REGISTRATION AND REGULATORY CONTROL OF VETERINARY PRODUCTS IN MALAYSIA. National Pharmaceutical Regulatory Agency (NPRA)

REGISTRATION AND REGULATORY CONTROL OF VETERINARY PRODUCTS IN MALAYSIA National Pharmaceutical Regulatory Agency (NPRA) 1

PRESENTATION OUTLINE INTRODUCTION LEGISLATION & REGULATORY CONTROL PRODUCT CLASSIFICATION CONTROL OF VETERINARY ANTIBIOTIC USAGE LIST OF ACTIVE INGREDIENTS BANNED BY DCA REGISTRATION REQUIREMENTS CONCLUSION 2

INTRODUCTION Implementation of veterinary products registration: 1 st August 2007 Implementation of Licensing: 1 st July 2015 Drug Control Authority (DCA) ensures: all veterinary products are safe, efficacious and of good quality, the well-being and safety of the target animals; safety of the surrounding animals; safety of the personnel handling the animals/products and also safety to the environment the food derived from the food producing animals is safe to be consumed 4 4

Legal requirement : Sale of Drug Act 1952 Control of Drugs and Cosmetics Regulations (CDCR) 1984 - Regulation 7(1) - No person shall manufacture, sell, supply, import or possess or administer any product unless: a) the product is a registered product; and b) the person holds the appropriate license required and issued Poison Act 1952 Dangerous Drugs Act 1952 LEGISLATION 6

DEFINITION A Product means a drug in a dosage unit or otherwise, for use wholly or mainly by being administered to one or more human beings or animals for a medicinal purpose 7

DEFINITION Medicinal Purpose means any of the following purposes: *alleviating, treating, curing or preventing a disease or a pathological condition, or symptoms of a disease; *diagnosing a disease or ascertaining the existence, degree or extent of a physiological or pathological condition; *contraception; *inducing anaesthesia; *maintaining, modifying, preventing, restoring or interfering with, the normal operation of a physiological function; *controlling body weight; *general maintenance or promotion of health or well-being 8 (CDCR 1984)

REGISTRABLE PRODUCTS SCHEDULED POISONS All products containing scheduled poisons (substances listed in First Schedule of the Poison Act 1952) e.g. Antibiotics, Antiprotozoals, Antifungals Registration number ending with alphabet HA e.g MAL 10061234HA 11

REGISTRABLE PRODUCTS NON-POISONS (OTC) All products which do not contain scheduled poison and products other than Dietary/Health Supplement & Herbal/Natural products e.g. Antiseptic, Dental products, Analgesic (e.g. Paracetamol) Registration number ending with alphabet HX e.g MAL 10061234HX 12

Antibiotics indicated for disease treatment and disease prevention/metaphylaxis are regulated by NPRA. Disease treatment The treatment of an individual animal, or a group of animals showing clinical signs of an infectious disease. Metaphylaxis The administration of the product at the same time to a group of clinically healthy (but presumably infected) in-contact animals, to prevent them from developing clinical signs, and to prevent further spread of the disease. The presence of the disease in the group/flock must be established before the product is used. A metaphylaxis claim will always have to be combined with a treatment claim. 13

Premixes containing antibiotics for disease prevention/prophylaxis and growth promotion Controlled by the Department of Veterinary Services (DVS), Ministry of Agriculture. The emergence of resistance to antimicrobial drugs mainly antibiotics used in food producing animals have led to the revision of list of antibiotics. Registration Guideline of Veterinary Products (REGOVP ) - Appendix 1: - List of antimicrobials (premix) used in food producing animals for disease treatment and disease prevention/ metaphylaxis 14 Only registered antibiotics are allowed to be used

REGOVP- Appendix 8: List of ingredients (active) not allowed to be registered by the Drug Control Authority. A. Ingredients not allowed in veterinary products 1. Avoparcin B. Ingredients not allowed for food-producing animals and aquacultures 1. Chloramphenicol 2. Nitrofurans such as: i) Nitrofurantoin ii) Nitrofurazone iii) Furazolidone iv) Furaltadone 18

