Risks And Challenges Of Having Multiple Products In Your Pipeline
By Yonatan Levinson, process development associate, Pluristem Therapeutics
As the cell therapy industry matures, many cell therapy companies are already focusing on developing and scaling up production processes for their products. Furthermore, many such companies have multiple products in their developmental pipeline, and as these products move from basic research into development and production, the risks and challenges of developing multiple products become clear.
New products begin in R&D. At this stage, one goal is to demonstrate how a company’s second product is different from its first product. This may seem obvious, as new products generally include new processing steps and are ultimately intended for different clinical applications. Down the road, however, regulators will require proof that the new product is using a mechanism of action that is distinct from its predecessor. Furthermore, they will want to make sure the new product can be reliably characterized in a distinct way from its predecessor, which can be challenging, especially when developing a product from multiple donors. For this reason, we recommend making it an early R&D priority to define the differences between your products in terms of identity and activity.
Once product and process development is underway for a second product, it is important to validate and modify all tests and assays inherited from the first product. Cell counting provides a good illustration of this principle. If a company’s second product has a different cell size or morphology, then cell counts will be inaccurate if run using parameters from the first product. A new counting protocol must therefore be developed. At the same time, safeguards must be put in place to ensure Product 2 isn’t tested using the protocol for Product 1.
Similar risks exist when the company begins to manufacture Product 2. For example, Product 2 will likely use many raw materials that are similar to, but slightly different than Product 1. This includes a different growth medium or even the same medium with a different concentration of serum or other nutrients. There are also risks when it comes to equipment and protocols for expansion, harvest, and final formulation. On the one hand, it is advantageous to have flexible platforms such as bioreactors and harvest systems that can accommodate multiple products, as these platforms save on costs, space, and logistics. On the other hand, it increases the need for quality control steps to ensure that the final product wasn’t grown or harvested according to the wrong protocol.
In addition, using the same clean room facilities for two products introduces the possibility of mixing between products. This is especially important when one considers that two different products may have some overlap in their identity markers, making it difficult to determine if Product 1 contains some Product 2 mixed in.
Fortunately, there are ways that companies can manage this risk from the start. First and foremost is to establish a system of SOPs and batch records for all steps in the process. These documents must be subject to oversight by QA personnel. They should be initially created by the Development team, which best understands Product 2 and how the product and its processes differ from Product 1. Production versions of these documents can then be written as the process is transferred from Development.
In order to prevent mixing between two or more products, production should be conducted in campaigns, with extensive cleaning procedures conducted between campaigns. It is critical that these cleaning procedures be validated in order to ensure that they effectively remove all trace of one product before the next is produced.
Human error is always a risk, but it can be addressed by enacting safeguards and training personnel. Safeguards include clear labelling and separate storage of all raw materials, process solutions, and equipment, as well as restrictions on automated controls to prevent operators from mistakenly choosing the wrong protocol. Personnel training means that even workers who are already qualified to perform various operations for Product 1 must be retrained on the same operation for Product 2, even if it is similar.
Ultimately, the exact risk management strategy depends largely on the type of cell therapy products being developed and the differences between the various products in the pipeline. However, it is always important to start working on such a strategy as early as possible, even before new products have made it to production.
Additional Authors:
Arik Livni, QA Manager, Pluristem Therapeutics; Ariella Ben-Haim, Planning Manager, Pluristem Therapeutics, and Lior Raviv, Development Director, Pluristem Therapeutics