A potent cocktail: How to reduce risk during HPAPI manufacture?
Michael Avraam, head of solutions engineering at ChargePoint Technology explains how containment valves and wireless monitoring mitigate risk during HPAPI manufacture.
Analysts estimate that the oral solid dosage (OSD) market will reach the trillion-dollar mark in the next decade, having rocketed to nearly US $21.5bn in 2018 [1]. Similarly, the highly potent API (HPAPI) market is expected to rise, reaching $26bn by 2023.[2]
Further knowledge of existing compounds is one of the forces behind this momentum – as new toxicity data is produced, some of these compounds are reclassified as HPAPIs. In addition, there is increasing demand for more effective, better-targeted medications; hence manufacturers are handling more and more HPAPIs. However, containment strategies are required to protect both operator safety and the drug product itself.
As OSD forms such as capsules and tablets continue to make up almost 50% [3] of the total pharma products market, the industry is seeing an increase in regulatory pressures and quality demands in this area and the need for efficient, flexible and modular processes.
Working with highly potent substances in a complex manufacturing environment poses a significant challenge for manufacturers. During material transfer, effective engineering controls are crucial as employee safety is the primary focus, however companies also aim for minimal disruption to the manufacturing process. Because of this, new and re-classified HPAPIs present a challenge for existing manufacturing facilities, which are increasingly looking to outsource to specialists with the necessary controls and equipment.
Containment during production
Whether a manufacturer is using an established containment solution like a rapid transfer port (RTP) or an isolator, or a more versatile solution like a split butterfly valve (SBV), or disposable technology, materials transfer during solid dose manufacturing can be complex. Materials must be transferred from one process to the next in a contained manner. Closed transfer valves such as SBVs are continuing to replace traditional open transfer techniques. This technology is made up of a passive unit attached to the mobile container and an active unit attached to the processing equipment. Both halves of the valve are combined during powder charging, enabling contained and efficient materials transfer.
Transferring material from one closed system into a separate closed system is one of the key difficulties in powder transfer. It’s important to ensure that the design specifications of the technology or device used in this process will meet the required accessibility, batch size and containment performance. Regardless of the process, containment integrity remains the key challenge, requiring effective performance testing and maintenance programmes.
Performance testing
Performance testing is usually assessed in line with the ISPE (International Society for Pharmaceutical Engineering) SMEPAC (Standardised Measurement of Equipment Particulate Airborne Concentration) guidelines before a manufacturer can implement a new control device within its process.
Users generally perform analyses and compare different technologies using SMEPAC as a guide for containment performance testing. It has been adopted by containment equipment manufacturers to appraise and benchmark the performance of equipment capabilities and is often utilised to influence the selection process of containment devices. However, the guidance only demonstrates how a device performs in theory in a laboratory setting – qualifying the testing in an environment as close as possible to real world parameters is still necessary.
Testing with placebos
Results obtained during performance testing are influenced by the type of placebo used. The placebo of choice most commonly used by equipment manufacturers is lactose. This is readily available, is non toxic and is supplied in varied micronised grades. It’s important to consider the best match to the API in terms of particle size and bulk density, which will affect levels of detection, airborne characteristics and consequential results.
Preparation and dispensing of the placebo batches are critical operations due to the risk of contaminating the outside surfaces of bags or bottles, which could compromise the test. Consideration needs to be taken to wipe down, and batches should be stored carefully as differing temperature, light, humidity and length of storage could all have a bearing on the result.
In addition, using differing sampling devices to test the same equipment, with the same placebo, under identical test conditions, will give variable results. Understanding how each batch has been tested and how the performance results have been obtained helps manufacturers to interpret the results and understand any potential variations.
Transfer performance
Multiple transfers will improve statistical understanding and offer greater assurances of the capabilities of containment equipment. This will allow for a superior continuity of results. The guide indicates that recovery of all potential material from the sampler should be achieved, to ensure that as much of the particulate material captures, is analysed.
Most performance results will be obtained from the analysis of combined filter and cassette arrangements, however, there will be test data still available and present on promotional literature covering only filter analysis. In-depth research into containment figures published must be done to check data and the criteria by which it has been produced.
The technology in this field is evolving and new single use, one piece samplers have been developed to avoid any risks involved with handling of the device and also standardising on the analysis. Furthermore, operator training and equipment familiarity is necessary to avoid wide ranging operating methods, resulting in potential variations in performance.
Maintenance and ongoing monitoring
As well as testing equipment before it is introduced to a process, maintenance and ongoing operational performance monitoring are vital parts of a containment strategy. For example, wireless technology can record usage data and provide insights into the health status of SBV, giving safety and compliance teams the necessary information to make informed choices about required maintenance.
Decontamination and cleaning of process equipment also needs to be undertaken in a contained manner. As disposable technology continues to be adopted within the industry, manufacturers are starting to look to this as an inexpensive alternative to conventional containment equipment.
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