Highly potent API (HPAPIs) are highly challenging, and not all CDMOs have the true capability to manufacture or package them. PCI Pharma Services has significant experience in the handling of highly potent products and has recently further invested in its Tredegar site in Wales, UK by adding a second contained manufacturing facility and a state-of-the-art potent packaging suite. In this roundtable, PCI experts run us through the project by discussing the attention to technical detail required to ensure that the required high standards and regulatory controls were not only met but also exceeded.
Why invest in the Tredegar site?
SE: PCI is growing, and we want to provide an even more expanded range of services at our center of excellence here in the UK. As well as manufacturing highly potent dosage forms, we can now pack them safely into bottles or blister packs, for example. We also offer secondary packaging and serialization capabilities. This investment is a major step forward for us and allows us an increased capacity to deliver end-to-end services from clinical supply to commercial launch. Our philosophy is to invest today to deliver the demands of tomorrow, and this investment should future proof us for many years to come.
RJ: Many clients today are interested in small-volume products, such as orphan drugs or highly targeted therapies for very small patient populations. As a service provider, we need to build flexibility into our equipment to ensure we can cope with these requests. The new blister line we’re installing as part of the new packaging suite is one good example of how we achieve this goal. We have installed our first HAPA digital printer, which means that with just one reel of lidding foil, we can now print artwork for different market requirements on one line, all within an envelope of very high grade control of airborne particulates. This, in turn, grants our clients considerable flexibility and reduces waste of pre-printed materials.
What informed the design of the facility and its equipment?
RJ: First, our team gave their views on what an ideal, latest-generation facility should include. There were multiple questions that had to be considered, including, “What does the market need? What do regulations require? What is today’s best practice and will it hold or shift in the coming years?”. After answering these questions and many more, the team were able to write a wish list and outline specification. A primary consideration was the need for an excellent flow of materials, from manufacture to primary and secondary packaging, and the final serialized pack at the end. We also wanted a really good flow for personnel in terms of how staff enter the facility, where they gown, and how they enter the factory floor.
SE: This expansion is the largest in terms of footprint that our Welsh site has undertaken. It’s undeniably exciting, and a great deal of consideration has gone into the personnel and material flows, the facility design, the engineering requirements, the environmental monitoring systems for the critical environments, and more. It was built from the ground up and there were many considerations and best practices that we wanted to incorporate including integration with the existing site, as well as potential future expansion.
AP: We were already highly experienced in the area of contained manufacturing and packaging at both clinical and commercial scale, and the equipment involved given our 35 plus years of experience in the processing of highly potent drug products. We picked the best in-line equipment for the new facility, drawing much of it from existing suppliers, which meant that our staff would already have the relevant experience and feel comfortable in using the equipment.
BP: In terms of the actual facility design, containment and control was absolutely central. We conduct SMEPAC testing as part of the qualification process, which allows us to understand the process and the level of containment required. We do this by running the line with a surrogate drug that enables us to model the generation of airborne particles. We then analyze how well we are able to contain those particles. We have segregation of rooms, dedicated HVAC systems, conditioned environments for packaging activities, and dust extraction units.
AP: We have HVAC throughout the facility. In high risk areas, we have isolated conditions with a minimum of 20 air changes per hour. Air is constantly being circulated through the facility, meaning that if there was a loss of highly potent material it would be captured in the HVAC and drawn through very high classification filters. The HVACs also help provide a pressure cascade in the area.
How do you approach cleaning?
BP: As the high potent packaging facility has been designed as a multi-product, excellent cleaning procedures are robust and this was factored into the facility design. The walls are made of a surface that is easily cleanable and the equipment has a low Ra (surface roughness) value of 0.8 or less, which essentially gives a mirror finish to equipment and prevents product from being ingrained. This makes it easier to clean and prevents the risk of contamination and carryover.
With packaging equipment, it’s often difficult to employ automated cleaning methods, so we rely on manual cleaning techniques. We look at risk assessments surrounding the equipment, identify the hard-to-clean areas, and build up a knowledge base of how to clean the equipment. We monitor the product through regular cleaning checks, ensuring that the standard procedures are still robust and that there remains no risk of carryover. We will also purchase dedicated tooling if necessary as part of client onboarding, allowing us to manufacture and package products with an even greater reduced risk of contamination.
How do you handle regulations?
NE: As the pharmaceutical industry has a global supply chain, we at PCI have embedded Global regulations and industry best practice into our design, processes and procedures. We ensure the delivery of right first time quality products with increased customer satisfaction. Our team of dedicated experts on site are experienced in the preparation and hosting of Regulators from a range of Competent Authorities including MHRA, FDA, ANVISA, Turkish Ministry of health, Russian Trade and Industry ministry of health and PDMA.
With regards to ensuring the facility’s design (inclusive of equipment, utilities and associated systems) met regulatory requirements, the associated design qualifications included regulatory requirements matrices which were used to analyze the different requirements from each regulatory body and establish evidence as to how both the user Requirements were met in addition to regulatory requirements.
Over the past few years, some audits have highlighted the use of cardboard within our facility so we have implemented policies to reduce this as much as possible in the expansion. As part of the packaging facility, we have introduced a de-boxing room. Raw materials and packaging materials are taken out of the secondary packaging, cleaned within the de-boxing room, and then taken into the facility in polyethylene bags. This is just one example of how findings of regulatory audits helped to inform our decisions for these expansions.
Also, the fundamental design of both sides of the production floor now separates the primary packaging from the subsequent secondary packaging using physical barriers, in line with requests from regulators.
BP: We’ve also installed specific systems on our automated production lines to secure a high degree of confidence that what is coming off the end of the line is exactly what has been specified by the client. For example, our bottling line has a sophisticated array of measures and checks to ensure the right label has been applied to the right bottle, that the desiccant is present, the bottle is sealed correctly, and the cap is tight enough. We also have tablet counting technology that uses EMF and infrared sensors; the technology basically plays both sensors off against each other to ensure that both have seen the right count of product through the counting head. We employ similarly smart technologies for capping, labeling, serialization (in line with the EU Falsified Medicines Directive), and so on. For serialization, we use cameras that perform and enforce multiple checks and standards. Crucially, it’s important to ensure or a budget reader – the barcodes can be read correctly.
Why is this investment so important for the company?
RJ: It’s been a very strange couple of years because of the pandemic, but as a company, we haven’t stood still! We’ve continued to push forward in terms of building capability, capacity, adding new technologies and expertise, and we’re very excited to show clients what we have been working on.
PCI Pharma Services has been operating at the Tredegar site since 1985, providing a range of services to an international client base. Around 10 years ago, we reviewed our business model and had the opportunity to make a significant increased focus and investment in our site capabilities. We added a Contained Manufacturing Facility to further expand our manufacturing and handling of HPAPIs. Why? Because there was investment from the pharmaceutical industry in oncology and other areas where the drug substances are classified as highly potent. It’s been a huge success – and research into drug products containing highly potent actives continues to grow. This has led us to invest further in the site by doubling our commercial manufacturing capacity with a second contained facility and a potent packaging suite – both of which will be operational in the third quarter of 2022. This increased capacity will enable PCI to become an even stronger CDMO partner, able to supply highly targeted and lifesaving therapies to patients around the globe, from concept to commercialization.
Rob Jones: Executive Director, Business Development, Manufacturing EMEA/APAC
Adam Pugsley: Program Lead for CAPEX Projects
Natashia Eales: Head of Technical and Regulatory Quality
Shaun Engelhardt: CAPEX Programme Manager
Ben Potter: Validation Manager
Highly Potent, Perfectly Packaged. | As seen in The Medicine Maker