SA guide

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GUIDELINES FOR THE

REGISTRATION OFMEDICINES IN

SOUTH AFRICA

Version 6

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GUIDELINES FOR THE REGISTRATION OF MEDICINES.

INDEX:

1. INTRODUCTION ......................................................................................P007

2. GENERAL .................................................................................................P0082.1 HOW TO APPLY ...............................................................................P0082.2 ELIGIBILITY ......................................................................................P0092.3 LANGUAGE ......................................................................................P0092.4 WHERE TO SEND APPLICATIONS..................................................P0092.5 TRANSITIONAL CONVERSION TABLE...........................................P009

3. WHEN IS A PRODUCT REGARDED A MEDICINE ...................................P010

4. PREPARING AND SUBMITTING AN APPLICATION FOR

REGISTRATION OF A NEW MEDICINE....................................................P0114.1 CONFIDENTIALITY...........................................................................P0114.2 TYPES OF APPLICATIONS..............................................................P0114.3 GUIDELINES ON SAME/SEPARATE APPLICATIONS ....................P0124.4 FORM AND FORMAT OF AN APPLICATION FOR .........................P013

REGISTRATION4.4.1 General ..................................................................................P0134.4.2 Presentation of copies and number of copies required ....P014

4.5 FEES .................................................................................................P0154.6 REQUIREMENTS FOR COMPLETION OF AN .................................P016

APPLICATION FOR REGISTRATION DOSSIER4.6.1 Administration Data (front page).........................................P016

4.6.2 Part 1 A - Professional Package Insert................................P0174.6.3 Part 1 B - Patient Information Leaflet ..................................P0224.6.4 Part 1 C - An example or facs imi le of the label...................P0234.6.5 Part 1 D - Foreign registration .............................................P0244.6.6 Part 1 E - Pre-clinical studies...............................................P0244.6.7 Part 1 F - Clinical studies .....................................................P0264.6.8 Part 2: Pharmaceutical and Analytical ...............................P029

Requirements4.6.8.1 Part 2A -The active raw material (Development ...P030

Chemistry and characterisation)4.6.8.2 Part 2B - Formulation .............................................P0324.6.8.3 Part 2C - Raw material speci fications and raw.....P033

control procedures4.6.8.4 Part 2D - Containers and packaging materials .....P0354.6.8.5 Part 2E - The manufactur ing procedures .............P0364.6.8.6 Part 2F - The finished product...............................P0364.6.8.7 Part 2G - Stabi li ty ...................................................P0374.6.8.8 Part 2H - Pharmaceutical development ................P0384.6.8.9 Part 3 - In vivo and/or in vitro equivalence ...........P039

studies as proof of efficacy4.6.8.10 Part 4 - Details relating to the premises on ..........P041

which primary production is undertaken and tothe staff involved in production and testingof a biological medicine

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ADDENDA TO 4.6Addendum A - Guideline for s tab il ity test ing ................................P042Addendum B - Submission of Validation protocols and ..............P068

Validation reportsAddendum C - Exempt ion from re-identif ication and ...................P073

Re-assay of imported medicinesAddendum D - (1) Manufac turing process flow diagram..............P075Addendum E - Alcohol content o f medicines for oral ..................P077

Ingestion

4.7 CRITERIA FOR FAST-TRACK ASSESSMENT.................................P0794.7.1 Types of products that will be considered for an...............P079

expedited review4.7.2 Criteria and other factors that wil l be examined ................P079

in making a decision for fast-tracking

4.8 PROPRIETARY NAME POLICY........................................................P079

4.9 STANDARD PACKAGE INSERT INFORMATION FOR....................P082CERTAIN CATEGORIES/INGREDIENTS4.9.1 General drowsiness warning for Antihis tamines ...............P082

(Old Generation)4.9.2 General drowsiness warning for Antihis tamines ...............P082

(New Generation)4.9.3 Non-content claim: "Contains no Aspirin " .........................P0834.9.4 Dependence producing potential of medicines..................P0834.9.5 Important patient information to be included in all ............P083

package inserts o f medicines intended for Malaria

Prophylaxis4.9.6 Use of medicines dur ing pregnancy and lactation.............P0834.9.7 Package inserts/slogans ......................................................P0834.9.8 Package insert requi rements: Water for Inject ion ..............P0844.9.9 Products containing Ace-inhibitors ....................................P0844.9.10 Antibioti cs ind icated for the treatment of ...........................P084

Beta-Haemolytic Streptococcal infections4.9.11 Reye's Syndrome warning for medicines containing ........P084

Aspirin4.9.12 Benzalkonium Chloride-preserved Ophthalmological .......P084

preparations4.9.13 Package inserts for Benzodiazepine...................................P085

4.9.14 Benzodiazepine or Benzodiazepine-like .............................P0864.9.15 Beta-2 Agonists ....................................................................P0874.9.16 Standardized package inserts for Beta-Blocking agents...P0874.9.17 Warning for inclusion in Beta-Blocker and Clonidine........P089

package inserts4.9.18 Beta-Lactam Antibiotics.......................................................P0894.9.19 Bismuth containing medic ines ............................................P0894.9.20 Package inserts for Clof ibrate containing medicines ........P0894.9.21 Contrast Media - Water Soluble - Boxed Warning ..............P0904.9.22 Exemption from package insert requirements in ...............P090

respect of contact lens solutions

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4.9.23 Warning for inclusion in Potent Topical Corticosteroid ....P091package inserts

4.9.24 Products for topical use containing Corticosteroids .........P0914.9.25 Co-Trimoxazole.....................................................................P0914.9.26 Dicyclomine in infants ..........................................................P0914.9.27 Package inserts for Disopyramide preparations ................P0914.9.28 Fluoroquinolone Antibiotics ................................................P0914.9.29 Boxed warning for Glibenclamide & Gliclazide ..................P0924.9.30 Iodine and Iodine containing medic ines .............................P0924.9.31 Package inserts for Metoc lopramide preparations ............P0924.9.32 Warning to be included in the package inserts for all .......P092

products containing Metronidazole4.9.33 Non Steroidal Ant i-Inflammatory Agents ............................P0924.9.34 Package insert warning for Oestrogen-containing ............P092

Products4.9.35 Phenylbutazone & Oxyphenbutazone.................................P0934.9.36 Potassium Supplementation................................................P093

4.9.37 Long-acting Sulphonamides................................................P0944.9.38 Tamoxi fen .............................................................................P0944.9.39 Tartrazine (FD & C Yellow No 5) Warning ...........................P0944.9.40 Topical Tretinoins - statement of Pregnancy and ..............P094

Lactation4.9.41 Tricycli c Antidepressants ....................................................P0954.9.42 Statement on Eosinoph ilia Myalgia Syndrome to be .........P096

included in package inserts of L-Tryptophancontaining products

4.9.43 Codeine Warning ..................................................................P097

4.10 PROOF OF EFFICACY......................................................................P097

4.10.1 General ..................................................................................P0974.10.2 Bioavailabil ity and Bio-equivalence ....................................P100

4.10.2.1 Introduction ............................................................P1004.10.2.2 Defin it ions ..............................................................P100

4.10.3 Preliminary considerations for a generic or new ...............P101formulation registration application4.10.3.1 Registration dossier...............................................P1014.10.3.2 Standards of active ingredient(s)..........................P1014.10.3.3 Criteria for waiver of in vivob ioequivalence........P102

testing4.10.3.4 Interspecies extrapolation .....................................P1024.10.3.5 Selection of reference product..............................P102

4.10.4 In VivoBioequivalence Testing ...........................................P1034.10.4.1 Comparative bioavailabili ty s tud ies......................P103

4.10.4.1.1 Type of design ......................................P1034.10.4.1.2 Treatment and dose selection..............P1044.10.4.1.3 Trial subjects and number ...................P1044.10.4.1.4 Sample collection .................................P1054.10.4.1.5 Drug analysis ........................................P1064.10.4.1.6 Pharmacok inetics analysis ..................P1064.10.4.1.7 Statistical analysis................................P1074.10.4.1.8 Trial report ing .......................................P109

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4.10.4.2 Pharmacodynamic (Pharmacological ...................P109end-point) studies

4.10.4.3 Clinical end-point (efficacy) stud ies .....................P1094.10.5 Trial Protocol Requirements................................................P1104.10.6 Dissolution............................................................................P1104.10.7 Other......................................................................................P112

4.10.7.1 Disintegrat ion .........................................................P1124.10.7.2 Acid-neutralising capacity.....................................P1124.10.7.3 Microbial growth inhibit ion zones.........................P1134.10.7.4 Proof of release by membrane dif fus ion ..............P1134.10.7.5 Particle size distribution........................................P1134.10.7.6 Blanching test ........................................................P1134.10.7.7 Any other method ..................................................P113

