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Pierre FABRE CDMO: Manufacturing for your Health

Pierre FABRE is one of the leading pharmaceutical companies rooted in France, which sells its pharmaceuticals, healthcare and dermo-cosmetic products all over the world1. With more than 50 years of activities and an annual turnover exceeding 2 billion euros, Pierre FABRE is a well-established player, firmly anchored in the south-west of France and with a growing footprint in Africa and Asia, as well as in America, either on its own or through strategic partnerships. For more than 30 years, the Pierre FABRE Pharma division has offered CMO activities to clients, mostly in the field of injectable products. Recently, the initiative to turn to a CDMO model was launched, with a new team and a redesigned organisation, in the frame of a global strategic plan “Trajectoire 2018”2. « Manufacturing for your Health » is the watchword for the Pierre Fabre CDMO newly-organized franchise, and they are words the CDMO team members have taken to heart in developing their new business activities.

The global pharma outsourcing market is growing fast, with an estimated market value of about $300 billion this year, thanks to the contribution of contract research organisations (CROs), contract manufacturing organisations (CMOs), and contract development and manufacturing organisations (CDMOs). After more than 30 years of CMO activities, CDMO has now become an integral part of the development and manufacturing strategies of the Pierre FABRE Pharma division. The turn from CMO to CDMO is not new in the pharma & biotech industry. A trend towards outsourcing earlier-stage analytical and formulation capabilities was already noticed in the past 5-10 years. Small biotechs are particularly eager to get their products into the clinic more quickly and raise value earlier in their development, with the assistance of global service providers. Pierre FABRE follows this CMO-to-CDMO evolution, with the objective to reinforce its competitiveness within three specialised poles of activity: 1. injectable products, including

conventional cytotoxic and biotechnology products;

2. API chemistry, in particular for natural products;

3. the niche market of pharmaceutical lozenges.

Each of these three business lines is associated with technical innovations and linked to R&D knowledge (Figure 1).

CDMO Division for Injectable and Biotech ProductsOne of our main services focuses on manufacturing (+/- packaging) of very large batch sizes of marketed products owned by medium and big pharma partner companies essentially. This is the recognised expertise of our agencies-accredited site located in Pau (PFMP, France). This site, organised around nine independent workshops, specialises in aseptic processing and isolator manufacturing of anticancer and biotech products in vials, syringes and infusion bags, liquid or freeze-dried (Figure 2). Each workshop provides customer-oriented innovations, such as ATEX compliance for sterile processing and freeze-drying processes with organic solvents, compact loading/unloading systems, sterile capping, laser printing devices, etc. The onsite service also includes purchase and control of raw materials/components, cold storage of active ingredients, manual or semi-automatic visual inspection and specific packaging in bulk or finished products, and delivery. In addition, we now offer a broader service linking manufacturing to product development services for both chemical and biological entities, via two R&D facilities based in Toulouse and Saint-Julien-en-Genevois (France). This CDMO model thus integrates key components of drug development (process development and validation, formulation and analytical support, stability storage and testing, clinical batches production, etc) into the manufacturing process at early stages. Clients - be it a large global pharmaceutical company, a mid-sized biotech, or a virtual firm - are particularly keen to find a one-stop-

shop for their product. Whatever the perception of the so-called “shop”, which may propose activities from “Gene to Syringe” or from “Compound to Clinic” or from “Bench to Market”, the objective is always to offer a broader service for our clients. In this context, and as a typical example, we are a key partner for the fill and finish of a registered immuno-conjugate owned by a US big pharma company relying on our high-capacity manufacturing capacities, as well as the strategic partner for an emerging European biotech developing a new generation of antibody-drug conjugate. Both ADC companies, the large and the small ones, request from us a high-quality organisation and good people and infrastructures to handle their products, with guarantee to respect their timeline and financial constraints. We demonstrated a cost-effective partnership for quality services from development to manufacturing, based on our solid expertise of sterile

CDMO divisions & industrial plants

Partners Demands

Natural productsPlant/animal extractsHP-cytotoxic drugs

Filled aseptic vials, syringes

LozengesPastillesPharmaceutical lozenges

API chemistry

Injectable & Biotech Products

Development activities(chemical and biological products)

R&D operations

PCC SCF

Raw materials, ingredients, components, etc

PFCDMOteam

External innovation(alliance, partnership)

