What facilities, equipment and processes are required when working with HPAPIs and how do these differ from those for traditional
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
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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
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.