AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Oct 072017
 

 

Sustainable chemistry: how to produce better and more from less?

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02006F, Perspective
P. Marion, B. Bernela, A. Piccirilli, B. Estrine, N. Patouillard, J. Guilbot, F. Jerome
This review describes the rapid evolution of chemistry in the context of a sustainable development of our society. Written in collaboration between scientists from different horizons, either from public organizations or chemical companies, we aim here at providing recommendations to accelerate the emergence of eco-designed products on the market.

Sustainable chemistry: how to produce better and more from less?

 Author affiliations

Abstract

The International Symposium on Green Chemistry (ISGC) organized in 2013, 2015 and 2017 has gathered many senior and young talented scientists from all around the world (2200 attendees in three editions), either from academia or industry. Through outstanding conferences, communications, debates, and round tables, ISGC has been the witness of the rapid evolution of chemistry in the context of a sustainable development of our societies, not only at the scientific and industrial levels but also on education, networking and societal aspects. This critical review synthesizes the different points of view and the discussions having taken place at ISGC and gives a general picture of chemistry, including few scientific disciplines such as catalysis, processes, resource management, and environmental impact, among others, within the framework of sustainable development. This critical review, co-authored by researchers from public organizations and chemical companies (small, medium and large industrial groups) provides criteria and recommendations which, in our view, should be considered from the outset of research to accelerate the emergence of eco-designed products on the market.

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Conclusions

Sustainable chemistry is the only mean to generate performant  products and long lasting  solutions able  to  generate  business  and  profit  for  chemical  industry.  Performance  is  the  best  systemic answer for customer needs and our societies. Defining  sustainable  chemistry  is,  however,  far  to  be  an  easy  task  because chemistry is a highly dynamic system. The sustainability of a value chain is for instance directly depending on the access  to energy (and above all to its origin – coal, gas, biomass…) and  on the supply of raw materials. In the current economic context,  it could be not so easy to predict what will be the best source of  energy or raw materials for a desired product in the future. The  development  of  predictive  tools  is  now  essential  and  will  represent probably one of the next scientific challenges in the coming years.  During the last 20 years, utilization of renewable feedstocks in  chemical processes has become a strategy of growing interest  but  it  definitely  does  not  guarantee  the  establishment  of  a  sustainable  chemistry.  Indeed,  in  some  cases,  it  is  more  sustainable to produce a chemical from a fossil carbon source  using decarbonized energy than the reverse. It is very important  to  distinguish  the  carbon  found  in  the  final  product  from  the  carbon content corresponding to the energy which is required  the  product  production  (going  from  raw  materials  to  manufacturing,  end  of  life,  etc.).  In  this  area,  the  concept  of biorefinery can help  to secure developments and  to minimize  investments  in  production  plant  by  mutualizing  facilities  and  R&D initiatives. Cooperation with local producers can also be a valuable  way  to  implement  new  bio‐based  products  while  favouring sustainable agricultural practices.  Whatever  the  raw materials  (renewable or  fossil), a complete  and systemic life cycle analysis of the whole chain value (from resources  to  manufacturing,  use  and  end  of  life)  must  be  performed because it gives us an accurate picture of the overall  economic,  environmental  and  societal  performances  of  a  product in an application for a defined market. In general, one should never forget that sustainable chemistry should help the  society to produce more and better (products).   Emergence of sustainable innovations on the market takes a lot  of  time  because  chemists  have  to  reinvent  chemistry.  To  achieve our  transition  to a sustainable society, we must  think  differently  and  bring  together  the  worlds  of  finance,  manufacturers, researchers and public authorities. The current  method of funding of research and innovation is not satisfying  yet because  too often based on  short‐term  projects and with  high Technology Readiness Level. Governments have to realize  that  this  funding  method  slows  down,  and  sometime  also  hampers, the emergence of future sustainable innovations.   Evolution of regulations with the aim of banning toxic, eco‐toxic  or  poor  biodegradable  products  is  an  important  driver  for  sustainable innovation. It is now seen and shared as a positive sign  providing  opportunities  to  develop  systemically  better  solutions  and  allowing  chemical  companies  advocating  sustainable development and products as a must to stay in the  competition.  As  examples,  ban  of  CFC,  replacement  of  chlorinated  or  other  toxic  solvents,  substitution  of  endocrine  disruptors lead to better solutions for the global benefit of our  societies.  Improving  public  perception  and  awareness  on  sustainable  chemistry is on the way but more efforts will be needed in the  future  to  definitely  contribute  to  the  emergence  of  eco‐ designed chemicals on the market.

