Manufacturing Materials for Clinical Trials

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The speed at which the industry has been moving vaccines and treatments for the COVID-19 pandemic into trials and commercial production is unprecedented, and contract development and manufacturing organizations (CDMOs) are playing an important role in quickly adding capacity for clinical trial and commercial manufacturing. Lessons learned during the pandemic may also benefit manufacturing for clinical trials in general, as companies implement best practices for speeding up tech transfer processes.

Ron Chantung, associate director of Drug Substance Manufacturing at global CDMO Ajinomoto Bio-Pharma Services (Aji Bio-Pharma), notes, “While there is always a constant influx of drug products to the market, since the start of the pandemic, the speed and the number of vaccines, therapeutics, and candidates that have entered in clinical development has been extraordinary, making CDMOs and their capacity for manufacturing these products in high demand.”

Aji Bio-Pharma entered a manufacturing agreement in May 2020 with CytoDyn, a late-stage biotechnology company developing leronlimab, a monoclonal antibody CCR5 antagonist, for multiple therapeutic indications, including a clinical trial for patients with severe-to-critical COVID-19 indications (1). CDMO Cascade Chemistry is also providing clinical trial materials for COVID-19; in June 2020, Cascade was selected to manufacture the API for clinical trials of an investigational therapy from Renibus Therapeutics, RBT-9 (stannous protoporphyrin), an antiviral with organ-protective attributes that received Fast Track designation from FDA and is being tested in high-risk COVID-19 patients (2). CDMO Purysis says it is supplying companies conducting COVID-19 research, whether by manufacturing repurposed antiviral compounds that do not have readily available good manufacturing practice (GMP) supply chains or by development and manufacturing of novel small molecule therapeutics for investigative new drug applications.

Pharmaceutical Technology spoke with Chantung; Scott Mohler, director of Business Development at Cascade Chemistry; and Joshua Hoerner, Chief Innovation Officer at Purisys, about how CDMOs involved in clinical trial materials’ manufacturing are responding to the current environment and what can be done to speed their clients’ projects.

Current trends

PharmTech: How has the COVID-19 pandemic affected clinical trials materials manufacturing and packaging, and what do you see as key industry trends and challenges?

Hoerner (Purisys): The global pandemic has presented challenges to clinical trials in general, limiting the availability of trial slots and, in some cases, delaying trials for indications other than COVID-19. Securing raw materials for clinical trials, such as those aimed at evaluating therapies for COVID-19, can be especially difficult where the synthetic route is not fully mapped out, particularly for companies operating in the early biotech space where demonstrating proof-of-concept is vital to secure further funding.

Mohler (Cascade): Timing is a major challenge. It seems every year the desired timelines from clients grow shorter while the chemistry gets more complex. Having enough process research and development time to fully understand a process before it reaches the manufacturing space is essential. However, in many cases, synthetic routes have not been fully mapped out, and this means additional work is frequently required. With COVID-19 trials, the time pressure is even greater.

The biggest trend we have seen is an overall lack of capacity in the API industry. We have had to rapidly expand our current GMP space as well as adding a second shift and weekend shifts to continue to meet demand. We doubled our GMP capacity in spring 2020 with new manufacturing space. Our new facility construction will continue through fall 2021 when we will more than double our GMP capacity again as well as quadrupling our maximum batch size.

Chantung (Aji Bio-Pharma): In unparalleled ways, COVID-19 has altered the landscape of how CDMOs provide for clinical trials. After months of seeing disruption to clinical trials from travel restrictions and site closures to interrupted supply chains, we are now starting to see that trend slowly reverse.

One interesting development that we have been keeping an eye on is the supply and demand for cold-chain shipments. With countries imposing travel restrictions due to COVID-19, which may therefore present challenges within shipping lanes, re-assessing validated shipping containers has become a priority to ensure the biologic’s quality attributes maintain stability in transit. CDMOs need to gauge their internal capacity of temperature storage units, form strategic partnerships with logistics companies, and potentially offer validated temperature storage of clinical trial material.

In response to this ever-changing environment, it is more important than ever for CDMOs to ensure they are proactive with how they plan, resource, and execute programs with their customers, rather than reacting to the larger challenges they are facing with supply chain and general product development.

