Welcome to the CMC Strategy Forum Latin America 2015 On behalf of the CMC Strategy Forum Global Steering Committee and the CMC Strategy Forum Latin America Scientific Program Committee, we would like to extend to you a warm welcome to the 2nd meeting of the CMC Strategy Forum Latin America 2015. We are very pleased that with the strong support from the Brasilian National Health Surveillance Agency (ANVISA); as well as Grupo FarmaBrasil; ISP, (Public Health Institute, Chile); DIGEMID (General Directorate of Medicines, Supplies and Drugs, Peru), and with the continued organization by CASSS and the support of the EMA (European Medicines Agency) and the United States Food and Drug Administration, that we are continuing with the CMC Strategy Forum Latin America 2015. The Forum will follow the established model of the CMC Forum series with focus on topics and regulatory updates relevant to Latin America and will feature an opening regulatory session – Regulatory Convergence: Recent Trends in the Regulations of Biotherapeutic Products in Latin America - that will include presentations from ANVISA Brasil, DIGEMID Peru, ISP Chile, COFEPRIS Mexico, Finnish Medicines Agency (representing the European Medicines Agency) and the US FDA. The technical sessions will include discussions on: Cold Chain Management and Qualification for Biological Products Transportation; Characterization, Control and Regulation of Protein Glycosylation; and Technology Transfer for Biopharmaceuticals. The success of the CMC Strategy Forum will depend on your active participation in discussing and raising issues pertaining to development of biologics. We encourage you to participate wholeheartedly in the panel discussions that have been designed to stimulate exchange of ideas and information. We would like to thank the speakers and panel members who are giving generously of their time and resources and to you for your attendance. We would also like to acknowledge the generosity of our program partners for the continued support of the Forum series.

ACKNOWLEDGEMENTS

CMC STRATEGY FORUM LATIN AMERICA SCIENTIFIC PROGRAM COMMITTEE: Reginaldo Braga Arcuri, GrupoFarma Brasil, Brasil Adriana Diaféria, Grupo FarmaBrasil, Brasil John Dougherty, Eli Lilly and Company, USA Daniel Durand, Amgen Brasil, Brasil Rocio Delgado Montero, DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru Marcelo Moreira, ANVISA – National Health Surveillance Agency, Brasil Fabiola Muñoz, ISP, Public Health Institute, Chile Ana Padua, F. Hoffmann-La Roche Ltd., Brasil Marcelo Quintao, Grupo FarmaBrasil, Brasil Carmilia Jimenez Ramirez, Gilead Sciences, USA Zunilda Ruiz, DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru Priscila Scheinberg, Orygen Biotecnologia, Brasil Thomas Schreitmüller, representing FIFARMA, Latin America Federation of the Pharmaceutical Industry Vanessa Schiavo, Libbs Farmacêutica, Brasil Orlando Vitor da Silva, Eli Lilly do Brasil Ltda., Brasil Vanessa Lucas Xavier, ANVISA – National Health Surveillance Agency, Brasil CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, KemWell Biopharma, USA John Dougherty, Eli Lilly and Company, USA Steven Kozlowski, CDER, FDA, USA Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Rohin Mhatre, Biogen, USA Anthony Mire-Sluis, Amgen Inc., USA Marcelo Moreira, ANVISA – Brasilian National Health Surveillance Agency, Brasil Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland (Chair) Ilona Reischl, BASG/AGES, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Daisaku Sato, PMDA – Pharmaceutical and Medical Devices Agency, Japan Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, MedImmune, A member of the AstraZeneca Group, USA Karin Sewerin, BioPharma Linx AB, Sweden

The Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous

support of the CMC Strategy Forum Latin America 2015

SUSTAINING DIAMOND FORUM PARTNER

F. Hoffmann-La Roche Ltd. BRONZE FORUM PARTNER

Grupo FarmaBrasil

LEADING MEDIA PARTNERS

BioProcess International International Pharmaceutical Quality

MEDIA PARTNERS

The Analytical Scientist BioProcessing Journal The Medicine Maker

The Pathologist separationsNOW.com Technology Networks

CMC Strategy Forum Latin America 2015 Scientific Program Summary

Monday, 24 August 2015

06:00 – 10:00 Breakfast Buffet for all CMC registered guests of the Meliá Brasil 21 in Norton Grill (Meliá Brasil 21)

07:30 – 17:00 Registration in the Mundo Novo Foyer (Bloco G, Brasil 21 Convention

Center) 08:45 – 09:15 CASSS Welcome and Introductory Comments Nadine Ritter, Global Biotech Experts, LLC, USA

CMC Strategy Forum Latin America 2015 Welcome and Introductory Comments

Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland

An Update / Overview on Regulatory Convergence, Predictability, Transparency and Priority Reviews in Latin America

Plenary Session In Mundo Novo 1 and 2 (Bloco G, Brasil 21 Convention Center)

Session Chairs: Marcelo Moreira, ANVISA, Brasilian Health Surveillance Agency and Ana Padua, EFPIA LATAM Network Chair

09:15 – 09:30 Updates on Regulatory Issues for Biotherapeutic Products License in

