CHAPTER 219
">PHARMACEUTICAL AND POISONS ACT

[SUBSIDIARY LEGISLATION]

INDEX TO SUBSIDIARY LEGISLATION

   NOTICES

      The Pharmaceuticals and Poisons (Code of Conduct for Drug Promoters) Notice

   ORDERS

      The Poisons List (Declaration) Order

      The Pharmaceuticals and Poisons (Guidelines for Good Manufacturing Practice) Order

      The Pharmaceuticals and Poisons (List of Human Notified Drugs) Order

      The Pharmaceuticals and Poisons (Registered Veterinary Drugs List) (Notification) Order

      The Pharmaceuticals and Poisons (Human Drugs List) (Notification) Order

   REGULATIONS

      The Pharmacy Board Inquiries Regulations

      The Recruitment and the Activities of Medical Representatives Regulations

      The Pharmaceutical and Poisons Regulations

NOTICES

THE PHARMACEUTICALS AND POISONS (CODE OF CONDUCT FOR DRUG PROMOTERS) NOTICE

(Section 49)

[1st October, 1999]

G.N. No. 440 of 1999

   WHEREAS Section 49 of the Pharmaceutical and Poisons Act * prohibits the advertisement of certain diseases.

   AND WHEREAS the Act requires the Minister upon recommendation of the Board by Notice published in the Gazette to prohibit the advertisement certain diseases.

   AND WHEREAS the Board has recommended to the Minister to publish in the Government Gazette the Code of Conduct For Drug Promoters public awareness.

   Now THEREFORE, the members of public are hereby notified as follows:

   1. This Notice may be cited as the Pharmaceuticals and Poisons (Code of Conduct for Drug Promoters) Notice.

   2. [Omitted.]

   3. The members of public are hereby notified that any person intending to conduct drug promotion activities in Tanzania shall be required to abide by the Code of Conduct for Drug Promoters set out in the Schedule to this Notice.

   4. Any person who fails to comply with the terms and conditions set out in the Code of Conduct For Drug Promoters shall be guilty of an offence punishable under the Pharmaceutical and Poisons Act *.

SCHEDULE

FOREWORD

   The code highlights the requirements to be borne in mind by all people intending to conduct drug promotion activities in Tanzania. Special emphasis of this code is to maintain and develop excellence in collection, processing and dissemination of drug safety information.

   This code is targeted to manufacturers and distributors, advertising agencies, market research organisations and health personnel involved in the distribution of medicines. The general media including publishers and editors of medical journals and related publications are also an important group of professionals to whom this code is focused.

   The code of conduct for Drug promoters has been prepared in reference to the requirements stipulated under section 49 of the Pharmaceutical and Poisons Act * and the Tanzania National Drug Policy, 1991.

   All health care professionals and the general public are advised to assist the Drug Regulatory Authority in ensuring that promotional activities are done in an ethnical manner in order to protect the public health.

Aaron D Chiduo
Minister for Health

1.   INTRODUCTION

   Drug promotion is defined as all informational and persuasive activities conducted by manufacturers and distributors, the effect of which being to induce the prescription, supply, purchase and/ or use of medicinal drugs.

   Promotional activities can be in form of seminars, news broadcasts, rallies, advertisement in any media, use of medical representatives who may distribute printed audiovisual materials, displays, and exhibition materials at conferences, free samples and gifts.

   Examples of forms of promotion activities targeted at health workers include industry sponsorship of professional activities such as scientific meetings, supplements of medical journals, research, television and radio programs.

   Promotion targeted to the public includes advertisement in the public media, point of sale displays in pharmacies, sponsorship of radio, television programs and sports promotion. This also includes production of articles in newspapers, television and radio programs addressing individual or classes of drugs, using news releases or other materials to encourage news or stories about new drug discoveries.

   Advertisements are part of a drug promotion targeted to the consumers and health care professionals at large. Medicines advertised as such eg. "Over The Counter drugs (OTC)" are intended for self-medication and therefore accurate information is necessary to help the consumer make rational choice on use of the drug. For health workers, advertisements are also educative as they give the prescriber or dispenser more information on that particular drug.

   Irrational drug use could lead to treatment failures being a result of wrong drug therapies caused by economic hardship as drugs are expensive, wastage of scarce national health resources, economic hardship to the needy patients and emergence of drug resistant strains of microorganisms.

   This code constitutes standard principles, which should be adhered to by all persons involved in the pharmaceutical industry in the United Republic of Tanzania. All these are required to use the code as appropriate to their spheres of competence, activity and responsibility.

   The code applies to prescription medicines, non-prescription medicinal drugs ("over the counter drugs"), and to any other product promoted as a medicine.

   Any promotional activities (advertisement) not conforming to this code should be reported to the Registrar, Pharmacy Board.

   The complaints can be verbal or written giving the following details:

   (i)   Name of the product advertised;

   (ii)   The name of the advertising company;

   (iii)   The media used;

   (iv)   The day it appeared on the media; and

   (v)   Any other information on the advertisement or activity involved.

   The Pharmacy Board would like to assure all reporters of any complaints that such information shall be kept confidential.

2.   WHY HAVE LIMITATIONS TO DRUG PROMOTION

   Control of drug promotion must be looked as a way–

   2.1 To support and encourage the improvement of health care provided on through the rational use of medicinal drugs.

   2.2 To ensure that only reliable drug information is available and disseminated in order to support and encourage rational use of drugs.

   2.3 To encourage Good Manufacturing Practice (GMP). This is because GMP does not end only with the manufacturing process but includes all other processes like marketing and post-marketing surveillance.

   2.4 To protect consumers whose lack of medicinal knowledge could lead to their exploitation by unscrupulous people.

3.   PRINCIPLES OF DRUG PROMOTION

   3.1 All drug promotion activities shall be done in accordance with the National Drug Policy, in compliance with Part IV of the Pharmaceutical and Poisons Act * and this Code.

   3.2 All drug Promotion activities in the country shall take place only with respect to drugs that have been registered by the Pharmacy Board.

   3.3 All promotion-making claims concerning medicinal drugs should be reliable, accurate, truthful, informative, balanced, up to date, and capable of substantiation and in good taste.

   3.4 Promotion material should not contain misleading or unverifiable statements or omissions likely to induce medically unjustifiable drug use or to give rise to undue risks.

   3.5 Promotional material making safety claims should only be used where properly qualified.

   3.6 Comparison of products for competition purposes is prohibited.

   3.7 Promotional material should not be designed so as to disguise a drug's real nature.

   3.8 Scientific data in the public domain should be made available to health care workers, on request, as appropriate to their requirements.

   3.9 Financial or material benefits should not be offered to or sought by health care workers to influence them in the prescription or dispensation of drugs.

4.   PRINCIPLES OF DRUG ADVERTISEMENT

4.1   ADVERTISEMENTS IN ALL FORMS TO HEALTH WORKERS

   4.1.1 Advertisement should contain full product information, as defined by the approved scientific data sheet or similar document approved by the Pharmacy Board during registration of the drug concerned.

4.2   ADVERTISEMENTS IN AIL FORMS TO THE GENERAL PUBLIC

   4.2.1 Only Over the Counter (OTC) drugs shall be targeted to the general public.

   4.2.2 Advertisements to the general public should help people to make rational decisions on the choice and use of drugs determined to be legally available without a prescription.

   4.2.3 Advertisements should take account of people's legitimate desire for information regarding their health.

   4.2.4 Contents of advertisements should not take undue advantage of people's concern for their health.

   4.2.5 Drug advertisements should not be directed at children.

   4.2.6 Advertisements should indicate appropriate limitations to the use of the drug.

   4.2.7 When lay language is used, the information should be consistent with the approved scientific data sheet or other legally determined scientific basis for approval.

   4.2.8 Language that brings about fear or distress should not be used.

   4.2.9 The following are the minimum information requirements for a drug advertisement targeted to the general public:

   (a)   The name(s) of the active ingredient(s) using either international non-proprietary names (INN) or the approved generic name of the drug.

   (b)   The brand name.

   (c)   Approved major indication(s) for use.

   (d)   Major precautions, contra-indications and warnings.

   (e)   Name and address of manufacturer or distributor.

   4.2.10 The advertisement should explicitly indicate the dosage regimen of the drug.

4.3   MEDICAL REPRESENTATIVES

   4.3.1 Medical representatives should make available to prescribers and dispensers complete and unbiased information for each product. The information provided should be within the limitations of the law, regulations and policies of the country.

   4.3.2 Pharmaceutical companies shall be responsible for the statements and activities of their medical representatives.

   4.3.3 Medical representatives should not offer inducements to prescribers and dispensers to prescribe/dispense or sell their products.

4.4   FREE SAMPLES

   4.4.1 Free samples of legally available prescription drugs may be provided in small quantities to prescribers and dispensers on request.

   4.4.2 1 Free samples of non-prescription drugs to the general public for a promotional purpose is prohibited.

4.5   SYMPOSIA, PRODUCT LAUNCHING AND OTHER SCIENTIFIC MEETINGS

   4.5.1 Scientific contents and objectives of any symposium related to drug should be sent to the Pharmacy Board at least 2 weeks prior to the event for approval.

   4.5.2 Sponsorship by a pharmaceutical manufacturer or distributor should be clearly stated in advance, at the meeting and in any proceedings.

   4.5.3 Presentations by independent scientists and health professionals are only allowed if the information being presented is not biased towards the companies' products.

   4.5.4 Presentations should be factual and accurate without omissions.

   4.5.5 Presentations which call for comparison of a new drug presumed to be better than existing ones, should be done in a scientific and factual way.

   4.5.6 Any support to individual health practitioners to participate in any domestic or international symposia should not be conditional or an obligation to promote any medicinal product.

4.6   POST-MARKETING SCIENTIFIC STUDIES, SURVEILLANCE AND DISSEMINATION OF INFORMATION

   4.6.1 All clinical trials must be approved by the Board.

   4.6.2 The Pharmacy Board should be made aware of any clinical trials being conducted in this country or even when a small part of the trial is conducted locally.

   4.6.3 The results of such trials should also be reported to the Board before their dissemination.

   4.6.4 All such trials should have been approved by the appropriate ethical committee approved by the Ministry of Health.

   4.6.5 Wing scientific studies and surveillance should not be used as a form of promotion.

   4.6.6 All drug promoters should report any information on suspected adverse drug reactions to the Pharmacy Board immediately.

4.7   PACKAGING, LABELLING AND INFORMATION TO PATIENTS

   4.7.1 All packaging and labelling materials should provide information consistent with that approved by the Pharmacy Board as specified in the Pharmaceutical and Poisons Act * and consistent with product Registration.

   4.7.2 Adequate information on the use of medicinal drugs should be made available to patients.

   4.7.3 When package inserts or leaflets are provided, manufacturers or distributors should ensure that they reflect only the information that has been agreed upon in this document.

   4.7.4 For imported products, importers should make sure that the information provided is in English or Swahili in compliance with market authorisation of the product.

4.8   PROCEDURE FOR APPROVAL OF ADVERTISEMENTS BY THE PHARMACY BOARD

   4.8.1 Two copies of the advertisement should be sent to the Registrar, Pharmacy Board P. 0. Box 77150 Dar es Salaam. Telephone No. +255 (51) 450512, +255 (51) 45075 1, Fax No. +255 (51) 450793 and E-mail: pharmacy This email address is being protected from spambots. You need JavaScript enabled to view it..

ORDERS

THE POISONS LIST (DECLARATION) ORDER

(Section 33)

[1st January, 1980]

G.Ns. Nos.
22 of 1980
61 of 1988

   1. This Order may be cited as the Poisons List (Declaration) Order.

   2. The list of substances set out in the Schedule to this Order is hereby declared to be the Poisons List the substances specified in which shall be treated as poisons for the purposes of the Pharmaceutical and Poisons Act *.

   3. In construing the contents of the list, unless the contrary intention appears–

   (a)   a reference to a substance shall include a reference to that substance prepared either from natural sources or artificially;

   (b)   a reference to a substance shall include a reference to that substance when contained as such in any preparation, solution, admixture or natural substance.

   4. [Revokes the Poisons List (Confirmation) Order *.]

SCHEDULE
THE POISONS LIST

PART I

   Acebutalol.

   Acetazolamide.

   Acetohexamide.

   Acetylcarbromal.

   Acocanthera, glycosides of Acyclovir.

   Adrenaline.

   Alkali fluorides, except as provided in Part II of this list.

   Alkaloids, the following: their salts, simple or complex; their quaternary compounds.

   Atropine.

   Belladonna, alkaloids of, except as provided in Part II of this list.

   Calabar Bean, alkaloids of Colchicum, alkaloids of Curare, alkaloids of curare bases.

   Ergot, alkaloids of and its esters and semisynthetic alkaloids.

   Emetine.

   Ephedra, alkaloids of Homatropine.

   Hyoscine.

   Hyoscyamine - except as provided in Part II of this list.

   Jaborandi, alkaloids of Lobelia, alkaloids of Raowolfia, alkaloids of their derivatives.

   Solanaceous alkaloids not otherwise included in this list except as provided in Part II of this list.

   Strychnine - except as provided in Part II of this list.

   Amino-alcohols esterified with benzoic acid, phenylpropionic acid, cinnamic acid or the derivatives of these acids; their salts.

   P-Aminobenzenesulphonamide; its salts; derivatives of P-aminobenzenesulphonamide having any of the hydrogen atoms of the P-amine group of the sulphonamide group substituted by another radical; their salts.

   P-Aminopropylbenzene and P-aminoisopropylbenzene and any compound structurally derived from either of those substances by substitution in the side chain or by ring closure therein (or by both such substitution and such closure) except ephedrine.

   N-ethylephedrine N-diethy-laminoephedrine and phenylamine; and salt of any substance falling within this item.

   P-Aminosalicylic acid; its salts

   Any preparation of P-aminosalicylic acid; its salts.

   Amitriptyline; its salts.

   Amylnitrite.

   Angiotensinamide.

   Antibiotics: That is to say, any substances produced by a living organism and which have suppressive or destructive action on other organisms; their synthetic equivalents; their salts, preparations of such substances and their salts; their esters and salts or such esters.

   Antihistamine Substances; all their salts and esters except as provided in Part II of this list.

   Substances being tetra-substituted N-derivatives of ethylenediamine or propylenediamine.

   Antimony, chlorides of; oxides and sulphides of; antimonates; organic compounds of antimony.

   Arsenical substances, the following, except as provided in Part II of this list; halides of arsenic; oxides of arsenic, sulphides of arsenic; arsenates; organic compounds of arsenic.

   Atenolol.

   Azacyclonol; its salts.

   Barium, salts of; other than barium sulphate and except as provided in Part II of this list.

   Benactyzine; its salts.

   Bendrofluazide.

   Benzactamide.

   Benzhexol; its salts.

   Benztropine and its homologies; their salts.

   Bethanidine; its salts.

   Bismuth; salts of; compounds of in a form suitable for injection.

   Bromhexine.

   Bromvaletone.

   Buphenine hydrochloride.

   Bulsuphan; its salts.

   Butylchloral hydrate.

   Captotril.

   Caramiphen; its salts.

   Carbachol.

   Carbamazepine.

   Carbenoxolone.

   Carbromal.

   Carisprodol.

   Chloral; its addition and its condensation products; their molecular compounds-except as provided in Part II of this list.

   Chlorambucil.

   Chlormethiazole; its salts.

   Chloroform, except as provided in Part II of this list.

   Chlorothiazide and other derivatives of benzol-1.2.4-thiadazine-7-sulphonamide-1-dioxide whether hydrogenated or not.

   Chlorphenoxamine.

   Chlorphentermine; its salts.

   Chlorpropamide; its salts.

   Chlorprothixine and other derivatives of 9-methylenethixanthen; their salts.