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Below  we  provide  a  bulleted  list  to  summarize  the  main  recommendations that are, in our views, essential for designing sustainable products.  (1) Products  design  &  Manufacture:  For  the  intended  application, sustainable chemicals must imperatively bring a  global  benefit,  created  by  a  scientific  or  technological  breakthrough,  while  minimizing  risks.  They  should  also  generate profit to emerge on the market. Products should  be  produced  according  to  the  12  principles  of  green  chemistry. In addition, their end of life should be integrated  at the outset of research,  (2) Resources: They should be available for future generations  and  should  have  low  environmental  impact  (protecting  endangered species, deforestation, erosion of biodiversity,  contamination of natural resources, global warming, etc.), it  should  make  progress  the  societal  development  of  concerned area (sharing any benefits with local producer, no  child  labour,  help  developing  countries,  etc.)  and  their  utilization  should not destabilise other  supply  chains. Non  edible raw material, a return to the idea of ‘localness’ and  the need for closeness should be preferred,  (3) Process:  The  ideal  process  would  be  a  low  Capex  or  a  progressive  Capex  process and  should  be energy‐efficient,  not  use  solvents,  be  without  effluents,  should  limit  the  number of reactional and purification steps and should be  developed  rapidly  to  limit  the  associated  risks  and  costs.  Efforts  are  still  needed  for  miniaturisation  of  equipment,  intensification and development of continuous reactors,  (4)  Energy:  The  chemical  industry  is  also  energy  intensive.  Although  less  than  10%  of  fossil  carbon  is  used  for  the  manufacture of chemicals, finding decarbonized sources of  energy  is  mandatory  to  avoid  the  depletion  of  carbon  reserves  and  price  increase  and  to  ensure  that  future  generations  will  have  access  to  the  same  resource  in  the  same amount,   (5)  Life cycle assessment: it should be assessed in all cases, the  earlier the better, by preferring a ‘cradle to grave’ approach. It should give an accurate picture of the overall economic,  environmental and societal performances of a product in an  application for a defined market,  (6)  Education:  we  should  improve  public  awareness  and  perception  on  sustainable  chemistry  to  facilitate  the  acceptation of sustainable products by the consumer. More  education  programs  should  be  launched  in  the  future  not  only to reassure the consumer but also to create a pool of  students  better  armed  to  tackle  the  future  challenges  of  (sustainable)  chemistry.  The  rapid  development  of  digital  tools should be helpful to address this issue,  (7) Network: we should prefer working in an open innovation  mode  by  bringing  together  the  worlds  of  finance,  manufacturers,  researchers  and  public  authorities  to  accelerate the emergence of eco‐designed chemicals on the  market. Networks  should enable local  players  to adapt  to  changes  in  their  environment  while  optimising  their  economic and environmental efficiency,  (8)  Funding:  A  good  balance  between  funding  to  applied  research and basic research must be addressed in order to continuously  generate  scientific  innovation.  However,  public authorities must  realise  that societal challenges are  more  important  than  the  short  term  financial  challenges  faced  by  businesses.  The  current  model  of  our  economy  based  on  rapid  profitability  is  unfortunately  not  well  adapted  for  these  advances  since  long‐term  investments  will be needed for a more sustainable development of our  society,  (9)  Legislation & Regulation: it should facilitate the emergence  of sustainable chemicals by banning harmful chemicals  for  the  human  health  and  the  environment,  even  those  nowadays  generating  substantial  profits.  The  registration  process  of  improved  sustainable  chemicals  by  the  concerned agencies should be quicker than now to speed up  their integrations on the market,  (10)  Predictive  methods:  the  development  of  tools  to  accurately  predict  the  technical  and  application  performances, the economic efficiency, the environmental  and societal performance of a  targeted product should be  developed  to  limit  the  risks  and  costs  associated  with  potential  failure  and  to  reassure  the  investors.  It  is  also  urgent  to  develop  these  tools  for  chemicals  that  are  intended to be dispersed in nature.
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Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

