Considerations for the development and manufacture of highly potent drug products, particularly in oncology treatments
As biopharmaceutical companies continue to invest in precision oncology treatments, the development and manufacture of drug products containing highly potent active pharmaceutical ingredients (HPAPIs) remain in high demand. These versatile compounds deliver therapeutic benefits at low doses with less toxicity than conventional cancer treatments. HPAPIs can be used as stand-alone therapies, as part of antibody drug conjugates (ADCs), or in immuno-oncology agents.1 According to one report, about 60% of oncology drugs contain HPAPIs.2
Scientific and technical advances have enabled the development of HPAPIs that were previously limited due to safety and toxicity challenges. However, safety remains the primary concern to protect not only patients but also facility staff from overexposure to potentially harmful substances.
A rigorous containment strategy, validated cleaning protocols and an established track record in handling HPAPIs are critical for any contract development and manufacturing organisation (CDMO) responsible for developing and/or manufacturing such therapies. Experience in the development and manufacturing of drug products containing HPAPIs is essential, as it enables successful translation of highly potent drug substances into safe, effective therapies for patients who urgently need them.
Trends in highly potent oncology APIs
Because of their ability to target diseased cells at low doses, HPAPIs are well suited to oncology in a range of dosage forms. The more traditional oral solid dosage (OSD) forms (tablets and capsules) remain a strong driver for growth. A Research and Markets report states that the global OSD market is expected to exceed $72bn by 2030, registering a compound annual growth rate (CAGR) of around 8.6%.3 There is also a growing interest in antibody-drug conjugates (ADCs), which use extremely potent and effective antineoplastic payloads linked to a monoclonal antibody. Roots Analysis has estimated that the ADC contract manufacturing market will hit around $7bn by 2035, registering a CAGR of about 13%.4
HPAPIs require special handling, however, due to their toxic potential to cells. A strict containment strategy is therefore essential for patient and worker safety. Because of the toxic nature of HPAPIs, traditional open processing methods for handling a non-potent API are insufficient. Among other differences, formulators and manufacturing personnel must rely on data from processing machines rather than information obtained first-hand. HPAPI drug products are generally manufactured at smaller production scales due to the low doses required to initiate advantageous pharmacological effects. This means production facilities must have both small-scale operations as well as an ability to scale up to large-scale clinical and commercial operations if demand is high. Because of the strict handling protocols, iterative data-driven processes, and specialised equipment and personnel required to develop HPAPIs, success and speed-to-market can hinge on CDMO selection.
A proactive approach to highly potent OSD manufacturing
Pharmaceutical companies and their CDMOs classify APIs based on occupational exposure limits (OEL). OEL assessments are used to measure the acceptable concentration of API in workplace air; the lower the limit, the higher the toxicity. HPAPIs typically fall into the toxic or extremely toxic categories, with an OEL at or below 10μg/m.5
To ensure drug substance exposure to the workforce remains at or below defined limits, an experienced CDMO will practice robust new product introduction (NPI) processes. NPI starts with proof-of-concept testing to assess whether the product and processes achieve the desired result. Once this benchmark is met, the CDMO can expand production to the predetermined clinical or commercial scale.
Other protocols CDMOs must use during NPI include:
- Performing the required activities in a contained facility, using totally enclosed process equipment
- Producing suitable data (eg, torque, tablet hardness, compaction) for risk assessments, since the product cannot be observed during processing
- Preventing cross-contamination and exposure in all circumstances.
CDMO partners with HPAPI experience use validated, automated clean-in-place or wash-in-place systems for equipment. Cleaning processes are notoriously difficult from an exposure protection perspective, as the introduction of huge amounts of cleaning solutions using pressurised systems can stress the containment design of the equipment, potentially resulting in exposure leaks.
In addition, compounds must be treated so they do not contaminate the watersupply. In all, CDMO facilities must build multiple levels of containment into their design – a prerequisite for the development, clinical production and commercial supply of products with an OEL down to 0.01μg/m3.
Dispensing for OSD products is performed within either rigid-walled isolators or flexible isolators. Here, CDMOs use various methods to safely transfer HPAPI with excipients to the sieving equipment or next stage in the process. Split butterfly valves and flexible containment bags mitigate risk during product transfer.
