ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
Non-confidential Report
Legal name of applicant(s): Sanofi Pasteur
Submitted by: Sanofi Pasteur
Substance: 4-(1,1,3,3-Tetramethylbutyl) phenol, ethoxylated
EC No: -
CAS No: -
Use title: Use of Octoxynol-9 for virus splitting and inactivation step in the manufacturing of influenza vaccines
Use number: 1
Use number: 1 Sanofi Pasteur
1 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
CONTENTS
LIST OF ABBREVIATIONS ...... 7
GLOSSARY ...... 8
DECLARATION ...... 9
SUMMARY ...... 10
1 AIMS AND SCOPE OF THE ANALYSIS ...... 15
1.1 Aims ...... 15
1.2 Scope - use of the Annex XIV substance ...... 16
2 “APPLIED FOR USE” SCENARIO ...... 17
2.1 Background information ...... 17
2.1.1 Influenza ...... 17 2.1.2 History of the influenza vaccine ...... 18 2.1.3 Regulatory requirements for medicinal products ...... 21 2.1.4 Safety of biological products ...... 22 2.2 Analysis of substance role...... 22
2.2.1 Sanofi Pasteur’s influenza vaccine products ...... 22 2.2.2 The biotechnological production process at Sanofi Pasteur ...... 25 2.2.3 Performance parameters / key functionalities for alternative assessment ...... 28 2.3 Market and business trends including the use of the substance ...... 29
2.3.1 About Sanofi and Sanofi Pasteur ...... 29 2.3.2 The site concerned by this AfA: Val-de-Reuil ...... 30 2.3.3 Sanofi Pasteur as a supplier of Pandemic vaccines for the World Health Organization (WHO) and the French Ministry of Health ...... 30 2.3.4 Recent investments in Val-de-Reuil ...... 31 2.3.5 Other Sanofi Pasteur sites producing flu vaccines worldwide ...... 31 2.3.6 Supply chain ...... 32 2.3.7 Financial and employment information related to the affected Sanofi Pasteur’s flu vaccines and operations in EEA ...... 33 2.3.8 Market, trends and Flu vaccine industry...... 34 2.4 Annual tonnage ...... 35
2.5 Remaining risk of the “applied for use” scenario ...... 35
2.6 Environmental impacts of the applied for use scenario ...... 36
2.6.1 Assessment of Octoxynol-9 emissions/releases and consequent environmental impacts ...... 36 2.6.2 Suggested approaches to perform the assessment: advice from a paper published by ECHA ...... 36
Use number: 1 Sanofi Pasteur
2 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
2.6.3 Efforts to monetise environmental impacts of endocrine disrupting substances: taking advantage of the PBT and vPvB case to derive an auxiliary monetised value of impacts ...... 37 2.6.4 Qualitative assessment of environmental impacts in the applied for use scenario following the approach suggested by ECHA...... 40 2.6.5 Derivation of an auxiliary monetary value for the environmental impacts based on the volume of Octoxynol-9 emissions ...... 51 2.6.6 Conclusions on environmental impacts in the applied for use scenario ...... 53 3 SELECTION OF THE “NON-USE” SCENARIO ...... 53
3.1 Efforts made to identify alternatives ...... 53
3.1.1 Research and development ...... 53 3.1.2 Data searches ...... 54 3.1.3 Consultations ...... 54 3.2 Identification of known alternatives ...... 55
3.3 Assessment of the two potential strategies to substitute Octoxynol-9 ...... 56
3.3.1 Main alternative: Transition to a new generation of flu vaccine ...... 56 3.3.1.1 Technical feasibility ...... 58 3.3.1.2 Availability of Alternative...... 60 3.3.1.3 Hazards and risks of alternative substances ...... 60 3.3.1.4 Economic Feasibility ...... 60 3.3.1.5 Conclusions ...... 61 3.3.2 Substitution in the current Vaxigrip® process ...... 61 3.3.2.1 Substance ID and properties ...... 61 3.3.2.2 Technical and Economical feasibility of substituting in the current process 61 3.3.2.3 Conclusions on substituting Octoxynol-9 in the current process ...... 63 3.4 Overview on BPIV development and substitution process ...... 63
3.4.1 Substitution tasks and timeline ...... 64 3.4.2 Transition period after launch of BPIV ...... 68 3.5 The most likely non-use scenario (NUS) ...... 70
3.5.1 Scenario 1: Permanent shutdown of the production lines manufacturing flu vaccines in Val-de-Reuil (stop of production) AND relocation of production to a non-EEA country ...... 71 3.5.2 Scenario 2: Permanent shutdown of the production lines manufacturing flu vaccines in Val-de-Reuil (stop of production) WITHOUT relocation to a non-EEA country ...... 73 3.5.3 Likelihood of the presented scenarios and definition of the most realistic NUS 74 4 IMPACTS OF NOT GRANTING AUTHORISATION ...... 74
4.1 Public Health impact: Wider economic impacts ...... 76
4.2 Economic impacts ...... 80
Use number: 1 Sanofi Pasteur
3 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
4.2.1 Losses in terms of BOI for Sanofi Pasteur’s commercial operations and industrial Affairs due to the stop of flu vaccines production ...... 81 4.2.2 Restructuring costs appearing to Sanofi Pasteur when implementing the NUS .. 83 4.2.3 Summary of economic impacts for the applicant ...... 85 4.3 Environmental Impact ...... 85
4.4 Social impacts ...... 86
4.5 Uncertainty analysis ...... 89
5 CONCLUSIONS ...... 92
5.1 Comparison of the benefits and risk ...... 92
5.2 Information for the length of the review period ...... 93
5.3 Substitution efforts taken by the applicant if an authorisation is granted ...... 97
6 REFERENCES ...... 98
Use number: 1 Sanofi Pasteur
4 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
TABLES
Table 1: Environmental impacts versus socio-economic benefits of continued use of Octoxynol-9. . 14 Table 2: Substance of this AfA...... 15 Table 3: Key performance parameters...... 29 Table 4: implementation of risk management measures at the current facility ...... 43 Table 5: Planned schedule for moving to production to new flu building from existing facility...... 45 Table 6: Predicted Release of Octoxynol-9 from Steps 16 and 17 in the BX Building due to implementation of enhanced Release Minimisation Measures ...... 46 Table 7: Use of Octoxynol-9 at the new facility flu building (BW)...... 47 Table 8: Predicted Release of Octoxynol-9 in the new facility due to implementation of enhanced Release Minimisation Measures...... 47 Table 9: Derivation of an auxiliary monetary value for the environmental impacts based on the volume of Octoxynol-9 emissions...... 52 Table 10: Short list of substance alternatives...... 56 Table 11: Substance ID and properties of substance-level alternatives...... 58 Table 12: Technical limitations of potential alternative substances...... 59 Table 13: Lost operating business income...... 82 Table 14: Discounted impacts on BOI...... 82 Table 15: Investment details carried out by Sanofi Pasteur...... 83 Table 16: socio-economic impacts derived from restructuring costs possibility 2...... 84 Table 17: Summary of economic impacts...... 85 Table 18: Summary of potential employmentlosses due to the most realistic non-use scenario...... 87 Table 19: Summary of social impacts appearing in the NUS given average social cost of one job loss in France...... 88 Table 20: Uncertainties on socio-economic and environmental impacts...... 90 Table 21: Comparison of impacts for the applied for use and the non-use scenario...... 92 Table 22: Quantitative comparison of impacts...... 93
Use number: 1 Sanofi Pasteur
5 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
FIGURES
Figure 1: Virus splitting with Octoxynol-9...... 11 Figure 2: History of Sanofi Pasteur's Influenza vaccine...... 20 Figure 3: Flu vaccine production process for the northern hemisphere...... 24 Figure 4: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx ...... 27 Figure 5: Supply chain of Sanofi Pasteur’s flu vaccines in EEA...... 32 Figure 6: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX ...... 34 Figure 7: Median unit costs of different cost types, excluding outliers ...... 39 Figure 8: Visual representation of VU’s cost-effectiveness ‘grey zone’ ...... 40 Figure 9: Schematic of inputs to and outputs from the municipal wastewater treatment facility...... 49 Figure 10: Summary of octylphenol and Octoxynol-9 concentrations in feed water to and wastewater from the site...... 50 Figure 11: xxxxxxxxxxxxxxxxxxxxxxxxxx ...... 65 Figure 12: Costs considered in the evaluation of the Influenza Economic Burden...... 77 Figure 13: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx ...... 96
Use number: 1 Sanofi Pasteur
6 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
LIST OF ABBREVIATIONS
AfA Application for Authorisation AoA Analysis of Alternatives BPIV Broadly Protective Influenza Vaccine CAGR Compound Annual Growth Rate CPMP Committee for Proprietary Medicinal Products CSR Chemical Safety Report ECHA European Chemicals Agency EEA European Economic Area EMA European Medicines Agency EPRUS Établissement de préparation et de réponse aux urgences sanitaires (French sanitary agency) EU European Union EUR Euros GMP Good Manufacturing Practice HA Haemagglutinin Kg Kilograms NUS Non-use Scenario OPnEO Octyl phenol -n- ethoxylate PBT Persistent, Bioaccumulative and Toxic R&D Research and Development RAC Risk Assessment Committee REACH Registration, Evaluation, Authorisation and Restriction of Chemicals SEA Socio-economic Analysis SEAC Socio-economic Analysis Committee SVHC Substance of Very High Concern UIVI Universal influenza vaccine initiative USA United States of America USD United States Dollar VIA Vaccine and Industrial Affairs vPvB very Persistent and very Bioaccumulative VU Vrije Universiteit Amsterdam WHO World Health Organization WTP Willingness To Pay WWTP Wastewater Treatment Plant
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7 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
GLOSSARY
Term Definition Alternative Potential alternative to Octoxynol-9 in the manufacture of influenza vaccines. Molecules, usually proteins, capable of binding to specific antigen-receptor sites and triggering an immune response. In the case of influenza viruses, these are proteins on the virus’ surface which recognize and bind to the host cell’s Antigen membrane receptors at the beginning of infection. Antigens can be administered to patients to induce the formation of antibodies against pathogens expressing those same proteins thanks to the action of the adaptive immune system. Changes in the protein structure of a virus strain through spontaneous Antigenic drift mutations that occur normally as the virus replicates Biological products are those produced using living organism or their products, Biologics including many therapeutics, vaccines, recombinant proteins and coagulation factors. Type of virus enclosed in a lipid envelope usually derived from the host cell’s Enveloped membrane. This envelope may also include some virus glycoproteins which viruses help it attach to host cells and evade the immune system. Biological machinery used to translate a genetic sequence (DNA or RNA) into Expression a protein. These could be, for example, mammalian cells, bacterial cells, or system/platform recombinant approaches, among others. Combination and rearrangement of genetic material to produce a new genetic Genetic make up. In influenza viruses, this happens when viruses from the same type reassortment exchange whole portions of their genomes to create a virus with a new genetic profile. Hemagglutinin Virus-encoded glycoproteins found on the surface of influenza viruses. These and proteins play a major role during infection and constitute the main components neuraminidase of influenza vaccines. Phospholipid layer enclosing cells and some viruses that acts as a permeable membrane and a barrier to the surrounding media. It consists of a double layer Lipid bilayer of lipid molecules arranged with their hydrophilic ends pointing to the inside and the outside of the cell and the hydrophobic chains forming the centre of the membrane. A disease outbreak affecting a relatively high portion of the population and Pandemic spread across a wide geographic area Process by which the influenza virus is disrupted and inactivated in vaccine manufacturing. A detergent is used to solubilize make upthe lipid membrane Virus splitting surrounding the virus, to which the surface antigens that constitute the main ingredients for the vaccine are anchored. Influenza outbreaks occurring on a yearly basis due to the spread of type A and Seasonal type B influenza viruses. The viruses circulate worldwide and are especially influenza active during a time of the year known as the influenza season.
Use number: 1 Sanofi Pasteur
8 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
DECLARATION We, Sanofi Pasteur, request that the information blanked out in the “public version” of the Analysis of Alternatives and Socio-economic analysis is not disclosed. We hereby declare that, to the best of our knowledge as of today (2019, May 13th) the information is not publicly available, and in accordance with the due measures of protection that we have implemented, a member of the public should not be able to obtain access to this information without our consent or that of the third party whose commercial interests are at stake.
Signature: Date, Place:2019, May 13th Lyon
Xavier Coron
Head of Legal Affairs Sanofi Pasteur
Use number: 1 Sanofi Pasteur
9 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
SUMMARY Sanofi Pasteur wishes to apply for an authorisation for the continued use of Octoxynol-9 beyond the sunset date of January 4, 2021 in order to be able to continue the production of influenza vaccines at its site in Val-de-Reuil, France.
In total, more than 15,000 employees of Sanofi Pasteur develop, produce and market more than one billion doses of vaccines per year to immunize 500 million people around the world. Sanofi Pasteur supplies more than xxxxxxxxxx doses of influenza vaccines every year to the European market. With over 40 years of experience, the site is among the world's leading producers of seasonal and pandemic influenza vaccines, being considered the site of reference for Flu antigens production and the first manufacturer in the world for seasonal and pandemic Flu production. Val-de-Reuil is the only flu vaccine production site in France, covering all stages of vaccine manufacturing. The production activities in Val-de-Reuil cover all the steps involved in manufacturing a vaccine: seeds, antigen production, formulation, stages of pharmaceutical preparation (filling, inspection and packaging) and quality control. The site also includes Sanofi Pasteur's global vaccine distribution center, exporting all vaccines manufactured by Sanofi Pasteur in France to 150 countries.The site in Val-de-Reuil is designated as France’s centre for pandemic vaccines. Since 2014, Sanofi Pasteur holds a Pandemic Influenza Preparedness contract with the World Health Organization (WHO) for the sharing of influenza viruses and access to vaccines and other benefits. According to this contract, Sanofi Pasteur, as a manufacturer of flu vaccines, commits to a) donate a fixed percentage of real time pandemic flu vaccines production to the WHO and; b) reserve a defined percentage of real time pandemic influenza vaccine production at affordable prices to the WHO.
Influenza is a highly contagious and common disease affecting large portions of the population. In humans, influenza is caused by type A and type B influenza viruses. These viruses mutate easily through various mechanisms, changing their genetic material to express different surface proteins. In this way, they can overcome detection by the immune system and cause regular outbreaks on a yearly basis (seasonal influenza). More radical changes in the viruses’ genetic make up may result in a new virus against which little to no protection is present in the population, giving rise to an influenza pandemic. The WHO has established a surveillance program worldwide whose aim is to determine which strains of the influenza viruses are the most likely to circulate each season and, based on this information, to make a recommendation about the composition of the influenza vaccines to be manufactured before the start of the influenza season.
Sanofi Pasteur uses limited quantities of Octoxynol-9 at its Val-de-Reuil site during the production process of its seasonal influenza vaccines Vaxigrip® and Vaxigrip Tetra®, and the pandemic vaccine Panenza®. Octoxynol-9 fulfils the following key functionalities in the vaccine manufacturing process:
Use number: 1 Sanofi Pasteur
10 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
• It splits the influenza virus by disrupting its lipid bilayer and solubilizes the HA and NA antigens without damaging them or compromising their integrity • It inactivates influenza viruses and thus prevents their transmission to patients through administration of the vaccine. This is also attributed to its capacity to disrupt the lipid bilayer of enveloped viruses. • It inactivates a wide range of enveloped viruses that may be introduced into the process as adventitious agents, thus contributing to ensure the safety of the final vaccine • It stabilizes the antigens in the final vaccine, assuring its potency up to the expiration date and minimizing activity loss due to temperature excursions but not claimed as an excipient
A schematic of the Octoxynol-9 dependent virus splitting process is shown below in Figure 1.
Figure 1: Virus splitting with Octoxynol-9
These key functionalities constitute a critical aspect of the manufacturing process and thus have a considerable impact on the vaccines’ safety and efficacy. Substituting Octoxynol-9 in this process would therefore have a major effect on the final vaccines. Moreover, due to the strict regulations pertaining to the commercialization of pharmaceutical products in general, such a change would also require significant efforts in terms of reapproval in each of the countries where a marketing license is available, including revalidation through new clinical studies to demonstrate that the vaccines’ safety and efficacy are not affected by the change.
For this reason, Sanofi Pasteur intends to substitute Octoxynol-9 by developing a new generation of influenza vaccine, called the broadly protective influenza vaccine (BPIV), which will not use this substance and is planned to replace the current vaccines completely by the end of xxxx. Nonetheless, it is important to recognise that, as with any innovative development, the success and timing of the program cannot be assured in advance; This vaccine will immunize vaccinees against a broader range of circulating influenza viruses for a longer time, thus reducing the frequency of vaccination while
Use number: 1 Sanofi Pasteur
11 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS improving protection. An alternative fulfilling the same key functionalities as Octoxynol-9 must be identified and implemented in the new process as well. Sanofi Pasteur thus applies for a review period of 21 years for completely transitioning to the new generation vaccines and stop all Octoxynol-9 dependent processes. There are certain key parameters that underlie the conditions of use of Octoxynol-9 and support Sanofi Pasteur’s request for a longer review period:
• Octoxynol-9 is used in very low concentration (0.5% (v/v), with an amount of around xxxx used per batch of vaccines; one vaccine batch can contain several hundred thousand doses of finished vaccine) • Octoxynol-9 is used in a sophisticated and technologically advanced pharmaceuticals manufacturing facility • The current releases of Octoxynol-9 from the Val-de-Reuil facility are limited: - release of very limited quantities in wastewater (maximum quantity of Octoxynol-9 released in wastewater would be around 10-20 kg per annum XXXXXXXXXXX in the current facility, subject to a biological decontamination by heat before being discharged to the municipal wastewater treatment plant, Station d’epuration urbaine de Louviers, and then to the Eure (with a dilution factor); assuming that 10-20 kg per annum XXXXXXXXxXX are released to the environment over xxx production days, the average amount of Octoxynol-9 discharged to wastewater on a production day is XXXX Assuming 270 m³ of wastewater per day would suggest a daily concentration of Octoxynol-9 in wastewater of 250-350 µg/l XxxxxXX, - negligible potential for release of Octoxynol-9 to air - no release of Octoxynol-9 to soil; • For the future, Sanofi Pasteur will implement all feasible minimization measures in the existing old facility minimizing the environmental impact by 5.9 %. In parallel Sanofi Pasteur will remove 99% of Octoxynol-9 releases to the environment by commissioning its new building incorporating specific collection and treatment measures in XXx with a switch of manufactuting activities from the existing facility to the new one starting in XXx. On this basis, the amount of Octoxynol-9 released from the site to the municipal wastewater treatment will be reduced substantially, reaching 0.1-0.4 kg XXXXxX per annum from XXx. • According to the Chemical Safety Report (CSR), “Sanofi Pasteur has no measurable impact on levels of octylphenol (degradants of Octoxynol-9) at the wastewater treatment facility. The data also indicates around half the octylphenol is being degraded in the wastewater treatment process. Concentrations of Octoxynol-9 in the Eure attributable to the municipal wastewater treatment facility will be substantially less than 0.1 µg/L based on information on the hydrology of the Eure at Louviers available from Banque Hydro. Based on a worst-case (lowest) dilution
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12 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
factor of 200, it will be <1ng/L. Concentrations of octylphenol in wastewater cannot be attributed to the Sanofi Pasteur facility.”
The result of the Socio-Economic Analysis (SEA) carried out by Sanofi Pasteur is that:
(i) the environmental benefits from a “Non-Use Scenario” (refused authorization) would be limited since < 80 kg XXXXxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxX of Octoxynol-9 would no longer enter the environment; these benefits should be balanced with regards to the environmental risks associated with the continued use of the Octoxynol-9 beyond the sunset date of January 4, 2021 in the production of influenza vaccines at its production site in Val-de-Reuil, which are quite limited and will be further lower in xxxx by commissioning its new building incorporating specific collection and treatment measures removing 99% of Octoxynol-9 release to the environment;
(ii) the “Non-Use Scenario” would result in the permanent shutdown of the production lines manufacturing flu vaccines in Val-de-Reuil (stop of production), which would have substantial consequences for:
• vaccines in Europe and other countries: with more than xxxxxxxxxxx of influenza vaccines supplied every year to the European market; at least in the short term, a supply shortage would have to be expected. Even if Sanofi Pasteur is not the only supplier of these vaccines in Europe, it is unlikely that other existing suppliers would be able to completely compensate the market share xxxxxx which Sanofi Pasteur has in Europe; • Sanofi Pasteur’s employees currently working on the manufacturing of flu vaccines in Val-de- Reuil, but also for workers from others Sanofi Pasteur sites (distribution center, commercial operations, etc.) and third parties (i.e. suppliers such as egg farms and service contractors) amounting to EUR 130-200 million XXXXXxXXXxX in 2021. • economic situation of Sanofi Pasteur (losses in terms of Business Operating Income amounting to EUR 1-4 billion XXXXxxXXXXXx and restructuring costs associated with the implementation of the “Non-Use Scenario” amounting to EUR 145-185 million XXXXxxXXXXX; (iii) as a result, the socio-economic benefits associated with the continued use of the Octoxynol-9 by Sanofi Pasteur outweigh the potential limited remaining risks to the environment (Table 1).