4.10.8 Definitions.............................................................................P1134.10.8.1 Pharmaceut ical equivalents ..................................P1134.10.8.2 Therapeutic equivalent ..........................................P113

4.10.9 Application Control Document for Bioequivalence............P117

Studies

5. APPLICATION FOR THE AMENDMENT TO A REGISTRATION..............P120DOSSIER FOR A MEDICINE5.1 General information applicable to all applications for ..................P120

amendments5.2 Application to amend the particulars regarding proprietary.........P121

name, applicant, manufacturer, packer, final product releasecontrol and final product release responsibility5.2.1 General information..............................................................P1215.2.2 Change of proprietary name ................................................P1225.2.3 Change of appl icant .............................................................P122

5.2.4 Change of /addi tional: Manufacturer,...................................P124Packer/FPRC/FPRR

5.2.5 Change of name of appl icant only.......................................P1265.2.6 Change of address of appl icant...........................................P1265.2.7 Change of address of applicant / manufacturer / ...............P127

packer / laboratory

Appendix A1 .....................................................................................P128Appendix A2 .....................................................................................P129

5.3 Application for the amendment to a Package Insert......................P1315.4 Guidelines for amendment of registration dossier already...........P131

lodged with MCC, pertain ing to Parts 2A, 2B, 2C, 2D, 2E, 2F,2G and 2H of the application regist ration dossier5.4.1 General ..................................................................................P131

5.4.1.1 Format of submission of Amendments to ............P132MRF 1.0 Parts 2 A-H orMBR1 Annexures 2 to 11, 13 and 16

5.4.2 Permitted amendments pertain ing to Parts 2A-H...............P135of the application registration dossier5.4.2.1 Permitted amendments ..........................................P136

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5. FORMSMRF 1.0......................................................................................................P139

PART 1 A SCIENTIFIC PACKAGE INSERT........................................P141PART 1 B PATIENT INFORMATION LEAFLET ..................................P142PART 1 C FACSIMILE OR SPECIMEN OF THE LABEL .....................P143PART 1 D FOREIGN REGISTRATION ................................................P144PART 1 E PRE-CLINICAL STUDIES...................................................P145PART 1 F CLINICAL STUDIES ...........................................................P146PART 2 A (i) MEDICINES OTHER THAN BIOLOGICALS .......................P147

ACTIVE RAW MATERIAL (DEVELOPMENT CHEMISTRYAND CHARACTERISATION)

PART 2 A (ii) PRIMARY PRODUCTION LOT (BIOLOGICAL ...................P148MEDICINES)

PART 2 B (i) FORMULATION ..................................................................P149PART 2 B (ii ) FORMULATION OF THE RECONSTITUTING LIQUID.......P150

FOR THE FINAL FILLING LOT FOR BIOLOGICAL

MEDICINESPART 2 C SPECIFICATIONS AND CONTROL PROCEDURES..........P151FOR RAW MATERIALS USED IN THE MANUFACTUREOF THE FINAL PRODUCT (MEDICINES) OR FINALFILLING LOT AND DILUENT (BIOLOGICALS)

PART 2 D CONTAINER AND PACKAGING MATERIAL .....................P152PART 2 E MANUFACTURING PROCEDURES...................................P153PART 2 F FINISHED PRODUCT - FINAL FILLING LOT & .................P154

DILUENT (BIOLOGICALS)PART 2 G STABILITY DATA - THE FINISHED PRODUCT.................P155PART 2 H PHARMACEUTICAL DEVELOPMENT...............................P156PART 2 I EXPERTISE AND PREMISES USED FOR .........................P157

MANUFACTURING OF BIOLOGICAL MEDICINESPART 3 IN VIVO AND/OR IN VITRO EQUIVALENCE STUDIES .....P158

AS PROOF OF EFFICACY

MRF 2.0 MCC SCREENING FORM FOR APPLICATIONS FOR ......P159REGISTRATION OF MEDICINES

MRF 3A.0 MCC - AMENDMENT APPLICATION .................................P163MRF 3B.0 MCC - AMENDMENT APPLICATION FORM......................P166MRF 3C.0 MCC - APPLICATION FORM FOR THE AMENDMENT .....P169

TO A PACKAGE INSERT

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MCC

GUIDELINES FOR THE REGISTRATION OF MEDICINES.

NOTE: These guidelines outline the format and data requirements for preparationand submission of an application for registration of medicines, and should be read inconjunction with Medicines and Related Substances Control Act 101 of 1965, andthe regulations to this Act.

1. INTRODUCTION

The registration of medicines in South Africa is governed by the provisions andrequirements of the Medicines and Related Substances Act 101 of 1965, and the

Regulations and Guidelines published in terms thereof.

These Guidelines describe the information required with the application form forregistration of medicines. The information submitted will be evaluated by theMedicine Registration Section of the Medicines Control Council in terms of Section.

The aim of these Guidelines is to assist applicants in the preparation ofdocumentation for the registration of a new medicine (for a new chemical entity or fora multi source interchangeable product), an old medicine, or for an amendment of anexisting medicine registration or old medicine application.

It is a legal requirement that data submitted for evaluation must satisfactorilysubstantiate the quality, safety and efficacy of the product for the purposes forwhich it is intended. The Guidelines are meant to assist the applicant in meeting therequirements of the Act. It is acknowledged that in some instances scientificdevelopments may dictate alternative approaches. Hence, where the applicantchooses to deviate from a guideline, the decision must be fully explained, motivatedand justified in the expert reports submitted with the application.

Whenever there is doubt, applicants are advised to consult the Medicines ControlCouncil for confirmation and clarification before completing the application form.

Applicants must always refer to thecurrentversion of the relevant Guidelines for

the registration of Medicines in South Africabefore completing the applicationform.

Guidelines are constantly evolving as a result of scientific developments and harmonisationof the requirements of the major overseas regulatory authorities. MCC endeavours to keepabreast of such developments and keep its application requirements and evaluation policiesin line with best international practice.

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2. GENERAL

2.1 HOW TO APPLY

The Medicines Control Council requires that an application be submitted forauthorisation to market a medicine, veterinary medicine, complementary medicineand a medical device in South Africa.

These guidelines are relevant only to medicines.

2.1.1 General Information

2.1.1.1 The administrative processing of the application cannot proceed unless the basicrequirements that are checked for during the screening process, outlined in the

regulations, are complied with.

2.1.1.2 The application will be considered complete only if the submission is in the properformat, with the required data packages, the correct number of copies and theappropriate prescribed application fee.

2.1.1.3 All applications must be accompanied by a duly completed screening form thatshould be used by the applicant as a checklist for completeness before submittingan application.

2.1.1.4 Applicants should ensure that only the required and relevant information is includedin all submissions. (No raw data i.e. individual patient data are to be included

unless considered necessary)

2.1.1.5 The application will not be allocated an application number until such time that ithas been successfully screened and the non-refundable screening fee paid in full.

2.1.1.6 Once the application has been accepted, it will be logged in, acknowledged, andprocessed for evaluation. At this point, time lines will be allocated for theevaluation, and this will be communicated to the applicant.

2.1.1.7 All applications will be subjected to an in-house pre-evaluation process, from whichthe application will be forwarded to an in-house or external evaluator depending on

the nature of the application. Once the evaluation is in progress, the applicant willbe informed on when the report will be presented to the Standing Committee.

If any additional information is required for completion of the evaluation of theapplication, this will be communicated to the applicant, with time lines within whichto respond.

2.1.1.8 At no stage will the applicant be permitted to communicate directly with theevaluator. All queries and concerns must be communicated through the regulatoryauthority so that they can be logged in and processed.

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2.2 ELIGIBILITY

An application must be made by a person resident in South Africa, a closedcorporation incorporated in South Africa or a company with at least a responsibledelegated person residing in South Africa. An Applicant Master File must have been

submitted to MCC and a satisfactory Applicant Inspection performed (incorporaterelevant circular). The Managing Director or designated pharmacists are eligible tosign the applicant form.

2.3 LANGUAGE

All applications and supporting data submitted to the Medicines Control Council mustbe presented in English. Any documents in languages other than English must beaccompanied by a translation into English.

2.4 WHERE TO SEND APPLICATIONS

Applications should be posted to Private Bag X 828, Pretoria 0001 or delivered toRoom 1133, Hallmark Building, 237 Proes Street, Pretoria, where they will be loggedand acknowledged. All correspondence should be addressed to the Registrar ofMedicines. Applications received in any other manner other than as stated above willnot be considered for processing.

2.5 TRANSITIONAL CONVERSION TABLE

For application for registration of medicines the old MBR1 form for application forregistration prescribed by Act 101 of 1965 is now replaced by the MedicinesRegistration Form (MRF) 1.O. There will no longer be a separate form for biologicalmedicines.

Circulars issued before and during the transformation process referred to theAnnexures of the previous MBR1 application form. In the transitional period thecirculars will still be applicable. These Guidelines will be continuously updated toreflect policies developed by the Medicines Control Council.

