HIGH POTENCY APIS used to verify the performance of the engineering controls .
Twin chamber with container carrier for raw material loading
limiting the synthesis of highly potent intermediates . In this case , by applying this chemical strategy , only the final product and the N-1 intermediate were classified as OEB 4 .
Through bond disconnections and employing enabling synthetic methodologies to maximise convergence , one will not only deliver process efficiency but could also minimise the risk of developing high OEB intermediates and / or starting materials , while defining the route strategy .
Knowing that quantitative structureactivity relationship models based on chemical structure information can aid to predict hazard in the absence of experimental data , we systematically evaluate the risks based on the structure ’ s intermediates and potential impurities . Two complementary methodologies are required : statisticsbased and expert rule-based . Other in silico models can also be considered in order to fill in data gap .
For implementing the final crystallisation stage of the product , kinetic models were developed during the scale-up studies in order to determine the unique seeding time precisely . This leads to a single addition in the media and ensures crystal growth for yielding efficiently in the final product .
Containment strategies involve glovebox isolators with a rapid transit port , an appropriate transfer system and a closed or dust-tight system with closed transfer . The containment strategy that is chosen is verified with EHS personnel prior to selection of the containment equipment and technologies to be used .
The powder transfer system with integrated dosing and dispensing valves mounted inside the isolator enables the automated transfer and dosing of compounds that are contained in an external bulk container . The isolator chambers are also connected to IBCs capacity to the underside of the isolator . This system works for all powders , regardless of their characteristics .
The isolator and process equipment have been designed for wash-in-place . Each chamber can be connected to an external clean-in-place ( CIP ) system .
Upstream and downstream processes also contribute to containment strategy selection . For waste treatment , we privileged incineration . For cleaning procedures , it is essential to determine whether a process is dedicated or not , which cleaning materials will be used for deactivation and which cleaning methods is used , such as CIP .
Applying engineering controls in the manufacturing process reduces the risk of contamination of the manufacturing environment and is the preferred method of controlling employee exposure . Occupational hygiene monitoring techniques and methods of analysis can then be
Conclusion
The manufacturing of HPAPIs requires an adequate working environment ( to prevent cross-contamination within multi-product assets ), stringent manufacturing protocols ( to comply with the established regulatory standards ) and a trained workforce ( to handle highly potent materials satisfactorily ).
Chemical process development that optimises safety and efficiency from lab-scale to full commercial production , appropriate process equipment , the use of advanced cleaning and trace analytical testing methods , are all key considerations . It requires comprehensive management systems , including industrial hygienists , maintenance teams , quality assurance experts , operations teams , and engineering and automation personnel for risk prevention , such as occupational exposure or cross-contamination .
In addition , it requires an expensive infrastructure , which is often complex to engineer , install and maintain . Track record experience in manufacturing through a broad technology portfolio , together with excellence in process engineering and safety standards , are the ultimate criteria .
For these reasons , many pharmaceutical companies rely on third party service providers to leverage their technologies for manufacturing highly potent and achieve greater operational flexibility . The essential expertise of integrated CRDOs and CMOs is believed to be capable of enabling reduction in the time-to-market a product and offer significant cost-benefits . ●
Juliette Martin
SCIENTIFIC COMMUNICATION MANAGER
References : 1 : E . P . Hayes , R . A . Jolly , E . Faria , E . L . Barle , J . Bercu , L . Molnar , B . Naumann , M . Olson , A . Pecquet , R . Sandhu , B . K . Shipp , R . Sussman , P . Weideman , Regulatory Toxicology & Pharmacology ( 2016 ), doi : 10.1016 / j . yrtph . 2016.06.001 2 : The NIOSH Decision Logic for OEBs , The Synergist , American Industrial Hygiene Association , March 2016
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SEQENS juliette . martin @ seqens . com www . seqens . com
14 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981