Figure 1: Illustration of Pierre FABRE CDMO business capabilities and outputs. Innovation platforms, such as

Supercritical Fluid (SCF) and Plant Cell Culture (PCC) function in a semi-independent mode from core mainstream activities

Figure 2: Manufacturing of injectable products (Pau, France)

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injectable products. In this domain, the international competition is fierce and the market tends to concentrate around a few big players selected by large/mid-sized pharmaceutical companies. A full product offering is key to keep our partners and bring newer, smaller players which tomorrow will be the leaders through their novel drugs. Said in another way, there is no choice but to offer our present and future clients the D they demand, in addition to the M we are mandated to do. With an agile organisation and adapted equipment, we can be brought in on a new project, let’s say a new vaccine for example, at the early stage of protein development with a small batch scale-up to the late stage of registration with a commercial dimension, depending on the wish and strategy of the partner. Needless to say, in this domain of highly-active products (generally for oncology and inflammatory diseases), our production processes are subject to rigorous quality control procedures and testing, and are GMP-compliant in accordance with requirements of international agencies (ANSM, FDA, PMDA, ANVISA…). The Pierre FABRE CDMO division for injectable cytotoxic and biotech products is the partner of choice for a number of European, US and Japan pharma companies. All our partners are different; we adapt to their need and profile. Our perspective is to broaden our international presence and to be continuously pioneers in the manufacturing process.

CDMO Division for Pharmaceuticals LozengesFor more than 30 years, the Pierre FABRE plant in Aignan (France) has offered a cost-effective service for the manufacturing of hard-boiled lozenges and pastilles/gums that are sucked in the mouth and traditionally used for cold and throat OTC preparations, but also for smoking cessation or other nutraceutical applications. A variety of well differentiated products can be made, based on our custom formulation and taste-masking capabilities. Different production lines offer variable capacities, from batches of 65kg to large volumes of 5000kg using a fully automatic continuous manufacturing process (Figure 3). This later up-to-date technology of continuous flow enhances the production capacity as well as product quality and security. Our R&D teams provide the necessary support to create new products or to modulate lozenges formulation

or product stability, to optimise local exposure of the active ingredient in the oral cavity for a predetermined period of time, for example. We offer a full CDMO lozenge service to our clients, from product development to product launch. The service can include both manufacturing and packaging, with a variety of packaging solutions: blister packing, bag in box and flow wrap. The development service is broad: optimisation of formulations, scale-up services (pilot batches, clinical batches, registration batches), biological tests, stability testing, validation batches, regulatory support, technical transfer for commercial production, and other custom services. Our dedicated plant in Aignan produces a variety of lozenges, from Drill® Pierre FABRE’s famous brand of cough relief lozenges, renowned for their unique flavour and active qualities, to a range of partner products with different forms and applications (pastilles to soothe and relieve sore throats, coughs or colds; lozenges containing flavour modulators, nicotine, etc...). We currently produce more than 300 million lozenges per year. Electronically controlled, automated, high-performance machines carry out all the processes right from weighing the raw material, to cooking, blending, flavouring, cooling and forming the hard candy. The Pierre FABRE CDMO division for Pharmaceuticals Lozenges can assist you in the manufacturing and supplying of medicated and herbal lozenges in various sizes and types of packaging. We are engaged to complete projects at a reasonable cost and to deliver expeditiously according to stringent timelines. Our dedication to our clients and their business contributes to a differentiated product capable of competing in both domestic and international markets (European and US markets). Our Aignan facility is robustly implanted in the pharmaceuticals lozenges niche market. We are upgrading the plant to ensure that it meets

the rigorous requirements demanded by both our customers and the health authorities. Facility expansions are also planned for the near future and further down the line. This CDMO division will continue to grow sweetly.

