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The manufacture of high potency active pharmaceutical ingredients (HPAPIs) is on the rise with R&D projects showing a continuing interest in these products.
What facilities, equipment and processes are required when working with HPAPIs and how do these differ from those for traditional APIs?
In essence, highly potent active pharmaceutical ingredients (HPAPIs) present a high pharmacological activity at very low doses and thus, raise a number of issues when it comes to their manufacture; the main concern being the occupational hazard associated with their handling. Indeed, because of the substantial toxicity of HPAPIs — especially cytotoxic compounds — the risk of direct contact between the substance and either the operators or an open environment should be eliminated. Consequently, the manufacture of HPAPIs requires highly contained facilities that include different levels of protection. For instance, typical equipment includes isolators and glove boxes while HPAPI plants are isolated from the rest of the facility through negative differential pressure and efficient air treatment. It is worth noting that because of their high potency, HPAPIs are produced at a smaller scale than traditional APIs, with annual commercial production of a cytotoxic compound rarely exceeding 10s to 100s of kilograms, which makes confinement easier to control. Careful attention should also be paid to cleaning, waste management and destruction. For example, equipment should include cleaning in place devices and operators should wear special personal protection equipment adapted to the level of risk associated with the handling of a specific HPAPI. Another important aspect to consider is the set up of specific procedures, controls and practices to ensure that the appropriate level of safety is reached.
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In addition to the equipment and procedures, chemical processes and unit operations might be different than with traditional APIs. For instance, product drying will be avoided wherever possible and preparative chromatography is commonly used for purification because HPAPIs are often complex molecules and difficult to purify with crystallisation (low yields). Moreover, chromatography allows safe purification because this technique is fully automated and the confinement of highly active compounds is easily maintained.
How has pharma's increased use of HPAPIs influenced the development of specialised manufacturing equipment?
A large variety of specialised equipment, such as isolators, glove boxes, highly efficient particle air filters, etc. is now available. However, building HPAPI capabilities requires strong experience in the field in order to design the appropriate installations. Thus, specialised manufacturing equipment alone is not sufficient and the plant should be considered as a whole.
What common mistakes, dangers and challenges should companies be aware of when first handling HPAPIs?
Since no general guidelines have been issued for HPAPI manufacturing, this mastery can only be obtained through extensive and long-lasting experience in handling highly potent molecules. We would discourage any company from handling highly potent molecules for the first time without the support of experts in the field. Manufacturing HPAPIs is not only a question of equipment and procedures, but also a question of know-how and commitment to ensure the safe handling of highly potent molecules.
Does the manufacture of HPAPIs present any specific quality control challenges?
Yes. First of all, the majority of analyses have to be performed in-house since HPAPI analysis is not commonly done on a subcontract basis. As a result, HPAPI manufacturers need dedicated equipment for quality control. Because levels of highly potent impurities must be very low, highly effective analytical equipment and measurement methods are absolutely necessary. Lastly, given the risk associated with the handling of HPAPIs, quality control is subjected to the same constraints as R&D and production, and needs to be performed in the appropriate environment (e.g., lab hoods equipped with glove boxes and HEPA filters) and using very specific procedures.
What are the most effective methods and best practices for preventing operator exposure and contamination?
Physical barriers must be installed to prevent any contact between the product and the operators. In terms of facilities and equipment, it means that processscale systems are equipped with isolators for product introduction and/or recovery, while R&D and analytical labs are equipped with specific glove boxes and laminar flow hoods with HEPA filters. Personal protective equipment (PPE), such as hazmat suits, P3 masks, double gloves, supplied air respirator hoods, etc., should be worn depending on the product potency, quantity and physical state, as well as the working area and the unit operation. In addition, it is important to eliminate the risk of dispersion of the highly active compounds in a nondedicated environment to ensure that no one without appropriate protection can be accidentally in contact with such a compound. Closed systems with air decontamination for each HPAPI unit are, therefore, the best option and also prevent product crosscontamination. Pressure in the areas where HPAPIs are handled should be lower than the surrounding environment (negative differential pressure) to prevent contamination by highly potent airborne particles.
Although physical barriers are the first step toward the safe handling of HPAPIs, operating procedures are of equal importance. Operating procedures encompass product toxicity evaluation and categorisation (SafeBridge class 1 to 4 or other) and the development of adapted practices, as well as monitoring the impact on both the working environment and employee health. Product potency assessment should be performed by a team of experts to define the risk associated with the compound to then define appropriate procedures to safely handle this product. Risk assessment is also performed for each operation of the chemical processes and safety redundancies have to be implemented. All operations have to be strictly controlled using established, welldefined and validated procedures. These procedures include PPE donning and removal, equipment use, personnel and material flow, cleaning, emergency response, etc. Particular attention should be paid to the training of operators; establishing new procedures requires a compulsory training session and verification to assess the ability of the operators to work properly and safely. Another important aspect consists of monitoring occupational hygiene with sampling plans for each area during production to ensure the monitoring is representative of the working environment. In addition, the employees' health is closely monitored through blood testing and individual medical assessment. Together with the occupational hygiene monitoring, it demonstrates the efficiency of both procedures as well as personal and collective protections.
Do any regulatory guidelines/standards exist specifically for HPAPI production and handling? If not, who defines whether the handling of HPAPIs is safe, adequately controlled and monitored?
No guidelines are available so far and the control and monitoring of the safe handling of HPAPIs is basically left in the company's hands. Fortunately, a very thorough assessment of HPAPI production safety is provided by SafeBridge consultants. SafeBridge certification is the only independent evaluation system to date and for a good number of customers, being SafeBridgecertified is almost a prerequisite. The SafeBridge Potent Compound Safety Certification programme verifies performance in the management, evaluation, containment, control and communication of HPAPI production operations through a 60element review of programmes, procedures, containment and control of the HPAPIs.
Are there any challenges involved in handling HPAPIs that you think still need to be overcome?
The large scale manufacturing of HPAPIs is now well mastered by experts, but some challenges still remain to safely manage development and scale-up because some of the required equipment does not exist at a small scale. A new therapy class, known as antibodydrug conjugates (ADC), is currently under development that although appearing very promising, will present some manufacturing challenges. These compounds are composed of a toxic substance ("payload") linked to a monoclonal antibody (MAb). The purpose of such a compound is to directly target cancerous cells. The MAb will specifically bind an antigen on the outer surface of cancerous cells and the ADC is absorbed inside the cell via endocytosis; the labile linker is then cleaved while releasing the toxic substance within the cell. This therapy, currently under development, is very promising because of its high selectivity and fewer side effects. However, the production of such compounds and, more specifically, the linkage between the payload and the MAb, present quite a few challenges. Firstly, the working area needs to combine the requirement of both low bioburden and a high potency environment. For instance, a sterile environment requires positive differential pressure to prevent any contaminant from entering the area while a high potency environment requires negative differential pressure to prevent any highly potent contaminant from leaving the area. This issue can be remedied by implementing a special design for smart air flow control. Furthermore, since ADCs are biopharmaceutical derivatives, they have to be produced under very stringent quality and microbiological protection guidelines, with some chemical steps of the linkage being performed in water. Therefore, dedicated procedures have to be defined to comply with both HPAPI and sterile working requirements. In addition, the manufacture of ADCs requires great expertise in biological purification (downstream processing), as well as special technologies (including low pressure chromatography and membrane filtration), which are not familiar to HPAPI chemists. As a result, the manufacture of ADCs can only be performed by a handful of companies capable of combining expertise in HPAPIs and biomanufacturing.