LIBERIA MEDICINE AND HEALTH PRODUCTS REGULATORY AUTHORITY (LMHRA) 24 and 3" Floor, Clay Building Sekou Toure Avenue, Mamba Point Monrovia, Montserrado County Republic of Liberia Guidelines on Inspectorate and Post-Market Surveillance (PMS) Version No. 003 Py are “Fasaring Safety, Elficsey and QQeality of Medtcines aval Health Products” P.O BOX 1994 Cell: +231-777140555/888 140555 Email: info@Imhra.gov.Ir Website: www.Imhra.gov.Ir Document Code: DOC-GDL-008 Date of Issue: Apri; 13, 2026 Version: 01 Date of Implementation: April 16, 2026 Guidelines on Inspectorate and Post Market Surveillance (PMS), DOC-GDL-018 Version 3, 2025 i
TABLE OF CONTENTS EESTI, es orenssrctinntaninitisnenoilonggahitaiiee sl logan... 6 CW etic mening em eneexiesantadsiiii, cece 7 SESE oer carom uencnnorinm eases ala alc Rh la el a 8 a aa re ee 14 STATEMENT FROM THE MANAGING DIRECTOR j.oscsssssstsstinestsststneetecec. 15 1.0 PROCEDURES FOR REGISTRATION & LICENSING OF PREMISES FOR IMPORTERS AND WHOLE SATEBS ss seuiowininsseatosidsnayissnitanssimasa nid. caccoans 16 1.1. a ane ae eS Strader 16 1.2. PROCEDURES FOR LICENSING OF PREMISES FOR IMPORTERS AND 13: LOCATION OF BELARMAGHUTICNLES BUSINESS sssssectsssstecasie6escseesusesess 19 1.4, PREMISE DESIGN AND LAYOUT (IMPORTATION AND WHOLESALE) 20 15, GOOD STORAGE AND WAREHOUSING FACILITIES eecccccseccccccccsseee 21 1.6. SANITATION AND HYGIENE OF PREMISES ......ssssssss0sessssscsssssesssssssoce 22 1.7. RESPONSIBILITY OF THE PHARMACIST... 1.8. INSPECTION. .ssssnssenseteverssisiisscviussivstrueniysevnats 1.9. STOCK CONTROL AND HANDLING......c0.c000+. 1.10. RECORDS AND DOCUMENTATION ....csceccsssssssssssssssccscses TAd. RECALLS AND WITHDRAWAL. ....sssscccssssssscsssssssssssssssssessssssesssssssssssece. 1.12; TERMINATION OF BUSINESS ...ccccsssssssssscssssscsssersorsccssssseescessscsssssssevessecce 23 1.13; VALIDITY OF PREMISE REGISTRATION CERTIFICATE oeecesscssssssssss... 23) 2.0 GUIDELINES ON IMPORT & EXPORT PROCEDURES .eeecsscssesccccsssssss-.. 24 2.1 INTRODUCTION. sssesscasescccunessesssgepstocausspcraie$s csstasacscensaescsnesvenssowwenalincin 24 22 LEGAL CONSIDERATIONS .......ssssssssssssssssssssssssssessesssssssscsesssssasssesecsssssees 25 2:3 IMPLEMENTATION OF CONTROLS ....sseccssssssssssesesssssssscessssssssssescccssssses 25 2.4 EXEMPTIONS FROM REQUIREMENTS OF A PHARMACEUTICAL IMPORT/EXPORT LICENCES 26 2.4.1 Importation of Donated Pharmaceutical Products .......cssss00000++sssss0seeccssssss.., 26 Guidelines on Inspectorate and Post Market Surveillance (PMS), DOC-GDL-018 Version 3, 2025 i
2.4.2 2.4.2 2.4.3 2.4.4 & Vaccines 25 Importation of Donated Pharmaceutical Products in Emergency .........000000 26 Importation of Pharmaceutical Products for Personal Use ...........cc0c0c0000000- 26 Importation of Medicines to be used for Clinical Tridls......c.ccccceseseessvees 26 Importation of Bio-Technological/Biological/Blood Products, SERA 26 DOCUMENTATION :escessccunsssscussvsssasessecensnvnsacosdivontasenowconsaisuncian tsucistecieoniuess 27 2.6 IMPORTATION AND EXPORTATION OF CONTROLLED SUBSTANCES 2.6.1 CRITERIA FOR