CDMO Division for API ChemistryThe Pierre FABRE company was founded more than fifty years ago and it is today a firm of international repute, renowned for its high-quality and innovative products, in particular natural substances extracted from plants. For example, Pierre FABRE is the world leader for the extraction of vinca-alkaloids from the tropical periwinkle (e.g. the cytotoxic products Navelbine® and Vinflunine®, both prescribed in oncology). The group has an incredible culture of natural substances, used in the pharmaceutical field and even more extensively in the dermo-cosmetic domain. Located in Gaillac (F), the dedicated site “Plantes & Industrie” offers high technologies for the extraction, purification and chemical synthesis of APIs (Figure 4). A speciality of our operators is the handling of high potent APIs, in particular naturally-occurring cytotoxic agents manipulated in specific workshops to enable their extraction and purification, and in specific cases their chemical modulation (e.g. low-temperature fluorination in superacidic media). Another site located in Bagnère-de-Bigorre (France) is dedicated to the preparation of floral waters, and two other complementary plants in Virey-del-Pino (Argentina) and Palézieux (Switzerland) provide specific expertise in animal extraction, with the production of chondroitin sulphate sodium (extracted from chicken wishbones), hydroxyapatite (from bone extracts) and other animal specialities. These plants operate in full compliance with current good manufacturing practices (GMP, ICHQ7A) and are regularly inspected by international agencies, including EMA and FDA. Gaillac’s core capabilities

Figure 3: Manufacturing of pharmaceutical lozenges (Aignan, France): batch production (left) and continuous flow (right)

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include controlled substances, plant alkaloids, complex amino acids, and many other technically complex APIs. The specific and independent workshops allow manufacturing for clinical trials or commercialisation, either for defined chemicals or natural extracts. The expertise for purification and extraction is large, using counter current continuous extraction (multi-solvents) and batches, also using industrial HPLC purification and specific technology innovations (e.g. supercritical fluids, see below). The CDMO Division for API chemistry provides pharmaceutical chemistry services to large and emerging pharma and biotech companies across the globe, helping accelerate candidates from discovery to production. We support clients from medicinal chemistry services through Phase I-III to large-scale commercial API production, with a focus on natural products and highly potent

cytotoxic products. Our specialisation in natural products chemistry (extraction, analytics, hemisynthesis) and compound classes that require strict regulatory and safety controls, such as potent compounds and controlled substances, differentiates us from our competitors. CDMO officers provide a centralised approach to project management, to ensure on-time and on-budget completion of API development projects for both clinical trials and commercial supply. Over the past five decades, Pierre FABRE has carved out a groove in the natural products market, offering capabilities for several classes of molecules such as amino acids, biopolymers, cytotoxic agents and more recently immuno-conjugates (ADC, see below).

Technology InnovationsAnother key aspect of Pierre FABRE CDMO is to offer a palette of innovative

technologies in order to provide customers with the highest levels of development, quality, productivity and reliability of health products. Our engineers adapt and optimise key technologies to broaden our services. Here are two segments, both related to green chemistry, which we have significantly investigated and invested in over the past ten years:

Plant Cell Cultures (PCC)Biomanufacturing is a major activity to ensure flexible and low-cost production of complex biomolecules using microbial, cell cultures or transgenic technologies. In this context, based on its 50 years of botanical expertise, Pierre FABRE has developed a plant cell culture technology platform and leading know-how to manufacture plant biomass, extracts and secondary metabolites. The PCC technology is based on the isolation of stem cells from a given plant, which are then grown in a bioreactor (Figure 5) to produce an optimised biomass. A modulation of the production of secondary metabolites (elicitation and/or addition of precursors) can be applied to stimulate the production of the desired product(s). The biomass is then treated, purified and formulated to obtain the whole active mixture of active ingredients. Our flagship commercialised product is Cell Capital® from Galénic brand (FABRE dermo-cosmetic), a potent anti-ageing lifting elixir from native argan cells. This preparation derives from an in vitro culture of dedifferentiated, non-elicited cells of the argania tree (Argania spinosa, endemic to Morocco but today under threat), used for treating skin ageing, inflammation and scarring. A specific industrial process to ensure the cultivation of these argan plant cells has been designed and implanted within a dedicated workshop, equipped with various incubators and wave bioreactors, under GMP conditions3. This bioprocess can be tailored to produce other active substances on demand in a human-controlled environment, independently of the original plant’s ecosystem, while respecting green chemistry principles (e.g. limited solvent use). It is particularly adapted to plant species that are difficult to cultivate on a large scale, that grow slowly or that have not been domesticated, or are protected or threatened with extinction, without endangering them. This is the case for the diterpenoid epoxide triptolide, an investigational anticancer agent4, usually isolated from the traditional Chinese

Figure 4: Extraction (top) and chemical synthesis (top) of active pharmaceutical ingredients (Gaillac, France)

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medicinal plant Thunder God Vine (Tripterygium wilfordii Hook. f.) and for which we have established a specific PCC process to facilitate the production of the drug and analogues5. The PCC technology is well adapted to produce highly certifiable, environment-friendly products, free of micro-pollutants like heavy metals, aflatoxins, pesticides and herbicides. The goal of our CDMO PCC team is to supply new active substances using various plant cells for use in the cosmetic and pharmaceutical fields. Pierre FABRE has registered several patents in this breakthrough R&D area and offers a full PCC service.

