amorphous solid drug substances , usually generated by spray drying , together with stabilising excipients . 13 While amorphous solid dispersions offer the advantage of improved solubility , this comes at the cost of reduced stability . Providing the drug substance is crystallisable , it will transform to a crystalline form given time and conditions conducive to such transformation . It is therefore necessary to ensure that the solid dispersion is stable over the intended lifetime of the product .
particle properties ) when developing a continuous crystallisation process . In addition , techniques for online analytical monitoring of solid formation and characterisation are very limited . Neither of these are conducive to the agility and costeffectiveness required in custom development and manufacturing . Nonetheless , there are still opportunities . For drug products with foreseeably small product volumes , end-to-end continuous manufacturing could conceivably be carried out at the lab scale with lower investment costs and less intervention by manufacturing staff , minimising the risks of unwanted exposure of both staff to the product and product to the environment . In combination with additive manufacturing , novel crystalliser geometries with improved processing properties can be realised rapidly and can be tailored to a specific task . With sufficient understanding of the factors governing the crystallisation and resulting powder properties of a given API – solubility , nucleation and growth kinetics , solid form landscapes and phase diagrams , as well as equipment-dependent factors like heat transfer and mixing , and their effect upon the product – selecting suitable crystallisers from a library of options via intelligent models becomes a viable prospect . The challenge of poor solubility , increasingly observed in INDs is not easily solved by suitable crystallisation technologies . Solubility can be increased by selecting crystalline solid forms containing a second component as an integral part of the crystal structure – for example co-crystals . Finding suitable co-crystals is , in itself , a challenge , and manufacturing these solid forms using batch processing technologies requires detailed knowledge of their phase diagrams in order to ensure sufficient control over the process . A seemingly simpler alternative is to use
References :
1 : // www . pharmavoice . com / article / 2020-01-pharma-innovation /
2 : // www . fda . gov / drugs / new-drugsfda-cders-new-molecular-entitiesand-new-therapeutic-biologicalproducts / novel-drug-approvals-2020
3 : // www . nature . com / articles / s42004-020-00388-9
4 : // www . ncbi . nlm . nih . gov / pmc / articles / PMC7022426 /
5 : // www . fda . gov / media / 77391 / download
6 : // www . fda . gov / files / drugs / published / Advancement-of- Emerging-Technology-Applicationsfor-Pharmaceutical-Innovationand-Modernisation-Guidance-for- Industry . pdf
7 : // www . ema . europa . eu / en / humanregulatory / research-development / innovation-medicines
8 : // www . ema . europa . eu / en / ich-guideline-q13-continuousmanufacturing-drug-substancesdrug-products
9 : C . M . Thompson et . al ., Molecules 2011 , 16 , 9161-9177
Outlook
We have shown some directions technology developments might take in the foreseeable future to meet the needs of today ’ s pharmaceutical development projects . Price pressure , time pressure and the need for rapid development of affordable medicines while keeping essential strategic capabilities and supplies close to their established markets will motivate further development of manufacturing technologies that meet these needs . Regulatory bodies are very supportive of the respective changes . CDMOs will continue to play a critical role in developing and applying these technologies . •
* - Also contributing to this article was Wolfgang Skranc
Dr Peter Poechlauer
PRINCIPAL SCIENTIST
PATHEON FINE CHEMICALS AUSTRIA GMBH & CO KG
k + 43 664 316 8293 J peter . poechlauer @ thermofisher . com j www . thermofisher . com / patheon
10 : A . Cote et al ., Crystal Growth & Design , 2020 , 20 , 7568 – 7581
11 : Y . Ma et al ., Organic Process Research & Development , 2020 , 24 , 1785 – 1801
12 : J . Orehek et al ., Organic Process Research & Development , 2021 , 25 , 16 – 42
13 : A . C . Templeton , S . R . Byrn , R . J . Haskell & T . E . Prisinzano ( Eds ), Discovering and Developing Molecules with Optimal Drug-Like Properties , Springer , New York , 2015 , ISBN 978-1-4939-1398-5
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