by Elena Meurer
As ATMP start-ups mature, they will face the following challenging decision: whether to develop, test, and manufacture its products in-house or to outsource the activities to a contract manufacturer (CMO).
While the US is following a phase-appropriate approach, manufacturing of investigational medicinal products in the EU must be performed in accordance with GMP requirements. Developers who do not have their own GMP facility or plans to set-up their own plant, will need to look for a contract manufacturing organization, CMO (or contract development manufacturing organization, CDMO, if development activities are part of the project). For some developers it is a routine process with an established check-list but for some, especially for small start-ups, looking for a CMO is not trivial. Often, there is as much at stake as the fate of the project. Therefore, it is a bit like looking for a reliable life partner: some say (s)he should be smart, diligent, preferably without expensive habits. Some will put other qualities first, but it must be a match.
But what is commonly expected from a CMO and what should the developer bring with him to facilitate a rational choice?
In the first CMO selection round, those five aspects are primary in the focus:
A first assessment can be done relatively fast with a paper-based review of available CMOs, company visits and/or information provided by the company. More in-depth information about the infrastructure, quality and experience of the company will be obtained during the project, but the overall picture will mostly remain the same. However, time and prize are the variables that are sometimes difficult to estimate correctly at the beginning as the need may arise to re-adjust the original timelines and costs in the course of the project. To make a realistic estimate of these parameters, a well-elaborated scope of project and proposal are essential.
Scope of project and following proposal are two key points where both partners equally contribute to the success. For the CMO, its previous experience is important to make a realistic offer: what is the general build-up of the quote, which modules the quote should include; how to provide a realistic estimate for technology transfer activities and to handle process changes during the transfer; what to communicate to a client as requirements. For the developer, it is of advantage to understand the principles of manufacturing in GMP regulated environment, as it has direct impact on the project setup, costs, and timelines. And for both, the transparency and communication are highly essential for the optimal result.
Scope of project issued by the customer should generally include:
Overall project scope
Project size and duration (e.g. number of manufacturing batches within a defined period, overall project duration)
Regulatory requirements for facilities and quality system; also, product-related requirements such as biosafety level if applicable
List or description of most essential / critical technical requirements and devices
If transfer of the manufacturing process is part of the scope, detailed process description including duration of major steps and personnel requirements if possible
Anticipated timelines for (as applicable):
Process translation into GMP status
Outlook and special requirements such as commercial manufacturing after licensing may be helpful to understand the prospective of customer - CMO relationship
Based on the information provided, the CMO will issue a quote. There are different ways of designing a quote that can be applied dependent on the project structure and customer expectations as well as available budget. We will not go into details of this complex process but just delineate the most essential points that need to be considered to make sure that the proposal is realistic as much as possible.
concomitant with project feasibility assessment, first gap analysis should be performed by the CMO (in collaboration with the client, where required); if gaps are identified, these gaps and their impact on the project development and costs should be clear from the proposal.
the structure of the proposal should allow to reconstruct which work packages are covered by it; whether all activities required for the project completion are listed, and if not, which activities are outstanding. In other words, the constituents of the named prize should be clear.
timelines should be described as detailed as possible; dependent on the complexity of the project and preliminary agreements, timelines for the overall project duration or single milestones may be suitable.
it should be clear which assumptions are made, their impact, and how the change in the assumptions may influence the prize and the timelines.
Beside evaluating these parameters, the customer should also address other aspects, not so clearly expressed on the paper but equally essential for the project success. Thus, it is very important to understand if the project will get a required priority level. Negative signs are overloaded or insufficient personnel, unclear or unrealistic timelines. While technical personnel are often hired for a specific project, the middle management most often remains the same and will just take up one more responsibility in addition to the existing ones. If already during the negotiation phase there are difficulties to find a free slot with all participants available, ask why, and how it is going to be handled for your project. In general, estimate at least 6 months to recruit and train the necessary personnel.
Also, an attractive below average price may turn out to be a potential pitfall and always needs additional questioning. One of the reasons could be that extra cost items are not clearly understood by both sides or not clearly stated in the proposal. In this case, a seemingly low prize can turn into a very expensive investment at the end of the path. Be sure that you double checked this. Altogether, making a correct cost estimation for manufacturing an ATMP is by far not a trivial task. Despite rapid progress in the field of cell and gene therapy applications, there are still not many prize benchmarks for both CMOs and customers to orient themselves. This remains one of the challenges of being a pioneer in a highly innovative field.
And, setting up your project timelines, please do not forget: contract negotiations take time! Depending on the complexity of the product, a time estimate is between 3 to 12 months.
In summary, you should be guided by the following principles:
Outsourcing is a challenging effort for the developer as well as the CMO. It should be a well-structured partnership approach with thorough planning and efficient communication.
Biopharma Excellence has extensive experience with the manufacture of ATMPs and the selection of CMOs. If you would like to learn more, please contact us.