A straightforward tool for developing a raw material supply strategy for cell & gene therapies

Cell & Gene Therapy Insights 2023; 9(11), 1539–1543

DOI: 10.18609/cgti.2023.201

Published: 8 January
Expert Insight
K Kulenkampff, R Eigenmann, D Karlstetter et al.

Raw materials used in manufacturing processes for cell and gene therapies may carry a supply risk due to the unavailability of GMP-grade material, unique biological and chemical components, or limited supply options. This Expert Insight outlines a tool that allows an objective and straightforward assessment of supply risk for raw materials and identifies feasible options for mitigating such risk.

Background

Reliable procurement of raw materials poses a challenge for cell and gene therapy development and manufacturing. The manufacturing process commonly requires a wide variety of materials, raw material suppliers may not be familiar with cGMP manufacturing, and second or tertiary supplier sources are rare. Materials often are biological, human or animal-derived, and can present a risk of lot-to-lot variability. Nevertheless, in preparation for launch and commercial production, the regulator requires companies to establish a robust raw material supply strategy to secure the supply of therapies to patients—even in the case of expedited drug development pathways [1][2][3]. Because changes in the manufacturing process are difficult to adapt as clinical development progresses, this strategy should be developed early in development. Part of the strategy development is to evaluate materials and manufacturers in terms of their supply risk and, if required, mitigate that risk [4]. Procurement and supply chain teams and adjacent teams such as process development or quality control face the challenge of prioritizing their work with a substantial number of raw materials, potentially across several parallel programs. They require a framework to identify risk materials and define risk mitigation options in an efficient manner. Based on three previously published articles [5][6][7] we developed a framework that serves as a straightforward tool to evaluate raw materials, including supplier risk scoring, ranking, and proposing mitigation options for the materials.

Case evaluation

As a first step, we defined the requirements for the tool. The desire was to develop a straightforward and quick-to-use tool that reliably identifies high supply risk materials and ranks them. The tool also had to be unbiased and consistently yield identical results among different users.

The BioPhorum article mentioned above lists different questions to assess supplier risk and thus provided the basis for a questionnaire used in our evaluation [7]. We identified and adapted the relevant questions and introduced a two-step approach to reduce the time required for completing the assessment (Figure 1BOM: Bill of materials. The process flow for the supply risk assessment tool. BOM: Bill of materials. ). In the first step, we wanted to shortlist materials from the bill of materials which carry a minimal risk based on seven pre-assessment questions. We modified the questions to offer binary ‘yes’ or ‘no’ response choices, with ‘no’ suggesting a potential risk. Once one of these seven questions is answered with ‘no’, the material is flagged as requiring further assessment and ten more ‘further assessment’ questions were answered to rank the material according to its risk status. Based on the answers given to each of the questions, a score was calculated. Each question also holds a weighting dependent on the impact on risk (Table 1 & Table 2). We have selected a higher weight factor for pre-assessment compared to further assessment questions. The weight factor corresponds to the impact of this question on supply disruption. Thus, each material receives a risk score, and is ranked among all materials.

Table 1. Pre-assessment questions.

QuestionAnswer optionsWeighting
1.1Can a risk assessment approach be used to introduce material from a different manufacturer?Yes/No10
1.2 Do other supplier(s) manufacture the material (e.g., not sole-source)?Yes/No10
1.3 Is GMP readiness of the supplier for this product givenYes/No10
1.4 Is the supplier/manufacturing site located in a low-risk geopolitical region?Yes/No10
1.5 Is there a low chance that the supplier may face capacity issues?Yes/No10
1.6 Has the supplier been reliable and have there never been major supply issues (e.g., OTIF, complaint rate) in the past?Yes/No10
1.7Is the risk of IP restrictions low?Yes/No10


Table 2. Further assessment questions.

QuestionAnswer optionsWeighting
2.1Does the supplier adhere to certified or regulated quality system standards (e.g., ISO, IPEC, GMP, etc.)?Yes/No/Unknown5
2.2Is the supplier qualified at your company?Yes/No/Unknown10
2.3What is the insolvency risk for the supplier?Low/ Medium/High/Unknown10
2.4How large is the company in terms of sales volume (in USD)?

<5 million/year

<50 million/year

<500 million/year

>500 million/year

Unknown


5
2.5How long is the estimated lead time?