Brazil Marcelo Moreira, ANVISA, Brasilian Health Surveillance Agency, Brasil

09:30 – 09:45 Recent Trends in the Regulation of Biotherapeutic Products in Peru

Edith Roxana Vásquez Alayo, DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru

09:45 – 10:00 Advances in Regulation of Biotech Products in Chile

Fabiola Muñoz Espinoza, ISP, Public Health Institute, Chile 10:00 – 10:15 Regulatory Changes in Mexico

Esenbeckia Yureri Torres Guzman, COFEPRIS, Federal Commission for the Protection against Sanitary Risk, Mexico

10:15 – 10:45 AM Break in the Mundo Novo Foyer

Monday, 24 August continued… 10:45 – 11:00 EU Regulatory Update – Innovative Marketing Authorisation

Approaches and Regulatory Transparency Policies Niklas Ekman, Finnish Medicines Agency, Finland

11:00 – 11:15 Recent Trends in the Regulation of Biotherapeutic Products: US FDA

Perspective Sarah Kennett, CDER, FDA, USA

11:15 – 11:30 TBD

Reginaldo Braga Arcuri, Grupo FarmaBrasil, Brasil 11:30 – 11:45 A Call for a Harmonized, Risk-based Lifecycle Management

Approach for Biologics Thomas Schreitmüller, representing - Latin America Federation of the Pharmaceutical Industry (FIFARMA)

11:45 – 13:15 Hosted Lunch in Lucca Restaurant (Bloco F, Brasil 21 Convention

Center)

An Update / Overview on Regulatory Convergence, Predictability, Transparency and Priority Reviews in Latin America

Panel Discussion In Mundo Novo 1 and 2 (Bloco G, Brasil 21 Convention Center)

Session Chairs: Marcelo Moreira, ANVISA, Brasilian Health Surveillance Agency and Ana Padua, EFPIA LATAM Network Chair

13:15 – 14:45 PANEL DISCUSSION - Questions and Answers

Edith Roxana Vásquez Alayo, DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru Reginaldo Braga Arcuri, Grupo FarmaBrasil, Brasil Niklas Ekman, Finnish Medicines Agency, Finland Sarah Kennett, CDER, FDA, USA

Marcelo Moreira, ANVISA, Brasilian Health Surveillance Agency, Brasil Fabiola Muñoz, ISP, Public Health Institute, Chile

Thomas Schreitmüller, representing - Latin America Federation of the Pharmaceutical Industry (FIFARMA) Esenbeckia Yureri Torres Guzman, COFEPRIS, Federal Commission for the Protection against Sanitary Risk, Mexico

14:45 – 15:15 PM Break in the Mundo Novo Foyer

Monday, 24 August continued…

Characterization, Control and Regulation of Protein Glycosylation Workshop Session

In Mundo Novo 1 and 2 (Bloco G, Brasil 21 Convention Center) Session Chairs: Leda dos Reis Castilho, Universidade Federal do Rio de Janeiro and Ana Moro,

Instituto Butantan 15:15 – 15:40 The Importance of Protein Glycosylation – Why Do We Have It?

What Does It Do? Guillermina Forno, University of Litoral and Zelltek S.A., Argentina 15:40 – 16:20 State of the Art Glycosylation Analysis of Biotherapeutic Products

and its Application to Control Glycosylation Martin Blüggel, Protagen Protein Services GmbH, Germany 16:20 – 17:05 Glycosylation of Biosimilar mAbs – The Challenge of Assessing

Similarity ByoungOh Kwon, Celltrion Research Institute of Biotechnology, Korea 17:05 – 18:15 PANEL DISCUSSION – Questions and Answers Martin Blüggel, Protagen Protein Services GmbH, Germany Niklas Ekman, Finnish Medicines Agency, Finland

Guillermina Forno, Zellteck S.A., Argentina Sarah Kennett, CDER, FDA, USA ByoungOh Kwon, Celltrion Research Institute of Biotechnology, Korea 18:15 – 19:30 Networking Reception in Restaurante Miró (Bloco B, Brasil 21

Convention Center) 19:30 Adjourn Day One

Tuesday, 25 August 2015 06:00 – 10:00 Breakfast Buffet for all CMC registered guests of the Meliá Brasil 21 in

the Norton Grill (Meliá Brasil 21) 08:30 – 17:00 Registration in the Mundo Novo Foyer (Bloco G, Brasil 21 Convention

Center)

Technology Transfer for Biopharmaceuticals Workshop Session

In Mundo Novo 1 and 2 (Bloco G, Brasil 21 Convention Center) Session Chairs: Carmilia Jimenez Ramirez, Gilead Sciences and Vanessa Schiavo, Libbs

Farmacêutica 09:00 – 09:25 Quality Assessment for Tech Transfer Cláudio Cabral, Instituto Butantan, Brasil 09:25 – 09:50 How to Overcome the Challenges of Stability Studies to Support

Global Tech Transfers Mary Cromwell, Genentech, a Member of the Roche Group, USA 09:50 – 10:15 The Importance of Establishing Analytical Comparability in the