 SYNTHESIS, Uncategorized  Comments Off on Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept
Jan 062017
 

Image result for Frank Roschangar

 

 

Image result for Frank Roschangar

Scheme 1. Pfizer’s Commercial Synthesis of sildenafil citrate (Viagra™)

Image result for Overcoming Barriers to Green Chemistry in the Pharmaceutical Industry - The Green Aspiration Level™ Concept

 

 

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Image result for Frank Roschangar

Image result for Frank Roschangar

“Green chemistry” refers to the promotion of safe, sustainable, and waste-minimizing chemical processes. The proliferation of green chemistry metrics without any clear consensus on industry standards is a significant barrier to the adoption of green chemistry within the pharmaceutical industry. We propose the Green Aspiration Level™ (GAL) concept as a novel process performance metric that quantifies the environmental impact of producing a specific pharmaceutical agent while taking into account the complexity of the ideal synthetic process for producing the target molecule. Application of the GAL metric will make possible for the first time an assessment of relative greenness of a process, in terms of waste, versus industry standards for the production process of any pharmaceutical. Our recommendations also include a simple methodology for defining process starting points, which is an important aspect of standardizing measurement to ensure that Relative Process Greenness (RPG) comparisons are meaningful. We demonstrate our methodology using Pfizer’s Viagra™ process as an example, and outline aspiration level opportunities for industry and government to dismantle green chemistry barriers.

 

Graphical abstract: Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

 

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

*Corresponding authors
aChemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com
bDelft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands
Green Chem., 2015,17, 752-768

DOI: 10.1039/C4GC01563K, http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01563k#!divAbstract

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

///////////green chemistry,  pharmaceutical industry

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A deeper shade of green: inspiring sustainable drug manufacturing

 drugs  Comments Off on A deeper shade of green: inspiring sustainable drug manufacturing
Jan 062017
 

Graphical abstract: A deeper shade of green: inspiring sustainable drug manufacturing

Green and sustainable drug manufacturing go hand in hand with forward-looking visions seeking to balance the long-term sustainability of business, society, and the environment. However, a lack of harmonization among available metrics has inhibited opportunities for green chemistry in industry. Moreover, inconsistent starting points for analysis and neglected complexities for diverse manufacturing processes have made developing objective goals a challenge. Herein we put forward a practical strategy to overcome these barriers using data from in-depth analysis of 46 drug manufacturing processes from nine large pharmaceutical firms, and propose the Green Aspiration Level as metric of choice to enable the critically needed consistency in smart green manufacturing goals. In addition, we quantify the importance of green chemistry in the often overlooked, yet enormously impactful, outsourced portion of the supply chain, and introduce the Green Scorecard as a value added sustainability communication tool.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02901A?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

The Green Aspiration Level (GAL) has been constructed on four pillars to ensure consistent application, namely (1) clearly defined synthesis starting points,1 (2) unambiguous complete E factor (cEF)2,3 or Process Mass Intensity (PMI) waste metrics, (3) historical averages of industrial drug manufacturing waste, and (4) complexity of the drug’s ideal manufacturing process (Supplementary Figure 6). cEF or PMI can be used interchangeably in GAL-based analysis enabling organizations using either to calculate their green performance scores. cEF and PMI differ by just one unit (Supplementary Equation 6) and share the same commercial waste goal for an average manufacturing step4 – the transformation-GAL or tGAL – that results in negligible numerical differences from the inclusion of one or the other. The pharmaceutical industry has generally adopted PMI. However, our publication utilizes cEF values due to literature prevalence and potentially broader appeal of E factors.5 It is important to note that all reaction and workup materials are included in the analysis, but excluded are reactor cleaning6 and solvent recycling.7 Standardized process starting points are a critical component of the GAL methodology. A starting material for some may be an intermediate for others. Until recently, the scientific community lacked an unambiguous definition of process starting points in the assessment of process greenness. This has been a bothersome source of inconsistency. Failure to define an appropriate starting material can lead to exclusion of significant amounts of intrinsic raw material waste created during earlier stages of manufacture. We therefore utilize these updated definitions of process analysis starting points to ensuring higher quality of data:8