   Chlorthalidone.

   Choline theophylinate.

   Cimetidine.

   Clofazimine.

   Clofibrate.

   Clomiphene.

   Clonidine hydrochloride.

   Clonitazene; its salts.

   Cloquinate (natural salts of chloroquinol and chiniaform).

   Chlorexolone.

   Corticosteroids, natural and synthetic.

   Coumarin; its salts and derivatives.

   Creosote obtained from wood.

   Cyclarbamate.

   Cyclopentamine hydrochloride.

   Cyclophosphamide.

   Cycloserine.

   Cycrimine; its salts.

   Dapsone.

   Debrisoquine; its salts.

   Dehydroemetine; its salts.

   Desipramine; its salts.

   Di-(4-amidinophenyl)-triazine (N-1:3).

   Diaceturate; its salts; derivatives of and their salts.

   4-4-Diamidino-diazoaminobenzene; their salts (diminazene aceturate).

   Diclofenac acid; its salts.

   Diels-alder compounds, except as provided in Part II of this list.

   Diethylcarbamazine; its salts.

   Diethylether.

   Diethylpropion.

   Diflunisal.

   Digitalis, glycosides of; other active principles of digitalis.

   Dihydroergocristine.

   1:3-Dimethyl-4-phenyl-4-propenyl-oxyhexametheneamine; its salts.

   Dinitrocresols (DNOC); their compounds with a metal or a base except as provided in Part II of this list.

   Dinitronaphthyls.

   Dinitrophenols.

   Dinitrothymois dinosam; its compounds with a metal or base, except as provided in Part II of this list.

   Diperodon; its salts.

   Dipyridamole; its salts.

   Dipyrone.

   Disopyramide.

   Disulfiram.

   Diethylallylamines; their salts.

   Dopamine.

   Dothiepin; its salts.

   Doxepine.

   Dyflos.

   Econazole.

   Ecothlopate iodide.

   Ectylurea.

   Elantrine; its salts.

   Emylcamate.

   Endosulphan; except as provided in Part II of this list.

   Endothal; its salts, except as provided in Part II of this list.

   Enflurane.

   Erythrityl tetranitrate.

   Ethacrynic acid.

   Ethambutol.

   Ethchlorvynol.

   Ethidium bromide.

   Ethinamate.

   Ethionamide.

   Ethosuximide.

   Fenfluramine; its salts.

   Fenoterol hydrobromide.

   Ferrous salts.

   Flavoxate; its salts, its esters; their salts.

   Fluothane.

   Flupenthixol.

   Fluphenazine.

   Folic acid.

   Flusemide.

   Gallamine; its salts, its quarternary compounds.

   Glibenclamine.

   Glipizide.

   Glyceryl trinitrate.

   Griesofulvin.

   Guanethidine; its salts.

   Guanidines, the following polymethylene diguanidines; di-P-anisylphenetyl guanidine.

   Haloperidol and other 4-substituted derivatives of N-(3-fluorobenzopropylpiperidine).

   Haloprogin.

   Hexapropymate.

   Hormones, natural and synthetic; any preparation, admixture, extract or other substances containing any proportion of any substance having the action of any hormone.

   Hydrazines, benzyl, phenethyl or phenoxyethl; their alphamethyl derivatives; acyl derivatives of any of the foregoing substances comprised in this item; salts of any compounds in this item.

   1-(3-hydroxyphenyl)-hydroxy-2-ethylaminethane hydrochloride.

   Hydroxyzine; its salts.

   Ibuprofen.

   Impramine; its salts.

   Indometheqin; its salts.

   Iprindole; its salts.

   Isoaminile; its salts.

   Isoetharine; its salts.

   Isometheptene hydrochloride, mucate.

   Isoniazid; its salts, derivatives of isoniazid, their salts.

   Isoprenaline and salts.

   Isopropamide.

   Isosorbide nitrate.

   Ketoconazole.

   Ketoprofen.

   Ketotifen.

   Lanatoside C.

   Levamisole.

   Levodopa.

   Lithium carbonate.

   Mannityl hexanitrate.

   Mannomustine; its salts.

   Maprotiline.

   Mebutamate.

   Meclofenoxate; its salts.

   Mefenamic acid; its salts; its esters; their salts.

   Mephenesin; its salts.

   Mephentermine; its salts.

   Mercaptopurine; its salts; derivatives of mercaptopurine; their salts.

   Mesterrolone.

   Metaraminol; its salts.

   Metaxalone.

   Methixene; its salts.

   Methocarbomol.

   Methotrexate.

   Methoxamine hydrochloride.

   Methoxyphenamine hydrochloride.

   Methylaminoheptane; its salts when present in nasal preparation.

   Methyldopa.

   Methylpentynol; its esters and other derivatives.

   Methyprylone.

   Metopon; its salts.

   Metoprolol.

   Metrifonate.

   Metronidazole.

   Miconazole.

   Minoxidil.

   Monofluoroacetic acid; its salts.

   Mustine and any other N-substituted derivatives of di-(2-Chloroethyl) amine; their salts.

   Nalidixic acid.

   Narcotics, all narcotics controlled under the International Narcotics Conventions.

   Niflumic acid.

   Niridazole.

   Nitrobenzene except as provided in Part II of this list.

   n-Nitrophenol; o-Nitrophenol; p-Nitrophenol.

   Nortriptyline; its salts.

   Opipramol hydrochloride.

   Orciprenaline sulphate.

   Organotin compounds, the following fentin compounds.

   Orthenadrine; its salts.

   Oxalic acid; metallic oxalates - except as provided in Part II of this list.

   Oxaminiquine.

   Oxethazaine.

   Oxprenolol.

   Oxyphencyclimine hydrochloride.

   Oxytocins, natural and synthetic.

   Pamaquin.

   Paraldehyde.

   Paramethadione.

   Pargyline; its salts.

   Pemoline; its salts.

   Penfluridol.

   Pentacrylthritol tetranitrate.

   Phenaglycodol.

   Phenamidine; its salts - except as provided in Part II of this list.

   Phenanthridium: its salts; its derivatives, their salts; its compounds with other substances.

   Phenindione.

   Phenols (any member of the series of phenols of which the first member is phenol and of which the molecular composition varies from member to member by one atom of carbon and two atoms of hydrogen) except in substances containing less than sixty per cent weight of phenols; compounds of phenol with a metal, except in substances containing less than the equivalent of sixty per cent, weight in weight, or phenols.

   Phenothazine; derivatives of; their salts - except dimethoxanate; its salts; promethazine; its salts and its molecular compounds.

   Phenoxybenzamine.

   Phenylbutazone; its salts.

   5-Phenylhydantoin; its alkyl and acyl derivatives; their salts.

   Phenylpropanolamine hydrochloride.

   Phosphorus, yellow - except as in Part II of this list.

   Phosphorus compounds, the following except as provided in Part II of this list–

   amiton, azinophos-ethyl, azinophos-methyl demeton-o, demeton-s, demeton-o-methyl, demeton-s-methyl, dichlorvos, diethyl 4-methyl-7-coumarinyl phosphorathionate, diethyl p-nitrophenyl phosphate, dimefox, ethyl-p-nitrophenyl, phenylphosphonathionate, mazidox, mecarbam, mevinphos, mipafox, oxydemeton-methyl

   parathion, phentapton, phorate, phosphamidon, sulffotep, TEPP (HEPT) thionazin, triphosphoricpentadimen-thylamide, vamidonthion.

   Picric Acid.

   Picrotoxin.

   Pindolol.

   Pirenzepine.

   Pirprofen.

   Poldine methylsuphate.

   Praziquantel.

   Prazosin.

   Prenylamine.

   Primawuine.

   Primidone.

   Probenecid.

   Procainamide; its salts.

   Procarbazine; its salts.

   Procylidine; its salts.

   Proguanil.

   Propantheline bromide.

   Propranolol; its salts.

   Propylhexedrine; its salts.

   Propinylcyclohexanol.

   Prothidium bromide.

   Prothionamide.

   Prothipendyl; its salts.

   Protriptyline hydrochloride.

   Psychotropic substances, all psychotropic substances controlled by the Psychotropic Substances Convention of 1971.

   Pyrithioxine base.

   Quinapyramine; its salts; its derivatives, their salts compounds of quinapyramine with other substances.

   Quinethazone.

   Quinidine; its salts.

   Quinine hydrochloride; its salts.

   Quinuronium; its salts - except as provided in Part II of this list.

   Salbutamol; its salts.

   Selenium; its compounds.

   Spirolactone.

   Strophanthus; glycosides of strophanthus.

   Styramate.

   Sulphin pyrazone.

   Sulphones; their salts; their derivatives.

   Suramin.

   Syrosingopine.

   Telbutaline sulphate.

   Terbutatine.

   Tetrabanazine; its salts.

   Thalidomide; its salts.

   Thiacetazone; its salts; its derivatives.

   Thiocarlide; its salts.

   Thioridazine hydrochloride.

   Tiaprofenic acid.

   Timolol.

   Tinidazole.

   Tolbutamide.

   Tozaphene - except as provided in Part II of this list.

   Tretamine; its salts.

   Triamterene.

   Triaziquone.

   2:2:2-trichloroethyl alcohol; esters of; their salts.

   Trifluoperazine.

   Trimipramine; its salts.

   Tropicamide.

   Troxidone.

   Vesopressin, natural and synthetic.

   Verapamil; its salts.

   Zidovudine.

   Zinc phosphide, except as provided in Part II of this list.

   Drugs in a form prepared for injection.

PART II

GROUP C

Poison

Percentage pharmaceutical form

Alkaloids, the following and their salts, simple or complex; their quarternary compounds

Less than 0.15 percentage calculated as hyoscyamine.

   Belladonna, alkaloids of ..........................

   Ephedrine salts, when contained in a preparation containing less than 0-2 percent of the alkaloids of ephedra.

Ethylmorphine .........................................

Less than 0-2 percent

Hyoscyamine ..........................................

Less than 0-15 percent

Morphine in approved preparation containing less than 0-2 percent of anhydrous morphine.

Nux Vomica .............................................

Less than 0-2 percent of alkaloids calculated as strychnine.

Opium .....................................................

Preparations for external use containing less than 0-2 percent alkaloids as calculated as anhydrous morphine.

Pholcodine; its salts .................................

Less than 1 percent calculated as pholcodine in approved preparations.

Stramonium, alkaloids of ...........................

Less than 0-15 percent calculated as hyoscyamine.

Strychnine................................................

Less than 0.2 percent.

Antihelminthitics, the following:

   Albendazone ...........................................

Oral form

   Bephenium hydroxynaphtoate....................

Oral form

   Mebendazole............................................

Oral form

   Niclosamide ............................................

Oral form

   Piperazine ...............................................

Oral form

   Pyrantel ..................................................

Oral form

   Thiabendazole .........................................

Oral form

Antihistamines, only when contained in preparations for external application only other than for the eye or nose, and in preparations containing not more than 1 percent of an antihistamine substance intended for application only to the eye or nose.

Arsenical substances ..............................

Less than equivalent of 0.01 percent less than 0.5 percent acetarsol in dentifrices.

Bis(p-acetoxyphenyl)-2-pyridylmethane .....

Oral and rectal form.

Chloral.....................................................

Less than 10 percent of chloral hydrate.

Magnesium trislicate compounds of ...........

In oral form.

Mercury oxide...........................................

Yellow oxide of mercury ointment.

Vitamins, the following:

Vitamin B. Complex .................................

Oral form.

Vitamin C. ..............................................

Oral form.

Multivitamins ..........................................

Oral form.

THE PHARMACEUTICALS AND POISONS (GUIDELINES FOR GOOD MANUFACTURING PRACTICE) ORDER

(Section 58)

[1st May, 1999]

G.N. No. 352 of 1999

   WHEREAS section 58 of the Pharmaceutical and Poisons Act * requires the Minister upon recommendation of the Board, by Order published in the Gazette to prohibit, control, the preparation, importation or sale of any pharmaceutical.

   AND WHEREAS the Board has recommended to the Minister to declare and publish in the Gazette the Guidelines for Good Manufacturing of pharmaceuticals for public awareness.

   NOW THEREFORE, it is hereby declared as follows–

   1. This Order may be cited as the Pharmaceuticals and Poisons (Guidelines for Good Manufacturing Practice) Order.

   2. [Omitted.]

   3. It is hereby provided that after the date of the commencement of this Order no person shall be allowed to manufacture any pharmaceutical without following the Guidelines provided in the Schedule to this Order.

   4. Any person who contravenes or fails to comply with this order shall be guilty of an offence punishable under the Pharmaceutical and Poisons Act *.

SCHEDULE

GUIDELINES FOR GOOD MANUFACTURING PRACTICE

FOREWORD

   The manufacture of pharmaceutical preparations is a basic philosophy which embraces many clearly defined principles, each of which combines certain specialised features and functions requiring constant attention and vigilance by highly trained personnel.

   Quality cannot be tested into a product, but must be built into it by conscientious workers in every phase of processing and production. The excellence of a company's products reflects the integrity, competence, and pride of all the men and women involved in the design, production, and marketing of the products.

   Quality is a summation of the intangible factors necessary and sufficient to assure performance of desired functions.

   One of the most well known sets of regulations that have had a major impact on the drug industries are called Good Manufacturing Practices (GMP). These guidelines describe the minimum requirements that the Government consider necessary for the production of human drugs, veterinary drugs, or medical devices. They address the manufacturing methods, facilities, controls, packaging, storage, and installations for medical devices and drug manufacturing operations.

   The guidelines should be considered as general guides and should be adapted to meet individual needs, making sure that the established standards of drug quality are still achieved. They are intended to apply to the manufacturing processes including packaging and labelling used in the production of drugs in their finished dosage forms.

   This guide to GMP shall be used to justify GMP status through the assessment of applications for manufacturing authorisations and as a basis for the inspection of manufacturing facilities. It will also be used as training material for Pharmacy Board Inspectors, as well as for production and quality control personnel in the industry.

   It is my sincere hope that all concerned will adhere to the guide for the benefit of Tanzania community.

DR. AARON D. CHIDUO,
Minister for Health

TABLE OF CONTENTS

      FOREWORD

      CHAPTER 1: DEFINITIONS

      CHAPTER 2: INTRODUCTION

      CHAPTER 3: QUALITY MANAGEMENT

      Principle

      Quality Assurance

      Good Manufacturing Practices for Pharmaceutical Products (GMP)

      Quality Control

      CHAPTER 4: PERSONNEL

      Principle

      General

      Key Personnel

      Training

      Personnel hygiene

      CHAPTER 5: PREMISES AND EQUIPMENT

      Principle

      General

      Production area

      Storage areas

      Weighing areas

      Quality control area

      Ancillary areas

      Equipment

      Equipment cleaning and use log

      CHAPTER 6: DOCUMENTATION

      Principle

      General

      Documents required

      Labels

      Specifications and testing procedures

      Specifications for starting and packaging materials

      Specifications for intermediate and bulk products

      Specifications for finished products

      Master formulae

      Packaging instructions

      Batch processing records

      Batch packaging records

      Standard operating procedures and records

      Records and reports

      Distribution records

      Complaint files

      Returned drug products

      Drug product salvaging

      Batch envelope

      General

      Contents of the batch envelope

      Control of the batch envelope

      File sample retention

      CHAPTER 7: PRODUCTION

      Principle

      General

      Prevention of cross-contamination and bacterial contamination in production

      Processing operations

      Packaging operations

      Materials

      Principle

      General

      Starting materials

      Packaging materials

      Intermediate and bulk products

      Finished products

      Rejected and recovered materials

      Recalled products

      Returned goods

      Waste materials

      Miscellaneous

      Component, drug product container, closure, and labelling records

      Master production and control records

      Batch production and control records

      CHAPTER 8: QUALITY CONTROL

      Principle

      General

      Control of starting materials and intermediate, bulk, and finished products

      Test requirements

      Production record review

      Stability studies

      Reagents and culture media

      Reference standards

      CHAPTER 9: CONTRACT MANUFACTURE AND ANALYSIS

      Principle

      General

      The contract giver

      The contract acceptor

      The contract

      CHAPTER 10: COMPLAINTS AND PRODUCT RECALL

      Principle

      Complaints

      Product recalls

      CHAPTER 11: SELF-INSPECTION AND QUALITY AUDITS

      Principle

      Items for self-inspection

      Self-inspection team

      Frequency of self-inspection

      Self-inspection report

      Follow-up action

      Quality audit

      Supplier's audits

      CHAPTER 12: MANUFACTURE OF STERILE MEDICINAL PRODUCTS

      Principle

      Explanation

      General

      Manufacture of sterile preparations

      Terminally sterilised products

      Sterile filtered products

      Personnel

      Premises

      Equipment

      Sanitation

      Processing

      Sterilisation

      Sterilisation by heat

      Sterilisation by moist heat

      Sterilisation by dry heat

      Sterilisation by radiation

      Sterilisation by ethylene oxide

      Filtration of pharmaceutical products that cannot be sterilised in their final container

      Finishing of sterile products

      Quality control

CHAPTER 1
INTRODUCTION

   In the manufacture of drugs, overall control is essential to ensure that the consumer receives drugs of high quality. Haphazard operations cannot be permitted in the manufacture of substances that may be necessary to save or to restore or preserve health.

