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GMP raw materials: A critical factor in commercial scale ATMP manufacturing

GMP raw materials: A critical factor in commercial scale ATMP manufacturing

With the FDA approval of the first CAR-T therapies, the cell and gene therapy space has reached another milestone in 2017. Kymriah™ and Yescarta™ are pioneers of a fast growing field in which an increasing number of advanced therapy medicinal products (ATMP) manufacturers are reaching commercial phase.

The strong expansion of the cell and gene therapy space brings many challenges to the manufacturers of ATMPs. As a result we’ve seen a lot of progress in accomplishing consistent large-scale manufacturing on a global scale. One of the biggest challenges in achieving this is the elimination of variations, especially in starting and raw materials (also called ancillary materials) and manual manufacturing steps. To eliminate variations in raw materials we see an increased demand for GMP raw materials and an increased need for regulatory guidance. As a provider of GMP raw materials we are actively raising awareness of the need to use high quality GMP raw materials and are in constant interaction with regulatory authorities worldwide.

Furthermore, as described in the guidance on microbial and viral safety of Ph. Eur. chapters 5.2.12 and 5.1.7, recombinant proteins must be derived from fully traceable and well-characterized Master Cell Banks.

  

Selecting the right GMP raw materials

The quality, safety and efficacy of ATMPs are dramatically influenced by the raw materials used in the manufacturing process. Successful ATMP manufacturing is therefore dependent on the use of high quality GMP reagents. We believe that the following three critical quality requirements are vital to meet increasing quality and safety concerns:

1. 

Raw materials must be safe. The origin and impurity profile of all materials used for the manufacture of raw materials intended for further manufacturing of ATMPs must be assessed, including an assessment of all materials for the presence of animal-derived components. Only safe and traceable materials must be used throughout the raw material manufacturing process. We follow a strict animal-derived component-free (ADCF) policy and serum-free policy to ensure maximum safety of our products. As a result all media are produced without the addition of human or animal serum and no animal or human-derived components are part of any of our cytokine products. Our cytokine product portfolio is divided into two distinct ADCF levels:

GMP raw materials ple phacilitate

Furthermore, as described in the guidance on microbial and viral safety of Ph. Eur. chapters 5.2.12 and 5.1.7, recombinant proteins must be derived from fully traceable and well-characterized Master Cell Banks.

 

2.

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 manufacturing

3.

Raw materials must comply with regulatory requirements:

  • USP <1043>, USP <92> and Ph. Eur. General Chapter 5.2.12
     
  • ISO 9001:2008 or ISO 9001:2015 certified Quality Assurance (QA) system, which is constantly improved and regularly inspected by certified bodies.
     
  • Manufacturing according to 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- and ADCF manufactured raw materials, derived from well-characterized cell banks, will significantly reduce qualification and validation efforts of ATMP manufacturers. All these factors help to ensure consistency, safety and purity of the final cell therapy products and contribute to the seamless transition from research to commercialization.

    

Securing your raw material supply chain

Scale up or scale-out is among the key challenges faced by companies in the cell and gene therapy space. Scaling up from clinical trials phase 1 to largescale commercial manufacturing the number of patients (i.e. doses to be produced) might go up by several orders of magnitude. As more ATMPs will reach commercial phase the supply of increasing amounts of high quality GMP raw materials is getting more critical. If high quality GMP 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 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 products available on demand. As supplier, this for instance allows us to produce large size batches that are reserved for one customer.

In case unique bio-processing models are used for ATMP manufacturing, customized GMP raw materials might be desired. For customized products the supply chain gets even more complex. The initial setup and full validation process of a customized product under GMP requires a good amount of time. If full stability of the final products has to be demonstrated, more than a year 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.

To be able to provide our high quality raw materials at strongly increasing quantities we started facility expansions and took scale-up measures. We have also set up a warehouse at our US office to further improve our overseas supply chain for our American customers. 


Author: Bernd Leistler, Vice President Development & Production, CellGenix GmbH

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