Keep it all in: How to handle demand for HPAPIs
Sylvain Querol (MEng), tendering manager, Europe, at Powder Systems Limited on how to achieve high containment for HPAPI small-scale production.
Over 25% of the total drugs produced worldwide are being classified as highly potent. The High Potency Active Pharmaceutical Ingredient (HPAPI) market is rapidly growing creating new opportunities in a competitive landscape. Process technology providers need to keep up with stringent regulations to meet the market demand for high containment solutions.
Targeted therapeutics using HPAPIs and cytotoxic drugs show effective treatment at low concentration. HPAPIs and cytotoxic drugs account for a quarter of the entire API market, but are rapidly growing thanks to their numerous advantages compared to traditional therapeutic products. They cover major therapeutic areas from oncology, cardiovascular, anti-diabetic to antibody drug conjugates (ADCs) and have become the key focus of researchers and manufacturers. Oncology treatment is one of the main drivers behind this growth with around 60% of the HPAPIs being developed for cancer treatment.
HPAPI is the fastest growing segment of the worldwide API market, but the US FDA announced a shortage of FDA-approved manufacturing sites. Manufacturing technologies need to evolve to maintain the protection of operators but also the integrity of these highly potent compounds regarding cross-contamination risks. Occupational exposure limit (OEL) for APIs classified as highly potent is less than 10µm/m3 per eight hours time weighted average (TWA).
The growing demand for HPAPIs and cytotoxic drug manufacturing causes significant challenges relating to the production process. These products can lead to serious occupational hazards if not handled safely. Patient and operator health and the environment have to be protected from these hazards. A special focus is required for R&D and lab development operation. Many innovative drugs for targeted therapy are still at early stages and their toxicity levels are often unknown, so additional precautions should be taken. New containment strategies need to be implemented in HPAPI manufacturing plants to address these risks and strengthen safety requirements. Accurate OEL levels need to be defined along with testing and validation methods. How material is transferred from one process to another and what type of process equipment will be required is the first step to evaluate the best containment solution suitable for HPAPI manufacturing.
CMOs have been eager to adopt single-use systems compared to traditional dedicated systems that are not practical for multi-product facilities. A survey from 2015 from BioPlan Associates showed that cost became a growing concern amongst manufacturers. Indeed the operating cost linked to consumables are inhibiting CMOs to increase the use of disposable technologies. The main concern with single-use technology is the risk of breakage of flexible bags and loss of production material. An issue that is of higher importance with HPAPI production is the health of the operator being at risk, and highly valuable product being potentially lost. Regulatory concerns, especially regarding leachables and extractables, is next on the list of issues to consider when adopting single-use technologies. In contrast, the use of rigid high containment systems, mainly gloveboxes or isolators working under negative pressure, is the safest protection for HPAPI manufacturing. Containment technology is not always readily suitable for small-scale production though. Installing such isolators for every transfer point and process equipment would not be practical. Latest innovations are focused on the integration of entire process lines including all the process equipment inside a single high containment rigid process isolator or suite of connected isolators.
A process isolator provides a fully integrated synthesis and formulation process of HPAPIs, cytotoxic, ADCs and any other potent compounds. Process steps such as lab scale reaction, hydrogenation, filtration, drying, chromatography, dispensing, packing and weighting of clinical trial batches are performed safely in one single system. CMOs and pharma manufacturers are adopting such approaches for the containment of their lab and kilolab scale HPAPI manufacturing.
Enclosing for what benefits?
Rigid isolators provide a physical barrier and containment of fragile glassware while guaranteeing high level of operator safety from toxic liquids and dust, but also vapour and solvent. The targeted OEL will depend on the required operations and quantities but for typical applications of less than 1kg the enclosed installation can achieve OEL down to the nanogram levels of 20ng or less per meter cubed, eight hours TWA.
