As the world of small molecule pharmaceuticals advances, the combination of high pharmacological activity with greater selectivity is delivering therapeutic effects precisely where needed. This is crucial in areas like oncology, where precision targeting and efficacy at low doses are reducing systemic toxicity in therapies such as targeted protein degraders.
With increasing numbers of highly potent oral solid dose (HP-OSD) products entering development pipelines, and many companies outsourcing their drug鈥檚 manufacturing to specialists in high potent active pharmaceutical ingredient (HPAPI) handling, CDMOs are under growing pressure to safely integrate these complex and potent molecules into multiproduct facilities.
Handling a new HPAPI carries significant risks, including potential operator exposure, environmental contamination, and the risk of contaminating other products. Meanwhile, with recent years highlighting an increase in drug shortages, supply chain robustness is also under focus. Technical transfer can typically occur during the late stages of clinical development, just before the drug becomes more widely available to patients. With this timing in mind, the successful and efficient completion of these transfer activities has a critical role to play in safeguarding future patient supplies.
鈥淵ou don鈥檛 want to see any issues and challenges during that phase, because then you鈥檙e ultimately preventing patients from receiving what could be a life-changing, and in some cases lifesaving, medication,鈥� says Dr Rebecca Coutts, Senior Director of Pharmaceutical Development at PCI Pharma Services.
In this article, Dr Coutts shares the essential steps for a successful technical transfer of HP-OSD pharmaceuticals, guiding us through the key actions, expectations, and milestones at every stage of the process.
1: Choosing the right partner
Choosing the right manufacturing partner is arguably the most important step in the transfer of high potent drugs. Above all else, the CDMO should have a comprehensive approach to safety, with facilities and processes designed to minimise risks and protect operators and the environment through the safe flow of air, material, and people.
Keep in mind that not all CDMOs will have the same approach to contamination control. Some rely heavily on personal protective equipment (PPE) such as respirators and full-body suits, while others remove the risk of exposure through flexible or hard-walled containment solutions, sometimes resulting in operator exposure levels (OELs) as low as 0.01碌g/m鲁. Whatever the approach, the importance of validated processes, an experienced team with specialised knowledge of HPAPI handling, and a strong track record of safety and regulatory compliance cannot be underestimated.
鈥淪afety is paramount,鈥� says Dr Coutts, explaining that cross-contamination risk assessments should be guided by four key principles: airborne, mechanical, personnel transfer, and retention of product on contact surfaces. By applying these four principles to facility design, PCI Pharma Services has designed and executed two fully contained manufacturing facilities and a contained packaging facility utilising hard-walled engineered solutions.
Providing a few examples of this, she adds: 鈥淲e specifically look at high-risk areas, and product transfer is one. We use a very well-demonstrated containment strategy 鈥� a BUCK庐 containment valve system that allows you to have full containment when you鈥檙e transferring material from one piece of equipment to another. We look at every molecule individually, applying specific limits to each one, and we also verify our cleans to demonstrate that there is no cross-contamination potential.鈥�
2: Knowledge transfer and initial assessments
Once a CDMO has been lined up, the initial stages of technical transfer can begin. At the initial kickoff, all available information must be shared with the CDMO upfront, often starting with safety data such as toxicological information and material safety data sheets 鈥� critical for helping the CDMO assess whether the API can be safely handled within its manufacturing, packaging, and analytical facilities. If such data is limited, which can be common in early development, the company may collaborate with an external vendor to conduct an independent evaluation.
Meanwhile, the CDMO will work with the sponsor to understand the requirements of the target product profile and the product鈥檚 existing development and manufacturing history to date. Executed batch record documentation can be particularly helpful in giving the CDMO a strong understanding of the current manufacturing process and how it might be mirrored or even improved.
During this stage, Dr Coutts says it鈥檚 best that sponsors hold nothing back. 鈥淲e would rather know if there鈥檚 a challenge with a product that we鈥檙e transferring in,鈥� she explains. 鈥淚t allows us to put the most appropriate mitigation strategies in place, rather than finding that out during the first transfer manufacture, which doesn鈥檛 really benefit either party.鈥�
3: Conducting a gap analysis
Once all information has been shared, the responsibility shifts to the CDMO to perform an in-depth gap analysis, identifying any differences between the sending and receiving site鈥檚 capabilities.
鈥淲e would look at the process and equipment that has been undertaken at the sending site and compare that with the equipment and processes that we have here,鈥� explains Dr Coutts. 鈥淲e then identify where there might be any gaps and we use our experience and knowledge to mitigate those.鈥�
Minor differences in equipment, such as a specific sieve screen, are often addressed through a simple purchase of the necessary part, but larger equipment variations require deeper evaluation. In this scenario, PCI often refers to published literature or its own extensive experience to understand which parameters may need to be adjusted in order to achieve equivalent results from differing equipment. The company鈥檚 35-year history of high potent drug processing is particularly valuable here, enabling informed decisions based on previous results and knowledge.
4: Defining the deliverables 聽
Before commencing manufacturing, the CDMO prepares a technical transfer protocol 鈥� a comprehensive document outlining the entire manufacturing process that will be followed for the initial technical transfer batch, the sampling plan, and the analytical testing that will be performed. If any product or process improvements were suggested by the client or identified by the CDMO during earlier transfer activities, the protocol should clearly capture how these enhancements will be implemented.
鈥淲e use our technical transfer protocol as our guiding document,鈥� says Dr Coutts. 鈥淲e get it signed off by our own SMEs internally but also by our client to make sure that everybody is fully aligned with the expectations of the initial transfer activities.鈥�
5: Preparing to receive the new material
As preparations progress, the CDMO may need to set up several documentation systems to allow the safe onboarding of the HPAPI. At PCI Pharma Services, for example, Dr Coutts explains that no new molecule is brought into the multiproduct facility in Tredegar, Wales until approval has been received within the company鈥檚 safety and quality management system.
This is essential for cross-contamination control and prevention, especially given the potent nature of the APIs. The same stage-gates apply when bringing new products into the company鈥檚 analytical laboratory, where special safety weighing enclosures and transfer vessels ensure safe handling of HPAPIs.
6: Executing the initial batches and reviewing results
As the day to start manufacturing initial batches nears, the customer鈥檚 technical team may decide to be on hand at the CDMO site, offering clear benefits such as faster decision-making and collaborative problem-solving.
Dr Coutts explains: 鈥淚f there鈥檚 an unexpected result, [the client] may have information that is not in a report but could help move the project forward and prevent any delays. That joint sharing of challenges (should they arrive) and joint decision-making to move forward together is generally the way that we prefer to do our technical transfers.鈥�
During the initial technical transfer batch, the goal is to monitor closely and collect as much manufacturing data as possible, from processing parameters like tableting speed and yield to any in-process checks such as tablet weight, thickness, and hardness. Samples are provided to the analytical team to test aspects like blend uniformity, tablet uniformity, and dissolution profiles.
By assessing all of this information, the CDMO can produce a technical transfer report which answers the all-important question: is the product to specification? In other words, has the transfer been a success, or is there room for optimisation? If the answer is yes, the process can advance to scale-up and validation.
Conclusion
The development and manufacturing of highly potent oral solid dose products brings both promising therapeutic benefits and significant challenges, specifically when it comes to finding a CDMO with the necessary capabilities and expertise to handle these molecules safely. Following that, effective technical transfers 鈥� which involve thorough information sharing, careful risk assessments, clear deliverables, robust safety controls, and collaborative problem-solving and decision-making 鈥� are essential in establishing a reliable supply of life-changing medications to patients.