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13 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
Table 1: Environmental impacts versus socio-economic benefits of continued use of Octoxynol-9
Type of impact Applied for use scenario Non-use scenario(s)
• Release of < 80 Kg of Octoxynol-9: o Cumulated Releases via wastewater of < 70 Kg XXXXXX XX xxxxxXX Octoxynol-9 in from the existing facility limited to the • No release (< 80 Kg) of Octoxynol-9 Environment period from 2021 to xxxx to the environment XXXXXXXXXXX o Releases via wastewater in the new facility summing up to 0.1 to 0.4 Kg XXXXxX per year < 10 Kg XxX XX for the whole review period applied for) • Positive health impact with theSafe supply of seasonal (XXXXXXXX) • Significant Worldwide and European and pandemic flu vaccines Impact with the disruption in the worldwide supply of flu vaccines worldwide • XXX doses of seasonal Flu available and especially for Europe where for European citizen Sanofi Pasteur is the main supplier • Sustainability of Sanofi Pasteur in XXXXXXXXXXXXXXXXXX) Val de Reuil • Increasing of Health cost linked to • Positive flow of investments at Flu disease in EU countries Sanofi Pasteur in Val-de-Reuil • Impairment of Sanofi Pasteur • XXXXXXXXXXXXXXXXXXXX investments in Val-de-Reuil • Losses of business operating income Socio-economic XXXXXXXXXXXXXXXXXXXX for Sanofi Pasteur in the flu vaccines impacts XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX business XXXXXX • XXXXXXXXXXXXXXXXXXXX • XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXX XXXXXXXXXXXXX • 1000-1500 job maintained for Sanofi • XXXXXXXXXXXXXXXXXXXX & suppliers XXXXXXXXXXXXXXXXXXXX • Benefits along the supply chain with XXXXXXXXXXXXXXXXXXXX generation of surpluses and XXXXXXXXXXXXXXXXXXXX employment for egg farms and XXXXXXX service contractors • 1000-1500 job losses for Sanofi & • Positive impacts on employement, suppliers economy and states taxes
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1 AIMS AND SCOPE OF THE ANALYSIS
1.1 Aims
The aim of these Analysis of Alternatives (AoA) and Socio-Economic Analysis (SEA) is to provide further evidence to support the case for authorisation of the following substance use in the Sanofi Pasteur flu vaccines manufacturing process.
Table 2: Substance of this AfA
# Substance Intrinsic property(ies)1 Latest application date2 Sunset date3 4-(1,1,3,3-Tetramethylbutyl) phenol, ethoxylated
(covering well-defined
substances and UVCB Endocrine disrupting 42 4 July 2019 4 January 2021 substances, polymers and properties – environment homologues)
EC No: -
CAS No: -
1 Referred to in Article 57 of Regulation (EC) No. 1907/2006 ² Date referred to in Article 58(1)(c)(ii) of Regulation (EC) No. 1907/2006 3 Date referred to in Article 58(1)(c)(i) of Regulation (EC) No. 1907/2006
4-(1,1,3,3-Tetramethylbutyl) phenol, ethoxylated (OPnEO), was added to REACH Annex XIV in June 2017 because of the endocrine disrupting properties with probable serious effects to the environment through its degradation products. Sanofi Pasteur applies for authorisation to continue the use of Octoxynol-9 a mixture of homologue molecules of the 4-(1,1,3,3-Tetramethylbutyl) phenol, ethoxylated, substance group. The Chemical Safety Report (CSR) prepared as part of this application of authorisation (AfA) is referenced here to provide context for the SEA part of this document.
The aim of this combined AoA + SEA is to show that
(i) Octoxynol-9 is a critical reagent in the flu vaccines manufacturing process applied by Sanofi Pasteur that cannot be easily replaced due to its high impact on the vaccine’s safety profile and efficacy; Sanofi Pasteur has developed a clear strategy to cease the use of Octoxynol-9, and currently works on substituting it by developing a new generation of influenza vaccine, called the broadly protective influenza vaccine (BPIV), which will not use this substance and will replace the current vaccines completely by the end of 2042; in
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this context, Sanofi Pasteur applies for a review period of at least 21 years after the sunset date for a successful development and full transition to the new process. (ii) as demonstrated by the CSR, after implementation of minimization measures in the current facility the environmental risks associated with the continued use of the Octoxynol-9 beyond the sunset date of January 4, 2021 in the production of influenza vaccines at its production site in Val-de-Reuil are quite limited: release of very limited quantities in wastewater (XXXXXXXXXXXXXXXXXXXXXX) subject to a thermal decontamination before being discharged to the municipal wastewater treatment plant, Station d’epuration urbaine de Louviers, and then to the Eure; assuming XXXXXX per annum is released to the environment over xxx production days, the average amount of Octoxynol-9 discharged to wastewater on a production day is XXXX. Assuming a dilution factor of 270m³ of wastewater per day would suggest a daily concentration of Octoxynol-9 in wastewater of 250-350 µg/l XXXXXX, (iii) in any case, Sanofi Pasteur will remove 99% of Octoxynol-9 release to the environment by commissioning its new building incorporating specific collection and treatment measures, so that the environmental risks associated with the continued use of the Octoxynol-9 beyond the sunset date of January 4, 2021 in the production of influenza vaccines at its production site in Val-de-Reuil will be extremely limited in xxxx; according to the CSR, “the final concentration of Octoxynol-9 and octylphenol in water discharged to and in the River Eure that is attributable to the site is expected to be negligible and undetectable”; (iv) as a result, the socio-economic benefits associated with the continued use of Octoxynol-9 by Sanofi Pasteur outweigh the potential remaining risks to the environment.
Potential risks have been evaluated using theoretical and maximizing hypotheses, out of an abundance of caution. The result of these analyses may not be interpreted as providing for actual risk for the environment.
1.2 Scope - use of the Annex XIV substance
Sanofi Pasteur uses Octoxynol-9 at its Val-de-Reuil production site in France in the manufacturing process of three influenza vaccines: the seasonal influenza vaccines Vaxigrip® and Vaxigrip Tetra®, and the pandemic influenza vaccine Panenza®. Octoxynol-9 is added during antigen production at a concentration of 0.5% (v/v) to disrupt the membrane of the influenza virus and extract the surface antigen hemagglutinin and neuraminidase (HA and NA), which constitutes the active ingredient of the vaccines. This step is crucial in the manufacture of Sanofi’s influenza vaccines. The use of Octoxynol-9 in this production step is critical for the quality of the final products in several ways, as it ensures their purity (purification of the antigen), safety (inactivation of the influenza virus, adventitious agents risk
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16 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
neutralization) and efficacy. It is also scientifically known and demonstrated that Octoxynol-9 has also an effect on the potency of the vaccine (stabilization of the antigen).
This document describes the research activities carried out by Sanofi Pasteur to substitute Octoxynol-9 in the production of its three influenza vaccines manufactured in the European Union (EU). A substitution timeline is presented along with an assessment of the substances considered as potential alternatives. Finally, the most feasible strategy is described in detail.
2 “APPLIED FOR USE” SCENARIO
2.1 Background information
2.1.1 Influenza Influenza, commonly known as flu, is a highly contagious, acute, viral respiratory infection caused by various viruses exhibiting a high degree of variability. It is marked by fever, chills, generalized feeling of weakness and pain in the muscles and varying degrees of soreness in the head and abdomen. Depending on the extent of the genetic mutations of each virus from one year to another, the degree of protection in the population fluctuates and influenza epidemics of different intensity occur.
Influenza viruses are transmitted from one person to another through the inhalation of droplets or contact with respiratory secretions. According to estimates from the World Health Organization (WHO), the number of influenza-related deaths per year ranges between 250,000 and 650,0001.
Influenza in humans can be caused by influenza type A and type B viruses, which belong to the genus Orthomyxoviridae and are characterized as enveloped, negative-strand, segmented RNA viruses. The viral envelope contains two virus-coded glycoprotein spikes, the hemagglutinin (HA) and neuraminidase (NA) proteins, which are key antigens in the host response to the influenza virus in both natural infection and vaccination. Antigenic variation is an important feature of the influenza virus. The viral HA and NA surface antigens are subject to continuous and sequential evolution within immune or partially immune populations. Influenza A (H1N1 and H3N2) accounts for most of the circulating influenza viruses in most countries and seasons. Influenza B viruses also circulate almost every year worldwide (on average later in the season compared to influenza A viruses). Two distinct genetic lineages of influenza B virus (the Victoria and the Yamagata lineages) co-circulate worldwide, and both are responsible for influenza illnesses. To predict the characteristics of the strains responsible for the next epidemic, the WHO has established a global monitoring network. Based on the localization of foci
1 http://www.who.int/influenza/en/
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of the epidemic and the strains identified as the most prevalent, the WHO publishes recommendations on the qualitative composition of annual vaccines for the coming influenza season, in February/March for the northern hemisphere and in September for the southern hemisphere.
An influenza pandemic can occur when a new influenza virus emerges, usually from animals, against which the human population has no immunity. Unlike seasonal influenza, an influenza pandemic is an unpredictable event that occurs when a flu virus evolves and travels rapidly around the world infecting many people. Both forms of the disease can be effectively prevented through vaccination.
2.1.2 History of the influenza vaccine After the flu pandemic of 1918, which became known as the Spanish flu and killed over fifty million people, the worldwide interest on finding a vaccine against influenza grew significantly. In 1933 one type of influenza virus was isolated, thereby demonstrating the viral nature of the disease. Soon after, the first influenza vaccines were developed. However, initial lack of standards for vaccine testing and quality assessment led to the commercialization of several vaccines that did not offer effective protection against the disease, and further developments in various areas had to be made before effective vaccines were available to the public.
One of the main obstacles for developing a vaccine was growing and maintaining the virus in a controllable way. Initially, influenza viruses could only be studied and isolated from infected animals, making the manufacture of a vaccine difficult and unsafe. This issue was solved with the demonstration that influenza viruses could be cultivated in the embryos of chicken eggs in high enough quantities, offering a plentiful and relatively cheap means to investigate and multiply them. Embryonated chicken eggs are therefore commonly used as hosts for multiplying and incubating influenza viruses for vaccine manufacturing.
Another major challenge for the production of a vaccine against influenza is the genetic reassortment of the influenza virus’ genome and its antigenic drift. Genetic reassortment produces major changes in the virus’ protein composition and infectivity and can happen between influenza A subtypes affecting different species, such as an animal and a human subtype. This may produce strains capable of causing large regional or global pandemic outbreaks. Antigenic drift, on the other hand, results in minor changes in the protein structure of Influenza A and B strains that allow these to cause outbreaks and evade recognition by the immune system. These changes occur frequently and are the main contributors to the seasonal variation in the makeup of the different viruses. The recognition of these processes initially undermined the belief in developing a vaccine that could offer universal protection against influenza. Even though a universal vaccine has not yet been developed, the problem of the antigenic shift has been addressed by the careful studying and tracking of the mutations displayed by influenza viruses worldwide and by the development of techniques that allow the “engineering” of vaccines that match
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the genetic profile of the predicted prevalent influenza viruses for each season. This has been facilitated by rigorous surveillance systems established by the WHO globally and scientific developments in several areas. However, vaccination must be carried out seasonally and the composition of vaccines must be adjusted according to the prevalent strain for each season.
Viral splitting technology, the method currently used by Sanofi Pasteur to produce its influenza vaccines, was introduced in 1960 and was originally based on diethyl-ether extraction of the virus antigen (Lina, Fletcher, Valette, Saliou, & Aymard, 2000). However, the use of this substance for virus splitting posed several safety risks such as a high risk of explosion and toxicity after prolonged exposure resulting in organ damage (Lupulescu, et al., 1997). Later, in the 1980’s, Octoxynol-9 was first used in a virus inactivation step in the production of biologics known as solvent detergent (S/D) treatment, where it proved to be an efficient agent for disturbing the lipid bilayer of enveloped viruses and inactivating them. This property also proved to be useful for virus splitting, which also relies on disrupting the lipid membrane of enveloped viruses for recovering their surface antigens. Since then, this substance has been widely used for vaccine manufacturing as well as a virus inactivation agent in the production of different biologics, including several plasma-derived and recombinant proteins for human use.
Vaccines are one of the most successful and cost-effective public health tools available today. It is estimated that up to 3 million deaths are prevented each year through their use, in addition to millions of cases of illness and disability. Sanofi Pasteur’s experience with the influenza vaccine dates to 1947, when it was developed by Pocono Biological Laboratories, the present-day Sanofi Pasteur Inc., in Swiftwater, Pennsylvania, USA. In France, Sanofi Pasteur has produced this vaccine for more than 50 years: in 1968, the Institut Pasteur Production and the Institut Mérieux (known today as Sanofi Pasteur S.A.), based in France, launched the production of the seasonal influenza vaccines. Since then, several innovations in manufacturing techniques and infrastructure, along with scientific breakthroughs in the areas of genetics and epidemiology have led to the development of the current vaccines Vaxigrip®, Vaxigrip Tetra®, and Panenza®. Sanofi Pasteur thus has significant know-how, infrastructure, and expertise for manufacturing its influenza vaccines. Figure 2 below shows an overview of the history of Sanofi Pasteur’s influenza vaccines.
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Figure 2: History of Sanofi Pasteur's Influenza vaccine
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2.1.3 Regulatory requirements for medicinal products Medicinal products are strictly regulated throughout their entire life cycle by various directives, regulations and guideline notes to ensure their quality, safety and efficacy. They are not only subject to regulations restricting the use of hazardous substances but, additionally, must comply with special guidelines and directives applying to medicinal products only, including those from the European Medicines Agency (EMA) or from national competent authorities (e.g. Directive 2003/94/EC, Directive 2001/83/EC, Regulation (EC) No. 726/2009, Regulation (EC) No. 37/2010). For medicinal products marketed in the EU, the selection, use and approval of substances used in their manufacture are therefore strictly regulated by the EMA and by national competent authorities.
Biologics are complex mixtures of substances that cannot be easily characterized. In this sense, they are sensitive products in which small changes in the manufacturing process can have a significant impact on their composition, safety, and efficacy. Vaccines, particularly, are products of inherent complexity due to the variable and sensitive processes used for their manufacture, and, as such, require equally complex testing and a strict quality and regulatory environment. Their development not only includes the technical realization of the drug substance, a long and costly process itself, but also continuous testing and monitoring after commercialization (pharmacovigilance of vaccines) to ensure the safety of the vaccinees. Testing oif each batch is also performed byHealth authorities.
The laboratory development of a potential new drug molecule may take up to 6 years before starting clinical trials. Afterwards, the clinical trial stage takes on average 14 years, although this time varies across manufacturers depending on protocol complexity, study design or the required number of vaccinees. During this period, extensive data is collected regarding the efficacy and safety of the substance.
Once a marketing authorization has been obtained, amendments to the terms of this authorization are addressed by Directive 2001/83/EC, by Regulation (EC) No. 726/2004 and by the Commission Regulation (EC) No. 1234/2008 of 24 November 2008. Any material changes in the substances used during the manufacturing process is subject to prior review and approval by each Member State of the EU. In case any changes are introduced into the process, sufficient evidence must be provided to show that the change does not have an impact on the final drug substance for the marketing authorization to still be valid (European Medicines Evaluation Agency, 2005).
For vaccines, any change in the manufacturing process usually triggers more variations and changes to the market authorization than is usual for other types of medicinal products due to the complexity of manufacturing process and number of quality control tests. Any material changes in the substances used for manufacturing or in the process must be previously approved by the EMA and by competent
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authorities from each country where the vaccine is marketed. This change may also include conducting new clinical trials, making it a time-consuming process that can delay the timely supply of vaccines to the population.
Non-EU countries have their own regulations. While technical requirements are quite similar to those described for member states of the European Union, both for the marketing authorization application and for amendment to regulatory dossiers, there are specificities depending on countries and procedures and timelines are different, resulting in heterogeneous regulatory situations in the world. Depending on changes, it may take up to 5 years to get regulatory approvals in all countries in the world.
2.1.4 Safety of biological products Assuring the safety of biological products is one of the main priorities of pharmaceutical companies. In the 1980’s, several cases of virus transmission through infected biologics, mostly of human immunodeficiency virus and hepatitis A virus, raised a big concern over the safety of this type of products. This lead to the establishment of several guidelines and directives that aimed to minimize the risk of infection to vaccinnees (see the previous section), as well as to the development of technologies designed specifically for eliminating pathogens from the production lines and their implementation into all processes where viral transmission constitutes a risk.
Octoxynol-9 is a non-ionic surfactant with a hydrophilic polyethylene oxide chain. It disrupts the cellular membranes of viruses and solubilizes the proteins anchored to or embedded in it (virus splitting). It is highly effective for disrupting lipid bilayers, has little or no impact on the target proteins, and is compatible with many processes. It has also been shown to meet expectations from the Committee for Proprietary Medicinal Products (CPMP) for split virion- influenza vaccines (Lina, Fletcher, Valette, Saliou, & Aymard, 2000). Virus splitting and S/D treatment using Octoxynol-9 are well validated steps with significant research supporting the use of this substance. Octoxynol-9 inactivates a wide range of adventitious agents and enveloped viruses. However, the possibility always exists of new viruses emerging that cannot be easily detected. Companies must therefore adhere to guidelines from health authorities and ensure that their production lines are able to get rid of unforeseen pathogens. Validating their processes according to the recommendations from authorities and regular testing of the manufacturing conditions are the best means to ensure the safety of their products.
2.2 Analysis of substance role
2.2.1 Sanofi Pasteur’s influenza vaccine products Several types of influenza vaccine are available today. Each year, the composition of influenza vaccines is adapted according to the dominant strains of the influenza virus in circulation. In general, there are
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two types of influenza viruses: the A-type, which comprises dozens of different sub-types and strains, and the B-type, of which only two lineages exist. The A-strains mutate constantly through two processes known as genetic reassortment and antigenic drift. In the first, viruses from different sub-types exchange genetic material when co-infecting the same cell, resulting in a new virus with a genetic make up that is a combination of the genetic material from the original viruses. Antigenic drift, on the other hand, is a change of the viral antigen structure due to natural mutations resulting from errors during replication. These processes also occur to a lesser extent in B-type viruses. Each year, the WHO recommends two A-strains and one or two of the B-strains for producing the upcoming season’s flu vaccine, based on global surveillance programs which identify the strains that are more likely to be predominant during the upcoming season. In the northern hemisphere of the world, the annual cycle starts in February, when the WHO recommends strains for the next winter flu season. In the southern hemisphere, this process starts in September. After receiving the recommendation, flu vaccine producers start the development and the production of the new antigen combination for the year’s vaccine. The seasonal vaccines are then manufactured according to this recommendation to offer protection against the predicted prevalent strains. The annual development process is carried out for both nominated A-strains and either one or both of the recommended B-strains.
Sanofi Pasteur manufactures influenza vaccines for both the northern and the southern hemispheres, according to the timelines and cycles of these regions. This means that two manufacturing campaigns are carried out every year. FIGURE 3 below shows an overview of the influenza vaccine production process for the northern hemisphere. The production process for the southern hemisphere is identical except that the process starts in September.
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Figure 3: Flu vaccine production process for the northern hemisphere
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Sanofi Pasteur’s flu vaccines are split inactivated virus vaccines. These are vaccines in which the active virus has been disrupted by a detergent, and some viral components besides the surface antigens are still present. The current portfolio of influenza vaccines manufactured in EU includes:
• Vaxigrip®, a so-called trivalent flu vaccine, offering protection against three virus strains: the two recommended A-strains and the recommended B-strain for each season. • Vaxigrip Tetra®, a quadrivalent flu vaccine, providing immunity against the two nominated A-strains and two B-strains. • Panenza®, a vaccine developed to fight one specific influenza virus strain (e.g. H1N1). It has been used in the past during a flu pandemic (2009). All of Sanofi Pasteur’s facilities for producing seasonal influenza vaccines are specially designed to be able to switch to the production of pandemic influenza vaccines should the need arise.
All three influenza vaccines use the same manufacturing process, and Octoxynol-9 fulfils the same function in the production of all three of them (these are discussed in section 2.2.3). The only difference between the three production processes is the virus strain used as starting material.
2.2.2 The biotechnological production process at Sanofi Pasteur The time between the manufacture of a vaccine and its delivery to vaccinees typically spans about two years. In the case of influenza vaccines, however, this period must be more than halved: the short time available between identification of the prevalent influenza strains and the start of the flu season leave only a few months available for producing the vaccines. The manufacturing process must therefore run as efficiently as possible to meet the global demand on time.
Since decades, Sanofi Pasteur uses an egg-based process for manufacturing its flu vaccines. The process starts with the development of seed virus cultures based on the recommendation from the WHO for the seasonal vaccine, its represents the starting material for production. These are prepared by accredited laboratories worldwide. The result is a virus with a genetic profile matching the predicted seasonal or pandemic strain. The recommended virus strains are then distributed to manufacturers across the world, which subsequently produce virus seeds and use them in further production steps. Sanofi Pasteur injects these virus seeds into embryonated chicken eggs, which are used as a replicative system to amplify the influenza virus and produce enough viral antigen for the season’s vaccine production. After several days of incubation, the viruses are harvested from the egg allantoic fluid and further purified using different methods. The main step for isolating the viral antigens is the virus splitting step, in which the lipid membrane of the influenza virus is disrupted and the viral antigens (hemagglutinin and neuraminidase) are solubilized and recovered. This step uses Octoxynol-9 at a concentration of 0.5% (v/v), with an amount of around XXX used per batch. One vaccine batch can contain several
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hundred thousands doses of finished vaccine. Virus splitting also contributes to virus inactivation because split viruses are not infectious anymore. Additional virus inactivation steps are also needed to meet safety standards from health authorities, including treatment with other substances. Part XXXXXXXXXXXX of the Octoxynol-9 is then removed from the harvested medium in the following filtration steps, achieving an infinitesimal XXxX Octoxynol-9 concentration in the monovalent antigen XXXxXXxX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. The remaining Octoxynol-9 intentionally present in the vaccine contributes to the stabilization of the viral antigens in the final vaccine, preserving these and thus ensuring its potency and efficacy. The presence of Octoxynol-9 in the vaccine final product is clearly indicated in the vaccine’s information leaflet (not as an excipient).
