The PDA Ireland Chapter hosted an event to discuss how innovation and technology are embraced in the industry of Biopharmaceutical manufacturing. The event took place on Thursday the 26th of September 2024 and was led by industry leaders, experts, regulators, and technology company representatives. Attended by professionals from across Ireland as well as overseas it led to interactive discussions during the event that centered on the new technology and innovations that are available for the biopharmaceutical industry. Points of discussion were also the potential challenges industry are now facing during inspections as industry and regulators navigate to use these new technologies.
Common Deficiencies – Implementing New Technology and Innovation in Aseptic and Low Bioburden Processes
The MHRA inspector’s presentation highlighted the importance of knowledge management as it is often overlooked and is required by ICH Q8(R2) ‘Pharmaceutical Development’[1] as part of new technology and innovation. It was stressed that regulatory inspectors are looking to see how knowledge gained is being documented and if a site has clear procedures in place for knowledge reproducibility. The expectation is that what is contained within a dossier needs to be very clear so it can be fully understood by regulators. ICH Q9(R1) on Quality Risk Management[2] can be related to knowledge management both handling knowledge and building on this knowledge. Severity, Frequency and Detection of risks can be based on the current knowledge available to a site. ICH Q10 ‘Pharmaceutical Quality System’[3] applies to systems supporting the production of drug substances and drug products, including biotechnology and biological products, throughout their entire lifecycle and expected to be applied to knowledge management. With regards to new technology; knowledge on process and equipment etcetera would be low as it does not have a long history one can avail off. As such, uncertainty would be high and therefore the overall risk of new technology would initially be classified as high. However, as the technology matures through the lifecycle and more knowledge is gained; knowledge will become high and uncertainty will get lower, eventually with the technology classified as low risk.
The MHRA inspector shared some common deficiencies from the FDA Forum (2018-2024). Below is a summary of deficiencies that were presented;
- Dossier to onsite process – The process viewed at site did not match the process as described in the dossier.
- Pharmaceutical Quality System(PQS) – Change control process associated with the manufacturing process or facility were not deemed effective as either the change control document was not sufficient or was not there at all to support the change. Change Controls failed to assess product impact.
- New technologies- Incomplete assessment with regards to impact on for example; environmental monitoring, data integrity (computerized systems), aseptic process controls, equipment cleaning and contamination control.
The take home from this presentation is that implementing and making changes to new technology and innovation should be treated the same as any other change being managed by your PQS.
A large biotech company gave a presentation on operator engagement where ‘shop floor operators’ are deemed the heart of the critical path and need to be empowered to bring ideas to their line managers. An ‘Empower’ culture where resources, leadership and feedback is encouraged was shared with the audience by the presenter. In the program, line managers and supervisors are encouraged to give the feedback in real time to operators who present them with an idea. Action tracking was done using an idea board to show visibility, and to create a safe space environment with a ‘we win as one team’ mentality. It was presented that an idea that is being embraced requires the following; sponsorship from site leaders, operator responsible for the idea must be afforded time, access to subject matter experts (SMEs), vendors and budget allocated to make it happen and finally no idea should be dismissed. The company’s take is that a bad idea can be reinterpreted as the wrong solution to a real problem and this is where feedback is key! If you or your company are going to tap into the knowledge pool of your operators you need to ensure by leveraging this knowledge that it makes their lives easier, safer and they are empowered to make the change.
Operator training and consistency in procedures are important aspects in the manufacture of a safe product that meets its quality requirements. A company providing training solutions presented their Automated Process Design and Risk Assessment Solution which aims to cut production risks and time-to-market while ensuring quality and compliance. This tool aims to remove subjectivity from the quality risk management (QRM) process, reducing time and errors. It was presented that this technology has the capability to generate standard operating procedures (SOPs) and uses artificial intelligence (AI) to translate the process frames as captured into usable work instructions. This allows for consistent language across procedures and associated work instructions.
An aseptic manufacturing company presented on their use of digital twins and showcased how they were using digital twins to aid with reducing product development and engineering runs, reduce cycle development time, reduce line downtime and to aid with operator training and safety. It was encouraged that industry embrace these new technologies so as not to fall behind with these advancements.
Data integrity was and still remains a big point of attention when it comes to regulatory inspections. With more digital applications being used, the amount of data that is to be processed also significantly increases. A very thorough and informative presentation on data integrity and its place with regards to the application of new technology and innovation was discussed. The presenter indicated that there needs to be systems in place around digitalization and robotics where the company fully understands where the data is coming from with an audit trail. The ISA-95 standard about Enterprise-Control system integration is now more relevant and useful than any other time with the advancements in technology and it now serves as a foundational data model for modern manufacturing IT. It was presented that the current situation with a lot of industries is that these operate a hybrid system using some automatic systems for data generation along with a manual paper based version. The objective for sites in the future with technology advancements would be AI driven processes, digitalization, robotics, continuous Environmental Monitoring and an advanced manufacturing execution system MES.
