How Knowledge Gaps Delay Phase 1 Trials (and Cost Biotechs Millions)

Your science is ready. Your IND/IMPD is almost complete, your Clinical Trial Application is being finalized, trial sites are selected. Thoughts are turning to commencing clinical supply operations.

Phase 1 trials are expensive operations, typically costing between $1M and $5M+(1). In this context any errors arising from a lack of expertise of clinical trial supply management and operation has the potential to result in delayed trial start up and can cost biotechs a substantial amount of money. In addition to direct financial costs, delayed trials can also result in a loss of investor confidence, missed funding milestones, or even trial cancellation, never mind the negative impact on the well being of the patients involved.

Common Knowledge Gaps

Early stage pharma and biotech sponsors have a deep knowledge of the science, manufacturing, and therapeutic effect of their drug. However, given their stage of development, these companies and the pressure of other priorities they can lack the expertise (or simply the available resources) to manage and execute the clinical supply chain operations.

Knowledge gaps have been observed in several key areas:

Regulatory Expectations (US vs EU)

Clinical trial supply chains must be compliant with global and local regulations in each of the countries in which the trials are being conducted. These often vary from country to country, and can result in differing supply chain qualification and batch certification processes. Of particular note are differences in regulatory expectations between the US and the EU. The EU has more extensive regulatory requirements.

The Quality Unit at the batch release and certification site must ensure that each node or element in the supply chain is GMP compliant. For example, for trials conducted in the EU, the Quality Unit at the release site must ensure that each manufacturing site and any laboratory performing release testing, irrespective of where they are based, meet not only the local GMP requirements but also the specific requirements of EU GMP regulations. Consequently, clinical trial applications in the EU must be supported by a Declaration of (EU) GMP (Supply Chain) Compliance based on an audit of each manufacturing nodes in the non-EU part of the supply chain. It is worth noting that since Brexit this also includes the UK.

In the US, GMP inspections at manufacturing sites producing only clinical trial material are not usually required by the FDA and the focus being mostly on high-risk facilities(2) producing authorized medicines. On the other hand all drug product manufacturing, packaging, testing and depot sites in the EU are typically inspected every 3 years by the national regulatory Hence US sponsors supplying trials in the EU or the UK for the first time can be caught offside by the different requirements in Europe. These differences must be understood to successfully follow compliance regulations and avoid delays in trial start up and execution.

Stack of thick binders filled with white papers in an office setting.

Batch Certification and QP release

Batch certification in the EU is carried out by a Qualified Person (QP). The QP has to verify that the manufacturing and testing processes for the specific batch have met EU GMP standards2, comply with the registered particulars in the IND/IMPD, and satisfy regulatory requirements.. To achieve this, they must review all of the required documentation, including batch records, Certificates of Analysis (CoA), deviation investigations, and Certificates of Conformance (COC)(3). These documents must all be readily available to the QP in real time.

This role of the QP as such does not exist in the US where batch release is usually performed by a member of the QA or QC team, and hence the need for QP services can be somewhat of a surprise when building programs and budgets for EU clinical supply.

Cold-Chain Storage Requirements and Temperature Excursions

Detailed temperature records must be kept for the product, during both storage and shipping. Temperature excursions outside the limits determined by stability testing must be minimized. Excursions can affect the stability of the product, making it unsuitable for use in patients.

With the growth of new investigative biotech therapies in particular, the demand for low (-20⁰C) and ultra-low (-80⁰C) temperature storage and shipping solutions has expanded rapidly. This brings many challenges for both real time temperature measurement and shipment tracking. For example, Dry-ice is used extensively to maintain ultra-low (-80C) conditions during transport by both air and surface. However, when shipping by air the differences in aircraft types and their operating air pressure can result in the sublimation temperature of dry-Ice to drop from the normal -78.5⁰C at atmospheric pressure to lower than -90⁰C, which in some cases, can be below approved stability limits. This risk is not widely known or understood. At the same time, maintaining full on-line GPS tracking of the exact location along with real time temperature measurement of a critical shipment at each stage in the journey to a clinical site can facilitate replenishment of dry-ice if delays arise along the journey.

Secondary Labeling and Post-Packaging Operations

Secondary labeling provides essential information, such as batch numbers, dosing instructions, safety warnings, blinding codes, and expiration dates. These must meet the regulatory and language requirements specific to each country in which the trial is being conducted. Typically, external expertise with local knowledge and certified language translation services is beneficial

Expertise in ultra-low labelling is often not available with emerging sponsor organizations. Given the growth in the biotech materials going into trials across the globe, expertise in the design, sourcing and application of labels to frozen (-80⁰C) vials without thawing the vials (this could impact stability)(5)), and labels that maintain adherence at and with later loss of adherence is crucial

Two glass vials on a white background; one with a red cap. Both have blank labels, creating a clean, clinical appearance.

Documentation Alignment Between Partners

Documentation flow must be carefully managed to ensure that the correct documentation is available to different partners in the supply chain at the correct time. To prevent delays it is crucial that the next vendor in the supply chain has the relevant documentation from the previous vendor ahead of time. This can be particularly challenging when moving between countries due to language barriers and different regulatory requirements(6) and having a well defined documentation work flow from the outset can be hugely beneficial.

Vendor Management

Biotech companies often outsource to several vendors for their clinical trials, including contract research organizations (CROs), contract development and manufacturing organizations (CDMOs), storage facilities, courier providers, and testing laboratories. By outsourcing these activities new biotech firms can take advantage of the experience and expertise of specialized companies. However, these vendors must be carefully managed to ensure that the product moves smoothly through the supply chain. The management effort to do this successfully can often be underestimated, especially by firms engaging for the first time in multi-centre - geographically dispersed trials. Engaging with external resources who have the necessary expertise in clinical supply management can help mitigate the risk of errors.

Real-World Impacts of Getting it Wrong

The impact of knowledge gaps in clinical trial supply chains can be catastrophic. One misstep can have a ripple effect, for example, a delayed COA can delay batch certification and release, leading to a delay in patient treatment, and ultimately to wasted trial site costs7. Delays in producing the correct documentation when needed can result in missed regulatory windows and protocol deviations. Not only could this have devastating effects on severely ill patients who are relying on the clinical trial but due to the costs involved in developing, manufacturing, and testing a product, a single ruined batch of product could have a very significant negative economic impact on a startup.

What Biotechs Can Do to Get Ahead of the Problem

Emerging pharma and biotechs should take action early to minimize the potential impact of knowledge gaps and lack of capacity to manage the clinical supply chain effectively:

Mapping flow paths before initiating operations – understanding your product and associated information flows across the supply chain very early on allows you to establish ahead of time what documentation is needed and who needs it when.
Assigning a dedicated supply chain lead or external expert – reduces the risk of key tasks and/or information being missed as personnel juggle crucial supply chain tasks with other key priorities.
Centralizing documentation on a common platform accessible to all affected parties and setting up review milestones early – streamlines the supply chain review and approval process,, enables document transparency, provides visibility of task statuses, and ultimately maximizes the efficiency of batch certification and release.
Understanding region-specific compliance requirements – getting ahead of regulatory requirements reduces the risk of noncompliance and the resulting delays in the trial.