Submitted by BioPhorum
Cell banks represent the fundamental starting substrates for biological Drug Substance/Drug Substance intermediate (DS/DSi) manufacturing. Therefore, the availability of well-characterized cell banks capable of supporting manufacturing processes is imperative to ensure uninterrupted drug product supply to patients and global markets. To this end, a two-tier cell banking system is developed, consisting of a Master Cell bank (MCB) and a Working Cell Bank (WCB).
Typically, WCBs are derived from the MCB to preserve the long-term integrity of the MCB. Although WCB inventories (e.g., vials, ampoules and bags) are generally developed in plentiful supply, over time, it is necessary to replenish WCB inventories to meet product demand. However, recent experience shows regulatory requirements for introducing replenishment WCBs in many countries are highly variable. This results in inconsistent expectations among different Health Authorities (HAs).
This is why BioPhorum has published A risk-based scientific approach to qualify replenishment working cell banks, an industry view (https://bit.ly/3S2t6he).
This paper examines the various scenarios under which replenishment WCBs are manufactured, including when they are replenished and introduced according to the initially registered process (‘like[1]for-like’ replenishment) and highlights several changes to cell bank manufacturing and materials that can occur when WCBs are replenished. The paper assesses the likely impact on product quality from these variations and proposes an appropriate qualification and regulatory filing strategy in each case.
Cell Banks as Critical Starting Material
Over the past 40 years, many biologic products have been developed to treat and prevent a wide range of disease states, with more than 300 biologics now marketed worldwide.
In the early 1980s, bacterial strains were predominantly used to produce recombinant proteins. In 1982, Eli Lilly’s E. coli-derived recombinant insulin was approved for human use by regulatory agencies in the US, the UK, the Netherlands and West Germany. Microbial strains are still commonly used in the production of vaccines. During the late 1980s, mammalian cell lines (e.g., Chinese hamster ovary (CHO)) came into use to generate recombinant mAbs, mAb-like proteins and some peptides. In 1986, Genentech’s tissue plasminogen activator (t-PA), Alteplase, became the first US FDA-approved recombinant biopharmaceutical produced in a CHO cell line. Now, almost 40 years after the approval of Alteplase, the CHO cell line has been established as a workhorse producing many marketed biologics.
Cell lines, referred to as cell substrates, used to manufacture biologics can be of mammalian, yeast, insect, or bacterial origin and are derived using recombinant DNA technology or, in the case of some vaccines and proteins, the propagation of native microbial strains.
To provide a consistent cell source to initiate the manufacturing process, cell banks must be established and maintained in accordance with strict quality, manufacturing and regulatory standards. As such, the cell bank represents a critical starting material for the manufacturing of biotechnological DS/DSi and drug product, and ensures a consistent cell source is available for the product lifetime. Therefore, the two-tiered cell banking system is the best approach for the continued manufacture of a product.
Regulatory Guidance for Registration of Cell Banks
Overarching regulatory guidance for cell banks is described in ICH Q5D: “This document provides guidance on standards for the derivation of human and animal cell lines and microbial cells to be used in biotechnological/biological products”.
It outlines recommendations for the preparation and characterization of cell banks to be used for production. In addition, the guidance describes requirements for the preparation of the cell substrate and any parental cell line that contributes to the manufacture of the cell substrate. For mammalian cell substrates, this includes a description of the cultivation history and methods used to originally isolate and/or genetically modify the cell substrate, as well as all available information regarding testing for endogenous and adventitious agents. For microbial cell substrates, the species, strain and known genotypic and phenotypic characteristics are also described.
Regulatory Considerations When Replenishing a WCB
Whether WCBs are replenished using a like-for-like (no changes) approach or whether changes need to be implemented to the cell banking process, the path to the global approval of these replenishment WCBs is not clearly defined. It may depend on the regulatory strategy the manufacturer pursues at the time of the initial Marketing Authorization Application (MAA).
Generally, any proposed changes (classified as minor, moderate, or major) impact the filing strategy employed in major markets, including the US and the EU. However, neither the US nor EU regulatory guidance provide specific details for data requirements that apply when companies need to manufacture a replenishment WCB.
For example, in the US and the EU, the introduction of a replenishment WCB would be classified as a change requiring a regulatory action before implementation (Prior Approval Supplement (PAS) in the US; Type IB/Type II variation in the EU). Following the guidance of ICH Q12, another option is to submit a post-approval change management protocol. This protocol can be submitted in either the initial MAA or during the lifecycle after the marketing authorization approval (i.e., post-approval).