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For ease of reference the following conversion table is included.

MBR1 FORM MEDICINESREGISTRATIONFORM 1.O

SUBJECT

Annexure 1 Part A, B, C PI / PIL / LabelAnnexure 2 Part 2B FormulationAnnexure 3 Part 2A Active raw material

Annexure 4 Part 2C Raw materials

Annexure 5 Part 2C Raw materialsAnnexure 6 Part 2C Raw materials

Annexure 7 Part 2F Finished productAnnexure 8 Part 2D Container and packaging

materialAnnexure 9A Part 2F Finished product

Annexure 9B Part 2D Container and packagingmaterial

Annexure 10 Part 2G Stability data

Annexure 11 Part 2E Manufacturingprocedures

Annexure 12 Part 1D Foreign registration

Annexure 13 Part 3 Part 3Annexure 14 Part 1E Pre-clinical studies

Annexure 15 Part 1F Clinical studies

Annexure 16 Part 2H Pharmaceuticaldevelopment

3. WHEN IS A PRODUCT REGARDED A MEDICINE

A product is liable for registration with the Medicines Control Council if:

a. Any of the ingredients of a product is listed in one of the Schedules to the Act

b. The product is a medicine by virtue of the definition of a medicine. TheMedicines and Related Substances Control Act, 1965 (Act 101 of 1965) defines amedicine as:

"any substance or mixture of substances used or purported to be suitable for use or

manufactured or sold for use in:

(1) the diagnosis, treatment, mitigation or prevention of disease, abnormal physicalor mental state or the symptoms thereof in man; or

(2) restoring, correcting or modifying any somatic or psychic function in man;and includes any veterinary medicine.

c. If the product falls under any of the pharmacological classifications as specifiedin Regulation 4 & 5 of the Regulations to Act 101 of 1965.

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d. In addition, the intended use of a product, even if no claims are reflected on thelabel, may still render a product registerable. If a substance is not ordinarilyeaten or drunk by man, it cannot be considered a foodstuff only because thereare no apparent claims. Legislation requires that every medicine shall beregistered by the Council before it may be sold/marketed.

Note: Unregistered medicines in terms of the Act are also included and will requiredto be registered.

4. PREPARING AND SUBMITTING AN APPLICATION FOR REGISTRATION OF ANEW MEDICINE:

4.1 CONFIDENTIALITY

The confidentiality of information submitted to the Medicines Control Council ispreserved by the Act. The MCC, Committee member or staff member may discloseto any person any information in relation to the acquisition, supply, marketing,importation, export, development, manufacture or research in connection with anymedicine, complementary medicine, veterinary medicine or medical device or anyother matter related thereto. Information may only be divulged following an orderissued by a court of competent jurisdiction. The MCC may insist on writtenconfirmation of the identification and affiliation of an individual inquiring telephonicallyor in person about a product.

4.2 TYPES OF APPLICATIONS

Medicines are divided into the following classification for purposes of evaluation anddetermining of application fees:

4.2.1 New chemical entities

4.2.2. Multi-source / generic applications (e.g. line extensions) where clinical information ispresented to support:

efficacy [and safety] of the formulation safety and efficacy of a new indication

4.2.3 multi-source / generic applications with:

dissolution studies as evidence in support of comparative efficacy

bio-availability studies as evidence in support of comparative efficacy other availability data as evidence in support of comparative efficacy

4.2.4 Other multi-source generic applications e.g. liquids/solutions not mentioned under4.2.3 above.

4.2.4 Biological medicines

4.2.5 Vaccines

4.2.6 Biotechnological products

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4.3 GUIDELINES ON SAME/SEPARATE APPLICATIONS

For the purpose of registration:

Type of applications Sameapplica-

tion

Separateapplica-tion

requiredEach individual dosage form of a particular medicine X

Deviations or variances of the active ingredient of a product X

Tablets/Capsules/Suppositories/Lozenges1. Different pack-sizes of exactly the same strength and formulation2. Different strengths and formulations3. Uncoated and coated tablets of the same strength and formulation

XXX

Syrups/Liquids/Solutions(excluding parenterals) /Creams/Ointments1. Different container sizes of the same strength and formulation

2. The same container size of different strengths and formulations

XX

Ampoules and Vials and Large Volu me Paren teral s1. Ampoules containing identical solutions of the same strength (provided the dose remains

constant) but of different volumes2. Ampoules containing solutions of different strengths3. Ampoules, single dose vials containing masses of dry powder, crystals etc. of different mass4. Ampoules, single dose vials containing the same respective masses of dry powder, crystals etc.5. Ampoules, single dose vials, as well as pre-filled disposable syringes and cartridges containing

identical solutions of the same strength and same volume of liquid6. Dental cartridges containing fluids of the same strength (provided the dose remains constant)

but different volumes7. Ampoules containing water for injection, but of different volume8. Special ampoules of dry powder and water for injections contained in the same unit, but

intended for mixing at the time of injection9. Ampoules containing identical solutions of different volumes used only as a diluent in the

reconstitution of a preparation for parenteral use10. Multi-dose vials of the same strength and formulation in different volumes11. Multi-dose vials and a single dose ampoule of the same formulation if the single-dose ampoule

corresponds to the dose indicated for the multi-dose vial;

12. Multi-dose vials containing dry powder of different mass and the same formulation, and havingthe same concentration when reconstituted

13. An ampoule of diluent packed together with any preparation including biological medicines14. Infusion solutions of the same or different volumes and of the same formulation which are

packed in containers of exactly the same type of material depending on the relevant informationsubmitted

15. Infusion solutions of the same or different volumes and of the same formulation which arepacked in containers made of different types of materials

16. A preparation, packed in plastic containers, intended to be marketed in glass containerscontaining the same volume and the same formulation provided the following data aresubmitted:-

- characteristics of the rubber stopper;- specifications for the glass;

- a comprehensive manufacturing process with particular reference to thewashing and sterilising cycles and apparatus

used;

- data on particulate matter (contamination);- stability data with reference to the effect of the pH of the solution.

X

X

X

XX

X

XX

X

X

X

X

X

XX

X

Products with the same strength and formulation but with different colours and/or flavours X

Applications containing the same active ingredient(s), and where additional indicationsare sought,where such new indications render the product in a different scheduling status, or differentpharmacological classification or have any other restrictions imposed other than the originalapplication

X

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4.4 FORM AND FORMAT OF AN APPLICATION FOR REGISTRATION

4.4.1 General

4.4.1.1 Application for registration of a medicine must be submitted on the MEDICINEREGISTRATION FORM (MRF) - Form 1 O

4.4.1.2 Each page of the application must be numbered and the printing must be clearlylegible. Paginate all pages and index according to the FORM 1.O PART e.g.2.B1 (referring to PART 2 B, first page). Double-sided copies are allowed except forpackage inserts.

4.4.1.3 The requirements with regard to metrication in accordance with the TradeMetrology Act must be applied.

4.4.1.4 The application for registration dossier must be properly indexed by the use of

clearly labelled tabs to indicate each SECTION of the dossier

4.4.1.5 Each PART must contain a complete index to that specific PART.

4.4.1.6 The application for registration must be properly bound on the left side as thisallows for easy update/addition of pages. Binding is left to the discretion of theapplicant; however, the use of lever-arch files is not accepted.

4.4.1.7 The correct number of copies of applications and additional documents required forprocessing of the application must be submitted in the format detailed below.

4.4.1.8 The accompanying covering letter must be bound into each application dossier.

4.4.1.9 All applications must be accompanied by a duly completed PharmaceuticalEvaluation report that must reflect the page number of the dossier where thespecific information is contained. A copy of this must be bound in each copy of theapplication for registration dossier.

4.4.1.10 Each pre-screening application must be accompanied by a completed pre-screening form, Form 2.O, and a non-refundable pre-screening fee.

4.4.1.11 After completing the pre-screening process successfully, each application must beaccompanied by the appropriate application fee.

4.4.1.12 The containers/boxes in which documentation is submitted to the MCC must beclearly labelled. The following details should appear clearly on each box:

the contents of the container e.g. Parts, samples, cover letters etc. product identification code for each application applicant name number of boxes e.g. 1 of 10 type of application e.g. fast-track, AMRP

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4.4.2 Presentation of copies and number of copies required

4.4.2.1 Presentation of copies

In order to facilitate processing of the application for registration it is required that

certain Parts of the application for registration be duplicated and submitted asprescribed in the pre-screening approval letter together with the application fee. Alldocumentation must be in English or the original document must be accompaniedby a translation into English.No additional documentation other than that which has been clearly stipulatedbelow may be bound in any of the files identified below.

