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8/8/2019 Parallel Importation of Medicines s. Africa

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PARALLEL IMPORTATIONOF MEDICINES

7.2 Council may imposeanyconditionsnecessary for the egistrationof hemedicine.

7.3 TheRegistrarshall lkeep aseparate egister orparallel mportedmedicines.

8. CANCELLATION OF REGISTRATION OF PARALLEL IMPORTED MEDICINES

Council may, on good cause shown and in consultation with the Minister, cancel the registration ofany parallel imported medicine.

9. INFORMATION TOE PROVIDED TOHEATENTOLDEROROLDERORHECERTIFICATE OF REGISTRATION

The mporter must, within 30 days after registration of the medicine, nform the patent holder or theholder of the certificate of registration in South Africa, of this fact and submit a copy of the letter tothe Registrar.

I O . IMPORTATION OF MEDICINES

10.1

10.2

The parallel mporter must inform he holder of he certificate of registration at east fourweeksprior to importation,ona form determinedbyCouncil,ofhis or her intention toparallel-import the medicine. The requirements for post-importation identification and testingofmedicines,asdescribednAddendum 2 ofheGuidelines fo r the Registration ofMedicines in South Africa, will apply.

The parallel mporter may not manufacture or re-export any medicine registered n SouthAfrica as a parallel imported medicine.

11. REPACKAGING AND REL.ABELING OF PARALLEL-IMPORTED MEDICINES

11.1 Where the medicine is to be repackaged n South Africa after mportation, this must be doneat a site approved and licens)ed y the Council for this purpose.

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11.2

11.3

11.4

11.5

PARALLEL IMPORTATION O F MEDICINES

Themedicinemust be labelled,packagedand have apackage nsertan dpatient nformationleaflet as prescribed n terms of regulations 8, 9 an d 10.

The parallel importer may use the proprietary name approved in South Africa as well as any trademarks applicable to the medicinen order to ensure the public health intere sts.

The words Parallel im po rted medicine or the abbreviation PIMmus t be included on he label ofeach distribution pack.

The batch numbers of repackaged medicines mustbe identical o those of the original medicinesand all original packagingmaterial must be destroyed.

12 INFORMATION TO BE PROVIDED TO THE MEDICINES CONTROL COUNCIL

The following information m ust be supp lied to Council by the parallel mporter:

12.1 Any change inthe conditions under which he medicine was registered;

12.2 Any adverse drug reactions or ever,ts arising from th e use of the m edicine;

12.3 Any report of risks assoc iated with the m edicine that may a ffect its quality, safety or efficacy.

13. TRANSFER OF CERTIFICATE OF REGISTRATION

A certificate of registration for an imported m edicine ma y onlye transferred o another person or companywith the approval of the Minister.

14. AMENDMENTS TOTHE DETAILS OF A PARALLEL IMPORTED MEDICINE

The importer must apply to Councilon form PIF 1, available from the office of the Reg istrar, for approvalofany chan ge in the conditions of e gistration of an imported medicine or change in the storage conditions orchange in any of the particulars of the medicine.

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STAATSKOERANT, 27JUNIE 2003 No. 25145 177

PARALLEL IMPORTATION OF MEDICINES

15 . F E E S PAYABLE

An applicant or the registration of a medicine o be parallel mported shall pay an application ee and aregistration fee as determined by Council.

16. FORMS TO BE COMPLETED

The following forms, obtainable from the office of the Registrar, must be completed in respect of anapplication for amendment .fo the details of a parallel imported me dicine and for informing the pate nt holderof the intention of the parallel importer to import a medicine, respectively: PIF 1 an d PIF2.

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178 No. 25145 GOVERNMENT GAZETTE. 27 JUNE 2003

PIF 1

MEDICINES CONTRO L COUNCIL

NES CONTROL COUNCIL

1 APPLICATION TO AMENDMENTDETAILS OF A PARALLEL IMPORTEDMEDICINE


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PIF 1

1. Details of the importerName:Business Address:Postal Address:Tel:Fax:Wh olesale Distribution License Num ber:(Issued i n terms o fRegulation 19)

Responsible Pharm acist (To be contacted in case of safety and quaiiw problemsof the medicine):Name:Address:Registration num ber (in terms of Act No. 54 of 1974):Cell phone number:Fax:E-mail:

2. Details of the med icineProprietary Name:INN or Approved n ame:Strength:Pharmaceutical Dosage Form:Pack size(s):Registration num ber:Date of MCC notice submitted:

3. Scope of the change(s)0 hange(s) resulting from amendm ents o the MCC DecisDn0 hange(s) proposed by the importer no t related to the MCCDecision

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180 No. 25145 GOVERNMENT GAZETTE, 27 JUNE 2003

PIF I

Provide details of change and Parts of dossier affected:

0 t is certified that the original condition of the product has not beendirectly orindirectly affected by the proposed change (Submit transport validation datawhere applicable).