   Difficulties will undoubtedly arise in establishing the necessary criteria for the manufacture of drugs that will meet the established specifications and that can therefore be used with confidence. Recommended practices for the manufacture of drugs of desired quality are set forth below. Adherence to these practices, complementing the various control tests followed from the beginning to the end of the manufacturing cycle, will contribute substantially to the manufacture of consistently uniform hatches of high quality drugs.

   The manufacturer must assume responsibility for the quality of the drugs he produces. He alone can avoid mistakes and prevent mishaps by exercising adequate care in both his manufacturing and control procedures.

   The good practices outlined in this guide are designed to ensure that drugs received by the consumer have been subjected to stringent controls from the beginning to the end of the manufacturing cycle to ensure that they are of high quality. The expression "manufacturing" for this purpose refers to all operations involved in the production of a drug, including processing, compounding, formulating, filling, packaging, and labelling.

   The requirements set forth in this guide are intended to apply primarily to preparations for human administration. However, this should not detract from the need for similar quality considerations in the manufacture of veterinary preparations. The requirements represent general guides stipulating minimum standards. They are not designed to replace other legal controls, but rather to complement or supplement them.

   The principle of Good Manufacturing Practice and its related guidelines are applicable to all operations of manufacturing of pharmaceutical products. They are also relevant for all other large scale pharmaceutical manufacturing processes, such as that undertaken in hospitals and for the preparation of products for use in clinical trials.

   The Pharmacy Board having recognised the need to upgrade the status of manufacturing pharmaceuticals in Tanzania, has developed the first guide of its own kind to form the minimum requirements in pharmaceutical manufacturing.

   This guide forms the basis for licensing pharmaceutical manufacturers in the country. It should therefore be used as a training material for the holder of a manufacturing licence and a guide to drug inspectors performing inspectorate activities to the manufacturing plants.

CHAPTER 2
DEFINITIONS

   These Guidelines may be cited as the Pharmaceuticals and Poisons (Guidelines for Good Manufacturing Practice), Notice 1999.*

   In these Guidelines, unless the context otherwise requires–*

   "Active pharmaceutical ingredient" means a substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a pharmacologically active compound (ingredient).

   "Airlock" means an enclosed space with two or more doors, which is interposed between two or more rooms, e.g., of different classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for and used by either people or goods.

   "Authorised person" means a person(s) responsible for the release of batches of finished product for sale. The batch documentation of a batch of finished product must be signed by an authorised person from the production department and the batch test results by an authorised person from the quality control department for batch release.

   "Batch (or lot)" means defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it could be expected to be homogeneous. In the case of continuous manufacture, the batch must correspond to a defined fraction of the production, characterised by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.

   "Batch number (or lot number)" means a distinctive combination of numbers and / or letters which specifically identifies a batch on labels, the batch records, the certificates of analysis, etc.

   "Batch numbering system" means standard operating procedure describing the details of the batch numbering.

   "Batch records" means all documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product.

   "Bulk product" means any product that has completed all processing stages up to, but not including, final packaging.

   "Calibration" means the set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.

   "Clean area" means an area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.

   "Consignment (or delivery)" means the quantity of starting material, or of a drug product, made by one manufacturer and supplied at one time in response to a particular request or order. A consignment may comprise on or more packages or containers and may include material belonging to more than one batch.

   "Critical process" means a process that may cause variation in the quality of the pharmaceutical product.

   "Cross-contamination" means contamination of a starting material, intermediate product, or finished product with another starting material or product during production.

   "Finished product" means a product that has undergone all stages of production, including packaging in its final container and labelling.

   "In-process control" means checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product confirms to its specifications. The control of the environment or equipment may also be regarded as part of in-process control.

   "Intermediate product" partly processed material that must undergo further manufacturing steps before it becomes a bulk product.

   "Large-volume parenterals" means sterile solutions intended for parenterals application with a volume of 100 ml or more in one container of the finished dosage form.

   "Manufacture" means all operations of purchase of materials and products, production, quality control, release, storage, shipment of finished products, and the related controls.

   "Manufacturer" a company that carries out at least one step of manufacture.

   "Marketing authorisation (product licence, registration certificate)" means a legal document issued by the Pharmacy Board or any other drug regulatory authority that establishes the detailed composition and formulation of the product and the pharmacopoeial or other recognised specifications of its ingredients and of the final product itself, and includes details of packaging, labelling, and shelf life.

   "Master formula" is a document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.

   "Master record" a document or set of documents that serve as a basis for the batch documentation (blank batch record).

   "Packaging" all operations, including filling and labelling, that a bulk product has to undergo in order to become a finished product. Sterile filling is not normally regarded as part of packaging, the bulk product being the filled, but not the finally packaged, primary container.

   "Packaging material" any material, including printed material, employed in the packaging of a pharmaceutical product, excluding any outer packaging used for transportation or shipment packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.

   "Pharmaceutical product" means any medicine intended for human use or veterinary product administered to food-producing animals, presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation (The Pharmaceutical and Poisons Act * and its respective regulations).

   "Processing instructions" - see the meaning of the phrase "Master formula".

   "Production" means and includes all operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing and packaging, to completion of the finished product.

   "Quality assurance" as provided for under Chapter Three;

   "Quality control" as provided for under Chapter Three;

   "Quarantine" means the status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a decision is awaited on their release, rejection, or reprocessing.

   "Reconciliation" means a comparison, making due allowance for normal variation, between the amount of product or materials theoretically produced or used and the amount actually produced or used.

   "Recovery (or blending)" means the introducting of all or part of previous batches (or of re-distilled solvents and similar products) of the required quality into another batch at a defined stage of manufacture.

   "Reprocessing" means the reworking of all or part of a batch of product of an acceptable quality from a defined stage of production so that its quality may be rendered acceptable by one or more additional operations.

   "Returned product" means the finished product sent back to the manufacturer.

   "Specification" means a document describing in detail the requirements with which the products or materials used or obtained during manufacture have to conform. Specifications serve as a basis for quality evaluation.

   "Standard operation procedure (SOP)" means an authorised written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g., equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control, sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.

   "Starting material" means any substance of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials.

   "System" means a regulated pattern of interacting activities and techniques that are united to form an organised whole.

   "Validation" means the documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.

CHAPTER 3
QUALITY MANAGEMENT

Principle:

3.0   In the drug industry at large, quality management is the aspect of management function that determines and implements the "quality policy", i.e., the overally intentions and direction of an organisation regarding quality, as formally expressed and authorised by top management.

The basic elements if quality management are:

•   An appropriate infrastructure or "quality system", encompassing the organisational structure, processes, and resources; and

•   Systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed "quality assurance".

Within an organisation, quality assurance serves as a management tool. In contractual situations, quality assurance also serves to generate confidence in the supplier.

In drug manufacture and supply, the terminology differs. In particular, the term "Quality Control" is inter-related of quality management. They are described here in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products.

Quality Assurance:

3.1   Quality assurance is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangement made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality assurance therefore incorporates Good Manufacturing Practice and other factors, including those outside the scope of this guide such as product design and development.

   The system of quality assurance appropriate to the manufacture of pharmaceutical products should ensure that–

   (a)   pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of Good Laboratory Practice;

   (b)   production and control operations are clearly specified in a written form and GMP requirements are adopted;

   (c)   managerial responsibilities are clearly specified in job descriptions;

   (d)   arrangements are made or the manufacture, supply, and use of the correct starting materials;

   (e)   all necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations, and validations are carried out;

   (f)   the finished product is correctly processed and checked, according to the defined procedures;

   (g)   pharmaceutical products are not sold or supplied before the authorised persons have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorisation and any other regulations relevant to the production, control and release of pharmaceutical products;

   (h)   satisfactory arrangements exist to ensure as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf life;

   (i)   there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system.

3.2   The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorisation and do not place patients as risk due to inadequate safety, quality, or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of the staff in many different departments and at all levels within the company, the company's supplier, and distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of quality assurance incorporating GMP and quality control. It should be fully documented and its effectiveness monitored. All parts of the quality assurance system should be adequately staffed with competent personnel, and should have suitable and sufficient premises, equipment, and facilities.

3.3   Sanitation and hygiene

3.3.1   A high level of sanitation and hygiene should be practised in every aspect of the manufacture of drug products. The scope of sanitation and hygiene should cover personnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection, and anything that could become a source of contamination to the product. Potential sources of contamination should be eliminated through an integrated comprehensive programme of sanitation and hygiene. (For Hygiene refer to Chapter 4, "Personnel", and for Sanitation refer to Chapter 5, "Equipment".)

3.4   Validation

3.4.1   Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarising recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.

3.5   Process validation

3.5.1   Critical process should be validated, prospectively or retrospectively.

3.5.2   When any new master formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.

3.5.3   Signification amendments to the manufacturing process, including any change in equipment or materials that may affect product quality and/or the reproducibility of the process, should be validated.

Good Manufacturing Practices for Pharmaceutical Products (GMP):

3.6   Good manufacturing practices is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate for the intended use and as required by the Pharmaceutical and Poisons Act *. GMP rules are directed primarily to diminishing the risks, inherent in any pharmaceutical production, that cannot be prevented completely through the testing of final products. Such risks are essentially of two types: Cross-contamination (in particular by unexpected contaminants) and mix-ups (confusion) caused by false labels being put on container. Under GMP:

   (a)   all manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;

   (b)   critical steps of manufacturing processes and any significant changes made to the processes are validated;

   (c)   all necessary facilities are provided, including–

      (i)   appropriately qualified and trained personnel;

      (ii)   adequate premises and space;

      (iii)   suitable equipment and services;

      (iv)   correct materials, containers, and labels;

      (v)   approved procedures and instructions;

      (vi)   suitable storage and transport; and

      (vii)   adequate personnel, laboratories, and equipment for in-process controls under the responsibility of the production management;

   (d)   instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;

   (e)   operators are trained to carry out procedures correctly;

   (f)   records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected, any significant deviations are fully recorded and investigated;

   (g)   records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

   (h)   the proper storage and distribution of the products minimises any risk to their quality;

   (i)   a system is available to recall any batch of product from sale or supply;

   (j)   complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products and to prevent recurrence.

Quality Control:

3.7   Quality control is that part of GMP concerned with sampling, specifications, and testing and with the organisation, documentation, and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. Quality control is not confined to laboratory operations but must be involved in all decisions concerning the quality of the product.

3.8   Each holder of a manufacturing authorisation should have a quality control department. The independence of quality control from production is considered fundamental. The quality control department should be independent of other departments and under the authority of a person with appropriate qualifications and experience who has one or several control laboratories at his or her disposal. Adequate resources must be available to ensure that all the quality control arrangements are effectively and reliably carried out.

3.9   The basic requirements for quality control are–

   (a)   adequate facilities, trained personnel and approved procedures must be available for sampling, inspecting, and testing materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;

   (b)   samples of starting materials, packaging materials, intermediate products, bulk products and finished products must be taken by methods and personnel approved by the quality control department;

   (c)   test methods must be validated;

   (d)   records must be maintained (manually and/or by recording instruments) demonstrating that all the required sampling, inspecting, and testing procedures have actually been carried out and that any deviations have been fully recorded and investigated;

   (e)   the finished products must contain ingredients complying with the qualitative and quantitative composition of the product described in the marketing authorisation; the ingredients must be of the required purity, in their proper container, and correctly labelled;

   (f)   records must be made of the results of inspecting and testing materials and intermediate, bulk, and finished products against specifications; product assessment must include a review and evaluation of the relevant production documentation and an assessment of deviations from specified procedures;

   (g)   no batch of product is to be released for sale or supply without prior certification by the authorised person(s) that it is in accordance with the requirements of the marketing authorisation;

   (h)   sufficient samples of starting materials and products must be retained to permit future examination of the product if necessary; the retained product must be kept in its final pack unless the pack is exceptionally large.

3.10   The quality control department as a whole will also have other duties, such as to establish, validate, and implement all quality control procedures, to evaluate, maintain, and store the reference standards for substances, to ensure that the stability of the active pharmaceutical ingredients and products is monitored, to participate in environment monitoring. All these operations should be carried out in accordance with written procedures and recorded.

3.11   Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for finished product, and an examination of the finished pack.

3.12   Quality control personnel must have access to production areas for sampling and investigation as appropriate.

CHAPTER 4
PERSONNEL

Principle:

4.0   The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture and control of pharmaceutical products and active ingredients rely upon people, for this reason there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly understood by the individuals concerned and recorded as written descriptions. All personnel should be aware of the principles of GMP that affect them.

General:

4.1   The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.

4.2   The manufacturer should have an organisation chart. All responsible staff should have their specific duties recorded in written descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP.

4.3   All personnel should be aware of the principles of GMP that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs, all personnel should be motivated to support the establishment and maintenance of high-quality standards.

4.4   Steps should be taken to prevent unauthorised people from entering production, storage, and quality control areas. Personnel who do not work in these areas should not use them as a passageway.

Key Personnel:

4.5   Key personnel include the head of production, the head of quality control, the head of sales/distribution, and authorised person(s). Key posts should be occupied by full-time personnel. The heads of production and quality control should be independent of each other. In large organisations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated.

4.6   Key personnel responsible for supervising the manufacture and quality control of pharmaceutical products should possess the qualifications of a scientific education and practical experience as stipulated in the Pharmaceutical and Poisons Act *. Their education should include the study of an appropriate combination of:

   (a)   Pharmaceutical sciences and technology;

   (b)   chemical engineering;

   (c)   microbiology;

   (d)   chemistry (analytical or organic) or biochemistry;

   (e)   pharmacology and toxicology;

   (f)   physiology; or

   (g)   other related sciences.

   They should also have adequate practical experience in the manufacture and quality assurance of pharmaceutical products, in order to gain such experience, a preparatory period shall be required, during which they shall exercise their duties under professional guidance. The scientific education and practical experience of experts should be such as to enable them to exercise independent professional judgement, based on the application of scientific principles and understanding to the practical problems encountered in the manufacture and quality control of pharmaceutical products.