Successful Transfer of Manufacturing Processes from One Region to Another

Christina Vessely, Biologics Consulting Group, Inc., USA 10:15 – 10:45 AM Break in the Mundo Novo Foyer 10:45 – 12:00 PANEL DISCUSSION – Questions and Answers Edith Roxana Vasquez Alayo, DIGEMID, General Directorate of

Medicines, Supplies and Drugs, Peru Cláudio Cabral, Instituto Butantan, Brasil Mary Cromwell, Genentech, a Member of the Roche Group, USA Rodrigo Coelho Ventura Pinto, Bio-Manguinhos/Fiocruz, Brasil

Esenbeckia Yureri Torres Guzman, COFEPRIS, Federal Commission for the Protection against Sanitary Risk, Mexico Christina Vessely, Biologics Consulting Group, Inc., USA

12:00 – 13:30 Hosted Lunch in Lucca Restaurant (Bloco F, Brasil 21 Convention

Center)

Tuesday, 25 August continued…

Cold Chain Management and Qualification for Biological Products Transportation Workshop Session

In Mundo Novo 1 and 2 (Bloco G, Brasil 21 Convention Center) Session Chairs: Daniel Durand, Amgen Brasil and Liana Montemor, Polar Técnica

13:30 – 13:55 Current Strategies on Cold Chain Management and Product

Transport Validation Anthony Mire-Sluis, Amgen Inc., USA 13:55 – 14:20 Challenges Faced by Manufacturers in the Cold Chain

Transportation and Different Scientific Approaches Adopted Claudio Cappai Correa, F. Hoffmann-La Roche Ltd., Brasil 14:20 – 14:45 Sharing Expectations on New Guideline under Development by

ANVISA Bernardo Moreira, ANVISA, Brasilian Health Surveillance Agency, Brasil 14:45 – 15:15 PM Break in the Mundo Novo Foyer 15:15 – 16:30 PANEL DISCUSSION – Questions and Answers

Anthony Mire-Sluis, Amgen Inc., USA Fabiola Munoz, ISP, Public Health Institute, Chile Bernardo Oliveira, ANVISA, Brasilian Health Surveillance Agency, Brasil Claudio Cappai Correa, F. Hoffmann-La Roche Ltd., Brasil Fernanda Silva, F. Hoffmann-La Roche Ltd., Brasil

16:30 – 17:00 Recap of Program Summary Slide Presentation Nadine Ritter, Global Biotech Experts, LLC 17:00 Adjournment

An Update / Overview on Regulatory Convergence, Predictability,

Transparency and Priority Reviews Session Chairs: Marcelo Moreira, ANVISA, Brasilian Health Surveillance Agency and Ana Padua, EFPIA LATAM Network Chair WHO draft for Good Review Practices (GRevPs) from 2014 states that “RAs are increasingly seeking ways to improve their performance and ensure the quality of their regulatory systems. GRevPs are an integral part of overall good regulatory practices and focus on the medical product review aspect of regulatory work. Review is a highly complex, multidisciplinary assessment of the medical product applications in meeting scientific and evidentiary standards. It forms the scientific foundation for regulatory decisions. The extent to which an RA can achieve the review goals of timeliness, predictability, consistency, transparency, clarity, efficiency and high quality can have significant impact on public health (for example, delays in patient access to important medical products, added costs to government and applicants). Implementation of GRevPs help to achieve these review goals by ensuring those involved in the review process have the critical thinking skills and tools needed to optimize scientifically sound, evidence-based decisions. It also facilitates progress towards regulatory convergence through the development of common platforms for exchanging review reports and the enhancement of mutual trust among RAs. Several RAs have introduced ways of monitoring and improving their review process through structured approaches or moving towards stepwise implementation of GRevPs. RAs should consider review models and best practices within the context of available resources and legal requirements. The GRevP principles and elements described in this document can be adapted to meet the continuous improvement needs of a diverse range of RAs.” This regulatory plenary session will cover two review goals established in the above WHO draft guideline: Transparency and Predictability. Additionally, Regulatory Convergence and Priority Reviews Programs will also be part of the discussion as per their relevance for the Latin America region. Both are key areas that can accelerate access of high quality medicines to the patients. In this panel, some Latin American regulators, FDA, EMA and industry representatives – Grupo FarmaBrasil and Interfarma, are invited to provide their updates on the selected topics (Transparency, Predictability, Regulatory Convergence and Priority Review Programs), sharing their best regulatory practices, improvements, challenges and opportunities in their respective countries. Industry representatives will also provide their perspective including proposals for further collaboration on this regard. NOTES:

Presenter’s Abstracts and Presentations

Updates on Regulatory Issues for Biotherapeutic Products License in Brazil Marcelo Moreira ANVISA, Brasilian Health Surveillance Agency, Brasil Since 2002, when ANVISA published the first regulatory act regarding biological, the Agency started a race to follow the trends in regulation of Biotherapeutics Products, around the world. During these years the Agency has published three Resolutions and many documents to guide the Industry as the trend in other Agencies. There´s always a new technical issue to learn about and it´s necessary create a space for discussion between the biological manufacturer´s and the Agency. Besides to the present specific requirements for biosimilars at ANVISA, in this session we will tell how's going on the biosimilars in Brazil, and to present lessons learned with the applicants to anticipate near future, pointing new guidelines documents, and other unique topics to our country. NOTES:

