Regulatory requirements of row countries

Regulatory Requirements OF REST OF THE WORLD Countries
by DIVYA PUSHP

1. PRESENTATION ON- ‘REGULATORY REQUIREMENTS OF ROW COUNTRIES’ UNDER THE GUIDANCE OF Dr. Janaki Devi Sirisolla PRESENTED BY- DIVYA PUSHP VP21PHAR0100004 M.PHARM.(1st YEAR) GITAM INSTITUTE OF PHARMACY VISAKHAPATNAM

2. CONTENTS Row countries Importance of harmonization Introduction Division of pharmaceutical market Overview of emerging market Difference between Regulated and Emerging Market Registration Requirement For Rest Of the World Queries raised by various ROW countries Comparative study of Registration requirements of emerging countries

3. ROW COUNTRIES ROW refers to the Rest Of The World countries, also known as the emerging market or semi regulated market. These regions consist mainly the countries from Asia pacific, Latin America, Eastern Europe, Africa and Gulf countries. Countries from Asia pacific and Gulf have harmonized their regulatory environment upto some extent through The Association of Southeast Asian Nations (ASEAN) and Gulf Co-operation Council (GCC) organizations. ROW countries need to harmonize regulations in their respective regions .

4. IMPORTANCE OF HARMONIZATION Reduction in the cost involved in availability of drugs. For maintaining quality requirement of premise. Because of the regional registration requirements. INTRODUCTION Regulatory requirements are harmonized in regulated countries by Common technical document (CTD) filing, while there is a diversity of requirements in emerging markets. There are different requirements in different countries for registration. It is difficult for any company to develop product for each region. Therefore one needs to consider majority of requirements during technical data submission which will help in export registration.

5. PHARMACEUTICAL MARKET IS DIVIDED INTO FOLLOWING GROUPS 1. Regulated Market: US, EU (UK, Germany, France, Ireland, and Sweden etc.), Japan, Canada, Australia, New Zealand, and South Africa. 2. Semi regulated Market: (a) Asia: (Sri-Lanka, India, Bangladesh, China, Pakistan, Bhutan, Nepal). (b) ASEAN : 10 Countries group - Philippines, Vietnam, Singapore, Malaysia, Thailand, Indonesia, Laos, Cambodia, Brunei Darussalam, and Myanmar. (c) African countries: (Algeria, Zambia, Ethiopia, Ghana, Kenya, Malawi, Mozambique, Namibia, Nigeria, Sierra Leone, Tanzania, Zimbabwe etc.) (d) Middle East countries: (Gulf Co-operation Council countries i.e. Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE) (e) Latin America (Mexico, Brazil, Panama, Peru, Guatemala, Argentina, Chile, Dominican Republic) (f) CIS: (common wealth of independent states): Russia, Ukraine, Post Soviet States (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kirghizstan, Moldova, Tajikistan, Turkmenistan, and Uzbekistan etc.)

6. GLOBAL SHARE OF THE EMERGING MARKET TIER MARKETS GLOBAL SHARE% 1. China, Japan 24 2. Brazil, Russia, India 8 3. Algeria, Egypt, Nigeria, Saudi Arabia, South Africa, Indonesia, Pakistan, Thailand, Vietnam, Poland, Romania, Turkey, Ukraine, Argentina, Colombia, Mexico, Venezuela 10

7. EMERGING MARKET OVERVIEW The optimization in requirements is mandatory keeping in mind the incidence of higher cost involved in availability of drugs, research and development facilities. The WHO and other developed country drug regulatory authorities, should be encouraged and supported so that they can expand their current programmes which are supporting to developing countries. DIFFERENCE BETWEEN REGULATED AND EMERGING MARKET There is difference in degrees of implementation of regulations. Intensity of conducting audits and inspections is different. In case where GMP is violated, then penalties for both are different. Regulated market guidelines are very clear unlike that of the emerging market s. Regulated market adhere 100% to the guidelines whereas no such adherence is observed in the emerging market as the regulations are not harmonized. There is a difference in their region. They also differ in certain aspects such as regulation of Pharmaceuticals, using different Guidelines for registration, registration fees, requirements to maintain registration, duration of registration, Patent regulation and legislation for the drug.