5. Submission of copies of inner and outer labels and p ackage insertCopies of the am ended outer and/or inner package labels and/or package insert f themedicine must be enclosed where applicable together with an electronic version inMicrosoft Word (on diskette or by Email).

Copy of the amended outer package label enclosedCopy of the amended inner package label enclosedCopy of the amended package insert enclosed

Signature

Name

Designationr \ l o t e : Please return the form and its required annexes to:

The Registrar of MedicinesMedicines Control CouncilPrivate Bag X828Pretoria 00 0

YES NOremainsunchanged0 00 00 0

Place

Date

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PIF 2

MEDICINES CONTROL COUNCIL

NOTIFICATION F0R .M-

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PIF 2

NOTICE OF INTENTION TO PARALLEL IMPORT AMEDICINE UNDER PATENT

I DETAILS PARALLEL! IMPORTATION PERMITi HOLDER:I

I1 DETAILS OF MEDICINE~ DETAILS OF MEDICINE TOI BE PARALLEL IMPORTED:

I REGISTERED I N SOUTHAFRICA:

I

INTENTION TO PARALLELI IMPORT THE ABOVEi MEDICINEI DETAILS OF PATENT, HOLDER:

c

IcII

SIGNATURE OF PERMITHOLDER:DATE: i

Name:Business address:PermitNumber:Proprietary name:Registration No.Proprietary name:PIM Registration No:Country of origin:Manufacturer:Price of medicine:R PerApproximate date of importation:

Name:Business address:

A copy of the completed form must be sent to the Medicines ControlCouncil

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GENERIC SUBSTITUTION

MEDICINES CONTRQL COUNCIL

1 GUIDELINE ON GENERIC SUB.STITUTPON 1I Thisocumentas been prep ared to servesecommendationoauthorised health practitioners involved in the dispensing and administrationof medicines. It rep resen ts the M edicines Control Councils curre nt thin kingon the safety , qua lity and efficacy of medicines. T he MC C is comm itted toen su re th at all medicines in use will be of the required quality, safety and

efficacy. It is imp orta nt for allwho dealwith medicines to adh ere to th eadministrativeand echnical equirem ents o avoid unwanted oradverseevents that maycompromise hehealth of th epopu lation. This guidelinemust be read in conjunction with the definition of interchangeable mu1t.isource medicine in the Act a nd Regu lation 2 of the Medicines and RelatedSubstances Act No. 101 of 1965, as amended.

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184 NO.25145 GOVERNMENT GAZETTE, 27 JUNE 2003

GENERIC SUBSTITUTION

GUIDELINE ON NON-SUBSTITUTABLE MED ICINES1. This guideline replacesircular 16 of 1994. L IS T OF NON-SUBSTITUTABLE MEDICINES. This list will bepdateds newinform ation on generic ubstitution becomes available. T he absence ofsubstance fro m th is list must not be construed t o mean th at such a substancewill be substitutable. The attention f all health practitioners who dispense oradminister medicines is drawn to this list to assist in taking decisions whereone or more a lternatives are available .2. Thenterchangeable use of differentrand s of chemically equiva lentmedications (i.e. those which contain the sam e activ e ingr edie nts, the sam e

quantities hereof, in the amepharmaceuticaldosage orm,orasmorecommonlyamed, "generics") could un dererta ini rcumstancescom prom ise therapeutic esponse and safety of the patient.3. Th e Medicines Control Council, havi ng stud ied the m atter in dep th on both alocal and international level, recomm ends that substitution should not occurwhen p rescr ibin g and dispensing "generic" medicines which:

i) have a narrow therapeutic range;ii) have been known to show errati c intr a- an d int erpa tient respo nses;iii) ar e contained in dosage forms th at ar e likely to give rise to clinicallysignifican t bio-availability problem s, e.g. extended or dela yed releasepreparations, aswell as thoseknown to be super ioavailable";iv) ar e inten ded for the ritically ill and /or geria tric and paed iatric patie nt.

4. In terms of theafore-m entioned actors, the following list of med icineshaveon occasion, been know n opresentbieequivalenceproblemsandshouldideally not be inter cha cged wi th othe r "generics" unless ad equ ate provisionis mad e for mon itoring the patien t during the transitioneriod.Alendronate tablets or capsulesAtenolol table ts orcausulesCarbamazepine tabletso r capsulesChlor prom azine tab lets or apsulesDexam ethasone tablets or capsulesDiethylstilboestrol tablets or capsulesDigoxin tab lets or capsulesDisulfiram tablets orcapsulesEthinyl O estradiol tablets r capsulesFluoxymesterone tablets orcapsulesFurosemide tablets or apsulesGlibenclamide tablets or capsulesHydralazine, Hydrochlorothiazide and R eserpine combination tablets or capsulesHydralazine and Hydrochlorothiazide combination tablets orapsules