Beyond monitoring stock and working closely with outside suppliers, we have found that providing customers options to select from in stock, preferred components and excipients from GMP-audited and qualified vendors helps reduce variables and speeds up the manufacturing timeline. Additionally, utilizing an existing library of packaging and labeling components and employing existing validated shipping configurations and preferred couriers can help drug sponsors overcome any logistical hurdles to clinical trials.

Technology developments

PharmTech: Can you comment on any technology developments or best practices that are helping to speed up processes?

Chantung (Aji Bio-Pharma): One aspect is the limitations placed on travel and onsite visitors at a CDMO. Organizations are becoming creative in hosting virtual, video audits to maintain the regulatory and quality commitments to agencies and clients, as well as showcase capabilities to prospective business partners. The ability to observe the manufacturing process is something that varies among CDMOs. A virtual and online site visit and audit experience helps ensure customers are meeting their quality obligations for selecting or maintaining a qualified vendor. Through the use of secure document sharing platforms, remote viewing systems, and virtual site tours, clients can be assured they will be able to perform a thorough review of facilities and quality systems and have connections with the subject matter experts and remote access to live action activities to meet their program requirements and quality standards.

For example, we are offering personalized, secure remote viewing platform for clients to monitor their filling process through our secure portal. This provides the sponsor with the ability to monitor the operations in real time and to stay connected to their product even when they cannot be physically present. In addition, procedures are in place to host remote audits via technology platforms that support live, interactive conversation and interviews with subject matter experts, guided walk-through of operational areas, and the ability to securely review documents and data.

Mohler (Cascade): Virtual audits and video teleconferencing have helped maintain communication with clients and their quality teams during the COVID-19 pandemic. The faster things go, the more important frequent communications are. For instance, quality groups need to be in constant communication, while technical teams need to be emailing and calling ad hoc as well as having regular update meetings. To ensure projects continue to run to time, it is vital that upper management and business development have the ability to check in constantly.

Hoerner (Purisys): Modeling and simulation tools have been extremely valuable to reduce the amount of work required for scale-up; for example, engineering technologies such as Scale-up Systems’ Dynochem can model solvent swaps, drying, distillation, off-gassing, and many other fundamental elements of synthetic and chemical processes. Small-scale reaction calorimetry tools are helpful to determine the safest process to scale up. Automating unit operations like lyophilization can reduce the need for manual intervention.

Speeding tech transfer

PharmTech: What are some best practices for tech transfer in clinical trial manufacturing?

Chantung (Aji Bio-Pharma): Some program details tend to have a bigger impact on the timeline for a client’s tech transfer and clinical program design. We have found that performing compendial methods verifications in parallel with manufacturing activities and working concurrently on batch documentation reviewing supports a quicker release. Performing risk assessments early in clinical development can help fast-track the clinical process and expedite the path to filing.

Other efficient tools for speeding up time to release include working from templated batch documentation to quickly generate a master batch record, utilizing an existing library of packaging and labeling components, and employing existing validated shipping configurations and preferred couriers.

Concurrent and in-parallel reviews and method verifications, minimized analytical transfer scope, and satellite identification samples for bulk drug substance lots sent back to the drug substance manufacturer can decrease the cost and time associated with method transfer. Additionally, early and regular collaboration with an experienced regulatory team can help expedite regulatory submissions, clinical filings, and commercial launches.

Taking all this into account, Ajinomoto Bio-Pharma Services launched the AJILITY platform. AJILITY is designed for novel therapeutics/vaccines and existing drug products with a new indications that can be used in COVID-19 trials, FDA Emergency Use Authorizations (EUAs), or other programs, providing enhanced flexibility by leveraging our existing, streamlined project configurations. The goal of the AJILITY platform is to minimize variables during tech transfer, manufacturing, and shipping processes and rely on our regulatory expertise to navigate traditional production hurdles to quickly get therapies to clinics.

While the pandemic has presented a unique opportunity for our customers to capitalize on Ajinomoto Bio-Pharma Services’ regulatory and manufacturing expertise with our AJILITY integrated drug product manufacturing platform, it will be available beyond the pandemic, for any therapeutic program that needs flexible and responsive support for expediting your lifesaving therapeutic to the clinic.

Tech transfer

PharmTec: In tech transfer, what are typically the rate-limiting steps, and how can these be optimized?