8. REGISTRATION REQUIREMENTS FOR REST OF THE WORLD ADMINISTRATIVE DOCUMENTS Certificate of Pharmaceutical Product Product Permission Manufacturing License WHO-GMP Certificate Free Sale Certificate/Export Certificate Artwork (Carton, Label & Package Leaflet) CHEMISTRY, MANUFACTURING AND CONTROL DOCUMENTS API DMF Open part – Following data should be available in Open Part Nomenclature General Properties Name of the Manufacturer and Site of manufacture Route of Synthesis, flow diagram in brief Structural Elucidation Impurities Specifications and Method of Analysis Container Closure System Stability testing – Retest period & Storage API Specification and Method of Analysis & COA of API by the Applicant

9. DRUG SUBSTANCE AND DRUG PRODUCT IUPAC Names CAS Number Nature of drug substance Polymorphism and chirality Description of physical constants such as solubility and pKa values. Description of Particle size distribution, hygroscopicity, flowability, granularity. JUSTIFICATION FOR IMPURITY LIMITS The following factors to be considered while fixing the specification limits API impurity limits data (COA) Check ICH requirements. Check pharmacopoeial limits, if any. API stability data. Finished product stability data etc.

10. MANUFACTURING FORMULA AND PROCESS Manufacturing Formula Description of manufacturing/packaging Scale, Equipment by type, capacity, process parameters for steps (e.g. time, temp, pH), Environmental conditions, e.g. relative Humidity for Hygroscopic materials Description of In process controls/test Flow Diagram indicating critical steps , In-process controls Master formula Batch manufacturing Record – Copy of the Master BMR or Completed BMR Process Validation Protocols and /or reports-3 batches process validation reports and /or protocol is to be submitted. 3 Batches should be of the same size and should be similar to the batch size mentioned above in the manufacturing formula BATCH ANALYSIS Results of at least one batch should be given. It should be preferably of the batch of which the samples will be submitted for registration or it can be of the latest batch, as required by the agency in the respective country. It should be given as certificate of analysis.

11. EXCIPIENTS For Excipients of natural origin microbial limits should be specified For Human or Animal origin TSE/BSE certificates from the manufacture should be incorporated Information on Adventitious Agents should be provided, such as Asbestos in Talc Permitted & approved Colors and Flavors should be used. Excipients not in compendia are not recommended. Some standard mixtures comprising excipients in Pharmacopoeia are allowed (e.g. Opadry Colors). In such cases table with composition of such mixtures and specifications with test form the supplier should be provided For Excipients described in compendia, copy of Monograph along with copies of the methods referred to in monograph but not appearing in monograph should be provided. Current Pharmacopoeial monograph is always applicable. Details of any specifications additional to monograph should be provided.(e.g. particle size, residual solvents) Excipients Certificate of Analysis tested against the full set of specifications.

12. FINISHED PRODUCT SPECIFICATION AND METHOD OF ANALYSIS If not as per Pharmacopoeia specifications, it should be prepared as per ICH Q6A. Methods of Analysis should be described in details. If based on Pharmacopoeia additional product related specifications should be included as in-house specifications (e.g. Description, Hardness, Friability, Average weight, Dimensions, Identification of colorants, MLT). Methods of the additional tests should be given. If a test is based on a compendia monograph, a copy of the monograph plus any methods referenced in the monograph must be submitted. Details of any specifications and test methods additional to those in the Pharmacopoeia must be submitted. METHOD VALIDATIONS FOR FP AND API In few countries Validation of analytical methods is still not mandatory if the Pharmacopoeial method is followed. Non-Compendial method needs to be validated if required by the Agency.

13. STABILITY DATA AND STABILITY PROTOCOL Stability studies should include testing of those attributes of the finished product that are susceptible to change during storage and are likely to influence quality, safety and efficacy Testing should cover the physical, chemical, biological and microbiological attributes, preservative content and functionality tests (e.g. Nebulizer). Microbial limits should be mentioned at release and end of shelf life. Dissolution limit should be same as for release. API used shall preferably be of different batches. Stability to be performed on each individual strength & container size of drug product, unless bracketing or matrixing is applied. In conclusion shelf life should be proposed / concluded including the storage condition. 3 batches (2 pilots, 1 smaller) data is required to be submitted. A pilot scale batch is one tenth of a full production scale or 100,000 units, whichever is larger. Recent modification of 30°C/70%RH condition to 30°C/65%RH – an attempt at a single long-term global testing condition. Testing frequency and storage conditions should as per the ICH guidelines Stability data as per Zone: {Acc.: 0, 1, 2, 3 & 6 months; Long term: 0, 3, 6, 9, 12, 24 and 36 months}

14. Local Stability Requirements for different countries PACKAGING MATERIAL Packing material should be suitable for storage, transport and compatible. For Primary packing material detailed specifications and method of analysis including Identification for material of construction required. For Secondary packing material specifications and method of analysis required Printed packing material and PIL specimens and /or colored artworks Certificate of Analysis & Batch Packaging record required.

