1. Module I Basic knowledge for registration of biological products การอบรมหลักสูตรประกาศนียบัตรการขึ้นทะเบียนยาชีววัตถุ 7-11 มีนาคม 2559 ธีรนารถ จิวะไพศาลพงศ์, กรมวิทยาศาสตร์การแพทย์ & ปราโมทย์ อัครภานนท์, สำนักงานคณะกรรมการอาหารและยา 1 ธีรนารถ จิวะไพศาลพงศ์ 2016

2. Contents Definition and type of biological products and vaccines Development processes of biological products from R&D to registration and post marketing surveillance WHO Six control functions Drug act and ministerial regulation Biological products (definition, classification and origins) Biosimilar 2 ธีรนารถ จิวะไพศาลพงศ์ 2016

3. Biological products Biological products are drug products made from a biological sources (such as human, animal or microorganism, natural or genetically modified). In general, they are complex molecules and cannot be fully characterized by using only physico-chemical testing methods, bioassays, biochemical assays, and immunological assays may be required. 3 ธีรนารถ จิวะไพศาลพงศ์ 2016

4. For prevention Vaccines For treatment Serum, anti-venom, antitoxin Blood products Biotherapeutic products: cytokines (eg. Interferons, interleukins ), growth factors, enzymes, Immunoglobulins, monoclonal Abs Toxin (Botulinum toxin) Cell therapeutic products Gene therapeutic products Human cells and tissues used for transplantation Allergens For diagnostic Allergens Tuberculin test Type of Biological products 4 ธีรนารถ จิวะไพศาลพงศ์ 2016

5. Vaccine WHO A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. 5 ธีรนารถ จิวะไพศาลพงศ์ 2016

6. Type of vaccines (differentiated by production process) Killed/Inactivated whole cell vaccines (ex: Pw, Inactivated JE, Rabies) Toxoids (ex: D, T, Pa) Live attenuated vaccines (ex: OPV, M, M, R, BCG, LAIV, Live JE) Subunit vaccines (ex: IIV, HBV) VLP (HPV) Conjugated vaccines (Hib) Combined vaccines (DTP-HB- Hib, MMR, DTPa, OPV, HPV) 6 ธีรนารถ จิวะไพศาลพงศ์ 2016

7. Type of vaccines (differentiated by routes of administration) – Parenteral vaccination: most of vaccines – Oral vaccination: OPV, Typhim Vi – Aerosol / intranasal: LAIV 7 ธีรนารถ จิวะไพศาลพงศ์ 2016

8. Development processes of biological products from R&D to registration and post marketing surveillance 8 ธีรนารถ จิวะไพศาลพงศ์ 2016

9. Large scale production Clinical trial phase III Marketing Authorization (MA) Distribute to the market Clinical trial phase IV Post- marketing surveillance Steps of Vaccine R & D Lab scale Preclinical study Clinical trial phase I Clinical trial phase II 9 ธีรนารถ จิวะไพศาลพงศ์ 2016

10. Lab scale research Active ingredients: Source materials : Nature / Recombinant technology Production processes: cultivation/induction/extraction, purification, conjugation/formulation Presentation Route of administration Monovalent/ multivalent (combined vaccines) No mandatory requirements of QMS. 10 ธีรนารถ จิวะไพศาลพงศ์ 2016

11. Preclinical studies (1) Characterization Immunogenicity/ pharmacodynamic studies provide – “Proof of concept” information for clinical development plan – Information to guide selection of the doses, schedules and routes of administration in clinical trials – HIR & CMIR (e.g. neutralizing antibodies, opsonophagocytic activity, sinterference between antigens, etc.) Note: Animal models frequently fail to predict immunogenicity and efficacy in humans. It may be used in to measure the potency of vaccine if appropriate. 11 ธีรนารถ จิวะไพศาลพงศ์ 2016

12. Preclinical studies (2) Safety assessment : Toxicity assessment – Basic toxicity assessment : single dose, repeated dose, (+ local tolerance): Dose used should be equal or more than SHD Animals used should be more than one species – Additional toxicity assessment Special immunological investigations To investigate immunological aspects of toxicity (e.g. precipitation, autoimmune pathology, etc.) 12 ธีรนารถ จิวะไพศาลพงศ์ 2016

13. Preclinical studies (3) – Additional toxicity assessment Developmental and reproductive toxicity studies Genotoxicity and carcinogenicity studies Safety pharmacology To investigate the effects of the candidate vaccine on vital functions (e.g. central nervous system, respiratory, cardiovascular and renal functions) Pharmacokinetic studies: Novel adjuvants, alternative routes of administration 13 ธีรนารถ จิวะไพศาลพงศ์ 2016

14. Preclinical studies (4) Special considerations: adjuvants, additives, vaccine formulation and delivery device, alternative routes of administration Specific considerations for particular types vaccines: live attenuated vaccines, combined vaccines, etc. 14 ธีรนารถ จิวะไพศาลพงศ์ 2016