Super Critical Fluids (SCF)Over the past 12 years, Pierre FABRE has extensively developed the use of supercritical carbon dioxide as a solvent-free (green) approach to improve the formulation of APIs. Several patented processes have been set up to help the development of products, lifecycle management or formulation: Formulcoat® (particle-coating for taste-masking), Formulplex® (inclusion complex with cyclodextrin), Formuldis P® (solid dispersion in excipient matrix). Our supercritical fluid experts operate in a state-of-the-art and independent SC CO2 platform (Figure 6), using top-quality equipment and infrastructure (high pressure pumps 20 kg/h to 500 kg/h; Cyclonic separators 10 and 20 litres; mixer dryer, high potent drug area; etc) in compliance with cGMP to manage a large diversity of therapeutic classes of APIs, including poorly bioavailable

and insoluble APIs, from a few grams to commercial batches (reactors from 0.25 to 50 litres), within our EMA-certified and FDA-inspected site in Gaillac. For example, the supercritical process has been used to improve the dissolution rate of eflucimibe, a cholesterol acyltransferase inhibitor, used to lower serum cholesterol concentration6. More recently, the methodology was used todevelop and to produce a taste-masked Ibuprofen for orodispersible tablets. We also work on the purification of a polymer. Several phase III batches have been manufactured and the polymer is now

being produced at the commercial scale under GMP conditions. Our scalable, GMP-compliant and cost-effective supercritical fluid technologies can bring high value to challenging health projects. The CDMO supercritical fluids division has been recognised by international experts and has been awarded with a CPhI Innovation prize for its innovation.

These two examples, PCC and SCF, illustrate our efforts to promote green chemistry by complementary approaches. They demand a long-term vision and commitment to yield results, but innovation is clearly not just about technical research and development. Innovation is not the technique itself, it is the output, such as a new natural product obtained by PCC or a valuable polymer purified by SCF. Moreover, we also rely on organisational innovation, with the aim to improve processes and workflows. Solid functional capabilities are important to develop technical knowledge. We are largely open to external innovations to bring in new methods, principles and ideas (Figure 1). Networks, alliances of customers, suppliers and competitors are also source of innovation. Integrative, functional and organisational capabilities are the pillars of our CDMO franchise.

Today, at its heart, Pierre FABRE CDMO is essentially an engine for the manufacturing of injectable products, for “fill & finish” operation via its Pau site facility. This activity represents more

Figure 5: Plant cell culture in a wave bioreactor (Gaillac, France)

Figure 6: Manipulation of supercritical carbon dioxide (Gaillac, France)

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than 70% of the current annual CDMO revenue, and the most competitive service. Our objective is to maintain a sustainable international position in this domain, including more biotech products, through additional capacities and equipment and workshops, robustness of processes, and a strong link with drug development teams. But we are not committed to one dominant technology. In parallel, we intend to reinforce our competitiveness in API natural products chemistry and develop the pharmaceutical lozenges branch. In the field of API chemistry, we face a major challenge – the requirement to innovate, not just occasionally but often, quickly and with a solid success rate. For lozenges, hand in hand with our clients, the goal is a continuous stream of new products at low price, high quality and for a mass market. In the short term, our position will be reinforced via novel production and packaging lines and development capacities to touch new markets and new therapeutic applications.

Clearly the company takes a specialised approach, making investments in the three above mentioned business lines and a few technology platforms, such as PCC and SCF. A key aspect is also to cross this know-how with a clear articulation between services, platforms and organisation. An example of that is given below.

A Case Study in Translational Capability: Manufacturing of Antibody-drug Conjugates (ADC)With two products on the oncology market (Adcetris® and Kadcyla®), ADCs may still be considered as an emerging class of anticancer products, although the concept of attaching a potent cytotoxic agent to a cancer cell delivery vector is quite old7. The first ADCs were proposed more than 30 years ago. Now, technologies have evolved and the field is mature, with more than 50 ADCs under clinical development8,9. ADCs are complex molecules, not only intrinsically with three designed and joined components (antibody, linker, cytotoxic), but also in terms of chemistry, manufacturing and controls. The supply chain for a given ADC usually requires multiple partners and a tight management of suppliers, manufacturers, delivery processes, etc. The continuum in the process, from initial synthesis to the finished dosage form is key and few companies can offer the full service.