15. BIOEQUIVALENCE Comparison of the systemic exposure profile of a test product (Generic) to that of a reference product (Innovator Brand) For the test product to be bioequivalent it should exhibit the same rate and extent of absorption as the reference product Required for Tablets, Capsules and Oral Suspensions etc It can be waived for aqueous oral solutions, parenteral solutions or solutions which are locally applied and locally acting, for example eye drops topical products, inhalators or nasal spray products. If Bioequivalence study is not available then multimedia, multipoint comparative dissolution profile data of the product with innovator product should be submitted. Data should be complied the requirement for F2 factor. PHARMACOLOGICAL,TOXICOLOGICAL DATA Published References on Toxicological & Pharmacology studies are attached in the dossier. Published data on clinical trials and references are attached in the dossier. REGISTRATION FEES Registration fees should be paid as per the requirements of the Agency of importing country.

16. OTHER REQUIREMENTS Working Standard along with certificate of analysis Samples of API and Excipients Chromatograms, Spectra of the identification tests wherever applicable SAMPLES As per the quality, it is mandatory to submit fresh finished product samples along with the dossier. The quantity of the sample varies as per the requirements of the Agency of importing country. QUERIES RAISED BY VARIOUS ROW COUNTRIES GENERAL PROPERTIES Nature of drug, polymorphism and chirality is not mentioned adequately. Detailed description of particle size distribution, hygroscopicity, granularity, flowability is not there. pH buffers (pH 1.2, 4.6 & 6.8) not provided, pKa value not included in section. API Overages qty. not mentioned in formula. Functions of material details not provided.

17. DESCRIPTION OF RAW MATERIAL REQUIRED IN MANUFACTURING PROCESS Name and complete contact details of each API-Vendor are not given even though it is manufactured from two different manufacturers The process control information such as, weight variation, average weight, hardness, friability, thickness and disintegration time are not provided for tablet dosage form. PDR (Pharmaceutical development reports) are not complete. Manufacturer complete address for manufacturing plant & Head office with contact of Quality person not mentioned. For the sensitive Excipients e.g. Mg-stearate TSE/BSE declaration is not provided. CONTROL OF MATERIALS The residual materials from the reaction procedure are poorly addressed. The raw materials, reagents, intermediates and solvents used in the process are not described properly for possible impurities. In FP (Finished Product) specification microbial limit is not included. ELUCIDATION OF STRUCTURE AND OTHER CHARACTERISTICS The spectral data such as NMR, X-ray Diffraction, Elemental Analysis and IR as a means for evidence of chemical structure is missing. For Drug substance spectral graphs for UV Spectra, NMR & IR studies performed are unacceptable and interpretation of the studies is inadequate.

18. IMPURITIES Potential impurities are not described in the impurity profile In the synthesis raw materials and intermediates are used. Their specifications are not described. Hazardous reagents and inorganic toxic substances residual limits are not given. Justification for the use of excipients which carry reactive impurities such as hydrogen peroxide, formic acid is not provided as per impurities in residual solvents (ICH Q3C). Absence of Genotoxicity study, testing and data designed to detect compounds that cause genetic damage. CONTROL OF DRUG SUBSTANCE The quality of the APIs meet only the requirements of specific monographs but does not meet to specifications described in the general monographs of a pharmacopoeia. ANALYTICAL PROCEDURES The Limit of Quantification (LOQ) and the limit of detection (LOD) are not provided for GC and HPLC methods used to control residual solvents and impurities in the Drug substance. The method used for the study of Drug substance is not specific. For the Analysis of impurities specific method is used which are not provided. Certificate of Analysis (COA) and other Quality Control (QC) documents are not signed dated and certified by Quality Assurance (QA) department.