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GENERIC SUBSTITUTIONHydrocort isone tablets orapsulesHy droc ortiso ne Acetate injectionIsoproterenol Metered Dose inhalerIsoethrane M etered Dose inhalerIsosorbide Dinitrate sustained release table ts and capsulesItraconazole tablets or capsulesLevodopa tablets and capsulesNifediDine: all extendedldelaved release formulationsOestrogens, C onjugated tablets o r capsulesOestrogens, Esterified table ts or cap sule sPenicillin G Benzathine injectionPhenytoin tablets and capsulesPhytomenaclione injectionPrazosin Hydrochloride tablets 5mg"Prednisolone tablets o r capsu lesPrednisolone Acetate injectionPredn isolone Teb utate njectionPrednisone tablets or capsulesPromethazine tabletsPropylthiouracil tabletsReserpine tabletsReserpin e and Chlomthiazirle combination tabletsReserpin e and Trichlorom ethiazide ombination tabletsTamoxifen tablets orcapsulesTheophy lline controlled release tablets o r capsu lesTriamcinolone tablets o r capsulesTrichloromethiazide tablets or capsulesWa rfarin Sodium tablets or apsulesThe list is subjecto eriodic review and lteration at the discretion ndrecommen dation of the Medicines Con trol Council.

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MEDICINES CONTROL COUNCIL

NES CONTROL COUNCIL

[ p v b e e n repared as a guid{i requirements orSiteMaster Files with11 business. The MCC is committed to ens1 manufactured, stored or tcsted are of an aL--*--~=--~=~~-__~pplicmts must endure thatI I trdrninistr!!1 where pharmaceutical business is conduc

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INDEX1. INTRODUCTION

2. PURPOSE

3. SCOPE

4. SITEMASTERILE

5. PREPARATION OF SITEMASTER FILE

6. APPENDIX

7. REFERENCES

8. CONTACTETAILS

9. UPDATEISTORY

10. REFERENCES

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1. INTRODUCTIONTh e Site Ma ster File is prepared by the manufacturer and contains specif ic information aboutthe quality assurance, the produ ction and/or quality control of pharmaceutical manufacturingoperations carried out at the named site and any closely integrated operations at adjacent andnearby buildings. If only part of apharmaceutical operation is carried out on the site, a Site Master File need only d escribe thoseoperations, e.g. analysis, packaging, etc.When subm itted to a regulatory authority, the Site Ma ster File provides information on themanufacturer's operations and procedu res that can be useful in the effic ient planning andundertaking of a GM P inspection.These guidance notes have been set out in such a manner that each chapter and the paragraphsnoted under "REQ UIRE ME NT" is followed by "GUIDANCE" o provide details of how therequirements should be interpreted.A Site Master File should be succinct and, as far as possible, not exceed approx imatelytwenty-five to thirty A 4 pages.Th e Site Master File should have an edition num ber and an effective date.Wherever possible, sim ple plans, outline drawings or schematic layouts should be usedinstead of narrativ e. Th ese plans etc. should f i t on A 4 sheets of paper. A deliberate limit hasbeen set on the length of the narrative. If mo re detailed information is required, then this willbe taken up by the nspector in hi sh er part of the report.2. PURPOSEThe aim of these Explanatory Notes is to guide the manufacturer of m edicinal products in thepreparation of a Site M aster File that can be useful to the regulatory authority in planning andconducting GMP inspections.3. SCOPEThese Explanatory Notes apply to the preparation of the Site Ma sterFile. Refer to nationalregulatory requirements to establish whether it is mandatory formanufacturers of m edicinalproducts to prepare a Site Master File.4. SITE MASTER FILERefer to Annex for the format to be used.

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5 . P R E P A R A T I O N OF SITE MASTER FILEREQUIREMENTC.1. G E N E R A L I N F O R M A T I O N

GUIDANCEC.1.1. In not more than 250 words (one A4 pa ge) outline t h e ji m 's activities, other sites, inaddition to the site which is the subject of this report.R E Q U I R E M E N TC.1.2 .Pharmaceutical manufacturing act ivi t ies as l icensed r approved by t h eCompetent Authorities.GUIDANCEC.1.2.Quote the relevant docum ent as issued by the Com petent Authority. State period ofvalidity of licence docum ent (if th e validity of the document isgiven in the countryconcerned). Any conditions a n d o r restrictions should bestated.R E Q U I R E M E N TC.1.3. Any other m anufacturing act ivi t ies carr ied out on theite.GUIDANCEC.1.3. This covers both pha rma ceutica l and non-pharm aceutical activities. NB: See paraC.1.6R E Q U I R E M E N TC.1.4. Name and exact addressof the site, including telephone, fax and4 h rs telephonenumbers.GUIDANCEC.1.4. Name and Address of SiteC.1.4.1. N am e of C omp any (and trading style if different). Postal Address including. Code(street address if different).C.1.4.2. Telephone No. of contactperson.C.1.4.3. Fax No. of contactperson.Version 2003MCCil Page 4 of 20


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C.1.4.4. hour contact T elephone No .' R E Q U I R E M E N T

