HIGH POTENCY APIS
PI
Figure 2 – Custom pyrophoric atmospheric distillation design
FI
Nitrogen Solvent In
Regulator
1 – 5 ( 3 psig ) SCFH
Closed solid
PI port
30 L Dist . Unit
Vigreux Column chain is a key requirement for any outsourcing partner as it limits the number of tech transfers and vendors needed . When working with HPAPIs , some CDMOs focus on lead optimisation , others on commercial production . Both cases require knowledge transfer . This is always a challenge , especially when it involves the added complication of an HPAPI . Ideally , a partner should be able to manage the entire life cycle of a molecule from initial development to scale-up and full commercial manufacture .
Case study
Applying risk-based engineering solutions to a complex process is illustrated in this example . There was a need to atmospherically distil a pyrophoric , highly potent intermediate formed from a highly potent powder starting material as a partial azeotrope with toxic dichloromethane . The solution required dose control transfer of the intermediate to a heated reaction mixture to generate solid HPAPI for isolation and drying . This complex process required many levels of risk consideration unrelated to the HPAPI itself .
TI
TI
Condenser
Dual Take-off
2 3
4 5
10L Receiver
6
13
1
10L Receiver
Balance
FM
7 8
9
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O2 analyzer
Regulatory standards exceeded simply cGMP execution , but included OSHA-governed containment requirements for the HPAPI and dichloromethane , and the NFPA69 requirements for handling a pyrophoric compound . 3 It needed to meet the 30 ng / m 3 containment target for the solids , vapour containment for the dichloromethane , and online oxygen monitoring for safe management and handling of the pyrophoric material . This was all carried out under a quasi-open system to perform an atmospheric distillation . Glass visualisation of the distillation was required to observe a key physical change that confirmed points of fraction collection . Finally , there were very large fluctuations in volume across the process , ranging from 100 ml to 40 litres . This required many pieces of equipment that consumed a large footprint . A full process risk assessment was carried out , covering all of the identified hazards . A highly customised point-of-use containment plan for the handling of the solids was devised , as well as installing a specialised distillation set-up to carry out the atmospheric azeotropic
AE
10
DFB
Scrubber distillation with online oxygen monitoring and balanced interlocked inerting controls ( Figure 2 ). Having a flexible containment arrangement allowed the necessary equipment to be integrated into the high potency suite with little or no capital outlay . Yet it still benefitted from the facility protocols and layers of protection established in the room differential pressures , downflow booth and contained processes systems . After successful clinical development , the process was fully validated for commercialisation with no further tech transfer needed . Incremental containment was added at any point of increased risk around the existing levels of protection , leveraging engineering controls as the primary basis of safety . Prior to validation , PPE was added to further reduce risk until product-specific validation could be performed . Whilst surrogate monitoring protocols had verified that containment design targets were met , the particular hazard types of the reaction warranted productspecific surface and air sampling . This typically uses Naproxen sodium as a worst-case scenario because of its fluffy morphology and likelihood to become airborne . However , this process had hazards present as solids , liquids and vapours . The complexity of this process is not necessarily uncommon , and it illustrates that the hazards that exist within any chemical synthesis are not related solely to the toxicological properties of the molecule that is being manufactured – that is only one consideration . The facility controls , mature processes and experienced staff , and flexible suite design enabled programmatic success that culminated in a successful NDA filing . •
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References :
1 : Roots Analysis : HPAPI & Cytotoxic Drugs Manufacturing Market ( 3rd Ed .) 2020-2030 ( https :// www . rootsanalysis . com / reports / view _ document / hpapi-and-cytotoxicdrugs-manufacturing / 299 . html )
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2 : QYResearch : Global HPAPI Market Report , History & Forecast 2014-2025 ( https :// www . qyresearch . com / index / detail / 1147258 / global-hpapi-highpotency-active-pharmaceuticalingredients-market )
3 : NFPA 69 : Standard on Explosion Prevention Systems ( https :// www . nfpa . org / codes-andstandards / all-codes-and-standards / list-of-codes-and-standards / detail ? code = 69 )
Sterling Pharma Solutions
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