Check List for Documents Submit for Registration Dossier

Ministry of Health وزارة الصحة Central Administration for الادارة المركزية للشئون الصيدلية Pharmaceutical Affairs الادارة العامة للتسجيل General Registration Department إادارة تسجيل المستحضرات الحيوية Department of Biological Products Registration Code No. CL-RBP-01

Date of Submission: Product Name: Applicant Name: Applicant Representative: Biological Registration Specialist:

Prepare 5 separate dossiers as follows Check Notes Dossier I: Core Registration Dossier First: Administrative data 1 Index Covering letter on applicant head letter signed and stamped by 2 the registration general manager 3 Copy of Box approval 4 Copy of pricing certificate 5 Copy of Preliminary approval 6 C.D containing all content of the five dossiers A certification that all data in the file is true and accurate and 7 identical to the CD Authorization letter for the person responsible for 8 communication on behalf of applicant during the procedure and this letter should be certified as truly signed 9 Payment receipt 10000 L.E Application form for registration of biological medicinal 10 products. Signed by the Applicant Stamped by the applicant (each page) 11 Composition Certificate On license holder letter head Signed by the license holder Stamped by the license holder Notarized and Authenticated Trade name of the product is specified Dosage form of the product is specified

Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194 Website: www.eda.mohp.gov.eg Version: 2.1 Email: [email protected] Ministry of Health وزارة الصحة Central Administration for الادارة المركزية للشئون الصيدلية Pharmaceutical Affairs الادارة العامة للتسجيل General Registration Department إادارة تسجيل المستحضرات الحيوية Department of Biological Products Registration Code No. CL-RBP-01

Active ingredient (s) with its (their) quantity (ies) per unit dose is (are) specified inactive ingredient (s) with its (their) quantity (ies) per unit dose is (are) specified Active & inactive ingredient is specified (in house specification , USP ,EU ,JP ,British pharmacopeia) The overage should be mentioned API name is specified (the INN, scientific, pharmacopoeia, common name accompanied by its salt or hydrate form (if any)) API Manufacturer’s name + Country + City are specified API manufacturing site address is specified 12 Reference: The latest version(BNF ,Swiss compendium Rote list, Vidal) WHO prequalification, FDA, EMA Free sale certificate or CPP issued by Competent Authorities in 13 Country of Origin Authenticated Valid The Arab Republic of Egypt is mentioned as Importing Country (Optional) Number of product license is specified Date of issue is specified Trade name of the Product is specified (in COO and A.R.E) Dosage form (s) and Strength (s) are specified. License Holder (address, city, country) is specified Role of License Holder is specified Product marketed in the COO (if not, explain why marketing is lacking?) Manufacturing site(s) is/are specified, registration for other manufacturing, packing & batch release site(s) involved in the manufacturing of the product is available (If any) Good Manufacturing Practice (GMP) of the manufacturer is specified (or in separated certificate if manufacturing site is not in the same country, it must by valid and authenticated) Pack Presentation and pack size(s) of the Product is (are) specified (could be as attachment) Inner leaflet recent modification (could be as attachment) Active Ingredient(s) by its salt or hydrate form (if any) with its (their) quantity (ies) per unit dose is (are) specified Inactive Ingredient(s) with its (their) quantity (ies) per unit dose is (are) specified (could be as attachment) Shelf-life of the Product is specified (could be as attachment) Storage Conditions of the Product is specified (could be as attachment) SPC or package insert of the product is attached If the Name of the product may change in Egypt it must by noted or clarified by other letter. If there are two manufacturing site in the COO it must be clarified which site will be the supplier. GMP of all the manufacturers involved in the production process 14 (Manufacturer of active substance, Manufacturer of finished, Manufacturer of solvent, Batch releaser, primary packager,…….)