Recent Trends in the Regulations of Biotherapeutic Products in Peru Edith Roxana Vásquez Alayo DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru Peru with 30 million of people, with three main public health system, ESSALUD, MINSA, FOSPOLI covering over 80% of the Peruvian population has needed since 2009 to issue regulations that ensure access the quality, safety and efficacy products. Law 29459 specifies that all the products require a Marketing Authorization (Registro Sanitario). The Marketing Authorization (MA) enables the holder to perform the following activities: manufacturing, import, storage, distribution, marketing, promotion, dispensation, dispatch or use of these products. Such authorization must be obtained from the General Directorate of Medicines, Supplies and Drugs - DIGEMID. According to Art. 6 of Law 29459 and Title III of Decree 016-2011-SA, the term “pharmaceutical products” includes Biological products. Biologic products classified as vaccines, plasma derived, allergens, antigens, hormones, cytokines, immunoglobulins, similar biological products, biotechnological products, where Monoclonal antibodies (mAbs) are the largest and fastest growing segment. So it represents a challenge in implementing the new regulations. Therefore, currently two new regulation for Biotechnological product has been issued, focused mainly on biotechnological products and similar biological products, taking into account the progress of science and the WHO recommendations, after complying with the regulations of the World Trade Organization and the Andean Community of Nations with regard to issue of technical barriers to trade. This new regulation has explored the main concerns regarding for similar biological products where general scientific principles in conducting comparative structural and functional analysis, clinical immunogenicity assessment, and pre-clinical and clinical comparative studies have been taking account. Finally, DIGEMID has leaded a big effort to get new draft regulations with different approaches developing high quality standards on a worldwide regulatory framework. Currently DIGEMID has two Technical Documents on review about biotechnological products, which establishes specific requirements for registration and re-registration, these guidelines established two pathways to approve similar biological products. NOTES:

Advances in Regulation of Biotech Products in Chile Fabiola Muñoz Espinoza ISP, Public Health Institute, Chile During 2011, the new “Regulation for the National Control of Pharmaceutical products for Human Use” (D.S. 3/2010 of MINSAL) came into force, in which it was established that all pharmaceutical products of biological origin, including biotech drugs, should be considered for the sanitary licensing as a new product (item 53) and preclinical, clinical and immunogenicity studies should be presented to substantiate its safety and efficacy. It also included the development of a Technical Standard (developed by ANAMED and approved by MINSAL), which in the case of biotech products, establish the active ingredients and their presentations,for which abbreviated pre-clínical andclinical studies could be admitted to substantiate its safety and efficacy, based on the existence of another registered biotech product that uses the same active ingredient, dosage, dosage form and route of administration (article 42 DS 3/2010) In this context, ANAMED drafted the proposal entitled "Technical Standard for Sanitary Registration of Biotech Products Derived from Recombinant DNA Technique" which is based on the document "Guidelines on Evaluationsof Similar Biotherapeutics Products(SBPs)" released by the WHO Expert Committee on Biological Standardization in 2009, the Guidelines of the EMA and Guidelines ICH. The Technical Standard N°170 was approved in August of 2014 by the Ministry of Health and is actually in a phase of implementation. NOTES:

Regulatory Changes in Mexico Esenbeckia Yureri Torres Guzman COFEPRIS, Federal Commission for the Protection against Sanitary Risk, Mexico Mexican Health framework has been restructured since 2009 in order to establish a strong legal framework to regulate biotech products. Before 2009, regulatory framework lacked specific elements for evaluation of these products but was in this year when General Health Law was modified in his 222 article, incorporating the first definition of these products and the requirements to register and marketing. In 2011, Regulation for Health Products was created the Subcommittee on Assessment of Biotech Products as part of the New Molecules Committee and his evaluation was established as an essential requirement for the application for registration. Characterization, non-clinical and clinical studies are considered essential elements to ensure the quality, safety and efficacy of these products. It was also in this regulatory change when definition of biosimilar and innovative drug was described. Official Mexican Standards have been a mainstay in the changes to the regulatory framework in Mexico, providing requirements of good manufacturing practice and requirements for the sanitary registration and Pharmacovigilance as in the case of Official Mexican Standards NOM-EM-001-SSA1-2012 and establishing the criteria to evaluate Bio-comparability and Criteria for regularization process through the official Mexican standards NOM-177-SSA1-2013 and NOM-257-SSA1-2014. These changes have allowed establishing international equivalence agreements for biotech drugs registry (for products previously approved for some Regulatory Agencies), this regulatory convergence also helps to decrease time evaluation and allow predictability. General Law of Transparency and Access to Public Information (LGTAIP) ensures transparency of the regulatory process related to evaluation and approval of every biotech product. Actions to ensure transparency during review and approval of biosimilar drugs are also established in Regulation for Health Products (art. 177-bis 4 fraction V); establishing that once the first biosimilar biotech drug had been approved, the technical information based on which registration was supported shall be published by the Secretariat Official Gazette. Finally, regulatory framework for Priority review is defined in General Health Law art. 181, 183 and 184 fractions I and V and establish that in Serious Epidemic, emergencies, disasters and other contingencies affecting the country, Federal Executive can declare actions in sanitary issues. This is an opportunity area where some regulatory framework changes could be implemented to ensure the supply of medicines not only during disaster-contingency conditions but also by the growing demand of drugs in chronic degenerative diseases. NOTES:

