Drug products containing highly potent active pharmaceutical ingredients (HPAPIs) are becoming an increasingly important part of the pharmaceutical outsourcing market, and their growth is showing no signs of slowing down. But bringing HPAPIs into a facility and scaling up as they progress through development presents substantial challenges that require both experience and expertise across many fields.
Many companies—including both emerging pharmaceutical companies and established large pharma players—lack such capabilities, hence the increasing use of contract development and manufacturing organizations (CDMOs) who specialize in the field. That in turn brings up the challenge of taking projects with extremely precise specifications into the kind of multipurpose facilities CDMOs typically work with, in the absence of overarching guidance on how to do it.
CONTEXT
The panelists discussed the importance of new product introduction (NPI) and tech transfer in the context of highly potent drug products; the key challenges of NPIs in terms of categorization, classification of risk, containment, process flow, and cross-contamination compliance; essential processes for assessing new molecules; best practices for tech transfer in the absence of overarching guidance; how sponsors and suppliers can best work together to support tech transfer; and the outlook for emerging challenges in the next few years.
KEY TAKEAWAYS
NPI and tech transfer are critically important issues in the context of highly potent drug products.
The term ‘HPAPIs’ refers to a range of pharmaceutical substances designed to impact human physiology and elicit a biological response. Because those drugs are highly effective but also highly toxic, they must be delivered at extremely low doses in a very precise manner, such that they only affect isolated disease targets (organs, tissues, or cells). Examples of HPAPIs include cytotoxic substances and immunotherapy anti-cancer drugs.
In this context, NPI and tech transfer are highly relevant because they concern the safety of production workers who are exposed to those compounds’ toxicity as the drugs move from the R&D stage to manufacturing, and also of patients taking other drugs produced in the same facilities. Yet currently there are no standardized monitoring tools or methods to ensure the environments in which those substances are produced are safe.
This is the fundamental scientific challenge when handling HPAPIs, in the view of Justin Mason- Home, director of HPAPI Project Services. “We can’t see these materials; they don’t have any warning properties—a few micrograms per cubic meter of a powder in the air will never be seen by anybody.”
To mitigate the uncertainty and health risks associated with toxic exposure, CDMOs should ideally collect information about the protective equipment that is used at the R&D stage, before they initiate a pilot or full-scale production, said Andrea Guytingco, global environmental, health & safety lead, industrial hygiene at Takeda.
“Tech transfer really comes down to the management of risk and layering in safety controls.”
Judd Taylor, Head of Tech Transfer and Process Validation, Takeda Pharmaceuticals
In any case, when handling HPAPIs in a multi-product facility, CDMOs should take extreme caution with cleaning and swabbing—process steps that follow batch validation, but that are not always strictly observed by all manufacturers.
“What we do at PCI is clean and swab after every single batch to make sure that we haven’t got any carryover from one product to the next. That way we’re not just reducing risk—we’re excluding risk.”
Kerry Kingdom, PCI Pharma Services
The processes and mindset companies use to manage HPAPI challenges determine their success.
Another challenging aspect for technology transfer involving HPAPIs concerns material implementation, which requires an assessment of how materials needed to produce a new compound integrate into an existing facility, while reducing the risk of cross-contaminating other products manufactured in the same facility.
To cope with the uncertainty around material implementation, as well as with the broader risks and unknowns associated with introducing HPAPIs into a multi-product manufacturing facility, companies can use several approaches (ideally in combination). Those approaches include:
- Incorporating exposure modeling into risk assessment.
- Designing material segregation and cross-contamination prevention controls, including a robust ‘cleaning philosophy’ and validated cleaning procedures. “Tech transfer companies must ensure and be able to prove that their equipment and shared product contact surfaces are clean, so that any soils from a previous product are removed prior to the introduction of a new product,” Judd Taylor, head of tech transfer and process validation at Takeda Pharmaceuticals, explained. He emphasized the importance of using qualified cleaning methods.
- Designing engineering controls to mitigate risk instead of relying on employees wearing personal protective equipment (PPE).
- Putting in place well-designed, well-thought-through processes to underpin those controls.
- Making decisions based on specific risk scenarios rather than on one-size-fits-all scenarios.
- Using a structured, formal methodology to weigh tech transfer risks and develop appropriate mitiga-tion controls, rather than defaulting to emotional positioning, instinct, or guesswork. “We hear all the time that ‘It’s the way we’ve always done it before, and nobody died yet’ argument. But every accident in the world—whether it’s a boat that hits an iceberg or an oil platform that blows up—the day before the accident, it was all fine,” Mason-Home said.Beyond these considerations, CDMOs must assess the toxicology of any new HPAPI molecule before they agree to produce it, as well as ensure that they have the necessary equipment to produce it.
- Beyond these considerations, CDMOs must assess the toxicology of any new HPAPI molecule before they agree to produce it, as well as ensure that they have the necessary equipment to produce it.
Companies can use these best practices for implementing HPAPI tech transfer in the face of lacking or too-fast-evolving guidance.
In the absence of both monitoring tools and overarching guidance when it comes to tech transfer involving HPAPIs, there are several best practices biopharma companies can use to evaluate potential CDMO partners, with an eye to limiting risks and maximizing the odds of successful production.
“We get as much information as we can from the supplying side by first looking at the raw materials supply and making sure that we get the same grades for all of the excipients. Then we look at our supply chains and if we are already using a supply for a given excipient, we’ll try and get the same excipient from them for the new product. Then we look at the supplier’s methods of manufacture, equipment, cleaning procedures, and analytical methods. And then we carry out gap analysis to identify any changes we might need to make.”
