1. How do you approach the initial mapping of the value chain for clinical drug supply, and what are the key elements you prioritize during this process?
The initial mapping of the value chain for clinical drug supply and which key elements to prioritize is dependent on the stage of clinical development and any unique attributes of the drug substance and drug product that require specialized development capabilities and/or supply chain strategies. Unique attributes of drug substance such as a controlled substance, high potency compound, or deuterated compound and that of drug product such as formulating an unstable, low solubility/ permeability, or amine compound susceptible to nitrosamine formation.
For instance, for mapping the value chain for phase 1, the focus is on speed in ensuring that the development and manufacture of drug substance and drug product are conducted in an expedited manner to meet early-stage clinical study timelines to get a quick readout on the potential candidate compound. So the key elements to prioritize are the sourcing of starting materials, selection of drug substance form and synthetic route to scale from gram to kilogram scale, selection of a drug product formulation and manufacturing process, selection of drug substance and drug product CDMOs capable of quick process development/optimization and GMP manufacture of the drug substance and drug product especially within the constraints dictated by the unique attributes of the drug substance and drug product, and packaging vendor if blister packaging is needed.
2. Can you describe the most critical challenges in managing the transition from drug substance to drug product manufacturing and how you address these challenges?
Some challenges in managing the transition from drug substance to drug product manufacturing include drug substance properties such as particle size is consistent and appropriate for manufacture and drug release for drug product, managing formation of nitrosamines in drug substances with amine functional groups, ensuring that there is adequate retest period for the drug substance to manage inventory levels to meet clinical demand.
3. How do you ensure that the quality requirements of clinical drug supply are consistently met throughout the manufacturing process?
Quality has to be built into the product and process. To ensure quality requirements are consistently met throughout the manufacturing process, it is essential that the decisions regarding the chemical development (solid state form, stability, etc.) of the drug substance and formulation development (excipient choices) of the drug product are made considering their impact to quality. The manufacturing process has to be designed to be robust with sufficient process capability, to minimize variability, with an understanding of any interaction effects between parameters, failure modes, etc. with an approach to continue to learn and incorporate improvements into the manufacturing process as part of the development.
If we use internal manufacturing sites then we know the quality and compliance of our site, but if we partner with CDMO sites then it is critical to ensure our partner CDMOs that support us with the development and manufacture of drug substances and drug products for clinical supply share our commitment to quality and compliance and have a strong quality system in place. This starts with having compliance and quality assessment included as a critical part of the CDMO selection process and our quality assurance and quality control colleagues participate in on site visits and the due diligence process. Together the technical operations and quality teams examine the inspection history of the CDMP site and perform a complete audit/inspection of the site.
After selection, we partner with our drug substance and drug product CDMOs to ensure that in our preparation for routine clinical batch manufacture, we review the last manufacture to ensure the lessons learned and any manufacturing and testing nuances from the past experience are captured as part of documentation to be used for the upcoming manufacture such as master batch records and analytical methods for testing and the operators and testing analysts are trained and prepared to handle these nuances and incorporate the lessons that we have learned as part of development and prior manufacturing and testing.
For any critical or challenging drug substance or drug product manufacture, it can be important to be onsite to monitor manufacturing at the drug substance and drug product sites to both learn and ensure the right processes are being followed as part of manufacturing.
Finally, when any systemic or significant quality or compliance issues are observed as part of manufacture or audit by the quality team, and if these issues are not addressed or rectified the decision to not work with an existing CDMO partner has to be made to ensure that we deliver the highest quality clinical supplies for subjects/patients participating in our clinical trials.
4. What strategies do you employ to align drug development and manufacturing with clinical demand, especially in the context of varying phase-specific requirements
In terms of manufacturing, depending on the complexity and lead times associated with the drug substance and drug product manufacture, having adequate safety stock of bulk and packaged drug substance and drug product inventories to support clinical demand and attendant choices such as collecting stability data early in the program for drug substance and bulk hold time and packaged drug product to support clinical inventory have to be made. Also having secondary sources for key starting materials, and second drug substance and drug product CDMOs as we move to later stages in development can mitigate supply risk that comes with the higher clinical demand associated with phase 2 and phase 3 studies and any open label extensions.