After antigen monovalent production, the final vaccine product is formulated with additional components necessary for its administration. The vaccine is filled into a syringe or a vial, checked for quality and then packaged for distribution to different countries. Figure 4 below shows an overview of the influenza vaccine’s production process.
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Figure 4: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
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2.2.3 Performance parameters / key functionalities for alternative assessment The virus splitting step using Octoxynol-9 is a critical step for the production of Sanofi Pasteur’s influenza vaccines. It is also crucial for ensuring the safety of the process as it inactivates enveloped viruses that might be present in the harvested medium. The use of Octoxynol-9 in this process has four major functions that must also be met by a suitable alternative (key functionalities):
• Octoxynol-9 is a strong surfactant (detergent) that can split the different types of influenza virus. The virus membrane, a lipid bilayer, is disrupted by the detergent, whereby the virus antigens are released and solubilized. The vaccine itself consists mainly of virus antigens (HA and NA) derived from the whole virus membrane that are solubilized into an Octoxynol-9 rich phase. A suitable alternative to Octoxynol-9 must be able to split the influenza virus membrane and solubilize the antigen proteins while preserving their integrity.
• Octoxynol-9 also contributes to the inactivation of the influenza virus. Split viruses are no longer infectious, so this step also serves as a virus inactivation step against the influenza virus itself. This step is of utmost importance to ensure that no active viruses are still present in the final vaccine.2 A suitable alternative should also be able to inactivate the influenza viruses used for producing the vaccines. The presence of active influenza viruses in the flu vaccines would pose a risk to vaccinnees.
• For the same reason, it is important that the chosen alternative inactivates a wide range of adventitious agents and enveloped viruses which can be present from the eggs used for incubation or from the virus strains supplied by the WHO. The mechanism behind virus inactivation with Octoxynol-9 is the same as that for virus splitting: Oxtoxynol-9 disrupts the lipid membrane of enveloped viruses and destabilizes its integrity, thereby inactivating them.
• Octoxynol-9 also plays a main role in stabilizing the viral antigen in the finalized vaccine. Some analyses reveal that this substance helps preserve the potency of the influenza vaccine and increases its resistance to temperature deviations from the optimal handling temperature. Preservation of the potency during the storage is higher for technical batches with standard concentrations of Octoxynol-9 than for the ones with low concentrations. This action is attributed to the solubilizing effect of Octoxynol-9 on the viral antigen, which, as a membrane component of the lipid bilayer, also has a hydrophobic region that can be solubilized by this detergent. This also prevents aggregation of the antigen. A suitable alternative should also contribute to stabilize the viral antigen in the finished vaccine, ensuring that the vaccines’ potency and shelf life are not affected.
2 Other types of vaccine use live pathogens as active components, but this is not the case for Sanofi Pasteur’s current flu vaccines.
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The characteristics mentioned above constitute the key functionalities that must be assessed in searching for an alternative to Octoxynol-9. These key functionalities are summarised in TABLE 3 below together with the respective quantitative requirement and the respective testing methods used by Sanofi Pasteur.
Table 3: Key performance parameters
Key performance parameters Quantitative statement Assessment method
Capacity to split the influenza virus The vaccine consists predominantly In-house method developed by of split virus particles Sanofi Pasteur, registered in the marketing authorization dossier (qualitative method on sucrose gradient particles separation) Capacity to inactivate influenza Inactivation validation; virus load In-house testing methods virus inactivation by up to XXXXXXXX developed by Sanofi Pasteur, registered in the marketing authorization dossier (viral titration on eggs) Capacity to inactivate potential Viral clearance studies of a range of Spiking experiments on Sanofi adventitious agents (viral risk potential extraneous agents ; load Pasteur product with prevention) reduction by XXXXXXXX adventitious agents, followed by detection & quantitation of residual active adventitious agents Capacity to confer good stability to Capacity to deliver a product which Produce vaccine with the the vaccine remains conform up to expiry date, alternative product and store up with the right amount of active to expiry date (1 year) tracking ingredient antigen concentration
Please note that it is crucial that all above-mentioned key functionalities and related minimum requirements are sufficiently fulfilled by an alternative substance or technology.
As indicated by the key functionalities and process parameters listed above, the substitution of Octoxynol-9 by a surrogate chemical can significantly change the attributes of the influenza vaccines in terms of yield, purity, safety and potency profile. Intensive testing is thus needed to ensure that any potential alternative minimizes these changes. This ultimately guarantees the protection of vaccinees.
2.3 Market and business trends including the use of the substance
2.3.1 About Sanofi and Sanofi Pasteur Sanofi, a global healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients' needs. Sanofi is organized into the different global business units. Sanofi Pasteur is the vaccine business unit and focus of this application for authorisation. It operates 15 R&D and industrial sites worldwide.
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In total, more than 15,000 employees of Sanofi Pasteur produce more than one billion doses of vaccines per year to immunize 500 million people around the world. The portfolio comprises high quality vaccines for infants, children, adolescents and adults, including influenza, meningitis, travel and endemic diseases. New scientific knowledge and technologies are continuously harnessed to drive innovation. Sanofi Pasteur produces 200 million doses of vaccines against seasonal influenza each year.
2.3.2 The site concerned by this AfA: Val-de-Reuil
Sanofi Pasteur uses Octoxynol-9 at its Val-de-Reuil production site. With over 40 years of experience, the site is among the world's leading producers of seasonal and pandemic influenza vaccines, being considered the site of reference for Flu antigens production and the first manufacturer in the world for seasonal and pandemic Flu production. Val-de-Reuil is the only flu vaccine production site in France, covering all stages of vaccine manufacturing. Val-de-Reuil site covers about 29 hectares and was founded in 1973 in the Normandy Region of France, 100 km northwest of Paris. It is located in the Parc Industriel d’Incarville, just outside Louviers (Eure), in a major pharmaceutical area. The production activities in Val-de-Reuil cover all the steps involved in manufacturing a vaccine: seeds, antigen production, formulation, stages of pharmaceutical preparation (filling, inspection and packaging) and quality control. The site also includes Sanofi Pasteur's global vaccine distribution center, exporting all vaccines manufactured by Sanofi Pasteur in France to 150 countries.
The site in Val-de-Reuil is designated as France’s centre for pandemic vaccines. This means that the site supports a fast change from the seasonal flu vaccine to pandemic vaccine production.
2.3.3 Sanofi Pasteur as a supplier of Pandemic vaccines for the World Health Organization (WHO) and the French Ministry of Health Sanofi Pasteur holds since 2014 a Pandemic Influenza Preparedness contract with the WHO for the sharing of influenza viruses and access to vaccines and other benefits. According to this contract, Sanofi Pasteur, as a manufacturer of flu vaccines, commits to a) donate a specific percentage of real time pandemic flu vaccines production to the WHO and; b) reserve a specific percentage of real time pandemic influenza vaccine production at affordable prices to WHO.
With regards to the supply of pandemic vaccines to the French Ministry of Health (via the French sanitary agency EPRUS), Sanofi Pasteur was awarded in 2015 with a public contract according to the following conditions:
• Firm supply: reservation of production capacity for a specified number of egg-based pandemic influenza vaccine doses;
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• Conditional supply: triggered by French Minister decision based on WHO & EC pandemic declaration, minimum production order of a specified quantity of doses and additional potential orders up to a specified number of doses.
Previous to that, Sanofi Pasteur signed a contract with the French Ministry of Health in 2005 for the supply of H5N1 pandemic vaccines. The same contract was amended in 2009 to include the supply of H1N1 vaccine and expired in 2011.
2.3.4 Recent investments in Val-de-Reuil
Sanofi Pasteur announced in October 2017 that it is investing EUR 178 million to expand the vaccine manufacturing site in Val-de-Reuil. The expansion is important to maintain Sanofi’s world-leading capability in seasonal flu vaccine providers.
The new facilities will allow Sanofi Pasteur to expand supply of VaxigripTetra® The new quadrivalent influenza vaccine was launched in 2017 in 24 countries and contains two A strains and two B strains of influenza virus, as per World Health Organization recommendation. Sanofi Pasteur estimates that, with VaxigripTetra®, at least 1.03 million cases of influenza, 10,000 deaths and 24,000 influenza-related hospitalizations will be avoided (forecasts made between 2002 and 2013 in five European countries including France).
This investment is one of several major capital expenditures Sanofi has made in recent years to improve and expand its influenza vaccine production capacities in France.
Sanofi Pasteur plans to complete the Val-de-Reuil expansion by 2021, subject to relevant environmental and health authority approvals, and target to begin producing vaccines in this new facility in 2023. This date is subject to change as a result of external factors like delay in approval process of the new building BW by health authorities.
In addition to the EUR 170 million xxxxXXXXXXX investment, a new syringe filling line at Val-de- Reuil is under construction (amounting more then EUR 20 millions in investments) and with a start of production in 2019.
2.3.5 Other Sanofi Pasteur sites producing flu vaccines worldwide Sanofi Pasteur has antigen production of Vaxigrip® products at three different facilities worldwide (Val- de-Reuil in France, Ocoyoacac in Mexico and Shenzhen in China). In France, Sanofi sites in Marcy l’Etoile and Le Trait are specialized into filling and packaging activities. The sites are prepared for the production of Panenza® (pandemic flu vaccine) as required in an emergency situation.
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2.3.6 Supply chain
Figure 5 shows the supply chain of Sanofi Pasteur’s flu vaccines in EEA.
Quality control centres and laboratories
Suppliers Egg suppliers (Poultry farms and incubators)
Other raw materials (e.g. Octoxynol-9)
Val de Reuil (all stages of vaccine manufacturing) Sanofi Pasteur Marcy L’Etoile, Le Trait (vaccine filling and packaging)
Distributors
Government
Figure 5: Supply chain of Sanofi Pasteur’s flu vaccines in EEA
Suppliers: after input from the WHO regarding the strain selection, collaborative centers are involved in the process by selecting the vaccine strain candidates. The vaccine strain candidate is chosen and sent for seed manufacturing. After control, the candidate vaccine virus is sent to the manufacturing facility where antigens are produced. Standardized eggs are supplied to Sanofi Pasteur via numerous
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poultry farms. Multiple quality checks are applied through this process. Sanofi Pasteur is also related to multiple other suppliers, including the firm supplying Octoxynol-9.
Sanofi Pasteur: as noted above, the candidate vaccine virus is sent from the supplier to Sanofi Pasteur’s vaccine plants in Val-de-Reuil for seed and antigen production, vaccine formulation, filling and packaging. The eggs are inoculated with the seed lot (previously manufactured by Sanofi Pasteur from virus strain received from WHO collaborating center) and incubated. The antigen is harvested, then purified splitted, inactivated and stored under appropriate conditions. The vaccine is then formulated, filled and packed. All stages of vaccine manufacturing are performed at the site in Val-de-Reuil. Filling and packaging activities only are performed in Marcy L’Etoile and Le Trait. The plant in Marcy L’Etoile is specialized in various antigens production (excluding flu), formulation as well as filling and packaging.
Distributors: flu vaccines are segregated into pandemic and seasonal vaccines and distributed to their respective customers directly by Sanofi Pasteur or via specific vendors and contractors. These vaccines are shipped during Flu seasonal campaigns.
Customers: downstream supply chain comprises of clients based on seasonal and pandemic use of the vaccine. For seasonal vaccines, the customers include large clients such as pharmacies, hospitals, mass immunizers and small clients such as physician offices, clinics, nursing homes and other providers. Pandemic vaccines are sent to the government for use in case of emergencies.
2.3.7 Financial and employment information related to the affected Sanofi Pasteur’s flu vaccines and operations in EEA In the past 3 years, Sanofi Pasteur’s average annual turnover related to the production of flu vaccines at the facility in Val-de-Reuil amounted to XXXXX XXX X XXX XX XXXXX XXXXX XX XXXXXXXxX With regards to purchases from suppliers based in the European Economic Area (EEA), Sanofi Pasteur’s facility in Val–de-Reuil spends XXXXX XXX X XXX XX XXXXX XXXXX XX XXXXXXXxXXXXX required for the manufacturing of flu vaccines. The amount spent annually on salaries concerning the flu vaccines business in EEA reaches XXXXXXXXX.
Currently, including permanent and temporary contracts, XXXXX XXX X XXX XX XXXXX XXXXX XX XXXXX. At the sites in Marcy l’Etoile and Le Trait, xx full time equivalents (in each site, 20 in total) are devoted to filling and packaging of flu vaccines. Considering Sanofi Pasteur’s employees engaged in flu vaccines commercial operations in European Economic Area (EEA), approximately 120 additional full-time equivalents should be taken into account.
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With regard to employment along the supply chain, at least XX full-time equivalents related to external services contracts and XXX full-time equivalents working at egg farms must be considered dependent on the business of Sanofi Pasteur’s flu vaccines manufactured in Val-de-Reuil.
Overall the total of headcounts devoted to flu vaccines production is 1000-1500 HC for Sanofi & suppliers.
2.3.8 Sanofi Pasteur market position Sanofi Pasteur Val-de-Reuil’s (VdR) production of Vaxigrip® products represents xxxxx of the doses XXXXXXXXXXXXXXX supplied to the market within Europe. The remaining xxx of the market are mainly shared by other 4 companies, see Figure 6.
Figure 6: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
The out-of-EU export share of the Vaxigrip® portfolio produced in France is approximately XX, which contributes to a global market share (out of US) of xxx. Vaxigrip® portfolio is the most used worldwide with over 40 years of experienced and licenses in over 122 countries as of 2018. Annually, XXXxXX XXXXXXXXXXXXXXXXX are vaccinated with Vaxigrip® portfolio produced at the French sites.
Sanofi Pasteur is currently pursuing efforts to develop and launch a new generation of influenza vaccine with increased breadth of protection (capable of covering more influenza virus strains) and longer lasting immunisation (no need for an annual vaccination); this project is in alignment with the World Health Organization strategy for global flu immunisation, described in the document “WHO preferred
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product characteristics for next generation Influenza Vaccines”3 issued in 2017 (World Health Organization, 2017). The corresponding project launched by Sanofi Pasteur is named Broadly Protective Influenza Vaccine (BPIV). It is expected that others companies are also working on the development of similar vaccines. Such efforts made by Sanofi Pasteur on the development of a new influenza vaccine generation are critical to keep Europe at the forefront of flu vaccination technology.
2.4 Annual tonnage
As described in the CSR, an average of XXX of Octoxynol-9 is used per antigen production day XX XXXXXXXXXXXXXXXXXXXx in the current facility (BX). Based on Sanofi Pasteur records, an average of 20 to 40 kg XxxX Octoxynol-9 has been used per annum in this process over the last 3 years (2015 to 2017) in the current facility (BX).
In the new facility (BW), Sanofi Pasteur currently anticipates an increase to XXXXXXXXXXX used per annum, consistent with an increase in production capacity XXXxXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXxX < 100 kg/yr XXxXxXX is the maximum anticipated quantity of Octoxynol-9 needed in case of a flu pandemic which would entail using the new facility at its maximum capacity. Normally (i.e. when there is no flu pandemic), however, the maximum anticipated quantity of Octoxynol-9 needed is XXXXXXXX.
Octoxynol-9 (Triton™ X-1004) is supplied by XXXXXXXXXXXXXX imports the Octoxynol-9 from the US and purifies it. Triton™ X-100 (Triton) consists entirely of t-octylphenoxypolyethoxyethanol. In this report, the product is referred to as Octoxynol-9.
2.5 Remaining risk of the “applied for use” scenario
Octoxynol-9 has been listed in Annex XIV because of the “equivalent level of concern due to its degradation to a substance with endocrine disrupting properties”. The concern is however limited to effects on the environment. Potential environmental impacts related to the substance use are assessed in the next section.
3 http://apps.who.int/iris/bitstream/10665/258767/1/9789241512466-eng.pdf?ua=1
4 TritonTM is a trademark of the DOW Chemical Company.
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2.6 Environmental impacts of the applied for use scenario
2.6.1 Assessment of Octoxynol-9 emissions/releases and consequent environmental impacts
The environmental impacts of any releases to the environment are open for discussion given the lack of knowledge and uncertainties surrounding the effects of Octoxynol-9 (and endocrine disruptors in general) at different concentration levels of exposure in the environment. The uncertainty regarding the possibility to derive a threshold for Octoxynol-9 does not allow the definition of exact impacts in the ecosystem neither the consequent monetisation of impacts on ecosystem services.
Given the issues discussed above, the assessment of any potential environmental impacts related to the use of Octoxynol-9 requires the use of qualitative information and alternative quantification methods.
2.6.2 Suggested approaches to perform the assessment: advice from a paper published by ECHA The uncertainties surrounding the evaluation of environmental impacts caused by endocrine disruptors has led to some high-level discussions on the best approach to conduct such assessments. For octylphenol ethoxylates (OPnEO)(the generic class of substances that includes Octoxynol-9) and nonylphenol ethoxylates (NPnEO) specifically, ECHA published the article “SEA-related considerations in applications for authorisation for endocrine disrupting substances for the environment, specifically OPnEO and NPnEO” (SEAC/37/2017/03) (ECHA, 2017) which provides suggestions about possible approaches to be followed in the assessments conducted in the SEAs.
According to the approach ECHA describes in the above-mentioned paper, it is important to recognize that the full quantification of both benefits and risks is not mandatory under REACH, and that a mixed qualitative and quantitative socio-economic analysis can be used to demonstrate the continued use of a substance outweigh the risks (ECHA, 2017). Indeed, ECHA further states that in some cases a qualitative assessment can be sufficient when the benefits to society from continued are considerable and the environmental emissions are properly controlled. Costs for additional risk management measures that could be implemented or currently in place are not relevant for the assessment; however, ECHA states that such costs can be provided to justify releases, by demonstrating releases are minimised as much as possible both technically and practically (ECHA, 2017).
The main suggestion provided by ECHA on how to conduct a SEA in the case of endocrine disrupting substances (specifically OPnEO and NpnEO) is that: “…monetise benefits of continued use and quantified release estimates, complemented with qualitative information, form the basis of a semi- quantitative approach to justifying that the benefits of continued use outweigh the risks.” ( (ECHA, 2017), page 2).
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Besides the monetised estimate of the benefits of continued use of a substance (which have commonly been provided in the previous applications), ECHA states in its paper from November 2017 (ECHA, 2017) that the following information seems to be necessary to be included in the applications:
• “quantified release estimates accompanied with a qualitative description of where the releases occur (e.g. dilution capacity of a river and number of release sources and their temporal and geographical distribution)” ( (ECHA, 2017), page 2); • “a qualitative description of the potential impacts (e.g. on fish populations)” ( (ECHA, 2017), page 2).
In ECHA’s opinion, the information listed above should be sufficient to qualitatively conclude whether the benefits of a use outweigh the risks. However, still according to ECHA (ECHA, 2017), further contextual information on the likelihood and significance of potential impacts can be provided to support the case - “e.g. the margin of safety between predicted or measured environmental concentrations and relevant thresholds of exposure/adverse effect in biota or quality standards from other legislation” ( (ECHA, 2017), page 2). A qualitative comparison of benefits and risks explaining why, from a societal perspective, it is better to continue the use of the substance should be performed by the applicant.
ECHA has declared that “any benchmarks (e.g. EUR of reducing kg of release) above which an authorisation would always be granted cannot be set” ( (ECHA, 2017), page 3). A magnitude of such a benchmark has been reported in the form of a range for PBT/vPvB substances in the SEAC PBT approach (European Chemicals Agency, 2016), however ECHA notes that such benchmark cannot be directly transferred for use in the case of endocrine disrupting substances.
Despite the fact that ECHA states that such ranges cannot be directly applicable to the case of endocrine disruptors, since the use of only qualitative information is always open to subjective interpretations, the benchmark ranges derived in the paper about PBTs/vPvBs will be used in this SEA at least as an auxiliary measure for the assessment (see the following section).
2.6.3 Efforts to monetise environmental impacts of endocrine disrupting substances: taking advantage of the PBT and vPvB case to derive an auxiliary monetised value of impacts Due to the issues surrounding the assessment to endocrine disruptors and Octoxynol 9 specifically, alternative methods for evaluating the environmental impacts need to be considered. Taking into account the existing limitations to an ecosystem services valuation and other preferred methods, an auxiliary estimation for environmental impacts caused by endocrine disrupting substances can be based
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on a cost effectiveness method which ECHA discusses for PBT and vPvB substances (European Chemicals Agency, 2016).
A PBT/vPvB benchmark study by the Vrije Universiteit Amsterdam (VU) (Oosterhuis & Brouwer, 2015) which is referred to by ECHA as a useful information for the topic (European Chemicals Agency, 2016) is used here as an initial basis for the analysis. This assessment was conducted by VU with the aim to develop a benchmark for regulatory decision making under REACH restriction and authorisation processes of PBT and vPvB substances under the premise that in order to decide whether a regulatory action results in net benefits for the society, it is useful to have a comparator or benchmark which reflects the amount of costs that are considered to be worth taking for the reduction of PBT and vPvB.