– Kerry Kingdom, PCI Pharma Services
In addition to following the steps outlined by Kerry Kingdom, head of process optimization and validation at PCI, companies should make sure they are consistently communicating, documenting, and validating everything before they move to each consecutive step.
“It’s always easier to plan forward than it is to retrofit. So, the more you’re collecting, communicating, documenting, and validating information along the way, the easier, faster, and cheaper it’s going to get a process up and running.”
Andrea Guytingco, Takeda Pharmaceuticals
A similar logic applies when there are no established analytical methods for novel HPAPI assets. In that case, a best practice would be to apply a systematic approach, categorizing existing methods into simple methods, which do not vary much between one project or another, and sophisticated methods, which can have a lot of variability, depending on the analysis instruments used and on the asset itself. Once there is clarity about the type of method that needs to be used, simple methods can be applied independently by the receiving unit, whereas sophisticated ones call for an alignment plan between the sending unit (supplier) and the receiving unit (CDMO).
Conclusion
As high potent drug product manufacturing and the science behind it move forward, there are several opportunities and challenges likely to impact the industry. Top of mind among those challenges—which can also be opportunities, depending on what companies make of them—is the role of artificial intelligence (AI).
“Could AI do our risk assessment for us—can it help write a risk assessment? How will AI change how we do toxicology assessments—can it help toxicologists do data gathering and processing? Can AI help write a protocol or a method transfer validation report? The possibilities are endless there, but it remains to be seen whether AI will help or hinder.”
Judd Taylor, Takeda Pharmaceuticals
Taylor noted that while has not become mainstream yet, some firms are already experimenting with it to see what impact AI has or may have on their operations.
On the regulatory front, another challenge will be the discrepancies between how different regulatory bodies around the globe assign occupational exposure limits for the same compounds and how those limits change over time.
A variation of that challenge is the question of how a regulatory ban on a given chemical in one part of the world may impact CDMOs’ supply chains or ability to manufacture a product containing that chemical. “It’s not just exposure-related regulations, it’s also how the regulation of something affects your total workflow,” Guytingco said.
Ending on a slightly somber but also optimistic note, Mason-Home said he is saddened to perceive a decline of standards when it comes to occupational health and safety process design—but that he is also hopeful companies can embrace more rigorous scientific standards going forward. “Let’s build some fabulous facilities and fabulous processes and deliver some great therapies. That’s what it’s about.”
BIOGRAPHIES
Andrea Guytingco Global Environmental, Health & Safety Lead, Industrial Hygiene, Takeda Pharmaceuticals
Andrea Guytingco is the Global Environmental, Health & Safety Lead for Industrial Hygiene at Takeda Pharmaceuticals. In her role at Takeda, Andrea provides industrial hygiene expertise and guidance for 30+ global sites in R&D and manufacturing. She has a Master of Public Health degree in Environmental Health Sciences – Industrial Hygiene/Exposure Science with certificates in Risk Science and Human Health and Global Public Health. She is also a Certified Industrial Hygienist and Certified Safety Professional, and is based in Massachusetts, USA.
Kerry Kingdom Head of Process Optimization and Validation, PCI Pharma Services
Kerry Kingdom is Head of Process Optimization and Validation at PCI. She has worked for the company for six years, currently focusing on technical transfer, late-stage development, together with the subsequent process validation and process support for the commercialized product. She has worked in the pharmaceutical industry for 30 years primarily for CDMOs, providing subject matter expertise on the manufacture and packaging of most dosage forms from concept to launch. She has led R&D, validation, and process support teams, and works collaboratively with clients to expedite speed to patient and commercial market.
Justin Mason-Home Director, HPAPI Project Services Ltd.
Justin Mason-Home is director of HPAPI Project Services Ltd. (HPSL). He is a fellow of the UK’s Royal Society of Chemistry, with over 20 years’ experience in supporting pharma companies to manage potent drug safety, is published and a frequent chair and presenter at international HPAPI conferences. Justin formed HPSL in 2017, offering a high-level, practically-focused, and pragmatic resource, to support (bio)pharma companies to design, develop and deliver potent and HPAPI projects; from R&D, scale-up and formulation development, right through to full scale manufacturing. He has been involved in and worked on potent and highly potent API projects over more than 22 years and specializes in technical complex and strategic projects, including unique experience in managing sensitive highly potent and toxic biopharmaceutical compound matters.
Judd Taylor Head of Tech Transfer and Process Validation, Takeda Pharmaceuticals
Judd is a seasoned biotech industry professional with over two decades of experience, particularly in cGMP operations and product life-cycle management. Throughout his career Judd has developed a robust expertise in biologics manufacturing and quality, medical devices, and cell therapy products, more recently becoming a subject matter expert in technology transfer and product commercialization. He currently leads the New Product Introduction function for Takeda’s Biologics Operations site in Lexington, Massachusetts.
Andrew Warmington Manufacturing Editor, Custom Content, Citeline (Moderator)
Andrew Warmington has been writing about pharmaceuticals and related industries since becoming editor of Speciality Chemicals Magazine in 2002. His particular area of expertise is in the C(D)MO drug substance and CRO markets, plus the regulatory side, which was developed during a stint with Chemical Watch. He has also been a freelance proofreader within the industry, notably for a major drug packaging company. He joined Citeline as Manufacturing Editor in 2022.
Roundtable Discussion with Andrea Guytingco, Kerry Kingdom, Justin Mason-Home, Judd Taylor and Dr. Andrew Warmington | Published September 2023.
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