Authors:

Shawn Cain:                      SVP Development and Manufacturing, Injectables

Louise Carpenter:             Head of Pharmaceutical Development

Picture the scenario. You’ve spent several years, and hundreds of millions of dollars, developing your new critical therapy which is destined to improve the lives of patients around the globe. You’re approaching commercial launch. You know that, for every single day your drug launch is delayed, you could lose millions of dollars in revenue, with estimates varying from $600,000 to $8 million per day¹. Not to mention the suffering of patients who are unable to access your critical therapy to treat their condition. Ideally, this would not happen. But—critically—you did not conduct the proper long-term due diligence on your chosen CDMO partner(s), and your development and manufacturing strategy was suboptimal. As such, not only are delays a possibility, they are inevitable.

In this Q&A, PCI Pharma Services’ Shawn Cain and Louise Carpenter discuss best practices when it comes to outsourcing development and manufacturing programs, covering both sterile, non-sterile and highly potent drug products, and why it’s so important to choose the right CDMO partner to accompany you throughout the drug product lifecycle. Louise specializes in solid oral and liquid dosage forms in the high potent space, and Shawn’s area of expertise is sterile-fill finish and lyophilisation. Together, they bring a vast amount of experience in their fields, and share their experiences across multiple dosage forms.

What are the essential attributes of an industry-leading CDMO?

LC: In terms of technology and manufacturing equipment, it’s incredibly beneficial to work with a CDMO able to conduct small-scale development and manufacture (D&M), while also offering in-house scalability for late-stage clinical and ultimately commercial supply. This flexibility, and access to an extensive range of equipment and processes, ensures that various challenges can be addressed, and the most suitable solution for each unique project can be found. A major benefit of in-house scalability is that no additional tech transfers are required; switching CDMOs throughout the product’s lifecycle can be costly and introduces additional risk.

But equipment and facilities are only as good as their staff. Successful D&M requires strong cross-functional collaboration between highly experienced teams across a variety of disciplines, such as analytical, manufacturing, quality assurance and control and, of course, formulation development. A deep knowledge of their equipment and processes, and a strong awareness of alternative D&M methods, enables them to determine how various formulation attributes can impact the final drug product, both positively and negatively, and advise their sponsors accordingly throughout the process.

SC: You should be searching for a CDMO that has both the analytical equipment and experience to efficiently develop or transfer your analytical methods.  If you select a core team that has the experience and flexibility to work with new products or technologies, you can always acquire equipment to support complex or novel technologies. Without effective analytical capabilities in place, it would be difficult to develop and manufacture the product.

A CMDO that supports multiple products in various countries is another critical factor if you plan on trialling or commercializing your drug products globally. If so, the regulatory support you’ll need is multifaceted. Another question to ask is: is your selected CDMO experienced with drug product, medical device, and combination products? If so, this demonstrates that the CDMO’s quality systems are robust and flexible enough to meet the requirements of a specific region.

Other fundamental questions to ask of your CDMO candidates are:

• What is their regulatory inspection history? Have they been successfully audited by major regulatory bodies, such as the FDA, EMA, MHRA, ANVISA?
• Is your product in its final presentation, or is additional work needed? And if so, does your CDMO have development capabilities and have phase appropriate guidelines in place?
• If your product requires lyophilization to ensure stability, does your CDMO have the experience and equipment to develop an efficient, but robust lyophilization cycle?

For example, analytical research equipment for lyophilization development, such as Modulated Differential Scanning Calorimetry (mDSC) and Freeze-Dry Microscopy (FDM), help define and understand the physical characteristics of the formulated product, such as a product’s freezing point, glass transition, eutectic temperature, and collapse temperature. This enables the CDMO to tailor a lyophilization cycle that will produce a stable and elegant pharmaceutical product.  Additionally, the use a ‘sample thief’ to collect numerous samples during development lyophilization runs to assess moisture content or residual solvents in real-time, can be instrumental in establishing an efficient secondary drying cycle and fully characterize the lyophilization process parameters.

LC: From a solid oral dose perspective, understanding the CDMO’s containment strategy is vital when outsourcing highly potent programs. You need to understand the containment measures in place, and the level of potency the facility is able to handle safely. Oncology dominates the formulation development market with a 25% share in 2022, and an estimated Compound Annual Growth Rate (CAGR) of 8.3% to 2030². Around half of oncology drug candidates contain highly potent APIs, so along with scalability and development capabilities, safe handling of these dangerous substances is a key consideration.

What are the main challenges facing CDMOs during D&M programs?

LC: Clients occasionally withhold critical reports and information about the product or overall project strategy, preventing their CDMO partner from analysing the data themselves and being able to develop a longer-term strategy for their product. This lack of transparency can lead to issues that surface when problems arise, making it difficult for the CDMO team to address them effectively. It also means that the CDMO’s processes are generated based on second-hand information, increasing the risk of critical information being missed by the CDMO.

Another challenge is the establishment of unrealistic or aggressive timelines, which can force the acceleration of development activities. This rushed approach may create problems during later stages of development and scale-up, potentially compromising the overall success of the project, as more formulation development may inevitably be required at a later, more time-critical stage.

SC: The ability to perform analytical or bioactivity testing quickly after each experiment or lyophilization cycle allows the program to move as efficiently as possible through the experimental design plan. Outsourced testing could become a bottleneck for a development program if turnaround times to receive test results take longer than originally anticipated. Planning ahead is critical.

