Key Considerations For Early-Stage CGT Companies When Selecting A CDMO

By Steve Kornher, Halloran Consulting Group, a PLG company

For preclinical or early-stage biopharma companies developing cell or gene therapies, selecting the right CDMO is critical to ensure future success. The ability to make the right choice in manufacturing partner hinges upon the ability to properly assess and evaluate the trade-offs each candidate manufacturer presents. Typically, early-stage biopharma companies are faced with two categories of CDMO to choose from: large contractors that serve all phases of clinical development as well as licensed products and small contractors that focus on early-stage clinical development clients.

Large, established CDMOs will typically have an infrastructure designed to support good manufacturing practice (GMP) manufacturing and testing of Phase 3 and licensed products. This imposes significantly more quality assurance (QA) oversight and regulatory requirements on all aspects of manufacturing and quality control (QC) testing than are required for preclinical or Phase 1 drug candidates. If the large CDMO’s quality system does not allow flexibility for early-stage development programs, this can be problematic for an early-stage biopharma company. When the development phase of the sponsor’s project and the CDMO quality processes aren’t aligned, this can add significant cost and timeline delays to a clinical program whose fate may determine the success or failure of the sponsor organization. The advantages to hiring a large, well-established CDMO include an extensive regulatory and client audit history, regulator familiarity with the CDMO manufacturing facility through IND submissions and BLA filings, volume purchasing power that may reduce raw material and consumable costs, and so on. An early-stage biopharma should carefully assess the pros and cons of working with a large, established CDMO.

Small CDMOs may have more flexible manufacturing schedules than their larger counterparts, but they may lack a mature operations infrastructure that can make GMP compliance challenging. Functions such as materials management, supply chain, metrology, etc., may not be sufficiently developed to adequately support GMP manufacturing. They may lack personnel with the requisite manufacturing experience or QC testing experience. Their quality management system (QMS) may be under construction. In short, working with small CDMOs requires extensive oversight of their efforts to manufacture, test, and release an early-stage biopharma product. Significant deviations to batch record execution may be more likely to arise with a small CDMO due to their developing quality systems and evolving operations infrastructure, which could consume a considerable amount of time and effort to investigate and resolve. Investigations into manufacturing or operations failures can take significant time to resolve and result in potentially expensive and time-consuming corrective actions. The impact of such investigations and their resolution on a client’s timeline and budget can be significant. The advantages of working with a small CDMO are, in addition to a more flexible manufacturing schedule, the opportunity to work very closely with their subject matter experts to resolve technical issues in manufacturing and testing as well as reduced manufacturing and testing costs. An early-stage biopharma should carefully assess the pros and cons of working with a small CDMO.

Selection of the wrong CDMO can result in an early-stage biopharma eventually having to replace that CDMO. If that effort is undertaken after launching a clinical trial, the challenges become significant and costly. More specifically, the following steps must be taken:

• Transfer the manufacturing process and, possibly, the QC tests from the previous CDMO to the new CDMO.
• Demonstrate the products produced by the two CDMOs meet all acceptance criteria for comparability as defined in a comparability protocol.

Process transfer and the required comparability assessment can take a year or more to execute and require a significant financial outlay. If the switch to a new CDMO can be executed prior to launching a Phase 1 clinical trial, a comparability assessment of clinical material will not be required.

Selection of the right CDMO represents a long-term commitment that will require significant investment by the early-stage biopharma in terms of their time, resources, and money. Making the correct CDMO selection at the outset is critical to a sponsor’s long-term prospects for success.

In this article, we will explore CDMO selection for early-stage biopharma, including criteria to consider during the CDMO selection process. Criteria for CDMO selection should include, but not be limited to, the following.

Quality Assurance Group

During the CDMO vetting process, candidate CDMOs should be asked to specifically describe how they manage the quality requirements for early-phase verses later-phase development programs. CDMOs will often state their QA approach is friendly to early-stage biotechs. However, if the CDMO supports Phase 3 or licensed products, their QA systems will reflect the level of stringent oversight required of late-stage or licensed products. It is very difficult to manage a two-tiered QA system that can service all stages of clinical development. A CDMO will typically require clients to meet the QA standards currently enforced in their facility for their most clinically advanced client programs.