EU Regulatory Update - Innovative Marketing Authorisation Approaches and Regulatory Transparency Policies Niklas Ekman Finnish Medicines Agency, Finland This presentation will focus on two topics relevant for development, authorisation and commercialisation of drugs in the European Union. In the first part, the status of the new adaptive approach for marketing authorisation will be discussed. The second part of the presentation will review current transparency policies applied in the EU pharmaceutical sector. NOTES:

Recent Trends in the Regulation of Biotherapeutic Products: US FDA Perspective Sarah Kennett CDER, FDA, USA The advancement of medicine and rapid and continual patient access to high quality effective therapeutics are global aspirations in which global health authorities play a critical role. The global manufacturing, marketing, and regulatory environments provide many opportunities for enhancing public health, but they also create many challenges for both manufacturers and regulatory agencies. Global organizations and multi-country initiatives, such as WHO and ICH, have helped facilitate regulatory convergence. While additional regulatory convergence might promote more rapid product development and approval, given differences in laws and practices, differences in considerations of product and patient risk, and differences in organizational structures and resources, regulatory convergence is a great challenge. Increased transparency, leading to increased understanding of the regulatory and scientific thinking of different regulatory agencies, might help the process of regulatory convergence. The U.S. government has initiated a higher level of general transparency. However, while the U.S. FDA has routinely participated in significant discussions and publication of clinical science, limited trade secret/commercial confidential information can be shared, which impacts the Agency's ability to provide detailed scientific discussions or publications regarding product manufacturing and quality attributes of specific products and reviews. Increasing access to improved and innovative medicines might also be enhanced through providing manufacturers with standard timeframes within which new drugs and changes to manufacturing and control strategies will be reviewed, helping to create a more manageable global supply framework, and with possibilities for more rapid development and review of products expected to lead to significant advancements in patient therapies. Standard review and sponsor meeting timelines are consistently met for CDER regulated biological products and many other products regulated by the U.S. FDA, and a number of programs for rapid development exist within the U.S. regulatory environment. These programs and expectations do not exist without challenges to both the Agency and product manufacturers. Initiatives related to regulatory convergence, transparency, and expedited review programs and recent associated experiences and challenges will be presented. NOTES:

Reginaldo Braga Arcuri Grupo FarmaBrasil, Brasil Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

NOTES:

A Call for a Harmonized, Risk-based Lifecycle Management Approach for Biologics Thomas Schreitmüller Representing – Latin America Federation of the Pharmaceutical Industry (FIFARMA) While significant progress has been made with respect to the establishment of regulations for approving biologics (incl. biosimilars) we see gaps in the regulatory approaches governing the life-cycle management of these products. With more and more biologics and biosimilars getting approved in the region there is an urgent need to establish proper risk based approaches regulating post approval changes for biologics and thus overcoming growing complexities of supply chains, by increasing the predictability of data requirements as well as timelines for regulatory approvals. Having in mind capacity constrains at many agencies and following ICDRA recommendations a global/regional approach to be outlined by respective WHO/PAHO guidance/technical documents is recommended to overcome these gaps and helping to drive global and regional convergence at the same time. NOTES:

An Update / Overview on Regulatory Convergence, Predictability,

Transparency and Priority Reviews Panel Discussion

PANEL DISCUSSION - Questions and Answers Edith Roxana Vásquez Alayo, DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru Reginaldo Braga Arcuri, Grupo FarmaBrasil, Brasil Niklas Ekman, Finnish Medicines Agency, Finland Sarah Kennett, CDER, FDA, USA Fabiola Muñoz Espinoza, ISP, Public Health Institute, Chile Thomas Schreitmüller, representing - Latin America Federation of the Pharmaceutical Industry (FIFARMA) Esenbeckia Yureri Torres Guzman, COFEPRIS, Federal Commission for the Protection against Sanitary Risk, Mexico The following questions will guide the panel discussion:

1) Talking about predictability, what are the measures planned and implemented to enable the correct estimative of evaluation review deadlines?

2) Considering the Latin American regulatory environment, what are the barriers for development of integration and cooperation among NRA’s in order to promote the regulatory convergence? What are the main hurdles and how they could be overcomed?

3) In the context of regulatory convergence, it is evident that transparency is required. How transparency could be provided? What tools could be used? How to ensure transparency in regulatory decisions?

4) Are there Priority Reviews Programs in place or under implementation in your country? How has been the experience and timelines achieved?

5) What have been the top 3 priorities established in your Regulatory Agencies/Industry Representatives for 2015? What about the evolution of theses priorities during the past months?

6) What are the most important regulatory perspectives for 2016?