ISSUE OF AUTHORISATION TO IMPORT ..........sesc0e00+ 28 2.6.2 APPLICATION FOR ISSUE OF AN IMPORT PERMIT.............:::ssseeeseeeees 28 2.6.3 APPLICATION FOR ISSUE OF AN EXPORT PERMIT .............:esessseees 29 2.6.4 Conditions of issue / renewal for import liCONSC....cccccccseseeecsseseeseteeteceesensees 31 2.6.5 CONGIUONS JOR PREMISES: sevsicssenccrescctrscin wacenatscoteta selene TA TETAS 31 2.6.6 CONGItONS fOP_AMCNAMEMS ssvccssccscsccsscrsicrscirninninamRTa aT 31 2.6.7 VGH pes ssssscswscavia sass tees iwat ees cta sie REeS UNCER TA TREEOT EIDE ES TALEO RES 31 2.6.8 Suspension:or cancellation Of UCenses siscsccssesscaccscscesissssscatssieasscs eatssaus sees 31 2.6.9 Conditions of issue / renewal for export TiceNSC ....ccccccccsseseessesetseseeetsenseneeee 34 2.6.10 CONGIIONS JOP PREMISES, ..2..ceosanescease-sensazvaes visszeaneaisneasiessrieseneantsaranenrsestaseeiaee 34 2.6.11 Conditions for, AmendMe mss: ceornecierensnersbssisennrserteononessnsnasnssesvansvsasstenenssnbaoy 34 2.6.12 VALID a3 wae cose ives taxed cecaa¥ soho ae eee a ee ee eee 34 2.6.13 Suspension or cancellation of licenses 3.0 GUIDELINES ON POST MARKETING SURVEILLANCE ..........::s0s0ees000+ 36 3.1 TNT RODUGCTION sceseraisssasessooennsensnestnenterenseusistssl snyendheasussconio een ia eee 36 3:2. PUR POSE os cssnserenvavesnest ererthscesccontereseateeze arieaes sis eee ae 36 3.3 OBJECTIVES wsccssseseccsosesresnslecsurctvevesosnuss axcesrinstyessasssteatbrssexenessenteserstincrstaaes 36 3.4 Procedures for Post-Marketing Surveillance...........::cscssessessessessseseeseeeeeeeeees 37 3.5 Tnispectioniatid Testing: Priorities’. ...ccsssseecesccosssncsonsssnsysonervansenseseceoaasnsnecoaduorats 37 3.6 Sattipling Plan .cicscccccsssessesseconsssssrsscssssesssvevesevsesssaseavsissesansavecssaseossserssevisssevens 37 3.7 Handling, storage, and transportation of samples... eeeeeeeeees 38 3.8 "POSH G essssssscopszscsscar en seessccnesiscececmacacaescenrserecncuccance seinen ttuasseNTaasereauaeaeBsaeteTN 38 4.0 GUIDELINES FOR LICENSING LOCAL MANUFACTURE OF PHARMACEUTICAL FACTORY. IN. LIBERIA bos csscsssscsvsseconssstansvonevonsstnsreassoaovstensegussonedonitenes 39 Guidelines on Inspectorate and Post Market Surveillance (PMS), DOC-GDL-018 Version 3, 2025 L
4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.7 4.3.8 4.3.9 4.3.10 4.3.11 4.3.12 4.3.13 4.3.14 4.3.15 4.3.16 4.3.17 4.3.18 4.3.19 4.3.20 4.3.21 4.3.22 4.3.23 4.3.24 4.3.25 4.3.26 4.3.27 4.3.28 4.3.29 Procedure for Licensing of Local Manufacturer ......cccsessssccsssssseeeeeecse 39 Basic Requirements for the Establishment of Local Pharmaceutical Factory 40 Environmental Sanitation ....seoossssssssssissssusssusrisneinssiisssisesiunieisseees, 40 Factory Buildings and Facilities FOCUS scscocscxsssersesereseti veces sarsuesuceci Management of Raw Materials and Product Containers and Capi .......c..00004. 