Raw Materials Control Program

Ensuring control of the raw materials to be used in the manufacturing process is critical to successful manufacturing. The CDMO’s QA organization should closely monitor the quality of the raw materials coming into the manufacturing facility. Animal-derived raw materials pose immediate QA concerns due to the possibility they could introduce adventitious agents (virus, fungi, bacteria, prions) into the manufacturing process.

For Phase 1 products, acceptance of raw materials based on a review of each certificate of analysis (CoA) and certification that the raw material is transmissible spongiform encephalopathy (TSE)/bovine spongiform encephalopathy (BSE)-free and was not manufactured using animal-derived materials is acceptable. When animal-derived raw materials are used (e.g., monoclonal antibodies for cell type immunoselection), the supplier must certify these materials are suitable for GMP manufacture, including certification that they are TSE/BSE free. Potential pitfalls to selecting animal-derived raw materials will be discussed later in this article.

Compendial grade raw materials are ideal for GMP manufacture as they have met testing standards established in the United States Pharmacopoeia (USP). If GMP drug product is supplied to clinical sites outside the U.S., the relevant pharmacopoeia for raw material testing standards should be consulted. However, compendial monographs are not available for many raw materials. Always use the highest quality raw materials available for GMP manufacturing. Pharmaceutical grade raw materials are preferred over research grade raw materials. Pharmaceutical grade raw materials will typically be manufactured to higher purity and be subjected to a more thorough battery of QC tests to confirm appearance, identity, potency, purity, and stability than the corresponding research grade raw material; their CoA also will contain a statement that the material is suitable for use in GMP manufacturing, which will not appear on the CoA of a research grade raw material. If a research grade raw material is intended for use in the manufacture of clinical drug product for which there is an available compendial grade or pharmaceutical grade alternative, the justification for this choice should be discussed with the FDA prior to IND submission.

As the program enters Phase 2, identity testing of each lot of raw materials should be conducted for every raw material used in the manufacturing process. As the program approaches Phase 3, full CoA testing of three lots of each raw material will be required to qualify the supplier of each raw material used in the manufacturing process, including backup suppliers. This qualification should be completed by the time of BLA filing, though some supplier qualification work may be included in a post-licensure commitment from the sponsor. Specific raw materials may have to be tested prior to Phase 3 for their suitability in the manufacturing process.

Plasticware brought into contact with the product during manufacture should meet requirements for Pharmaceutical Grade Polymeric Materials (also known as Class VI plastics) as described in USP<88> or meet ISO 10993 requirements for medical devices. Plasticware brought into product contact for extended periods (e.g., drug substance storage containers and drug product container/closures) should also be evaluated for extractables as described in USP<661> and <665>. The CDMO should confirm that the plasticware manufacturer has tested the plastic used to make their product for Class VI plastics compliance and recoverable extractables.

The level of detail described in the CDMO’s raw materials specification (RMS) for each raw material and plasticware item will provide valuable insights into the level of scrutiny QA applies to incoming raw materials and consumables.

Supply Chain

The CDMO’s QA group should qualify all suppliers of raw materials and plasticware that will be used in the manufacturing process. If the sponsor requires a particular supplier of a raw material or plasticware item that has not been qualified by the CDMO’s QA group, expect that qualification effort to take two to three months, even if only a paper qualification is required. 

If the CDMO uses an intermediary to receive and store these materials before they are delivered to the manufacturing facility, understand the costs associated with that arrangement. Verify the intermediary properly stores the materials, as described in the Materials Management section in this article.

A supplier may sell research use only (RUO) grade for a particular raw material as well as a version suitable for GMP manufacturing. The CDMO’s supply chain management must be aware of this distinction so they do not accidentally order the RUO grade of that material. They must also be aware of supply chain bottlenecks that can derail clinical timelines and prepare contingency plans to ensure the manufacturing schedule is not comprised or delayed.

Consider how far away the CDMO is located. CDMOs located in Asia, for example, can pose a significant challenge for time-sensitive starting materials like leukopaks. Not only will shipment of these materials be very expensive, but their age upon arrival at the CDMO may be suboptimal for the manufacturing process. Verify that the CDMO requires temperature monitoring of labile raw materials during shipment from the supplier to their facility. CDMOs located outside the United States should also be assessed in the context of the current geopolitical climate.

