Nicholas.Longworth_89 Mar 08

[Interview] - For cell - and tissue - based products, what are the development processes to ensure product success?

Interviewer: In terms of cell- and tissue-based products, researchers are focusing on a number of design and development processes to ensure product success. As a provider of raw materials for the manufacture of advanced therapeutics, can you tell us how the field has processed in the last 12 months?

What stood out for us is the rapid expansion and maturation of the field as more players are approaching late-stage clinical development and market authorization. We see this reflected in an increased demand for GMP-grade raw materials and discussions about how to ensure their availability throughout late clinical stages and commercialization. These developments show the importance of high quality GMP-grade reagents for safe, reliable and successful ATMP manufacturing. To be able to fulfill this increasing demand we have started facility expansions at our headquarters. This will enable us to grow with our customers into their commercial phase.

Furthermore, we saw an increased focus on automation and customization. As a provider of GMP-grade raw materials we are very interested to see how this will impact the need for customized raw materials. In certain production settings it would be advantageous to have for example medium in a special bag or cytokines in different forms (e.g. larger fill sizes, bulk material, mixture of cytokines).

Interviewer: In recent years, regulatory agencies have begun to recognise an increasing need for guidance of raw materials used for the production of ATMP. Despite arising guidance, dedicated regulations for the GMP compliant manufacturing of ATMPs and associated quality requirements of raw materials are still in development. Which quality requirements do you think are vital to meet increasing quality and safety concerns?

We think the following three critical quality requirements are vital to meet increasing quality and safety concerns:

Raw materials must be safe. The origin and impurity profile of all materials used for the manufacture of GMP-grade raw materials must be assessed. They should be procured from reliable manufacturers and suppliers. Whenever possible, the use of animal- or human-derived components should be avoided and only safe and traceable materials must be used throughout the raw material manufacturing process.

Raw materials should be manufactured following applicable GMP guidelines to provide documented evidence of purity, potency, consistency, and stability:

  • Manufacturing and QC according to Standard Operating Procedures (SOPs)
  • Qualified and trained personnel
  • High class clean room facility and qualified equipment
  • Validated and consistent processes (manufacturing, cleaning, QC methods)      
  • Monitoring of product quality by in-process controls (IPC) at each manufacturing step
  • Product release according to pre-defined specifications by a QC completely independent from manufacturin

Raw materials must comply with regulatory requirements:

  • USP <1043>, USP <92> and Ph. Eur. General Chapter 5.2.12
  • ISO 9001:2008 certified Quality Assurance (QA) system, which is constantly improved and regularly inspected by certified bodies.
  • Manufacturing in compliance with relevant GMP guidelines; including key GMP demands such as change control, Out of Specification (OOS) procedure, etc.
  • Analytical methods are based upon relevant International Council for Harmonization (ICH) quality guidelines

Overall, we believe that the use of GMP-grade and animal-derived component-free (ADCF) manufactured raw materials, derived from well-characterized cell banks, will significantly reduce qualification and validation efforts of ATMP manufacturers. 

A lot of our discussion at the Leaders Forum is directed towards the scale-up and commercialization of this research field. What are the risks associated with developing unique bio-processing models in order to scale up a manufacturing and supply a large number of patients with these advanced therapeutics?

Scale up from clinical trials in phase I to large-scale commercial manufacturing the number of patients (i.e. doses to be produced) might go up by several magnitudes. As a consequence the supply of high-quality GMP-grade raw materials is getting more critical. If high-quality GMP-grade raw materials are not available in time this could lead to delays in ATMP production. This does not only increase costs but also puts precious patient samples in jeopardy. The safest way to eliminate possible problems with the supply of GMP-grade raw materials is having a supply agreement in place well before large-scale manufacturing is planned to start. Giving the supplier a clear and reliable forecast of doses to be produced and consequently the amounts of raw material needed will allow the supplier to have enough product available on demand.

In case unique bio-processing models are used for ATMP manufacturing, customized GMP-grade raw materials might be desired. For customized products the supply chain gets even more complex. The initial setup and full validation process under GMP of a custom product requires a good amount of time. If full stability of the final product has to be demonstrated, one or two years might be needed from initial design to delivery of the first batch. We therefore recommend getting a clear understanding on time needed from design to delivery of these customized products well in advance.

One of the challenges on the path to commercialisation is the transition from preclinical development to the clinical stage. Which challenges are associated to the use of raw materials and how can they be overcome/prevented to ensure a seamless transition?

The most important challenge is a difference in safety and quality requirements between use in preclinical development and the clinical stage. Safety and quality requirements often have a lower priority in the initial preclinical phase, but become crucial in the late clinical phases and during commercial production. To enable a seamless transition we recommend identifying the appropriate GMP-grade raw materials and reliable suppliers prior to clinical development of the ATMP. Changing raw materials at a late stage in clinical development in order to meet regulatory requirements often creates significant additional costs. This is only to a small extend caused by the increased costs of GMP-grade raw materials. These additional costs are primarily related to the need to perform clinical comparability studies. Switching to the required GMP-grade raw materials at an early stage, i.e. after preclinical development, will however prevent the need for such studies and thereby brings a significant economic benefit.