.45m/s, a probe must have an appropriately adapted diameter, he said. If the diameter is too small the particles will be over-estimated, too big and they will be under-estimated. Devices that operate at 28–50L/min (or more) usually have different colours and pipe diameters adapted to particular probes. His advice was to request an isokinetic certificate from suppliers.

Starting anew

David Keen, Site Microbiology Manager, GlaxoSmithKline, dealt with the issues of microbiologists moving to a new site. Such a move involves understanding a new process, new company language/acronyms and a new company culture. In such situations, microbiologists have quickly to establish a good relationship with management and operators alike, he said. Therefore, it is important to get a quick handle on the operating culture, current practices and techniques (microbiological and engineering) to find out the strengths and weaknesses of the new site and to identify the critical control points.

To improve the relationship with operations, he suggested that microbiologists should educate, engage and influence

He looked at how to establish effective relationships by getting out and around the plant without being perceived as ‘enforcers’ or ‘police’ but rather ‘as a valued support function, helping to cut downtime and making production more efficient through lower batch rejection’. To improve the relationship with operations, he suggested that microbiologists should educate, engage and influence. Show employees microbes growing on agar plates, talk about the bugs that humans often carry, he said, but talk in language that they can understand.

When it comes to changing company culture, use the efficiency programmes already in place to embed a quality-led culture, he suggested. Also use the success of other industries, like the car industry, to inspire a ‘right first time’ culture.

Keen said that to tackle issues of reinvestment in new infrastructure that would ensure future quality, it was important to talk to engineers and gain their support. Find out who’s in charge of the HVAC, water, steam and compressed gas supplies, and talk to them about their systems. Find out how much microbiology knowledge they have. ‘Engineers can design very efficient systems but such systems may have a number of microbiological flaws, so work with them to design a suitable compromise. Work out what micro techniques will alert you to any problems,’ he said.

He reiterated Blount’s message that education comes before training, and added: ‘Check that engineers understand what is important for ‘change control’ and establish exactly how they will notify you of any changes made.’

Biofilms

Biofilm creation and remediation strategies was covered by Paul Lopolito, Global Technical Services Manager, Life Sciences, Steris. An expert in this field, he explained why biofilms are of concern, and looked at when microbial contamination becomes a biofilm issue, and what the potential sources of microbial contamination might be. He also looked at biofilm removal, testing methods for residue and case studies involving biofilm remediation strategies (see Cleanroom Technology, Vol. 23 (8) pp30–31).

Tim Eaton, Sterile Manufacturing Specialist with AstraZeneca, looked at ways to assess the microbial risk to patients from aseptically manufactured products. The aim was to help delegates understand where to look for the risks in their process and where to focus efforts.

Eaton first looked at methods of calculating contamination during manufacture, some preventative treatments during manufacture, and the risk of microbial growth during the shelf-life of the product. He explained how to get an accurate determination of microbial contamination during manufacture, first from sterility tests and process simulation tests, and then by appropriate risk assessment and calculation.

Risk model limitations

He also considered the limitations of the risk model, pointing out that while the vast majority of patients will cope with a few live organisms but not with a large number, this does not take into consideration individual or unusual risks (such as those with lowered immunity). Despite these limitations, he said that such methods can be used to minimise patient risk by including consideration of product formulation, the production process and the facility.

while the vast majority of patients will cope with a few live organisms but not with a large number, this does not take into consideration individual or unusual risks, such as lowered immunity

Tim Sandle, Site Microbiologist, BPL, also discussed risk assessment and how to decide where to take EM samples. He used case studies to illustrate the key concepts of HACCP, to look at isolator risks, and how to use Failure Mode Effects Analysis (FMEA). He also looked at some of the difficult aspects of balancing compliance and a budget. To finish he looked in detail at the setting up of a cleanroom EM programme.

In the next presentation, Sandle also gave an update on the scope and the progress of the Pharmig Cleanroom Action Group that was set up in November 2014. The aims of the CAG are to establish a common understanding of world class aseptic processing, to share best practice and offer informed opinion on guidance from regulators, to provide technical publications and guides, and to become a key influencing group with regard to standards and regulations on behalf of the pharmaceutical industry.