On the one hand, we do perform the fill & finish operation for ADC clinical batches and commercial supply. Pierre FABRE Medicament Production (Pau site) is Seattle Genetics’ operator for cGMP fill/finish manufacture of commercial quantities of brentuximab vedotin (Adcetris®)10. On the other hand, our different R&D teams possess the necessary skills and pilot units to prepare non-GMP and GMP batches of monoclonal antibodies, (high potent) cytotoxic natural products, and hemi-synthetic analogues with appropriate linkers. Most importantly, they know perfectly how to handle these individual components, assemble them into effective ADCs, and how to analyse such complex and costly hybrid molecules and characterise integrity, activity, stability, etc… API chemistry, with an emphasis on high potent natural products is a core competence at Pierre FABRE (see above). Our chemists are also engaged in the synthesis of linkers (cleavable, non-cleavable) which require traditional small molecule technology for production. Discovery and early development of antibodies, and more recently ADC, is a speciality of the Pierre FABRE Immunology Center, based in Saint-Julien-en-Genevois11. With the CDMO franchise, we have now created fully permeable business boundaries between the different entities in R&D and industry, to offer the full service. Cross-functional exchanges encourage innovation and performance. Manufacturing of ADC is considered as a strategic initiative for Pierre FABRE, requiring a good combination of chemical synthesis with biologics engineering. There are several leading companies which best combine the art of chemical synthesis and biological technologies. We jump into the field with a competitive offer based on our reputation in cytotoxic natural products and excellence in performing fill & finish operations. The goal is to provide a full service (Figure 7) to ADC-owners, from biotechs at early stages of development

to mid-size and big pharma requiring essentially terminal manufacturing of their drug products. We see our role as a pure service provider and wish to offer a simplified supply chain from early drug synthesis and antibody production to ADC linking services and fill & finish operation (Table 1). We manufacture the cytotoxic agent and linker at one facility (Gaillac site). We produce the antibody from mammalian cells and provide drug conjugation at our Saint-Julien facility. And then we offer terminal aseptic filling and packaging at our Pau site. All steps are realised in high containment environments. Detailed analytic investigations of ADCs can also be proposed, based on a state-of-the-art analytical platform and experts12-15.

ConclusionThe outsourcing service industry is playing a significant role in moving the entire pharmaceutical industry forward. Along with CROs and CMOs, CDMO players can help with their specialised know-how and deep experience, but players are numerous and specialisation is necessary. Pierre FABRE CDMO offer concentrates on three specific axes, with the aim of capturing a significant share in R&D and in commercial production. The new CDMO team is up and running, with division-dedicated business developers, technical experts and project managers. Strong orientations are fixed (including ADCs, biotech products) and we are in the process of establishing partnerships and alliances to promote our position within the worldwide CDMO arena. Looking forward to the future, we expect to see even more connectivity between pharma R&D and manufacturing industry to facilitate the productive use of knowledge and to best answer the needs of our partners.

HP-API production & linker chemistry

Antibody production ADC conjugation Aseptic filling

clinical batches (R&D)

Commercial scale (Industry)

Manufacturing capacities for antibody-drug conjugates (ADC)

Figure 7: Pierre FABRE CDMO manufacturing capabilities for antibody-drug conjugates (ADC). At present, HP-API production and aseptic filling can be performed for both (pre)clinical batches and commercial use, whereas antibody production and ADC coupling are

realised for (pre)clinical batches only.

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Acknowledgements: I am grateful to Ms Corinne Alaux for useful comments and corrections to the manuscript. I also wish to thank several Pierre FABRE CDMO, Industry and R&D colleagues for providing me with their insights into the processes mentioned here.

References1. http://www.pierre-fabre.com2. http://www.pierre-fabre.com/en/

news/pierre-fabre-laboratories-present-their-new-strategic-plan-trajectoire-2018

3. Steward N, Mandeau A, Castex Rizzi N. (2010) Préparation issue d’une culture in vitro de cellules dédifférenciées non élicitées d’arganier, leur utilisation pour le traitement du vieillissement cutané, de l’inflammation et de la cicatrisation, et leur obtention. Patent FR2958163 – A1.

