Companies developing biologicals are frequently small start-ups or small to mid-size enterprises with a few projects in the pipeline. Even virtual companies develop biologicals where they outsource all their activities. Being responsible for CMC or quality in such a company is challenging.
Typically, you will have to cover a broad spectrum of different areas when developing the drug product. To have your clinical supplies ready for your company’s first trial there is a sequence of activities that you need to initiate, source and monitor closely. With this article, I intend to share the structure and timelines of each step.
Your clinical colleagues may be planning for a first-in-human (phase I) clinical trial in two years. Typically, the study outline is drafted a year before the investigational new drug (IND) or the clinical trial application (CTA). The protocol will define a lot of critical things, such as the administration route, the dose and the number of patients in the trial. To have IMP ready in 12 months, you will need to start the CMC work at least two years in advance.
Clinical vs CMC Timelines: Planning for Clinical Supply
Once you have an understanding of the clinical study, you will need to estimate the amounts of IMP. Although it is typically the responsibility of the clinical team to order these, they will need a lot of support and collaboration is key. The amounts needed depend on different parameters, as shown in Table 1. Beside all these parameters, it is also a matter of the level of supply security you want to have for the study.
Companies typically use overages of 20-50 percent of estimated supply, sometimes even 100 percent to guarantee there is no risk of stock-out. However, for a biological IMP, this can become very costly as these drugs may be very expensive, i.e. $500-1000 USD per vial. You can design your own system or use commercial software. Whatever system you select, you must be aware that input parameters are critical and the system should be periodically re-evaluated.
To manage the actual ordering and distribution of IMP during a study with multiple sites, different interactive response technology (IRT) systems are used. These are computerized systems that manage patient randomization and IMP orders. These are typically web-based and have different degrees of sophistication. There is number of commercial vendors available but typically bespoke systems are used to allow sufficient adaptation for your particular trial. To set up the programming of the system, there are a number of factors and decisions that need to be taken, such as site seeding levels, trigger points, re-supply levels, safety stocks, and other details.
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Selecting and Developing Dosage Form
Due to poor stability and limited oral uptake, biological drugs are typically injectables. Developing any stable and robust drug formulation may take time, several years in fact. There are different dosage forms possible depending on your biological drug properties and your end-user need. To meet the timelines of the different clinical phases, formulators often propose step-by-step development as presented in Figure 1.
In the development of the dosage form, one must fully understand the clinical situation, namely, how the drug will be administered, by who, where and what additional components or devices required to dose. The IMP may need to be diluted, mixed or measured before use. All these factors may interact or interfere with the drug and this must be investigated in advance.
Typically, in-use stability must be performed to document the drug performance and compatibility with these factors and components. You must prepare specifications for a number of items, including storage conditions for the IMP during shipment, and storage and final use. Furthermore, another activity to remember is to write detailed instructions for use considering the clinical situation. Additionally, you will need to identify any other supplies needed for the use at the sites or at the patient’s home. Sharp bins, infusion sets, torniquets, cooler bags, etc. must be sourced as needed.
In the regulatory file (IND or CTA), the product must be described in detail, both the raw material, such as the drug substance and the actual drug product. Additionally, must the manufacturing process be described. An important part of the CMC sections is the stability section. Typically you must present data demonstrating stability during long term storage but also stability during in-use conditions relevant for the clinical dosing.
Relevant stability generated by appropriate analytical methods must be included to demonstrate the developmental IMP is sufficiently stable to allow completion of a clinical study. Typically, development data may be limited at this stage and a clear plan must be outlined for how the quality and shelf-life of the IMP will be managed over the study duration.
Preparing for First Dosing
Once either the IND or CTA is approved, the team gear up for the first patient dosing. This is when the clinical team initiates the patient recruitment and site activation activities. Additionally, ordering and distribution mechanisms start up. To be aware, there will be excursions for specified storage and shipment conditions. Refrigerators may break down or shipments may be delayed. To handle these, you must have appropriate data for what can be allowed while also developing appropriate SOPs together with your QA colleagues.