Gloveless robotic systems within aseptic filling also emerged as a more frequently seen technology. Options are available for open-isolator settings where automated systems or robots reduce the need for glove handling by automation. A case study was presented on Grade A/B mobile collaborative robots and how they can reduce human interaction and streamline compliance with Annex 1[4] requirements. These advancements in robotics have been utilized to change out environmental monitoring plates and perform glove integrity testing without the needs for human interaction.
In the area of glove integrity there was also a presentation about innovative gloves using color indicator technology that will highlight any piercing of the gloves that would render them non integral. The glove was demonstrated where a ‘normal’ blue cleanroom under glove can be worn in combination with the glove using the colour indicator technology as an over-glove to form a breach indication system. It was presented that the gloves are suitable for use in aseptic and Class 100 (ISO 5) / EU GMP Grade A environments.
As per Annex 1, air visualization studies are also an important aspect when it comes to cleanroom qualification, development of environmental monitoring programs and operator qualifications. New innovations in smoke studies or rather smokeless smoke studies were demonstrated where image based technology was used. With this application, invisible clean gas is used negating the need for smoke or seeding particles meaning zero contamination in the cleanroom. An illuminated background imaging technique shows the air motion over varying flow scales and rates giving live real time feedback of air flows to a computer or tablet. This technology can also be used to assess thermal images from cleanroom personnel and other equipment in the Aseptic Processing Area (APA) to assess the impact on air flows. The use of this technology shortens downtime in the production area as there is no after treatment required as the seeding gas utilized is harmless and clean
Cell and gene therapies are at the forefront in the development of medicinal products and therewith the use of novel technologies. CRISPR is a technology that can be used to edit genes and examples of CRISPR and mRNA therapeutics were showcased. Both of these technologies are open processes within a Grade A and B Biological Safety Cabinet. EudraLex Volume 4, Part IV ‘Guidelines on Good Manufacturing Practices specific to Advanced Therapy Medicinal Products’[5] describe the GMP requirements that should be applied in the manufacturing of ATMPs. An example of in vivo and in vitro processes were stepped through by the presenter, highlighting areas where Single Use Systems and isolator technology are being embraced by the institutions involved in the development and manufacture of the ATMPs.
Shortening time to results allow to act quicker on potential issues and decision making using real time monitoring is another development in the manufacture of pharmaceutical products. Case studies were presented that highlighted where industry are utilizing real time monitoring technology as an early detection tool to give sites heads up that something is going on within the critical zone and allow immediate action to be taken. It was mentioned that by utilizing this technology the companies felt it lessened the risk to product quality and potentially save a batch. A second case study highlighted how the real time monitoring technology was used as part of an enhanced investigation and aided with determining root cause for observing increased microbial counts in a cleanroom. The shift in real time monitoring application, in particular for monitoring viable and non-viable particulates has come about as a result of Annex 1. Annex 1 is steering the industry to consider alternative and rapid methods for monitoring critical processes and to reduce the risk of contamination to the product.
Key takeaways from this event;
- Technology is evolving with new innovations designed to ensure compliance with current regulations such as Annex 1 to help reduce contamination risk.
- Data integrity is fundamental and essential, and is applicable everywhere in the manufacturing facility not just the laboratory. Regulations are not changing however regulator’s expectation are.
- Multiple parties need to be involved to stay informed about development of new technologies and their potential applications. This includes end users, manufacturers and regulatory bodies.
About the author:
Louise Uí Fhatharta Manager/ Consultant with Pharmalex
Louise is a quality professional with over 20 years’ experience in Microbiology, Quality Control and Quality Assurance roles in the Pharmaceutical Industry including Sterile Fill Finish and Medical Device (including Combination Products).
Louise has been Involved in site and laboratory expansion projects from design through to method transfer and operational readiness. Supported site in a capacity of Quality, Sterility Assurance and Microbiology Lead oversight during projects.
Through industry experience strong analytical and problem-solving skills have been attained and highly developed strong leadership skills.
Successful experience with several competent authority inspections including but not limited to FDA, HPRA and DEKRA inspections.
References:
- ICH Q8R2 – Pharmaceutical Development (2017). Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-considerations-ich-guideline-q8-r2-pharmaceutical-development-step-5_en.pdf
- ICHQ9(R1) – Quality Risk Management (2023). Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-ich-guideline-q9-r1-quality-risk-management-step-5-revision-1_en.pdf
- ICHQ10 – Pharmaceutical quality system (2015). Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-guideline-q10-pharmaceutical-quality-system-step-5_en.pdf
- EudraLex Volume 4 Good Manufacturing (GMP) Guidelines – Annex 1, Manufacture of Sterile Medicinal products (2022) . Accessed through: https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
- EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 Good Manufacturing Practice Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (2017). Accessed through: https://health.ec.europa.eu/document/download/ad33d9dd-03f0-4bef-af53-21308ce2187d_en?filename=2017_11_22_guidelines_gmp_for_atmps.pdf