Granulation, milling, blending, encapsulation, tabletting and film coating use enclosed processing design techniques such as isolator units, negative pressure processing and enclosed movement of powdered product from one process to another – again, to minimise exposure. The ISPE Standard Methodology for the Evaluation of Pharma Airborne Particle Emissions from Containment Systems Good Practice Guide is used to determine OELs.6
ADCs: a different approach for a novel technology
HPAPIs previously deemed too potent for administration are moving through clinical trials as ADCs – to date, the US Food and Drug Administration (FDA) has approved 15 ADCs.7 Due to their ability to selectively deliver antineoplastic payloads to target cells, ADCs are a promising area of cancer treatment.8 Because of their composition – typically a monoclonal antibody (mAb) covalently attached to a cytotoxic drug via a chemical linker – careful selection of target antigen, antibody, payload, linker and conjugation methods are critical to achieve safety and efficacy.9
CDMOs tend to specialise in either bioanalytical services or later-stage services, such as fill-finish and lyophilisation for ADCs. Concerning the latter, operator safety remains paramount, though the processes differ from conventional methods. Instead of using positive pressure to protect the product in fill-finish, ADCs require negative pressure isolator technology to handle some formulation and compounding aspects of the liquid and mixing. The drug product is fed into a positive-pressured aseptic filling zone to ensure sterility, then filled into glass vials and capped. To ensure that potential exposure risk is reduced, vials should be fed into a further negative pressure isolator for a final outer-vial clean.
Lyophilisation requires a hybrid isolator that begins with positive pressure to protect the product, followed by negative pressure to ensure containment during vial exterior cleaning. This prevents HPAPI from adhering to the glass, mitigating cross-contamination.
Quality considerations
A robust quality management system (QMS) is an essential requirement for successful development and regulatory approval of any product. For products using HPAPIs, OEL, risk assessment and other product data must be acquired early to ensure safe, efficient developmentand manufacturing that meets good manufacturing practice (GMP) quality and purity standards.
When developing and manufacturing drug products containing HPAPIs, quality assurance (QA) and quality control (QC) are intertwined. QA functions include, but are not limited to, ensuring that no cross-contamination between equipment has occurred, that operators have suitable protection and that the facility uses negative-pressure equipment systems.
Tests that relate to QC, such as Karl Fischer titration (a common test for moisture), will need to be modified to protect analysts when handling highly potent drug products. Analysts grinding up tablets or pooling capsules require the same level of exposure protection as manufacturing operators.
During formulation development, experts typically devise a suitable Design of Experiment (DoE)/Quality by Design (QbD) approach at early stages in a product’s life cycle. DoE is statistical and systematic, with the goal of optimising the product and process by understanding the relationship between various input and output variables.10 This method helps identify the most influential factors, determine their optimal levels, and establishes robust and efficient processes while minimising the number of experimental runs.
Future outlook for HPAPIs in oncology
While drug products containing HPAPIs are beneficial to a range of therapeutic areas – including neurology, autoimmune disorders and women’s health – oncology is currently a major driver. The versatility of HPAPIs to target disease cells at low doses makes them attractive for oral solids, immunotherapies and hybrid therapies such as ADCs. Additionally, from an OSD perspective, highly targeted, non-injectable drug products are easier to administer and are therefore more patient-centric. CDMOs with dedicated facilities, engineered containment technologies, and deep scientific knowledge and experience with HPAPIs are most likely to possess the containment strategies necessary to deliver safe, quality products with the least amount of risk. Those with broad, end-to-end capabilities reduce risk further while potentially accelerating speed to market.
As the global oncology landscape evolves, it is imperative for CDMOs to refine their containment strategies to accommodate emerging products such as combination therapies and ADCs. They must also have the flexibility to manufacture not only smaller clinical batch sizes, but commercial batch sizes in the hundreds of kilograms range based on commercial success and demand.
Large biopharma companies, as well as emerging biotech start-ups, are exploring oncology therapies containing HPAPIs. Meeting the needs of both types of customers requires both extensive scientific expertise as well as enabling technologies. By offering both from early development through to commercialisation, a CDMO can develop and test prototypes and then scale up to clinical trials and beyond, all while reducing the number of technical transfers. CDMOs that can provide integrated services for clients will ensure the development of safe, effective and personalised oncology therapies for patients facing life-altering diseases.
References:
1. Visit: themedicinemaker.com/discoverydevelopment/getting-a-handle-on-highpotency
2. Visit: rootsanalysis.com/reports/hpapi-and-cytotoxic-drugsmanufacturing/299.html
3. Visit: researchandmarkets.com/report/oral-solid-dosage-contractmanufacturing
4. Visit: rootsanalysis.com/reports/adccontract-manufacturing-market/218.html
5. Visit: europeanpharmaceuticalreview.com/news/171969/update-on-settingoccupational-exposure-limits
6. Visit: ispe.org/publications/guidancedocuments/good-practice-guidesmepac-standardized-methodologyevaluation-pharma-airborne-particle
7. Visit: adc.bocsci.com/resource/review-and-formulation-analysis-of-14-antibody-drug-conjugates-adcsapproved-by-fda-up-to-2022.html
8. Tsuchikama K et al (2024), ‘Exploring the next generation of antibody-drug conjugates’, Nat Rev Clin Oncol, 21(3), pp203-223
9. Fu Z et al (2022), ‘Antibody drug conjugate: the “biological missile” for targeted cancer therapy’, Signal Transduct Target Ther, 7(1), p93
10. Visit: pci.com/resources/cdmo-insightshigh-potent-formulation-development-in-oncology
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