One of CAG’s first areas of discussion within its Forum has been gowning and, in particular, supplier policies for reusable laundered gowns. Topics included what to look for in laundering agreements, when to renew gowns and requesting folded gowns for easy donning. More recent discussions have looked at best practice in cleaning and changing frequency of isolator gloves. The publication of a practical guide to cleaning of classified areas is expected to be finalised in Q1 of 2016, he said.

Educating suppliers

Supplier education on microbiological issues was discussed by Hans Noordergraaf, Global Subject Matter Expert for microbiological issues at sites within the Established Products Division of Abbott. Noordergraaf looked at a case study where a ‘single source’ supplier’s operation became the subject of an investigation due to unusual isolates identified in a buffer solution. It focused on how this particular event was tackled quickly and efficiently to ensure there was no patient risk nor drug shortages.

Use of a filter with the incorrect diameter for its housing created the possibility of a bypass during filtration

A visit to the supplier revealed various deficiencies, but most importantly, incorrect use of sterilising filters. Use of a filter with the incorrect diameter for its housing created the possibility of a bypass during filtration. The supplier agreed to new practices to prevent the incident happening again and a corrective and preventative action (CAPA) plan was drawn up. Bi-weekly telephone calls were set up with the supplier to discuss the status of the CAPA plan.

As a result of this work with the supplier, the sterility testing area was totally revamped, a daily management system (DMS) was introduced to all areas, which included specific quality improvement measures, and DMS boards in all areas were made visible to visitors. Noordergraaf said that a proactive attitude and awareness of risk now prevailed throughout the company and there had been no micro-related events since. As a result, the time and investment made was considered both worthwhile and a cost-efficient outcome.

Change on the way

GMP inspector Andrew Hopkins returned to the podium for the last presentation covering recent and proposed updates to Annex 1. Revised in 1996, 2003, 2005, 2007 and in 2009, there has not been a complete review of Annex 1 since it was originally issued, he said. Since that original issuance there have been significant changes in technologies and in GMP practice, partly as a result of the adoption of the ICHQ9 and Q10 guidelines, which needed to be integrated into Annex 1.

Hopkins said the updates will reinforce the need to keep up with new technologies, such as restricted access barriers and isolators.

Cleanroom ISO classification 14644-1 has also been revised and released recently and has new guidance on cleanroom qualification. It has reviewed the use of 5µm particles for qualification and says this particle size isn’t appropriate here and it has a new sub-section on macro particles. The proposed changes split non-viable particle monitoring into two parts – qualification and continuous monitoring, which changes the way cleanrooms are classified. For example, ISO Class 5 will in future need a suffix for the particle size used in qualification, he said.

There may be some new provisos affecting pre-use post sterilisation integrity testing (PUPSIT), which is currently required every time a filter is employed

Because of changes to the European Pharmacopeia Monograph on water for injection (WFI), there will also be a new section on utilities. This change will allow other modes of WFI generation, e.g. reverse osmosis (RO), rather than simply distillation. Other new production-specific technologies for which guidance needs to be updated include Blow/Fill/Seal systems and other completely closed production-related systems.

Hopkins also said there may be some new provisos affecting pre-use post sterilisation integrity testing (PUPSIT), which is currently required every time a filter is employed. This change will take account of special circumstances when it may not be appropriate to do this testing.

All the monitoring requirements have been moved to one section in the Annex, said Hopkins. And for the continuous monitoring of non-viable particles (NVP), in contrast to ‘qualification’ mentioned earlier, the 5µm and 0.5µm requirements have been kept. Hopkins felt this was necessary as he has seen for himself incidences where stopper handling bearings break down and the 5µm particle counts have gone off the scale long before 0.5µm counts reached their action limits.

There will also be a section on Process Simulations to reinforce their use in risk assessment. Another section in the new guidance will look at setting action limits and evaluating trends.

In conclusion, Hopkins said with many new technologies being introduced (e.g. single-use and closed systems) and with many emerging markets starting new businesses in this field, Annex 1 is being updated to meet the changing nature of the industry. He added that such changes were also needed because industry is losing these technical skills.

For details of future Pharmig events visit www.pharmig.org.uk.

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