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Clinical Trial Manufacturing

Clinical Manufacturing: What it is, how it works & FAQs from drug developers

Clinical Scientist Colleague at Quotient Sciences

As drug developers approach the pivotal milestone of starting their early-phase first-in-human clinical trial, they must be aware of the possible challenges that can arise when preparing for clinical manufacturing of their investigational medicinal product (IMP). Clinical manufacturing and supplying the right quantities of the IMP at the right time and maintaining high quality and safety standards are crucial to maximizing the likelihood of a successful clinical trial. This requires specific expertise, state-of-the-art facilities and equipment, careful planning, and a great deal of flexibility.

At Quotient Sciences, we partner with our customers to provide a streamlined approach to clinical manufacturing and supply that reflects their clinical study design and timeline. Using a variety of manufacturing approaches, we make only the product our customers need, in a flexible and on-demand manner. Each manufacturing program is bespoke and tailored to meet the unique program needs and goals of the customer in order to improve cost efficiency by reducing drug substance and drug product waste. With expertise in both non-potent and high-potency manufacturing, we help our customers move rapidly through clinical development. With the capability to efficiently scale up to meet the demands of later clinical trial requirements, we ensure a seamless transition to larger-scale manufacturing and commercialization.

In this article, Kieran Edwards, Head of Manufacturing at Quotient Sciences, answers some frequently asked questions about clinical manufacturing.

What is clinical manufacturing, and how does it differ from commercial manufacturing?

Clinical manufacturing, also known as clinical trial material (CTM) manufacturing, is the process of turning an investigational material/active ingredient into an IMP, for dosing within a Phase I, II, or III clinical trial setting.

Typically, commercial manufacturing (post-Phase III) batches are larger in scale to create drug products for the market. In contrast, clinical manufacturing is typically a small-scale, unique process, which may only need to be performed once. Vast flexibility is required, something which we excel at in Quotient Sciences, as there are many unknowns around the IMP and the scope of a project can change in an instant.

What are the regulatory guidelines for clinical manufacturing, and how do you comply with them to ensure safety and quality?

All clinical manufacturers must conform to current Good Manufacturing Practice (cGMP) guidelines and work in line with the regulatory authority in which the IMP will be dosed. These guidelines cover all aspects of the manufacturing process, from development to making, testing, and shipping a product.

To maintain quality, at Quotient Sciences, we have quality management systems (QMSs), including policies, processes, and procedures, as well as teams of highly skilled workers focused on continually improving and adhering to the latest regulatory guidelines.

Both safety and quality are built into the Quotient Sciences culture and systems by design. Quotient Sciences provides comprehensive training for personnel, performs numerous assessments and observations, and utilizes the latest flexible containment measures in order to protect both the employees and facilities, to highlight just a few areas.

How should you plan ahead for clinical manufacturing?

At the point that a project is signed, we will instantly start thinking forward to the clinical manufacturing and dosing requirements. At Quotient Sciences, multiskilled personnel are assigned lead roles to allow a collaborative approach for study deliverables. Early on in a project, identification is required for novel excipients and equipment, which will allow the correct routes of onboarding to be implemented. Any process that requires significant technical input will have the development and manufacturing teams working closely in tandem.

For clinical batches, we are expected to create and assign a study box with all required materials that is based on the bill of materials generated from the formulation development work. These will have to be fully released through the Quotient Sciences systems, with enough quantity and expiry to last the entirety of the study. Study-specific paperwork is also generated in parallel, based on all the information and knowledge gained from the process up to that point.

What are the benefits of integrating real-time adaptive clinical manufacturing with formulation development and clinical testing?

The main benefit is the reduction in the time taken to get a drug product through development and into a clinical trial, ultimately providing a major cost saving for the customer.

The knowledge of the entire drug development process is all kept in-house, streamlined by a team of collaborative colleagues continually engaged to deliver a quality product and meet study deliverables. This is best demonstrated by Quotient Sciences’ unique Translational Pharmaceutics® platform, which integrates drug substance synthesis, drug product design and manufacturing, and clinical testing all within a single organization and a single program manager. Our history and expertise in integrating real-time adaptive manufacturing with clinical dosing enable us to manufacture, package, and release products in a matter of days or weeks rather than months. This means that we can maximize flexibility around the batch size and timing supply to the clinic in response to emerging clinical data, accelerating clinical development timelines.

What are the unique challenges of clinical manufacturing for global patient studies, and how do you overcome them?

Clinical manufacturing for both onsite and global dosing will have common challenges dependent on the process required. However, for global studies, the unique challenges typically relate to the packaging and shipment of the products.

  • Importation challenges into different territories: The team at Quotient Sciences keep up to date with any new shipping regulations/requirements by working with our approved couriers. During the start-up for each study, this topic is discussed with the customer so that any applications for import licenses or setting up of brokerage services into the specific territory can be made in advance, prior to any shipments.
  • Lead times between request to manufacture and patient dosing dates can vary, with challenges arising when this window is short: It is important to understand the clinical study protocols, assess the particular study design, and discuss this with the customer to get a robust process in place for clinical sites to request drug product within a specified window prior to dosing. Additionally, it is important to take into account the location of the clinical trial, so that shipping timelines can be factored into this window as well as the product's shelf-life. 
  • Shipping lead times: Specific shipping lanes to each territory will be determined at the start of the study. Shipments into the EU will go through our third party based in Ireland for Qualified Person (QP) release, which means that lead times into the EU are longer than they were previously before Brexit. However, our strong relationship with our third party provides a very efficient service, which is routinely undertaken. For any territory that is 'new' to Quotient Sciences, a shipping study will be considered on a case-by-case basis. When shipping to the US, you need to consider whether the IMP is 100% synthetic or whether it contains any animal-derived products. For example, you would have to apply for a gelatin permit to be able to import gelatin capsules into the US. In addition, the FDA can review any shipment when clearing customs and hold it for up to 3 days without disclosing a reason for the review, so you need to factor that into project timelines.
  • The specific formulation of the drug product: For example, oral solutions contained in glass bottles that need to be shipped to a long-haul destination may warrant a shipping study to be performed to ensure that the product does not leak or to ensure that the pressure from air freight does not have an effect on the product. Similarly, any product that is deemed fragile will undergo a shipping study to ensure that the intended packing configuration provides the appropriate protection.
  • Radioactive or dangerous goods products: These are reviewed on a case-by-case basis depending on the desired territory. We will have a discussion and plan for this with the courier and customer at the start of the study to assess any specific requirements. 
  • Controlled temperature conditions: High and low excursions outside of the specified storage conditions can be overcome by utilizing approved vendors, with shipping containers that are validated to cover the anticipated shipment period and conditions. Temperature monitoring devices are used as standard. At Quotient Sciences, we use approved couriers, who are responsible for maintaining those conditions during transit by replacing ice/gel packs in the shipping containers or ensuring storage in controlled conditions.

We have a specialized team that is dedicated to the management and shipment of supplies for global patient studies. They ensure clinical supplies are prepared and distributed globally and that there is a continuous supply of clinical trial material for all ongoing studies and projects.

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