4.7   The heads of the production and quality control departments generally have some shared, or jointly exercised, responsibilities relating to quality. These include–

   (a)   the authorisation of written procedures and other documents, including amendments;

   (b)   the monitoring and control of the manufacturing environment;

   (c)   plant hygiene;

   (d)   process validation and calibration of analytical apparatus;

   (e)   training, including the application and principles of quality assurance;

   (f)   the approval and monitoring of suppliers of materials;

   (f)   the approval and monitoring of contract manufacturers;

   (h)   the designation and monitoring of storage conditions for materials and products;

   (i)   the retention of records;

   (j)   the monitoring of compliance with GMP requirements;

   (k)   the inspection, investigation, and taking of samples, in order to monitor factors that may affect product quality.

4.8   The head of the production department has the following responsibilities–

   (a)   to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;

   (b)   to approve the instructions relating to production operations, including the inprocess controls, and to ensure strict implementation;

   (c)   to ensure that the production records are evaluated and signed by a designated person before they are made available to the quality control department;

   (d)   to check the maintenance of the department, premises, and equipment;

   (e)   to ensure that the appropriate process validations and calibrations of the control equipment are performed and recorded and the reports made available;

   (f)   to ensure that the required initial and continuing training of production personnel is carried out and adapted according to need.

4.9   The head the of quality control department has the following responsibilities–

   (a)   to approve or reject starting materials, packaging materials, and intermediate, bulks, and finished products;

   (b)   to evaluate batch records;

   (c)   to ensure that all necessary testing is carried out;

   (d)   to approve sampling instructions, specifications, test methods, and other quality control procedures;

   (e)   to approve and monitor analyses carried out under contract;

   (f)   to check the maintenance of the department, premises and equipment;

   (g)   to ensure that the appropriate validations, including those of analytical procedures, and calibrations of control equipment are done;

   (h)   to ensure that the required initial and continuing training of quality control personnel is carried out and adapted according to need.

   Other duties of the quality control department are summarised in section 3.7-3.10

Training:

4.10   The manufacturer should provide training in accordance with a written programme for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance, and cleaning personnel), and for other personnel whose activities could affect the quality of the product.

4.11   Besides basic training on the theory and practice of GMP, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by the head of either production or quality control, as appropriate. Training records should be maintained.

4.12   Personnel working in areas where contamination is a hazard, e.g., clean areas or areas where highly active, toxic, infectious, or sensitizing materials are handled, should be given specific training.

4.13   The concept of quality assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions.

4.14   Visitors or untrained personnel should preferably not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.

Personnel Hygiene:

4.15   All personnel, prior to and during employment, as appropriate, should undergo health examinations. Personnel conducting visual inspections should undergo periodic eye examinations.

4.16   All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing processes. In particular, personnel should be instructed to wash their hands before entering production area. Signs to this effect should be posted and instructions observed.

4.17   Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials, or drug products until the condition is no longer judged to be a risk.

4.18   All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment, or personnel) that they consider may adversely affect the products.

4.19   Direct contact should be avoided between the operators' hands and starting materials, primary packaging materials, and intermediate or bulk product.

4.20   To ensure protection of the product from contamination, personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, should be stored in separate closed containers until properly laundered and, if necessary disinfected or sterilised.

4.21   Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material, and personnel medicines should not be permitted in production, laboratory, and storage areas or in any other area where they might adversely influence product quality.

4.22   Personal hygiene procedures including the use of protective clothing should apply to all persons entering production areas, whether they are temporary or full time employees or non-employees - e.g., contractors' employees, visitors, senior managers, and inspectors.

CHAPTER 5
PREMISES AND EQUIPMENT

Principle:

5.0   Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and in general, any adverse effect on the quality of products.

General:

5.1   Premises should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of material or products.

5.2   Premises used for the manufacture of drug products should be suitably designed and constructed to facilitate good sanitation.

5.3   Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products. Premises should be cleaned and, where applicable, disinfected according to the detailed written procedures.

5.4   Electrical supply, lighting, temperature, humidity, and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.

5.5   Premises should be designated and equipped so as to afford maximum protection against entry of insects or other animals.

Production area:

5.6   In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillin) or biological preparations (e.g., live microorganisms). The production of certain products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in the premises used for the manufacture of pharmaceutical products.

5.7   Premises should be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

5.8   The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimise the risk of omission or wrong application of any of the manufacturing or control steps.

5.9   Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors, and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, where appropriate, disinfection.

5.10   Pipework, light fittings, ventilation points, and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

5.11   Drains should be of adequate size and equipped to prevent back-flow. Open channels should be avoided, if they are necessary they should be shallow to facilitate cleaning and disinfection.

5.12   Production areas should be effectively ventilated, with air-control facilities (including control of temperature and, where necessary, humidity and filtration) appropriate to the products handles, to the operations undertaken, and to the external environment. These areas should be regularly monitored during production and non-production periods to ensure compliance with their design specifications.

5.13   Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.

5.14   Production areas should be well lit, especially where visual on-line controls are carried out.

Storage areas:

5.16   Storage areas should be of sufficient capacity to allow orderly storage of various categories of materials and products: starting and packaging materials, intermediates, bulk and finished products, products in quarantine, and released, rejected, returned, or recalled products.

5.17   Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity) these should be provided, checked, and monitored.

5.18   Receiving and dispatch bays should protect materials and products from whether, Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned if necessary before storage.

5.19   Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. Any system replacing the physical quarantine should give equivalent security.

5.20   There should be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.

5.21   Segregation should be provided for the storage of rejected, recalled, or returned materials or products.

5.22   Highly active materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire, or explosion should be stored in safe and secure areas.

5.23   Printed packaging materials are critical to the conformity of the pharmaceutical product to its labelling, and special attention should be paid to the safe and secure storage of these materials.

Weighing areas:

5.24   The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing designed for that use, for example with provisions for dust control.

Quality control area:

5.25   Quality control laboratories should be separated from production areas. Areas where biological, microbiological, or radio-isotope test methods are employed should be separated from each other.

5.26   Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples, reference standards (with cooling), and records.

5.27   The design of the laboratories should take into account the suitability of construction materials, prevention of fumes, and ventilation. Separate air-handling units and other provisions are needed for biological, microbiological, and radio-isotope laboratories.

5.28   A separate room should be allocated for instruments to protect them against electrical interference, vibration, contact with excessive moisture, other external factors and to isolate the instruments.

Ancillary areas:

5.29   Rest and refreshment rooms should be separate from other areas.

5.30   Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not communicate directly with production or storage areas.

5.31   Maintenance workshops should be separate from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.

5.32   Animal houses should be well isolated from other areas, with separate entrance (animal access) and air-handling facilities.

Equipment:

5.33   Equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. The layout and design of equipment must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products.

5.34   Equipment should be installed in such a way as to minimise any risk of error or contamination.

5.35   Fixed pipe-work should be clearly labelled to indicate the contents and, where applicable, the direction of flow.

5.36   All service piping and devices should be adequately marked and special attention paid to the provision of non-interchangeable connections or adapters for dangerous gases and liquids.

5.37   Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated on a scheduled basis.

5.38   Production equipment should be designed, located, and maintained to serve its intended purpose.

5.39   Production equipment should be designed so that it can be easily and thoroughly cleaned on a scheduled basis.

5.40   Control-laboratory equipment and instruments should be suited to the testing procedures undertaken.

5.41   Washing and cleaning equipment should be chosen and used so as not to be a source of contamination.

5.42   Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to an extent that would affect the quality of the product.

5.43   Defective equipment should, be removed from production and quality control areas, where this is not possible, it should be clearly labelled as defective.

Equipment cleaning and use log:

5.44   A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.

5.45   If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical sequence.

5.46   In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.

CHAPTER 6
DOCUMENTATION

Principle:

Good documentation is an essential part of the quality assurance system and, as such, should be related to all aspects of Good Manufacturing Practice. Its aims are to define the specifications for all materials and methods of manufacture and control. This is to ensure that all personnel concerned with manufacture know what to do and when to do it. It is also necessary to ensure that authorised persons have all the information necessary to decide whether or not to release a batch of drug for sale, and to provide an audit trail that will permit investigation of the history of any suspected defective batch. The design and use of documents depends upon the manufacturer.

General:

6.1   Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorisations.

6.2   Documents should be approved, signed, and dated by appropriate authorised persons. No document should be changed without authorisation.

6.3   Documents should have unambiguous contents: the title, nature, and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

6.4   Documents should be regularly reviewed and kept up to date. When a document has been revised, a system should exist to prevent an advertent use of the superseded version.

6.5   Where documents require the entry of data, these entries should be clear, legible, and indelible. Sufficient space should be provided for such entries.

6.6   Any alteration made to a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

6.7   Records should be made or completed when any action is taken and in such a way that all-significant activities concerning the manufacture of pharmaceutical products are traceable. Records and associated standard operating procedures should be retained for at least one year after the expiry date of the finished product.

6.8   Data may be recorded by electronic data processing systems or by photographic or other reliable means. Master formulae and detailed standard operating procedures relating to the system in use should be available and the accuracy of the records should be checked, If documentation is handled by electronic data-processing methods, only authorised persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper print-outs, or other means. It is particularly important that, during the period of retention, the data are readily available.

Documents required:

Labels:

6.9   Labels applied to containers, equipment, or premises should be clear, unambiguous, and in the company's agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example: quarantined, accepted, rejected, or clean).

6.10   Labelling should identify all finished drug products, as required by the Pharmaceutical and Poisons Act * and its respective regulations, bearing at least the following information–

   (a)   the name of the drug product;

   (b)   a list of the active ingredients (if applicable, with the International Non-proprietary Names), showing the amount of each present, and a statement of the net contents, e.g., number of dosage units, weight, or volume;

   (c)   the batch number assigned by the manufacturer;

   (d)   the expiry date in an uncoded form;

   (e)   any special storage conditions or handling precautions that may be necessary;

   (f)   directions for use, and warnings and precautions that may be necessary; and

   (g)   the name and address of the manufacturer or the company or the person responsible for placing the product on the market.

6.11   For reference standards, the label or accompanying document should indicate concentration, date of manufacture, expiry date, date the closure is first opened. and storage conditions, where appropriate.

Specifications and testing procedures:

6.12   Testing procedures described in documents should be validated in the context of available facilities and equipment before they are adopted for routine testing.

6.13   There should be appropriately authorised and dated specifications, including tests on identity, content, purity, and quality, for starting and packaging materials and finished products; where appropriate, they should also be available for intermediate or bulk products. Specifications for water, solvents, and reagents (e.g., acids and bases) used in production should be included.

6.14   Each specification should be approved and maintained by the quality control department. Specifications for starting materials, intermediates and bulk and finished products refer to sections 5.18-5.23 of these guidelines.

6.15   Periodic revisions of specifications may be necessary to comply with new editions of the Tanzania National formulary or other official compendia.

6.16   Pharmacopoeias, reference standards, reference spectra, and other reference materials should be available in the quality control laboratory.

Specifications for starting and packaging materials:

6.17   Specifications for starting and primary or printed packaging materials should provide, if applicable, a description of the materials, including–

   (a)   the designated name (if applicable, the International Non-proprietary Name) and internal code reference;

   (b)   the reference, if any, to a pharmacopoeia monograph; and

   (c)   qualitative and quantitative requirements with acceptance limits.

6.18   Other data may be added to the specification, such as:

   (a)   the supplier and the original producer of the materials;

   (b)   a specimen of printed materials;

   (c)   directions for sampling and testing, or a reference to procedures.

6.19   Packaging material should conform to specifications, with emphasis placed on the compatibility of the material with the drug product it contains. The material should be examined for critical and major physical defects and as well as for the correctness of identity markings.

6.20   Documents describing testing procedures should state the required frequency for re-assaying each starting material, as determined by its stability.

Specifications for intermediate and bulk products:

6.21   Specifications for intermediate and bulk products should be available if these are purchased or dispatched, or if data obtained from intermediate products are used in evaluation of finished product. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Specifications for finished products:

6.22   Specifications for finished products should include–

   (a)   the designated name of the product and the code reference where applicable;

   (b)   the designated name(s) of the active ingredients(s) (if applicable, the International Non-proprietary Name(s));

   (c)   the formula or a reference to the formula;

   (d)   the description of the dosage form and package details;

   (e)   directions for sampling and testing or a reference to procedures;

   (f)   the qualitative and quantitative requirements, with acceptance limits;

   (g)   the storage conditions and precautions, where applicable; and

   (h)   the shelf life.

Master formula:

6.23   A formally authorised master formula should exist for each product and batch size to be manufactured.

6.24   The master formula should include–

   (a)   the name of the product, with a product reference code relating to its specification;

   (b)   a description of the dosage form, strength of the product, and batch size;

   (c)   a list of all starting materials to be used (if applicable, with the International Non-proprietary Names), with the amount of each, described using the designated name and a reference that is unique to that material (mention should be made of any substance that may disappear in the course of processing);

   (d)   a statement of expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable;

   (e)   a statement of the processing location and the principal equipment to be used;

   (f)   the methods, or reference to methods, to be used for preparing the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilising;

   (g)   detailed stepwise processing instructions (e.g., checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);

   (h)   the instruction for any in-process controls with their limits–

      (i)   where necessary, the requirements for storage of the products, including the container, the labelling and any special storage condition; and

      (ii)   any special precautions to be observed.

Packaging Instructions:

6.25   Formally authorised packaging instructions should exist for each product, pack size, and type. These should normally include, or make reference to–

   (a)   the name of the product;

   (b)   a description of its pharmaceutical form, strength and method of application where applicable;

   (c)   the pack size expressed in terms of the number, weight, or volume of the product in the final container;

   (d)   a complete list of all the packaging materials required for a standard batch size, including quantities, sizes, and types, with the code or reference number relating to the specifications for each packaging material;

   (e)   where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked;

   (f)   special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before operations begin;

   (g)   a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and

   (h)   details of in-process controls with instructions for sampling and acceptance limits.

Batch processing records:

   A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the currently approved master formula. The method of preparation of such records should be designed to avoid transcription errors.

6.26   Before any processing begins, a check should be made that the equipment and workstation are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded.

6.27   During processing, the following information should be recorded at the time each action is taken, and after completion the record should be dated and signed by the person responsible for the processing operations:

   (a)   the name of the product;

   (b)   the number of the batch being manufactured;

   (c)   dates and times of commencement, of significant intermediate stages, and of completion of production;

   (d)   the name of the person responsible for each stage of production;

   (e)   the initials of the operator(s) of different significant steps of production and where appropriate, of the person(s) who checked each of these operations (e.g., weighing);

   (f)   the batch number and / or analytical control number and the quantity of each starting material actually weighed including the batch number and amount of any recovered or reprocessed material added);

   (g)   any relevant processing operation or event and the major equipment used;

   (h)   the in-process controls performed, the initials of the person(s) carrying them out, and the results obtained;

   (i)   the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield; and

   (j)   notes on special problems including details, with signed authorisation for any deviation from the master formula.

Batch packaging records:

6.28   A batch packaging record should be kept for each batch or part hatch processed. It should be based on the relevant parts of the packaging instructions, and the method of preparing such records should be designed to avoid transcription errors.

6.29   Before any packaging operation begins, checks should be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. These checks should be recorded.

6.30   The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password:

   (a)   the name of the product, the batch number, and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the actually obtained, and the reconciliation;

   (b)   the date(s) and time(s) of the packaging operations;

   (c)   the name of the responsible person carrying out the packaging operations;

   (d)   the initials of the operators of the different significant steps;

   (e)   the checks made for identity and conformity with the packaging instructions, including the results of in-process controls;

   (f)   details of packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product unpacked or a record of returning product that has not been packaged to the storage area;

   (g)   whenever possible, samples of the printed packaging materials used, including specimens bearing the batch number, expiry date, and any additional overprinting;

   (h)   notes on any special problems, including details of any deviation from the packaging instructions, with written authorisation by an appropriate person; and

   (i)   the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed, or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

Standard operating procedures and records:

6.31   There should be standard operating procedures and records for the receipt of each delivery of starting material and primary and printed packaging material.