(i) File 1 (With or iginal submission for screening)Copy of the latest Inspection Report (not older than 4 years) from the MedicinesControl Council for the manufacturer of imported productsInspection flow diagramWHO certificateCertificate of analysis for the sample submittedBatch manufacturing documents for the sample submitted

(ii) File 2

Covering letter

Pharmaceutical evaluation reportParts 1 A, 1C, 1D, 2A, 2B, 2C, 2D, 2E, 2F, 2G and 2H

(iii ) File 3Covering letter

Application for registration front pageParts 1A, 1C, and 2B

(iv) File 4Covering letter

Application for registration front pageParts 1A, 1C, 2B, 2E, and 2F

(v) File 5

Covering letter

PART 2A

(vi) File 6

Covering letter

SBRA, if applicable

(vii)File 7Covering letter

Application for registration front pageParts 1 A, 1C, and 1D.

Approved foreign package insert/sClinical and Toxicological Expert reports

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(viii) File 8

Covering letterApplication for registration front pagePharmaceutical evaluation report

Parts 1A, 1C, 1D, 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H, Pharmaceutical Expertreport

4.4.2.2 SBRA (Summary Basis of Registration Application)

a) General

To expedite the review process of the safety and efficacy of medicines it isrequired that an Summary Basis for Registration Application (SBRA)accompany each application for registration where a clinical/ toxicologicalexpert report is not presented and clinical/ pre-clinical data is submitted insupport of the application.

The SBRA is intended to be a very brief and concise document containingthe core data on the basis of which the applicant intends to obtain registrationfor the product. It is to be presented as a summary only: therefore no articles,reports etc. are to be incorporated into the SBRA nor should such papers beattached to it either, as these belong with the full submission.

Adaptation to the format prescribed in b) below, to suit each individualproduct/dosage form at the discretion of the applicant, where specific itemsare not applicable, may be necessary. Applicants are kindly requested toleave a wide left-hand margin (of at least 5 cm), for office use.

b) SBRA format

Refer to Form xxxx for details and a completed hypothetical example.

4.5 FEES.

For medicine registration the following fees are relevant:

i) A pre-screening feeii) An application fee, accompanying the application for registration;iii) A registration fee, payable when the application complies to all requirements

for registration, and is payable before a registration certificate is issued;

iv) An annual retention fee to maintain registration.v) A fee to cover any amendments to the dossier or certificate.

The fees are determined according to the type of application and will be published inthe Government Gazette.

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4.6 REQUIREMENTS FOR COMPLETION OF AN APPLICATION FORREGISTRATION DOSSIER.

4.6.1 Adminis trat ive Data (front page)

Details as per application form must be completed.

i) Business address in relation to a business that is carried on in the Republic ofSouth Africa, means the full physical address of the premises where such businessis conducted.

ii) Proprietary name means the name which is unique to a particular medicine andby which it is generally identified and which, in the case of a registered medicine, isthe name approved in terms of section 24 (8) in respect of such medicine. (Refer tosection 4.8 of these guidelines.) It should be noted that medicines which are notidentical in composition or strength are not regarded as the same medicine

iii) Dosage form: Select the most appropriate dosage form from this list, whencompleting the administrative data. This dosage form will also be reflected on theregistration certificate. For the purpose of the package insert application may bemade to give more detailed description of the dosage form e.g. chew tablet, slowrelease tablet etc.

Blood bag Globule Pessaries

Bone cement Granules Plaster

Beads Gum Pods

Capsules Implant Powder

Cleansing bar Infusion (parenteral) Shampoo

Combination of dosage forms Inhaler Soap

Condom Injection Solution

Cone Insert Sponge

Cord Intra-uterine device Spray

Cream Jam Stick

Cardioplegic solution Leaves Suppository

Chip (dental) Liquid Suspension

Decoction Lotion Swab

Dialysate Lozenge Syrup

Diluent for injection Lump Tablet

Dental material Medical device Tampon

Dressing Mouthwash Test kit

Drops Nasal inhaler Tincture

Elixir Nasal spray Toothpaste

Emulsion Oil Towelette

Enema Ointment Transdermal therapeutic syste

Foam Ovule Vaginal ring

Gas Paste Wafer

Gel Pellet

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iv) Descriptive name of biological medicine e.g. viral vaccine, viral antiserum,bacterial vaccine, bacterial antiserum, allergen, immunoglobulin or bloodproduct, as given in a recognised pharmacopoeia or where such name doesnot exist, a name determined by the MCC

v) The name and full physical address, including the country, of themanufacturer/s, packer/s, final product testing laboratory/ies (FPRC) andfinal product release responsibility (FPRR).

The Administrative data of the Registration dossier must be correlated withthe data reflected in the relevant Parts/Annexures as follows:

Manufacturer PART 2 E (Annexure 11)

Packer PART D & E (Annexures 9B and 11)

Testing laboratory/ies (FPRC) PART 2 F (Annexure 9A) (It is proposedthat this is stated in full on the front pageonly, and referred to only as FPRC in

Annexure 9A)

Final product release responsibility(FPRR)

PART 2 F (Annexure 9A) It is proposedthat this is stated in full on the front pageonly, and referred to only as FPRR in

Annexure 9A)

vi) Pharmacological classification. Refer to regulations ........

vii) Particulars with regard to Section C of the front page of the MRF must besupplied by the applicant in cases where an application for registration of amedicine has already been submitted

viii) The responsible person filling in the form should provide his e-mail address.

4.6.2 PART 1 A -PROFESSIONAL PACKAGE INSERT

The professional package insert is regarded as the document that ensures the safeand effective use of the medicine under most circumstances. It presents a scientific,

objective account of the medicines uses and limitation as established by thesupporting evidence. Ensure that all statements are adequately cross-referenced. Nopromotional material may be included. Promotional statements and comparisons toother agents, indicative of any potential advantage over competitors will not beallowed.

After registration, the professional package insert may not be altered without theapproval of the Medicines Control Council. In the case of safety-related matters theCouncil should be informed immediately, with submission of an approved professionalpackage insert, a proposed amended package insert and the evidence/motivation forthe change. (refer to Section 5.3 Application for the Amendment to a package insert).

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The professional package insert must contain the required information under theheadings as prescribed in the Regulations:

1. Scheduling status.

The scheduling status as prescribed in the Regulations to Act 101 should beincluded here.

2. Proprietary name

That is the trade name of the medicine as approved by the Medicines ControlCouncil as stipulated in the Act. Such proprietary name shall be unique to aparticular medicine. It should further comply with the guidelines to proprietarynames as detailed in this document

3. Dosage formThe dosage form should be chosen from one of the following: (Refer 4.6.1 (iii)of Administrative data dosage forms)

4. Composition.

The following information is required under this heading:

(i) the approved name of each active ingredient and the quantity thereofcontained in a dosage unit or per suitable mass or volume or unit of themedicine;

(ii) the approved name and percentage of any bactericidal or bacteriostaticagent which has been added to the medicine as a preservative;

(iii) the approved name of any anti-oxidant contained in the medicine;

(iv) the quantity of ethyl alcohol contained in the medicine if intended for oralor parenteral administration to humans as given in PART 2 B of theapplication for registration form;

(v) the warning in block letters 'CONTAINS TARTRAZINE' if the medicinecontains tartrazine and if intended for administration to humans;

(vi) the approved name of any other inactive ingredients contained in theformulation;

The "approved name" is defined in the Act, and in relation to a medicine itmeans the internationally recognised name of such substance, or such othername as the Medicines Control Council may determine, which is not a brandname or trade name registered in terms of the Trade Marks Act, 1993 (Act 194of 1993)

5. Pharmacological classif ication.

The category as well as the description of the classification as required byRegulation needs to be reflected here.

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6. Pharmacological action.

A description of the pharmacological action of the medicine, especially inhumans is required. The pharmacokinetic properties of the medicine shall bedescribed, where applicable under a subheading: Pharmacokinetics. Allstatements in the submitted draft of the professional package insert shall be

cross-referenced to the actual pages of the documents attached to PART 1F &and PART 3 of the application form and/or to the standard books of reference.The standard books to be referred to are the latest edition of Goodman &Gilmans: The Pharmacological Basis of Therapeutics and the United StatesPharmacopoeia Drug Index.

7. Indications.

The indications shall be clearly stated to avoid confusion. It should be statedwhether the treatment is curative, palliative or adjunctive and should includeany statement imposed by the Medicines Control Council.

All claims in the submitted draft of the package insert shall be cross-referencedto the actual pages of the documents attached to PART 1F & and PART 3 ofthe application form and/or to the standard books of reference. The standardbooks of reference referred to are the latest edition of Goodman & Gilmans:The Pharmacological Basis of Therapeutics and the United StatesPharmacopoeia Drug Index

8. Contra-indications.

This should state situations where patients should never or generally not betreated with the agent. Cases where patients should never be treatedshould bespecifically outlined.

All safety aspects in the submitted draft of the package insert shall be cross-referenced to the actual pages of the documents attached to PART 1F & andPART 3 of the application form and/or to the standard books of reference. Thestandard books of reference referred to are the latest edition of Martindale: TheComplete Drug Reference and the United States Pharmacopoeia Drug Index.