1) The material is commercially available from a major reputable chemical laboratory catalog company, and its price is listed in the (online) catalog. Materials requiring bulk or custom quotes do not qualify as process starting material. AND 2) The laboratory catalog cost of the material at its largest offered quantity does not exceed US $100/mol. Therefore, published literature must be researched if the material does not qualify as process starting material in order to determine its correct intrinsic cEF. However, we realized that determination of literature cEF values is tedious and involves making assumptions since literature procedures are often incomplete compared to internal or external manufacturing batch records. Thus, standardizing Literature cEF quickly became a desirable goal. In order to facilitate literature analysis we introduced Supplementary Equation 7 that just requires determination of literature step count from ≤$100/mol starting materials without having to retrieve literature waste information.9 The literature step multiplier of 37 kg/kg represents the average literature step cEF across the analyzed projects (Supplementary Table 1), so it equals their average literature cEF (76 kg/kg) divided by average literature step count (2.1). The process cEF and Relative Process Greenness (RPG) derived from the simplified calculated cEF literature values are shown next to their progenitors in Supplementary Table 3. We observe that average calculated and manually determined cEF and RPG values are comparable and within 10% of their means across the three development phases. Thus, we consider the simplified method sound and an importtant element to achieving consistency in green process analysis.

 

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A deeper shade of green: inspiring sustainable drug manufacturing

 *Corresponding authors
aChemical Development, Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com
bPharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA
cPfizer, Sandwich, UK
dChemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland
eAPI Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK
fSmall Molecule Process Chemistry, Genentech, a Member of the Roche Group, South San Francisco, USA
gSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA
hChemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA
iProcess Chemistry, Merck, Rahway, New Jersey 07065, USA
jProcess Development, Amgen, Thousand Oaks, USA
kMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa
lDelft University of Technology, 2628 BL Delft, Netherlands
Green Chem., 2017,19, 281-285

DOI: 10.1039/C6GC02901A

Frank Roschangar, PhD MBA

Frank Roschangar, PhD MBA

Pharmaceutical process research director, passionate about accelerating drug development and driving green chemistry.

