Preparing your raw materials for commercial manufacture: an interview with Bernd Leistler

In this interview, part of our in focus on raw materials, Bernd Leistler (CellGenix, Freiburg, Germany) discusses batch-to-batch variability, maintaining a consistent manufacturing workflow and the future of raw materials.

Please introduce yourself and your company

My name is Bernd Leistler, Vice President Production, CellGenix (Freiburg, Germany). I joined CellGenix in 2003 and am responsible for all CellGenix® cytokines for ex vivo cell processing.

CellGenix is a leading global supplier of high-quality raw materials for the expanding cell and gene therapy and regenerative medicine space. We develop, manufacture and market human cytokines and growth factors in preclinical and GMP quality along with GMP serum-free media for further manufacturing of cell & gene therapies.

With 25 years of experience we are experts in the GMP manufacturing of raw materials for the cell and gene therapy space. As a former ATMP developer and manufacturer we gained in-depth cell culture knowledge and superior regulatory expertise. With this unique background we understand the high requirements our customers face during product development and the regulatory approval process. We help simplifying raw material qualification and validation efforts by offering expert technical and regulatory support.

How should therapy developers prepare for commercial manufacture in terms of raw materials?

The initial focus when choosing raw materials is usually the functionality of the raw materials: their effect on cell expansion, phenotype and viability. What is often neglected is that at a later stage in the development process, for example the clinical stages and commercial manufacturing, the raw materials need to meet higher safety and quality requirements as well as international regulatory guidelines. We therefore recommend choosing GMP raw materials which are compliant with international regulatory guidelines as early as possible in process development. Since individual countries can have special local requirements, it is beneficial to select raw materials that comply with all major regulatory standards, and to choose a supplier who can give customized regulatory support.

We recommend establishing a serum-free cell culture protocol and to use GMP raw materials that are animal-derived component-free (ADCF). This is also a critical consideration for the commercial manufacturing stage because of the high cost, supply limitations, safety issues and high lot-to-lot variation of human serum. Human serum is however still frequently used to enhance cell expansion and promote cell adherence. As a cell culture media developer, we focus on designing serum-free media that offer these functionalities without the need for serum addition.

Next to regulatory and quality considerations, continuity of supply should be considered while preparing for commercial manufacture. Scaling up from Phase I clinical trials to large-scale commercial manufacturing, the number of patients and doses to be produced might go up by several orders of magnitude. To eliminate possible scalability issues, it is important to think about how the cell manufacturing workflow will be scaled up/out. Is the cell culture protocol suitable for production in a different or larger cell culture system? Are the GMP raw materials available in all global regions where you want to manufacture your cell therapy? Is there a secured supply chain available? Is the supplier willing and able to cope with a highly increased demand?

We recommend identifying and qualifying the appropriate GMP raw materials at least prior to clinical development of a cell therapy. This will prevent the need for expensive and time-consuming clinical comparability studies to prove raw material changes do not alter the final cell therapy product. A study performed by the Tufts Center for the Study of Drug Development (MA, USA) estimated that the costs of an amendment for a Phase III trial costs more than three times as much as an amendment for a Phase II trial¹.We offer both preclinical and GMP cytokines that are produced under the same conditions in a GMP facility. This enables a seamless transition from preclinical development to the clinical stage.

How can you minimize any potential batch-to-batch variability in your raw materials?

Inconsistent product performance of raw materials causes deviations in the cell therapy manufacturing process. It is therefore crucial to choose GMP raw materials with a high and reliable batch-to-batch consistency. In order to determine the quality of raw materials, detailed information should be provided on the Certificate of Analysis. The raw material supplier should in addition facilitate audits of their production site and provide additional documentation to provide proof of a consistent manufacturing process.

To minimize batch-to-batch variability, raw material suppliers should take the following measures:

• Manufacturing and quality control according to all applicable GMP guidelines to provide documented evidence of purity, potency, consistency and stability
• Manufacturing according to a certified quality management system (ISO 9001 or ISO 13485)
• Qualification of raw materials and vendors for all critical production materials
• Product release according to pre-defined specifications
• Monitoring of product quality by in-process controls at each manufacturing step
• Qualification of facility and process equipment
• Validation of all production and control procedures
• Comprehensive stability studies

We have performed extensive batch-to-batch consistency studies for all our CellGenix® GMP cytokines. This ensures our customers that their manufacturing process is not influenced by using different batches of our GMP cytokines.

Raw materials can be supplied in a range of formats, such as syringes or cartridges. How can you identify the most suitable format for your application?

It is important to identify a format that can be easily integrated in your (closed/automated) cell therapy manufacturing process. Important things to consider are: Can the format be easily connected to your cell culture process in a sterile manner? Can it reduce manual handling steps such as reconstitution? Is there a secured supply chain available? Is the format offered by different suppliers, is there a 2^nd supplier available? What are the shelf life and stability of the raw materials in the respective format? Can the format be integrated in an automated workflow?

Currently it can be quite challenging to find a format that offers all the above. Despite all efforts there are still some challenges that need to be overcome. A major challenge in Europe is that raw material handling must be performed in a Grade A clean room as long as there are no sterile connectivity solutions available. The addition of small volumes is also still challenging due to dead volumes and stability constraints. We for this reason initiated an open discussion within the cell and gene therapy community about current challenges and how we can overcome these (see infographic).

How can you identify and minimize the risk of leachables?

It is important to use materials that are at least compliant with relevant EP and USP chapters and of which detailed leaching and extraction characteristics are available. To minimize the risk, it is desirable to use materials with intended use in pharmaceutical production.

What are the challenges in maintaining a consistent manufacturing workflow as you scale your process up or out?

Scaling up/out the manufacturing process often means that different systems and technologies are used for the different clinical phases, from flasks to bioreactor to closed system automation. In addition to increased regulatory and quality needs, it remains a challenge to maintain a consistent product quality at different production scales.

Since scale up/out is associated with an increased need of raw materials this could lead to supply issues as well as storage issues. Distribution of raw materials over several (global) manufacturing sites can in addition be a logistical challenge. Moreover, if the raw material handling is done manually it greatly increases labor hours and thereby cost of goods.

To prevent these challenges from occurring it is important to choose a reliable raw material supplier early in the development process. We offer supply agreements to prevent supply issues and offer preclinical and GMP cytokines that have an equal product quality and performance.

How do you see the landscape of raw materials supply and usage evolving in the future?

As more cell and gene therapies become approved, we see a rapid growth in the demand for high quality GMP raw materials. We for this reason are constantly expanding our production facilities and are currently upgrading to automated fill and finish capabilities. This not only increases the amount of product that can be manufactured, it also allows us to offer much larger batch sizes, saving time and cost of goods on incoming controls and revalidations.

We believe that innovative raw material formats will help overcome current manufacturing challenges and will help standardization of cell therapy manufacturing processes.

References

1. Getz KA, Stergiopoulos et al. Ther. Innov. Regul. Sci.50 (4) 436-441 (2016)