As ECHA has already acknowledged, due to the specific properties of substances such as PBTs and vPvBs, a full cost-benefit analysis is not always feasible. Therefore, a cost-effectiveness analysis is in some cases more appropriate (European Chemicals Agency, 2016). A cost effectiveness analysis implies the requirement for a benchmark, for which OPnEO currently lacks. For the case of OPnEO there are several difficulties revolving around the lack of different type of data necessary, depending on the approach used, such as the lack of specific historical data, and the high level of uncertainty a benefit transfer of such data would incur.
The VU assessment project collected information on costs to reduce the stocks, presence, flows and emissions to the environment of eight groups of PBT substances and, where possible, related this information to the final decision making (whether the reduction measure had been implemented or rejected due to excessive costs). The cost levels of rejected measures can provide an indication of the maximum willingness to pay for the reduction of PBTs. This can be considered in the context of OPnEO to the extent that ECHA’s Risk Assessment Committee (RAC) has suggested the approach for PBTs might be applicable for this substance. By the same token, the conclusion from the VU study which states “once control is included for other influencing factors…the average unit costs per kg seem transferable across substances” for the mean unit costs (Oosterhuis & Brouwer, 2015) can also be considered relevant for this discussion.
The report by VU examines 36 studies from 10 countries spanning 25 years, with approximately 80 % of these being from the EU. Most of these studies were carried out after 2009. In this report, VU considers three main cost categories for the reductions described (Oosterhuis & Brouwer, 2015):
• Substitution costs - which is either the replacement of the substance with another, or the elimination the substance with a new process.
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• Emission reduction costs - cases where the use of the substance changed, such as a new process with closed applications that ensures drastically reduced (near zero) emissions and exposure. • Clean-up costs - also known as remediation costs; VU includes many forms of clean up from the studies ranging from the removal of the substance from the environment to removal of the substance from man-made structures and equipment. • Other costs – VU notes that each of the examined studies varies in which costs are included or excluded, and that some of the outliers failed to include the ‘real cost’ due to various factors such as secondary benefits, for this reason among others, the outliers are excluded from the final conclusion.
In the studies reviewed by VU, the range of costs was found to be highly sensitive to outliers due to many factors, primarily a difference in methodology between the studies, such as the exclusion/inclusion of secondary benefits and certain extreme scenarios e.g. the economic impacts of temporarily closing a high traffic tunnel down as part of clean-up costs. In addition, a pattern of increasing costs with decreasing concentrations of a substance is observed. Figure 7 below is adapted from the VU report, it demonstrates the median costs per kg for the three different cost types, with remediation having nearly double that of emission control.
Figure 7: Median unit costs of different cost types, excluding outliers (adapted from Oosterhius & Brouwer, 2015)
While the previous figure represents the median cost per kg, in order to conservatively estimate the potential environmental impacts, the upper bound of acceptable cost-effectives is of interest for a conservative estimation. VU concludes that the viable range depends on the specific substance and situation, though with a broad ‘grey zone’ in which the cost-effectiveness per kg is no longer considered
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acceptable, while there are some outliers, VU suggests that 1,000 – 50,000 EUR/kg demonstrates a probable ‘grey zone’, though VU notes that the range is not based on specific cases, but is their general conclusion and that accuracy of this range could be improved with additional data in future studies. This range of potential WTP for the cost-effectiveness is demonstrated below in Figure 8.
Figure 8: Visual representation of VU’s cost-effectiveness ‘grey zone’ (adapted from Oosterhius & Brouwer, 2015)
Despite the fact that no benchmark could be defined by the VU project, VU concludes that the range of the so-called ‘grey zone’ is the range in which the measures to reduce the use, presence or emission of PBTs may be prohibitive from a cost-effectiveness standpoint, depending on the specific case. As the sample is limited and there are significant outliers, VU emphasizes that the use of this “grey zone” cannot be used as a pass-fail criterion in decision making. However, VU suggestions such a grey zone could be used in the benchmarking process as an initial screening for which further situation-specific assessments would be required on a case-by-case basis. While this grey zone is provided with caution and is based on limited data, it is currently the best estimate for the mean costs that are still considered cost effective, and therefore can be considered as the range for the WTP for these substances (Oosterhuis & Brouwer, 2015). VU’s linear regression analysis finds “…that the type of substance does not have a significant effect on the mean unit costs…” (Oosterhuis & Brouwer, 2015) which further supports the case for the relevance of these figures with the endocrine disruptor OPnEO.
With this data and range for the estimated WTP for cost-effectiveness per kg, it is important to note that this estimate is provided as a general measure only, and should only be used to form an opinion when also considering the qualitative aspects described in this report, as well as the results of the uncertainty analysis in section 4.5. With this consideration, an auxiliary monetised measure of environmental impacts is estimated using the range of EUR 1,000 to 50,000 EUR per kg of OPnEO emissions.
2.6.4 Qualitative assessment of environmental impacts in the applied for use scenario following the approach suggested by ECHA a) Introduction
Octoxynol-9 is a process agent and a functional ingredient of the flu vaccine and so a substantial fraction of the Octoxynol-9 used remains intentionally in the final vaccine. A proportion of the Octoxynol-9 is however removed in aqueous solution during antigen production. As described in the CSR, this wastewater is biologically contaminated with pathogens and, according to law and contract, must be
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contained on-site until it is treated to remove the biological contaminants and address the associated risk to human health. This requirement to manage the biosafety has important implications for management and chemical treatment of the wastewater at both the existing and planned new Val-de- Reuil building.
Regulatory requirements relating to the production of and control of biological hazards set down clear, unavoidable and tightly enforced obligations for Sanofi Pasteur in terms of the management of Octoxynol-9 releases to the environment.
b) Risk management measures to reduce emissions and quantity of releases
In order to discuss risk management measures and releases to the environment, it is important to differentiate the situation currently and what is planned to happen when the new facility which is being built and will start operating in xxxx. Production of the concerned vaccines will be gradually transfer from the current facility to the new one with a 100% of the production taking place at the new facility as of xxxx.
• Current facility
o Releases to wastewater:
Wastewater from the antigen room connects to the site wastewater system. In the existing site permit, there are no specific obligations relating to Octoxynol-9 however, Article 4.3.8.1 “Water waste potentially contaminated with biological pathogens” of the Prefectoral operating permit of Val-de-Reuil dated February 21, 2017 provides that “Effluents and liquids produced in a biological safety zone, and if necessary shower water, are qualified as potentially contaminated. These effluents cannot leave the production building and remain confined in zone BSL2+. Thermal processing will destroy any virus at this level before release downstream. For the collection, storage and, generally speaking, any action involving potentially contaminated effluents, measures are taken against the risk of spreading biological agents into the environment”.
Moreover, a report of the Haute-Normandie DREAL (Local Environmental Agency) dated June 15, 2009 entitled “Surveillance initiale des rejets de substances dangereuses dans le milieu aquatique” (“Initial monitoring of hazardous substances released into the aquatic environment”), in application of a circular dated January 5 2009, concerning the Val-de-Reuil site operated by Sanofi Pasteur, specifically takes into account the substance octylphenol. In a letter of April 3, 2013, the DREAL indicated, based on the monitoring measures taken by the company Sanofi Pasteur, that it was not necessary to continue monitoring octylphenol given
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41 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS the limited daily average flow of the substance and the fact that this latter was not “behind any local incidence”.
Therefore, specific processing of water waste potentially contaminated with biological pathogens also applies to effluents containing Octoxynol 9 in as far as this Octoxynol-9 is used in the same zone as the biological pathogens. Effluents likely to carry virulent agents must be collected in the waste water network and conveyed to the decontamination station to be thermally inactivated before disposal by the wastewater network. All wastewater from flu vaccine production is directed to one of two storage tanks. The tanks feed a thermal decontamination station. The decontamination station is designed to kill all microorganisms in the wastewater by exposing them via any of 5 units of 1.5m3 capacity each to heat (the water is heated to 80°C during 10min). The water is then cooled to 35-40°C. This decontamination process is a regulatory requirement, as described in the CSR. It is necessary to inactivate the microorganisms and so remove the risk to human health associated with exposure to pathogens in the wastewater. The thermally treated process wastewater is released directly to the effluent treatment station in the south-west of the site. There the water is collected in holding tanks. The temperature and pH of the water is automatically monitored and adjusted as necessary to meet requirements of its wastewater discharge license. The effluent treatment station in the south-west corner of the site comprises wastewater holding (retention) tanks with a simple recirculation system and dosing to adjust pH. 24-hour sampling facilities are provided, by which 70 ml of wastewater is collected every 4m3 of effluent to provide a composite sample. Wastewater from the effluent treatment station is discharged to the municipal wastewater treatment plant, Station d’epuration urbaine de Louviers, and then to the Eure river.
Currently, the maximum quantity of Octoxynol-9 released to the environment is more likely to be 10-20 kg xxxxxxxx per annum, though this is expected to be conservative. Assuming 10-20 kg xxxxxxxx per annum is released to the environment over xxx production days, the average amount of Octoxynol-9 discharged to wastewater on a production day is xxxxx. Assuming 270 m3 of wastewater per day would suggest a daily concentration of Octoxynol-9 in wastewater of 250-350 µg/l xxxxxxxx.
As indicated in the CSR, Sanofi Pasteur is working on the implementation of additional risk management measures at the current facility (BX) which will be operational before the sunset date and reduce emissions by 5.9%, see Table 4.
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Table 4: implementation of risk management measures at the current facility % of octoxynol-9 Current (old) facility reduction in wastewater
Cylinder wash 2.7 Use of disposable cylinder => no more wash
Centrifuge rotor 3.2 Specific Collect in infectious clinical waste draining bags and incineration
In the future, the maximum quantity of Octoxynol-9 released to the environment will be approximately XXXX XXXXXXx in the current facility, though this is expected to be conservative (see discussion about measured emissions in the CSR). Assuming XXXXX per annum is released to the environment over XXXXXXxXXXX X the average amount of Octoxynol-9 discharged to wastewater on a production day is XxXXX Assuming 270 m³ of wastewater per day would suggest a daily concentration of Octoxynol-9 in wastewater of 250-350 µg/L XXXXX
o Releases to air: As stated in the CSR, there is negligible potential for release of Octoxynol-9 to air. Octoxynol-9 is not expected to partition to the air compartment. No energetic processes are involved, and no aerosols are generated in the process. Furthermore, exposure to air is minimised by stringent quality control procedures. The processes are carried out with extreme care to avoid accidental spillage or release. Procedures to prevent spillage or agitation of the mixture are used, e.g. when transferring Octoxynol-9 samples to the quality control laboratory or transferring Octoxynol-9 from storage to the production area. Air from the entire flu vaccine production area is extracted via HEPA filters, which are incinerated as hazardous wastes.
o Releases to soil: There is no release under any circumstances of Octoxynol-9 to soil.
• Plans for the new facility
As described in the CSR, the same antigen and flu vaccine processes will be conducted at the new flu vaccine production facility. The new facility is being designed to enhance production according to Good Manufacturing Practice (GMP). The process will be more highly automated and, fortunately, since the timing of design phase has coincided with preparations for authorisation, can incorporate specific measures to minimise release of Octoxynol-9.
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43 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS o Releases to wastewater: A comprehensive evaluation of opportunities to reduce releases of Octoxynol-9 to the environment has been carried out. The aim was to identify those steps in which Octoxynol-9 is incorporated and eliminated from the process, and to identify opportunities to eliminate or reduce sources. The assessment considered options to treat wastewater from XssXX Fragmentation, Xsss X Diafiltration and subsequent steps Xsss XX XXXXXXXXXXXXX Xsss XX XXXXXXXXXXXXX Xsss XX XXXXXXXXXXXXX in which the monovalent antigen is rendered inactive.
A feasibility study has been carried out and, based on extensive review, concluded that the following approach to minimise release of Octoxynol-9 will be implemented (see the CSR for details): - Closed measuring and delivery of Octoxynol-9 to remove measuring cylinder wash XXXXX - Collect and incinerate supernatant from the centrifuge rotor XXXX - Capture and incinerate permeate of diafiltration XXXX
By incorporating the measures above, Sanofi Pasteur will remove 99% of Octoxynol-9 release to the environment. Based on this, it is expected that release of Octoxynol-9 from the xxx XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXx There will be no release of Octoxynol-9 on other days. It is estimated that approximately 0.1 to 0.4 Kg XXxxXX of releases to wastewater per year will then result from remaining activities per year.
As it also stated in the CSR, the treatment of wastewater considering the steps XX xx XX (XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXxxxxxxxxxxXXXXx is considered not to be economically justifiable since major investments would be required for a relatively low benefit in terms of reduction of releases to the environment (see CSR). No Octoxynol-9 is intentionally removed in steps XX x XX; wastewater contains only very tiny amounts of residual Octoxynol-9 from washing of vessels that were in contact with the antigen containing a maximum of XXXXXXXXXXXXXXX Octoxynol 9. Losses of antigen are carefully avoided throughout the process. Assuming a dilution factor of 100 during washing the concentration is <<0.01%.
o Releases to air: As stated in the CSR, there will be negligible potential for release of Octoxynol-9 to air.
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o Releases to soil: There will be no release under any circumstances of Octoxynol-9 to soil.
• Justification to focus environmental risk management investment to recover permeate of diafiltration in the new flu vaccines manufacturing building
A critical commitment has been made by Sanofi Pasteur through investment in a new flu vaccine production facility. As noted in the CSR, this new facility provides an opportunity to ‘build-in’ measures to minimise release of Octoxynol-9.
As the new flu building is commissioned and brought on line, this major investment will be realised. The existing flu building is scheduled to scale back operations from xxxx, two years after the sunset date, and to cease operations by xxxx. On current schedule, there will be no release of Octoxynol- 9 from the existing flu building after xxxx. As such, the main opportunities to reduce releases could be realised in the new flu building, noting the transition plan shown in Table 5.
Table 5: Planned schedule for moving to production to new flu building from existing facility
Use of Octoxynol-9 at Production capacity at existing existing flu vaccine Year flu vaccine production building production building per [%] annum (Kg) 2018 – 2021 XXXXX XXXXX 2022 XXXXX XXXXX 2023 XXXXX XXXXX 2024 XXXXX XXXXX 2025 XXXXX XXXXX Total XXXXX XXXXX
Release of Octoxynol-9 to the environment from the existing building is a fraction of the total possible use. XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXxxxxx, the total amount of Octoxynol-9 released to the environment from the existing building between 2021 and 2024 is approximately < 70 kg 55.16 Kg. Table 6 shows the total releases from the current building as production is gradually moved to the new one.
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Table 6: Predicted Release of Octoxynol-9 from xxxxxxxxxxxx in the BX Building due to implementation of enhanced Release Minimisation Measures
Year Release Octoxynol-9 in Kg
2021 XXXXX
2022 XXXXX
2023 XXXXX
2024 XXXXX
2025 XXXXX
Total XXXXX
Due to the discussed transition to a new building, any further risk management measures to be implemented in the existing facility (besides the ones discussed in Table 4) would be in place for only 4 years, when flu production is already scaling back. Therefore, additional investments would have to be amortised over only 4 years.
Given the above, substantial investments in reducing releases to the environment from the existing facility are not economically pragmatic. Nonetheless, technical feasibility has been also assessed and demonstrated that such additional risk management measure to collect permeate of diafiltration would have workers safety and organizational impacts. Furthermore, as the wastewater from antigen production must be contained and thermally or chemically treated to remove biological contaminants before further treatment to reduce Octoxynol-9 can occur, options are limited, expensive and present significant practical problems.
Due to limited space to accommodate new tanks and decontamination equipment, physical constraints mean it is not possible to modify the process to divert, contain, decontaminate and treat Octoxynol-9 in wastewater at the existing facility. Furthermore, this would require substantial modifications to the existing process, involving disruption and substantial investment, for a limited period (<4 years) of diminishing return. The minimum possible cost of such modification is estimated to be EUR 3 million at a minimum , based on implementing a new decontamination station for XXXxxxXXXXX alone. As shown above, the benefit of the improvements would be limited to a total of < 70 kg xxXxxxXX of Octoxynol-9. The cost of such improvements can thus be represented in terms of cost per unit of Octoxynol-9 removed (xXxxxXX per kg Octoxynol-9). These costs would increase the cost of the flu vaccine significantly since the cost would be amortised over 4 years. Furthermore, on closure of the facility, any new investment becomes redundant and, indeed, there is a further cost for dismantling and disposing of materials. The environmental impact of installing, operating and then disposing of a new facility within a 4-year
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timeframe should not be overlooked. Additionally, substantial resource would need to be diverted from existing efforts to develop the new facility to design and implement the new treatment facility.
Considering this, it makes clear sense to rather focus effort and investment on optimising the new flu antigen production facility BW to minimise release of Octoxynol-9 to the environment. Since there is the opportunity to amend the design of the new building (although not the process), the evaluation shows that investment in the new building yields greater environmental benefit overall.
On the basis of measures which will be implemented at the new facility, the amount of Octoxynol- 9 released from the site to the municipal wastewater treatment facility will be reduced substantially, see Table 7 and Table 8.
Table 7: Use of Octoxynol-9 at the new facility flu building (BW)
Production capacity at new flu Use of Octoxynol-9 per annum Year vaccine production building [%] (Kg) XXXX XXX XXX XXXX XXX XXX XXXX XXX XXX XXXX XXX XXX XXXX XXX XXX
XXXxxxXXXXXXXXXXXX is kept in the antigen and that the release minimization measure will reduce by 99% the Octoxynol-9 release, future releases from the new facility are predicted as shown in Table 8.
Table 8: Predicted Release of Octoxynol-9 in the new facility due to implementation of enhanced Release Minimisation Measures
Year Annual release Octoxynol-9 (Kg) from the new facility XXXX XXXX XXXX XXXX XXXX XXXX XXXX XXXX XXXxxxXXxXX XXXX
• Summary of total Octoxynol-9 releases planned to happen due to transition to new facility
As discussed, the total emissions resulting from the plan presented above (transition of production from the existing facility to the new facility which is being built) would result in two components of Octoxynol-9 releases via wastewater during the review period applied for:
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1) Releases from the existing facility during the transition period in an amount of < 70 kg XXXxxxXX of Octoxynol-9 until 2024. 2) Releases from the new facility amounting to approximately 0.1 to 0.4 Kg XXxxxXXx per year when entire production is transferred from the existing to the new building. Measures to be implemented at the new building will therefore vastly minimise emissions to the city WWTP of Louviers. c) Description of where the releases occur: dilution capacity of the river Eure and number of release sources and their temporal and geographical distribution
As presented in the CSR, information on the hydrology of the Eure at Louviers (Code H9501010) is available from Banque Hydro. Flow data is available for 1971 to 2018. The Eure has very low seasonal flow fluctuations, with high winter-spring water resulting in an average monthly flow to 29 to 34.6 m3 per second, from December to early April inclusive (with a maximum of January- February), and low summer water from June to October inclusive. The minimum known flow over 3 consecutive days occurred in 2012 (9.480 m3 per second). The theoretical low flow over a 5 and 10 year period is 11.8 m3 and 10.5 m3 per second respectively, with a confidence interval of 95%. This indicates, even under worst case conditions, substantial dilution of treated wastewater from the treatment works in the Eure (factor of >200).
Sanofi Pasteur worked with the local wastewater treatment facility to further quantify release to the environment from the facility. A schematic of the wastewater treatment facility, showing inputs to and outputs from the facility is provided below. As noted above, the Sanofi Pasteur facility discharges wastewater to the drain that flows to the wastewater treatment facility via the industrial (80% of the volume) and residential area of Incarville. Wastewater from Louviers and ZAC Louviers (a relatively small commercial area that includes a supermarket and a garage) enter the wastewater treatment facility via separate drains. Sanofi Pasteur arranged to measure the concentration of Octoxynol-9 and octylphenol upstream and downstream of the WWTP, see Figure 9.
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Figure 9: Schematic of inputs to and outputs from the municipal (‘City’) wastewater treatment facility
Measurements conducted at the wastewater treatment facility (see CSR for details) show that there are no detectable concentrations of Octoxynol-9 in wastewater entering or treated wastewater existing at the wastewater treatment facility. There are measurable concentrations of octylphenol in both wastewater entering and in treated wastewater exiting the wastewater treatment facility. However, concentrations of octylphenol in wastewater from Incarville, which includes wastewater from the Sanofi Pasteur site, is significantly lower than that entering the wastewater treatment facility from the ZAC Louviers commercial district and similar to that entering the wastewater treatment facility from the residential district of Louviers. Furthermore, and importantly, the concentration of octyphenol in wastewater from Incarville was higher on the occasion that antigen production was not being carried out at the site than on two other occasions when it was being carried out. It has to be concluded that the Sanofi Pasteur site has no measurable impact on levels of Octoxynol-9 or octylphenols at the wastewater treatment facility.
Therefore, while there is release of octylphenol from the municipal wastewater treatment facility, the levels observed cannot be attributed to the Sanofi Pasteur operations. There appears to be multiple other sources of octylphenol to the wastewater that is resulting in the observed concentrations, since all incoming waste streams are impacted. There is no information to characterise these sources.
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The CSR shows that concentrations of Octoxynol-9 in the Eure attributable to the municipal wastewater treatment facility will be substantially less than 0.1 µg/L. Based on a worst-case (lowest) dilution factor of 200, they will be <1 ng/l.