9. Warnings.

This section should be reserved for pertinent safety issues or any precautionsthat need the specific attention of the prescriber or the user. Information underthis heading shall be cross-referenced to the actual pages of the documentsattached to PART 1F & and PART 3 of the application form and/or to thestandard books of reference. The standard books of reference referred to arethe latest edition of Martindale: The Complete Drug Reference and the UnitedStates Pharmacopoeia Drug Index.

10. Pregnancy and Lactat ion :

It should be clearly indicated whether pregnancy and lactation are contra-indicated or whether limited or no information in pregnancy and lactation isavailable.

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In the case of a medicine where the safety of a medicine with regard to its usein pregnancy has not been established, the following statement must beincluded: The safety of this medicine in pregnant and lactating woman has notbeen established. While applicants may reformulate this statement to suit theirown style, deviation of the essentials of this message will not be acceptable.

11. Dosage and directions for use.

The dosage and dosage interval should be clearly described. The maximumdosages should be clearly stated where relevant. Any recommended children'sdosage shall be indicated where applicable. When relevant, the dosages andwarnings for special population groups should also be clearly addressed, e.g.the elderly or population groups such as the renally impaired etc. Directions forreconstitution/dilution must be clearly indicated where relevant including thetime period and conditions for storage after reconstitution/dilution. Suitablediluents must be indicated

Proposed dosages in the submitted draft of the package insert shall be cross-referenced to the actual pages of the documents attached to PART 1F & andPART 3 of the application form and/or to the standard books of reference.Thestandard books of reference being referred to are the latest edition of Goodman& Gilmans: The Pharmacological Basis of Therapeutics, Martindale: TheComplete Drug Reference and the United States Pharmacopoeia Drug Index.Stability claims on reconstituted/diluted products and storage thereof must besupported by data in PART 2G .

12. Side-effects and special precautions

An indication of the severity, clinical importance and frequency should be given.Frequency should be reflected as frequently and less frequently. Alternatively,the definitions according to the CIOMS classification may be used. (referencedocument required for CIOMS listing)

All the side-effects which are likely to occur for each of the active in the dosageform shall be described, unless the Medicines Control Council decidesotherwise.

Include known clinically relevant interactions and other potentially seriousinteractions based on the pharmacology of the medicine. It is useful to groupinteractions according to outcome e.g. potentiation or reduction in effect and toexplain the mechanism of the interaction if it is known. All safety aspects in the

submitted draft of the package insert shall be cross-referenced to the actualpages of the documents attached to PART 1E, 1F and PART 3 of theapplication form and/or to the standard books of reference. The standard booksof reference referred to are the latest edition of , Martindale: The CompleteDrug Reference and the United States Pharmacopoeia Drug Index.

13. Known symptoms of overdosage and Particulars of its treatment.

The symptoms and signs of overdosage should be stated including specificrecommendations for treatment, when such treatment is accepted practice. Allsafety aspects in the submitted draft of the package insert shall be cross-

referenced to the actual pages of the documents attached to PART 1F & and

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PART 3 of the application form and/or to the standard books of reference. Thestandard books of reference referred to are the latest edition of Martindale: TheComplete Drug Reference and the United States Pharmacopoeia Drug Index.

14. Identification.

A complete description of the medicines physical appearance. This shouldcorrespond to the specifications of the final product.

15. Presentation.

The quantity, volume or mass per package as well as colour and type ofpacking material e.g. amber glass bottle/ blister;

16. Storage instruct ions.

The storage instructions should be practically formulated and should quotestorage temperatures and other relevant storage conditions e.g. .Keepcontainer well closed, do not discard drying agent for hygroscopic products,or Do not remove from container. for light sensitive products

Protection that may be offered by a Particular container shall not be regardedas a reason for omitting certain storage instructions.

In-use storage instructions must be stated, where relevant.

The words 'Keep out of reach of children' must be included in all packageinserts

17. Registration number (or reference number).

The number as allocated by the Medicines Control Council.

18. Name and Business address of the Applicant.

The physical address of the Applicant is required. Business address should bedefined as stated above.

19. Date of noti fication of approval of the professional package insert.

This date refers to the date on which the package insert was approved by theMedicines Control Council. Subsequent printing dates should only be used when theMedicines Control Council has approved changes.

The professional package inserts of multi-source equivalent products shall beessentially similar to the innovators package insert, a recently approved packageinsert of the same active ingredient(s), the standard books of reference and /or amonograph, when relevant, for that category of medicines.

Note: Any deviations from the requirements as described in these guidelines willrequire approval by the Council prior to implementation.

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4.6.3 PART 1 B -PATIENT INFORMATION LEAFLET

The patient information leaflet must be written in easily understandable English, beconsistent with the professional package insert and in accordance with the regulations,in terms of the legibility, language and format. (refer to Addedum for lay terms).

Each immediate contained should have a patient information leaflet and should reflectthe following:

(a) Scheduling status

That is the scheduling status of the medicine as determined from time to time by theregulation;

(b) Proprietary nameand dosage form of the medicine;

When umbrella / brand names are used, the applicants would be responsibleto include precautionary statements of usage of these products simultaneously

so as to inform patients of the correct usage and potential safety concerns.Example, if a range of products under the same umbrella name containsparacetamol, it should not be used in conjunction with another products in therange also containing paracetamol.

(b) What this medicine contains

The composition of the medicine, that is -

(i) the approved name of each active ingredient and the quantity thereof containedin a dosage unit or per suitable mass or volume or unit of the medicine;

(ii) all inactive ingredients must be listed qualitatively;

(c) What this medicine is used for

The registered indications for use of the medicine as accepted by the Council in theprofessional package insert;

(e) Before taking this medicine the following information should be included

contra-indications precautions warnings eg warnings concerning sedative properties of the medicine, warnings

concerning the risks involved with sudden withdrawal of the medicine etc must beincluded here

interactions General statement must be included in this section:

If you are taking medicines on a regular basis, concomitant use of the medicinemay cause undesirable interactions. Please consult your doctor, pharmacist orother health care professional for advice.If you are pregnant or breast feeding your baby while taking this medicine pleaseconsult your doctor, pharmacist or other health care professional for advice.

(f) How to take this medicine

The recommended dosage must be included here. (Any special information which thepatient may require for the proper and safe use of the medicine should be provided)

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Information on what to do in specific circumstances, for example in the case of amissed dose, an unexpected reaction or in the case of an overdose should be included.Do not share medicines prescribed for you with others. must be stated. In the eventof overdosage, consult your doctor or pharmacist. If neither is available, rush thepatient to the nearest hospital or poison control centre:

(g) Side-effects

This section should be in laymans terms for the consumer to understand -

(i) the side-effects associated with the use of the particular medicine listing themore frequently side-effects firstly.

(ii) those side-effects which can be easily recognised by the patient;(iii) the following general statement: Not all side-effects reported for this medicine

are included in this leaflet. Should your general health worsens while takingthis medicine, please consult your doctor, pharmacist or other health careprofessional for advice.

(h) Storage and disposal information -

Should contain information on how to store the medicine properly and how to dispose ofunused medicine. The statement Store all medicines out of reach of children. must bestated.

(i) Presentation

The number, volume or mass per package unit must be mentioned. A description ofthe packaging material (i.e. bottle, blister, etc.) should be included.

(j) Identification of the medicine

A complete description of its physical appearance of the medicine.

(k) Registration number

The number allocated to the medicine;

(l) The name, business address and telephone number of the applicant

(m) The date of publishing the patient info rmation leaflet

Note:The responsibility for ensuring that the patient information leaflet is in line with theregulations, including assurance that the patient information leaflet corresponds with

the information in the professional package insert will essentially rest with theapplicant. Any deviations from the requirements as described in these guidelines willrequire approval by the Council prior to implementation.

4.6.4 PART 1 C- AN EXAMPLE OR FACSIMILE OF THE LABEL

An example of the facsimile of the label must be included here. Requirements eg fontsize as stipulated in the Regulations should be adhered to.

The following inclusions are permitted:

For state use only Not for sale for tender items

Professional sample samples for professionals

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Note: Any deviations from the requirements as described in these guidelines willrequire approval by the Council in terms of Section 36 of the Act, prior toimplementation.

4.6.5 PART 1 D - FOREIGN REGISTRATION

4.6.5.1 A list of countries in which an application has been lodged and the status of suchapplications shall be furnished. Countries that are members of the PER Scheme,other EU countries and the USA should specifically be identified. Approvals (withindications), deferrals, withdrawals and rejections should be stated. If the medicinehas already been registered in any of the countries mentioned above, a copy of theregistration certificate and the approved package insert (data sheet) as well as theconditions of registration, should be provided.