B. Ingredients not allowed for food-producing animals and aquacultures 3. Beta agonists such as: i) Salbutamol ii) Terbutaline iii) Clenbuterol iv) Fenoterol v) Salmeterol vi) Bambuterol HCl vii) Bitolterol Mesilate viii) Broxaterol ix) Eformoterol fumarate x) Pirbuterol HCl xi) Procaterol HCl xii) Reproterol HCl xiii) Rimiterol HBr xiv) Tretoquinol HCl xv) Tulobuterol HCl 19

B. Ingredients not allowed for food-producing animals and aquacultures 4. Chlorpromazine 5. Carbadox 6. Olaquindox 7. Chloroform 8. Colchicine 9. Dapsone 10. Nitroimidazole such as: i) Dimetridazole ii) Ipronidazole iii) Metronidazole iv) Ronidazole 20

B. Ingredients not allowed for food-producing animals and aquacultures 11. Teicoplanin 12. Vancomycin 13. Norfloxacin 14. Halogenated Hydroxyquinoline 15. Arsonic acid, (4-hydroxy-3-nitrophenyl)- 4-hydroxy-3 nitrobenzenearsonic acid All related substance C. Any products containing Chlorofluorocarbon D. Combinations not allowed in veterinary products 1. Herbal + Scheduled poison 2. Herbal + OTC *This is not an exhaustive list, it will be reviewed when necessary. 21

Avoparcin glycopeptides antibiotic; shares a chemical similarity with vancomycin Vancomycin resistant enterococci (VRE) Teicoplanin glycopeptide; a spectrum of activity similar to vancomycin glycopeptide-resistant enterococci Vancomycin glycopeptide Vancomycin resistant enterococci (VRE) 22

*Via Quest 3+ ONLINE APPLICATION https://quest3plus.bpfk.gov.my/front-end/loginchrome.php 24

REGISTRATION REQUIREMENTS Data required to support an application is divided into : a. Administrative documentation (Part I) b. Quality documentation (Part II) c. Non Clinical Documents (Safety and Residues Documentation) (Part III) d. Clinical Documents (Efficacy Documentation) (Part IV) Data to be submitted will be based on each application type as follows: * Innovator Product : Part I to IV * Generic Product : Part I & II 25

PRODUCT VALIDATION 1. PRODUCT NAME Product name + strength + dosage form 2. DOSAGE FORM 3. ACTIVE SUBSTANCE 4. EXCIPIENT 5. INGREDIENTS OF HUMAN OR ANIMAL ORIGIN 6. MANUFACTURER 7. CONTRACT MANUFACTURER 26

PRODUCT VALIDATION 8. SECOND SOURCE PRODUCT 9. REPACKER 10. PATENT PROTECTION 11. DATA EXCLUSIVITY (DE) 12. PREMIX 13. REPLACEMENT PRODUCT 14. IMPORTED PRODUCT 27

Administrative documentation (Part I) Quality documentation (Part II) 28

ADMINISTRATIVE DOCUMENTATION (PART I) SECTION A: PRODUCT PARTICULARS Product Description Pharmacodynamics- Main and supplementary pharmacological effects (mechanism of action, actions other than the therapeutic effects) Pharmacokinetics- Absorption, plasma-protein binding, distribution, biotransformation, metabolism, excretion, etc Environmental Properties Indication(s)- Recommended clinical use(s) of product, indicating clearly whether the indication is curative, palliative, adjunctive, diagnostic, etc. Target species Recommended dose- Dose (normal dose, dose range) and dosage schedule (frequency, duration) appropriate for each therapeutic indication and target species Route of administration 29

SECTION A: PRODUCT PARTICULARS Contraindication- Conditions for which or under which the product shall not be used. Warning & Precautions - Precautions and warnings necessary to ensure safe and efficacious use of the drug, including special precautions for use, special warnings for each target species, special precautions to be taken by the person administering the products to animals. Interactions with other medicaments- Interactions which are observed and/or for which there is potential clinical significance. Pregnancy & Lactation- Recommendations regarding the use of the product in pregnant/ lactating animals or laying birds. Side effects- State in order of severity and frequency, the side effects, adverse reactions, toxic effects, etc 30

SECTION A: PRODUCT PARTICULARS Symptoms and Treatment of Overdose- Symptoms of overdose/ poisoning, the recommended treatment and antidotes Instructions for use- Specific instruction Storage Conditions- Recommended storage conditions (temperature, humidity, light etc.) Shelf Life as packaged for Sale- Supported by stability data. Shelf Life after first opening of container Shelf life after reconstitution or dilution Therapeutic code- ATCVet Code 31