6.32   The records of the receipts should include:

   (a)   the name of the material on the delivery note and the containers;

   (b)   the "in-house" name and/ or code of material if different from (a) above;

   (c)   the date of receipt;

   (d)   the supplier's name and, if possible, manufacturer's name;

   (e)   the manufacturer's batch or reference number;

   (t)   the total quantity and number of containers received;

   (g)   the batch number assigned after receipt; and

   (h)   any relevant comment (e.g., state of the containers).

6.33   There should be standard operating procedures for the internal labelling, quarantine, and storage of starting materials, packaging materials, and other materials, as appropriate.

6.34   Standard operating procedures should be available for each instrument and piece of equipment and placed in close proximity to the equipment.

6.35   There should be standard operating procedures for sampling, which specify the person(s) authorised to take samples.

6.36   The sampling instructions should include–

   (a)   the method of sampling and the sampling plan;

   (b)   the equipment to be used;

   (c)   any precautions to be observed to avoid contamination of the material or any deterioration in its quality;

   (d)   the amount(s) of sample(s) to be taken;

   (e)   instructions for any required subdivision of the sample;

   (f)   the type of sample container(s) to be used, and whether they are for aseptic sampling or for normal sampling;

   (g)   any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material.

6.37   There should be a standard operating procedure describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk, or finished product is identified with a specific batch number.

6.38   The standard operating procedures for batch numbering that is applied to the processing stage and to the respective packaging stage should be related to each other.

6.39   The standard operating procedure for batch numbering should assure that the same batch numbers will not be repeatedly used; this applies also to reprocessing.

6.40   Batch-number allocation should be immediately recorded, e.g., in a logbook. The record should include date of allocation, product identity, and size of batch.

6.41   There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded.

6.42   Analysis records should include at least the following data–

   (a)   the name of the material or product and, where applicable, dosage form;

   (b)   the batch number and, where appropriate, the manufacturer and/or supplier;

   (c)   references to the relevant specifications and testing procedures;

   (d)   test results, including observations and calculations, and reference to any specifications (limits);

   (e)   dates of testing;

   (f)   the initials of persons who performed the testing;

   (g)   the initials of the persons who verified the testing and the calculations, where appropriate; and

   (h)   a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.

6.43   Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by an authorised person.

6.44   Complete records of distribution should be maintained of the distribution of each batch of drug in a manner that will facilitate its recall if necessary. Such records should be retained for at least 1 year after expiry date of the batch, and shall include the name and address of the consignee, the date and quantity shipped, and the lot or control numbers identifying the batch of drug.

6.45   Standard operating procedures and associated records of actions taken or, where appropriate, conclusions reached should be available for–

   (a)   equipment assembly and validation;

   (b)   analytical apparatus and calibration;

   (c)   maintenance, cleaning and sanitation;

   (d)   personnel matters including qualification, training, clothing, and hygiene;

   (e)   environmental monitoring;

   (f)   pest controls;

   (g)   complaints;

   (h)   recalls; and

   (i)   returns.

6.46   Logbooks should be kept with major and critical equipment and should record, as appropriate, any validations, calibrations, maintenance, cleaning, or repair operations, including dates and the identity of the people who carried these operations out.

6.47   The use of major and critical equipment and the areas where products have been processed should be appropriately recorded in chronological order.

6.48   There should be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules methods, equipment, and materials to be used and facilities to be cleaned. Such written procedures should be followed.

Records and reports:

6.49   Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiry date of the batch.

6.50   Records shall be maintained for all components, drug product containers, closures, and labelling for at least 1 year after the expiration date of the last lot of drug product incorporating the component or using the container, closure, or labelling.

6.51   All records required under this part, or copies of such records, shall be readily available for authorised inspection during the retention period at the establishment where the activities described in such records occurred. These records shall be subject to photocopying or other means of reproduction as part of such inspection.

6.52   Records required under this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming are used suitable reader and photocopying equipment shall be readily available.

6.53   Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures.

Distribution records:

6.54   Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and the lot or control of the drug product. For compressed medical gas products, distribution records are not required to contain lot or control numbers.

Complaint files:

6.55   Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed.

Returned drug products:

6.56   Procedures for the holding, testing and reprocessing of returned drug products shall be in writing and shall be followed.

Drug product salvaging:

6.57   Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke. fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the market.

6.58   Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is:

   (a)   Evidence from laboratory tests and assays (including animal tests where applicable) that the drug products meets all applicable standards of identity, strength, quality, and purity;

   (b)   Evidence from inspection of the premises that the drug products and their associated packaging were not subjected to improper storage conditions as a result of a disaster or accident.

   i.   Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products meet appropriate standards of identity, strength, quality, and purity.

   ii.   Records including name, lot number, and disposition shall be maintained for drug products subject to this section.

Batch envelope:

General:

6.59   The purpose of batch envelope is to file all relevant manufacturing / quality control documents relating to a particular drug product lot. The batch envelope serves as an official record of the manufacture, filling, labelling and packaging of each product and the in-process testing and results obtained prior to release and any testing after release of the drug product. A procedure outlining the responsibilities of personnel in the preparation of batch envelope must be written and followed.

Contents of the batch envelope:

6.60   The batch envelope of any product should contain the completed originals of the following documents–

   (a)   manufacturing order;

   (b)   standard manufacturing procedure;

   (c)   material requisitions / materials returns to store;

   (d)   product yield statement;

   (e)   quality assurance profile;

   (f)   manufacturing quality control chart;

   (g)   fill - label - packing order;

   (h)   inspection start-up check list;

   (i)   record of inspection;

   (j)   fill quality control chart;

   (k)   packaging materials usage analysis;

   (l)   finished goods to store transfer note.

Control of the batch envelope:

6.61   The batch envelope should be held at all times by the quality control manager under lock and should not be given to other departments without his authority. Records shall be kept for at least 1 year after expiry of the drug product.

File sample retention:

6.62   A policy with the objective of establishing uniformity and procedure for the retention of file samples must be written and followed. The procedure must apply to samples of raw materials, finished pharmaceutical products, ethical veterinary and animal health products manufactured in Tanzania.

6.63   The procedure must cover the following areas:

   (a)   sample size;

   (b)   retention period;

   (c)   retention area;

   (d)   size;

   (e)   storage conditions;

   (f)   location;

   (g)   records;

   (h)   accessibility;

   (i)   responsibility.

CHAPTER 7
PRODUCTION

Principle:

Production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorisations, with the objective of obtaining products of the requisite quality.

General:

7.1   All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging, and distribution should be done in accordance with written procedures or instructions and must be recorded.

7.2   Any deviation from instructions or procedures should be avoided as far as possible. If deviations occur, they should be approved in writing by a designated person, with the involvement of the quality control department.

7.3   Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.

7.4   Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.

7.5   At all times during processing, all materials, bulk containers, major items of equipment, and where appropriate the rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength, and the batch number. Where applicable, this indication must also mention the stage of production.

7.6   Access to production areas should be restricted to authorised personnel.

7.7   Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.

7.8   In-process controls are mostly performed within the production area. They should not carry any risk for the quality of the product.

Prevention of cross-contamination and bacterial contamination in production:

7.9   When dry materials and products are used in production, special precautions should be taken to prevent the generation and dissemination of dust.

7.10   Contamination of starting material or of a product by another material or product should be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapours, sprays, or organisms from materials and products in process, from residues on equipment, from intruding insects, and from operators' clothing or skin. The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations such as living organisms, certain hormones, cytotoxic substances, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses and/or over a long time.

7.11   Cross-contamination should be avoided by appropriate technical or organisational measures such as–

   (a)   production should take place in segregated areas (this is required for products such as penicillin, live vaccines, live bacterial preparations and certain other biological preparations);

   (b)   providing appropriate airlocks, pressure differentials, and air extraction;

   (c)   minimising the risk of contamination caused by re-circulation or re-entry of untreated or insufficiently treated air;

   (d)   wearing protective clothing in areas where products with special risk of cross-contamination are processed;

   (e)   using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination;

   (f)   using a "closed system" of production;

   (g)   testing for residues;

   (h)   using cleanliness status labels on equipment.

7.12   Measures to prevent cross-contamination and their effectiveness should be checked periodically according to standard operating procedures.

7.13   Production areas where susceptible products are processed should undergo periodic microbiological monitoring.

Processing operations:

7.14   Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels, or documents not required for the current operation.

7.15   Any necessary in-process controls and environmental controls should be carried out and recorded.

7.16   Means should be instituted of indicating failures of equipment or of services (e.g., water, gas) to equipment. Defective equipment should be withdrawn from use until the defect has been rectified. Production equipment should be cleaned according to detailed written procedures and stored only under clean and dry conditions.

7.17   Containers for filling should be cleaned before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles.

7.18   Any deviation from the expected yield should be recorded and investigated.

7.19   Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.

7.20   Pipelines used for conveying distilled or deionized water and, other water-pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

7.21   Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at pre-specified intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when re-calibration is due should be clearly indicated.

7.22   Repair and maintenance operations should not present any hazard to the quality of the products.

Packaging operations:

7.23   When the programme for packaging operations is being set up, particular attention should be given to minimising the risk of cross-contamination, mix-ups, or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.

7.24   Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines, and other equipment are clean and free from any products, materials, or documents previously used and not required for the current operation. The line clearance should be performed according to an appropriate checklist and should be recorded.

7.25   The name and batch number of the product being handled should be displayed at each packaging station or line.

7.26   Filling and sealing should be followed as quickly as possible by labelling. If labelling is delayed, appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur.

7.27   The correct performance of any printing (code numbers, expiry dates, etc.) done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand, which should be rechecked at regular interval.

7.28   Special care should be taken when cut labels are used and when overprinting is carried out off-line, and in hand-packaging operations. Roll-feed labels are normally preferable to cut labels in helping to avoid mix-ups. On-line verification of all labels by automated electronic means is helpful in preventing mix-ups, but checks should be made to ensure that any electronic code readers, label counters, or similar devices are operating correctly.

7.29   Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.

7.30   On-line control of the product during packaging should include at least the checks on–

   (a)   the general appearance of the packages;

   (b)   whether the packages are complete;

   (c)   whether the correct products and packaging materials are used;

   (d)   whether the overprinting is correct;

   (e)   the correct functioning of line monitors.

   Samples taken away from the packaging line should not be returned.

7.31   Products that have been involved in an unusual event during packaging should be reintroduced into the process only after special inspection, investigation, and approval by authorised personnel involving the quality control department. A detailed record should be kept of this operation.

7.32   Any discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release.

7.33   Upon completion of a packaging operation any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock.

Materials:

Principle:

7.34   The main objective of a pharmaceutical plant is to produce finished products for patients' use from a combination of materials (active, auxiliary, packaging). Special attention should be given to the materials as such.

General:

7.35   All incoming materials and finished products should be quarantined immediately after receipt or processing, until they are released for use or distribution.

7.36   All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation by a first-in, first-out rule.

Starting materials:

7.37   The purchase of starting materials is an important operation that should involve staff who have a particular and through knowledge of the products and suppliers.

7.38   Starting materials should be purchased only from suppliers named in the relevant specification and, where possible, directly from the producer. It is also recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labelling, and packaging requirements as well as complaints and rejection procedures, are discussed between the manufacturer and the supplier.

7.39   For each consignment, the containers should be checked for integrity of package and seal and for correspondence between the order, the delivery note, and the supplier's labels.

7.40   All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled, with the prescribed data.

7.41   Damage to containers and any other problem that might adversely affect the quality of a material should be recorded and reported to the quality control department and investigated.

7.42   If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing, and release.

7.43   Starting materials in storage area should be appropriately labelled. Labels should bear at least the following information–

   (a)   the designated name of the product and the internal code reference where applicable;

   (b)   the batch number(s) given by the supplier and on receipt by the manufacturer, if any;

   (c)   where appropriate, the status of the contents (e.g., on quarantine, on test, released, rejected, returned, recalled);

   (d)   where appropriate, an expiry date or a date beyond which re-testing is necessary.

7.44   There should be appropriate procedures or measures to ensure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified.

7.45   Only starting materials released by quality control department and within their shelf-life should be used.

7.46   Starting materials should be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.

7.47   Each dispensed material and its weight or volume should be independently checked and the check recorded.

7.48 Materials dispensed for each batch of the final product should be kept together and conspicuously labelled as such.

Packaging Materials:

7.49   The purchase, handling, and control of primary and printed packaging materials shall be as for starting materials.

7.50   Particular attention should be paid to printed packaging materials. They should be stored in secure conditions so as to exclude the possibility of unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by designated personnel following an approved and documented procedure.

7.51   Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.

7.52   Outdated or obsolete primary packaging material or printed packaging material should be destroyed and its disposal recorded.

7.53   All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity, and conformity with the packaging instructions.

Intermediate and bulk products:

7.54   Intermediate and bulk products should be kept under appropriate conditions.

7.55   Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.

Finished Products:

7.56   Finished products should be held in quarantine until their final release, after which they should be stored as usable stock under conditions established by the manufacturer.

7.57   The evaluation of finished products and the documentation necessary for release of a product for sale are described in Chapter 8, "Quality Control".

Rejected and recovered materials:

7.58   Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers, or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved by the authorised personnel and recorded.

7.59   The reprocessing of rejected products should be exceptional. It is permitted only if the quality of the final product is not affected, if the specifications are met, and it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. A record should be kept of the reprocessing. A reprocessed batch should be given a new batch number.

7.60   The introduction of all or part of earlier batches, conforming to the required quality, into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf-life. The recovery should be recorded.

7.61   The need for additional testing of any finished product that has been reprocessed, or into which a recovered product has been incorporated, should be considered by the quality control department.

Recalled products:

7.62   Recalled products should be identified and stored separately in a secure area until a decision is taken on their fate. The decision should be made as soon as possible.

Returned goods:

7.63   Products returned from the market should be destroyed unless it is certain that their quality is satisfactory; they may be considered for resale, relabelling, or bulking with a subsequent batch only after they have been critically assessed by quality control department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered for re-issue or re-use. Any action taken should be appropriately recorded.

Waste materials:

7.64   Provision should be made for the proper and safe storage of waste materials awaiting disposal. Toxic substances and flammable materials should be stored in suitably designed, separate, and enclosed cupboards.

7.65   Waste material should not be allowed to accumulate. It should be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals.

Miscellaneous:

7.66   Rodenticides, insecticides, fumigating agents, and sanitizing materials should not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials, or finished products.

Component, drug product container, closure, and labelling records:

7.67   These records shall include the following–

   (a)   the identity and quantity of each shipment of each lot of components, drug product containers, closures, and labelling; the name of the supplier;

   (b)   the supplier's lot number(s) if known;

   (c)   the receiving code;

   (d)   the date of receipt;

   (e)   the name and location of the prime manufacturer if different from the supplier, shall be known;

   (f)   the results of tests or examination performed;

   (g)   the conclusions derived therefrom;

   (h)   an individual inventory record of each component, drug product container, and closure and, for each component, a reconciliation of the use of each lot of such component;

   (i)   the inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container, and closure;

   (j)   documentation of examination and review of labels and labelling for conformity with established specifications;

   (k)   the disposition of rejected components, drug product containers, closure, and labelling.

Master production and control records:

   To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.

   The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed.

