Safe HPAPI manufacturing :
Thinking outside the glovebox
Rachel De Luca and Bertrand Cottineau of the CDMO business unit at the new Novasep - PharmaZell Group share their knowledge on the risk management cycle related to HPAPI manufacturing
Hazard
Due to the risks associated with their high pharmacological activity , the development and manufacturing of HPAPIs needs to ensure the safety of both patients and employees . This requires a strong quality system and HSE culture , and specialised high containment facilities operated by experienced personnel . However , safe handling of HPAPIs does not depend on equipment alone ; CDMOs need to think outside the glovebox . In this article we would like to share our approach , based on more than 30 years of manufacturing of HPAPIs and cytotoxics .
Risk applied to HPAPI : A CDMO perspective
Whenever there is a probability of a hazard occurring , there is a risk . The first type of risk associated with HPAPI manufacturing concerns occupational hygiene ( OH ), that is to say the potential exposure of the workers to the products they handle . The possible routes of exposure for the workers are inhalation , dermal contact and ingestion . Another is the potential crosscontamination of one API by another . This deserves extra attention when APIs are produced in multi-purpose facilities , which is the case at most CDMOs . This induces a risk of a patient being exposed to another undesired API . In the case of oncology drugs , the patient route of exposure is intravenous . Once the risks have been identified , they must be rated . This is typically
H1 H2 H3 H4
Highly potent product toxicity
Hazard & severity of harm
done using a two-dimensional matrix combining the potential harm and its severity , with the probability of occurrence to calculate the level of risk ( Figure 1 ). Nevertheless , risk management is never a simple issue . HPAPI risk acceptability needs to be evaluated regarding health-based data . How , then , do we manage the OH risk associated with HPAPIs ?
HPAPI risk identification & assessment
When thinking about risk at a manufacturing site , the first situation that comes to mind is the handling of bulk drug substance in production but there are many more situations to consider . Even though the finished product is identified as the active ingredient , other products in the supply chain can be toxic and must be considered , including raw and starting materials , process intermediates and waste .
P4 P3 P2 P1
Workers exposure index
Occurrence of harm
Figure 1 - Evaluating the risk with a two-dimensional matrix
Probability
P4 P3 P2 P1
H1 H2 H3 H4
Risk
Although production is where the largest quantities of products are handled , activities involving the handling of smaller quantities must also be considered , such as receiving raw materials , sampling , weighing , product transfer , R & D bench work , QC testing , cleaning , packaging and shipping . Activities where HPAPIs are not directly involved , but may be present , such as maintenance , should also not be forgotten . HPAPI risk assessment is initiated with the evaluation of a product ’ s toxicity . It starts with the collection of available data , that is , therapeutic and toxicological data , such as mechanism of action , therapeutic dose and OEL . The client is the primary source of this information . To facilitate the collection of data , customer questionnaires are useful tools that should be shared as early as possible in the project , keeping in mind that such data is subject to change during the lifetime of the
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