Another important factor is the early understanding of the container closure system and the nature of the filters used to sterilize the product. In today’s supply chain, choosing a filter, stopper or vial that is not available slows down many development programs; it’s not uncommon to experience lead times of over 50 weeks with some components. When choosing key product components, there should be a risk-based approach taken with considerations of secondary suppliers, purchasing strategies, and key alliances. This could ensure on-time development of your program, avoiding delays to clinical and commercial timelines caused by supply chain difficulties.

LC: Limiting the amount of development activity prior to the clinical trial manufacturing (CTM) stage can also pose difficulties. Of course, limited development can be the result of a limited budget, but open and honest discussions during the proposals stages enables the CDMO partner to advise what is possible within the sponsor’s proposed budget.

Similarly, a limited supply of API can result in compressing multiple trials into a single batch. This reduces the usefulness of the data produced, making it challenging to draw meaningful conclusions from the results. Again, this can often be beyond the client’s control, but it does have an impact on the quality of formulation development activities and the data gleaned during the process.

What can sponsors do to maximise the efficiency of D&M programs?

SC: Talk with your CDMO early to ensure the stability indicating methods are optimized.  CDMOs with the capability to develop methods in-house can work with you to execute multiple development activities in parallel. The more information you can share with the CDMO about your molecule’s solubility, stability, pH sensitivity, intended route of administration, and possible degradation pathways (light, oxygen, temperature), the quicker the development team can get your product to the clinic—and, of course, to commercial launch.

LC: It’s essential to perform excipient compatibility and forced degradation studies upfront. These studies help identify potential incompatibilities or stability issues early in the development process, allowing for timely adjustments and mitigations.

Considering the scale-up process during development stages is also important. Doing so enables the formulation team to design processes that are more easily scaled, reducing potential challenges and delays during the transition from development, through clinical to commercial manufacturing. Considering scale-up early, along with clearly defined scopes of work, improves the workflow between the formulation and manufacturing operations teams within the CDMO, and contributes to a strong collaborative relationship between the CDMO and their sponsor—a relationship based on effective communication and a deep understanding of the long-term program goals.

SC: It’s advisable to take a proactive approach to ensure phase-appropriate development to speed up progress and minimize API or BDS loss. A few examples of this would be to develop an intravenous formulation for your Phase I clinical studies, even if you know you’ll be going to subcutaneous or intramuscular administration in the future.  The same can be true of opting for a simple vial presentation for your early-stage work while you’re finalizing your dosage or going with a frozen liquid at an early stage, instead of spending the time and money on lyophilization development and manufacturing. If the clinical program is successful, you may choose to spend additional time and money on further development as the product progresses through the clinical stages.

One newer technology that allows one the opportunity to explore speeding up the time to GMP clinical supply is to investigate using a small-scale fully robotic fill-finish system.  These advanced technologies not only expedite the filling process with automation, but this enables the flexibility to pivot between filling multiple dosage formats, bringing even broader sterile fill-finish solutions to PCI clients across the entire drug product lifecycle bringing therapies to market with increased speed and safety.

Can you briefly describe a real-world case study where D&M programs have been affected by poor strategy?

LC: One customer had experienced issues related to powder static and poor flowability of the blend during the development phase. However, this critical information was not shared with PCI at the time. It only came to light when the client requested that we use debossed tooling on the tablets. During the scale-up of the project using the new tooling, tablet splitting issues were observed halfway through the production run. The investigation into the cause revealed that the client had experienced these issues during the development phase.

Powder characterization is essential, as it provides insights into critical powder properties, such as particle size distribution, morphology, density, and flowability. In this particular case, powder characterization of the blend during the development stage could have identified the issue with static and flowability, allowing the problem to be addressed during development rather than at the scale-up phase.

A thorough understanding of powder properties and their impact on processing performance is crucial for the successful development of solid dosage forms. Techniques including particle size analysis, bulk and tapped density measurements, angle of repose, and shear cell testing can be employed to assess the flow properties of a powder blend. With this information, formulation scientists can modify the blend composition or implement suitable processing techniques, such as granulation, to enhance the flowability and processing performance of the blend.

SC: PCI sees hundreds of programs every year and we see regulatory strategies employed that are accepted and others which are rejected. Just this past year, we worked with several smaller companies to develop plans for phase appropriate CPP (critical process parameter) development, scale-up, filter and stopper pressure validation leading to successful process validations and filings. However, some clients are set on their own strategy rather than tapping into our expertise which has led to challenges that could have been avoided.

We had one client who wanted to move forward without performing mixing studies, resulting in two failed batches due to out of specification (OOS) results. Another client wanted to perform concurrent Process Validations (PV) with their regulatory submission. Whereas we advised them that the Agency was not always open to this approach, they filed anyway, and it was not accepted.

It’s important to remember that the right CDMO is there to help you achieve your clinical and commercial goals. They know their processes and equipment trains, and have a vast amount of experience in their areas of expertise. By identifying the right CDMO and establishing a strong collaborative relationship during the development stage, sponsors can rest assured that their drug product will achieve speed to patient, study, approval, and commercial launch.

References

¹https://mdgroup.com/blog/the-true-cost-of-patient-drop-outs-in-clinical-trials/#:~:text=Studies%20have%20shown%20that%2080,to%20get%20back%20on%20track

²Grand View Research (2023) Formulation, Development Outsourcing Market Estimates and Trend Analysis from 2018 to 2030