Batch production and control records:

7.70   Batch production and control records shall be prepared for each Batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include–

   (a)   an accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed;

   (b)   documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including;

   (c)   dates;

   (d)   identity of individual major equipment and lines used;

   (e)   specific identification of each batch of component or in-process material used;

   (f)   weights and measures of components used in the course of processing;

   (g)   in process and laboratory control results;

   (h)   inspection of the packaging and labelling area before and after use;

   (i)   a statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing;

   (j)   complete labelling control records, including specimens or copies of all labelling used;

   (k)   description of drug product containers and closures;

   (l)   any sampling performed;

   (m)   identification of the persons performing and directly supervising or checking each significant steps in the operations;

   (n)   any investigation made;

   (o)   results of examinations made.

CHAPTER 8
QUALITY CONTROL

Principle:

   Quality control is concerned with sampling, specifications, and testing as well as with the organisation, documentation, and release procedures that ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality control is not confined to laboratory operations, but must be involved in all decisions that may concern the quality of the product. The independence of quality control from production is fundamental.

General:

Control of starting materials and intermediate, bulk, and finished products:

8.1   All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected.

8.2   Samples should be representative of the batches of material from which they are taken in accordance with the approved written procedure.

8.3   Sampling should be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling.

8.4   Care should be taken during sampling to guard against contamination or mix-up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean. Particularly hazardous or potent materials require special precautions.

8.5   Sampling equipment should be cleaned and, if necessary sterilised before and after each use and stored separately from other laboratory equipment.

8.6   Each sample container should bear a label indicating–

   (a)   the name of the sampled material;

   (b)   the batch or lot number;

   (c)   the number of the container from which the sample has been taken;

   (d)   the signature of the person who has taken the sample; and

   (e)   the date of sampling.

Test requirements:

8.7   Starting and Packaging materials

   Before releasing a starting or packaging material for use, the quality control manager should ensure that the materials have been tested for conformity with specifications for identity, strength, purity, and other quality parameters.

8.8   An identity test should be conducted on a sample from each container of starting material. Each batch (lot) of printed packaging materials must be examined following receipt.

8.9   In lieu of testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the supplier's analysis through appropriate periodic validation of the supplier's test results and through on-site audits of the supplier's capabilities. Certificates must be originals (not photocopies). Certificates must contain the following information–

   (a)   identification of the issuing supplier, signature of the competent official, and statement of his or her qualifications;

   (b)   the name and batch number of the material tested;

   (c)   a statement of specifications and methods used; and

   (d)   a statement of test results obtained and the date of testing.

8.10   In-process control

   In-process control records should be maintained and form part of the batch records.

8.11   Finished Products

   For each batch of drug product there should be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to release.

8.12   Products failing to meet the established specifications or any other relevant quality criteria should be rejected. Reprocessing may be performed, if feasible, but the reprocessed product should meet all specifications and other quality criteria prior to its acceptance and release.

Production record review:

8.13   Production and control records should be reviewed and any divergence or failure of a batch to meet its specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action.

8.14   Retention samples from each batch of finished product should be kept for at least one year after expiry date. Finished products should be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials should be retained for at least one year beyond the expiry date of the last batch of finished product in which the material was used. Other starting materials (other than solvents, gases, and water) should be retained for a minimum of two years if their stability allows. Retention samples of materials and products should be of a size sufficient to permit at least two full re-examinations.

Stability Studies:

8.15   The quality control department should evaluate the quality and stability of finished pharmaceutical products, and when necessary, of starting materials and intermediate products.

8.16   The quality control department should establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions.

8.17   A written programme for ongoing stability determination should be developed and implemented to include elements such as–

   (a)   a complete description of the drug involved in the study;

   (b)   the complete testing parameters and methods describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability;

   (c)   provision for the inclusion of a sufficient number of batches;

   (d)   the testing schedule for each drug;

   (e)   provision for special storage conditions;

   (f)   provision for adequate sample retention; and

   (g)   a summary of all the data generated, including the evaluation and the conclusion of the study.

8.18   Stability should be determined prior to marketing and following any significant changes in process, equipment, packaging materials, etc.

Reagents and culture media:

   All reagents and culture media should be recorded upon receipt or preparation.

   Reagents made up in the laboratory should be prepared according to written procedures and appropriately labelled. The label should indicate the concentration, standardisation factor, shelf-life, the date when re-standardisation is due, and the storage conditions. The label should be signed and dated by the person preparing the reagent.

   Both positive and negative controls should be applied to verify the suitability of culture media. The size of the inoculum used in positive controls should be appropriate to the sensitivity required.

Reference standards:

   Reference standards should be available in the form of official reference standards. Reference standards prepared by the producer should be tested, released, and then stored in the same way as official standards. They should be kept under the responsibility of a designated person in a secure area.

   Official reference standards should be used only for the purpose described in the appropriate monograph.

   Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardisation. All in-house reference standards should be based on official reference standards.

   All reference standards should be stored and used in a manner that will not adversely affect their quality.

CHAPTER 9
CONTRACT MANUFACTURE AND ANALYSIS

Principle:

Contract production and analysis must be correctly defined, agreed, and controlled in order to avoid misunderstandings that could result in a product or work and analysis of unsatisfactory quality. There must be a written contract between the contract giver and the contract acceptor which clearly establishes the duties of each party. The contract must clearly state the way in which the authorised person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility.

General:

   All arrangements for contract manufacture and analysis, including any proposed changes in technical or other arrangements, should be in accordance with the marketing authorisation for the product concerned.

   There should be a written contract covering the manufacture and/or analysis arranged under contract and any technical arrangements made in connection with it.

   The contract should permit the contract giver to audit the facilities of the contract acceptor.

The contract giver:

9.4   The contract giver is responsible for assessing the competence of the contract acceptor in successfully carrying out the work or tests required and for ensuring by means of the contract that the principles of GMP described in this guide are followed.

9.5   The contract giver should provide the contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorisation and any other legal requirements. The contract giver should ensure that the contract acceptor is fully aware of any problems associated with the product, work or tests that might pose a hazard to premises, equipment, personnel, other materials, or other products.

9.6   The contract giver should ensure that all processed products and materials delivered by the contract acceptor comply with their specifications or that the product has been released by the authorised person(s).

The contract acceptor:

9.7   The contract acceptor must have adequate premises, equipment, knowledge, and experience and competent personnel to carry out satisfactorily the work ordered by the contract giver. Contract manufacture may be undertaken only by a manufacturer who holds a manufacturing authorisation.

9.8   The contract acceptor should not pass to a third party any of the work entrusted to him or her under the contract without the contract giver's prior evaluation and approval of the arrangements. Arrangements made between the contract acceptor and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract acceptor.

9.9   The contract acceptor should refrain from any activity that may adversely affect the quality of the product manufactured and/or analysed for the contract giver.

The contract:

9.10   A contract should be drawn up between the contract giver and the contract acceptor that specifies their respective responsibilities relating to the manufacture and control of the product. Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis, and GMP. All arrangements for production and analysis must be in accordance with the marketing authorisation and agreed by both parties.

9.11   The contract should specify the way in which the authorised person releasing the batch for sale ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the marketing authorisation.

9.12   The contract should describe clearly who is responsible for purchasing, testing, and releasing materials and for undertaking production and quality controls, including in-process controls, and who has responsibility for sampling and analysis.

9.13   Manufacturing, analytical, and distribution records and reference samples should be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the contract giver.

9.14   The contract should describe the handling of starting materials. intermediate and bulk products if they are rejected. It should also describe the processing of information if analysis shows that the tested product must be rejected.

CHAPTER 10
COMPLAINTS AND PRODUCT RECALL

Principle:

All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures.

Complaints:

10.1   A person responsible for handling the complaints and deciding the measures to be taken should be designated, together with sufficient supporting staff to assist him or her. If this person is different from the authorised person, the latter should be made aware of any complaint, investigation, or recall.

10.2   There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

10.3   Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for quality control should be involved in the study of such problems.

10.4   If a product defect is discovered or suspected in a batch, consideration should be given to whether other batches should be checked in order to determine whether they are also affected. In particular, other batches that may contain reprocessed product from the defective batch should be investigated.

10.5   Where necessary, appropriate follow-up action, possibly including product recall, should be taken after investigation and evaluation of the complaint.

10.6   All the decisions and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

10.7   Complaint records should be regularly reviewed for any indication of specific or recurring problems that require attention and might justify the recall of marketed products.

10.8   The Pharmacy Board should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, or any other serious quality problems with a product.

10.9   Written records involving a drug product shall be maintained until at least 1 year after the expiration date of the drug product, or 1 year after the date that the complaint was received, whichever is longer.

10.10   The written record shall include the following information: The name and strength of the drug product, lot number, name of complainant, nature of complaint, and reply to complaint.

10.11   Where an investigation under section 10.4 of these guidelines is conducted, the written record shall include the findings of the investigation and follow-up. The record of the investigation shall be maintained at the factory where the investigation occurred for at least 1 year after the expiration date of the drug product, or 1 year after the date that the investigation was concluded whichever is longer.

10.12   Where an investigation under section 10.4 of these guidelines is not conducted, the written record shall include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination.

Product recalls:

10.13   There should be a system to recall from the market, promptly and effectively, products known or suspected to be defective.

10.14   A person responsible for the execution and co-ordination of recalls should be designated, as well as sufficient staff to handle all aspects of the recalls with the appropriate degree of urgency. This person should be independent of the sales and marketing organisation. If this person is different from the authorised person, the latter should be made aware of any recall operation.

10.15   There should be established written procedures, regularly checked and updated, for the organisation of any recall activity. Recall operations should be capable of being initiated promptly at least down to the level of the hospital or retail Pharmacy.

10.16   All competent authorities of all countries to which a given product may have been distributed should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective.

10.17   The distribution records should be readily available to the person(s) responsible for recalls, and they should contain sufficient information on wholesalers and directly supplied customers (including, for exported products, those who have received samples for clinical tests and medical samples) to permit an effective recall.

10.18   The progress of the recall process should be recorded and a final report issued, including a reconciliation between the delivered and recovered quantities of the products.

10.19   The effectiveness of the arrangements for recalls should be evaluated from time to time.

10.20   An instruction should be included to store recalled products in a secure segregated area while their fate is decided.

CHAPTER 11
SELF-INSPECTION AND QUALITY AUDITS

Principle:

The purpose of self-inspection is to evaluate the manufacturer's compliance with GMP in all aspects of production and quality control. The self-inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections should be performed routinely, and may be, in addition, performed on special occasions, e.g. in case of product recalls or repeated rejections, or when an inspection by the health authorities is announced. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively; all recommendations for corrective action should be implemented. The procedure for self-inspection should be documented, and there should be an effective follow-up programme.

Items for self-inspection:

11.1   Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include questionnaires on GMP covering at least the following items:

   (a)   personnel;

   (b)   premises including personnel facilities;

   (c)   maintenance of buildings and equipment;

   (d)   storage of starting materials and finished products;

   (e)   equipment;

   (f)   production and in-process controls;

   (g)   quality control;

   (h)   documentation;

   (i)   sanitation and hygiene;

   (j)   validation and revalidation programmes;

   (k)   calibration of instruments or measurement systems;

   (l)   recall procedures;

   (m)   complaints management;

   (n)   labels control;

   (o)   results of previous self-inspections and any corrective action taken.

Self-inspection team:

11.2   Management should appoint a self-inspection team from local staff who are expert in their own fields and familiar with GMP. The members of the team may be appointed from inside or outside the company.

Frequency of self-inspection:

11.3   The frequency at which self-inspections are conducted will depend on company requirements.

Self-inspection report:

11.4   A report should be made at the completion of a self-inspection. The report should include:

   (a)   self-inspection results;

   (b)   evaluation and conclusions;

   (c)   recommended corrective actions.

Follow-up action:

11.5   The company management should evaluate both the self-inspection report and the corrective actions as necessary.

Quality audit:

11.6   It is necessary to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit should be conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits should also be extended to suppliers and contractors. (see Chapter 9 Contract Manufacture and analysis).

Suppliers' audits:

11.7   The quality control department should have responsibility together with other relevant departments for approving suppliers who can reliably supply starting and packaging materials that meet established specifications.

11.8   Before suppliers are approved and included in the specifications they should be evaluated. The evaluation should take into account a supplier's history and the nature of the materials to be supplied. If an audit is required, it should determine the supplier's ability to conform to GMP standards for active pharmaceutical ingredients.

CHAPTER 12
MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Principle:

The manufacture of sterile preparations has special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance bears a particularly great importance, and this manufacture must strictly follow carefully established and validated methods of preparation and procedures.

Explanation:

These guidelines do not replace any of the sections in chapter two to eleven but stress specific points for the manufacture of sterile preparations to minimise the risks of microbiological, particulate, and pyrogen contamination.

General:

12.1   The production of sterile preparations should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for goods. Clean areas should be maintained to an appropriate standard of cleanliness and supplied with air that has passed through filters of an appropriate efficiency.

12.2   The various operations of component preparation (containers and closures), product preparation, filling, and sterilisation should be carried out in separate areas within the clean area.

12.3   Clean area for the production of sterile products are classified according to the required characteristics of the air, in grades A, B, C, and D (see Table 1)

Table 1:

Air classification system for manufacture of sterile products

3500

none

Less than 1

Maximum number of particles permitted per m3 equal to or above

Grade

0.5 - 5m3

> 5m3

Maximum number of viable micro-organisms permitted per m3

A
(laminar - airflow
workstation)

B

3500

none

5

C

350000

2000

100

D

3500000

20000

500

It should be noted that:

•   Laminar-airflow systems should provide a homogeneous air speed of about 0.30m/s for vertical flow and about 0.45m/s for horizontal flow but precise air speeds will depend on the type of equipment.

•   In order to reach the B, C, and D air grades, the number of air changes should generally be higher than 20 per hour in a room with a good airflow pattern and appropriate HEPA (high-efficiency particulate air) filters.

•   Low values for contaminants are reliable only when a large number of air samples are taken.

•   The guidance given for the maximum permitted number of particles corresponds approximately to the United States Federal Standard 209E (1992) as follows: Class 100 (grades A and B), Class 10000 (grade C), and Class 100000 (grade D). And to British standard 3829 (adopted by the British Pharmacopoeia and the United States Pharmacopoeia).

It may not always be possible to demonstrate conformity with particular all standards at the point of fill when filling is in progress, owing to the generation of particles or droplets from the product itself.

12.4   Each manufacturing operation requires an appropriate air cleanliness level in order to minimise the risks of particulate or microbial contamination of the product or materials being handled. Section 12.5 gives the minimum air grades required for different manufacturing operations: The particulate and microbiological conditions given in Table 1 should be maintained in the zone immediately surrounding the product whenever the product is exposed to the environment. These conditions should also be achieved throughout the background environment if no personnel are present in the processing area, and if the standards fall for any reason it should be possible to recover the conditions after a short "clean-up" period. The utilisation of absolute-barrier technology and automated systems to minimise human interventions in processing areas can produce significant advantages in ensuring the sterility of manufactured products. When such techniques are used, the recommendations in these supplementary guidelines, particularly those relating to air quality and monitoring, still apply, with appropriate interpretation of the terms "workstation" and "environment".

Manufacture of sterile preparations:

12.5   Manufacturing operations are here divided into three categories: first those in which the preparation is sealed in its final container and terminally sterilised: second, those in which the preparation is sterilised by filtration; and third, those in which the preparation can be sterilised neither by filtration nor terminally and consequently must be produced from sterile starting materials in an aseptic way. Area grades as specified in sections 12.6 to 12.8. must be selected by the manufacturer on the basis of validation runs (e.g. sterile media fills).

Terminally sterilised products:

12.6   Solutions should be prepared in a grade C environment in order to give low microbial and particulate counts, suitable for immediate filtration and sterilisation. For parenterals, filling should be done in a laminar-airflow workstation (grade A) in a grade C environment. The preparation of other sterile products, e.g. ointments, creams, suspensions, and emulsions, and filling of containers should be done in grade C environment before terminal sterilisation.