Concentrations of octylphenol in wastewater cannot be attributed to the Sanofi Pasteur facility. Based on a worst-case dilution factor of 200, it will be 0.15µg/l. This is similar to concentrations in incoming water to the site. Figure 10 summarising the data is provided below.
Figure 10: Summary of octylphenol and Octoxynol-9 concentrations in feed water to and wastewater from the site. d) Qualitative description of the potential impacts
Available study data, as referred in the CSR, indicates that prolonged exposure to 4-t-OP (resulting from Octoxynol-9 and intermediate degradation products) can cause reproductive effects in fish, amphibians and invertebrates. This has been correlated to the xenoestrogenic potential of the substance.
For fish, a large amount of data is available for several species. This includes full life cycle tests on two species of fish. The studies indicate the most sensitive apical endpoints reported include the number of eggs produced, fertility of the parent generation and time to reach sexual maturity. Reported NOECs range between 12 μg/L and 30.4 μg/L (measured concentration). The most sensitive NOEC value for fish from the different key studies is related to reproductive endpoints in Danio rerio, amounting to 12 μg/L. The underlying effects are clearly identified as threshold effects.
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Data from amphibians covers life stages sensitive to effects on the endocrine system and relevant for assessing consequences for the living organism and for populations. The effects of 4-t-OP on larval growth, timing and rate of metamorphosis, and sexual development of Xenopus laevis and X. tropicalis are available and influence on sexual development, materialising in sex ratio shifts (feminisation) and formation/delayed regression of oviducts in males are reported. A NOEC of 3.3 μg/L is identified for these effects in amphibians.
Limited ecotoxicological data for gastropods considering exposure to 4-t-OP is available. The lowest reported effect concentrations with respect to embryo numbers were 1 μg/L water and 1 μg/kg sediment dry weight, respectively. In a weight-of-evidence approach taking into consideration the results of seven independent experiments from the OECD 242 range-finding study and six experiments reported in the UBA validation study, a NOEC for the total number of embryos of 0.34 μg/L (measured concentration) is carried forward. Applying a conservative Assessment Factor of 10 provides an indicative PNEC freshwater value of 0.034 μg/L.
Local concentrations in freshwater are expected to be less than 1ng/l for the existing facility based on measurement and conservative assumptions regarding dilution in the receiving freshwater. This will be further reduced once the new flu building is commissioned. Concentrations from the new Sanofi Pasteur will be approximately a factor of 100 lower still.
The concentration in surface waters relating to release from the existing Sanofi Pasteur facility is therefore substantially below predicted no effect concentrations.
e) Existing quality standards from other legislation applied to the location
Please refer to the CSR for the description of regulatory requirements as well as standards and procedures applicable to Sanofi Pasteur operations in Val-de-Reuil
2.6.5 Derivation of an auxiliary monetary value for the environmental impacts based on the volume of Octoxynol-9 emissions Taking into consideration that the monetary value per Kg of emissions provided in the paper from the VU in Netherlands (described in a range), the calculations of an auxiliary monetary value for the environmental impacts will also be performed in the terms of a range, see Table 9.
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51 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
Table 9: Derivation of an auxiliary monetary value for the environmental impacts based on the volume of Octoxynol-9 emissions Year Emissions Emissions Total Lower bound of Upper bound of (kg) from (kg) from emissions environmental impacts environmental impacts existing new building (kg) (EUR 1,000 per Kg of (EUR 50,000 per Kg of building emissions) emissions)
2021 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2022 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2023 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2024 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2025 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2026 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2027 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2028 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2029 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2030 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2031 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2032 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2033 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2034 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2035 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2036 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2037 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2038 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2039 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2040 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX
2041 XXXXXX XXXXXX XXXXXX XXXXXX XXXXXX Total XXXXXX XXXXXX XXXXXX over 21 < 70kg < 10kg < 80kg years (kgs) Sum of discounted monetary values as of 2021 using xxxxxxxxxxxXXX xxxxxxxxxxXXX a 4% annual discount rate EUR < 0.2 million EUR < 3 million
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52 ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
Since the ranges calculated in this section cannot be used as the only reference for final conclusions on environmental impacts (but only as an auxiliary value to support the analysis), a final assessment (also using qualitative information previously disclosed) is performed in the following section.
2.6.6 Conclusions on environmental impacts in the applied for use scenario
As it has been presented in this section, given the existing Sanofi Pasteur investment plans which should be approved by Health Authorities in 2022-2023, releases of Octoxynol-9 in the environment will be substantially reduced after 2024, amounting to only 0.1 to 0.4 Kg XXXXX per year at the new facility when production is fully transferred. In the new facility, wastewater containing residues of Octoxynol-9 will be almost completely incinerated.
In the meantime, while transition from the existing manufacturing building to the new facility happens, approximately < 70 kg XXxXXX of Octoxynol-9 should be released via the wastewater from the existing facility by applying the two technically feasible minimization measures.
Sanofi Pasteur is committed to reducing its emissions of Octoxynol-9 into the environment and this is clear given the additional investments the company is doing on its new facility. Despite the efforts, approximately < 80 kg xXxxxxXX of Octoxynol-9 will be released during the 21 years review period.
Local concentrations in freshwater are expected to be less than 1ng/l for the existing facility based on measurement and conservative assumptions regarding dilution in the receiving freshwater. This will be further reduced once the new flu building is commissioned. Concentrations from the new Sanofi Pasteur will be approximately a factor of 100 lower still.
The concentration in surface waters relating to release from the existing Sanofi Pasteur facility is therefore substantially below predicted no effect concentrations (see CSR for details).
3 SELECTION OF THE “NON-USE” SCENARIO
3.1 Efforts made to identify alternatives
3.1.1 Research and development Sanofi Pasteur has more than 70 years of experience in biotechnological processes and vaccine development. As mentioned in section 2.1.2, the company first commercialized its seasonal influenza vaccines in 1968 in France. Since then, Sanofi Pasteur has refined its manufacturing process with the continuous upgrading of its production line (e.g. new filling and visual inspection units), the construction and adaptation of new installations (Val-de-Reuil in France, Swiftwater in the USA,
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Ocoyoacac in Mexico and Shenzhen in China), and the improvement of its existing vaccines (development of high-dose and quadrivalent vaccines, for example). These activities have resulted in robust manufacturing processes that reliably cover an important fraction of the worldwide demand for influenza vaccines.
Current R&D activities:
New technologies are being investigated that will allow the development of more and better vaccines. Within this goal, Sanofi Pasteur is supporting ground-breaking efforts to develop and launch a new generation of Influenza vaccine, the BPIV. This new vaccine will offer increased breadth of protection (capable of covering more influenza virus strains) and longer-lasting immunization (no need for an annual vaccination) in alignment with the WHO strategy for global flu immunization. Sanofi Pasteur is one of several pharmaceutical companies currently working on the development of this vaccine. The process to purify the active substance for the new vaccine, the virus antigen, may also require the functionalities that are currently fulfilled by Octoxynol-9 (virus splitting, virus inactivation, stabilisation) in the current manufacturing process, so an alternative must still be identified and implemented.
3.1.2 Data searches As a basis for identifying alternatives to Octoxynol-9 for the production of its flu vaccines, Sanofi Pasteur started by conducting a benchmark study to determine whether alternatives are already in use. The alternatives identified through these studies were initially evaluated through a desktop research for scientific literature. This was based on the analysis of others companies’ products, including searches in product leaflets, competitive analysis information and patent analysis. This research resulted in the identification of analogue substances to Octoxynol-9 that are currently being applied in other related processes. These substances are described in more detail in section 3.3.2.
3.1.3 Consultations Multiple consultations with experts within Sanofi Pasteur were carried out for the elaboration of this AfA, covering the areas of R&D, legal issues, finances and administration, mainly. The result of these exchanges was an overview of the substitution strategy within Sanofi Pasteur and the collection of data related to its realization. Data collection was carried out in different ways: site visits were made to obtain information relevant for the CSR section of this document, while more technical questions were prepared and discussed with the corresponding experts within Sanofi Pasteur to collect and verify data related to the AoA and SEA sections. This information was then used to create a detailed description of the actual processes in which Octoxynol-9 is used within the company, the key functionalities that it fulfils in these processes, the status of research activities for finding an alternative, the foreseen
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substitution timeline and the impacts of substitution, among others. The information presented in this AfA is the result of this extensive in-house research.
Furthermore, Sanofi Pasteur has initiated consultations with the current supplier of Octoxynol-9 regarding potential alternatives. Information about a new potential alternative is expected to be available in 2019.
3.2 Identification of known alternatives
Sanofi Pasteur has started investigating alternatives to substitute Octoxynol-9 in the production of its influenza vaccines. Two substitution strategiens have been identified:
• Implementing an Octoxynol-9 free process by transitionning to a new generation of flu vaccine, the BPIV (main alternative) • Susbtituting Octoxynol-9 in the current Vaxigrip® brand process
For the reasons described in the following chapters, Sanofi Pasteur plans to substitute Octoxynol-9 by implementing an Octoxynol-9 free process in the development of the BPIV rather than by substituting it in the production of the current influenza vaccines (Vaxigrip®).
Laboratory tests to identify substitutes to Octoxynol-9 for the BPIV process will start in xxxx. The substances that have been idenditified as potential alternatives are shown below in Table 10. An alternative is expected to be implemented in the BPIV production process during clinical phase II, after an expression system has been selected. The substances in this list are used by other flu vaccine companies in other processes for recovering virus antigens in the production of different vaccines. Other candidates from other processes and from data searches are being investigated. However, because these processes and products are different to Sanofi Pasteur’s (some are subunit vaccines, for instance), it is not yet certain that these potential alternatives will fulfil the required functionalities of Octoxynol-9 in Sanofi Pasteur’s process.
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Table 10: Short list of substance alternatives
No. Alternative
1 Sodium deoxycholate (or taurodeoxycholate)
2 Alpha-tocopheryl hydrogen succinate
3 Polysorbate 80
4 CTAB (cetyltrimethylammonium bromide)
The suitability assessment of these potential alternatives for substituting Octoxynol-9 in Sanofi’s BPIV process is in early R&D phase. This assessment is still limited to initial suitability tests because the BPIV process itself is still under development. The technical limitations described in section 3.3.2.2 are based on literature as well as on the knowledge of other flu companies’ history with using the substance (troubleshooting, batches recall, pharmacovigilance issues). These alternatives are discussed in more detail in the following sections.
Alternative techniques were not considered as potential alternatives because, to Sanofi Pasteur’s current knowledge, no other technology (e.g. pasteurization, dry heat, vapour heat or treatment with low pH) shows the same virus splitting and virus inactivation properties as the current detergent treatment. Therefore, only alternative substances for such a treatment were considered.
3.3 Assessment of the two potential strategies to substitute Octoxynol-9
In this section, the two substitution strategies considered by Sanofi Pasteur are described in more detail. The main alternative consists in the complete transition to the new-generation of vaccines using an Octoxynol-9-free process (substitution at a process level). This approach is described in section 3.3.1. Section 3.3.2 describes the approach to substitute Octoxynol-9 in the current process. The alternative substances described in these sections have not been tested in process-specific tests, and therefore only constitute potential candidates that must still be further evaluated.
3.3.1 Main alternative: Transition to a new generation of flu vaccine As described in previous sections, Sanofi Pasteur currently develops a new type of influenza vaccine, the BPIV, in line with the WHO’s strategy to fight influenza . This vaccine will allow a broader protection against influenza and will better protect the vaccinee against current and future flu viruses. R&D efforts for the development of this new vaccine require enormous attention. On the one hand, the antigen itself must be developed in the form of a genetic sequence that yields the desired antigen when expressed, and, on the other, a suitable expression system must be established to multiply the antigen
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and obtain enough quantities for the manufacture of vaccines. Delivering this breakthrough in vaccine technology is of great importance for public health, and Sanofi Pasteur’s goal is to achieve this development and launch in all current market within a 20-year timeframe. Nonetheless, it is important to recognise that, as with any innovative development, the timing of the program cannot be assured in advance.
Sanofi Pasteur has already started the development of the BPIV and is currently conducting clinical trials (phase I). The lots used for pre-clinical and clinical studies have been manufactured using the egg-based expression system also used for producing the current seasonal and pandemic vaccines, and it therefore also used Octoxynol-9 for virus splitting. The egg-based system with Octoxynol-9-based virus splitting was chosen for manufacturing these first lots of the BPIV because Sanofi Pasteur already has the expertise and the technical resources needed for this platform, thus facilitating and speeding up the development and clinical testing of the BPIV. However, as described earlier, Sanofi Pasteur is investing significant R&D resources to develop a new platform that will replace the current egg-based one and that will not use Octoxynol-9 for virus splitting.
Sanofi Pasteur’s plan is to move away from its current egg-based expression system for the BPIV and to develop a different expression platform for producing the virus antigen that will constitute the main ingredient of its new-generation vaccines. Production of the virus antigen might be achieved through recombinant or cell-based production. The new platform is expected to offer an increased yield of antigen and will reduce the risk of contamination from adventitious virus agents normally found in poultry.
The expression system used will have an impact on the performance and the behaviour of the substance used for antigen extraction, so testing of alternatives can only start once an expression system has been selected. The main step for purifying the viral antigen in the new platform will be similar to the method applied in the production of the current vaccines. Once the technical development of the BPIV process is established and a suitable expression system for the viral antigen is selected, validation studies will be carried out using the specific process-conditions.
Studies to select an adequate expression system will start in xxxx, but regardless of the expression platform used for producing the viral antigen for the BPIV, Octoxynol-9 will be substituted. Implementing a potential alternative into the BPIV development rather than in the current vaccines provides an opportunity to transition in an economically viable manner to an Octoxynol-9-free process. It would not be viable to have a parallel investment for the implementation of an alternative to Octoxynol-9 in the current process for the seasonal vaccines and for the BPIV.
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3.3.1.1 Technical feasibility
The development of the next generation BPIV has been ongoing for several years. Early laboratory testing was initiated in xxxx. An expression system using Octoxynol-9 was used to develop the BPIV and to produce the material needed for preclinical and clinical trials. Preliminary testing of suitable alternatives will start in xxxx. The substitution strategy pursued by Sanofi Pasteur is discussed in section 3.4.
Since some competitors are already using various alternative expression platforms, Sanofi Pasteur is confident that a new production system can also be developed for its BPIV process and that a suitable substance can be implemented that fulfils the same functionalities as Octoxynol-9 in the current process.
Table 11 below shows the identification numbers of the substances currently considered for substitution of Octoxynol-9 in the BPIV production process.
Table 11: Substance ID and properties of substance-level alternatives
Alternatives Numerical Identifiers
Sodium deoxycholate/ CAS No: 302-95-4, 1180-95-6 Sodium taurodeoxycholate EC No: 206-132-7, 214-652-0
Alpha-tocopheryl hydrogen succinate CAS No: 4345-03-3 EC No: 224-403-8
Polysorbate 80 (Sorbitan monooleate, ethoxylated) CAS No: 9005-65-6 EC No: 500-019-9
CTAB CAS No: 57-09-0 (cetyltrimethylammonium bromide) EC No: 200-311-3
The technical feasibility of some of these substances for substituting Octoxynol-9 in the BPIV production process is currently under assessment at Sanofi Pasteur. At the current state of knowledge, based on literature and benchmark of others companies on the subject, all substances pose technical limitations. These are summarized Table 12 below and further explained in the following paragraphs. As discussed previously, laboratory testing of these alternatives will start after an expression system for the BPIV has been established, which is expected to take place in xxxx.
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Table 12: Technical limitations of potential alternative substances
Technical performance Performance Alternatives Consequences/comments parameter not fulfilled statement
Lower product safety – if Not as efficient as Sodium deoxycholate/ Flu virus splitting, antigen used, would need to Octoxynol-9 (low taurodeoxycholate) stabilization complement with other(s) splitting efficacy) surrogate(s)
Lower product safety – if Unknown – possibly flu virus Alpha-tocopheryl used, would need to splitting and adventitious agents’ Unknown efficiency hydrogen succinate complement with other(s) inactivation surrogate(s)
Lower product safety – if Not as efficient as Flu virus splitting, adventitious used, would need to Polysorbate 80 Octoxynol-9 (low agents’ inactivation complement with other(s) splitting efficacy) surrogate(s)
Lower product efficacy – if CTAB Unknown (today, used, would need to (cetyltrimethylammonium Antigen stabilization currently applied to complement with other bromide) sub-unit vaccines only) surrogate(s)
Virus splitting: The latest research results and information obtained from others companies suggest that all substances except CTAB are less efficient than Octoxynol-9 in terms of virus splitting. A low virus splitting efficacy negatively impacts product safety because unsplit viruses are potentially infectious and more reactogenic, and thus pose a major risk in the final vaccine. Additionally, antigen yield and recovery would be lower, making the overall process less efficient. These substances could only be used in combination with others to achieve the same virus splitting performance of Octoxynol-9. In the case of CTAB, current information suggests that this substance provides splitting efficacy and viral safety comparable to Octoxynol-9, but it is currently used only in sub-unit vaccine, whih is a totally different manufacturing process. In contrast to Sanofi Pasteur’s current flu vaccines, sub-unit vaccines are further purified and therefore contain less of the other viral proteins from the influenza virus used for their production, possibly leading to a lower efficacy of the vaccine.
Virus inactivation: General viral inactivation is not expected to represent a major limitation to substitution. Both deoxycholates and CTAB are efficient enough for pathogen inactivation. However, this is not the case with alpha-tocopheryl hydrogen succinate and polysorbate 80.
Stability: The stability of the flu vaccines produced using these alternatives has not yet been evaluated, as the BPIV is still under development. Stability tests usually take significant time (up to two years) as they must be conducted throughout the vaccine’s entire shelf life. The impact that substitution of Octoxynol-9 with these alternatives might have on the final vaccine is therefore still unknown. It is
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speculated, however, that none of these substances would offer the same stability as Octoxynol-9 in the current vaccines.
3.3.1.2 Availability of Alternative
All the substances discussed in this section are available from chemical suppliers in enough quantities for this application. However, due to the REACH impact on Octoxynol-9, the global demand for the surrogates may become higher than the supply capacity. Availability is not expected to constitute a significant drawback for selecting an alternative but will certainly be considered when a suitable surrogate is identified. In addition, some alternatives are not yet available at the purity level required for pharmaceutical use and some work will be needed by the suppliers to increase the purity of the selected candidates. Some of the alternatives shown in Table 12 are currently patent protected and therefore not available for use by Sanofi Pasteur.
3.3.1.3 Hazards and risks of alternative substances
As mentioned above, the substances considered for substitution are currently used by other pharmaceutical manufacturers in the production of vaccines. Major issues regarding the hazard and risk of the substances are not expected. However, a proposal has been submitted to categorize ammonium bromide, the main component in CTAB, as reprotoxic (Repr. 1B, H360FD) and with specific target organ toxicity with single exposure (narcotic effects) (STOT, SE 3, H336). No final opinion has been issued to the present day. This classification could impact the suitability of CTAB for substituting Octoxynol-9 in the new process. A similar situation (substance use under REACh authorization) as the current one for Octoxynol-9 could therefore occurs.
3.3.1.4 Economic Feasibility
The development of a new production process for BPIV will trigger significant financial and resources efforts: the development of a new expression platform for the next generation of Flu vaccine is already part of the Sanofi Pasteur flu strategic program and is a logical step aligned into the replacement of Octoxynol-9 in the company’s production methods.
Investment in the development of the BPIV will ensure the transition into a new generation of vaccines in a feasible manner while ensuring the complete stop of use of Octoxynol-9 for any vaccine manufacturing. Moreover, the development of this new generation of vaccines is in line with the WHO’s goals for fighting influenza and will contribute to increasing the production capacity in order to keep up with the global demand.
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3.3.1.5 Conclusions
The transition to a new generation of flu vaccine BPIV is a technically and economically viable transition to an Octoxynol 9 free alternative and in line with WHO strategy for global flu immunization. The development activity of this next generation vaccine is ongoing.
3.3.2 Substitution in the current Vaxigrip® process
3.3.2.1 Substance ID and properties
The substances that could potentially substitute Octoxynol-9 in the current process are those described in Table 11 (section 3.3.1.1). These are the same substances regarded as potential alternatives for substitution at the process level (BPIV development).
3.3.2.2 Technical and Economical feasibility of substituting in the current process
Substitution of Octoxynol-9 in the current egg-based process would be extremely challenging. Currently, no alternative has been identified that would fulfill all the functionalities of this detergent in Sanofi Pasteur’s process, and the identification of a potential substitute would also require significant technical development. From a technical perspective, this development is analogous to that needed for the development of the BPIV and following transition period (see section 3.4 Overview on BPIV development and substitution process for a description of the tasks needed for BPIV development).
For comparison , the mandatory activities for the replacement of Octoxynol-9 in the existing products would include:
• Investigation, demonstration and validation of the flu virus splitting efficiency. This is an absolute prerequisite as it is the primary function of Octoxynol-9 in the current process.
• Investigation, demonstration and validation of the flu virus inactivation efficiency. This could impact other process steps in the current manufacturing line leading to re-development of the entire process. Implementation of new steps or new chemicals in the process could be required in order to achieve the same inactivation efficiency as that of Octoxynol-9.
• Investigation, demonstration and validation of the inactivation of a range of potential adventitious agents (model viruses, mycoplasma). According to guidelines from the EMA and the WHO, an overall virus reduction capacity in the order of 10,000-fold or higher should be demonstrated. This could impact other process steps in the current manufacturing line leading to re-development of the entire process. Implementation of new steps or new chemicals in the process could be required in order to achieve the same clearance of adventitious agents as with Octoxynol-9.
