PHSS Challenges in Sterile Product Manufacturing 2019

By Hamish Hogg

On the 6th June 2019 the PHSS (The Pharmaceutical & Healthcare Sciences Society) held a conference at The Mere Golf Resort and Spa in Knutsford, which I attended with our Sales Manager, Andrew Barrow.

Regulatory and GMP Audit Session

The event had notable speakers and relevant topic presentations throughout the day. First to speak, after the opening welcome and address from the Chairman and the Vice Chair of the PHSS, was Phil Rose, a Senior Inspector from the MHRA. He briefly updated on Annex 1, of which there was not much to discuss: The ANSM (France) is the new rapporteur; work continues with MHRA representation and draft 9 imminent.

He discussed the deficiencies found in the industry (sterile and non-sterile) and that there were QRM issues across a number of sites. Some of the MHRA observations on site ranged from interesting problems, to the downright absurd, considering where we are in the Pharma industry today. For example he saw an operator eating in a cleanroom environment!


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Sites needed to show the ability to identify risk and assess the risk appropriately, not blindly following RPN (Risk Priority Number) scoring, but addressing the risk sensibly with an approach that applies the best control measures.

He looked at autoclave processes, media fills, EM and airflow and the deficiencies observed and provided advice on how to approach and rectify the issue, for example smoke studies are a very useful tool.

Slow reaction times to alert limits were also observed. With some cases taking up to two years to determine root cause and implement a CAPA. There were companies performing ‘Sat Nav’ investigations, already believing what has caused the issue and the investigation leading to that determination, rather than using a non-biased approach.

A constant with these deficiencies was the lack of knowledge and experience. Which led to the question - how do you retain this knowledge in the Pharma industry to allow it to be drawn on to implement the best processes?

He did insist that these examples were all rare exceptions and that in general quality and safety are well controlled across the pharmaceutical industry.

The overall message was that QRM in Pharma facilities needs to assess the process; compare the controls in place; add any additional control measures; involve the right people to work on the QRM; make sure it is a part of your quality system and then review the strategy at a later date to ensure it is still current.

He briefly talked about the implementation and striving for the innovation of new technologies used in the industry, which is hard to implement in an industry that has a fear of regulators and concerns on validation. The MHRA is not averse to the use of new methods and technologies. Phil is even a part of MHRA innovations office, who can be approached on novel implementations and how they stand with the regulators, to encourage and aid movement towards the use of new technologies. 

Product Manufacturing and Aseptic Processing Session

This followed on to Melanie Bull’s presentation on the new facility being built in Oxford for Oxford Biomedica. She talked about outlining the rationale for operation, designing the HVAC system, room classification and the flow of material and resource. This was a great lead on from Phil, as they have incorporated new isolator technology in their filling lines; a built in QC lab and having a suite design that allows for shutdown of partial operations, where other parts of the facility can remain functional. Providing flexibility for manufacture depending on the end product.

QRM has been in place since the design, but novel problems appear that require a thought-out process, for instance, challenges in working with a closed system, in relation to operators for necessary access and EM.

Although they have introduced new technology, they still use traditional methodology for their EM and the question was asked why they did not implement any rapid micro testing methods? Melanie said it is something that they are looking at for the future, also the design and construction of the facility needed quick EM implementation. The Chair of the PHSS made a statement of ‘new rapid methods as they come through need the building and capture of data to aid their implementation for the future’.

Then came the first break as it was definitely time to have a coffee and a pastry. The exhibitors room allowed for great interaction with the delegates, sparking interest in the product range we had displayed: air samplers, EM media and sampling accessories.

Current findings and challenges in QA Audits, GMP compliance expectations and lessons learned

The next speaker was Andrew Hopkins, the former individual dealing with Annex 1 as part of the MHRA. Now currently working for Abbvie as Quality and Compliance Director, Andrew gave an interesting point of view from both DARK sides of pharma to sterile manufacturing.

He started out highlighting that everything that is done and put in place to produce a sterile product, is done so with an emphasis in ensuring patient safety, and that this should always be a present thought that there is a patient at the end of this process.