SECTION A: PRODUCT PARTICULARS Is the product for food producing animal? Withdrawal period(s) meat and offal, milk, eggs etc Should be indicated in days, except for milk (expressed in hours). Mandatory to be stated on the label and package insert Maximum Residual Limit (MRL) According to target species Appendix 11 (REGOVP) Allowable MRL 32

SECTION B: PRODUCT FORMULA Batch size : kg, L Actual Batch Manufacturing Formula 33

SECTION C: PARTICULAR OF PACKING Pack size * Weight, volume, quantity, unit Immediate Container type * Type of packaging & description * Aluminium, glass, metal, paper, plastic, others * Bottle, sachet, bag etc. Packaging Picture- Actual photo of the container with product label 34

SECTION D: LABEL (MOCK UP) FOR IMMEDIATE CONTAINER, OUTER CARTON & PROPOSED PACKAGE INSERT Label - Immediate container Label Outer Carton Proposed Package Insert 35

SECTION E: SUPPLEMENTARY DOCUMENTATION/OTHER INFORMATION Product Owner Letter of Authorization from the Product Owner Letter of Appointment of Contract Manufacturer Letter of Acceptance from Contract Manufacturer Letter of Appointment of the Repacker from the Product Owner Letter of Acceptance from the Repacker 36

SECTION E: SUPPLEMENTARY DOCUMENTATION/OTHER INFORMATION Certificate of Pharmaceutical Product (CPP) * From the competent authority in the country of origin Certificate of Free Sale (CFS) * From the competent authority in the country of origin Certificate of Good Manufacturing Practice (GMP) * From the competent authority in the country of origin Manufacturer/ Other Manufacturer (s) Importer Store Address Summary of Product Characteristics (SPC) 37

SECTION E: SUPPLEMENTARY DOCUMENTATION/OTHER INFORMATION Company Core Data Sheet (CCDS) Analysis Protocol &Validation of Analysis Protocol - Appendix 10 (REGOVP) Other Supporting Document Worldwide Registration Status Post-Approval Commitment 38

Administrative documentation (Part I) Quality documentation (Part II) 39

QUALITY DOCUMENTATION (PART II) SECTION S: DRUG SUBSTANCE Nomenclature Structure- Structural formula, Molecular formula General Properties- Physico Chemical Properties Manufacturer- Manufacturing Process and Process control, Control of Critical Steps and Intermediates, Process Validation, Manufacturing Process Development Characterisation- Elucidation of Structure and Other Characteristic, Impurities 40

QUALITY DOCUMENTATION (PART II) SECTION S: DRUG SUBSTANCE Control of Drug Substance- Specification, Analytical Procedures and Validation, Batch Analysis, Justification of Specification Reference Standards of Materials - Reference standards /materials used for testing of the drug substance Container Closure System Stability 41

SECTION P: DRUG PRODUCT Description and Composition Pharmaceutical Development- Information on Development Studies, Microbiological Attributes, Compatibility etc. Manufacture- Manufacturing Process &Process Control, Control of Critical Steps and Intermediates, Process Validation Control of Excipients- Specification, Analytical Protocol & Validation, Justification of specification, Excipient of Human or Animal Origin Control of Finished Products- Specification (List of tests, limits or criteria of acceptance), Analytical Protocol & Validation, Batch Analysis- Certificate of Analysis (minimum 2 latest batches), Characterisation of Impurities, Justification of Specification 42

SECTION P: DRUG PRODUCT Reference Standards of Materials- The reference standards or reference materials used for testing of the finished product Specification of Container Closure System- Identity of materials of construction of each primary packaging component & it s specification Stability Data -Appendix 9 (REGOVP) Guideline for Stability Data Product Interchangeability/Equivalence Evidence (if applicable) 43

NON-CLINICAL DOCUMENT (PART III) Safety Documentation Pharmacology- Pharmacodynamics, Pharmacokinetics Toxicology Single Dose Toxicity- Should reveal the acute toxic effects of the substance and the time course for their onset and remission. Repeat Dose Toxicity- To reveal any physiological / pathological changes induced by repeated administration of the active substance or combination of active substances Tolerance in the target species- Summarise any signs of intolerance that have been observed during studies in the target species Reproductive Toxicity- Embryotoxicity/ foetotoxicity, including teratogenicity Mutagenicity- Tests to reveal changes which a substance may cause in the genetic material of cells. Carcinogenicity (if necessary) 44