(21.5. T yp e of actu al pro duc ts m anu fac ture d n the site see list at Appendix), an dinformation about specifically toxicr hazardous substances handled, mentioning theway they are m anu fac tur ed (in dedicated facilities or on a campaign basis).GUIDANCEC.1.5. Type of Actual Products ManufacturedC.1.5.1. Quo te the type of actual pro du cts asdescribed at A ppendix.C.1.5.2. Note any toxic or hazardous substances handled e.g. antibiotics, hormones,cytostatics. Note whether the produ cts are manufactured in adedicated facility or on acampaign basis.C.1.5.3. Mention ifh um an and veterinary produ cts are both prepare don the site.R E Q U I R E M E N TC.1.6.Short descriptionof the site(size . location and imm ediate environm ent and therman ufacturing activities o n the ite).GUIDANCEC.1.6, A Short Description of th e Site (not more than 250 words/one A4 pa ge )C.1.6.1. The location and im mediate environment.C.1.6.2. Th e size of the site, types of buildings and th eir ages.C.1.6.3. Other m anufacturing activities on the site.R E Q U I R E M E N TC.1.7.N um ber of employees engaged in the quality assurance, production, ualitycontrol, s torage and dis tribution.GUIDANCEC.1. Z (Note: Include em ployees working only part-time on full-time equivalent basis. Givethe rate of the academic and n on-academic person s.)C. 1.7.1.Qua lip AssuranceC. l .7.2. ProductionC.1.7.3. Qu alip ControlC.l.7.4. Storage and distributionC.l.Z5. Technical & Engineering Suppo rt ServicesC.l.Z 6. Total of the above

I

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(21.8. Use of outside scientific, analytical or other technical assistance in re lation toma nufacture and analysis.GUIDANCEC.1.8. For each outside contractor give:C.1.8.1. Name and address of the company.C.1.8.. Telephone No.C.1.8.3. Fax No.C.1.8.4. Brief outline of the activity being undertaken in not more than 1 00 words (harfan A 4page).REQUIREMENTC.1.9. Short description of the quality m anage men t system of the firmresponsible for manufacture.GUIDANCEC.1.9. (Not more than 750words or three A4 pages )C.1.9.1. State thef irm 's Quality Policy.C.1.9.2. Define the responsibility of the Quality Assuran cefunction.C.1.9.3. Describe the elements of the QA system e.g. organisational structure,responsibilities, procedures, pro cess es;C.1.9.4.Descnbe the audit program mes (self inspection or audits by external organisationsundertaken).C.i.9.5. D escribe how the results are reviewed to demonstrate the adequa cy of the qualitysystem in relation to the objective i.e. quality efficacy and safety of the product. See alsoparagraph 6.1.2C.1.9.6. Record if standards such as I S 0 9001-9004 are used by the company to asse ss tssuppliers.C.1.9.Z Whe n suppliers of c ritical starting m aterials and packing materials - actives,excipients, containers and closures and printed m aterials are assessed, give d etails of howthis is done.C. 1.9.8.Describe the release fo r sale procedu re o r inished products.REQUIREMENTC.2. PERSONNELC.2.1. Organisation chart show ing the arrangements for quality assurance, includingproduction and quality control. (see alsoC.1.9.3)C.2.2. Qua lifications, experience and responsibilities of key personnel.C.2.3. Outline of arrangements for basic and in-service training and how records aremaintained.Version 2003MCC/1 Page 6 of 20


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C.2.4. Health requirements for personnel engaged in production.C.2.5. Personne! hygiene ren,uirer?,ents, including clothing.GUIDANCEC.2. PERSONNEL (500words/two A4 page s)C.2.1. Organisation chartC.2.1.1. Orga nogra m o r quality assurance including pro duc tion and uality control. Recordsenior m anage rs and supervisors onb.C.2.2. Qual$ications, Experience and Responsibilities ofKey Personnel.C.2.2.1. Brief details of academic qualifications and work related qualifications andyeamrelevant experience since qua llbing .C.2.3. Outline of Arran geme nts o r Basic and In-service Training and how Record s aremaintainedGive brief details of the training pro gram me and nclude induction and continuous training,-a s oil0 ws:C.2.3.1. Describe how train ing needs are identijied and by whom.C.2.3.2. Give details of training relative to GM P requirem ents.C.2.3.3. State theform of training e.g. in-house, external, and how pra cticalxperience isgained andwhich staff are involved.C.2.3.4. Explain how the efficacy of the training is assessed e.g. byquestionnaires.C.2.3.5. Explain how retraining needs are identified.C.2.3.6. Give brief details of records kept.C.2.4. Health Requirements for Personnel Engaged inProductionC.2.4.1. Who is responsible or checking health of employees?C.2.4.2. Is there a pre-employment medical examination?C.2.4.3. Are employees routinely checked ro m time to time depending on nature of theirwork?C.2.4.4. Is there a system f o r reporting sickness o r contact with sick pe op le before w orking ina critical area ?C.2.4.5. Is there a system of reporting back after illness?C.2.4.6. Are those who work in clean areas (grade A- D) subject to additional mon itoring ?C.2.5. Personnel Hygiene Req uiremen ts Including ClothingC.2.5.1. Are there suitable washing, changing and rest area s?C.2.5.2. Is the clothing suitablefor the activity undertak en? Briefly describeVersion 2003MCCA Page 7 of 20


