Case Study
January 27, 2025
Development and Manufacture of a Highly Potent OSD Product
In today’s pharmaceutical landscape, CDMOs are ubiquitous. Prior to the CDMO boom in the 1990s, however, this wasn’t the case. What started in the 1980s as an industrial stopgap to fulfil capacity needs is now conservatively projected to become a $340+ billion dollar market in 20331.
Naturally, when an industry grows so quickly, so does the evolution of service offerings, such as the ability to handle complex and highly potent dosage forms, scalability from early clinical supply to commercial launch, and the continued investment in, and expansion of, industry-leading technology and facilities.
Whereas reports estimate that over 500 CDMOs are currently operating around the globe2 , only a small percentage are able to act as a long-term strategic partner to their clients. A strategic CDMO is more than just a service provider: it serves in a consultative capacity; it provides a range of non-core value-added functions alongside the core functions of development, manufacture and packaging; and, in doing so, becomes an extension of the sponsor organization rather than just another supply chain vendor.
With data suggesting that approximately 41% of drug compounds are considered highly potent, registering an Occupational Exposure Limit (OEL) of 10 µg/m3 or less3 , the ability to develop and manufacture such dosage forms is becoming an increasingly desirable skill in the CDMO space. This article explores a real-world case study of how a CDMO successfully on-boarded, developed, and manufactured a highly potent solid oral drug product, utilizing its global network and decades of experience to ensure a smooth journey from clinical supply to commercial launch.
Drug Product Overview
The drug product in question is a selective sphingosine 1-phosphate (S1P) receptor modulator used in the treatment of moderately to severely active ulcerative colitis (UC).
When it was first on-boarded, the Active Pharmaceutical Ingredient (API) registered an OEL of 0.1 µg/m3. As is often the case when developing highly potent drug products, more and more data becomes available over time, allowing the CDMO to re-evaluate the potency of the drug substance. The drug product was ultimately re-evaluated as having an OEL of 0.2 µg/m3—which is a relatively minor development overall, as both readings place it firmly within the arena of high potency. As such, all development and manufacturing activities would require engineered containment solutions, ensuring operator safety and drug product integrity.
NPI/Technical Transfer
When handling highly potent molecules, a fundamental step during New Product Introduction (NPI) is the performance of a robust COSHH assessment, which assesses all new molecules for their OEL and PDE before accepting them on site. The COSHH assessment process strongly defines the molecule, its mode of action and the appropriate handling requirements, allowing the CDMO to maintain environmental and operator safety at all times.
To satisfy the COSHH assessment a toxicological and pharmacological assessment is required for each molecule that enters the site. This information helps the CDMO to protect the scientists and operators who will work with the highly potent molecule, and helps provide a suitable cleaning assessment and cleaning verification parameters, eliminating the risk of cross-contamination to the next product. Following this, a GMP Failure Mode and Effect Analysis (FMEA) assessment is generated with the supporting data from the safety, licencing equipment and premises data review, ensuring the product can be safely processed.
An advisable approach to technical transfer is to manufacture an initial placebo batch. This allows the CDMO to establish the process parameters ahead of manufacturing any batches containing the active drug substance, thereby preventing the waste of potentially expensive API. For highly potent APIs, this approach has the added benefit of allowing a safe breach of containment to investigate issues or make observations of the product, which would not be possible with the active product. For the drug product in question, the initial placebo batch was manufactured at a scale of 100 kg, which was the proposed commercial scale.
With the process parameters established, the next step was to manufacture a small-scale active batch at 2.5 kg. This allows the CDMO to conduct a cleaning feasibility trial to establish a robust cleaning process for the equipment after being exposed to the highly potent API. Although this step isn’t always necessary, it can be useful when handling highly potent molecules as it helps to avoid cross-contamination in a multiproduct facility.
As with all drug development projects, timelines are critical. As performing each step in chronological order would increase the timeline beyond what is acceptable, analytical method development is performed in parallel with the placebo and small-scale active batch manufacture. Therefore, by the time the cleaning method and process parameters are established, an active large-scale batch can be manufactured and evaluated for uniformity of content, dissolution, assay and impurities.
Development Challenges
Formulation development, by its nature, is a dynamic and experimental process. Even when the relationship between the sponsor and the CDMO is strong and collaborative, every now and then challenges can arise that require special attention to overcome.
With regards to this drug product, there was a history of punch sticking observed throughout the development stages during tablet compression. Punch sticking occurs when powder material sticks to the punch face and leaves a defect on the tablet face, or material previously stuck to the punch face transfers to the next tablet causing a defect. Punch sticking is commonly caused by adhesive properties of the API or other materials in the formulation, or by insufficient lubrication. The issue can be exacerbated by tooling design, in particular the design of the embossing.
This issue was initially resolved by adjusting the amount of lubricant used during manufacture; however, when the tooling design was changed for the commercial image to create a debossing effect on the final tablet, the punch sticking issue re-emerged. As additional lubrication can have a negative impact on product dissolution, the issue was resolved by adjusting the tooling embossing, and introducing chromium nitride coated tooling, with support from our tooling manufacturer. The lubricant level was then further assessed during pre-validation trials to ensure process robustness prior to commercialisation.
A history of punch sticking is an important factor to consider when selecting tablet debossing. Certain characters or designs create a space on the tooling which can easily collect material through the batch compression. For example characters such as; 0, P, A, and 4 are prone to the centre portion of the character sticking to the punch. Tooling suppliers can often advise on alternative designs or considerations that minimise this risk, emphasising the importance of establishing strong relationships with suppliers.
An additional challenge arose from the miscounting of tablets during the bottling process, attributed to their unusually small size. These tablets didn’t align with the handling capabilities of the existing feed system on the bottling equipment, leading to discrepancies of +/- 4 tablets per bottle. Resolving this required specialist change parts tailored for the tablet dimensions, again relying on strong relationships with suppliers. Fortunately, the equipment within the site’s packaging facility had been carefully selected with a range of unique drug product requirements in mind, incorporating design considerations to address these size-related challenges. The testing and qualification phases for this equipment utilized placebo tablets to ensure it could reliably manage the product, ultimately eliminating the miscounting issue.
Summary
This case study demonstrates the critical role of strategic planning, robust testing, and strong supplier relationships in overcoming the challenges of developing and manufacturing highly potent oral solid dosage products. From resolving issues like punch sticking during tablet compression to ensuring accurate bottling despite unique size constraints, each step of the process required tailored solutions and advanced engineering. Through meticulous testing, including the use of placebo batches, and the integration of specialized equipment, the CDMO successfully ensured product integrity, operator safety, and process efficiency, exemplifying its capability to manage complex pharmaceutical projects from clinical supply to commercial launch.
1 https://www.globenewswire.com/news-release/2024/09/11/2944611/0/en/Pharmaceutical-CDMO-Market-Size-to-Achieve-USD-345-6-Billion-by-2033.html#:~:text=The%20global%20pharmaceutical%20CDMO%20market,7.2%25%20from%202024%20to%202033.
2 https://www.marwoodgroup.com/wp-content/uploads/2022/02/2022.02.14-Pharma-CDMO-Whitepaper.pdf
3 https://affygility.com/potent-compound-corner/2021/07/09/percentage-of-drug-compounds-highly-potent.html
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