By Janel Firestein and Linda Plumley, Clarkston Consulting
Many cell and gene therapy (CGT) startups are research-focused. As the scientific technology platform is discovered and potential therapies are identified, documents such as the Candidate Target Profile (CTP) and Target Product Profile (TPP) are created to ensure alignment across functional areas. These documents are used to assist the program team in decision-making and are key to the supply chain as a reference to understand what the potential product is and what support is needed. Even with these as a guideline, though, how does the supply chain team stay ahead of the expected changes and respond at the speed the developing program expects?
As the new technology is being developed, the team is learning what works, and it can be hard for the supply chain to keep up. The success of the supply chain depends on the team’s engagement with the candidate/program’s CMC (chemistry, manufacturing, and control) team. The CMC team is a cross-functional team, chartered to deliver content for regulatory submission. Decisions around milestones, formulation changes, and release testing strategy are where the supply chain learns about potential changes and can proactively do scenario planning. As an example, if a media being used is not providing the cell growth needed, the supply chain could contact the supplier to find suggested alternatives.
The supply chain can influence the overall end-to-end process for a successful clinical trial by executing its core competencies and providing expert guidance on:
- Supplier selection
- Raw materials
- Built-in quality
- Warehousing, logistics, and transportation
- Traceability: chain of custody (COC)/chain of identity (COI)
Supply chain leaders need to understand critical elements about their suppliers to ensure that services and materials are meeting standards. Many suppliers will claim they are manufacturing the materials to current good manufacturing practices (cGMP), but each may have their own definition. Some will claim they have certifications, such as ISO 9001 for quality management,1 or that they have been successfully audited by regulatory agencies. Both are important, but understanding the supplier’s quality management system is critical to making an objective determination if the supplier’s concept of cGMP is aligned with the company’s concept of cGMP.
Early in the product life cycle, the stringent good practice (GxP) controls are not required, to allow for innovation and quick changes in product development, but as the company moves from preclinical research to planning for clinical trials, more control is needed. Supplier audits play an important role to ensure the minimum acceptable quality requirements are being met for the manufacturing, processing, and packaging. Often, the supply chain is considered the primary point of reference for material suppliers; thus, the supply chain team brings its expertise to the audit process to spot gaps that may bring “manufactured to cGMP” into question.
A few considerations for selecting suppliers:
- Does the supplier demonstrate control of the material (quarantine to release)?
- Is the testing lab under the oversight of quality assurance (QA)?
- Is there a process to manage unexpected deviations and/or corrective and preventive action (CAPA)?
- Are operators qualified and trained?
- Is there environmental monitoring and cleaning?
- Is equipment calibrated and maintained?
- Does the supplier’s history demonstrate they will be in business for the duration of the product life cycle?
Once suppliers are selected, the focus moves to the materials that will be procured from them.
Raw materials are critical to the success of asset development and repeatability in the manufacturing of the drug product. When the critical quality attributes (CQA) are included in the TPP, the supply chain can move as quickly as the program requires because the framework has been documented.
Control of materials used for early processes can be more flexible and not constrain the creativity the research team needs. RUO (for research use only)-grade materials can be used but with care to ensure any gaps in testing or traceability are known and do not become an issue later in the product life cycle and manufacturing strategy. The supply chain should present all possible grades of materials whenever R&D is considering introducing new material or changing an existing one. The appropriate level of control aligned with the stage of the product life cycle is key, as is ensuring the materials will serve their intended use in manufacturing. It is important to remember that raw materials may include donor material that is used for research or testing purposes; these do not need a COI/COC process, as they are required to be treated just like procured raw materials.
Note: Here, we are not talking about donor material when the subject or patient is considered the raw material and a COI/COC process is required.
Raw material considerations:
- Is it important that animal or human-derived material is not used?
- Are the materials autologous or allogeneic?
- Are donor eligibility and screening important?
- What about purity, strength, or concentration of materials?
The supply chain can support the candidate program by creating a material strategy and considering commercial requirements. When the strategy includes the entire product life cycle, it is destined for long-term success with fewer unexpected costs. Documenting these requirements ensures that there is a clear understanding of what the commercial product design and process look like, but it is important to ensure that controls are aligned with the product’s stage.
Forward-looking companies will create a document as part of their QMS that focuses on introducing new materials. This document explains what level of control is needed for materials from early feasibility to Phase 3 clinical trials and beyond. As an example, supplier audits may not be required until reaching the late Phase 1 clinical trials stage.
The supply chain needs to understand the level of control the QA group is applying to guarantee proper planning and meet target release dates. Controls for a commercial product are much higher than those for early-stage clinical trials. If the higher controls for a commercial product are applied to early clinical products, it can slow down the discovery process, leading to missed program milestones and increasing the overall cost of the project.
The supply chain can support the QA processes by working with the selected suppliers to make sure lot-level performance data reflects how the material will be used in manufacturing. To use an analogy, if you are buying a vehicle for drag racing, the miles per gallon listed are of no value; however, the length of time to accelerate from 0 to 100 MPH is. If this data is not included, how can you determine if you are making the right choice?