Materials Management

Improper storage of raw materials by the CDMO can lead to reduced shelf life of critical and expensive materials. Confirm that materials requiring refrigeration or freezing for proper storage are kept in temperature control units (TCUs) that are fully qualified, including a temperature mapping of the storage chamber. All TCUs should be continuously monitored for temperature by a validated Part 11 compliant system that will go into alarm when temperature limits are breached for a defined time interval. Confirm light sensitive materials are shielded from warehouse lighting while in storage.

Animal-Derived Raw Materials

If the U.S. FDA has safety concerns with the use of a particular raw material in the manufacture of clinical drug product, it can and has imposed a clinical hold on an IND application until the issue is addressed to their satisfaction. To lift the clinical hold, the sponsor may have to perform more thorough and expensive testing for the presence of adventitious agents in the raw material. Alternatively, replacement of that raw material with one suitable for GMP manufacturing may be required. Verification will be required to show use of this new raw material does not adversely impact the manufacturing process or impact sponsor comparability claims between drug product manufactured for preclinical safety studies and drug product manufactured for clinical use.

Starting Materials

CDMOs manufacturing certain starting materials for use in the production of clinical trial material (e.g., plasmids) may offer a RUO grade of the starting material and a GMP grade. RUO plasmid starting material is suitable for Phase 1. However, a grade suitable for GMP manufacture should be introduced before manufacturing Phase 2 clinical trial material. For plasmids, this will require manufacture and testing of GMP master and working cell banks from which the plasmid will be manufactured. For starting material such as feeder cells, controls should be in place to limit the use of animal-derived raw materials in the production of the feeder cell banks. These banks should be characterized for identity, karyology, viral contaminants, arrested cell division upon irradiation (if irradiation of the bank is required), potency, sterility, and mycoplasma. Additional safety testing may be needed, depending on the source of the feeder cells. The sponsor also will be expected to demonstrate clearance of the feeder cells by the manufacturing process.

Quality Control Testing

Lot release and in-process testing will typically be carried out by the contract manufacturer’s QC group. Specific tests (e.g., potency tests) may be executed by a contract testing organization (CTO). The subject of QC testing will be explored in more detail in a separate article. Noteworthy points to consider:

• If the contract manufacturer subcontracts any of the QC tests to a CTO, ensure the CDMO’s QA group has formally qualified that CTO and is actively overseeing performance of the contracted tests.
  • CDMOs may not have adequate oversight of subcontracted tests. Test deviations and investigations may remain the sole responsibility of the subcontractor’s QA group, which can complicate timely resolution of testing issues and result in delaying release of drug product.
• Evaluate the CDMO QC group’s technical capabilities:
  • Does it have experience with specific techniques relevant to the needs of the development program (e.g., cell-based assay development and/or performance)?
  • Does it possess instruments and equipment that utilize current technology and are monitored by established calibration and qualification schedules? All critical lot release instruments should have undergone installation and operation qualification (IQ/OQ) to ensure proper performance of the associated QC test.
  • All lot release and stability tests should utilize qualified positive and negative controls whenever possible. Every test should have system suitability requirements to establish that the assay is working properly. System suitability requirements must be satisfied before test samples undergo testing with the assay in question.
  • The CDMO should demonstrate adherence to GMP compliant QC practices, including the use of QA approved SOPs and documented training of all QC analysts.

While the sponsor is responsible for ensuring assays are properly developed and qualified for the specific sample matrix to be tested, the CDMO QC group should be experienced in qualifying and validating the types of assays required for lot release.

Conclusion

Investing the time and energy into proper CDMO selection is critical for early-stage biopharma companies. It can mean the difference between success and failure for a product development program. A solid working relationship with a properly vetted CDMO is critical to a sponsor’s regulatory submission and clinical program timelines.

About The Author:

Steve Kornher has been with the Halloran Consulting Group for three years as a senior consultant, Regulatory CMC. Prior to joining Halloran, he was the executive director of quality systems at Vertex Cell and Gene Therapy. Kornher has over 35 years’ experience in biotechnology, primarily in quality control, quality assurance, and CMC regulatory affairs with an emphasis on cell and gene therapies.