Authenticated Valid The name of plant by its address should be specified The date of the last inspection should be specified The invalidation date should be mentioned The production lines are specified 15 Manufacturing license indicating production lines or equivalent TSE free certificate (if the product contains magnesium stearate, 16 lactose, or gelatin derived from animal source) Original letter from the company mentioning that Product is TSE free and mentioning Countries of origin of source materials Copy(s) of the Supplier company letter(s) stating the safety of 17 substance supplied to the concerned company available Notarized copy of the certificate of suitability from the concerned authorities in the country of origin (e.g.: Certification of 18 Suitability of Monographs of the European Pharmacopoeia) available List of the countries where the product is registered & sold, 19 notarized from the chamber of commerce or its equivalent in the country of origin and certified from the Egyptian embassy abroad Company profile (applied once for each company) recieval letter 20 from CAPA. Certificates clarifying the relationship between the manufacturing company, the importing company & the 21 distributor (for imported products) i.e Authorization letter or Agency agreement Certificate of the scientific office ( if scientific office is the 22 applicant) mentioning the name of the companies affiliating the scientific office A letter from the manufacturing company in the country of 23 origin authorizing packaging & registration of product in Egypt (for bulk products) 24 Tax Card 25 Commercial register 27 Certificate of importers register Certificate of approval of chamber of medicinal industries (for 28 local products) Outer label of the Product (for the COO product and the 29 proposed A.R.E product) 3 original packs and 4 layouts Page 3 of 12

Trade Name is typed in the same way and style, identical to the CPP or the approved one. The Pharmaceutical Form is identical to the CPP or the approved one The Pack Size is identical to the approved by pricing committee Active ingredients with their quantities are mentioned on the Outer pack, are identical to the CPP or the approved one, under the trade name

Manufacturer, license holder or any other participant in the manufacturing process, the name, address, city, country, (phone, Fax, web site) must maintained in addition to the specific logo or trade mark.

The brief indication or the therapeutic class is maintained Route of administration (in case of (IV, IM. SC, Ia, infusion…) injection, vaginal supp., Rectal supp., eye only, ear only, eye/ ear, vaginal or external cream/ ointment) Special precaution for handling (if any, as Shaking, dilution…) If the dosage form or the product related to special population (infant, Children, adults) Different concentration should have different printing color for easier identification Unit of the dosage form present in the container or box (the priced unit) The legalized price / unit Registration Number of Egyptian ministry of health / Year of registration Batch number is mentioned on the Outer pack Manufacturing date is mentioned on the Outer pack Expiry date is mentioned on the Outer pack In case, the product submitted for export only , export and tender, hospital use (must maintained) Storage conditions are mentioned on the Outer pack Contains the warning/ presence of some ingredients (for exp.: Aspartame. Sunset yellow, Benzalkonium chloride and others) if not mentioned in the package insert (leaflet) A clarification letter stating that the submitted samples are the COO or for registration purpose only, if these samples are not intended for the Egyptian market use. 30 Inner Label of the product 3 original labels and 4 layouts The manufacturer and / or the license holder by their logo should specified The trade name and strength are specified Batch number is specified Manufacturing date is specified Expire date is specified Package Insert (leaflet) of the Product (for the COO product and 31 the proposed A.R.E product) 2 original and 2 word copies On Company letter-head Contains the Composition of the product {Active ingredient(s) with quantity(ies) } Contains list of the Inactive ingredient(s) Contains the Pharmaceutical Form (s) Contains Storage Conditions The Storage Conditions are identical to the one available in the file & identical to the one mentioned on the outer pack and inner pack

Powder for reconstitution: The Storage Conditions before reconstitution and after reconstitution are mentioned in the insert. All Pack size (s) is (are) mentioned Manufacturer and License holder full name and address are mentioned Package insert reference no. and date of issue/revision are available 32 Reference for the insert (innovator insert) Declaration letter that the submitted insert is the most updated 33 and is the one marketed in the COO Second: Ingredients & packaging materials

A) Active ingredients: 34 Specifications of the active ingredients and the relevant tests. Justification of Specification 35 Certificate of Analysis Original & Signed by the Company or the concerned center or laboratory that held the analysis Stamped by the Company or the concerned center or laboratory that held the analysis Product name, strength and form are specified Manufacturing date is specified Expiry date is specified Batch number is specified 36 Methods of analysis and validation (soft copy only) 37 Supplier name & origin b) Excipients: 38 Specifications of the inactive ingredients and the relevant tests. 39 Certificate of Analysis Signed by the Company or the concerned center or laboratory that held the analysis Stamped by the Company or the concerned center or laboratory that held the analysis Product name, strength and form are specified Manufacturing date is specified Expiry date is specified Batch number is specified 40 Methods of analysis and validation (soft copy only) 41 Supplier name & origin 42 d)Packaging material: Type of packaging materials. Specifications of packaging materials. Supplier name & origin Third: Finished product 43 Specifications of the finished product and the relevant tests