NON-CLINICAL DOCUMENT (PART III) Studies of other effects- e.g. neurotoxicity, sensitisation, observations in humans, microbiological studies, Studies on metabolites, impurities, other substances & formulation User safety- Inherent toxicity or other harmful effects, Route and degree of exposure, Risk management proposal Environmental risk assessment (Environmental Safety)- Extent of exposure of the product to the environment, specific investigations of the following, as appropriate:- fate and degradation in soil, fate and behavior in water and air, effects on aquatic organisms, effects on other non-target organisms 45

NON-CLINICAL DOCUMENT (PART III) Residue Documentation (Human Food Safety)(For a product intended for use in food-producing animal species) Formulation used in residue studies - formulation, detailing active ingredients and excipients that may affect the residue profile Residue Studies Pharmacokinetics- highlighting the points relevant to residues. Depletion of residues- To measure the rate at which residues deplete in the target animal after the last administration of the product To determine the withdrawal periods & MRLs The withdrawal period should be set to ensure that the MRL is not exceeded Analytical Method (s)- Description and validation of the method 46

CLINICAL DOCUMENTS (EFFICACY DOCUMENTATION) (PART IV) Pre-Clinical Documentation Pharmacology- Pharmacodynamics, Pharmacokinetics Target Species Tolerance To characterise signs of intolerance and to establish an adequate margin of safety using the recommended route(s) of administration. Shall contain details of all expected pharmacological effects and all adverse reactions. Resistance applies to antimicrobial,antiparasitic products, anticancer products. Discuss how pathogens become resistant against the active substance Explain if and how resistant pathogens impact on the clinical efficacy of the product. Data on the potential emergence of resistant organisms of clinical relevance and the mechanism of resistance development. 47 VICH GL 27 (Antimicrobial resistance: pre-approval)

CLINICAL DOCUMENTS (EFFICACY DOCUMENTATION) (PART IV) Clinical Documentation Summary of the Results and Critical Evaluations of Dose Determination and Dose Confirmation Studies and Clinical Trials (Field Trials) Tabular Presentation of all Clinical Trials and Studies Individual Summary of the Most Important and Significant Studies Summary of Clinical Safety 48

REGISTRATION REQUIREMENTS Certain antimicrobial agents required special registration requirements e.g. fluoroquinolones (Enrofloxacin, Flumequine, Marbofloxacin) Development of fluoroquinolone-resistant Campylobacter species in poultry and human Only allowed to be registered with DCA for treatment purpose Statement To be prescribed by Registered Veterinary Surgeons only in the product label and package insert Close monitoring by the Department of Veterinary Services (DVS) at the farm level Colistin Only allowed to be registered with DCA for treatment purpose Statement To be prescribed by Registered Veterinary Surgeons only in the product label and package insert Close monitoring by the Department of Veterinary Services (DVS) at the farm level 49

REGISTRATION REQUIREMENTS Registration status of a product shall be valid for five (5) years or such period as specified unless the registration is suspended or cancelled by the Authority. Renewal of product registration can be done six (6) months prior to the expiry of the validity period of product registration. After the expiry date, status of product registration shall change to status of expired, and application for renewal of the product registration can no longer be submitted. Responsibility of Product Registration Holder to submit the renewal application 50

POSTMARKETING ACTIVITIES Post registration activities such as pharmacovigilance & market surveillance will also be implemented to ensure that the products being manufactured and sold comply to specified criteria /requirements Adverse event can be reported to NPRA via online reporting or manual submission by post, email or fax. Consumption Surveillance of veterinary medicines at the farm level is not under the jurisdiction of the Drug Control Authority (DCA) of Malaysia. However, if there is any quality/safety/efficacy issue pertaining to the use of veterinary medicines registered under DCA, user can report to NPRA for further investigation. 52

CONCLUSION REGOVP will serve as the reference guide for registration of products for animal use. The current Guideline (REGOVP) will be reviewed from time to time, as and when the need arises. 54

FOR MORE INFORMATION Log on to http://npra.moh.gov.my/ Guidelines Central Veterinary Registration Guidelines for Veterinary Products (REGOVP) - Version 3 July 2014 FAQ 55