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the clothing.C.2.5.3. Are there clear instructions on how protective clothing should be used and w hen itshould be changed? Detailedprocedures are not eeded. Is in house or external laundryused?REQUIREMENTC.3. PREMISES AND EQUIPMENTPremisesC.3.1. Simple plan or description of manufacturing areas with indication of scale(architectural or engineering drawings are not required).C.3.2. Nature of construction and finishes.C.3.3. Brief description of ventilation systems. More details should be given for critical areaswith potential risks of airborne Contamination (schematic drawings of the systems aredesirable). Classification of the rooms used for manufacture of sterile products should bementioned. nC.3.4. Special areas fo r the handling of highly toxic, hazardous and sensitising m aterials.C.3.5. Brief description of water systems (schematic drawings of the systems ar e desirable)including sa nitationC.3.6. Maintenance(descripti0n of planned preventive maintenance programmes andrecording system ).

EquipmentC.3.7. Brief description of major production and control laboratories equipm ent (a list ofequipment is not required).C.3.8. Ma intenance (description of planned preventative maintenance program mes andrecording system ).C.3.9. Qualification and calibration, including recording system. A rrangem ents forcomputerized systems va lidation.

SanitationC.3.10. Availability of written specifications and procedures for cleaning manufacturing areasan d equipment.

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GUIDANCEC.3. PREMISES AND EQU IPMEN TC.3.1. Prem ises(23.1.1. Provide a site pl an highIightingproduction areas.C.3.1.2. Provide a simple pla n of each production rea with indication of scale. Label areasand annotate pla n with names.C.3.1..3. Plans should be egible and on A 4 sheets ofpaper . Plans couldbe onA 3 sheets ofpa per if considered necessary.C.3.1.4. For sterile pro du ct areas indicate room andarea c1assifici;ltion an dp re ssur edifferentials betw een adjoining areas ofdifferent classifications.C.3.2. Nature of Construction and Finishes (500 wor&/two A 4 pages)C.3.2.1. To reduce narrativefor a large complex plant, he details should be limited tocritical areas.C.3.2.2. These areas m ust include all processing and packag ing and ritical stora ge areas.C.3.2.3. A narrative- or m at is preferred.

C.3.3. Br ie f Description of Ventilation Systems etc. (500 words/two A 4 pages)Note 1: More etails should be give nfor critical areas w ith pote ntial risks of airbornecontamination. This will include sterile produc t areas as well as areas or processingpowde rs, granulation and tabletting. For sterile product areas a summaryof the results ofthe most recent qualijiicatiodrequal@ication hould be iven.Note 2: To reduce the narrative, schematic draw ings shouldbe used.The following ata should be given: -C.3.3.1. Design c riteria e.g.- Specijication of the air supply- Pressure differentials and air change rate- Simple pas s or recirculation (%)-Temperature- HumidityC.3.3.2. Filter design and efficiency e.g.- Bag 99% e#- Hepa 99.997% e 6Details of any alarmson the ventilation system should be given.Version 2003MCC/1 Page 9 of 20


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C.3.3.3. The limits or changing theJIters should be given.C.3.3.4. r f D O P (dioctyl-phthalate) is introduced, the po in t must beshown.C.3.3.5. Give the frequen cy of revalidation of the system.C.3.4. Special Areas for the Handling of Highly Toxic Hazardous and Semitising M aterialsC.3.4.1. Follow the same layout as 3 .1 above.C.3.5. Br ief Description of Wa ter Systems, including sanitation (500 ords / t w o AQpages)Schematic drawings of the systems are prefewed.The ollowing information must ppear:C.3.5.1. The schematic must go back to the city supply system.C.3.5.2. The capacity of the system (maximum quantityp rodu cedp er hour).C.3.5.3. Construction materials of the vessels andpip ework.C.3.5.4. Specification of any ilter s in the system must be iven.C.3.5.5. Ijwater is stored and circulated, w hat is the temperature at the po int of return.C.3.5.6. The specification of the wa ter produ ceda) chemicalb) conductivityc) microbiologicalThe sampling points and frequ enc y testing.The procedure and frequency fo r sanitation.C.3.6.Maintenance (250words/one A 4 page)Note: For the purpose of this guid e Ma intenance s carried out by the ma nufacturer and?servicing by an outside contractor.C.3.6.1. Describe the planned preven tativemaintenance programm e.C.3.6.2. A re there written pro cedu res and suitable reporting for ms f o r maintenance andservicing? Do the documents record type frequ ency of sewiceskhecks, details of service,repairs and m odijications ?C.3.6.3. Are the maintenance routines thatcould affectproduct quality clearly identified?C.3.6.4. Are the reports made know n to the users?Equipment 0.50 worddone A 4 page)C.3.7. Brief Description of Ma jor Production and Control Laboratory EquipmentNote: Makes and model numbers equipment are not required. How ever the following pointsshould be addressed:C.3.7.1. Is the equipment designed with ease of cleaning in mind?k.C.3.%2.Only a generaldescription is required e.g. a rotar y table tpres s tc. rf th e equipmenthas additional devices, these should be recorded e.g. automa tic weighing machines withVersion 2003MCC/1 Page 10of 20