15. Mandatory requirements for QMS in Preclinical studies OECD-GLP for Safety Assessment only OECD-GLP – Characterization (in vivo & in vitro) – Animal test for safety 15 ธีรนารถ จิวะไพศาลพงศ์ 2016

16. Clinical studies (1) Phase I: preliminary study for safety and reactogenicity as well as information on vaccine immunogenicity in small numbers of healthy adults Phase II: to demonstrate the immunogenicity of the relevant active component(s) and the safety profile of candidate vaccine in larger number of subjects; to evaluate multiple variable parameters related to immune response (eg.age, ethnicity, gender, maternal immunity, etc.) 16 ธีรนารถ จิวะไพศาลพงศ์ 2016

17. Clinical studies (2) Phase III: pivotal studies for fully assessing the protective efficacy and safety of the vaccine in target population Marketing Authorization Mandatory requirements for QMS in CT are GMP, GCP, GLP 17 ธีรนารถ จิวะไพศาลพงศ์ 2016

18. Post –Marketing Authorization Phase IV: post-licensure studies to detect rare serious AR/AE, long term immunity, protective efficacy (in case no immune correlate of protection identified, long term disease development) Post marketing surveillance: National system for AR/AE after distribution 18 ธีรนารถ จิวะไพศาลพงศ์ 2016

19. Laboratory testing Laboratory testing GMP Compliance GMP Compliance Clinical trials (Ethical review process, compliance against GLP,GMP,GCP) Clinical trials (Ethical review process, compliance against GLP,GMP,GCP) Pre-marketing phase Post Marketing phase Post marketing AEFI surveillance Post marketing AEFI surveillance Lot release Market distribution Quality Safety Efficacy Product Evaluation Product Evaluation Licensing facility Licensing facility Dossier Licensing/Registration= evaluation process Applicants Dossier (manufacturer or distributor) Applicants Dossier (manufacturer or distributor) Marketing Authorization (M.A.) Vaccine regulatory process Regulatory inspections Regulatory inspections World Health Organization HTP/IVB/ATT/L.Belgharbi 19

20. WHO Six Control Functions 20 ธีรนารถ จิวะไพศาลพงศ์ 2016

21. Biological Products High variability: – Nature of the products – Production processes – QC methods Vaccines are mostly used in the healthy population for diseases prevention and control Global/National security Stringent control required 21 ธีรนารถ จิวะไพศาลพงศ์ 2016

22. Source of vaccines UN agency Procure Produce National Regulatory Functions recommended for vaccine development Regulatory functions Regulatory functions CTs : Clinical trials, UN: United Nations, AEFI: Adverse Events Following Immunization Marketing Autorization & Licensing activities Laboratory access Regulatory inspections Lot release Authorization & monitoring of CTs Postmarketing: AEFI Regulatory system For countries conducting Clinical Trials World Health Organization HTP/IVB/ATT/L.Belgharbi 22 ธีรนารถ จิวะไพศาลพงศ์ 2016

23. WHO NRA Assessment To define gaps in regulatory functions for NRA strengthening To support Vaccine Prequalification Scheme – NRA full functional – Manufacturer can apply for PQ scheme – Vaccines pass the evaluation can be listed for UN supply 23 ธีรนารถ จิวะไพศาลพงศ์ 2016

24. NRA assessment (1) 1.Licensing & 2. GMP Inspection Transparency, one standard, QMS system 3. Lot release For both local and imported products, summary lot protocol review, access to quality& safety data, test policy, QMS 4. Lab access Independent lab (NCL), Lab quality system( เช่น ISO 17025), reference materials, how to maintain expertise Regulatory system to enforce all six functions 24 ธีรนารถ จิวะไพศาลพงศ์ 2016

25. NRA assessment (2) 5. CT oversight Trials oversight by NRA, Ethics, Scientific review, compliance with GCP, GMP, GLP, QMS 6. PMS Guidelines, systems at national and sub-national levels, safety evaluation, participation/linkage among responsible organization (NRA, NCL, EPI), QMS 25 ธีรนารถ จิวะไพศาลพงศ์ 2016

26. QMS QMS policy/ standard Human resource (appropriate competency & adequate) Documentation system (traceability) – SOPs – Records – Doc. Control Audit system Facilities & equipment (where required) System/process/procedure validation/ verification 26 ธีรนารถ จิวะไพศาลพงศ์ 2016

27. MINISTRY OF PUBLIC HEALTH (Minister) Office of the Permanent Secretary Cluster of Medical Services Development Cluster of Public Health Development Cluster of public Health Service Support Department of Medical Services Department of Thai Traditional and Alternative Medicine Development Department of Mental Health Department of Disease Control Department of Health Department of Health service Support Department of Medical Sciences Food and Drug Administration Div. Of Biological Products (NCL) Bureau of Epidemiology (AEFI surveillance) Drug Control Division (NRA) 27 ธีรนารถ จิวะไพศาลพงศ์ 2016

28. Teeranart Jivapaisarnpong28