44 Certificate of Analysis of finished products Signed by the Company or the concerned center or laboratory that held the analysis (Authenticated

and Notarized) Stamped by the Company or the concerned center or laboratory that held the analysis Product name, strength and form are specified Manufacturing date is specified Expiry date is specified Batch number is specified 45 Methods of analysis and validation (soft copy only) 46 Supplier name & origin of finished products If the materials entering in the product formulation are from blood derivatives , the following will be presented besides the previous: (47-50) 47 Official certificates declaring plasma source 48 HV-1,HV-2,HBsAG,HCV freedom certificate for the plasma 49 Flow chart indicating sites and steps of product manufacture.

50 Certificate of release from Health authority

Method of manufacture including in process control & validation 51 (soft copy only) Manufacturing Process Development

Manufacturer (s) (Name, address, responsibility of each manufacturer including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided)

Information should be provided on the manufacturing process, which typically starts with a vial(s) of the cell bank, and includes cell culture, harvest(s), purification and modification reactions, filling, storage and shipping conditions.

Controls of critical steps and intermediates (Tests and acceptance criteria performed at critical steps of the manufacturing process to ensure that the process is controlled should be provided) 52 Site master file (soft copy only) 53 Description of cold chain maintenance procedure Submitted to stability Dossier II: Stability Studies of The Finished department

Product Authorization letter for the person responsible for 1 communication on behalf of applicant during the procedure and this letter should be certified as truly signed 2 Copy of the Preliminary approval 3 Composition Certificate (5 copies) Page 6 of 12

Copy of the Free sale certificate or CPP issued by Competent 4 Authorities in Country of Origin 5 Stability summary sheet (on website in stability committee) 6 Stability report 7 Certificate of Analysis of finished product 8 Stability decision (3 copies) (on website in stability committee) 9 stability report (on website in stability committee) Certificate of the lab where the stability studies id done ( for local 10 products) 11 Declaration of responsibility on the storage conditions 12 C.D containing all content of the stability dossiers Letter (on company head letter) confirm the all the documents 13 inside the C.D is identical to stability dossier (use the form on the website) 14 NORCB analysis report (if issued) 15 stability study (every paper should be stamped) 16 M.O.A of active substance in the finished product Validation of the M.O.A of active substance in the finished 17 product Declaration if the product is multi or single dose i.e immediate 18 use or there is stability after opening 19 Description of the packaging material

Dossier III: Inspection Dossier 1 Site master file (stamp each paper) Covering letter from the License holder declaring that the submitted SMF is the most updated and approved signed, stamped and Authorized 2 Active substance master file GMP of all the manufacturers involved in the production process 3 (Active substance, Manufacturer of finished, Manufacturer of solvent, Batch releaser, primary packager,…….) 4 Manufacturing license indicating production lines 5 Copy of CPP of the product Manufacturing process for Active substance and Finished 6 product 7 CD contains all contents the Inspection dossier Dossier IV: Quality Dossier 1 Copy of application form for biological products

2 Copy of composition 3 Copy of Preliminary approval a)Active ingredients: 4 Specifications of the active ingredients and the relevant tests. Justification of Specification 5 Certificate of Analysis Signed by the Company or the concerned center or laboratory that held the analysis Stamped by the Company or the concerned center or laboratory that held the analysis Product name, strength and form are specified Manufacturing date is specified Expiry date is specified Batch number is specified 6 Methods of analysis and validation 7 Supplier name & origin b)Excipients: 8 Specifications of the Excipients and the relevant tests. 9 Certificate of Analysis Signed by the Company or the concerned center or laboratory that held the analysis Stamped by the Company or the concerned center or laboratory that held the analysis Product name, strength and form are specified Manufacturing date is specified Expiry date is specified Batch number is specified 10 Methods of analysis and validation 11 Supplier name & origin 12 c)Packaging material: Type of packaging materials. Specifications of packaging materials. Supplier name & origin d)Finished product: 13 General Information Nomenclature (as INN, compendial name if relevant, chemical Name,…) Structure (Structural formula, relative & absolute stereochemistry, Molecular formula,..). Biotech : The schematic amino acid sequence indicating glycosylation sited or post translational modifications. General Properties (Physicochemical and other relevant properties) 14 Specifications of the finished product and the relevant tests 15 Certificate of Analysis of finished products Page 8 of 12