NOTES:

NOTES:

Characterization, Control and Regulation of Protein Glycosylation

Session Chairs: Leda dos Reis Castilho, Universidade Federal do Rio de Janeiro and Ana Moro, Instituto Butantan Most of the biotherapeutic products including similar biotherapeutic products currently under development are glycoproteins. The attachment of various types of complex carbohydrates to the protein backbone imparts a significant amount of heterogeneity to these proteins. The carbohydrates are known to affect biological activity, stability, solubility and clearance of the protein. Furthermore, the glycosylation of a protein is often dependent upon the cell line and the cell culture conditions applied during production. The characterization and analysis of carbohydrates and assessing the criticality of the different structures for the products safety and efficacy are quite challenging but important tasks in order to define a proper control strategy for glycoprotein products. This also holds true for the regulatory assessment of product applications sometimes leading to different decision of different agencies for the same application. NOTES:

Presenter’s Abstracts and Presentations

The Importance of Protein Glycosylation –Why Do We Have It? What Does It Do? Guillermina Forno School of Biological Sciences, University of Litoral and Zelltek S.A., Argentina Glycosylation plays an essential role in a wide range of biological processes. Specific change to a glycan structure can directly modulate its biological function, since it is a parameter which determines the efficacy, pharmacokinetics, stability and safety of most biological drugs, e.g. erythropoietin, pituitary hormones and monoclonal antibodies. Glycosylation processing pathways are not extent of complexity and are under a fine both environmental and genetic control. Therefore, since very early in process development the efforts must be directed through the identification of critical features of therapeutics and the understanding of the influence of glycosylated structures on those features and subsequently the influence of manufacturing strategy on glycosylation profile. That will enable to design an adequate glycosylation monitoring and controlling strategy. Rapid, detailed, quantitative glycan analysis will be required at all stage of bioprocessing, from quality by design and process analytical technologies to drug licensing, stability testing and batch release, but finally the appropriate strategy will depend on the information that is required NOTES:

State of the Art Glycosylation Analysis of Biotherapeutic Products and its Application to Control Glycosylation Martin Blüggel Protagen Protein Services GmbH, Germany Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

NOTES:

Glycosylation of Biosimilar mAbs - The Challenge of Assessing Similarity ByoungOh Kwon Celltrion Research Institute of Biotechnology. Korea Biosimilar or biosimilarity means that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. Monoclonal antibody biosimilars are large and complex and their structures are often further augmented by glycosylation and other molecular modifications. Glycosylation is an important feature of biopharmaceutical products as it has been shown that the type and degree of glycosylation affects product stability, activity, antigenicity, and pharmacodynamics. N-glycosylation of immunoglobulin G (IgG) at asparagine residue plays a critical role in antibody stability and cell-mediated immunity in Fc effector function. In developing biosimilar, it is necessary to characterize the glycosylation to ensure that it conforms to the original product. So, detailed and quantitative structural characterization of the glycosylation is required for comparability purpose. This is accomplished with the use of a number of glycoprofiling modules to measure different glycosylation parameters. Fluorescent labelling of glycans or glycan fragments is a key component of such glycoprofiling. Use of appropriate labelling methods and analytical platforms allows good separation of the individual species in complex glycan mixtures and reliable quantitation of those species. Remsima, the first biosimilar monoclonal antibody in the world, aims to provide cost-effectiveness and higher bio-accessibility to the healthcare industry. The clinical data demonstrating similarity between Remsima and reference product consisted of two main clinical trials: a pivotal pharmacokinetic study in patients with ankylosing spondylitis (PLANETAS) and a pivotal efficacy and safety study in patients with active rheumatoid arthritis (PLANETRA). As part of the comparability exercise, it was shown that most of major physicochemical characteristics and biological activities of Remsima were comparable to those of original product. A small difference was noted in the amount of afucosylation, translating into a lower antibody-dependent cellular cytotoxicity (ADCC) activity in the highly artificial model of assay. However, this difference was not considered clinically meaningful, because it did not affect the activities in pathophysiological conditions that were more relevant to the patients. Based on the biosimilar guideline, minor structural differences in the active substance such as variability in glycosylation may be acceptable, if sponsor supports satisfactory justification of the safety and efficacy of the similar biological medicinal product. NOTES:

Characterization, Control and Regulation of Protein Glycosylation

Workshop Session PANEL DISCUSSION – Questions and Answers Martin Blüggel, Protagen Protein Services GmbH, Germany Niklas Ekman, Finnish Medicines Agency, Finland Guillermina Forno, School of Biological Sciences, University of Litoral and Zelltek S.A., Argentina Sarah Kennett, CDER, FDA, USA ByoungOh Kwon, Celltrion Research Institute of Biotechnology, Korea The following questions will guide the panel discussion:

1. What is the state-of-the-art technology for oligosaccharide analysis? 2. What, if any, limitations exists with the current technology? 3. What high throughput methods are being used for carbohydrate analysis vs. for

detailed carbohydrate characterization? 4. What strategies are used in order to define the criticality of glycosylation? 5. What to consider when designing a control strategy for glycosylated

biotherapeutics/similar biotherapeutics? 6. What are the expectations from regulatory agencies for detailed carbohydrate

analysis?