Mohler (Cascade): Too often, the provided information is unclear or is delivered only gradually in installments, which can lead to wasted time and resource where process R&D work is repeated unnecessarily, for example, where research performed to improve a synthesis has already proven to be ineffective. Having a robust analytical package is also critical. All involved teams should understand what analytical is available, what has been used previously, what its limitations are, and how these factors can impact not only the process R&D that has already been carried out, but also that which still needs to be performed.

Hoerner (Purisys): Tech transfer for an early phase chemical process can occur relatively quickly provided a strong technical package is available. Where key technical or scientific information is missing, it is important that any gaps are filled to de-risk implementation of the technology. Effective de-risking strategies include running multifactorial design of experiments versus one variable-at-a-time studies, using modeling and simulation, and ensuring you have a robust, complementary analytical technology package. In terms of manufacturing compliance, it is important that any necessary environmental permitting is in place; government permitting can take time, especially when working with larger quantities of solvents or reagents.

Chantung (Aji Bio-Pharma): Tech transfer activities for bringing a new product or process into the facility are usually rate limited by analytical method transfers, process transfer, process development, availability of components, and formulation specifics. Especially in early-stage novel therapeutics, there are often gaps between the state of the methods for in-process control and product analysis and what is suitable for current good manufacturing practice (CGMP) operations.

Sound technical transfer at a CDMO is founded by aligning equipment, materials, and quality with its clients. Expertise within the technical transfer staff is a key building block. Experienced staff coupled with a sound training program, quality-by-design philosophies, and clear planning (including roles and responsibilities between the client and organization) play an active role in optimizing technical transfer. In addition, harmonizing documentation from technical transfer to GMP production to bridge a seamless transition to the manufacturing team, employing a repertoire of scalable and industry standard equipment, and executing parallel operations all blend to accelerate a client’s timeline to the clinic.

PharmTech: What new technologies in facilities and equipment benefit the tech transfer process or clinical trial material manufacturing? 

Hoerner (Purisys): Innovator companies use modeling and simulation tools that are typically supported by a strong technical core expertise and provide line of sight to scale-up and implementation in a given facility’s equipment train. Low bioburden capabilities are also beneficial; any drug delivered in a parenteral format—whether that be intravenously, intramuscularly, occularly, or topically—may be subject to higher sterility requirements. Additionally, further environmental controls can be advantageous, for example controls to prevent light, heat, moisture, and oxygen-sensitive chemical degradation. Lastly, broad milling capabilities are key, because small-molecule particle size requirements can vary considerably depending on the delivery technology.

Chantung (Aji Bio-Pharma): The technical transfer piece of clinical trial material manufacturing benefits from high-throughput screening equipment. A CDMO can clearly demonstrate its nimbleness as a business partner via a timeline- and results-driven process development team.

Systems geared toward wide vetting of critical process variables, such as media formulations, cell growth optimization, and resins to capture and polish biologics, are cost effective and time sensitive for the client. For CGMP production of clinical trial materials, a well-known model of single-use equipment returns to the forefront in light of the COVID-19 pandemic. Faster delivery of biologics and reduced validation time through single-use technology plays into a client’s budget, safety, expediency, reproducibility, and quality interests. Flexible, multi-purpose fill lines also provide a benefit by providing various filling options and multiple set ups. Finally, in-house, on-site packaging and labeling systems that are compliant with the Drug Supply Chain Security Act help support clinical success.

References

1. Aji Bio-Pharma, “Ajinomoto Bio-Pharma Services Announces Manufacturing Partnership with CytoDyn for Drug Product Used in COVID-19 Clinical Trials,” Press Release, May 5, 2020.
2. Cascade Chemistry, “Cascade Chemistry Selected to Produce Active Pharmaceutical Ingredient for Clinical Trial Supplies of COVID-19 Investigational Drug RBT-9,” Press Release, June 16, 2020.

About the Author

Jennifer Markarian is Pharmaceutical Technology's manufacturing editor.

Article Details

Pharmaceutical Technology Europe
Vol. 32, No. 12
December 2020
Pages: 37–40

Citation

When referring to this article, please cite it as J. Markarian, “Manufacturing Materials for Clinical Trials,” Pharmaceutical Technology Europe 32 (12) 2020.