In terms of development, for earlier stages of development using rapid drug substance synthesis adequate for low kg scale GMP drug substance manufacture and simpler drug product formulations to enable speed in clinical supply while in parallel developing the more robust and optimized drug substance manufacturing process for commercial scale (100s of kgs) GMP synthesis to meet late phase clinical demand and developing the late phase and commercial drug product formulation along with bridging studies can ensure the balance of the speed required for early stage clinical studies along with the higher demand and more robust development needed for late stage clinical studies are achieved.
Although in theory this sounds straightforward it rarely is as each compound, project and program has it’s own unique risks and challenges (such as deuterated compounds, controlled substances, potential mutagenic impurities, potential NDSRIs, insoluble impermeable compounds that are difficult to formulate, complex extended release formulations, etc.,) each of which require us to fluidly shift focus to ensure the program development stays on target.
5. How do you incorporate risk management practices into the manufacture of clinical drug supply to enhance supply resiliency?
Risk management practices such as risk assessment to identify potential risks in the supply chain quantifying the risk in terms of probability of occurrence, detectability, whether it can be monitored and controlled, and risk mitigation of the risks, are important to enhance supply resiliency. Some risks to manage are complexity, technical risk for the program, regulatory risk, quality and compliance risks from suppliers/CDMOs, sourcing issues, geopolitical risks, natural disaster risk, and financial risk.
6. Can you provide examples of how advanced technologies or innovations have improved the efficiency and effectiveness of drug substance and drug product manufacturing and clinical drug supply management?
Technologies such as continuous manufacturing, machine learning, blockchain, novel catalysts, and drug bioavailability enhancement and drug delivery technologies, and smart packaging are all playing increasingly important roles in improving the efficiency and effectiveness of drug substance and drug product manufacturing and clinical drug supply.
7. How do you handle the complexities involved in scaling up drug manufacturing processes from small-scale to full-scale production?
There are several commercial software that you can purchase and use to predict the process performance on scale-up from lab scale to pilot plant scale to commercial scale of reactions, workup and isolation unit operations. Also, certain unit operations for instance mixing, are more susceptible to scale effects than others, so as part of development and scale up, we focus on capturing data that will help us understand the anticipated effect of scaling these unit operations. Also, using existing knowledge from process development, batch history, and design of experiments (DOE) allows one to understand the process, the critical process parameters, interactions between parameters and scale-dependent parameters that will impact and determine the success of the scale up to full-scale or commercial scale production.
8. What role does collaboration with other departments or external partners play in ensuring the successful manufacture of clinical drug supply?
Collaboration with other departments and partnering with external CDMOs is critical to ensure the successful manufacture of clinical drug supply.
Technical operations team has to collaborate effectively with quality assurance and regulatory affairs to ensure the CMC pharmaceutical development and manufacture of drug substances and drug products for clinical supply is successful.
Partnering effectively with CDMOs who have complementary capabilities and manufacturing expertise allows us to make the optimal choice for any project, reduce risk, and improve the competitiveness and effectiveness of the CMC technical operations department. So partnering and working effectively with CDMOs is critical to the success of the drug substance and drug product development and successful manufacture of clinical drug supply.
9. How do you manage the regulatory challenges associated with the manufacture of clinical drug supply, and what best practices have you found effective?
To manage regulatory challenges, it is good to begin with the end in mind for instance for clinical drug supply what are the unique aspects of the drug substance or drug product that would invite regulatory questions, so that one can proactively collect the data needed to support that issue as part of your IND and IMPD submission and subsequent amendments. For an IND or IMPD questions around the drug substance characterization and impurities, process development, GMP manufacture of the drug substance, and any potential mutagenic impurities and nitrosamine impurities, the drug product formulation and manufacture, use of excipients such as antioxidants and levels, and the drug substance and drug product specifications and justification of specifications are important.
10. How do you balance the need for flexibility in manufacturing processes with the need for rigorous adherence to quality standards?
To achieve flexibility in manufacturing while strictly adhering to quality standards, it is essential to develop a robust and capable manufacturing process.
One can leverage process knowledge gained through data collection and analysis from development experiments, design of experiments (DOE) of important steps, historical batch manufacturing data, and prior knowledge from similar processes to establish a control strategy that ensures product quality while providing manufacturing flexibility. Then, demonstrate process control through process validation/process performance qualification and submit that data to the regulatory agencies as part of dossier submissions. Finally, as part of lifecycle of the product, process control needs to be monitored as part of continued/continuous process verification through the lifecycle of the product.