19. BATCH ANALYSES The batch formula not mentioned for the exhibit as well as the proposed commercial batch. Complete composition of the coating materials is not provided. The information on some hazardous materials like reagent and solvent is hidden . STABILITY DATA Zone-conditions for Real-time stability studies is not considered In stability report the packaging details are missing. The actual studies for stability are not provided. Microbial Attributes test not provided. CONTAINER CLOSURE SYSTEM Primary packaging material Certificate of Analysis (COA) & Standard Test Procedure (STP) are not given. Pack style and pack size discussion is not provided. For final packaging the extractable and leachable study for the plastic containers and stoppers used for the drug product packaging is not provided. MICROBIOLOGICAL ATTRIBUTES Microbial Contamination results are missing. Pathogen Count and Total Count not provided.

20. REGULATORY FILING PROCEDURE

21. COMPARATIVE STUDY OF REGISTRATION REQUIREMENTS Countries Group ASEAN GCC LATAM CIS ASIA PACIFIC (except ASEAN) AFRICAN COUNTRIES Site registration Yes Yes Yes Yes Yes Yes Dossier Format ACTD CTD/eCTD Country specific (CTD and eCTD in Chile Other: Country specific) Country specific (Resemble CTD Other: Country specific) Country specific (India: Resemble CTD Other: Country specific) Country specific (Resemble CTD Other: Country specific) COPP Legalized Legalized Country d Specific Legalized Legalized Legalized Legalized Manufacturing license Required Required Required Required Required Required Registration time 12 months 24-36 months Peru-7 days Brazil- 24 months Chile-6 -18 months. Russia-6-24 months Belarus-180 days 8-24 months 15-18 months Stability Zone Zone IV b Zone IVa IVa and IVb Brazil – Zone IVb Mexico- Zone II Chile - ZoneIVa Uzbekistan- Zone II Russia- Zone II Ukraine- Zone II Tajikistan- Zone II Zone IVa and Zone IVb India and Nepal –Zone IVb Sri-Lanka and Bhutan– Zone IVa Kenya and Uganda – Zone IVa Ghana – Zone IVb

22. Countries Group ASEAN GCC LATAM CIS ASIA PACIFIC (except ASEAN) AFRICAN COUNTRIES No. of submission Batches 3 pilot scale 3 pilot scale 3 pilot scale 3 primary batches, out of which min 2 are Pilot scale 3 primary batches, out of which min 2 are Pilot scale 3 primary batches, out of which min 2 are Pilot scale Minimum stability data LT-12 months ACC- 6 months LT-12 months ACC- 6 months LT-12 months ACC- 6 months LT-12 months ACC- 6 months LT-12 months ACC- 6 months LT-12 months ACC- 6 months Stability guideline reference ASEAN GCC ANVISA AND ICH ICH ICH/WHO WHO/OMS Labelling requirement Refer GMP Detail description of product. Should be in English and local language. Pack insert req. Detail description of product is required according to stability studies. As per local regulation. Mock ups required for submission. Local registration number and pharmacist detail Braille code is required on labeling with detail information of drug formulation. Packaging and product details with package insert. If without carton ,internal product should contain all the information. Uganda-Detail description of the product should be mentioned in both English and local language. Should be approved by NDA Number of subjects 12 12-24 24 12-24 12 12 Clinical study design Single dose Two period, two- sequence crossover study Single dose Two period, two- sequence crossover study Two-period, two-sequence crossover or four way crossover Russian patients in phase III or local trial. Local BE study For generics is required. India- Local study with pivotal design. Could be qualified for Waiver in case of unmet medical need. China- Phase I and Phase III (at least 100 patients each arm is Part of global trial). Two-period, two-sequence crossover or four way crossover.

23. CONCLUSION Any export market demands good quality dossier which can be generated through systematic Formulation Development. The proper planning and execution of Formulation development will help in quality dossier & in answering queries from Regulatory authorities. Asia Pacific market is expected to grow from USD 187 billion to USD 275 billion because of the low cost availability of generic medicines, growth of business, rising income. Moreover China has become a major market number two global pharmaceutical market. Now the concepts have changed from ‘developing’ to ‘emerging’ and now to growth markets.

24. REFERENCES Preeti Patela, Jitendra Kumar Badjatyab ,*, Madhuri Hingea [Comparative study of regulatory requirements of drug product in emerging market] Badjatya Jitendra Kumar*, Bodla Ramesh ( Department of Pharmacy, J.J.T University, Chudela , Jhunjhunu , Raj. India) ( Department of Pharmaceutical Chemistry, DIPSAR New Delhi, India) [Drug Product Registration in semi-regulated market]

25. THANK YOU...