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• Toxicity studies on the new compound(s) to determine the maximum allowable residual quantity of the new chemical(s) in the vaccine.
• Investigation, demonstration and validation of the clearance of the new chemical(s) through the process to reach the maximum allowed quantity. This could result in the implementation of new steps to handle the clearance of the new compound(s).
• Stability studies demonstrating that the vaccines with the new process remain effective and safe up to the expiry date.
• Robustness studies on all the bullet points listed above, to define the acceptable operating space through a Quality by Design approach.
• Demonstrating that the newly redeveloped vaccine is well tolerated and has an efficacy at least not inferior to the current vaccine containing Octoxynol-9 (i.e. Need for clinical studies phase II and III).
• Registration of the new process in some 120 countries. Substitution of Octoxynol-9 in the current process would be considered as a major change by health authorities because of the important role that this substance plays in the manufacturing process. Extensive data would thus have to be generated to demonstrate that the Octoxynol-9-free vaccine is as efficient and safe as the current one. Due to the usual duration of regulatory procedures, the various tasks involved in this step and the fact that applications for marketing approval cannot be submitted in parallel but rather in a staggered way, the transition between the “no Octoxynol-9” product and the previous “with Octoxynol-9” product would last around 10 years.
The completion of these task would also require significant time and efforts. In consequence, the costs associated with substitution in the current vaccines are comparable to those of developing the BPIV. Parallel development of the BPIV and the implementation of an alternative to Octoxynol-9 in the current flu vaccines would divert important time and resources from Sanofi Pasteur’s goal of transitioning to the new generation vaccines. The recruitment of participants for clinical trials would also result extremely difficult if simultaneously carrying out the BPIV development and substitution in the current process. In terms of investments, driven mainly by clinical costs, it makes no sense to invest on both developments, so one had to be chosen. Development of the BPIV is more relevant for Sanofi Pasteur because this new vaccine is aligned with expectations from health authorities and represents an important breakthrough for public health. In that context, the benefits of implementing a broader protection vaccine against influenza largely outweight the benefits of finding and implementing an alternative to Octoxynol-9 in the current process. It would also be hard to justify the investment of
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implementing an alternative in the current process on the basis that the new vaccine technology will replace the existing vaccines anyways, and that substantial efforts are required to qualify and implement an alternative. As a result, Sanofi Pasteur’s decision was to focus its R&D efforts on developing an Octoxynol-9-free process for the new BPIV rather than implementing an alternative in the production line of the current vaccines.
3.3.2.3 Conclusions on substituting Octoxynol-9 in the current process
The substitution of Octoxynol-9 would have a significant impact on the influenza vaccines currently produced by Sanofi Pasteur.
As explained below, the efforts associated with such a process change is comparable to developing a new product such as the BPIV. Taking these efforts and the ongoing development on the BPIV into account, Sanofi Pasteur aims to focus its R&D activities on the development of the BPIV to implement a Octoxynol-9-free vaccine.
Indeed, it is estimated that the cost and timing of Substituting Octoxynol-9 in the current Vaxigrip® process is comparable to that of developing a new vaccine, considering all the steps that would be required for implementing and validating this new process and demonstrating by clinical trials that the vaccines produced without Octoxynol-9 are as safe and efficient as the current ones. It would constitute a redundant investment for Sanofi Pasteur to implement an alternative of the actual egg process while also developing the next generation vaccines. Such an investment is not economically viable nor logical. Sanofi Pasteur has thus chosen to invest its resources into developing the BPIV in line with the WHO’s plans for fighting influenza worldwide.
3.4 Overview on BPIV development and substitution process
Sanofi Pasteur’s goal is to move away from the current egg-based expression system and to established a safer and more efficient alternative such as a recombinant-based expression system. Egg-based systems have some draw-backs that can be overcome if a different expression system is applied. These difficulties include transport logistics, availability, and large storage volumes. However, current R&D on the BPIV is carried out in a expression platform using Octoxynol-9 as Sanofi Pasteur is very experienced in this production process and the system offers a good productivity. Sanofi Pasteur’s strategy is to evaluate the level of protection for the use of BPIV in general before the most appropriate expression platform not containing Octoxynol-9 is developed in a next step. If a different expression system cannot be established according to Sanofi Pasteur’s timelines and development goals, the egg-based system will further be used to produce the BPIV, and alternatives to Octoxynol-9 will be
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tested in this platform. In any case, Sanofi Pasteur plans to replace Octoxynol-9 in its processes, regardless of the platform that is chosen for expression of the BPIV.
Sanofi Pasteur is currently performing two different R&D workstreams:
- Workstream 1: Development of BPIV on an expression platform using Octoxynol-9: This workstream is ongoing since several years. XXXX, the next phase of the development started with the identification of a gene that combines several antigens that are considered to protect against influenza for a couple of years. At the current stage, testing entered clinical phase I.
The aim of the current testing is to evaluated the potency of the protection of the BPIV. If this is sufficiently demonstrated, it needs to be analysed which platform is the most favourable for the expression of the antigens for the BPIV (tested in workstream 2).
- Workstream 2: Development of an Octoxynol-9-free expression platform for the BPIV. The aim of this development stream is to establish an expression system for producing the BPIV in a large scale. Here, different vaccine expression platforms such as egg-based, cell based or recombinant platforms will be tested with potential alternatives for virus splitting (see Table 11) to identify an Octoxynol-9- free platform that can be used for the BPIV.
After identification of promising alternatives, Sanofi Pasteur expects to start the development of an Octoxynol-9-free expression system for the BPIV, XXXXXXX. In this early R&D phase, alternatives will be tested in the laboratory for their virus splitting capacities and other key functionalities as described in section 2.2.3. In a next step, the most favourable expression system for the BPIV needs to be chosen because this has a direct impact on the process conditions used and, therefore, on the performance and behaviour of the substance used for virus splitting.
It is planned to bring together these two workstreams in XXXx: once the most appropriate Octoxynol-9-free expression system for BPIV is selected by the XXXXXXX, implementation of this alternative to the current Octoxynol-9 containing egg-based platform will start. Sanofi Pasteur aims to carry out clinical phase II for the BPIV in xxxx using the new expression platform.
3.4.1 Substitution tasks and timeline Based on this general plan, Figure 11 below shows a break down of the predicted time needed for a complete transition to the BPIV and, thus, into an Octoxynol-9 free manufacturing process for the influenza vaccine.
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Figure 11: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx yxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
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As shown in Figure 11, Sanofi Pasteur is currently carrying out several tasks for the development of its BPIV. A new expression platform without Octoxynol-9 is under technical development at a laboratory scale, while clinical trials with BPIV have already been started using material produced with the current Octoxynol-9 expression platform. During the technical development phase, all the necessary chemical, manufacturing and control (CMC) activities related to a new expression platform without Octoxynol-9 are carried out. At the end of this phase, the most appropriate platform for the production of BPIV is selected. In parallel, the industrial scalability of the laboratory scale process is also tested by assessing the biocharacterisitics in a phase dependant scale bioreactor under the set process conditions. However, the development of a pilot-plant scale has already started for producing the drug product material needed for the clinical trials.
Workstream 1 is already ongoing with the current BPIV being in clinical phase I. The BPIV lots produced for clinical trials were produced using the current Octoxynol-9-based process, due to Sanofi Pasteur’s experience with this platform that allowed the company to focus its resources into the development of the virus antigen for the BPIV and to evaluate the efficacy of the new product. Sanofi Pasteur has also dedicated significant R&D efforts to demonstrate that the expression system used does not affect the final structure of the virus antigen, so that the vaccine’s effectiveness will not be affected if a different platform is used to produce the final vaccine. This also serves to justify the implementation of a new expression system at a later stage of the BPIV development. This data will be used to transition to a new expression system during the development and is part of the regulatory data needed to obtain marketing approval. Merging of the two workstreams is planned for XXX: Implementation and production of clinical batches of BPIV using the new expression platform without Octoxynol-9 is planned for clinical phase II. By that time, clinical development of BPIV will not use any Octoxynol-9.
It is foreseen that pilot-scale testing using a new expression platform will take place XXxXXX, although an additional year might be necessary to fully transition into full-scale. Simultaneous to pilot-scale testing, analytical methods must be developed for the characterization and release methods of all components in the new vaccine, including an analytical method for measuring concentrations of an alternative to Octoxynol-9. This is considered a crucial part during vaccine development as the constant quality of the final product needs to be ensured and presented to the authorities. XXXxxxxxxXXXX XXXXXXXXXXXXXXXXXXX.
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The industrial scale validation is the final stage of the process development phase. At this point, all technical aspects of the process are transferred to full-scale and all industrial components supporting the commercialization of the BPIV are validated. XXXccccccccccccccccccccccccccccccxxxxxxXXXX XXX. In the meantime, a reliable supply chain must be secured for all new materials used in the BPIV process through discussions with suppliers.
Stability studies must also be carried out for all components of the BPIV. Long-term stability data are needed to document and license expiry dating for the new formulation. These studies are performed throughout the vaccine’s development phase and during clinical trials XXXXxxxxxxxxxxXXXXXX. XXXccccccccccccccccccccccccccccccxxxxxxXXXX XXXXXXXXXXXXXXXX
Using the information gathered throughout the clinical studies and the development phase, XXXX, XXXXxxxxxxxxxxXXXXXXXXXX. XXXccccccccccccccccccccccccccccccxxxxxxXXXX XXXXXXXXXXXXXXXXX. The approval phase is then expected to extend until the end of 2041. The main challenges to adress before and during this approval phase include:
• Collection of long-term stability data, which are required to document and license the expiry date of the new formulation, will be run in parallel of phase I and phase II. Multiple submissions may be needed to extend the initial dating. This will also likely impact the product’s label and require multiple changes. • Risk of impact to efficacy/safety profile of the product. Multiple clinical studies are needed to document the efficacy, safety and immunogenicity of the new vaccines. No bridging to previous formulations will be possible because the BPIV will be regarded as a completely new formulation by health authorities. • Long-term follow-up (pharmacovigilance) will likely be required to evaluate the long-term safety profile of the BPIV. Pharmacovigilance studies are managed after the launch of the new product. • Non-clinical safety studies are needed to evaluate potential safety in both repeat-dose toxicity and development and reproductive toxicity. These data are also needed for approval.
A phased launch of the BPIV is planned, XXXXXXXXXXXX with the first granting of marketing authorization, likely in the US. Marketing approval in the EU is expected to be obtained xxxxxxx. However, because Sanofi Pasteur produces vaccines for other countries outside the EEA in Val de Reuil site, production with Octoxynol-9 will continue until marketing approval has been granted in all of these countries. Registration review timelines vary significantly by country and can take up to 2 years,
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depending on standard registration review timelines or if additional data are requested. Health authorities from some countries wait that approval has been granted in other countries before accepting an application, so the process cannot be carried out in parallel in all countries. Based on previous experiences with authorization renewals, Sanofi Pasteur estimates that xxxxxx will be required to completely replace all Vaxigrip® licenses by BPIV licenses (transition period). This estimate is based on previous experiences such as the transition from a trivalent to a quadrivalent vaccine, which is not considered as a brand new vaccine and uses the same manufacturing process, the same technology and the same facilities, XXXXXXXXXXXXXXXXxXXxXX.
3.4.2 Transition period after launch of BPIV Sanofi Pasteur has identified 4 major drivers that contribute to the length of the transition period after the BPIV launch. These are:
• The seasonability of influenza, which limits the timelines for submission of regulatory documentations. Due to the annual update of the influenza vaccine’s composition linked to the prevalent strain of the virus for each year’s season, only restricted time windows are available to submit flu-related documentation. It is difficult to submit a change in the influenza vaccine along with the normal variation (change of strain) witin one same seasonal campaign, so submission of a new influenza vaccine altogether, such as the BPIV, is even more challenging. Moreover, the seasonability of influenza also limits the timline for performing clinical trials, as participants of these trials can only be immunized at specific times throughout the year.
• A staggered approach will be followed for requesting health authority approvals for the treatment of different population groups. The first requests for approval to be submitted will cover adults and the elderly populations. These are needed before submitting regulatory documents for the pediatric use, which also requires a specific clinical program. As an example, submission for approval for the change from a trivalent vaccine to a quatrivalent vaccine covering the adult population took place in 2015, while that for pediatric uses was completed in 2017. Considering that the BPIV is a completely new vaccine,and that more time will be needed to validate the broadly protective action of the BPIV across these populations, covering various influenza seasons, a bigger difference is expected between these two submission times for the BPIV.
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• Approvals from health authorities are granted in a staggered manner. The first launch of the BPIV will occur in the USA, followed by Europe. For the EU, one unique approval is necessary but the switch to the BPIV in all European countries will take several years as it depends on various factors:
o Each country’s willingness to transition to the new vaccine;
o Country-specific discussion about vaccine affordability and reimbursement. In France, for example, a dedicated committee (Comité Economique de Produits de Santé) sets the price of medicinal products, including vaccines. Similar committees in various EU countries must decide on the price for the new BPIV before an approval is granted; and
o Each EU country decides whether or not to recommend the new BPIV vaccine instead of the current one.
Sanofi Pasteur’s experience with the transition from a trivalent to a quadrivalent vaccine also supports the picture of a longer period needed for health authority approvals. Submission of the relevant documents for approval occurred in 2015, with the first market authorization being granted in 2016. The first commercial launch subsequently took place in 2017. However, the transition is not completed as of today, even though it only encompassed the addition of an additional strain to the vaccine. A longer time is thus expected for a completely new vaccine such as the BPIV.
Some countries outside the EU require specific clinical trials performed in their own countries. China and Japan, for example, require the full development plan to be carried out in their countries, while Korea, Taiwan, Vietnam and India require local clinical clinical studies for granting approvals. Sanofi Pasteur’s hexavalent pediatric vaccine was first approved in 2012 but is still under registration in some countries as a result of the differences in regulatory requirements, so a longer period is expected for the BPIV.
• Industrial footprint analysis is needed to allow the switch from the current vaccine to the BPIV. Because the manufacturing process of the BPIV is completely different, new buildings will have to be built. This may take between 6 to 8 years based on an internal benchmark. Additionally, more and more countries requires to have production based in their own territory, so industrial transition might result even more difficult.
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Sanofi Pasteur plans to phase out the current influenza vaccines according to the granting of marketing approvals for the BPIV. A smooth transition is important for securing a reliable supply of vaccines that can cover the global demand, including the expected increase, and to demonstrate the efficacy of the BPIV in all age groups of the population. The activities that must be completed during this transition period include:
• Application according to regulatory timelines in the about 120 countries in which Sanofi Pasteur’s influenza vaccines are registered to more than 235 licenses for all age groups; • Additional clinical studies to cover all age groups after the first marketing approval (paediatric, ederly, adults, pregnant, etc.); • Building of facilities or establishment of long-term contract manufacturing organization (CMO) partnership (outsourced manufacturing). For these changes, Sanofi Pasteur would need previous approval from the corresponding regulatory authority, further adding to the complexity of the implementation process; • Ensuring maximum commercial output from the BPIV to sufficiently replace the full product portfolio of current influenza vaccines.
There will be a significant increase in the number of influenza vaccine doses needed in the next 12 years. This means that, until full transition to the new generation of vaccines can be achieved, a larger production capacity needs to be build up to ensure the introduction of the new vaccines into the global market without compromising the vaccine supply. Additionally, facility adaptation and preparation is necessary to transition to the BPIV, as the manufacturing process of the current vaccines will no longer be used. The last marketing approval is expected to be obtained in XXXXXXXXXXXXXXXXXXXX. XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. Nonetheless, it is important to recognise that, as with any innovative development, the success and timing of the program cannot be assured in advance.
3.5 The most likely non-use scenario (NUS)
As described in Section 2.2, Octoxynol-9 is an indispensable element of the current flu vaccine production process.
Sanofi Pasteur has considered different scenarios in case authorisation for the continued use of Octoxynol-9 is not granted. A detailed assessment of those scenarios led to the definition of one most realistic Non-Use Scenario (NUS).
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The following potential scenarios have been assessed by Sanofi Pasteur: 1) Scenario 1: Permanent shutdown of the production lines manufacturing flu vaccines in Val- de-Reuil (stop of production) AND relocation of production to a non-EEA country 2) Scenario 2: Permanent shutdown of the production lines manufacturing flu vaccines in Val- de-Reuil (stop of production) WITHOUT relocation to a non-EEA country
The following chapters describe these scenarios in more detail.
Whatever the scenario considered it is important to note that given the nature of flu vaccines (seasonal changes), stock-piling to deal with demand will not be manageable and supply shortage of Flu vaccine with huge public health impact will be foreseen.
3.5.1 Scenario 1: Permanent shutdown of the production lines manufacturing flu vaccines in Val-de-Reuil (stop of production) AND relocation of production to a non-EEA country
This scenario involves the shutdown of the production lines manufacturing flu vaccines at the site in Val-de-Reuil and the subsequent relocation of production to a non-EEA country. In this case, the production of flu vaccines in Val-de-Reuil would be operative until the sunset date. After the decision not to grant an authorisation is made, the relocation process would start, and it is estimated that it would take at least eight years until the new facility in a non-EEA country could be fully operational and the first commercial doses could be distributed (considering the time required to receive approval from health authorities). The estimation of eight years for a complete relocation of production has been done based on the experience with the new facility which is being built in Val-de-Reuil and considers all the efforts which are required since the very initial steps, such as project planning, approvals and design. In this scenario, direct permanent employees currently working with the production of flu vaccines at Val-de-Reuil would be dismissed and purchases from local suppliers of eggs used to produce the affected vaccines would be interrupted. Given that the French sites in Marcy l’Etoile and Le Trait are also involved in the production of flu vaccines with the filling and packing steps, there would also be a loss of activity at these sites.
As previously mentioned, Sanofi Pasteur has confirmed its commitment to the site in Val-de-Reuil with an investment of EUR 170 million XXXXXXxxxxxxx in a new production building (subject to relevant health authority approvals, with production scheduled to start in 2023). The new Val-de-Reuil facility will be the only site of its kind in France and Sanofi Pasteur remains the sole influenza vaccine producer
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in the country which is critical for French Authorities for pandemic preparedness. It is estimated that the relocation production from Val-de-Reuil to a non-EEA country would require a similar investment as announced for Val-de-Reuil.
Besides the cost of the investment itself (e.g taking the recent investment in Val-de-Reuil as a proxy), it must be taken into account that additional internal costs (time of workers, other opportunity costs and usage of existing structure) and transfer of knowledge are also relevant.
It is important to note that transferring products to a new manufacturing site is an extremely challenging process in terms of process transfer and scale-up, validation, stability protocols, regulatory filings and more. With regards to regulatory filings, related efforts are very significant since Vaxigrip® products are registered in 122 countries in 2018.
Given the nature of flu vaccines (seasonal changes), stock-piling to deal with demand during the relocation period cannot be considered as a feasible option (vaccines are adapted twice a year). Neither it is an option for pandemic vaccines, as these are adapted to a given pandemic situation. Thus, supply disruptions during the relocation process are likely to occur in this scenario. Alternative supply for the products manufactured in Val-de-Reuil (e.g. products manufactured at other Sanofi Pasteur sites around the world) would be very limited in terms of volume and timing. Considering existing Sanofi Pasteur industrial capabilities, it would not be possible to globally compensate more than 25% of the current volume supplied with flu vaccines from Europe. This alternative supply, given the existing capacity occupation rates would be exclusively possible for the southern hemisphere, not for northern hemisphere countries. Sanofi facilities in Mexico and China support the local market only and are not designed to serve the EU market.
In case the relocation of flu vaccines production to a non-EEA country happens, several negative consequences, especially concerning the access to the market, are foreseen during and even after relocation is concluded. As time to market is crucial, any relocation of production to be placed far from the main market could negatively affect the delivery of vaccines and result in a loss of competitiveness. A relocation of the pandemic vaccines to non-EEA countries would induce a risk of supply availability (therefore these sites are usually located close to the main populations to be protected) maybe disputed by French government. As a result, Sanofi Pasteur competitiveness would be affected.
This relocation scenario would result in a loss of market share, especially on northern hemisphere and supply shortages can be expected at least for the time period until relocation is completed. If Sanofi is
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out of market for 8 years, competitors will take over its activities/market share before Sanofi can start commercial production at the new site. It will take competitors some time to increase capacities, but they will be faster than Sanofi Pasteur given that they would have to deal with lower regulatory efforts. If Sanofi Pasteur comes back to the market after 8 years, there will be an overproduction and consequently a very competitive situation. It would be almost impossible to re-enter the market.
Despite the aforementioned negative aspects connected to relocation, this scenario is not directly rejected and a conclusion on its feasibility in comparison to the scenario 2 is provided in the section 3.5.3, where the most realistic non-use scenario is defined.
3.5.2 Scenario 2: Permanent shutdown of the production lines manufacturing flu vaccines in Val-de-Reuil (stop of production) WITHOUT relocation to a non- EEA country In this scenario, Sanofi Pasteur would shut down the production lines manufacturing flu vaccines in Val-de-Reuil and no relocation would occur. As for the scenario 1, direct permanent employees currently working with the production of flu vaccines at Val-de-Reuil would also have to be dismissed and purchases from local suppliers of eggs used to produce the affected vaccines would be interrupted. Moreover, also as for scenario 1, given that the French sites in Marcy l’Etoile and Le Trait are also involved in the production of flu vaccines with the filling and packaging steps, there would also be a loss of activity at these sites.