NOTES:

NOTES:

Technology Transfer for Biopharmaceuticals

Session Chairs: Carmilia Jimenez Ramirez, Gilead Sciences and Vanessa Schiavo, Libbs Farmacêutica According to IMS Health, biologics are expected to account for approximately 17% of total global spending on medicines by 2016, and 7 of the top 10 global medicines by spending will be a biologic by mid-2017. As a consequence of the market attractiveness of biotherapeutic products, considering the possibility to increase patient access and reduce costs to public and private payers, especially in emerging countries, more players are now entering into the business of developing biotherapeutic products, biosimilars, alone or in partnership with other companies, building new, state of the art biotech manufacturing facilities in these countries, as potential new global sources of high quality biotherapeutic products. Particularly for Latin America region, and Brazil specifically, there are governmental development policies that provide incentives for manufacturing biotherapeutical products locally. The Product Development Partnerships (PDPs) are partnerships involving cooperation, by agreement, between public institutions and private entities for the development, transfer and absorption of technology, production, productive and technological capacity of the country in strategic products to meet the demands of the Public Health System. The general objectives of those regional development policies are:

• increase the patient access to the biotherapeutic products and reduce the costs of the Public Health System;

• reduce the productive and technological dependence to meet the health needs of the population in the short, medium and long term;

• promote technological development and the exchange of knowledge for innovation within public institutions and private entities, making them competitive and qualified.

Based on these incentives, local companies, public laboratories, and multi-national companies, are in different phases of planning the construction, or modernization of their biotherapeutic manufacturing plants, with some of these companies already undergoing construction, in order to manufacture biotherapeutic products locally, biosimilars in an initial phase, followed by biobetters and innovator products, such as vaccines and monoclonal antibodies. Based on this scenario, this session is intended to highlight the challenges associated with technology transfer, multi-product facilities, process validation, process optimization in facilities utilizing single-use disposable technology, transfer of quality control analytical methods, changes in production scale (scale up), comparability exercises for post approval changes and stability studies required for global submissions. NOTES:

Presenter’s Abstracts and Presentations

Quality Assessment for Tech Transfer Cláudio Cabral Instituto Butantan, Brasil Technology transfer is a promising approach to increase vaccine production at an affordable price in developing countries. This session will present a real case of Product Development Partnerships (PDPs) between Institute Butantan and Sanofi Pasteur, the Influenza Vaccine. In the case of influenza, it is imperative that developing countries acquire the technology to produce pandemic vaccines through the transfer of know-how, as this will be the only way for the majority of these countries to face the huge demand for vaccine created by influenza pandemics. Access to domestically produced influenza vaccine in such health crises is thus an important national defense strategy. However, technology transfer is not a simple undertaking. It requires a committed provider who is willing to transfer a complete production process, and not just the formulation and fill-finish parts of the process. It requires a recipient with established experience in vaccine production for human use and the ability to conduct research into new developments. Technology transfer should create a solid partnership that results in the joint development of new competency, improvements to the product, and to further innovation. This session will cover the practical experience and lesson learned during a tech transfer of the Influenza Vaccine to Institute Butantan. The technical challenges and how to overcome them will also be considered in the presentation, as well as recommendations for further improvements on this process. The regulatory, technical and quality aspects should be included. Slides were not available at the time of printing. NOTES:

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How to Overcome the Challenges of Stability Studies to Support Global Tech Transfers Mary Cromwell Genentech, a Member of the Roche Group, USA Abstract was not available at the time of printing. NOTES:

The Importance of Establishing Analytical Comparability in the Successful Transfer of Manufacturing Processes from One Region to Another Christina Vessely Biologics Consulting Group, Inc., USA The transfer of a manufacturing process from one location to another has many technical challenges due to differences in equipment, facilities, and other infrastructure between sites. One key to a successful transfer is the demonstration of analytical comparability for the drug substance that is produced at each site. This will reduce the need for additional clinical studies for the demonstration of safety, efficacy, and biological comparability. It is critical to realize that analytical comparability is not limited to final drug substance; critical quality attributes must be monitored and shown to be effectively controlled during the manufacturing process as well. This presentation looks at specific challenges that were encountered in the transfer of a manufacturing process from a manufacturing site within the EU to one located in the US. The process transfer itself was complicated by differences in quality systems between the facilities, since one was an internal company facility while the other was a CMO. The establishment of analytical comparability was complicated by the use of multiple laboratories both in the US and EU for the performance of in-process, release, and extended characterization testing. The lessons learned provide an opportunity to improve future facility transfers through the performance of risk assessments, alignment of analytical methods, alignment of general practices across sites and regions, and improving communication and understanding when language and other cultural barriers exist. Slides were not available at the time of printing. NOTES:

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Technology Transfer for Biopharmaceuticals

Workshop Session PANEL DISCUSSION – Questions and Answers Edith Roxana Vasquez Alayo, DIGEMID, General Directorate of Medicines, Supplies and Drugs, Peru Cláudio Cabral, Instituto Butantan, Brasil Mary Cromwell, Genentech, a Member of the Roche Group, USA Rodrigo Coelho Ventura Pinto, Bio-Manguinhos/Fiocruz, Brasil Esenbeckia Yureri Torres Guzman, COFEPRIS, Federal Commission for the Protection against Sanitary Risk, Mexico Christina Vessely, Biologics Consulting Group, Inc., USA The following questions will guide the panel discussion:

1) What are the most time-consuming and costly aspects of technology transfer? 2) What are best practices in deciding whether to engage a single supplier/partner for

manufacturing and quality control testing versus multiple suppliers/partner for manufacturing and testing?