Enclosing the production line allows operator intervention in a safe manner onto the glassware or reaction rigs. Manual handling is necessary when developing new products or producing contract batches as the operator needs to adjust and modify the installation to meet the process needs such as changes of fittings, valves, etc. Most synthesis processes are streaming in a closed system within reaction rigs and products are transferred through pipework and tubing. High containment isolators provide an additional protection layer in case the closed process is unsealed to adjust fittings, but also allow for fast and easy access without having to wear heavy personal protective equipment (PPE). Removing heavy PPE is one of the key advantages of using isolator technology. Enclosing all of the production process within an isolator eliminates the need of PPE and multiple decontamination chambers. The cleanroom does not require complex design to accommodate several rigs as all glassware is enclosed in the isolator chamber. The overall capital expenditure will therefore be reduced by adopting high containment systems.
During HPAPIs and cytotoxic drug manufacturing, the critical points are the open solid handling steps, generally at the upstream of the production line and, in most cases, at the end with the final or intermediate dried product. All these steps require extreme containment because of volatile dust in the air during sub-dividing and charging or raw materials, or offloading of the final powder. Even when handling small product quantities, there is a high risk of exposure and, more importantly, of cross-contamination when transferring the product from one step to another. Providing a unique isolator for the entire process reduces greatly this risk. During the entire process, products are never in contact with the external environment, eliminating any risk of cross-contamination.
New technology adoption
Integrating the whole production line in a high containment isolator provides undeniable benefits to a safe and efficient manufacturing of HPAPIs and cytotoxic drugs. However, designing and manufacturing large isolators is more than putting a box around process rigs. Initial process understanding is paramount to achieve high containment performances. Integrating full process lines is all about project management and communication with the different suppliers involved. The isolator manufacturer needs to understand how the operator will use the different process equipment to design a suitable solution. The integration relies on glassware skids to provide a robust configuration as versatile as possible especially for multi-product and contract manufacturing.
The containment solution designer should undertake a detailed technical review with the end users to clearly outline the proposed operation of the equipment to understand how the equipment will be used and under what conditions. This allows for the development of bespoke solutions to create a synergy between user requirements, technical regulations and equipment manufacture. The containment provider should have process engineers with hands on experience of operating such integrated equipment, such knowledge is invaluable for high quality engineering. The product quantities, handling instruction, access points, utility connections and cleaning methods are examples of process aspects to be known and fully controlled.
Glassware is one of the fiddliest apparatus to integrate, the turnkey provider needs to pay great attention to the ergonomics. The best way to address ergonomic design requirements is to work with the operators and glassware suppliers at the beginning of the project to review a full-scale mock-up. Typically the containment provider will build an exact model of the isolator in a robust but flexible material and will include all the glassware. The mock-up should allow for flexibility to change the glove port position of the window enabling a ‘try and test’ study resulting in the best ergonomic solution for the process handling. The positioning of the glove ports is a key ergonomic consideration. The window, usually glass, is the main physical barrier between the operator and the process. Through this rigid barrier the operator needs to perform all the necessary handling with ease of access to avoid breakage or product spillage. For optimal ergonomics and visibility, full-length windows on both sides of the isolator are recommended. The ergonomic features drive the design of the isolator as much as the process flow. The isolator design needs to be modular and provide handling assistance such as sliding rails, strategically placed connections plate, mounting frame, etc.
Ergonomics have a considerable impact on the cleanability of the isolator. Automated clean-in-place (CIP) systems, such as spray balls, are not appropriate in large isolators. They generate a lot of liquid waste and cannot guarantee 100% coverage with reaction skids obstructing the spray flow. It is recommended to do manual wiping first to eliminate any solid residues and then rinse down locally using integrated wash hoses and spray guns. This brings us back to the ergonomics and being able to reach all critical areas of the isolator for clean down through the restraint and protection of the gloves. Special features are necessary when it comes to cleaning glassware such as additional sinks and washing chambers for handling and cleaning glassware manually. Glassware is fragile and potential broken glass waste needs to be considered. Manufacturing plants may require decontamination capabilities not only with water or detergent but will require solvent inlets to address this requirement, linking back to the process understanding.