Signed by the Company or the concerned center or laboratory that held the analysis Stamped by the Company or the concerned center or laboratory that held the analysis Product name, strength and form are specified Manufacturing date is specified Expiry date is specified Batch number is specified 16 Methods of analysis and validation of finished product Validation information including experimental data used to test drug substance) 17 Supplier name & origin of finished products 18 Summary protocol 19 Pre-clinical data (soft copy only) 20 Clinical data (Soft copy only) 21 CD contains all contents the Quality dossier Submitted to Dossier V: Scientific Committee Dossier biologicals scientific committee team Covering Letter to Biological Manager (signed and stamped on 1 company Letter head) CD contains all contents of the Scientific documents of the 2 dossier List of countries where the product is being registered and 3 marketed indicating the registration number & date in each country 4 Copy of CPP in addition to SPC 5 Copy of reference(BNF 61,Vidal,Swiss Compendium,Rote liste) Covering Letter to EPVC Manager (signed and stamped on 6 company Letter head) PSUR (periodic safety update report)( Most updated) 7 Soft Copy ( 2 CDs) Approved or Suggested price 8 (signed and stamped on company Letter head)

9 plasma master file &viral inactivation (plasma derived product) Summary of the Quality, Pre-clinical and Clinical data including 10 the following ( all soft copy except clinical overview hard & soft copy) Quality Overall Summary Introduction

Drug substance General Information Manufacture Characterization Control of Drug Substance Reference Standards or Materials Container/Closure System Stability Drug Product Description and Composition of the Drug Product Pharmaceutical Development Manufacture Control of Excipients Control of Drug Product Reference Standards or Materials Container/Closure System Stability Appendices Facilities and Equipment Adventitious Agents Safety Evaluation Novel Excipients Regional Information Nonclinical Overview Overview of the Nonclinical Testing Strategy Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology Overview of Efficacy Overview of Safety Benefits and Risks Conclusions References Non clinical written and tabulated summaries: Pharmacology, pharmacokinetics, Toxicology Introduction Pharmacology Written Summary Brief Summary Primary Pharmacodynamics Secondary Pharmacodynamics Safety Pharmacology

Pharmacodynamic Drug Interactions Discussion and Conclusions Tables and Figures Pharmacology Tabulated Summary Pharmacokinetics Written Summary Brief Summary Methods of Analysis Absorption Distribution Metabolism (interspecies comparison) Excretion Pharmacokinetic Drug Interactions Other Pharmacokinetic Studies Discussion and Conclusions Tables and Figures Pharmacokinetics Tabulated Summary Toxicology Written Summary Brief Summary Single-Dose Toxicity Repeat-Dose Toxicity Genotoxicity Carcinogenicity Reproductive and Developmental Toxicity Local Tolerance Other Toxicity Studies (if available) Discussion and Conclusions References Toxicology Tabulated Summary Clinical Summary Summary of Biopharmaceutic and Associated Analytical Methods Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Appendix Summary of Clinical Pharmacology Studies Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies

Special Studies Appendix Summary of Clinical Efficacy Background and Overview of Clinical Efficacy Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Study Populations Comparison of Efficacy Results Across All Studies Comparison of Results in Sub-Populations Analysis of Clinical Information Relevant to Dosing Recommendations Persistence of Efficacy and/or Tolerance Effects Appendix Summary of Clinical Safety Exposure to the Drug Overall Safety Evaluation Plan and Narratives of Safety Studies Overall Extent of Exposure Demographic and Other Characteristics of Study Population Adverse Events Analysis of Adverse Events by Organ System or Syndrome Narratives Clinical Laboratory Evaluations Vital Signs, Physical Findings, Observations Related to Safety Safety in Special Groups and Situations Intrinsic Factors Extrinsic Factors Drug Interactions Use in Pregnancy and Lactation Overdose Drug Abuse Withdrawal and Rebound Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability Post-Marketing Data Appendix References Synopses of Individual Studies

Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194 Website: www.eda.mohp.gov.eg Version: 2.1 Email: [email protected]