By Mujtaba Ali, managing director, OCQ Solutions
Any company with successful Phase 1 study data must ensure sufficient and consistent supply of drug product for possible Phase 2 and Phase 3 trials. For this reason, Phase 1 companies planning to outsource manufacturing of their clinical supply should take some essential steps early in the clinical manufacturing campaign to assure a timely and reliable supply of material throughout their clinical trials. This article identifies seven speed bumps to avoid in selecting and onboarding a CMO for clinical supply.
1. Selecting A CMO Site That Lacks A Strong Quality Focus
Typically, an organization looking to manufacture Phase 1 clinical material focuses on the technical capability of the CMO and may not perform due diligence on the quality aspects of the organization. Although the focus on the technical capability is essential and critical, so is the focus on the quality systems and the quality team.
Selecting a CMO with strength in quality ensures compliance with existing regulations, along with an understanding of quality requirements such as data integrity, change control documentation, document control processes, material controls, and others. Any significant gap in these quality systems could not only slow down any scale-up efforts but could also put the data collected during Phase 1 into question. In one example, data integrity issues at a Phase 1 clinical manufacturer resulted in a significant delay for the sponsor. The Phase 1 clinical manufacturing site was a small organization run by an autocratic leader who was highly focused on meeting stated objectives and profits. Consequently, the organizational issues included: a) a lack of resources to execute the work, which enabled a culture of taking shortcuts, i.e., documenting work that was either not completed or not done correctly; and b) a focus on financial goals, which resulted in purchasing raw material from substandard suppliers.
Issues such as these resulted in the sponsor having to collect additional data and/or confirm the integrity of collected data to ensure it was defensible before moving on to Phase 2.
2. Selecting An Offshore CMO
It is true that the cost of manufacturing in parts of Asia, Eastern Europe, and other regions may be lower than in the U.S., but with that comes risks and expenses that need to be considered. Some of these include:
- Cost of providing effective CMO oversight. Typically, the sponsor organization, at least in the initial stages, is heavily involved in the technology transfer and scale-up phases. For these, the cost of travel, lodging, and other necessary expenses can become a significant burden if the project runs into issues.
- Shipment of product through customs could be another issue causing potential delays or even leading to temperature excursions due to lack of oversight by the logistics organization.
- Effective communication and cultural elements are always a significant consideration in dealing with overseas organization. Language and translation can be an issue, as in most cases, the manufacturing documents are in local languages. In many cases, the frontline staff, i.e., operators, technicians, and others are only familiar with local languages, which presents an additional challenge in investigating and understanding issues as they happen and for transferring the process out of the organization if required for scale-up or other reasons. As mentioned above, the alignment on quality systems with an overseas organization is critical.
3. Failing To Perform Necessary Diligence Around A Small CMOs’ Manufacturing Operations And Equipment
When dealing with smaller CMOs, sponsor organizations have to perform due diligence on the various facilities, utilities, equipment, and manufacturing aspects of the company. Some examples include:
- Appropriate flow of material and people: It is optimal to ensure that the flow of material and people allows for no cross-contamination. In an ideal flow, the facility design would be based on a single one-way flow. As an alternative, some companies have successfully created specific areas with two-way flows. In such cases, the sponsor should ensure that the CMO site has the appropriate quality system procedural controls in place.
- Lack of redundancy of critical equipment: A CMO typically has single units of manufacturing equipment and, at times, a minimum supply of spare parts. In such cases, the sponsor has to ensure that appropriate preventive maintenance procedures are in place to guarantee the continued functionality of equipment.
- Other potential issues with equipment include facility fit issues, where the CMO facility does not have the capacity but adapts its manufacturing equipment to meet the sponsor’s needs. In one such example, a filling machine was fitted with change parts to allow for filling bottles that were not specified by the filling machine manufacturer. Consequently, the filling reject rate for the product was consistently high.
- Lack of up-to-date validations: During audits of CMOs, I have found multiple CMO sites with outdated validations. In many cases, such sites do not have a periodic review or a revalidation plan in place to provide confirmation that the facility and equipment are operating within validated states.
4. Neglecting To Ensure A CMO Uses GMP-Qualified Material And Components
Another speed bump to watch out for at the Phase 1 level is the selection of raw material such as API, excipients, and others. Earlier in the development cycle, Phase 1-focused organizations do not focus on the GMP required material qualification aspects or, in some cases, they utilize material that is not GMP qualifiable, as the manufacturer does not manufacture the material under GMP conditions. Since the quantity of material being purchased for Phase 1 product is typically minimal, it does not justify the raw material manufacturer qualifying the material to meet GMP requirements. Procuring material from a non-GMP material manufacturer can become a hindrance in scale-up and can have a significant schedule impact as material may have to be resourced from another supplier or be qualified as GMP material.