Boehringer Ingelheim
Ingelheim am Rhein, Germany

Research experience

  • Feb 2002–Sep 2015
     Director
    Boehringer Ingelheim
    Germany · Nieder-Ingelheim
  • Aug 1996–Feb 1998
    Postdoc
    The Scripps Research Institute · Skaggs Institute for Chemical Biology · Prof. K.C. Nicolaou
    United States · La Jolla
  • Aug 1992–Aug 1996
    PhD Candidate
    Rice University · Department of Chemistry
    United States · Houston
Supplementary References
1. The $100 per mol laboratory catalog pricing requirement described in Supplementary Discussion 1 does not apply to reagents, catalysts, ligands, and solvents, since they are produced for widespread application and are not specific to the process being evaluated.
2. Since the original E factor has been applied inconsistently, the cEF metric was introduced for the purpose of GAL analysis. cEF accounts for all process reaction and process workup materials, including raw materials, intermediates, reagents, process aids, solvents, and water.
3. All E factors reported herein represent the cEF or sEF contributions of the overall manufacturing process or the sub-process (e.g. external cEF, literature cEF) to produce 1 kg of drug substance.
4. We define a step as a chemical operation involving one or more chemical transformations that form and/or break covalent or ionic bonds and lead to a stable and isolable intermediate, but not necessarily include its isolation. Examples: • Simultaneous removal of two or more protection groups involves multiple transformations, yet it is carried out in one chemical operation  counted as one step • Sequential transformations via a stable and isolable intermediate that are carried out in two operations but without intermediate workup  counted as two steps • Formation of covalent bonds or salts that occur during workup  not counted as an extra step • Separate operation of salt formation from an isolated intermediate  counted as one step • Isolation of a product, following work-up, as a solution that can be stored  counted as one step.
5. A SciFinder search for the terms ‘Process Mass Intensity’, and ‘E factor’ and ‘Environmental impact factor’ on Nov. 14, 2016 revealed that the PMI concept was present in 12, 8, 9, and 12 publications for the years 2013-2016, respectively, while the E factor concept was mentioned 39, 45, 57, and 46 times (76-86%), respectively.
6. The GAL considers only direct process materials, i.e. materials used in the chemical steps and their workups. It does not include solvents and aqueous detergents required for reactor and equipment cleaning between batches or steps, nor the frequency and duration of the equipment and facility specific cleaning operations. These parameters are considered for comprehensive environmental impact in Life Cycle Assessment (LCA) analysis.
7. In US pharmaceutical manufacturing, recycling accounts for 25% of waste handling, while energy recovery burning and treatment constitute 38% and 35%, based on 2012 data from ‘The Right-To-Know Network’ (RTKNET.ORG), Toxic Releases (TRI) Database: http://rtknet.org/db/tri.
8. The $100 per mol commodity pricing criterion was established in ref. 15 of the main article based on the author’s professional experience. The authors of this manuscript consider this figure appropriate and helpful for providing a consistent analysis.
9. If a detailed procedure is available for a particular literature step, its calculated waste can be used in place of the 37 kg/kg default value.
10. J. Li and M. D. Eastgate, Current Complexity: a Tool for Assessing the Complexity of Organic Molecules. Org. Biomol. Chem. 2015,13, 7164–7176.
11. D. P. Kjell, I. A. Watson, C. N. Wolfe and J. T. Spitler, Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 169– 174.
12. R. P. Sheridan, et al., Modeling a Crowdsourcing Definition of Molecular Complexity. J. Chem. Inf. Model. 2014, 54, 1604–1616.
13. M. F. Faul, et al., Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium. Org. Process Res. Dev. 2014, 18, 594–600.
14. Besides offering simplicity, the GAL’s process complexity model was selected vs. the alternative structural complexity measures due to its inherent ideality-derived consideration for available synthetic methodology.
15. See main article ref. 16: it defines Construction Reactions (CR) as chemical transformations that form skeletal C-C or C-heteroatom bonds. Strategic Redox Reactions (SRR) are construction reactions that directly establish the correct functionality found in the final product, and include asymmetric reductions or oxidations. All other types of non-strategic reactions are considered as Concession Steps (CS), and include functional group interconversions, non-strategic redox reactions, and protecting group manipulations.
16. M. E. Kopach, et al., Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3- yl]methanone. Org. Process Res. Dev. 2010, 14, 1229–1238.
17. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Improved Synthesis of 1-(Azidomethyl)-3,5-bis- (trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev. 2009, 13, 152–160. 18. RCI (Process B) = 1 − ( ) = 0.25. RCI (Process C) = 1 − ( ) = 0.38

//////////green chemistry, drugs

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Green chemistry makes ‘cents’ for cost-focused API firms says expert

 Uncategorized  Comments Off on Green chemistry makes ‘cents’ for cost-focused API firms says expert
Oct 092014
 

 

 

Green chemistry makes ‘cents’ for cost-focused API firms says expert

By Gareth MacDonald+, 07-Oct-2014

Making drugs generates a huge amount of waste but industry is showing signs of cleaning up its act according to Paul Anastas, the Yale scientist who coined the phrase “green chemistry.”

http://www.in-pharmatechnologist.com/Ingredients/Green-chemistry-makes-cents-for-cost-focused-API-firms-says-expert

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