4.6.5.2. It should be stated whether data packages submitted in the countries in 4.6.5.1 are

essentially similar to those submitted to the Medicines Control Council, including theproposed indications.

4.6.5.3. The Medicines Control Council should also be notified of any rejections, withdrawalsor approvals of applications in the EU commission (mutual recognition process),

Australia Canada, the Netherlands, Sweden, UK and USA during the evaluationperiod. Where the rejections or withdrawals relate to safety matters details in eachcase should be provided.

4.6.6 PART 1 E - PRE-CLINICAL STUDIES

4.6.6.1 Guidelines are constantly evolving as a result of scientific developments andharmonisation of the requirements of the major overseas regulatory authorities. TheMedicines Control Council endeavors to keep abreast of such developments andkeep its application requirements and evaluation policies in line with bestinternational practice.

4.6.6.2. Legislation to be read in conjunction with these guidelines is:

The Act

Application form - PART 1E

Regulations

4.6.6.3 For Biological Medicines the applicant must include details (published orunpublished) of the results of any trials or experiments carried out in man or in theanimal target species, or carried out in other animals, that establish and confirm thesafety of the medicine, with particular reference to the dosage and directions for use.

4.6.6.4 For medicines other than biological medicines

In PART 1 E the applicant needs to address the Pharmacology and Toxicology of themedicine;

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4.6.6.4.1 Pharmacology:

4.6.6.4.1.1 Pharmacodynamics:

i) The primary effects of the medicine, with results in different animal species(ED50values if possible) must be addressed.

ii) Comparison of the effects of the product with that of reference products isvaluable information.

iii) Where relevant, the pharmacology of significant metabolites must beinvestigated.

iv) Other pharmacodynamic effects, especially those that might be ofsignificance for adverse effects of the medicine, should be studied anddescribed.

v) Interaction studies, where relevant, should be included.

4.6.6.4.1.2 Pharmacokinetics:

i) To assist in the interpretation of toxicological studies, it is important tocompare the exposure of the animals used in the toxicity testing with thatanticipated in patients given the proposed therapeutic dose regimen.

ii) PART 1E should, therefore, include comparative pharmacokinetics data,which includes Cmax(after a single dose and at steady state) and AUC datafor the parent drug and major/active metabolite(s), where relevant, inhuman and all species used in the toxicity, carcinogenicity and reproductionstudies.

iii) These data should preferably be obtained from the toxicity studies.

iv) Other information (for example, tand clearance), may be of value whereimportant differences have been shown between animals and man.

4.6.6.4.2 Toxicology:

i) A summary or expert report must be submitted for each animal speciesstudied, including sex, number of animals, dosage, route of administration,duration of study and toxic manifestations.

ii) Important points pertaining to preclinical toxicity to consider and addressare:

Dose-response relationship

Time-response relationship

Species specificity

Target organ specificity

Reversibility / irreversibility of toxic effects.

iii) Medicines that show specific toxicological effects, such as immunotoxicity,hepatotoxicity or neurotoxicity, should be investigated further, taking intoaccount the points under ii)

iv) New medicines which belong to classes that are known to produce aparticular toxic effect, should be tested appropriately.

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v) The possible mechanism(s) underlying the changes observed in toxicitystudies need to be investigated and addressed.

vi) Due to the local climatic conditions the phototoxic potential of a medicineshould be considered.

vii) The points to address in the reproduction studies are: fertility, embryonal

toxicity, teratogenicity, peri- and postnatal effects.

4.6.6.5 The details of results from tests shall depend on the state of scientific knowledge atthe time when the application is lodged. Any interim and final results of ongoingstudies must be submitted as soon as these data become available.

4.6.6.6. A new route of administration or an increased daily dose of known excipients mayresult in the need for additional pharmaco-toxicological data.

4.6.7 PART 1 F - CLINICAL STUDIES

4.6.7.1 Guidelines are constantly evolving as a result of scientific developments andharmonisation of the requirements of the major overseas regulatory authorities(USA, UK, Sweden, EU, Canada, Netherlands, Australia). The Medicines ControlCouncil endeavors to keep abreast of such developments and keep its applicationrequirements and evaluation policies in line with best international practice as perintroduction. Please refer the Medicines Control Council Clinical trials guidelines.

4.6.7.2 Legislation to be read in conjunction with these guidelines are:

Act

Application form - PART 1 F.

Regulation.

4.6.7.3 A medicine cannot be marketed in South Africa without being registered by theMedicines Control Council. Data that satisfactorily establish the quality, safety andefficacy of the medicine, for the purposes for which it is to be used, must besubmitted for evaluation by the Medicines Control Council before consent can begranted.

Note: Old medicines that have been lodged with MCC and allocated a referencenumber are allowed to be marketed.

4.6.7.4 All applications and amendments must be accompanied by a covering letter. Theletter should briefly and succinctly state the purpose of the application.

4.6.7.5 All data must be submitted on A4 sized paper in compliance with the regulationsand each PART of the application should contain a detailed index. The data mustbe presented in such manner that allows for easy cross-referencing to the index,other studies and the professional package insert. [Applicants wishing to submit

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data in electronic form should discuss the requirements with the Registrar of theMedicines Control Council].

4.6.7.6 Data presented in support of the safety and efficacy of the medicine must bederived from clinical trials conducted in compliance with internationally accepted

GCP guidelines. The studies must be properly designed and conducted and mustbe of acceptable statistical power. Where relevant, results published in peerreviewed scientific journals should be submitted.

4.6.7.7 Clinical trials should be conducted with the formula as applied for. Where studieshave been conducted with different formulations, comparative equivalence studiesneed to be submitted to enable extrapolation to the formula intended for themarket.

4.6.7.8 Normally individual patient data from clinical trials need not be included in an

application dossier (except in the case of bioequivalence studies where theindividual plasma/serum concentrations and derived pharmacokinetic data are tobe supplied). Tabulated individual patient data may be included in the application ifthe applicant considers it appropriate.

4.6.7.9 Studies designed to demonstrate the pharmacodynamics of a medicine shouldaddress the effect of the medicine, duration of effect, dose-response and tolerance.

Additional action on the central nervous system, respiration, circulation, bloodchemistry, liver and kidney function, etc., should be considered at the proposedtherapeutic dose(s).

4.6.7.10 Pharmacokinetics studies should be conducted with the formula as applied for. Allrelevant pharmacokinetics data shall be given, such as amount and rate ofabsorption after various routes of administration, plasma concentration, half-lives,drug clearance, drug metabolism as well as the routes and rates of excretion.

The pharmacokinetics studies are to be carried out with both single dose andmultiple doses to steady state within the recommended dosage range.

Where applicable the plasma concentration(s) producing pharmacological and/ortherapeutic effects, as well as adverse effects should be presented.

Possible dose-dependent pharmacokinetics needs to be addressed.

4.6.7.11 The trial design of the relevant clinical studies should be such that the safety andefficacy of the medicine can be established in comparison to either placebo and/ora registered medicine in UK, USA, Sweden. Netherlands, Canada, Australia andEU. The description of the studies must include patient population size anddiagnosis, in- and exclusion criteria, test and comparator drug dosage regimensand duration of therapy, parameters assessed for efficacy and safety, includingresults of special investigations. Detailed statistical results must be presented. Itshould be noted that the randomised, double-blind, placebo and/or active controlledtrial design remains the gold standard for establishing the efficacy and safety ofmedicines.

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4.6.7.12 The dosage of the active comparator (refer to Section 4.10 Bio-equivalence of anew multi-source medicines) must be in line with that approved for the specificindication.

4.6.7.13 The patient drop-outs must be addressed, including the time of and reason(s) for

withdrawal.

4.6.7.14 To enable evaluation of safety of the medicine it should be noted that the long-termsafety, particularly for medicines proposed for chronic use, needs to be addressed.

4.6.7.15 While a product is being evaluated, applicants should notify MCC of:

i) any approvals, rejections or withdrawals of applications in other countries and

ii) any serious adverse effects observed for the first time, or at a frequency whichhas become a concern.

4.6.7.16 During the evaluation period, if new significant data becomes available that iscontrary to the use of the medicines, applicants must notify Council. With thisnotification the applicant should state its intention.

4.6.7.17 An application also needs to be submitted in the same format as outlined in PART1F form as well as the relevant regulations and guidelines for a registeredmedicine, when the following amendments are requested:

i) Deletion of contra-indication.

ii) Addition of or amendment(s) to indication(s).

iii) Dosage amendments.

iv) Deletion of safety related information, i.e. warnings and precautions.

