La sostenibilità nell'industria farmaceutica, 'ultima moda' o vera opportunità?

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1 1 a Conferenza Nazionale sulla Chimica Sostenibile La sostenibilità nell'industria farmaceutica, 'ultima moda' o vera opportunità? Rimini, 7 Novembre Alessandro Maiocchi Bracco Imaging Spa alessandro.maiocchi@bracco.com

2 Sustainability what does it mean? Meeting the needs of the present generation without compromising the needs of future generations to meet their own needs Brundtland Report, Our Common Future, 1987

3 What is a sustainable future for pharma? The pharmaceutical industry will be expected to meet the needs of patients around the world at a cost they can afford while minimizing our environmental footprint. Balance Social, Environmental & Economic Needs Globally and Across Generations

4 The changing healthcare scene Ageing population urgent need for new medicines & greater use of pharmaceuticals BUT Increasing healthcare costs pressure to reduce use (and price) of pharmaceuticals More informed payers & consumers greater need to demonstrate health and economic value Increasing regulatory requirements higher cost of product quality management

5 Sustainability and greenness Sustainability Green Chemistry Green Engineering Philosophy Green Chemistry Green Engineering Sustainability Key Concepts Benign Solvents, Reduced Derivatization level, Atom Economy, etc Recycle, Process Intensification, Design Optimization Ecological Integrity, Societal Responsability, Economic viability; Human healthiness

6 Pharma companies what are they doing? In 2005, the ACS Green Chemistry Institute and global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage innovation while catalyzing the integration of green chemistry and green engineering in the pharmaceutical industry

7 Pharma companies benchmark themselves. ACS GCI Pharmaceutical Roundtable members have developed a common process mass intensity metric that allows data from each company to be compared on a transparent and equitable basis Process Mass Intensity = quantity of raw materials input (kg) quantity of bulk API out (kg) The PMI has been used to compare the on-going green efforts throughout the industry in the pursuit of mass efficient pharmaceutical processes.

8 Pharma benchmarking results Composition of PMI Process Metrics by Industry Industy Annual Product Tonnage MI (kg / kg) E factor (kg / Kg) Oil refining ~ 1.1 < 0.1 Bulk chemicals < 2 to 6 < 1 to 5 Fine chemicals to > 50 5 to > 50 Pharmaceutics to > to > 100

9 Process Metrics: at Bracco - The Input Side - 1. Mass Intensity ( MI) = m Raw Material Product [ Kg] m [ Kg] Chosen Yardstick by ACS Green Chemistry Institute towards greener manufacturing. Collected information from Yield, Stoichiometry, Reagents, Solvents, Auxuliaries, Catalyists, Water. MI > Risk Exposure (Exp - R) = m Q m Raw Material Product [ Kg] m [ Kg] 3. E factor (E) = m Waste Product - The Output Side - m [ Kg] [ Kg] E = MI 1 (no-recycling, water included) Tipically water excluded

10 Process Metrics at Bracco: an example Conditions analysis: Indices Normalization: Mass of Final Product Water Included in MI calculation Water Included / Exlcuded in E calculation Activated / Disactivated Recycling in E calculation Raw Materials ineherent hazard evaluation ** No Recycling / Water Included *** No Recycling / Water Excluded Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7

11 Are manufacturing costs significant? Cost Distribution: Big Pharma (16 Companies) Total sales > $ 300 Bn Total costs ~ $ 250 Bn COS > $ 90 Bn

12 Where are the quality and financial opportunities? Manufacturing Costs: Big Pharma $45 Bn in materials $22.5 Bn in personnel costs $22.5 Bn in dep. and operating

13 The manufacturing pharma processes today Large inefficient batch equipment Low utilization % on average Capital and labor intensive High inventories and excessive warehouse space Elaborate HVAC and mechanical segregation High transportation costs High operating costs Low product yields Excessive amounts of product non-conformances Long lead-times due to stage and final product testing

14 How can we make a difference? MIT-Novartis project

15 Integration of chemistry and engineering Implementation of principles of continuous flow synthesis (e.g., recycling, membrane separation, high temperature and pressure regimes) Chemically compatible, easily integrated continuous flow reactors with operation conditions that can be scaled from research to production Knowledge based design, in-line monitoring and optimization approaches of synthesis, workup, and purification steps Immobilization and recycling of catalysts Development of workup techniques for integration with reaction sequences and when economically advantageous, recycle of regents Methods for handling (addition, formation, separation, ) of solids in continuous flow reactors

16 Advantages of Flow Chemistry Quality by Design (QbD): Integrated continuous flow reactors, work-up, and process analytics & control Safe handling of highly reactive systems and reduced quantities of hazardous materials Limited unstable intermediate accumulation Less raw material (solvents, starting materials, catalysts) Faster and predictable scale-up from efficient small continuous flow reactors Opportunities for reaction chemistry and conditions not easily accessed in batch Potential for greener and more sustainable operation

17 The added value of Real-time Data Acquisition... provided researchers with a vision into a process. What was accomplished? Composition Reaction Pathways & Kinetics Emission Monitoring Hazard Evaluation Issues On-line Feasibility Studies

18 Chemical Processes Looking Forward Process intensification also using the state of art microtechnologies

19 Explore new processes using continuous technologies in the industrial syntheses of iodinated contrast media and GBCA Microreactor technology at Bracco

20 X-Ray Contrast Agents Highly concentrated (up to 80% w/v) aqueous solutions Use: in CT and other X-ray procedures Dose levels: up to more than 100 ml/procedure

21 X-Ray Contrast Agents: API Needs Number of contrast-enhanced X-ray procedures per year worldwide: > 50 million API worldwide needs: > 5,000 ton/year!

22 Drugs and Environment: Is there a Problem? The presence of drugs in water is a clear evidence Drugs in the environment can affect cronically the health of humans and all the other species Drug pollution induce resistance to medications.

23 Fate of pharmaceutical in water treatements plants

24 Pharmaceutical monitoring in water is an issue At least 10 European projects dealing with pharmaceutical residues have received public money* (excluding Life calls) CM are drugs that are always found in water They can be (and eventually will be) seen as an environmental and health problem In some cases (X-Ray CM), toxicity of trace residues can be increased by disinfection treatments (chlorine) *HIWATE, EraPHARM, KNAPPE, MODELKEY, NEPTUNE, INNOVATECH under FP6; PILLS under INTERREG IV B programme; PHARMAS, CYTOTHREAT, ENDETECH under FP7

25 The era of Eco-Pharmacovigilance Directive 2010/84/EU and Regulation (EU) No 1235/2010 state that environmental endpoints should be considered as a PV approach (eco- PV) Member States should consider measures to monitor and evaluate the risk of environmental effects of medicinal products, including those which may have an impact on public health

26 Toxicity can be promoted by common treatements unlike iopamidol, which produced significant levels of iodo-dbps in real source waters treated with chlorine and monochloramine,..

27 What can be done: From PILLS Project PILLS is an international (DE, NL, L, CH, UK, F) project ( ) to find best strategies to prevent release of pharmaceutical substances from the hospitals to the environment

28 Conclusions Pharma companies have accepted the challenge of sustainble products Sustainability will change deeply the manufacturing approach of pharma industries The resistance to change is strong due to cultural, economical and regulatory reasons but the right direction is clearly defined The search for product sustainability is a true opportunity for pharma industries to change their business model

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