<1 month

1–6 months

>6 months

Unknown


10
2.6What shelf life does the material have?

Number of years

Unknown

10
2.7Is the supplier established or new in the market?Established/New/Unknown10
2.8Is your company considered as an important customer?Yes/No/Unknown5
2.9Is the RM custom manufactured on behalf of your company?Yes/No/Unknown5
2.10Is the full supply chain visible?Yes/No/Unknown5


In the final step, one or several of the following recommendations for mitigation may be given based on the 17 answers provided throughout the assessment 
(Table 3):

  • Improve supplier relationship, increase governance, or establish a contract with the supplier
  • Qualify second source
  • Hold increased safety stock
  • Build up in-house production capabilities

We identified these four mitigation options as the most common to reduce supply risk in our organization, but variations or other options may exist.


Table 3. Recommended mitigation options based on answers obtained from the questionnaire.
Recommended mitigation option for further evaluation
Driver/corresponding question
Improve supplier relationship, increase governance or establish contract with supplier

ONE of the following applies:

Material cannot be replaced per risk assessment (1.1)

GMP readiness is not given (1.3)

High risk of capacity issues (1.5)

Supplier/manufacturer has been unreliable in the past (1.6)

High risk of IP restrictions (1.7)

Insolvency risk is high (2.3)

Supplier/manufacturer is small company (2.4)

Your company is not an important customer (2.8)

Qualify second source

The following applies:

Second source is available (1.2)

Hold increased safety stock

The following applies

Long lead times (2.5)

Long shelf life (2.6)

Build up inhouse production capabilities

The following applies:

No second source available (1.2)

Supplier/manufacturer is small company (2.4)

Low risk of IP restrictions (1.7)

Conclusion

In this article, we present an easy-to-use tool, which uses a questionnaire format to calculate supply risk scores for raw materials used in cell and gene therapy manufacturing. The tool also suggests risk mitigation options for high supply risk materials. Using this tool, we evaluated all raw materials used in various programs across our cell and gene therapy platform and thus identified a supplier risk for 30–50% of materials. It is important to highlight that both risk evaluation and recommendations for mitigation rely on a simplified model and the outcome may require further evaluation. Teams can, however, prioritize and focus on raw materials ranked as high risk. The risk score can also serve as a key performance index to measure and track supply security defined by mitigation measures. Learnings from one program can subsequently be applied to other drug candidates, reducing risk from early development. Given that challenges often vary for each material along with their mitigation solutions, these options should be further assessed on a case-by-case basis for each specific material.

References

1. Eur-Lex. Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing, Mar 2015. Crossref

2. US FDA. Expedited Programs for Serious Conditions––Drugs and Biologics 2014. Crossref 

3. Parenteral Drug Association. Cell-based therapy control strategy 2019. Crossref 

4. The British Standards Institution. Evaluation of materials of biological origin used in the production of cell-based medicinal products 2015. Crossref 

5. BioPhorum. Perspectives on raw and starting materials risk assessment for cell and gene therapy (CGT) processes, Oct 2020. Crossref 

6. BioPhorum, Raw material risk assessments—a holistic approach to raw materials risk assessments through industry collaboration, Sep 2019. Crossref 

7. Shimoni Y, Srinivasan V, von Gruchalla-Wesierski M. A Risk-Based Approach to Supplier and Raw Materials Management. BioProcess International, 2015; Nov 17. Crossref

Affiliations

Klara Kulenkampff
Bayer AG

Reto Eigenmann
Bayer Consumer Care AG

Daniela Karlstetter
Bayer AG

Claudia Angenendt
Bayer Consumer Care AG

Rene Sielmann
Bayer US, LLC

Scott Probst
Bayer US, LLC

Authorship & Conflict of Interest

Contributions: The named authors takes responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: Kulenkampff K is an employee of Bayer AG, and Probst S is an employee of Bayer US, LLC.

Funding declaration: The authors received no financial support for the research, authorship and/or publication of this article.

Article & Copyright Information

Copyright: Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2023 Kulenkampff K, Eigenmann R, Karlstetter D, Angenendt C, Sielmann R, Probst S. Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited; externally peer reviewed.

Submitted for peer review: Oct 6, 2023; Revised manuscript received: Dec 11, 2023; Publication date: Jan 10, 2024.