MANUFACTURING
reference material characterization, and stability studies. The term “stability studies” may include: DS and DP; scale-up and GMP batches; BDS retests; testing of different reference standards generated during process development; and manufacturing, compatibility, and comparability studies. You need to define the different temperature ranges and time points for each of these studies and include them in the RFP and SoW to avoid pricy change orders later.
Q. Does process development raise any similar concerns? A. The process development preceding GMP manufacturing is less strict but requires extended technical knowledge of the latest trends in upstream, downstream and formulation development, as well as the scale-up and tech- transfer to GMP manufacturing. The process development team should be flexible to support multiple projects and modalities of molecules and have close communication with the analytical team to resolve different types of challenges. When selecting a CMO, it is important to ask the process development team open-ended questions to discuss their experience and approach in different scenarios. Also, some CMOs declare that they specialize in late-stage and commercial manufacturing. In reality, it means that they do not have proper process development teams and expertise.
Q. You mentioned that drug sponsors should be attentive to under- and overestimated budgets and timelines in RFPs and other early documents. What could those indicate about potential manufacturing partners? A. CMOs may provide an underestimated timeline and budget if they want to get the project. CMOs may intentionally exclude essential activities to reduce the proposed budget. Later, when the project is under way,
“It is important to build a partnership with the CMO through clear communication of your goals and expectations and a willingness to understand their limitations.”
40 | H1 Virtual Events: Review and Summary Handbook
change orders may need to be added at a premium cost. Frequently, the following parts are missing: scale-up/scale-down; demo or engineering runs; stability studies; production of reference material and its characterization; viral clearance studies; endotoxin reduction studies; retests; outsourced development and testing; raw materials; consumables; and components. Meanwhile, other CMOs may provide an
overestimated timeline when they’re understaffed, overbooked, or lack experience. The budget is overestimated when a CMO needs to support large infrastructure, makes a lot of mistakes and needs to cover their costs – or outsources a significant portion of activities, charging an extra 15% – 20% in service fees. Also, these days, the majority of CMOs use disposable systems to minimize their capital expenses. However, the cost of consumables could be higher than the cost of provided services. That’s why we always send RFPs to several CMOs, asking them to indicate the portions of in-house and outsourced services as well as to provide the fair cost of raw materials, components, and consumables including service fees.
Q. What advice do you have for developing risk mitigation plans? A. I would recommend the following steps: • Develop a detailed project roadmap with several technical options, such as the type of expression, purification, or analytical outsourcing. This will add flexibility to the scope of work.
• Define your primary CMO but keep the line of communication open with your second choice. You may run some portions of the project in parallel at two CMOs to leverage their expertise. This will assure timely project completion.
• Ask each CMO for a fixed project price and let them know change orders will not be placed in the future. This will create a more realistic budget. However, I’d recommend keeping an extra 20% – 30% as a budget contingency. This should cover additional expenses, which will likely happen.
• Split the project into several portions like a) process biochemistry; b) scale-up and non-GMP batches; and c) GMP manufacturing and stability studies.
• Source the project step by step and do not
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