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printer; a abeller incorporating a bar code eader f o r the label; a lot number andxpiryC.3.7.3. In the quality control laboratory on ly general descriptions such as H meters,chromatographic equipmentGLC (gas-liquid chrom atography), HPLC (high perfomza nceliquid chromatogra phy) with comp uter systems, partic le sizeanalysers.C.3.7.4. Is the mac hinery constructed of appropriate materiai (eg. AIS Pg rad e 316 stain lesssteel for produ ct contact equipment?)C.3.7.5. Have other materials been suitably validated e.g. polypropylene, chrome-platedbrass, PVC (poly vinyl chloride), non-reactive plas tic ma terials ?C.3.7.6. In microbiology use genera l descriptions such as incubators (temperature ranges)facilities f o r LAL (limulus ameb ocyte lysate) testing, memb rane iltra tion sterility testing,antibiotic assay, etc.C.3.7. Z In par ticula r give brief information on the use of computers, microprocesors etc. inthe factory.

ovwpr?'.cter;a,+eeze &+e+equipped with a steam ste;$isatio nfacZ p.

C.3.8. Maintenance (250worddone A4 page)C.3.8.1. Who is responsiblefor maintenance und servicing?C.3.8.2. Are there w ritten pro ced ures and contractual details f o r outside wo rk?C.3.8.3. Are maintenanceroutines which could affe ctp rod uct quality clearly iden tified?C.3.8.4. Are records kept 031 . ype and frequen cy of service/check;2. details of service repairs and m odifications?C.3.8.5. Are repo rts made know n to the users?C.3.9. Qualification, validation and Calibration (750wordslthree A 4 pages)C.3.9.I . Briefly describe the Company S general policy and protocolso r quall jkat ion andvalidation (prospective and retrospective).C.3.9.2. Is there regular revalidation of critical equipmen t?C.3.9.3. Describe equipm ent calibration po licy and records kept. (C.3.9.4. An outline ofprocess validation may be givenere or cross-referenced to produc tionpara 5.4C.3.9.5. Wha t are the arrangem entsfor com puter validation, including software validation?C.3.9.6. Describe the system for the releasefor sale or supply of develop ment and validationbatches.

C.3.10.1. Are there written specifications and proced ures or cleaning, cleaning agents andtheir concentrationfor the method of cleaning and the fieq ue nc j?C.3.10.2. Are cleaning agents chan ged ro m time to time?C.3.10.3. Have the cleaning pro ced ures bee nvalidated and what w as the method ofevaluating the effectiveness of cleaning?Version 2003MCCil Page 11 of 20


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C.3.10.4. Are cleaning methods m onitored routinely by chemical an d o r microbiologicalmethods?C.3.10.5. W hat are the cleaning methods (and their frequ enc y)o r the water supply system,air handling system and dust extraction system ?REQUIREMENTC.4. DOCUMENTATIONC.4.1.Arrangements for the preparation, revision an d distribution of necessarydocumentation for manufacture.C.4.2. Any other documentation related to product quality which is no tmentioned elsewhere (e.g. microbiological controls on air and water).GUIDANCEC.4. DOCUME NTATION (500 orddtwo A-4 ages)Note: This section refers to all documentation used in manufacture. Manufacture involves allactivities relating to the produc tion and control ofphann ace utica l prod ucts.C.4.1. Arrangements for the Preparation and Revision and Distribution ofDocumentationC.4.1.1. Is there adescnption of the documentation system?C.4.1.2. Who is responsible f o r the preparation revision and distribution of d ocuments?C.4.1.3. Where are the m aster documents stored?C.4.1.4. Is there a standard for m at and instruction of how docurnents are tobe prepared?Are there documents fo r:1. P roductproc ess specification2. Raw material specifications3. Packaging component specijications4. Standard process instructions including packag ing5.Batch records including packag ing1. Produc tProcess Specifications6.Analytical methodsZ QA release proced ures.C.4.1.5. How is the documentation controlled?C.4.1.6. For how long are docum ents kept after release of the batch?C.4.1.Z Detail any arrangements f o r electronic or microfilmed records.C.4.2. Other Docum entation related to Product QualityAre the ollowing documents available and in use?C.4.2.1. Specifications f o r disposables i.e. cleaning materials.C.4.2.2. Standard operating procedures.Version 2003MCCl1 Page 12 of 20


