Speciality Chemicals Magazine JUL / AUG 2023 | Page 13

• Solubility : HPAPIs may have poor solubility , which can make it difficult to develop stable and effective formulations
• Analytical testing : Analysing HPAPIs requires specialised analytical methods and equipment that can accurately detect and quantify trace amounts of the substance . Indeed , the required specifications of potential genotoxic impurities are in the range of ppm or ppb
• Scale-up : Scaling up the manufacturing process for HPAPIs can be challenging , due to the need for precise control and containment measures
• Engineering controls : Engineering controls , such as air handling systems and ventilation , can reduce the concentration of HPAPIs in the air . These controls can also help prevent cross-contamination and maintain product quality Overall , manufacturing HPAPIs requires specialised equipment , expertise and strict control measures to ensure product quality and safety . Once the planning of measures has been defined and implemented , strict , rigorous and precautionary measures will need to be taken continuously in order to guarantee full control of high potency manufacturing .
Case study 1
For several years , Seqens has been manufacturing an API in the oncology area at OEB level 4 . The route synthesis involves five chemical steps and the last two of these include potent intermediates . The final product is a salt derivative , isolated as a solid form .
This conducted us to implement stringent measures in order to prevent exposure at each step of the process . For designing the overall manufacturing process , a containment strategy was considered , with the objective of minimising direct or indirect handling within limited or repetitive handling , as well as the number of transfer steps .
Containment systems , especially for high potent compounds , such as isolators , glove boxes and containment chambers , are essential for handling HPAPIs safely . Based on the acceptable exposure risk , these systems prevent the release of the potent compound into the environment , protecting both workers and the surrounding areas . More generally , closed systems and automation will reduce the need for manual handling .
In order to avoid environmental contamination by HPAPIs , the potential for exposure was evaluated . Among the key factors to be considered were the quantity of material handled and the percent active , the potential for dust and the duration of the task .
Other considerations include product sampling requirements such as size , quantity , location , container type and any limitations of the receiving lab . Workers must wear appropriate PPE , such as respirators , gloves and protective clothing , when working with HPAPIs . PPE provides an additional layer of protection .
Among the different chemical steps , two generated solid forms . Compounds leading to dust are more difficult to contain , so process design that permits limit light and fluffy materials will help to ease the selection of contained equipment .
Overseeing as early as possible , the physical characteristics of solid forms , such as particle size , adhesion , viscosity properties , the selection of salts and the level of residual solvent content for intermediates , can help to target the right equipment . Indeed , whether intermediates or product are liquid or solid will affect the choice of containment control strategies .
Glovebox isolator for high containment environment at Seqens ’ Villeneuve-La-Garenne site
Case study 2
Seqens has developed another oncology API that is classified OEB 4 , due to its low-dose effect .
It is noteworthy that , based on toxicological data , there is a difference between potency and toxicity . Potency is a measure of how much of the API is required to have a therapeutic effect ; toxicity is a measure of its adverse effects . A cytotoxic drug to treat a specific pathology may be extremely toxic but its potency might be low and therefore , side effects are likely .
Synthetic route design remains a case-by-case product strategy , but it appears that developing a convergent synthesis may be a way of