Sterile filtered products:

12.7   The handling of starting materials and the preparation of solutions should be done in a grade C environment. After sterile filtration, the product must be handled and dispensed into containers under aseptic conditions in a grade A or B area with grade B or C background respectively.

12.8   The handling of starting materials and all further processing should be done in a grade A or B area with a grade B or C background respectively.

Personnel:

12.9   Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processes. Inspections and controls should be conducted from outside the areas as far as possible.

12.10   All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products, including reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g., building or maintenance contractors) need to be brought in, particular care should be taken over their supervision.

12.11   Staff who have been engaged in the processing of animal-tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined decontamination procedures have been followed.

12.12   High standards of personal hygiene and cleanliness are essential, and personnel involved in the manufacture of sterile preparations should be instructed to report any condition that may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person.

12.13   Outdoor clothing should not be brought into the clean areas, and personnel entering the changing rooms should already be clad in standard factory protective garments. Changing and washing should follow a written procedure.

12.14   The clothing and its quality has to be adapted to the process and the workplace, and worn in such a way as to protect the product from contamination.

12.15   Wrist-watches and jewellery should not be worn in clean areas, and cosmetics that can shed particles should not be used.

12.16   Clothing should be appropriate to the air grade of the area where the personnel will be working. The description of clothing required for each grade is given below.

   The hair and, where appropriate, beard should be covered. Protective clothing and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area.

   The hair and, where appropriate, beard should be covered. A single or two-piece trouser suit, gathered at the wrists and with a high neck, and appropriate shoes or overshoes should be worn. The clothing should shed virtually no fibres or particulate matter.

   Headgear should totally enclose the hair and, where appropriate, beard; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets; sterilised non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn; trouser-bottoms should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and should retain particles shed by the body.

12.17   For every worker in a grade B room, clean sterilised protective garments should be provided at each work session, or at least once a day if monitoring results justify it. Gloves should be regularly disinfected during operations, and masks and gloves should be changed at least at every working session. The use of disposable clothing may be necessary.

12.18   Clothing used in clean areas should be laundered or cleaned in such a way that it does not gather additional particulate contaminants that can later be shed. Separate laundry facilities for such clothing are desirable. If fibres are damaged by inappropriate cleaning or sterilisation there will be an increased risk of shedding particles and should therefore not be used. Washing and sterilisation should follow standard operating procedures.

Premises:

12.19   All premises should as far as possible be designed to avoid the unnecessary entry of supervisory or control personnel. Grade B areas should be designed so that all operations can be observed from outside.

12.20   In clean areas, all exposed surfaces should be smooth, impervious, and unbroken in order to minimise the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agent and disinfectants, where used.

12.21   To reduce the accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards, and equipment. Doors should be carefully designed to avoid uncleanable recesses; sliding doors are undesirable for this reason.

12.22   False ceilings should be sealed to prevent contamination from the space above them.

12.23   Pipes and ducts should be installed so that they do not create recesses that are difficult to clean.

12.24   Sinks and drains should be avoided wherever possible and should be excluded from areas where aseptic operations are carried out. Where installed they should be designed, located, and maintained so as to minimise the risks of microbial contamination; they should be fitted with effective, easily cleanable traps with air breaks to prevent back-flow. Any floor channel should be open and easily cleanable and be connected to drains outside the area in a manner that prevents ingress of microbial contaminants.

12.25   Changing rooms should be designed as airlocks and used to provide separation of the different stages of changing, so minimising microbial and particulate contamination of protective clothing. They should be effectively flushed with filtered air. The use of separate changing rooms (or entering and leaving clean areas is desirable. Hand-washing facilities should be provided only in the changing rooms, not in areas where aseptic work is done.

12.26   Airlock doors should not be opened simultaneously. An interlocking system and a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time.

Equipment:

12.27   A filtered air supply should maintain a positive pressure relative to surrounding areas under all operational conditions and flush the area effectively. Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which the product and the cleaned components in contact with it are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified in order to contain materials such as pathogenic, highly toxic, radioactive, or live viral or bacterial materials. Decontamination facilities and the treatment of air leaving a clean area may be necessary for some operations.

12.28   It should be demonstrated that airflow patterns do not present a contamination risk, for example care should be taken to ensure that airflows do not distribute particles from a particle-generating person, operation, or machine to a zone of higher product risk.

12.29   A warning system should be included to indicate failure in the air supply. An indicator of pressure difference should be fitted between areas where this difference is important and the pressure difference should be regularly recorded.

12.30   Consideration should be given to restricting unnecessary access to critical filling areas, e.g. grade A-filling zones, by the use of a physical barrier.

12.31   A conveyor belt should not pass through a partition between a clean area B and a processing area of lower air cleanliness, unless the belt itself is continuously sterilised (like in a sterilising tunnel).

12.32   Equipment used for processing sterile products should be chosen such that it can be effectively sterilised by steam or dry heat or other methods.

12.33   Equipment fittings and services should be designed and installed so that operations, maintenance, and repairs can be carried out outside the clean area. Equipment that has to be taken apart for maintenance should be re-sterilised after complete re-assembly.

12.34   When equipment maintenance is carried out within the clean area, clean instruments and tools should be used, and the area should be cleaned and disinfected before processing recommences.

12.35   All equipment; including sterilisers, air-filtration systems, and water-treatment systems including stills, should be subject to planned maintenance, validation, and monitoring; its approved use following maintenance work should be documented.

12.36   Water-treatment plants should be designed, constructed, and maintained so as to ensure the reliable production of water of an appropriate quality. They should not be operated beyond their designed capacity. Water should be produced, stored, and distributed in a manner that prevents microbial growth - for example, by constant circulation at 80ºC or not more than 4ºC.

Sanitation:

12.37   The sanitation of clean areas is particularly important. They should be cleaned frequently and thoroughly in accordance with a written programme approved by the quality control department. Where disinfectants are used, more than one type should be employed, with periodic alterations. Monitoring should be regularly undertaken in order to detect the emergence of resistant strains of micro-organisms. In view of its limited effectiveness, ultraviolet light should not be used as a substitute for chemical disinfection.

12.38   Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should not be stored for long periods unless sterilised. Partly emptied containers should not be topped up.

12.39   Fumigation of clean areas is necessary for reducing microbiological contamination in inaccessible places.

12.40   Clean areas should be monitored at planned intervals during operations by means of microbial counts of air and surfaces; where aseptic operations are performed, monitoring should be frequent to ensure that the environment is within specifications. The results of monitoring should be considered when batches are assessed for approval. Air particulate quality should also be evaluated on a regular basis. Additional monitoring is desirable even when there are no production operations, e.g., after validation of systems, cleaning, and fumigation.

Processing:

12.41   Precautions to minimise contamination should be taken during all processing stages, including the stages before sterilisation.

12.42   Preparations containing live microbiological organisms should not be made or containers filled in areas used for the processing of other pharmaceutical products; however, vaccines of dead organisms or of bacterial extracts may be dispensed into containers, after validated inactivation and validated cleaning procedures, in the same premises as other sterile pharmaceutical products.

12.43   The use of nutrient media that support microbial growth in trials to simulate aseptic operations (sterile media fills; "broth fills") is a valuable part of overall validation of an aseptic process. Such trials should have the following characteristics–

   (a)   they should simulate as closely as possible actual operations, taking into account such factors as complexity of operations, number of personnel working, and length of time;

   (b)   the medium or media selected should be capable of growing a wide spectrum of micro-organisms, including those that would be expected to be found in the filling environment;

   (c)   they should include a sufficient number of units of production to give a high degree of assurance that low levels of contamination, if present would be detected.

It is recommended that at least 1,000 units of production be included in each broth-fill trial. The target should be zero growth and anything above 0.1 % of units contaminated should be considered unacceptable. Any contamination should be investigated. Broth fills should be repeated at regular intervals, and whenever there is an alteration in the product, premises, equipment, or process warrants revalidation.

12.44   Care should be taken that validations do not harm the processes.

12.45   Water sources, water-treatment equipment, and treated water should be monitored regularly for chemicals, biological contamination, and contamination with endotoxins to ensure that the water complies with the specifications appropriate to its use. Records should be maintained of the results of the monitoring and of any action taken.

12.46   Activities in clean areas, especially when aseptic operations are in progress, should be kept to a minimum, and the movement of personnel should be controlled and methodical, to avoid excessive shedding of particles and organisms due to over-vigorous activity. The ambient temperature and humidity should not be uncomfortably high because of the nature of the garments worn.

12.47   Microbiological contamination of starting materials should be minimal, and the "bio-burden" should be monitored before sterilisation. Specifications should include requirements for microbiological quality.

12.48   The presence of containers and materials liable to generate fibres should be minimised in clean areas and avoided completely when aseptic work is in progress.

12.49   Components, bulk-product containers, and equipment should be handled after the final cleaning process in such a way that they are not re-contaminated. The stage of processing of components, bulk-product containers, and equipment should be properly identified.

12.50   The interval between the washing and drying and the sterilisation of components, bulk-product containers, and equipment, as well as between sterilisation and use, should be as short as possible and subject to a time-limit appropriate to the validated storage conditions.

12.51   The time between the start of the preparation of a solutions and its sterilisation or filtration through a bacteria-retaining filter should be as short as possible. A maximum permissible time should be set for each product that takes into account its composition and the prescribed method of storage.

12.52   Any gas that is used to purge a solution or blanket a product should pass through a sterilising filter.

12.53   The microbiological contamination of products ("bio-burden") should be minimal prior to sterilisation. There should be a working limit on contamination immediately before sterilisation that is related to the efficiency of the method to be used and the risk of pyrogens. All solutions, in particular large-volume parenterals, should be passed through a micro-organism-retaining filter immediately before the filling process. Where aqueous solutions are held in sealed vessels, any pressure-release outlets should be protected, e.g., by hydrophobic microbial air filters.

12.54   Components, bulk-product containers, equipment, and any other articles required in a clean area where aseptic work is in progress should be sterilised and, passed into the area through double-ended sterilisers sealed into the wall. Other procedures that achieve the same end of not introducing contamination (e.g. triple wrapping) may be acceptable in exceptional circumstances.

12.55   The efficiency of any new processing procedure should be validated, and the validation should be repeated at regular intervals thereafter or when change is made in the process or equipment.

Sterilisation:

12.56   Sterilisation can be achieved by moist or dry heat, by ethylene oxide (or other suitable gaseous sterilising agent), by filtration with subsequent aseptic filling of sterile final containers, or by irradiation with ionising radiation (but not with ultraviolet radiation unless the process is thoroughly validated). Each method has its particular applications and limitations. Where possible and practicable, heat sterilisation is the method of choice.

12.57   All sterilisation processes must be validated. Particular attention should be given when the adopted sterilisation method is not in accordance with pharmacopoeial or other established standard or when it is used for a preparation that is not a simple aqueous or oily solution. In any case, the sterilisation process must be in accordance with the marketing and manufacturing authorisations.

12.58   Before any sterilisation process is adopted, its suitability for the product and its efficacy in achieving the desired sterilising conditions in all parts of each type of load to be processed should be demonstrated. This work should be repeated at scheduled intervals, at least annually, and whenever significant modifications have been made to the equipment. Records should be maintained of the results.

12.59   Biological indicators should be considered only as an additional method for monitoring the sterilisation. If they are used, strict precautions should be taken to avoid transferring microbial contamination from them.

12.60   There should be a clear means of differentiating products that have not been sterilised from those that have. Each basket, tray, or other carrier of products or components should be clearly labelled with the name of the material, its batch number, and an indication of whether or not it has been sterilised. Indicators such as autoclave tape may be used, where appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilisation process, but not to give an indication that the lot is, in fact sterile.

Sterilisation by heat:

12.61   Each sterilisation cycle should be recorded by appropriate equipment with suitable accuracy and precision, e.g., on a time/ temperature chart with a suitably large scale. The temperature should be recorded from a probe at the coolest part of the load or loaded chamber, this point having been determined during the validation; the temperature should be checked against a second independent temperature probe located at the same position. The chart, or a photocopy of it, should form part of the batch record. Chemical or biological indicators may also be used but should not take the place of physical controls.

12.62   Sufficient time must be allowed for the whole of the load to reach the required temperature before measurement of the sterilising time is started. This time must be determined for each type of load to be processed.

12.63   After the high-temperature phase of a heat sterilising cycle, precautions should be taken against contamination of a sterilised load during cooling. Any cooling fluid or gas in contact with the product should be sterilised, unless it can be shown that any leaking container would not be approved for use.

Sterilisation by moist heat:

12.64   Sterilisation by moist heat is suitable only for water-wettable materials and aqueous solutions. Both temperature and pressure should be used to monitor the process. The temperature recorder should normally be independent of the controller, and there should be an independent temperature indicator, the reading from which should be routinely checked against the chart recorder during the sterilising period. For sterilisers fitted with a drain at the bottom of the chamber, it is necessary to record the temperature at this position, throughout the sterilisation period. There should be regular leak tests on the chamber when a vacuum phase is part of the cycle.

12.65   The items to be sterilised, other than products in sealed containers, should be wrapped in a material that allows removal of air and penetration of steam but prevents recontamination after sterilisation. All parts of the load should be in contact with water or saturated steam at the required temperature for the required time.

12.66   Care should be taken to ensure that steam used for sterilisation is of suitable quality and does not contain additives at a level that could cause contamination of the product or equipment.

Sterilisation by dry heat:

12.67   The process used for sterilisation by dry heat should include air circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non-sterile air. If air is supplied, it should be passed through a micro-organism-retaining filter. Where this process of sterilisation by dry heat is also intended to remove pyrogens, challenge tests using endotoxins should be done as part of the validation.

Sterilisation by radiation:

12.68   Radiation sterilisation is used mainly for the sterilisation of heat-sensitive materials and products. Many pharmaceutical products and some packaging materials are radiation-sensitive, so this method is permissible only when the absence of deleterious effect on the product has been confirmed experimentally. Ultraviolet irradiation is not an acceptable method for terminal sterilisation.

12.69   If radiation sterilisation is carried out by an outside contractor, the manufacturer has the responsibility of ensuring that the requirements are met, and that the sterilisation process is validated. The responsibilities of the radiation plant operator (e.g., for the right dose) should be specified.

12.70   During the sterilisation procedure the radiation dose should be measured. For this purpose, dosimeters that are independent of dose rate should be used, giving a quantitative measurement of the dose received the product itself. Dosimeters should be inserted in the load in sufficient number, and close enough together to ensure that there is always a dosimeter in the chamber. Where plastic dosimeters are used, they should be used within the time-limit of their calibration. Dosimeter absorbencies should be read within a short period after exposure to radiation. Biological indicators may be used only as an additional control. Radiation-sensitive colour discs may be used to differentiate between packages that have been subjected to irradiation and those that have not; they are not indicators of successful sterilisation. The information obtained should constitute part of the batch record.

12.71   Validation procedures should ensure that consideration is given to the effect of variations in the density of the packages.

12.72   Handling procedures should prevent any mix-up between irradiated and non-irradiated materials. Each package should carry a radiation-sensitive indicator to show whether or not it has been subjected to radiation treatment.

12.73   The total radiation dose should be administered within a predetermined time span.

Sterilisation by ethylene oxide:

12.74   Various gases and fumigants may be used for sterilisation. Ethylene oxide should be used only when other method is practicable. During process validation it should be shown that the gas has no damaging effect on the product and that the conditions and time allowed for degassing are such as to reduce any residual gas and reaction products to defined acceptable limits for the type of product or material. These limits should be incorporated into the specifications.

12.75   Direct contact between gas and microbial cells is essential; precautions should be taken to avoid the presence of organisms likely to be enclosed in material such as crystals or dried protein. The nature and quantity of packaging materials can significantly affect the process.

