Stephen Brown, Encap Drug Delivery, a division of Capsugel Dosage Form Solutions describes why the safe manufacturing of high potency drugs requires a specialised approach
Stephen Brown, Capsugel, explains the approach needed for safe manufacturing of high potency drugs
Highly potent active pharmaceutical ingredients (HPAPIs), including both small molecules and biologics, continue to increase as a share of the drug development pipeline facilitated by high throughput screening. More than 25% of total drugs worldwide today contain HPAPIs,[i] and projections show that the global market for HPAPI drugs will grow by an estimated compound annual growth rate of nearly 10% between 2012-2018.[ii] Growth in HPAPI use is largely driven by advances in clinical pharmacology and oncology research, including antibody drug conjugate applications.
When compared with traditional active pharmaceutical ingredients, HPAPIs have properties that enable them to target disease more selectively at significantly lower dosages with reduced side effects. Compounds are generally classified as highly potent due to an occupational exposure limit (OEL) of ≤10 μg/m3, a daily therapeutic dose of ≤10mg/day or if a 1mg/kg/day dose produces serious toxicity in laboratory animals.[iii]
HPAPIs are highly toxic compounds until they reach finished solid or liquid form. This poses an occupational risk to R&D and manufacturing employees. High potency formulations are also low dose applications by definition and as such, can require specialised approaches to ensure accurate dosing throughout the development cycle.
Because of the exposure risk, handling of HPAPI requires facilities with specialised equipment, infrastructure and expertise from pre-clinical development through commercial manufacture to protect employees. It also necessitates the development of innovative dosage form technologies that can help reduce occupational risk during the manufacturing process. As a result, pharmaceutical companies are increasingly seeking partners with specialised and proven HPAPI handling capabilities to help them develop and manufacture their HPAPI medicines in the safest possible conditions.
Specialised facilities and expertise
Specialised HPAPI manufacturers are addressing toxic exposure risk to their employees and the environment by implementing advanced capabilities in facility design, equipment, containment, air handling, monitoring and operational scale. Best practice facilities feature:
- Room pressure cascades designed for containment within the main HPAPI handling area.
- Airlocks and vestibules around laboratory and manufacturing suites to provide gowning and degowning areas and proper pressure differentials. Additionally, misting showers may be a part of degown and exit vestibules to allow for rinsing of personal protective equipment.
- HVAC systems designed for single-pass air (no return) with necessary controls for temperature, humidity and particulates. These systems must allow for filtration and capture of contaminants in the point source within the isolator and the general HVAC system.
- A good industrial hygiene programme to ensure that equipment and systems operate properly, meeting design specifications and demonstrating the effectiveness of the containment for the specific compound being handled.
- Restricted access to ensure that only properly trained employees who are well versed in HPAPI operating protocols enter designated HPAPI-handling spaces.
By outsourcing HPAPI manufacturing, pharmaceutical companies avoid the need to develop specialised infrastructure, engineering controls, and employee training and protocols that are expensive to implement, especially for the low volumes typically associated with HPAPI products. At Capsugel, we have invested in and maintain high containment capabilities across our technologies from design through commercialisation up to OEL < 1 μg/m3. This ensures that we can support customers with the manufacture of highly potent and cytotoxic applications while maintaining the highest standard of employee safety.
Innovative dosage form technologies
In addition to containment facilities, specialised HPAPI development and manufacturing organisations continue investing in innovative dosage form technologies that address the dose and handling challenges associated with HPAPI-based formulations.
Liquid fill hard capsules (LFHC) and soft gelatin capsules are examples of such technologies and minimise the risk of airborne contamination to being only possible at the initial powder handling stages of the manufacturing process. Following the initial wetting or dissolution of HPAPIs, the bulk formulation can be further processed through the capsule filling and sealing stages of the manufacturing processes with a significantly reduced risk of contamination to the operators and manufacturing environment. The finished dosage form also has a reduced risk of surface contamination with HPAPI and provides a product that can be safely processed and packaged with minimal risk to employees. Dose homogeneity and fill accuracy are also more easily assured through liquid and semi-solid fill compared to dry ingredient-based dosage forms.
Through a specialised approach to HPAPI-based products, from development through commercialisation, out client partners will be able to deliver promising new therapies to patients while protecting the safety of those who make them.
[i] HPAPIs and Cytotoxic Drugs Manufacturing Market, Roots Analysis, August 2014, http://www.rootsanalysis.com/reports/view_document/hpapis-and-cytotoxic-drugs-manufacturing-market/64.html
[ii] Transparency Market Research, High Potency Active Pharmaceutical Ingredients (HPAPIs) Market - Global Industry Analysis, Size, Growth, Share And Forecast 2012 – 2018, November 25, 2012, http://www.transparencymarketresearch.com/high-potency-active-pharmaceutical-ingredients-market.html
[iii] Molly Bowman, Development in high potency API manufacturing, Specialty Chemicals Magazine, July 2013, http://lifesciences.thomsonreuters.com/m/pdf/Bowman_SCM_Jul13.pdf