4. Meng C, Zhu H, Song H, Wang Z, Huang G, Li D, Ma Z, Ma J, Qin Q, Sun X, Ma J. Targets and molecular mechanisms

of triptolide in cancer therapy. Chin. J. Cancer Res. 2014, 26, 622-626.

5. Steward N, Chomarat N, N’Guyen, N.T. (2009) Method for producing triptolide. WO 2011/054929 – A2.

6. Rodier E, Lochard H, Sauceau M, Letourneau JJ, Freiss B, Fages J. A three step supercritical process to improve the dissolution rate of eflucimibe. Eur. J. Pharm. Sci. 2005, 26, 184-193.

7. Beck A, Haeuw JF, Wurch T, Goetsch L, Bailly C, Corvaïa N. The next generation of antibody-drug conjugates comes of age. Discov Med. 2010, 10, 329-339.

8. Gerber HP, Koehn FE, Abraham RT. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics. Nat Prod Rep. 2013, 30, 625-639.

9. Chari RV, Miller ML, Widdison WC. Antibody-drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed Engl. 2014, 53, 3796-3827.

10. http://www.seattlegenetics.com/pdf/SGEN_AR_2011.pdf

11. Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010, 10, 345-352.

12. Wagner-Rousset E, Janin-Bussat MC, Colas O, Excoffier M, Ayoub D, Haeuw JF, Rilatt I, Perez M, Corvaïa N, Beck A. Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion. MAbs. 2014, 6, 173-184.

13. Wagner-Rousset E, Janin-Bussat MC, Colas O, Excoffier M, Ayoub D, Haeuw JF, Rilatt I, Perez M, Corvaïa N, Beck A. Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion. MAbs. 2014, 6, 273-285.

14. Debaene F, Boeuf A, Wagner-Rousset E, Colas O, Ayoub D, Corvaïa N, Van Dorsselaer A, Beck A, Cianférani S. Innovative native MS methodologies for antibody drug conjugate characterization: High resolution native MS and IM-MS for average DAR and DAR distribution assessment. Anal Chem. 2014, 86, 10674-10683.

15. Janin-Bussat MC, Dillenbourg M, Corvaia N, Beck A, Klinguer-Hamour C. Characterization of antibody drug conjugate positional isomers at cysteine residues by peptide mapping LC-MS analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2015, 981-982:9-13.

Christian Bailly is the Pierre Fabre CDMO Director. Contract Development and Manufacturing Organization, CRDPF, 3 Avenue Hubert Curien - BP 13562, 31035 Toulouse cedex 1, France.Email: christian.bailly@pierre-fabre.com

Table 1: Pierre FABRE ADC capabilities__________________________________________________________________________1. HP-API production and • >30 years natural products extraction/purification

linker chemistry • Synthesis of HP-cytotoxic agents• API sourcing support• R&D and commercial production• Synthesis of cleavable or conditionally stable linkers• Diverse small molecule chemistry technologies (e.g. superacid chemistry, large-scale chromatography, etc)• Supercritical fluids technology platform• Plant cell culture platform and botanical expertise• GMP-compliance, FDA-approved facility

2. Antibody production • Process development and scale-up• Master and working cell bank manufacture• Mammalian cell culture (up to 1000L single-use bioreactor)• Fully single-use downstream platform (clarification, chromatography, viral filtration, SU TFF…)• Non-GMP and GMP grade production (kg scale)• Analytical methods development and validation• Formulation development, stability studies• Technology transfer• ANSM-approved facility

3. ADC conjugation • Aseptic biological manufacturing environment with safe manipulation of highly cytotoxic drugs• Cystein and Lysine coupling technologies • Pilot scale and GMP scale production (up to 100L ADC/batch)• Formulation development, stability studies• Analytical methods development and validation• State-of-the-art ADC analytical characterisation

4. Aseptic filling • >30 years sterile cytotoxic injectables expertise• Wet and dry vials, prefilled syringes • Nine independent workshops• Large lyophilisation capacity• R&D and commercial production• Packaging service• Conform to US/EU/Japan regulatory requirements

__________________________________________________________________________Different R&D and industrial sites are implicated, in Gaillac (API chemistry), Saint-Julien-en-Genevois (antibody production and ADC coupling), Pau (fill & finish) and Toulouse (R&D and CDMO offices).

9

Table 1: Pierre FABRE ADC capabilities