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4.6.8 PART 2: PHARMACEUTICAL AND ANALYTICAL REQUIREMENTS

The technical requirements for pharmaceutical and analytical information are divided into

several parts in the application form as follows:

PARTS TITLE CONTENTS

2A ACTIVE INGREDIENT(S) (1) CHEMICAL

(2) SOURCE (Name & address)

(3) ACTIVE INGREDIENTFILE (AIF)

(4) CERTIFICATE OFANALYSIS (COA)

(5) PROOF OF CHEMICALAND PHYSICALEQUIVALENCE

2B FORMULATION (1) UNIT FORMULA

2C RAW MATERIALS(1) SPECIFICATIONS

(2) CONTROL PROCEDURES

2D CONTAINER & PACKAGINGMATERIAL

(1) SPECIFICATIONS


2E MANUFACTURINGPROCEDURE

(1) MANUFACTURING

(2) PACKAGING

(3) VALIDATION PROTOCOL

(4) INSPECTION FLOWDIAGRAM

2FFINISHED PRODUCT (1) SPECIFICATIONS & LIMITS


(3) CERTIFICATE OFANALYSIS (CoA)

(4) VALIDATION

2G STABILITY (1) PROGRAM

(2) DATA

(3) SHELF-LIFE

2H PHARMACEUTICALDEVELOPMENT

(1) FORMULATIONS

2) PHARMACEUTICALEXPERT REPORT

3 IN VIVO AND/OR IN VITROEQUIVALENCE STUDIES ASPROOF OF EFFICACY

(1) PURPOSE OF STUDY

(2) REFERENCE PRODUCT

(3) METHOD

(4) DATA

(5) DISCUSSION

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4.6.8.1 PART 2A - THE ACTIVE RAW MATERIAL (DEVELOPMENT CHEMISTRY AND

CHARACTERIZATION)

4.6.8.1.1 The approved name(INN) or chemical description of the active ingredient(s) mustbe stated including the structural formula, the empirical formula and the molecularmass.

4.6.8.1.2 The solubility of each active ingredient must be stated in terms of a unit part of thesubstance per number of parts of the solvent, or in unit mass of substance in agiven volume of solvent, at a specific temperature. The solvents must include waterand the solvent(s) relevant to the formulation. Storage requirements of the rawmaterial and retesting period must be stated

4.6.8.1.3 The name and physical address of each manufacturer being applied for must be

stated. If one or more brokers are utilised, the name and physical address of eachbroker must be stated. Brokers must be clearly differentiated from manufacturersof raw materials. No active ingredient from any source other than the approvedsource(s) may be used.

4.6.8.1.4 A Ph. Eur. Certificate of Suitability or Active Ingredient File (AIF) including thefollowing information must be submitted:

The name and physical address of the manufacturer

History of the manufacturer (how long in existence, activities, types ofmaterials/products manufactured etc.)

The approved name of the relevant active

The chemical name and chemical structure

A description of the pathway of synthesis using a flow chart which includes thestarting materials, reagents, solvents, conditions, processes, duration oftreatments, intermediates formed and any other relevant aspects. Note thatspecifications and control procedures for substances used in this process arenot required.

Occurrence of isomers and polymorphism.

A description of impurities. Distinguish between actual and possible impurities

A description of possible degradation products

The physical and chemical properties of the active raw material

The detailed methods used for identification and assay, includingchromatograms wherever relevant

CoA results of at least two production batches

Results of stability studies performed on the raw material obtained by the abovemethod of synthesis. The conditions under which degradation products areformed must be included. A stability-indicating assay must be used in thesestudies, must be described in full and supporting chromatograms includingwherever relevant.

Stability data on new chemical entity raw materials generated according to the ICHguidelines (see Addendum A) Stability data derived from at least two production

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batches of well-known actives(generic), stored at accelerated conditions for at least6 months and for at least twelve months stored at the maximum recommendedstorage.

4.6.8.1.5 Certificates of analyses (CoA)

A CoA (a), which accompanied a batch of active raw material, received by themanufacturer of the final product must be submitted. Additionally, a CoA oranalytical report, reporting on the statutory identification and assay and any othertest which is specified in Annexure 4, but is not reported on in (a), issued by or onbehalf of the manufacturer of the final product, must be submitted.

4.6.8.1.6 Equivalence of active raw materials obtained from different manufacturers or bydifferent methods of synthesis.

When more than one manufacturer is being applied for or when an additional orchange in manufacturer is applied for, the following must be submitted in lieu of

each manufacturer:

A. An AIF or Ph. Eur. Certificate of Suitability.

Note that if the identical method of synthesis is used by each manufacturer(or the same parent company) or at different sites of the same manufacturer, astatement to this effect will suffice.

B. A communication pointing out the differences in the methods used, and thedifferences with regard to the impurity profiles.

C. CoA's issued by each manufacturer (approved source and additional source)and the analytical reports issued by the laboratory of the manufacturer of the

final product.D. Critical tests e.g. identification, assay, particle size, optical rotation, residual

solvents, etc performed on samples from each source to demonstrate physicaland chemical equivalence, must be performed by a laboratory (either thelaboratory of the manufacturer to an independent laboratory, for example). Thesame analytical methods must be used for these tests.

4.6.8.1.7 For biological medicines, specifications of raw material used in the primaryproduction lot are required:

a) In the case of a biological medicine of microbial origin, history and preparation

of the seed lot must be described with specific reference to the tests that arecarried out on such a seed to lot establish and maintain the integrity thereof.

b) Particulars of the composition of all culture media used in the preparation andtesting of a biological medicine must be given.

c) Particulars must be given of the other biological source material from which abiological medicine (e.g. blood fractions) is extracted, including origin of cultureor blood.

d) Specifications must be at the level of the latest editions of recognisedpharmacopoeial reference books and any deviations must be fullysubstantiated.

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e) Reference only to the recognised pharmacopoeial reference books shall beacceptable where the specifications correspond to the reference.

4.6.8.1.8 For biological medicines full details of tests carried out on the raw materials mustbe provided.( Refer to WHO guidelines on Biologicals)

4.6.8.2 PART 2B - FORMULATION

4.6.8.2.1 The formula must show the approved names (INN) or chemical names of all activeraw materials and excipients (inactive ingredients) including those that do notnecessarily remain in the final product after manufacturing, such as granulatingagents and gases used for flushing, etc. For excipients that do not appear in thefinal product, this must be so indicated. Each raw material must be listed togetherwith its quantity per dosage unit. This would include the vehicle(s), solvent(s) orbase(s). In the absence of an approved name (INN) or chemical name, a

chemical descriptionor characterisation of the substance must be given. Specialtechnical characteristics of the excipient, where applicable, must be indicated suchas lyophilised, micronised, solubilised, emulsified, etc.

Some excipients are single chemical entities while others are combinations. Someare chemically transformed, e.g. modified starch. For excipients that are mixtures ofchemically related or unrelated components, e.g. polyol esters (mixture of mono-,di- and triesters), direct compression excipients or film coating material, orexcipients that are chemically modified, the dossier must specify the nature andquantity of each component.

4.6.8.2.2 A product may contain more than one active ingredient provided that

i) each active ingredient makes a contribution to the claimed indications;

ii) the effect of combining the active ingredients in one product does not decreasethe safety, stability or efficacy of the product; and

iii) the product provides rational concurrent therapy for a significant proportion ofthe target population. e.g. tuberculostatic combinations

4.6.8.2.3 The purpose of each inactive raw material must be stated briefly. If the excipient isused for multiple purposes in the formulation, each purpose must be mentioned.

4.6.8.2.4 Any overages for the active ingredient must be stated separately and the reasonsfor it must be given. The label claim quantity must be stated and the excessquantity indicated as the actual amount or as a percentage. For example, 500 mg +5 mg (=1%) overage* .

*Use the asterisk to explain the purpose of the overage.

4.6.8.2.5 Where a potency adjustment for the active ingredient has to be made, a statementto the effect that the actual quantity of the active will depend on the potency, andthe excipient(s) that will be used to adjust the bulk quantity must be mentioned, aswell as the manner in which the adjustment will be made. Potency calculations,

where applicable, must be shown in PART 2E (Manufacturing Procedures).

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4.6.8.2.6 Flavouring and colouring agents, because of their complexity in many instances,may be described in terms of their main constituents only, provided that appropriatechemical identification and characterisation for them is given in the relevantsection. The Index Numbers of colourants must be included in the formula. The use

of dyes, printing ink, coating materials, flavourants and organic solvents is subjectto the same safety and quality requirements that apply to medicinal substances.

4.6.8.2.7 The content of alcohol, if included, for oral and intravenous medicines must notexceed the following maximum concentrations:

i) 0,5% (v/v) ethyl alcohol for children under 6 years of age;

ii) 5,0% (v/v) ethyl alcohol for children of 6 to 12 years of age; and

iii) 10% (v/v ethyl alcohol for adults and adolescents over 12 years of age.

The presence of alcohol in the product must be declared, and the concentrationstated, on the label, the package insert and in the patient information leaflet. (Referto Addendum F)

Products where higher concentrations of alcohol are required for specific purposes(e.g. plant extracts or where solubility or preservation might be problematic) may beexempted from the above alcohol concentration limits provided that justification andmotivation for it is submitted together with proof that the dosage will not result inblood alcohol levels of 25 mg/dl (milligram per decilitre) or higher.