The Val-de-Reuil site covers all stages of the manufacturing process of Influenza vaccines. In this scenario, the vast majority of existing markets could not be supplied any longer which will have a significant Public Health impact. The stop of flu vaccines production (and thus stop of Vaxigrip® portfolio) also requires withdrawing the license of Vaxigrip® vaccines in all concerned countries. The regulatory process to withdraw a regulatory license depends on the respective country and action plans based on local requirements.
Considering existing Sanofi Pasteur industrial capabilities, given the existing company sites outside EEA, it would not be possible to globally compensate more than 25% of the current volume supplied with Vaxigrip® from Europe.
The likelihood of this scenario is assessed in the next section (3.5.3) when it is compared to the scenario 1 in order to define what is the most realistic non-use scenario.
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3.5.3 Likelihood of the presented scenarios and definition of the most realistic NUS Both scenarios would have similar impacts for the society but would differ on the amount of private costs for Sanofi Pasteur. The definition of the most realistic non-use scenario for Sanofi Pasteur is based on the expected private costs of the two scenarios.
As it has been presented in section 3.5.1, the relocation of production lines from Val-de-Reuil to a non-EEA country has been estimated to require an investment of more than EUR 170 million xxxxxxxxxxxxxxxx and take around eight years to be completed. Given the impossibility to stock vaccines (due to the nature of flu vaccines, as explained before in section 3.5.1) and non-availability of enough capacity at non-EEA Sanofi Pasteur sites to supply the entire global demand during the whole relocation period (eight years), it is very likely that until production can be restarted at a non- EEA facility, others companies will have gained market share from Sanofi Pasteur to a point that it will be very difficult (or even impossible) to recover. In such a probable situation, Sanofi Pasteur would have made an investment in relocation that would not pay off.
Besides the consideration about required relocation investments and the unlikelihood of having positive returns on such investments, there are a few other reasons to decide against relocation as most likely non-use scenario. As explained in the section 3.5.1, time to market is crucial and any relocation (placing production far from the main market) would most likely negatively affect the delivery of vaccines and result in a loss of competitiveness. As previously mentioned, for the case of pandemic vaccines, relocation to non-EEA countries would induce a risk of supply availability in Europe.
Given the above, Sanofi Pasteur concludes that the most realistic scenario in the case of a non-granted authorisation would be shutdown of the production lines currently manufacturing flu vaccines in Val- de-Reuil without relocation (scenario 2).
4 IMPACTS OF NOT GRANTING AUTHORISATION
The impacts in the case of not granting an authorisation are broken down into relevant categories in the following sections. As described in section 3.5, the most realistic NUS is stopping production of flu vaccines in Val-de-Reuil without relocation outside the EEA.
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Socio-economic impacts in the NUS result in considerable negative impacts, whereas positive environmental impacts in all scenarios are minimal, as it can be seen in the description of environmental impacts.
For the assessment of impacts, the current flu vaccines market conditions have to be observed. As of 2018, the EU market is being under-supplied. At the moment two suppliers are responsible for approximately xxx of the flu vaccines supply flowing into the EU market (being Sanofi Pasteur one of them with xxx market share). The second main player, behind Sanofi Pasteur, could consider compensating for the market shares left by Sanofi Pasteur in case of a non-granted authorisation but, at the moment, this competitor does not have the capacity to do so. Therefore a significant investment will be required by the competitor to compensate for Sanofi Pasteur flu doses in terms of volume (at least doubling its own capacity), and also by ensuring a timely delivery required for a seasonal vaccine. In the case the competitor would decide to invest, this would lead to a situation with a sole supplier for at least xxx of the EU market, which would cause some risks on the public health sector (should this supplier face any production issue and/or be delayed in its capacity increase).
Other large EU competitors are focusing their supply on the North American market. More than 2/3 of their sales are focusing the supply of the U.S. and it is not clear if they will consider changing their strategy and access the European market, including facility investments in Europe. Any competitor wanting to cover for a possible exit of Sanofi Pasteur from the market will have to build new facilities/capacity to replace the Sanofi’s market share. The following efforts would be required from competitors:
• Large investment: bulk capacity and other production steps (formulation, filling and packaging lines) and distribution; • High risk investment: Because of Sanofi Pasteur’s size, it is unlikely that only one competitor would suffice to replace Sanofi Pasteur’s output. Competitors will not have access to the capacity increase plan of the competition and therefore build at risk their new capacity (without knowing the size of their future market shares) • Based on internal benchmark, 6 to 8 years will be needed to construct new facilities, qualify and register production in EU. Additional time is usually needed to ramp up production to full capacity.
All the above seems to indicate that, in case of a non-granted authorisation for Sanofi Pasteur, it is more likely that non-EU based competitors (such as companies from countries in emerging markets) could attempt to gain market share using their current idle capacities. Nevertheless for these competitors this
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would not be a quick process as registration of their product would be needed with clinical studies on adults and paediatrics.
4.1 Public Health impact: Wider economic impacts
As one of the market leaders for influenza vaccines in Europe, the non-use scenario would have consequences for vaccinnees in Europe and others countries. With more than xxxxxxxx doses of influenza vaccines supplied every year to the European market, at least in the short term a supply shortage would have to be expected. Even if Sanofi Pasteur is not the only supplier of these vaccines in Europe, it is unlikely that other existing suppliers would be able to completely compensate the lost capacity in regard to volume and timing on short notice, especially when it is considered the market share of xxx which Sanofi Pasteur has in Europe. Timing is critical for the supply of flu vaccines, therefore providing additional several million flu vaccine doses is very challenging.
In markets where prices are not fixed, the exceeding demand for Influenza vaccines would increase product prices and consequently increase costs to the national health systems.
Influenza constitutes a substantial socioeconomic burden for society in terms of medical treatments (increase in consultations, hospitalisations, treatment of clinical complications, drug use) and work absenteeism, see Figure 12.
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Cost studies use a variety of methods: the perspective taken will influence the cost included.
Figure 12: Costs considered in the evaluation of the Influenza Economic Burden.
A study from 2017 (Haugh, Gresset-Bourgeois, Macabeo, Woods, & Samson, 2017) assessed the health impact of 1.8 billion doses of Vaxigrip® which have been distributed over 120 countries along almost 50 years. It was estimated that more than 37 million laboratory-confirmed influenza episodes, 476,000 influenza-related hospitalizations, and 67,000 influenza-related deaths have been avoided.
The recent investments of EUR 170 million XXXXXXxxxxxx which Sanofi Pasteur is pursuing aims to increase its capacity to offer its quadrivalent vaccine Vaxigrip Tetra®. A study from 2016 (Uhart, Bricout, Clay, & Largeron, 2016) , based on data from 5 EU countries (France, Germany, Italy, Spain and UK) during 10 influenza seasons from 2002 to 2013, estimated epidemiological and associated economic outcomes comparing the actual scenario where the a trivalent vaccine was used versus a hypothetical scenario where a quadrivalent vaccine could have been used instead. By using the quadrivalent vaccine, this study estimated that for the 5 EU countries, an additional 1.03 million (327.9/100,000 inhabitants) influenza cases, 453,000 (143.9/100,000) general practitioners consultations, 672,000 (213.1/100,000) workdays lost, 24,000 (7.7/100,000) hospitalizations and 10,000 (3.1/100,000) deaths could have been avoided compared to the use of TIV over the 10-seasons- period.
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• Direct costs of Influenza
Influenza-related hospitalizations place pressure on healthcare systems and lead to an important economic burden. Several studies in different countries reflect the fact that the older adult population incurs higher direct costs of influenza than any other age segment.
A recent study in the United Kingdom estimated the average hospitalization cost per patient due to influenza to be £10,249.62 in 65y+ adults (Meier, 2015).
Cost drivers escalate with complications which occur most often in high-risk patients, including elderly population. (Cox, 2000).
Older adults are often already polymedicated especially those with chronic conditions. Around half of the older adults has 5 or more medications and patient drug non-adherence rates have been estimated to be between 25 and 75%. In this context, treatments of influenza illness and its complications worsen the health status of older adults what results not only in health consequences to patients but also in high costs to healthcare systems.
According to data reported by Vaccines Europe (Vaccines Europe) , Influenza vaccination protects patients with chronic diseases and can reduce by 50% the number heart attack ocurrences, by 28% the chance of death in diabetic patients and by 24% the risk of strokes after respiratory diseases. Vaccines Europe also reports that 25,000 lives are spared a year in EU due to Influenza vaccination.
Direct costs of influenza are the highest in older adults, driven by hospitalization costs following complications; Influenza also triggers significant indirect societal and individual costs.
Total impact of an influenza epidemic in industrialised countries may reach €57 million per million people (The European Public Health Alliance, 2009).
Cost drivers escalate with complications which occur most often in high-risk patients, including elderly population 2
• Indirect costs of Influenza
Even if the indirect costs of influenza are not the highest in older adults, they remain a significant burden for both society and individuals.
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Researchers have differentiated the indirect costs of the disease into societal and individual indirect costs. The former includes the indirect costs that affect society as a whole; the latter is formed by the indirect costs suffered by the patients and their family caregivers.
The origin of the societal indirect costs can be found in the fact that older adults, even though retired, still do relevant work in society through volunteering, supporting their families, and taking care of their grandchildren. When suffering influenza infection, they lose their capability to carry out these activities, which has a big impact on the normal functioning of their communities. On top of that, older adults tend to have an above average purchasing power, their expenses are important to the economy (eg: tourism, …), and not only diminishes greatly due to the direct costs incurred by hospitalization and care, but also stops being invested in the communities due to the lack of mobility and independence its older adult owners suffer due to disease-related complications.
Absenteeism in adults
Economic costs associated with influenza additionally include sickness-related absenteeism, disrupted work schedules and lost productivity to society and to employers. Indirect cost is a significant component of the financial burden of influenza (Newall & Scuffham, 2008). France and Germany have shown that indirect costs can be 5-10 times higher than direct costs (Szucs, 1999). In Europe, influenza accounts for approximately 10% of sickness absence from work. Indirect costs in France and Germany range from EUR 6.4 billion to EUR 9.8 billion per year. When estimating the total cost of hospitalization of children with influenza, the average indirect cost of working days lost by parents (EUR 70) had the greatest impact on the average total cost of an influenza case.Vaccines Europe (Vaccines Europe) reports that Influenza vaccination can save up to EUR 96 million by avoiding 715,000 lost days of work a year in EU (Preaud, 2014).
Influenza disease and associated complications among 65 years old and above adults can also be a heavy burden for family caregivers from an economic standpoint since it translates into absenteeism from the family members to take care of their older adults and/or investment in caregivers. The fact that influenza can worsen concomitant chronic conditions and trigger secondary infections aggravates the economic burden/loss for the families that need to take care in the long-term of older adults.
Absenteeism in children
An additional way in which influenza triggers indirect costs through older adults is by transmission from this age group to another at-risk group, the children. Older adults tend to have extensive contact
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with their grandchildren, since many of them will take care of them while their parents are at work. In this situation, the contact between infected or non-vaccinated older adults and children becomes a dangerous path for influenza transmission.
Influenza in children significantly increases both parental work absenteeism and school absenteeism and impacts school absenteeism in other children in the household.
A multicentre study in Italy analysed the burden of influenza in children less than 14 years of age with no chronic medical conditions and their households. The study found that the parents and siblings of children with influenza, had more respiratory illnesses, received more antipyretics and antibiotics, needed more medical visits, missed more work or school days, and needed help at home to care for the ill children for a longer period of time. (Principi, 2004)
• The cost of an Influenza epidemic
There are different estimates on the total economic impact of an influenza epidemic. For example, the total impact of an influenza epidemic (including direct and indirect costs) in industrialised countries may reach EUR 57 million per million people.
Several studies have estimated costs using a variety of methods. For Germany, it was estimated that the total costs of the 1996-1997 influenza epidemic amounted to approximately EUR 988 million; a study estimated the total cost of influenza at more than EUR 1,796 million in France.
4.2 Economic impacts
In order to minimize any possible uncertainties related to this impact assessment, the quantified economic impacts of the NUS have been mostly observed from the perspective of the applicant. Although being only a part of the economic impacts which may arise in the NUS for the society in EEA, data about the impacts to Sanofi Pasteur could be easily collected in comparison to data about economic impacts along the supply chain (which would require high efforts to collect and which could be associated with higher uncertainties in terms of validity for the whole supply chain). Further economic impacts along the supply chain (besides economic impacts to the applicant), although not quantified, are described in qualitative terms.
Economic impacts considered in this assessment can be divided into 2 components:
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• Losses in terms of Business Operating Income (BOI) for Sanofi Pasteur’s Commercial operations (COMOPS) and for Sanofi Pasteur’s Vaccines and Industrial Affairs (VIA) division; • Restructuring costs appearing to Sanofi Pasteur when implementing the NUS;
4.2.1 Losses in terms of BOI for Sanofi Pasteur’s commercial operations and industrial Affairs due to the stop of flu vaccines production In the NUS, Sanofi Pasteur would no longer earn any business operating income resulting from the sales of flu vaccines. These losses can be break down into two components: a) impacts on overall Sanofi Pasteur’s commercial operations and; b) impacts on the absorption of overhead costs (fixed) by Sanofi Pasteur’s Industrial Affairs (in Val de Reuil). The second component of business operating income losses in the NUS would appear at the level of the site in Val-de-Reuil (VIA: vaccines and industrial affairs). After the shutdown of the production lines manufacturing flu vaccines, the share of the site’s overhead (fixed) costs which were previously absorbed by flu vaccines would have to be absorbed by the products which would continue to be produced in Val-de-Reuil and would impact their costs and hence the margin. Overhead costs of the Val-de-Reuil site would have to be allocated to the remaining products, negatively impacting their margins, competitiveness and return of these products. Such situation would consequently pose the risk of the entire site shutting down due to economically unviable production.
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Table 13 shows the financial losses for Sanofi Pasteur through the 21-year period.
Table 13: Lost operating business income
2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 IMPACT ON ------SALES xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx
XXXXXXX ------XXXX xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx
If the forecasted amounts for Total impact on BOI (as detailed in Table 13) are discounted to the year 2021 (with an annual discount rate of 4%), the sum of these discounted flows can be seen as the loss to Sanofi Pasteur in terms of BOI due to the stop of flu vaccines production in Val de Reuil. See Table 14 for the calculation of the discounted impact of the NUS on Sanofi Pasteur’s BOI, amounting to EUR 1 – 4 billion XXXXXXXXXXXXX If only 1 year of losses are considered, these would amount to EUR 100 – 400 million XXXXXXXxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxXXXX.
Table 14: Discounted impacts on BOI
2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 Total impact -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx on BOI Discounted -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx -xxx impact on BOI in 2021 (using a 4% annual discount rate Sum of -xxxxxx discounted 1 – 4 billion impacts (EUR million)
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4.2.2 Restructuring costs appearing to Sanofi Pasteur when implementing the NUS Major restructuring costs will appear to Sanofi Pasteur in NUS, generating a significant impact on the company’s financial situation. Those costs are described below and summarized at the end of this section.
Impairment of recent investments at the facility in Val de Reuil
As it has been previously discussed, Sanofi Pasteur is investing EUR 170 million XXXXXXxxxxxx to expand the flu vaccines manufacturing facilities in Val-de-Reuil. The expansion strengthens Sanofi’s capacity to deliver seasonal flu vaccine providers. Sanofi plans to complete the expansion by 2021- 2022, subject to relevant health authority approvals, and will begin producing vaccines in this new facility in 2023.
Table 15 shows how the aforementioned investment can be broken down into multiple investment components.
Table 15: Investment details carried out by Sanofi Pasteur
Investment component Amount (in EUR million)
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XX XXXXXXXXXX XXXXXXXXXXXX EUR 170 million
Most of this investment has been designed and will be built specifically for Sanofi Pasteur and its needs to produce flu vaccines in Val-de-Reuil. Moreover, part of the investment is composed of planning, qualification and validation costs which do not have an intrinsic value but are just activities performed looking forward to future business opportunities. If any part of the investment could at all be recovered, it would in the best case be related to equipment or machinery only.
Sanofi Pasteur considers highly unlikely that a significant part of this investment can be recovered by selling these assets in the market. If those investments must be seen as sunk costs/impaired assets due to a non-granted authorisation, this situation would have a major negative impact on the company’s accounting records.
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Given the existing uncertainties [whether any part of this investment can be recovered via the sale of (part of) these assets in the market], this impact will be assessed in the uncertainty analysis in two scenarios:
• Possibility 1: nothing can be recovered via sale of the assets in the market (100% impaired assets: loss of EUR 170 million XXXXXXXX • Possibility 2: 50% of the equipment could be sold in the best case for EUR 10 – 60 million XXxxxXXXXXX (impairment: loss of EUR 140 – 165 million XXxxxXXxxxXXX)
Decommissioning/dismantling expenses
In case of a non-granted authorisation the manufacturing lines of flu vaccines would have to be shut down and Sanofi Pasteur would have to incur in dismantling expenses of the facilities which are currently being built.
Sanofi Pasteur has estimated that these dismantling expenses can be as high as EUR 5 – 20 million XXXXX xxx xxX due to the scale of the new investment/facilities which are currently being built.
Severance payments to be made by Sanofi Pasteur due to dismissals (distributional impact only, not taken into account for the final comparison with environmental impacts)
In the NUS, Sanofi Pasteur will have to bare the costs of severance payments due to the dismissal of hundreds of employees. Although those costs are considered distributional impacts from the perspective of a socio-economic analysis, such severance payments should be mentioned and kept in mind due to further consequences on Sanofi Pasteur’s financial and accounting management (i.e. impacting the company’s cash flow).
Summary of restructuring costs for Sanofi Pasteur (excluding distributional impacts)
In terms of socio-economic impacts, the restructuring costs appearing to Sanofi Pasteur would lead to the following MINIMUM socio-economic impacts when severance payments (distributional impacts) are excluded and the optimistic scenario (possibility 2) is considered, see Table 16.
Table 16: socio-economic impacts derived from restructuring costs possibility 2
xxxx xxxx
XXXXX xxx xxxxxxxxxxxxX XXX XXXXX xxx xxxxxxxxxxxxX XXX XXX XXX XXXXX xxx xxxxxxxxxxxxX XXXXX xxx xxxxxxxxxxxxX XXX XXX
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Using the future impact of XXXXX xxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxX, the discounted sum of these negative flows (in 2021, discounted using a 4% annual rate) results into an impact of at least EUR 145 – 185 million xxxxxxxxxxxxxxx. It is important to note, however, that there is a chance that nothing is recovered by Sanofi (no sales of used equipment) and therefore losses would amount to EUR 170 – 210 million xxxxxxxxxxxxx.
4.2.3 Summary of economic impacts for the applicant The different economic impacts discussed in this section can be summarised as follows in Table 17.
Table 17: Summary of economic impacts
Economic impact Amount (lower bound) Amount (Upper bound)
Losses in terms of BOI EUR 100 – 400 million XXXXXXxxx EUR 1 – 4 billion XXXXXXXXXX for Sanofi Pasteur xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx over the whole review period applied for xxxxxxxxxxxxxxxxxx (1 year of BOI (21 years) and discounted to 2021 using losses (2021)) a 4% discount rate. Restructuring costs EUR 145 – 185 million XXxxxxXxx EUR 170 – 210 million XxxxXxxX (excluding severance XXXXX (considering the optimistic XXXxxXX (considering no impaired payments and situation that 50% of impaired equipment can be resold) considering impaired equipment can be resold) investments, saving with the sales of assets and dismantling expenses
It is important to note that, while the economic impacts to the applicant have been on the center of the assessment so far (due to a matter of data availability), multiple economic impacts down the supply chain would arise due to the most realistic NUS. Although some of these impacts could be seen as distributional impacts, impacts to suppliers such as egg farms (which are extremely dependent on Sanofi Pasteur’s operations in Val de Reuil) as well as impacts to the general population currently supplied with the affected vaccines must be considered highly significant.
Social impacts to egg farms will be discussed in section 4.3 and general impacts to the population due to a constrained supply of Influenza vaccines are discussed from a perspective of health economics in the section 4.4.
4.3 Environmental Impact
As it has been presented in the section 2.6, approximately < 80 Kg XXxxxxXX of Octoxynol-9 would no longer enter the environment in case of a non-granted authorisation (21 years review period). It is important to note that this is the absolute total over the entire review period and that releases per day are on the range of grams.
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In monetary terms, following the methodology presented in the sections 2.6.3 and 2.6.5, in case it is accepted that a range of EUR 1,000 to EUR 50,000 per Kg of emissions (based on the case of PBT and vPvB substances) can be used as an auxiliary measure, the < 80 Kg XXxxxxXX of emissions would mean between < EUR 0.2 million XXXXXxxXXXXX and EUR < EUR 3 million XXXXXXXXXX in non-realised environmental impacts.
Environmental benefits of a non-granted authorisation are however limited given that local concentrations in freshwater are expected to be less than 1ng/l for the existing facility based on measurement and conservative assumptions regarding dilution in the receiving freshwater. As previously discussed, this concentration will be further reduced once the new flu building is commissioned. Concentrations from the new Sanofi Pasteur will be approximately a factor of 100 lower still. The concentration in surface waters relating to release from the existing Sanofi Pasteur facility is therefore substantially below predicted no effect concentrations.