Another similar issue could arise from the lead times for order to delivery of some components such as containers/closures. Sponsors should know which excipients and containers/closures will require long lead times and schedule their clinical dosing schedule appropriately. Another approach may be for the sponsor to take on the responsibility of qualifying the material and supplying to it the CMO. This is particularly effective if the sponsor needs multiple CMOS and/or for scale-up as the product development progresses. Sponsors would have a supplier and material qualification program in line with GMP requirements.
5. Selecting A CMO That Lacks Robust Manufacturing Controls
Another potential speed bump is a lack of robustness in manufacturing control. I have audited sites where a CMO did not have adequate controls for multiproduct manufacturing, had ineffective manufacturing scheduling, experienced delays in testing of material, allowed forward processing of material without sponsor agreement or alignment, and other similar issues. Several of these examples indicated a lack of CMO oversight by the sponsor’s organization.
Inherent in the CMO business is the exposure to multiproduct manufacturing. Although some CMOs may utilize single-use disposable materials, many do use multiproduct equipment. Such equipment/areas require assurances that any previously manufactured material is removed. Other multiproduct manufacturing controls include QA controls, line clearances, people and material flows, cleaning verification/validation sampling, risk assessment of multiproduct exposure, and others.
CMO scheduling issues can be significant. Delays are typically caused by lack of planning, time needed to procure raw material, and balancing the needs of multiple clients. For example, at one CMO, the sponsor’s product manufacturing was delayed for almost three months due to unavailability of the manufacturing suite at the CMO site.
6. Failing To Implement Sufficient CMO Oversight Controls
Oversight of the CMO during the early-phase manufacturing is essential to ensure effective transfer of the development efforts from the sponsors. This includes direct oversight by the sponsor’s CMO management staff and stationing a person in plant (PIP) at the CMO site.
I recommend a strong quality group presence from the sponsor’s organization on-site at the CMO. A PIP can fully engage with the CMO as manufacturing and quality issues develop. The PIP can also interface with the sponsor’s organization PM to expedite any document approvals, deviation approvals, release of material, or other items. During technical transfer, a PIP can also provide training to the CMO frontline staff.
7. Failing To Put Robust Master And/Or Quality Agreements In Place
Some organizations consider the quality agreement as a low priority and consider a master service agreement as an essential document that can manage the CMO relationship. Although it is true that an MSA is a crucial document, an MSA does not entail quality issues that are essential for the timely availability of the clinical supply. Examples of these include:
- Document and records review: An agreement on time to review documents, both at the CMO and the sponsor organization is essential. In many cases, post-manufacturing records review can take 45 to 90 days, which would include closure of deviations, review of QC testing records, review of batch records, and others. Having this alignment completed can allow the sponsor to develop a clinical supply schedule.
- Alignment on when the sponsor’s approval would be required for forward processing. An example of this is before any reprocessing or reworking, the sponsor’s QA group should review and provide written authorization. Another example would be forward processing drug substance into drug product before completing full testing.
- An understanding regarding sharing of information between the CMO and sponsor. In most cases, both the CMO and sponsor are open to sharing technical knowledge but are not forthcoming regarding quality and/or regulatory information. Examples of information that a CMO may consider company confidential are recent inspection findings, internal audit findings, and common systems issues such as facility deviations. In all cases, the item listed is critical to a sponsor’s manufacturing effort, even though the information may not directly impact the sponsor’s manufacturing campaign.
A typical clinical trial sponsor organization focuses on the technical capability of a CMO during the selection process. Although that is important, to ensure a reliable long-term clinical material supply, the sponsor should focus on the compliance/quality infrastructure and capabilities of the CMO. Throughout this article, we reviewed several potential roadblocks that sponsors can focus on as part of the CMO selection process, along with having a robust CMO management process including an effective quality agreement. Sponsor organizations that make the investment in up-front due diligence of the CMO will benefit significantly from the effort by assuring a timely and reliable supply of material throughout their clinical trials.
What are some of your blind spot risks for potential supply chain disruption? Please share them in the Comments section below.
About The Author:
Mujtaba Ali is the managing director of OCQ Solutions, a consulting organization based in Southern California. Over the last 30 years, Ali has held director and VP positions leading technical operations, validation, and quality organizations in biotech, pharma, and cell therapy companies for investigational and commercial products. His expertise includes operational, compliance, and quality best practices in building a quality culture, phase-appropriate quality systems, health authority inspections, program and project management, operational quality oversight, supplier quality oversight, technical transfer, operations implementation, and optimizing and enhancing existing business practices. You can contact Ali at OCQSolutions@gmail.com or Genentech.Mujtaba.Ali@gmail.com, or connect with him on LinkedIn.