Andrew underlined areas such as knowledge management, reflecting on that lack or loss of knowledge and experience and how to capture this information that was reflected in the 1st presentation. The pharma industry needs to have knowledge retention, but also to share and develop that knowledge outside of each site or company to improve the industry. Not only to share knowledge and experienced issues within the industry, but to work with suppliers as well.

He led on to, if knowledge management is a concern, then there is a need for training systems to pass on that knowledge. The suggestion was the potential for future bespoke college courses, the use of YouTube videos and even VR (virtual reality) training. Currently regulators and Pharmig do provide readily available training packages, including information on the PIC/S forum sharing information.

Andrew went into the use of new technology and how even though you can be against it, it is a requirement to look at new technology for your facility as part of GMP and the EU Directives. Pharma is slow to change, especially if a new facility has a short time frame to be productive and fear of regulators as previously mentioned by Phil and Melanie.

But why push on progressing new methods in the industry? It allows for a more consistent process, easy to operate, lowers incidents and excursions, less monitoring and less rejections, less stock outs, less regular scrutiny and yes there is financial benefit, but Andrew referred to his constant which is it would lower the possibility of patient harm.

Then came the lunch break. The exhibitor’s area experienced a continued interaction with delegates, getting to know more of the needs of each company. The delegates were a mixture of Microbiologists, Quality department and Qualified Person individuals, which help with the demographic of our key marketplace. Industries came from across the UK and even included other countries such as Italy and Germany.

Following the lunch break there was a presentation from Prof. C William Keevil on the interesting topic of viable but non culturable biocontamination (VBNC). The research has come from the biofilm initiative with Southampton University.

His research looked at how to determine what is present in clean environments and if it is viable. They started with work surfaces which may look smooth, but under a powerful microscope there are crevices that hold bacteria that the cleaning agents may not be able to reach.

Therefore, the methods used to identify and determine viability of present organisms were numerous. Molecular methods were used to help identify small composites of bacteria, Live/Dead stain, CTC measuring respiration and resuscitation of organisms indicated by cell elongation. Many methods were used to aid investigations on VBNC.

In the case of molecular testing, viability cannot be determined. The Live/Dead stain worked by showing the integrity of membrane of organisms, therefore if the organism was alive the membrane would be intact and the stain would come up green and if the membrane was not intact due to deceased cells it would show up red. However there are occasions where the stain becomes yellow/orange, so the question was, what is this indicating?

The professor performed several studies around this subject; one looking at the presence for bacteria in a cooling tower. The manufacturer could not grow bacteria on culture to indicate a viable organism present but it was identified using methods outlined by the professor above. The cooling tower was then properly sterilised and the organism and biofilm were eradicated.

There was also the use of copper surfaces that killed a number of VRE organisms proved by the Live/Dead stain and CTC, a potential simple solution to keeping surfaces clean.

There was a study on the survival of salmonella on spinach leaves rinsed in a chlorine solution that is 100ppm that did not show in traditional culture methods. By using the cell elongation method – that uses stain and microscopic observation to see if stressed cells elongate rather than divide to indicate viable organisms – it successfully identified viable organisms still present after being washed at 100ppm chlorine that induces VBNC biofilm of Salmonella.

Then the question is, are these VBNC’s infectious and a risk to health? There are many studies beyond what the professor has done into infection models, to show that VNBC’s are infectious. One free paper is into water research for Legionella.

A lot of the research was performed for other industries and not pharma, but this vital information can be then related to the Pharmaceutical industry and how we detect, identify and control VBNC for the future.

After the presentation I went back to the stand to await the final short break to allow any further approach from delegates. The conference continued with some final talks as we packed up the exhibition stand and headed for home.

The PHSS event was great to attend for the relevant and new content provided, presented by knowledgeable and experienced individuals. There were a great number of delegates to talk to, to capture the needs of our customers and the difficulties they face. It would be a conference I would attend for the following year for sure.


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