For an agile supply chain, the team needs to be current on all aspects of the end-to-end manufacturing to release process. Consider lot/batch testing, for example. Will it be performed in-house or using a contract testing lab (CTL)? Further, the length of time from sample availability from manufacturing until the final testing report submission to QA needs to be known. When global clinical trials are being considered, the material strategy should include global regulations with a testing strategy for the most constrained regulation.
Supply chain team members may ask a lot of questions that do not make sense to those on the CMC team. But, for supply chain to execute one of its core competencies, they need data to plan what material is needed, when the material is needed, and how much. It is important for the CMC team to answer those seemingly endless questions and to notify the supply chain team when something changes.
Although many research-focused companies align the responsibilities of the supplier and material selection to be led by the R&D teams, the supply chain brings a level of expertise to the process that takes into consideration not only the short-term but also the long-term commercial strategy.
For U.S.-focused clinical trials, additional information can be found in these helpful references:
Warehousing, Logistics, And Transportation
The distribution and logistics for cell therapies follow a familiar route: supplier to the manufacturing site to be converted into the drug product and returned for use by the end user. Although the mechanics sound simple, with changes to the fast-paced learning in CGT manufacturing, the supply chain needs to adapt quickly to new requirements. One of these requirements is regarding temperature storage.
Early-phase products may be stored and shipped cold (2 C to minus 8 C). As the product is further characterized, storage moves to ultra-cold (minus 80 C to minus 40 C) and cryogenic (minus 130 C to minus 196 C) storage. The supply chain must have a robust system for ultra-low temperature (ULT) and cryo storage, which mitigate many of the product quality issues that cold storage introduces. Robust in this instance means redundant systems that can accommodate a yet-to-be-defined capacity need. A carefully designed safe and efficient supply chain with critical temperature requirements identified is a crucial success factor. A released product that partially thaws during transportation may result in a product that is not fit for use and may put the subject/patient at risk. It is important to remember that these subjects or patients are sick and have joined clinical trials for potential lifesaving therapies — the concept of flawless execution is not treated lightly.
Select qualified shippers and the most appropriate temperature monitoring devices to objectively support the product quality. With so many unknowns due to fast-developing therapies, the supply chain needs to have several different types of qualified shippers, including different sizes as well as different types of temperature monitoring devices. Some companies are using GPS tracking temperature monitoring devices to provide details needed for the autologous COI/COC data.
A well-prepared supply chain selects a partner that understands CGT and will work together to resolve each new challenge presented.
Traceability, Chain Of Custody/Chain Of Identity
Supply chain experts are familiar with traceability, as they have long been using this process in support of materials management, product recall, and product investigations. However, in a CGT startup, supply chain team members may be new to the terms “autologous” and “allogeneic.” Autologous means the patient is the product, whereas allogeneic means that many donors are the product.
When working with autologous therapies, the concept of traceability translates into COC and COI, which are key quality deliverables. You must guarantee that the donor material from the subject/patient is returned to the correct subject/patient. This is where the COI/COC process comes into play. Every time the donor material is handled by another person, or another manufacturing process occurs, it must be tracked both by who received the material (date and time stamp) and the process step. The COC is the physical movement of the material, and the COI is the new, but linked, identity of the material. It is helpful to consider the standard way of operating that the supply chain team uses: if the fit, form, or function changes, the material gets a new identity (item number and/or batch number).
The COI/COC process can be paper-based, using commercially available software or in-house developed solutions. Regardless of the process used for COI/COC, the lot cannot be released by QA without complete reporting and documentation of the COI and COC. Having the supply chain on the team developing a COI/COC process can prevent an overly complex process or one with critical gaps that could delay the batch release process. The experience the supply chain team has with developing and following a traceability process is invaluable.
Building an agile and flexible supply chain is the best way for a company to be prepared to support the quickly changing therapies and material needs of clinical trials and commercial product delivery to the market.
- International Organization for Standardization. (n.d.). ISO 9000 family Quality management. https://www.iso.org/iso-9001-quality-management.html
About The Authors:
Janel Firestein is a partner with Clarkston Consulting and the leader of the firm’s life sciences practice. In her role as life sciences industry lead, she has been helping senior executives in the pharmaceutical, biotech, contract research and manufacturing, and medical device industries in strategy, operations, and technology. Additionally, Firestein has advised many of the world’s leading cell and gene therapy companies on their operations in preparation for pivotal trials and commercial operations.
Linda Plumley is a director at Clarkston Consulting, bringing experience working with companies that span virtual startups to Big Pharma in the areas of pharmaceuticals, biologics, medical devices, combinations, cell and gene therapy (CGT), oncology, and clinical and commercial products. She has experience with mergers, acquisitions, and divestures. Plumley’s career started in manufacturing and continued in quality control and quality assurance until she found her passion in supply chain, where her focus has been for the past 20 years. Additional experience areas include designing standard ways of working for pre-clinical CGT execution and commercial launch, and ERP readiness.