12.76   Before exposure to the gas, materials should be brought into equilibrium with the humidity and temperature required by the process. The time required for this should be balanced against the opposing need to minimise the time before sterilisation.

12.77   Each sterilisation cycle should be monitored with suitable biological indicators, using the appropriate number of test pieces distributed throughout the load. The information obtained should form part of the batch record.

12.78   Biological indicators should be stored and used according to the manufacturer's instructions, and their performance checked by positive controls.

12.79   For each sterilisation cycle, records should be made of the time taken to complete the cycle, of the pressure, temperature, and humidity within the chamber during the process, and of the gas concentration. The pressure and temperature should be recorded throughout the cycle on a chart. The records should form part of the batch record.

12.80   After sterilisation, the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to fall to the defined level. This process should be validated.

Filtration of pharmaceutical products that cannot be sterilised in their final container:

12.81   Whenever possible, products should be sterilised in the final container, preferably by heat sterilisation. Certain solutions and liquids that cannot be sterilised in the final container can be filtered through a sterile filter of nominal pore size 0.22µm (or less), or with at least equivalent micro-organism-retaining properties, into a previously sterilised container. Such filters can remove bacteria and moulds, but not all viruses or mycoplasmas. Consideration should be given to complementing the filtration process with some degree of heat treatment.

12.82   Owing to the potential additional risks of the filtration method as compared with other sterilisation processes, a double filter layer or second filtration via a further sterilised micro-organism-retaining filter immediately prior to filling may be advisable. The final sterile filtration should be carried out as close as possible to the filling point.

12.83   Filters that shed fibres should not be used. The use of asbestos-containing filters should be absolutely excluded.

12.84   The integrity of the filter should be checked by an appropriate method such as a bubble point test immediately after each use (it is also useful to test the filter this way before use). The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter should be determined during validation and any differences from this should be noted and investigated. Results of these checks should be recorded in the batch record.

12.85   The same filter should not be used for more than one working day.

12.86   The filter should not affect the product by removal of ingredients from it or by release of substances into it.

Finishing of sterile products:

12.87   Containers should be closed by appropriately validated methods. Samples should be checked for integrity according to appropriate procedures.

12.88   Containers sealed under vacuum should be sampled and the samples tested for maintenance of that vacuum after an appropriate predetermined period.

12.89   Filled containers of parenteral products should be inspected individually. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eyesight checks, with spectacles if worn, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals.

Quality control:

12.90   Samples taken for sterility testing should be representative of the whole of the batch but should in particular include samples taken from parts of the batch considered to be most at risk of contamination, for example:

   (a)   For products that have been filled aseptically, samples should include containers filled at the beginning and end of the batch and after any significant interruption of work;

   (b)   For products that have been heat sterilised in their final containers, consideration should be given to taking samples from the potentially coolest part of the load.

12.91   The sterility test applied to the finished product should be regarded only as the last in a series of control measures by which sterility is assured and should be interpreted only in conjunction with the environmental and batch processing records.

12.92   Batches failing an initial sterility test should not be released on the basis of a second test unless an investigation into the type of organism found, and into the environmental and batch processing records involved, show that the original test was invalid.

12.93   For injectable products, consideration should be given to monitoring the water and the intermediate and finished product for endotoxins, using an established pharmacopoeial method that has been validated for each type of product. For large-volume infusion solutions, such monitoring of water or intermediates should always be done, in addition to any tests required by the marketing authorisation (Pharmacy Board) on the finished product. When a sample fails a test, the cause of failure should be investigated and remedial action taken. The investigation and remedial action must be recorded.

THE PHARMACEUTICALS AND POISONS (HUMAN DRUGS LIST) (NOTIFICATION) ORDER

(Section 58)

[1st May, 1999]

G.Ns. Nos.
25 of 2001
93 of 2002

   WHEREAS section 58 of the Pharmaceutical and Poisons Act * requires the Minister, upon recommendation of the Board, by order in the Gazette to prohibit and control the manufacture, importation or sale of any drug.

   AND WHEREAS the Board has recommended to the Minister the list of registered human drugs to be gazetted for public awareness.

   NOW THEREFORE, the public is hereby notified as follows–

   1. This Order may be cited as the Pharmaceuticals and Poisons (Human Drugs List) (Notification) Order.

   2. [Omitted.]

   3. No person shall be allowed to circulate any drug which is not in the drug list specified in the Schedule to this Order.

   4. Notwithstanding the provisions of this Order, the registration unless it is earlier cancelled shall remain valid for five years from the date of issuing registration certificates, and shall be subject to payment of annual retention fees.

   5. Any person who contravenes or fails to comply with this Order commits an offence punishable under the Pharmaceutical and Poisons Act *.

SCHEDULE
REGISTERED HUMAN DRUGS LIST

Registration Number

Product Name

Active Ingredients

Strength

Manufacturer

Registrant

A. Menarini Industrie Farmaceutiche Riunite s.r.l - ITALY

1 TAN 00,1759 M01A AMI

Fastum Gel

A.Menarini Manufacturing Logistics and Services s.r.l - ITALY

Ketoprofen Ph.Eur

2.5%w/w

2 TAN 00,1760 M01A AMI

Fastum Capsules

A.Menarini Manufacturing Logistics and Services s.r.l - ITALY

Ketoprofen BP

50mg

Registrant

Albert David Limited - INDIA

3 TAN 00,1957 P01B ADL

Aldezol Injection

Albert David Limited - INDIA

Metronidazole USP

0.5%w/v

4 TAN 00,1958 J01K ADL

Cipad Injection

Albert David Limited - INDIA

Ciprofloxacin USP

0.2%w/v

Registrant

Alcon Cusi, S.A. - SPAIN

5 TAN 00,1761 S01G ALC

Cusicrom 4% Eye Drops

Alcon Cusi, S.A. - SPAIN

Sodium Cromoglycate Ph.Eur

40mg/ml

6 TAN 00,1537 V07A ALC

Opti-Free Multiaction Solution

Alcon Cusi, S.A. - SPAIN

Polyquad

0.001%

7 TAN 00,1538 S01E ALC

Cusimolol 0.5% Ear Drops

Alcon Cusi, S.A. - SPAIN

Timolol Ph.Eur

0.5%w/v

8 TAN 00,1762 S01D ALC

Cusimolol 0.25% Eye Drops

Alcon Cusi, S.A. - SPAIN

Timolol Ph.Eur

2.5mg/ml

9 TAN 00,1539 V07A ALC

Opti-Free Express Solution

Alcon Cusi, S.A. - SPAIN

Al-6289

0.0005%w/v

Polyquad

0.001%w/v

10 TAN 00,1540 S01D ALC

Cusicrom 2% Eye Drops

Alcon Cusi, S.A. - SPAIN

Sodium Cromoglycate Ph.Eur

20mg/ml

11 TAN 00,1541 V07A ALC

Opti-Free Supercleans

Alcon Cusi, S.A. - SPAIN

Registration Number

Product Name

Active Ingredients

Strength

Manufacturer

Soluble Pancreatin USP

1.700AU

12 TAN 00,1959 S03D ALC

Cusiviral Eye Ointment

Alcon Cusi, S.A. - SPAIN

Acyclovir Ph.Eur

5% w/w

13 TAN 00,1763 S01A ALC

Oftalmolosa Chloramphenicol Eye Ointment

Alcon Cusi, S.A. - SPAIN

Chloramphenicol Ph.Eur

10mg/g

14 TAN 00,1960 S03A ALC

Chloramphenicol 0.5% Eye Drops

Alcon Cuai, S.A. - SPAIN

Chloramphenicol Ph.Eur

5mg/ml

Registrant

Amman Pharmaceutical Industries Co.- JORDAN

15 TAN 00,1542 R01A AMM

Decozal 0.05% Nasal Drops

Amman Pharmaceutical Industries - JORDAN

Xylometazoline HCl BP

0,5mg/ml

16 TAN 00,1543 S01A AMM

Otocol Ear Drops

Amman Pharmaceutical Industries - JORDAN

Chloramphenicol BP

5%w/v

Benzocaine BP

5%w/v

17 TAN 00,1544 S01D AMM

Apimol 0.25% Eye Drops

Amman Pharmaceutical Industries - JORDAN

Timolol Maleate BP

0.25mg/ml

18 TAN 00,1545 R01A AMM

Decozal 0.1% Nasal Drops

Amman Pharmaceutical Industries - JORDAN

Xylometazoline HCl BP

0.1mg/ml

19 TAN 00,1546 S02D AMM

Dewax Ear Drops

Amman Pharmaceutical Industries - JORDAN

Dosucate Sodium BP

5,0mg

20 TAN 00,1547 S01D AMM

Apicarpin 4% Eye Drops

Amman Pharmaceutical Industries - JORDAN

Pilocarpine HCl BP

40mg/ml

Registration Number

Product Name

Active Ingredients

Strength

Manufacturer

21 TAN 00,1548 S01D AMM

Apimol 0.5% Eye Drops

Amman Pharmaceutical Industries - JORDAN

Timolol Maleate BP

0.5mg/ml

Registrant

AstraZeneca UK Limited - U.K

22 TAN 00,1764 N02A ASZ

Diprivan 1%w/v IV Injection

Fresenius Kabi AB - SWEDEN

Propofol

1%w/v

23 TAN 00,1549 C01D ASZ

Plendil 5mg Tablets

AstraZeneca AB - SWEDEN

Felodipine Ph.Eur

5mg

24 TAN 00,1550 C01D ASZ

Plendil 10mg Tablets

AstraZeneca AB - SWEDEN

Felodipine Ph.Eur

10mg

25 TAN 00,1765 A02C ASZ

Losec Mups Tablets

AstraZeneca AB - SWEDEN

Omeprazole

20mg

Registrant

Aurochem Laboratories - INDIA

26 TAN 00,1766 D01A AUC

Kandicide-V Tablets

Aurochem Laboratories - INDIA

Clotrimazole USP

100mg

Registrant

Aventis Pasteur S.A. - FRANCE

27 TAN 00,1767 J07A AVE

Oral Polio Vaccine

Aventis Pasteur - FRANCE

Poliomyelitis Virus Type 2

>100,000

Poliomyelitis Virus Type 3

>600,000

Poliomyelitis Virus Type 1

>1,000,000

Registrant

Beta Healthcare International Ltd - KENYA

28 TAN 00,1551 N02B BEH

Betafen Syrup

Beta Healthcare International Ltd - KENYA

Ibuprofen BP

100mg/5ml

29 TAN 00,1768 P01B BEH

Betaquine Tablets

Beta Healthcare International Ltd - KENYA

Amodiaquine USP

200mg

Registration Number

Product Name

Active Ingredients

Strength

Manufacturer

Registrant

Biodeal Laboratories Ltd - KENYA

30 TAN 00, 1552 J01B BIO

Biophenicol Suspension

Biodeal Laboratories Ltd - KENYA

Chloramphenicol Palmitate BP

125mg/5ml

31 TAN 00,1553 J01H BIO

Biocillin Dry Syrup

Biodeal Laboratories Ltd - KENYA

Ampicillin Trihydrate BP

143.75mg/5ml

32 TAN 00,1554 D01B BIO

Clomzole Cream

Biodeal Laboratories Ltd - KENYA

Clotrimazole BP

1g/100g

Registrant

Blue Cross Laboratories Ltd - INDIA

33 TAN 00,1555 J01K BLU

Bluspar Tablets

Blue Cross Laboratories Ltd - INDIA

Sparfloxacin BP

200mg

34 TAN 00,1556 V03A BLU

Ekon D.T Tablets

Blue Cross Laboratories Ltd - INDIA

Cetrizine Dihydrochloride BP

10mg

35 TAN 00,1557 A02B BLU

Omepren 20 Capsules

Blue Cross Laboratories Ltd - INDIA

Omeprazole BP

20mg

36 TAN 00,1769 A03D BLU

Meftal Spas Tablets

Blue Cross Laboratories Ltd - INDIA

Mefenamic Acid BP

10mg

37 TAN 00,1558 D07X BLU

Sonaderm GM Cream

Blue Cross Laboratories Ltd - INDIA

Gentamycin Sulphate BP

0.10%w/w

Clobetasol Propionate BP

0.05%w/w

Chlorocresol BP

0.10%w/w

Miconazole Nitrate BP

2.00%w/w

38 TAN 00,1559 R05C BLU

Tusq Tablets

Blue Cross Laboratories Ltd - INDIA

Guaifenesin USP

100.00mg

Phenylpropanolamine HCl

25.00mg

Bromhexine HCl BP

8.00mg

Chlorpheniramine maleate BP

2.00mg

Paracetamol BP

450.00mg

39 TAN 00,1961 M01A BLU

Meftal-250 Tablets

Blue Cross Laboratories Ltd - INDIA

Mefenamic Acid BP

250mg

Registration Number

Product Name

Active Ingredients

Strength

Manufacturer

Registrant

Chemical Industries Development - EGYPT

40 TAN 00,1770 A11A CHE

Fruital Syrup

Chemical Industries Development - EGYPT

Vitamin C BP

50mg/5ml

Nicotinamide BP

12.5mg/5ml

Vitamin A BP

5000iu/5ml

Vitamin B1 BP

1,5mg/5ml

Vitamin B2 BP

1,5mg/5ml

Vitamin B6 BP

1mg/5ml

Vitamin E BP

2.5mg/5ml

Vitamin D2 BP

1000iu/5ml

41 TAN 00,1560 N03A CHE

Tegral 200mg Tablets

Chemical Industries Development - EGYPT

Carbamazepine BP

200mg

42 TAN 00,1561 R03A CHE

Cidophylline Injection

Chemical Industries Development - EGYPT

Aminophylline BP

250mg/10ml

43 TAN 00,1962 S01A CHE

Optocetine Eye Drops

Chemical Industries Development - EGYPT

Chloramphenicol BP

0.5g/100ml

Registrant

Chinoin Pharmaceutical & Chemical Works - HUNGARY

44 TAN 00,1562 V03A CHI

Enzaprost F Injection

Chinoin Pharmaceutical & Chemical Works - HUNGARY

Dinoprost

5mg/ml

Registrant

Cipla Ltd., - INDIA

45 TAN 00,1563 D06A CIP

Cefadur 125 DT Tablets

Cipla Ltd - INDIA

Cefadroxil

125mg

46 TAN 00,1564 J01D CIP

Cefadur 125 Rediuse

Cipla Ltd - INDIA

Cefadroxil

125mg/5ml

47 TAN 00,1565 J05C CIP

Stavir-30 Capsules

Cipla Ltd - INDIA

Stavudine

30mg

48 TAN 00,1566 J05A CIP

Duovir Tablets

Cipla Ltd - INDIA

Registration Number

Product Name

Active Ingredients

Strength

Manufacturer

Zidovudine USP

300mg

Lamivudine

150mg

49 TAN 00,1567 J05C CIP

Stavir-40 Capsules

Cipla Ltd - INDIA

Stavudine

40mg

50 TAN 00,1568 D01A CIP

Zinoral Shampoo

Cipla Ltd - INDIA

Ketoconazole USP

2%w/v

51 TAN 00,1569 V03A CIP

Alerid - D ER Tablets

Cipla Ltd - INDIA

Cetirizine Dihydrochloride

5mg

Pseudoephedrine HCl

120mg

52 TAN 00,1570 A11H CIP

Vitamin E Capsules

Cipla Ltd - INDIA

Alpha Tocopheryl Acetate USP

400mg

53 TAN 00,1571 N05A CIP

Risnia-2 Tablets

Cipla Ltd - INDIA

Risperidone

2mg

54 TAN 00,1572 P01A CIP

Entosec Tablets

This section of the article is only available for our subscribers. Please click here to subscribe to a subscription plan to view this part of the article.