Whether the choice is to submit a protocol in the initial MAA or PAS/ variation, it is each company’s responsibility to propose the data package to support the introduction of a replenishment WCB. This may be further negotiated with the HA/agency before or during the review process. There is a wide variety of approaches that a company could propose, including cell line testing combined with small-scale studies and/or commercial-scale DS/DSi production or product quality assessment.
This paper proposes qualification approaches consistent with a risk based approach when making replenishment WCBs. It recommends that cell bank growth and viability assessments, and small-scale product quality assessments if warranted, using appropriate small[1]scale models are sufficient in most cases.
Problem Statement – Experience with HAs/Agencies
Historically, approved data packages to implement replenishment WCBs contained culture performance data measuring KPIs (e.g., viability and growth) as well as genetic characterization to demonstrate genetic stability, mostly performed on small-scale studies. WCB testing for sterility, adventitious agents (safety) and identity have also been conducted.
Our experience is that HAs have begun requiring at least one, and in some cases multiple, commercial-scale lots of DS/DSi to support the comparability of replenishment WCBs in terms of product quality and cell bank growth kinetics. This comparability exercise often includes release testing, extended characterization testing and stability studies. These are the same requirements needed to support the post-approval addition of a new DS/DSi manufacturing process or even a new DS/DSi manufacturing site. However, to collect all this information is resource intensive and of limited value when the cell line has a high probability of clonality, and when the manufacturing process for creating the new WCB follows well-established processes as defined by each company.
Feedback from HAs has been variable and inconsistent, both within the same HA as well as between HAs. Consistent regulatory guidance, and global alignment on regulatory requirements for manufacturing replenishment WCBs for marketed products, would streamline the post-approval process and help prevent delays that can lead to drug shortages and regional supply-chain constraints.
Solution – Proposed Technical Approaches to Qualifying Replenishment WCBs Using a Risk Based Analysis
We have developed a set of classed scenarios to qualify replenishment WCBs, based on the potential risk to cell bank growth, viability performance, and product quality. Taking a quality risk management approach, and given the lack of technical drivers and the possible risk to continuity of product supply, we make the following recommendations:
- When no changes are made to the cell banking process, equipment, or facility location, a Class 1 approach is suggested. This recommends the replenishment WCB can be implemented with minor regulatory actions if it meets the originally filed specifications.
- When analytical methods are changed, a Class 1a approach is suggested. This recommends a risk assessment to evaluate if methods are equivalent and if the replenishment WCB can be implemented with minor regulatory actions if it meets the originally filed specifications.
- When minor changes to the process, equipment, or facility location are made, a Class 2 approach is suggested. This recommends an appropriate change control and risk assessment process. Formal studies assessing cell bank viability upon thaw and/or growth rate data should be executed, and data evaluated against defined cell bank acceptance criteria. The replenishment WCB can be implemented with minor regulatory actions if it meets the originally filed specifications.
- When raw material changes are introduced, a Class 3 approach is suggested. This recommends an appropriate change control and risk assessment process using a representative small-scale model. The replenishment WCB can be implemented with minor regulatory actions if it meets the originally filed specifications.
- When the ‘limit of in vitro cell age’ is impacted or MCB clonality is in question, a Class 4 approach is suggested. This recommends an appropriate change control and risk assessment process and commercial-scale process, and product quality confirmation. In addition to commercial-scale confirmation, these changes require major regulatory actions and HA approvals.
Conclusion
There are few circumstances where replenishing a WCB is likely to impact the phenotype of the WCB or the quality of the DS/DSi. Even when changes are necessary to the cell banking process, cell bank materials, or location of cell bank manufacture, the risk of not meeting the criteria for qualification (e.g., KPIs) is low for replenishment WCBs. In addition, potential issues can be identified using risk assessments and, where necessary, representative small-scale data, examining the comparability of the cell bank phenotype and resulting DS/DSi quality, ensuring comparability to the original WCB. In rare cases, commercial scale data might be required.
Furthermore, harmonization or convergence toward a system of risk based categorization of post-approval changes is encouraged as an important step to achieving the objectives of ICH Q12. Such a system provides inherent, valuable flexibility in regulatory approach and a framework that can support the lowering of regulatory submission requirements.
A fully referenced version of this article can be downloaded at A risk based scientific approach to qualify replenishment working cell banks, an industry view (https://bit.ly/3S2t6he).
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