Quality, Non-clinical and Clinical Considerations for Biosimilar Monoclonal Antibody Development: EU, WHO, USA, Canada, and BRICS-TM Regulatory Guidelines

Objective: The aim was to critically evaluate well-established regulatory agencies mAb biosimilar guidelines for development and marketing authorization about quality, efficacy and safety and compare to BRICS-TM regulations to identify challenges. Materials and Methods: The current valid guidelines of EMA, WHO, USFDA, BGTD/HC, ICH, and BRICS-TM were obtained from official websites and comparative qualitative review was performed. Results: The review revealed that Health Canada uses mAb specific guidelines from EMA or USFDA when necessary. The BRICS agencies (except Russia) have incorporated some or most of the WHO SBP TRS and related annexes in similar national biotechnological/biological guidelines; however, gaps or insufficient information have been identified. The Russian Federation has issued general product registration guideline/s with very brief information about mAbs. The TMMDA (Turkey) has published an updated biosimilar guideline which parallels those of the EMA and the ones from WHO; however, no mAb specific guidelines are published. COFEPRIS (Mexico) has published a biotechnological/biological product registration guideline with no information about mAb. The SAHPRA biosimilar guideline has an annex on mAbs which focuses on non-clinical and clinical aspects. The comparative evaluation of BRICS-TM agencies indicates a gap pertaining to clarification for physico-chemical characterization, manufacturing process, overages and compatibility requirements between biological substances and excipients specifically on mAbs. In vitro assay requirements seem quite aligned with those of WHO, whereas in vivo studies mostly have disparity in terms of necessity, type of studies as well as design and criteria. Clinical safety and efficacy studies are indicated in emerging regulatory agencies, however detailed information pertaining to design, size of populations, requirements for primary and secondary endpoints, clarity and evaluation criteria differ. In general, BRICS-TM agencies allow extrapolation of indications provided that pre-defined conditions are met. Interchangeability, switching and substitution of biosimilars are not defined in most of BRIC-TM guidelines whereas South Africa, by law, allows neither interchangeability nor substitution. Pediatric research remains questionable across BRICS-TM. Conclusions: EMA, USFDA guidelines are broadly aligned with WHO and in addition, they also contain specific requirements pertaining to their own region. BRICS-TM has considerably less defined mAb specific biosimilar development and comparability parameters in their published guidelines.Peer reviewedFinal Published versio

Self-Nanoemulsifying Drug Delivery System (SNEDDS) Using Lipophilic Extract of Viscum album subsp. austriacum (Wiesb.) Vollm

Camila Faria de Amorim Pereira,1,* Michelle Nonato de Oliveira Melo,1,* Vania Emerich Bucco de Campos,2 Ivania Paiva Pereira,1 Adriana Passos Oliveira,1 Mariana Souza Rocha,1 João Vitor da Costa Batista,3,4 Valter Paes de Almeida,5 Irailson Thierry Monchak,5 Eduardo Ricci-Júnior,6 Rafael Garrett,7 Aline Gabrielle Alves Carvalho,7 Jane Manfron,5 Stephan Baumgartner,3,8,9 Carla Holandino1,3 1Multidisciplinary Laboratory of Pharmaceutical Sciences, Faculty of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 2Department of Pharmacy, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 3Society for Cancer Research, Hiscia Institute, Arlesheim, Switzerland; 4Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland; 5Postgraduate Program in Pharmaceutical Sciences, Universidade Estadual de Ponta Grossa, Ponta Grossa, Paraná, Brazil; 6Galenic Development Laboratory (LADEG), Department of Drugs and Medicines, Faculty of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 7Metabolomics Laboratory, Chemistry Institute, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 8Institute of Integrative Medicine, University of Witten/Herdecke, Herdecke, Germany; 9Institute of Complementary and Integrative Medicine, University of Bern, Bern, Switzerland*These authors contributed equally to this workCorrespondence: Carla Holandino, Multidisciplinary Laboratory of Pharmaceutical Sciences, Universidade Federal do Rio de Janeiro, Faculty of Pharmacy, Block B basement, Room 34, 373, Carlos Chagas Filho Avenue, Cidade Universitária, Rio de Janeiro, RJ, 21941-902, Brazil, Email [email protected] Stephan Baumgartner, Institute of Complementary and Integrative Medicine, University of Bern, Bern, Switzerland, Email [email protected] and Purpose: Natural products are potential sources of anticancer components. Among various species, the lipophilic extract of the Viscum album subsp. austriacum (Wiesb.) Vollm. (VALE) has shown promising therapeutic potential. The present work aimed to qualify the plant source and characterize the extract’s chemical profile. In addition, a self-nanoemulsifying drug delivery system (SNEDDS) containing VALE (SNEDDS-VALE) was developed.Methods: V. album subsp. austriacum histochemistry was performed, and the chemical profile of VALE was analyzed by GC-MS. After the SNEEDS-VALE development, its morphology was visualized by transmission electron microscopy (TEM), while its stability was evaluated by the average droplet size, polydispersity index (PdI) and pH. Lastly, SNEDDS-VALE chemical stability was evaluated by LC-DAD-MS.Results: The histochemical analysis showed the presence of lipophilic compounds in the leaves and stems. The major compound in the VALE was oleanolic acid, followed by lupeol acetate and ursolic acid. SNEDDS was composed of medium chain triglyceride and Kolliphor® RH 40 (PEG-40 hydrogenated castor oil). A homogeneous, isotropic and stable nanoemulsion was obtained, with an average size of 36.87 ± 1.04 nm and PdI of 0.14 ± 0.02, for 14 weeks.Conclusion: This is the first histochemistry analysis of V. album subsp. austriacum growing on Pinus sylvestris L. which provided detailed information regarding its lipophilic compounds. A homogeneous, isotropic and stable SNEDDS-VALE was obtained to improve the low water solubility of VALE. Further, in vitro and in vivo experiments should be performed, in order to evaluate the antitumoral potential of SNEDDS-VALE. Keywords: Viscum album subsp. austriacum, mistletoe, lipophilic extract, oleanolic acid, SNEDD

Regulatory capacity building and the governance of clinical stem cell research in China

While other works have explained difficulties in applying ‘international’ guidelines in the field of regenerative medicine in so-called low- and middle-income countries (LMICs) in terms of ‘international hegemony’, ‘political and ethical governance’ and ‘cosmopolitisation’, this article on stem cell regulation in China emphasises the particular complexities faced by large LMICs: the emergence of alternative regulatory arrangements made by stakeholders at a provincial level at home. On the basis of ethnographic and archival research of clinical stem cell research hubs, we have characterized six types of entrepreneurial ‘bionetworks’, each of which embodies a regulatory orientation that developed in interaction with China’s regulatory dilemmas. Rather than adopting guidelines from other countries, we argue that regulatory capacity building is more appropriately viewed as a relational concept, referring to the ability to develop regulatory requirements that can cater for different regulatory research needs on an international level and at home