4.6.8.2.8 Where the vehicle is added up to the required volume or mass of the product, the

actual or estimate quantity of that vehicle may be stated. However, expressionssuch as add up to and q.s. are acceptable. Solutions added to adjust the pHmust be described in terms of composition and strength (normality, molarity, etc.),but it is not necessary to state the actual quantity added as none may be added oronly minute quantities may be needed.

4.6.8.2.9 For biological medicines the details of any solution supplied by the manufacturer forthe reconstitution before use of a dried biological medicine that is offered for sale ina dried form shall be supplied.

4.6.8.3 PART 2C - RAW MATERIAL SPECIFICATIONS AND RAW MATERIAL

CONTROL PROCEDURES

4.6.8.3.1 Specifications and the limits of all raw materials, including the active ingredient(s)must be listed and must at least be at the level of the latest editions of recognisedpharmacopoeial reference books, (BP, USP, EP) Any deviation from suchspecifications and limits must be fully substantiated. More than one pharmacopoeiamay be used for the raw materials provided that the reference is used fully and notpartially or selectively. For example, USP may be used for starch, and BP forlactose, etc.

One ingredient may be tested in accordance with alternative pharmacopoeias,

depending on the site of manufacture.

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4.6.8.3.2 In-house specifications must at least be at the level of an approvedpharmacopoeia. Any in-house specifications that are at a lower level than those ofan approved pharmacopoeia must be fully motivated, subject to approval by theCouncil.(Cross reference to a Pharmacopoeia is necessary)

4.6.8.3.3 Additional specification parameters, over and above those stipulated in the officialcompendia, such as a very accurate description of isomers, polymorphs, etc., mustbe submitted for all active ingredient(s) where required by the Council.

4.6.8.3.4 Control procedures for all raw material specifications shall be fully described,unless a complete monograph appears in an approved pharmacopoeia. In the latterinstance, reference to the pharmacopoeia must be made as indicated in 1 above.

4.6.8.3.5 Specification limits and the control procedures for particle size of active ingredients

which have a solubility of less than 1 part in 200 parts water and for those whichthe Council may publish by notice, must be submitted. Particle size must be stated

in SI units (m) where the particle size is stated in sieve sizes, the correspondingsize in SI units should be included. Exemption from this requirement may begranted if the active ingredient is reconstituted into, or is administered as, asolution, or for any reason determined by the Council.

4.6.8.3.6 Colourants and flavourants must comply with either one of the following:

i) at least a specification limit and control procedure regarding chemical

identification and a statement that the flavourants comply with the generalrequirements and that the colourants comply with the purity criteria of Act 54 of1972 (The Foodstuffs, Cosmetics and Disinfectants Act, Act 54 of 1972).

ii) at least a specification limit and control procedure regarding chemicalIdentification and a statement that it complies with the directives of the EU orthe register of the FDA.

4.6.8.3.7 The following minimum requirement must be complied with by the applicant and aconfirmation given that:

i) Identification and assay of the active raw material will be performed irrespectiveof the possession of a certificate of analysis from the supplier;

ii) Identification of the inactive raw material will be performed irrespective of thepossession of a certificate of analysis from the supplier; and that

iii) Any tests not included in a valid* certificate of analysis will be performed.

*valid as defined by c GMP

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4.6.8.3.8 For those inactive ingredients for which a conclusive identification test is notincluded, all those parameters which are specific to the identification of that rawmaterial must be performed irrespective of the possession of a Certificate of

Analysis from the supplier.

4.6.8.3.9 For all raw materials of organic origin, microbial limits and test procedures must beincluded.

4.6.8.3.10 Frequency of testing of water and microbiological testing of water must be stated.Water must be tested at least once a week for microbiological contaminants, anddaily or just before use for conductivity and pH.

4.6.8.3.11 For a biological medicines:

a) Specifications for the primary production lot used in the manufacture of the finalfilling lot of a biological medicine and specifications for all raw materials for the

diluent must be listed.

b) Tests of a biological source material must include tests to confirm theidentification, safety and potency of the primary production or bulk lot used inthe manufacture of the final filling lot.

c) Parameters and criteria of acceptance to confirm the identification, safety andpotency of the product must be provided.

4.6.8.4 PART 2D - CONTAINERS AND PACKAGING MATERIALS

4.6.8.4.1 Full details of the immediate container specifications and limits, includingdimensions and sketches where applicable, as well as those of applicators andadministration sets, the closure system wadding and any other component in directcontact with the product, where applicable, and the control procedures thereof mustbe supplied.

4.6.8.4.2 A brief description of the outer container, if any, must also be given. At least thenature of the material must be mentioned. e.g. Outer cardboard carton.

4.6.8.4.3 The type of container described here must correspond to that described in the

package insert under Presentation and in the stability studies.

4.6.8.4.4 In cases where an equivalent or better immediate container packaging material isrequested, data to substantiate this claim must be submitted, i.e. USP Permeationtest. Refer to Addendum G on minor and major amendments for stability testingrequirements.

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4.6.8.5 PART 2E - THE MANUFACTURING PROCEDURES

4.6.8.5.1 The batch manufacturing formula and the batch size(s) must be included. Wheremore than one batch size is indicated, the batch formula of the smallest batch sizeonly may be given.

4.6.8.5.2 A copy of the Master Manufacturing document or a comprehensive flow diagram ora description of the manufacturing procedures detailing the various stages ofmanufacturing, packaging and labelling, including the type of equipment (includingsieve sizes), duration of treatment, temperature, light and humidity conditions, aswell as machine settings (e.g. rotation speed or rpm), must be submitted. All in-process controls (analytical, microbiological, and physical) must also be shown inthe flow diagram.

4.6.8.5.3 The Inspection Flow Diagram must be included.

4.6.8.5.4 A process Validation programme or process validation report (as per requirementsstipulated in Addendum B) must be submitted.

4.6.8.6 PART 2F - THE FINISHED PRODUCT

4.6.8.6.1 The name of each final product specification and the limits must be listed for in-process controls, final product controls, stability studies and manipulated finalproduct (if applicable).

4.6.8.6.2 All control procedures must be described in full.

4.6.8.6.3 The validation data of the assay method of the active ingredient must be submitted.It must be demonstrated that the assay method is stability indicating, i.e. willdistinguish between the active ingredient and the degradation product.(s) If theassay method is not stability indicating the validation data of the procedures usedto determine the assay and that used to determine the degradation product mustbe submitted. Chromatograms confirming the separation of the active from thedegradation products, if relevant, must be included (SeeAddendum A).

4.6.8.6.4 All other quantitative methods must be validated and the validation data included.

4.6.8.6.5 A complete analysis report or certificate of analysis for one batch (pilot- orproduction) of the finished product must be submitted with the application.

4.6.8.6.6 The final release criteria must include the checking of certificate of analysis,appearance of the dosage form, the container, the package insert, the label, thebatch number, and the expiry date of the product (FPRR functions).

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4.6.8.6.7 Content uniformity must be specified and a control procedure must be submitted ifthe quantity of the active ingredient is less than 2 mg or less than 2% mass permass of the total mass of the dosage unit (e.g. tablet, capsule, etc.). The assayneed not be performed in the case where Uniformity of Content has already beenperformed for batch release purposes.

4.6.8.6.8 For quality control and batch release purposes, final product specifications for alloral tablets and capsules (conventional oral dosage forms), shall include arequirement for dissolutionrate of active ingredient unless otherwise determined bythe Council. Dissolution rate of at least the least water-soluble active ingredient in acombination product should be tested as a release requirement.

4.6.8.6.9 Disintegration time, where relevant, for example for chew tablets, matrix tablets andsoft gelatine capsules will be determined as a lot release requirement on allbatches on which dissolution rate is not determined as a criterion for lot release.

Disintegration time can be used as a lot release requirement for multivitamins andmineral preparation, unless a dissolution requirement for a specific product isincluded in the USP, in which case dissolution must be done as a lot releaserequirement.

4.6.8.6.10 For a product from a non-biological origin which has endotoxin levels the validationdata as required by the USP / BP/ EP must be submitted to the Council. Theapplicant may thus employ the LAL method after informing the Council of theirintentions.

4.6.8.6.11 For products with a biological origin or any other products for which no endotoxin

levels have been specified in a pharmacopoeia, the validation data must besubmitted for evaluation. This must have been approved and accepted by theCouncil before the LAL test may be utilised. This information must include the initialquality control data, inhibition/enhancement data and the endotoxin limit for theproduct.

4.6.8.6.12 For imported products at least the identification, assay of the active ingredient mustbe performed after importation. This is intended to verify that the product has notbeen affected adversely during the transfer process. Exemption may be granted foran applicant not to

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