The Criticality of CMO Selection for Small Biopharma Companies

For pre-clinical or early-stage biopharma companies, selecting the right Contract Manufacturing Organization (CMO) is critical to ensure future success. The ability to make the right choice in partner hinges upon their ability to properly assess and evaluate the trade-offs each candidate manufacturer presents.

Large, established CMOs will typically have an infrastructure designed to support Good Manufacturing Practices (GMP) of phase 3 or 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 pre-clinical or phase 1 drug candidates. When the development phase of the sponsor’s project and the CMO quality processes aren’t aligned, this adds significant cost and timeline delays to a clinical program whose fate may determine the success or failure of the sponsor organization.

Small CMOs may not have a mature infrastructure with particular QA processes, materials management, supply chain, metrology, and more, to adequately support GMP manufacturing. They may also lack personnel with the requisite manufacturing experience.

A wrong CMO selection can result in a small biopharma having to replace a CMO. If that effort is undertaken after launching a clinical trial, then the challenges become significant and costly. More specifically, the following will need to be done:

• Transfer of the manufacturing process and, possibly, the QC tests from the previous CMO to the new CMO
• Demonstrate to the FDA’s satisfaction the products produced by the two CMOs are comparable

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 CMO can be executed prior to launching a phase 1 clinical trial, then a comparability assessment of clinical material will not be required. However, the FDA will expect the sponsor to demonstrate comparability of product used for critical pre-clinical safety studies with product obtained from the GMP manufacturing process.

But the right selection of a CMO represents a long-term commitment that will require a significant investment from a small biopharma with their time, resources, and money. Making the correct CMO selection at the outset is critical to a sponsor’s long-term prospects.

In this article, we will explore CMO Selection for small or early-stage biopharma criteria to consider during your CMO selection process, and key watch outs to observe.

Criteria for CMO selection should include, but not be limited to the following:

Quality Assurance Group:

During the CMO vetting and selection process, ask the question ‘Does the CMO oversee clients with phase 3 or a licensed product?’ CMOs will often state their QA approach is friendly to early stage biotechs. However, if the CMO supports phase 3 or licensed products, then 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 which can service all stages of clinical development. A CMO 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:

Control of the raw materials to be used in the manufacturing process is critical to successful manufacturing. The CMO’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 on Certificate of Analysis (CoA) and certifications that the raw material was not manufactured using animal-derived materials is acceptable. When animal-derived raw materials are used (e.g., monoclonal antibodies for cell type immunoselection), then the supplier must certify these materials are suitable for GMP manufacture.

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). However, compendial chapters 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 will also 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 used to manufacture clinical drug product for which there is an available compendial grade or pharmaceutical grade alternative, then be prepared to justify the selection to the FDA.

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 back-up suppliers. Plan to complete this qualification by the time of BLA filing. 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>. Typically, the manufacturer of the plasticware will have tested the plastic used to make their product for Class VI plastics compliance and will have tested their product for recoverable extractables.

The level of detail described in the CMO’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.

Supply Chain:

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

If the CMO 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.  Supply chain must be made aware of the discrepancy so that they do not accidentally order the RUO grade of that material. The CMO’s supply chain group must also be made aware of supply chain bottlenecks that can derail a small biotech’s development and prepare contingency plans to ensure the manufacturing schedule is not comprised or delayed.

Consider how far away the CMO is located. CMOs 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 CMO may be sub-optimal for manufacturing processes. Verify the CMO requires temperature monitoring of labile raw materials during shipment from the supplier to their facility.

Materials Management:

Improper storage of raw materials by the CMO can lead to reduced shelf life of critical and expensive materials. Confirm materials requiring refrigeration or freezing for proper storage are kept in temperature control units (TCUs) that have been fully qualified, including a temperature mapping of the storage chamber. All TCUs should be continuously monitored at all times for temperature by a validated 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. Food and Drug Administration (FDA) has safety concerns with the use of a particular raw material in the manufacture of clinical drug product, they can and have imposed a clinical hold on an Investigational New Drug (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 pre-clinical safety studies and drug product manufactured for clinical use.

Starting Materials:

CMOs manufacturing certain starting materials for GMP manufacture (e.g., plasmids) will offer research use only RUO-grade and a grade suitable for GMP manufacture. For example, RUO plasmid starting material is suitable for phase 1. However, prepare to switch to a grade suitable for GMP manufacture before the start of phase 2. For plasmids, this will require preparation of GMP master and working cell banks from which the plasmid will be manufactured. In this example, if the starting material is a feeder cell bank, ensure controls for the use of animal-derived raw materials are in place and the bank is well characterized for identity, karyology, viral contaminants, arrested cell division upon irradiation, potency, sterility, mycoplasma. The sponsor will also 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 a combination of the contract manufacturer’s QC group and 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 contracts out any of the QC tests, ensure the CMO’s QA group has formally qualified the CTO and is actively overseeing performance of the contracted tests
  • CMOs typically do not have control over contract tests. Test deviations and investigations often remain the purview of the testing lab’s QA group which can complicate timely resolution of testing issues and result in delaying lot release
• Evaluate the CMO QC group’s technical capabilities:
  • Experience with specific techniques
  • Possession of instruments and equipment that are not outdated and have been placed on calibration and qualification schedules
  • Adherence to GMP compliant QC practices including the use of QA approved Standard Operating Procedures (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 QC group should be experienced in qualifying and validating the types of assays required for lot release.

Conclusion

CMO Selection for small or early-stage biopharma and working through the optimal terms of the partnership is critical to the timely completion of a high-quality study and preventing costs due to a poor match. As we all know, timing is critical to clinical success. But a vetted selection process paired with a realistic set of selection criteria is essential when choosing the right CMO partner.

The next article installment on CMO (and Contract Development Considerations (CDMO)) considerations will be focused on Quality Control issues and navigating manufacturing space for lease. Keep a pulse on our insights.

Halloran’s Regulatory Chemistry Manufacturing and Controls (CMC) team are experts in product types ranging from small molecules to cell and gene therapies. Halloran works with clients to develop drug substance and drug product strategies fit for their stage of development, including CMO selections. Please contact our team today.