3) How can sponsors and partners balance the use of most cutting edge technologies and the availability of these technologies in emerging countries/markets?

4) What are the most useful points to consider when selecting an analytical comparability strategy?

5) What are the pro’s and con’s of staging and testing stability samples in satellite sites?

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Cold Chain Management and Qualification for Biological Products

Transportation Session Chairs: Daniel Durand, Amgen Brasil and Liana Montemor, Polar Técnica The cold chain is dynamic and ensuring an effective supply from manufacturer to the patient is needed. Maintaining supply chain integrity and patient safety remains the priority for manufactures. Process, temperature monitoring, qualification, validation of solution, and control improvement are an integral part of the cold chain management program. Clearly the quality of the product properties are affected by temperature to which they are exposed, so it is very necessary to have guidelines and technical guidelines to help ensure that the thermo-sensitive products remain within the temperature ranges specified for all stages its passage from manufacturing to the patient or end user, to ensure the quality and safety properties of the product. As the market for cold chain solutions as matured stakeholders have become more knowledgeable about challenges of temperature controlled supply, now companies are thinking about global approach to cold chain handling. Globalization is placing increasing trends on temperature controlled supply chains thus, manufacturers need to have solutions that work effectively in different regions of the world. Global approach and harmonize process, solution and control around the world taking into account several factors that can influence the transportation will be very beneficial. This session will provide the current strategies being used by manufacturers to handle cold chain transportation for biological/biotechnology products as well as the perspective of the LATAM regulators. NOTES:

Presenter’s Abstracts and Presentations

Current Strategies on Cold Chain Management and Product Transport Validation Anthony Mire-Sluis Amgen Inc., USA It is of little value for medicinal product manufacturers to produce high quality product if they are unable to supply that product to patients in a robust, controlled manner. Therefore it is critical that companies develop a system for ensuring that product is transported safely and consistently around the world in a way that ensures the product remains safe and effective by the time it is used by the patient. This involves the characterization of the transport lanes that shipments will use (land, sea or air) and how they can impact the product and containers they are shipped in (e.g. temperature, vibration, pressure etc.). Once such an understanding is gained, a two-fold process is undertaken. The first is to understand the ability of the product to withstand such environmental challenges and develop criteria to ensure that maximum exposure would not impact it (e.g. temperature fluctuations or vibration). This data can be used to understand how best to protect the product during transport or whether product can be acceptable or not after an excursion. Then shipping containers should be characterized to minimize any exposure to conditions that could negatively impact the product inside during shipment. This involves design and testing of containers to withstand the potential environmental conditions they might experience during shipment (dropping, denting, temperature etc.) to remain integral themselves, as well as having a configuration that protects the contents inside. NOTES:

Challenges Faced by Manufacturers in the Cold Chain Transportation and Different Scientific Approaches Adopted Claudio Cappai Correa F. Hoffmann-La Roche Ltd., Brasil Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

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Sharing Expectations on New Guideline under Development by ANVISA Bernardo Moreira ANVISA, Brasilian Health Surveillance Agency, Brasil Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

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Cold Chain Management and Qualification for Biological Products

Transportation Workshop Session

PANEL DISCUSSION – Questions and Answers Claudio Cappai Correa, F. Hoffmann-La Roche Ltd., Brasil Anthony Mire-Sluis, Amgen Inc., USA Fabiola Munoz, ISP, Public Health Institute, Chile Bernardo Oliveira, ANVISA, Brasilian Health Surveillance Agency, Brasil Fernanda Silva, F. Hoffmann-La Roche Ltd., Brasil The following questions will guide the panel discussion:

1. What are the main challenges and complexities regarding cold chain?

2. Is it possible to create a unified approach to global packaging solutions?

3. From global perspective what is expected with regards to qualification or validation of cold chain?

4. How to harmonize global regulatory perspectives and comply with cold chain requirements from different regions?

5. A growing list of documents, requirements, requests, recommendations and guidelines revel how fragmented is in cold chain management. If all of these have one common goal - ensure product with expected quality, safety and efficacy, which can be done using different approaches is it really useful that regulatory agencies seek for their own requirements/guideline?

6. When the storage and transport temperature may be different?

7. How to use a worst case scenario (time/duration, environment conditions, packaging, containers characterization, load size / thermal mass, positions of loggers, seasons, climatic zones, excursion allowed, etc.) in the cold chain management strategy?

8. How to link product stability study with cold chain management?

9. When the Operational Qualification and/or Performance Qualification is not needed?

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