4.4 Social impacts
As previously explained, the most-realistic non-use scenario for Sanofi Pasteur in case of a non-granted authorisation would be the shutdown of the production lines currently manufacturing flu vaccines in Val de Reuil. In terms of social impacts, this non-use scenario would have major consequences not only on the employees currently working on the manufacturing of flu vaccines at Sanofi Pasteur in Val-de- Reuil but also on workers from the sites in Marcy L’Etoile, in Le Trait, Sanofi Pasteur commercial operations and third parties (i.e. suppliers such as egg farms and service contractors).
With regards to Val-de-Reuil, the site currently employs more than 2200 workers. Out of these workers, xxx are directed employed in jobs which are dependent on the production of flu vaccines. The most realistic non-use scenario would mean that, for Val de Reuil, these XXx workers would be dismissed because of a non-granted authorisation. Val de Reuil has approximately 15,000 inhabitants and, although it is home to some other pharmaceutical companies, the simultaneous dismissal of xxx people only in Val de Reuil (excluding the impact down in the supply chain, see below) would have a major impact on the municipality and the whole region of Normandy.
Concerning the Sanofi Pasteur sites in Marcy L’Etoile and Le Trait (which perform filling and packing of flu vaccines together with the site in Val de Reuil), approximately xx people working in each of the sites xxxxxxxxxx have their jobs depending on the business of flu vaccines. Those xx workers would be made redundant in case of a non-granted authorisation and therefore dismissed.
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Regarding overall Sanofi commercial operations, it is expected approximately xxx employees which are directly involved/engaged on the business of flu vaccines in EEA would be dismissed (in addition to dismissals presented above in Val de Reuil, Marcy L’Etoile and Le Trait).
It is important to note that, besides the expected dismissals of Sanofi Pasteur workers, the most realistic non-use scenario in case of a non-granted authorisation would also be connected to social impacts on suppliers of Sanofi Pasteur. As previously mentioned, egg farms are very important suppliers for the production of flu vaccines at Val de Reuil and it is estimated that these farms have operations which are extremely dependent on the demand from Sanofi Pasteur for the production of flu vaccines in Val de Reuil. In case this demand is no longer there, it is expected that those farms would have to close and approximately xxx workers would have to be dismissed. In terms of other suppliers (external service contractors), Sanofi Pasteur estimates that another xx workers would have their jobs affected by a shutdown of the production lines manufacturing flu vaccines in Val de Reuil.
In summary, it is estimated that approximately 1000 – 1500 XXXX workers would be affected by the most realistic non-use scenario, losing their employment due to the shutdown of flu vaccines production in Val de Reuil, see Table 18.
Table 18: Summary of potential employmentlosses due to the most realistic non-use scenario
Description of potential dismissals Number of headcount
Workers related to the production of flu vaccines in Val de Reuil XXX Workers employed at the sites in Marcy L’Etoile and Le Trait with filling and XXX packaging activities Workers employed in Sanofi Pasteur commercial operations and related to the XXX business of flu vaccines Total dismissals Sanofi Pasteur XXX Workers employed at egg farms highly dependent from the demand from Sanofi XXX Pasteur Val de Reuil flu vaccines manufacturing Workers employed at service contractors XXX Total dismissals due to the most realistic non-use scenario 1000 – 1500 XXX
Following the methodology presented in a report commissioned by ECHA (Dubourg, 2016) the social costs related to expected dismissalsin the non-use scenario are valued considering the following components:
• The value of lost output/wages during the period of unemployment (based on the median duration of unemployment in France as for 2016)
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• The cost of searching for a new position
• Recruitment costs
• The “scarring costs” (i.e. the impact of being made unemployed on future earnings and employment possibilities)
• The value of leisure time during the period of unemployment
The latter component is seen as a negative cost (i.e. a benefit) of unemployment. As such it is subtracted from the total cost resulting from the first four components.
The figures from the aforementioned paper have been updated to 2016 levels by using the wages as updated in the paper from Rogers and Philippe (Rogers & Philippe, 2016) and using the proportions for duration of unemployment for France in 2016 as per Eurostat5. Afterwards, the figure for 2016 was projected to 2021 by considering the data from Eurostat (with an average of 10 years: 2007-2016) of the data set on Labour cost index by NACE Rev. 2 activity - nominal value, quarterly data (seasonally and calendar adjusted data) for the NACE R2 Industry (excluding construction) and only considering labour cost for LCI (compensation of employees plus taxes minus subsidies).6
The calculation of social impacts is shown in Table 19.
Table 19: Summary of social impacts appearing in the NUS given average social cost of one job loss in France
Item [EUR]
Unemployment social cost of one job position in France (2016 value in EUR XXXXXXX determined according to the methodology used in the study contracted by ECHA from September 2016 (Dubourg, 2016)) Unemployment social cost of one job position in France adjusted to 2021 values XXXXXXX (adjustment by 2.1% a year for 5 years) Total social cost due to dismissal of xxx workers at Sanofi Pasteur in 2021 XXXXXXX Total social cost due to dismissal of xxx workers at farmers and service providers in XXXXXXX 2021 TOTAL social costs in 2021 XXXXXXX
As shown in Table 19, social impacts considering the employees foreseen to be dismissed in the most realistic NUS would sum up to approximately EUR 130 - 200 million XXXXXXXXXccXXXXX.
5 http://appsso.eurostat.ec.europa.eu/nui/show.do?wai=true&dataset=lfsq_ugad 6 https://goo.gl/RyVzvT
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It must be noted that gross salaries (including social contributions) at Sanofi Pasteur are above the national average in France and therefore the social impacts provided in Table 19 are certainly underestimated.
4.5 Uncertainty analysis
The ECHA Guidance on SEA proposes an approach for conducting the uncertainty analysis. This approach provides three levels of assessment that should be applied if it corresponds:
- qualitative assessment of uncertainties;
- deterministic assessment of uncertainties;
- probabilistic assessment of uncertainties.
The ECHA Guidance further states: the level of detail and dedicated resources to the assessment of uncertainties should be in fair proportion to the scope of the SEA. Further assessment of uncertainties is only needed if the assessment of uncertainties is of crucial importance to the overall outcome of the SEA.
Hence, a qualitative assessment of uncertainties has been conducted to summarise and describe potential sources of uncertainty related to the impact categories.
Qualitative assessment of uncertainties
Table 20 illustrates the systematic identification of uncertainties related to socio-economic and environmental impacts.
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Table 20: Uncertainties on socio-economic and environmental impacts
Criteria and scaling (contribution to Identification of Classification Evaluation total uncertainty uncertainty and impact on the overall conclusion of the SEA)
It is not clear whether Sanofi Pasteur would be able to recover any part of its Amount of impaired Parameter recent investments in Val-de-Reuil flu investments Low uncertainty vaccines production lines. If anything (economic impacts) could be recovered, however, it would only be a minor part of the investment. Given the size of Sanofi Pasteur and its large market share in Flu vaccines market, it is unclear how many years it Time necessary for would be necessary for competitors to competitors to take take over the market shares currently over Sanofi market owned by the applicant the duration of shares period in the period in economic impacts would which financial Parameter apply for the society is uncertain but in losses for Sanofi Low uncertainty any case estimated to be much longer Pasteur can be than 1 year. Moreover, the market of flu considered economic vaccines in Europe is currently being losses for the society undersupplied, meaning that main players and duration of a are already not able to produce as much supply disruption as required and therefore it may be extremely difficult for competitors to absorb Sanofi Pasteur market shares Using the most up-to-date resources available based on a paper from ECHA The environmental (ECHA, 2017), (Oosterhuis & Brouwer, impacts of endocrine Parameter 2015) a range for the environmental Low disruptors, uncertainty impacts is considered as a rough WTP specifically OPnEO. [EUR 1,000 – 50,000 per kg of emissions]
As it is possible to see from the table above, none of the identified uncertainties can be seen as critical enough to change the outcome of this SEA. Uncertainties are minimised by the fact that even if a lower bound of socio-economic impacts is considered, consequences to the society would still be significantly higher than the benefits to the environment. Given the company size and market shares owned by Sanofi Pasteur in the European flu vaccines market, there are no doubts about how significant the socio- economic impacts of a non-granted authorisation could be. Efforts made by the applicant to minimise Octoxynol-9 emissions and reduce environmental impacts of its operations also contribute to the
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reduction of uncertainties. It is important to note that, whenever there were uncertainties related to the figures presented along this document, lower and upper bound estimations have often been provided for the comparison of impacts.
Given the arguments above, the applicant considers that the conclusions in this SEA are robust and a deterministic assessment of uncertainties is not necessary.
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5 CONCLUSIONS
5.1 Comparison of the benefits and risk
Table 21 below summarises the effects of a non-authorisation.
Table 21: Comparison of impacts for the applied for use and the non-use scenario
Type of impact Applied for use scenario Non-use scenario(s)
• Release of < 80kg of Octoxynol-9: o Cumulated Releases via wastewater of < 70 kg [XXXXXXXXXXXXXX Octoxynol-9 in from the existing facility limited to the period from 2021 to • No release of < 80 kg Environment xxxx xxxxxxxxxxxxxxxx of Octoxynol-9 to the environment o Releases via wastewater in the new facility summing up to 0.1 to 0.4 kg [xxxxxxx] per year (< 10 kg xxxxxx for the whole review period applied for) • Positive health impact with the safe • Significant Worldwide and European supply of seasonal (xxxxxxxxx doses) Impact with the disruption in the and pandemic flu vaccines worldwide supply of flu vaccines worldwide and • xxxxxxxxx doses of seasonal Flu especially for Europe where Sanofi available for European citizens Pasteur is the main supplier xxxxxxx • Sustainability of Sanofi Pasteur in Val xxxxxxxxxxxxxxxxxx de Reuil • Increasing of Health cost linked to • Positive flow of investments at Sanofi Flu disease in EU countries Pasteur in Val-de-Reuil • Impairment of Sanofi Pasteur • XXXXXXXXXXXXXXXxxxxxx investments in Val-de-Reuil XXXXXXXXXXXXXXXXXXxXX • Losses of business operating income Socio-economic for Sanofi Pasteur in the flu vaccines impacts XXXXXXXXXXXXXXXXXXXXXx XXXXXXXXXXXXXXXXX business • XXXXXXXXXXXXXXXXXXXXX • XXXXXxxxxxxxxxxxxxxxxxxxx XXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXxXX • 1000 – 1500 jobs maintained at Sanofi XXXXXXXXXXXXXX & suppliers • Xxxxxxxxxxxxxxxxxxxxxxxxxxx • Benefits along the supply chain with xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx generation of surpluses and xxxxxxxxxxxxxxxxxxxxxxxxxxx employment for egg farms and service xxxxxxxxxxxxxxxxxxxxxxxxxxxx contractors • 1000 – 1500 job losses at Sanofi & • Positive impacts on employement , suppliers economy and states taxes
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Table 22: Quantitative comparison of impacts
Upper bound scenario Lower bound scenario (considering the upper Type of impact (considering the lower monetary monetary value of reference value of reference ranges) ranges)
Potential environmental EUR < 0.2 million xxxxxxxxxxxx EUR < 3 million xxxxxxxxxxxxxx benefits associated with a non- xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxx authorisation (considering an xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxx auxiliary monetary measure xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxx from the PBT/vPvB case xxxxxx EUR 1,000 to EUR 50,000 per Kg of emission)
Negative socio-economic • Losses of at least EUR 145-185 • Up to EUR 170-210 impacts associated with a non- xxxxxxxxxxxxxxx in impaired xxxxxxxxxxxxxx losses in granted authorisation assets and dismantling expenses. impaired assets and • Losses of business operating dismantling expenses income of [EUR 100-400 million] • Losses of business xxxxxxxxx xxxxxxxxxxxxxxx operating income of xxxxxxxxxxxxxxxxxxxxxxxxxx EUR 1-4 billion xxxxx considering 1 year of xxxxxxxxxxxxxxxxx over financial losses (2021). the whole review period • Social cost of dismissals applied for (21 years) amounting to • Social cost of EUR 130-200 million EUR 130-200 million xxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx with dismissals xxxxxxxxx xxxxxxxxxxxx [EUR 100 – 500 million] xxxxxxxxxxxxxxxxxxxxxx [EUR 1 – 5 Billion] Net benefit to grant an Xxxxxxxxxxxxxxx Xxxxxxxxxxxxxxx authorisation [EUR 100 – 500 million] [EUR 1 – 5 Billion] Cost per kg of avoided Octoxynol-9 emission Xxxxxxxxxxxxxxx Xxxxxxxxxxxxxxx (socio-economic impacts [EUR 1 – 10 million] [EUR 12 – 80 million] over volume of emissions in kg)
5.2 Information for the length of the review period
Sanofi Pasteur is currently developing a new type of flu vaccine, the BPIV, which will substitute the current seasonal and pandemic vaccines. The development, approval and launch of the new vaccine generation is expected to take as long as a full development and approval of an Octoxynol-9-free version of the current vaccines. However, as described in section 3.4, it is not feasible from an economic
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perspective to invest on the substitution of the actual process, as full R&D activities, including clinical trials, would be required in both cases. Therefore, Sanofi Pasteur plans to focus its efforts on the development of the new flu vaccine generation while it ensures the supply of its seasonal flu vaccine for the time requested until all markets worldwide can be switched to the BPIV. The new generation vaccine will not use Octoxynol-9 at all. When the current product is phased out, no Octoxynol-9 will be required anymore. However, as long as the new vaccine is not fully implemented in the markets worldwide, the current vaccine will still be required to provide protection against influenza, and thus the use of Octoxynol-9 will also be required.
Using ECHA’s publication “Setting the review period when RAC and SEAC give opinions on an application for authorisation” and CARACAL’s “REACH Authorisation - Criteria for longer review periods” as a guideline, Sanofi Pasteur has drawn the following conclusions regarding the length of the review period applied for:
a) The information shown in this AfA shows that Sanofi Pasteur’s case meets the criteria and considerations that lead to a recommendation of review period longer than 12 years. b) Due to the long investment cycles associated with the development of pharmaceutical products and the extensive studies required for the commercialization of these drugs, a longer review period is suitable for this application. The concrete aspects supporting this review period are: a. Sanofi Pasteur is engaged on substituting Octoxynol-9 in its processes within the framework of the BPIV development. Transition to the new generation of vaccines offers an opportunity to substitute Octoxynol-9 in Sanofi Pasteur’s process in an economically feasible manner. b. Substituting Octoxynol-9 in the current vaccines would require a time period comparable to the one needed for transistioning to the BPIV, due to the complexity and strong reulations related to the production of biopharmaceuticals. R&D efforts and costs would also be similar to developing a new vaccine. c. Because of the large variation in the regulatory landscape of the countries where Sanofi Pasteur’s products are marketed and the multiple tasks required for this, the period needed for obtaining approval in all countries extends to 10 years. d. Important uncertainties exist regarding the development of the BPIV, as part of the normal development of pharmaceuticals. These uncertainties make it difficult to predict the course and length that substitution efforts will take. e. The high impact that Octoxynol-9 substitution would have on Sanofi Pasteur’s vaccines and the associated legislative measures for a successful transition (health authority
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approval of BPIV in countries worldwide) also support the length of the review period applied for. c) A longer review period is in line with the length of the testing and development periods required for transitioning from the current process to an Octoxynol-9-free one. d) In Sanofi Pasteur’s application, risks are effectively minimized by applying appropriate risk management measures and operational conditions, as discussed in the CSR report of this application. The socio-economic benefits associated with the development of the new generation of influenza vaccines also justify the time needed for its development. e) Vaccines constitute important tools for improving public health and combat disease. The global demand for these pharmaceuticals is continuously increasing and, in the case of the influenza vaccine, manufacturers must work against the clock to bring their products into the market in time before the influenza season starts. The withdrawal of Sanofi Pasteur’s vaccines from the market, in case an authorization to use Octoxynol-9 is not granted, would have a significant impact on the global supply of vaccines and, therefore, on the population.
In view of these arguments, Sanofi Pasteur applies for a review period of 21 years. This period comprises the time needed for several steps that need to be taken until the transition to BPIV is completed. The breakdown of the review period requested is shown below in Figure 13.
This schedule highlights the fact that Sanofi Pasteur will need an extended authorization period from ECHA; the current maximum period of 12-years will not allow to completely switch to the new vaccine.
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Figure 13: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
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5.3 Substitution efforts taken by the applicant if an authorisation is granted
As described in section 3.1, Sanofi Pasteur is currently dedicating a large portion of its R&D efforts to the development of the BPIV. Because of the substitution strategy set by Sanofi Pasteur, which focuses on substituting Octoxynol-9 at a process level rather than in the current vaccine manufacturing process, the efforts associated with a granted authorization correspond to those for the development of the BPIV (see section 3.3.1). A suitable alternative has not yet been identified, but the substances discussed in section 3.3.2 have been identified as potential candidates. Further testing will be carried out in the course of the BPIV’s development, according to the time plan shown in Figure 11. It is Sanofi Pasteur’s plan to identify an alternative that can be implemented in the new vaccine’s production and to further develop this alternative into a fully Octoxynol-9-free process, regardless of the expression system selected for manufacturing of the BPIV. Because the BPIV manufacturing process is under development itself, only a preliminary assessment of the suitability of these substances has been carried out. However, the key functionalities fulfilled by Octoxynol-9 in the current process are also those that a substitute will have to fulfil for the manufacturing of the BPIV. As described in this report, significant research and development efforts are still required to develop a robust manufacturing process that can satisfy the future demand for these vaccines. Once established, further legal requirements (validation and marketing authorization) must be fulfilled for transitioning into the new-generation vaccines while ensuring that these can be produced in sufficient amounts. It is Sanofi Pasteur’s opinion that these efforts are in line with the 21-years review period applied for.
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6 REFERENCES Cox, F. C. (2000). Cost of treating influenza in emergency department and hospital settings. Am.J.Manag.Care.
Dubourg, R. (2016, September). Valuing the social costs of job losses in applications for authorisation. Retrieved December 7, 2016, from https://echa.europa.eu/documents/10162/13555/unemployment_report_en.pdf/e0e5b4c2- 66e9-4bb8-b125-29a460720554
ECHA. (2017). SEA-related considerations in applications for authorisation for endocrine disrupting substances for the environment, specifically OPnEO and NPnEO. Helsinki: European Chemicals Agency.
European Chemicals Agency. (2016). Evaluation fo restriction reports and applications for authorisation for PBT and vPvB substances in SEAC. Helsinki: ECHA.
European Medicines Evaluation Agency. (2005, June). Note for guidance on biotechnological/biological products subject to changes in their manufacturing process, ICH Topic Q5E Comparability of biotechnological/biological products.
Haugh, M., Gresset-Bourgeois, V., Macabeo, B., Woods, A., & Samson, I. S. (2017). A trivalent, inactivated influenza vaccine (Vaxigrip®): summary of almost 50 years of experience and more than 1.8 billion doses distributed in over 120 countries. Retrieved from https://www.tandfonline.com/doi/full/10.1080/14760584.2017.1324302
Lina, B., Fletcher, M. A., Valette, M., Saliou, P., & Aymard, M. (2000). A Triton X100-split virion influenza vaccine is safe and fulfils the Committee for Proprietary Medicinal Products (CPMP) recommendations for the European Community for Immunogenicity in children, adults and the elderly. Biologicals, 28(2), 95-103.
Lupulescu, E., Ionita, E., Botez, D., Matepciuc, M., Tabra, M., Tecu, C., . . . Muntiu, A. (1997). An immunogenicity and reactogenicity study of a purified, inactivated trivalent influenza vaccine for parenteral administration prepared for the 1996-1997 season. Bacteriologia, virusologia, epidemiologia, 42(1-2), 110-112.
Meier, G. e. (2015). Cost-effectiveness analysis of quadrivalent influenza vaccination in at-risk adults and elderly: an updated analysis in the UK. Journal of Medical Economics.
Newall, A., & Scuffham, P. (2008). Infleunza-related disease: the cost to the Australian healthcare system. Vaccine, 26 (52), 6818-23.
Oosterhuis, F., & Brouwer, R. (2015). Benchmark development for the proportionality assessment of PBT and vPvB substances. Amsterdam: IVM Institute for Environmental Studies - University Amsterdam.
Preaud, E. (2014). BMC Public Health.
Principi, N. e. (2004). Burden of influenza in healthy children and their households. Archives of Disease in Childhood, 89(11).
Use number: 1 Legal name of the applicant: Sanofi Pasteur
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ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC ANALYSIS
Rogers, J., & Philippe, C. (2016). The Tax Burden of Typical Workers in the EU 28. Retrieved March 2018, from Institut Molinari: http://www.institutmolinari.org/IMG/pdf/tax-burden-eu-2016.pdf
Szucs, T. (1999). The socio-economic burden of influenza. Journal od Antimicrobial Chemotherapy, 44, 11-15.
The European Public Health Alliance. (2009). Retrieved from https://epha.org/IMG/pdf/seasonflu_rec2009_en.pdf
Uhart, M., Bricout, H., Clay, E., & Largeron, N. (2016). Public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines compared to trivalent influenza vaccines in Europe. Retrieved from https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1180490
Vaccines Europe. (n.d.). The EU vaccine industry in figures. Retrieved from https://www.vaccineseurope.eu/wp- content/themes/vaccines/images/Infographic_The_EU_Vaccine_Industry_In_Figures.pdf
World Health Organization. (2017). WHO preferred product characteristics for next generation influenza vaccines. Geneva. Retrieved from http://apps.who.int/iris/bitstream/10665/258767/1/9789241512466-eng.pdf?ua=1
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