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C.4.2.3. Equipment specijica tions.C.4.2.4. Quality Control Procedures.C.4.2.5. Training procedures.C.4.2.6. C ompu ter progra m pec$cations.C.4.2.7. Docum entation control of process deviations.C.4.2.8. Calibration and test documents (seepar a 3.9.5)C.4.2.9. Validation documents (see paras 3.9 and 5.4)C.4.2.10. Reconciliation of batches of raw materials, major pack ingcomponents i.e. produc t-contact and printed m aterials.C.4.2.11. List and brieJy exp lain the use of any additional standard documentation usedroutinely.REQUIREMENTC.5. PRODUCTIONC.5.1. Brief descriptionof production o perations using, wherev er possible, f low sheetsand cha rts pecifying important parameters see at Appen dix theist of pro duc tsmanufactured).C.5.2. Arrangem ents for the handling f start ing m aterials. pack aging materials, bulkand finished products, including sampling quarantine, release and storage.C.5.3. Arrangements for reprocessing or rework.C.5.4. Arrangements for the handlingf rejected materials and products.C.5.5. Brief descriptionof general policy for process validation.GUIDANCE.C.5.PRODUCTIONThis narrative should be kept to aminimum and generalized schematic layouts used wherepossible. The ollow ing points hould be addressed:C.5.1. Describe the operations capable of being carried out at the site w ith the existingfacilities and specify the types of pharmaceutical produc ts. (See par a 1.5. and the Appen dixfor types ofproducts manufactured).When packaging only is undertaken, give a brief des cnp tion onb , e.g. labelling, filling etc,and the nature of containers used e.g. sachets, tamper eviden t glasscontainers.I f cytotoxic or radio-active substances are han dledg ive deta ils f the products.Desc ribe the production ope rations using low charts ifpossible. Technical details are notrequired.

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(2.5.2.Arrangementsfor handling Starting Materials, Packing Materials, Bulk andFinishedProducts inch din g Samplinx Quarantine Release and StoraxeIdentification of suppliers lot numberwith the company's lotnumber. Status labelling e.g. byusing labels or by com puter. Issue of materials to manufacture andp ackag e. Thecontra1ofweighing.Sampling plan s.How are materials being used o r ma nufacture identified and released?Checking m ethodsC.5.2. I . Control o fBulk ManufactureChecks on key parame ters during manu facture e.g. b lend times, filte r int eg rig ests. Recordsof key parameters.Records of in-process checks.Compliance with theMarketing Authorisation.In-process checks.C.2.2.PackingRelease of bulk, semi-finished products, p ackin g materials;Confirmation of identity and line clearance checks;In-process checks.

C.5.2.4. Explain the role of the Authorized Person(s).C.5.3. Arrangements forReprocessing or ReworkC.5.3. I . What arrangements re in placeor reprocessing or rewo rking batches ofproducts?C.5.4. Arrangements for Hand1in.g Reject Materials and Produ:csC.5.4.1. Are reject materials and products clearly labe lled? Are hey stored s epara tely inrestricted areas?C.5.4.2. Describe arrangementsfor sentencing the materials and disposal. Is destructionrecorded?

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C.5.5. Brief Description o f he General Policy fo r Process ValidationAn outline ofpro cess validation protocol on& is required. (Se ep ara 3.9.3)R E Q U I R E M E N TC.6. QUALITY CONTROLC.6.1. Description of the Quality Control system nd of the activitiesof t he Q ua l i t yCont rol Depar tment Procedures or the releaseof f inished products .GUIDANCEC. 6. QUALITY CONTROLC.6.1. Activities of the Quality Control Dep artmen tC.6.1.1. (a ) Describe the elements of the QC system e.g. specifications, test methods, andother quality related data collection.(b) Briefly describe the activities of analytical testing, packaging, com ponent testing,biological and microbiological testing.(26.1.2. I f the review of batch docurnentation and release offi na l docum entation takes plac ein this department, give details. (See also par a 1.9.5)C. 6.1.3. Outline the involvement in the arrange men ts o r the preparation, revision an ddistribution of documents in particular thosefo r spec ljkation test methods and eleasecriteria if not mentioned elsewhere. (See also para 1.9 an d , Doclcmenlation)R E Q U I R E M E N TC.7. CONTRACT MANUFACTUREAND ANA LYSISC.7.1. Description of the way in which theGMP compliance of the contract acceptorsassessed.GUIDANCEC. Z CONTRACT MANUFACTURE AND ANALYSISC. Z 1. Describe briefly the details of the technical contract betwee n the contract giv er an dacceptor and the way in which the GMP com pliance is assessed to ensure pro duc tcompliance with the Mark eting Authorization.R E Q U I R E M E N TC.8. DISTRIBUTION, COMPLAINTSA ND PR O D U C T R EC A LLC.8.1. Arrangements and recording systemor distribution.Version 2003MCCll Page 15 of 20


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C.8.2. Arrangements for the hand ling of com plaints and product recalls.GUIDANCEC.8. DISTHBUTIONC.8. . A Description of Storaxe a nd Distribution PracticesC.8.1.1.C.8.1.2.(2.8.1.3.C.8.1.4.C.8.1.5.C.8.1.6.C.8.1.7.

Is the warehouse secure?Is it environmen tally controlled?Is there repigerated storage?How are the materials stored e.g. pa llet racking?How is the status ofpr od uc ts controlled e.g. by computer, by lab el?What are the meth ods of distribution to customers?Does the despatch order ensure fir st id fir st ut and identifv the lot numb er?C.8.2.Records ofDistributionDo the retained records per mit full batch traceability from the factory to theustomer. interms of the date of sale, customer details and quantitydespatched?ComplaintsC.8.2.1.1.Is there a written com plaintsprocedu re?C.8.2.1.2. Who is responsible fo r:1.Logging;2. Classlfiing;3. nvestigating complaints.C.8.2.1.3.Are written reports prep ared ?C.8.2.1.4. Who reviews these repor ts?C.8.2.1.5.For how long are complaints records kep t?C.8.2.2.Produ ct RecallsC.8.2.2.1. Is there a w ritten proc edu re which describes the sequence of actions to be followedincluding:1.Retrieval of distribution data;2.Notification of customers;3. Receipt/segregatiodinspectionof returned prod uct;4. Investigatiodreporting of cause;5. Reporting corrective action.C.8.2.2. Who is responsible for coordinating pro du ct recalls?C.8.2.3. Who notifies the Co mpeten t Authority of complaints and recalls.C.8.2.4.Is the Co mpe tent Authority involved in complaints and the decision t o recall?C.8.2.5.Can recalls be effected below w holesale level?Version 2003MCC/1 Page 16 of 20


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REQUIREMENTC.9. SELF INSPECTIONC.9.1. Short description of the self inspection system See also par a .9.4.).GUIDANCEC.9.1.1. Describe how the selfin spec tion system verifies that those activities that have abearing on quality comply with the plan ned arrangement.C.9.1.2. A re the quality system s effective?C.9.1.3. Are there documented procedureso r the self inspection system and for rhe follo w- upactions?C.9.1.4. Are the results of the self inspection system docum ented, brought o theattention ofthe pers onn el having responsibilityfor the area and activities inspected?C.9.1.5. D oes the system ensure that tho se responsible for the area or activity take timelycorrective action on the deficiencies fou nd ?

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APPENDIXTYPE OF PRODUCTS M ANUFACTURED (referred to in paragraph C.1.5)A. Sterile productsA.1 Liquid dosage forms (large volume solutions, including LVP and rinsing solutions)A. 1.1Aseptically preparedA.1.2 Terminally sterilized A.2A.2. Liquid dosage forms (small volume solutions, including SVP an d eye drops)A.2.1 A septically prepared

A.2.2 Te rminally sterilizedA.3 Sem i-solid dosage formsA4 Solid dosage formA.4.1 Solid f il lA.4.2 Freeze-driedB. Non-sterile productsB.1 Liquid dosage formsB.2. Semi-solid dosage formsB.3. Solid dosage formsB.4. Unit dose form (tablet, capsules, suppo sitories, pessaries)B.5 Multi dose form (powder, granules)C. Biological productsC. l. Vaccines C.(2.2 S era C .C.3 Blood productsC.4 Others (describe)D. Specifically toxic and hazardous substancesD .l PenicillinsD.2 CephalosporinsD.3. HormonesD.4. CytostaticsVersion 2003MCCl1 Page 18of 20


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GOVERNMENT GAZEi'TTE, 27 JUNE 2003

D.5. Othe rs (describe)E. Packaging; onlyE.l Liquid dosage formsE.2 Semi-solid dosage forms5 .2 Solid dosage formsF. Contract manufacturing (kind of products)F.l. Firm reported upon is:F.2. Acceptor .F.3. GiverG. Contract analysisFirm reported upon is:F. 1. AcceptorF.2. GiverH. Drugs for clinical triaisI. Others(e.g. veterinary products, cosmetics, etc)

9. REFERENCESCircular 34/93P I U S guide

IO. CONTACT DETAILS

1. Ms J. GouwsDirecto r: Inspectorate and Law Enforcem ent DirectorateTel: 012 312 0230/47Fax: 012 312 3114

2. Mr. .K MofokengDeputy Director: Inspectorate and Law E nforcement DirectorateTel: 012 312 0259Fax: 022 312 3114

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3. Mr P. SelekaPrincipal Medicines Control OfficerTel: 012 312 0252Fax: 01 2 31 2 3114

4.Ms P. MatsosoRegistrar of MedicinesTel: 012 312 0285Fax: 012 312 3105

11. UPDATE HISTORY

Date 1 Reason for update 2003/1pril 2003 I New Version

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parallel importation of medicines s. africa

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