46 Manufacturing Process Contr Ol ccccsccccsecccsscsccssss... Management of Packaging and Labeling... Storage, Shipping and SL@8....0..0...c0cc0ccccccc0--. Qualily COnPol:. Jac. Bn chet Handling of Complaints and Returned Products... Pharmaceuticals for Use in Clinical Trials.......... Good Manufacturing Practices for Medical Devices... Management Responsibility .....0..0.ssccssssssssssssssissssssssssssssssssssssssssseeeceeceesssscs, 56 QUOT SY METIS ory aaczok tron civil evecare nee Seen 57 CON ACE REVIEW, csreseccssssricrrscasnsmeurseeveasist ean: a eee Ae 58 Design COntt lens esviesstecotowrmunsnseeinan ain. nt aS, oe on ease ae 59 Document and Data Control sssssiscecsssesssesese sa ccccceonstas oechcatsaeascassieccs 60 BUNCROSING wissscscvesiasserusciearseusies ein opssaeesncscsxsssee eee 61 Control of Customer-supplied PrOdUCHS .....cc.ccccc0sessecssessees 62 Product Identification and Traceabilit).....c0.cc0cccessccsssseccssss 62 Production Process Control ..cccccsccssscesssssssssesssesssessecssssessessecs 63 Inspection and Testing..rsceccccccriescsesssscssrssssssisssiissssriissssusssisesssssessaeecsese. 65 Control of Inspection, Measuring and Test Facilities ....ccccccccsccscsssssscesssccoss.., 66 Identification of Inspection and Test Status ........ccccsscssssssssssscsssssssssssseccsseses, 67 Control of Nonconforming Products ...ecscccssssssssssssssisssssseesssssssisessssseeessecccc., 67 Corrective and Preventive ACHION .....sccccsssscessssesstissrisssssssssessisecsiessesecesccosecc, 68 Handling, Storage, Packaging, Preservation and DOLE isos 0555., co ocssnoraeven 69 Control of Quality RECOPAS .....c.ccscsssssessssscssssssesssesssissessssissssssssssesssssesssseeece., 70 Guidelines on Inspectorate and Post Market Surveillance (PMS), DOC-GDL-018 Version 3, 2025 i
4.3.30 4.3.31 4.3.32 4.3.33 4.3.34 5.0 5.1 5.2 5.3 S31 5:3;2 5.3.3 5.3.4 53:5 5.3.6 5.4 5.6 5.6.1 5.6.2 5.6.3 TRC OGL uel ty AGI eit acocbe sex stevcticegoneeresent te oe 71 Training INEROD UC TION say... 5.:cssassse) odhsnivtseel doctcistaccentcenrites oe ee ree 82 Prevention of waste from Pharmaceutical donations, Sale, and/ or purchase.. 83 Procedures for Handling and Disposal of Unfit Medicines and Health Products 83 Unfit medicines and health Product ....scscssssssssissssovessssssssssessssssssssesssssssessecc: 83 Handling of unfit medicines and health products at Sacility level... 84 Procedures for application to dispose of unfit medicines and health products 85 SORTING AND VERIFICATION EXERCISE .. 86 Costiof Waste: Disposal is scscscsssriscccsesinusnesneenteeteiieaceasas.cscs cae . 87 DESTRUCTION OF UNFIT MEDICINES AND HEALTH PRODUCTS... 87 ARNE XUES teres estrecho aadnes cacace aaeseatnas entestmneoelta brane ees ees 89 Standard Operating Procedures (SOP) for Pharmaceutical and other hazardous medical Wastes Management in Liberia.............ccecsssessessesssssecsecssesssessosceseese 98 Procedures for the Application for Pharmaceutical Wastes Disposal.............. 99 Procedures for pharmaceutical wastes Disposal.........:c..:.sscsesseesessees .. 100 Procedures for Wastes Management Team during Disposal Exercise . , 101 Guidelines on Inspectorate and Post Market Surveillance (PMS), DOC-GDL-018 Version 3, 2025 l
ACKNOWLEDGEMENT The writing of these Guidelines is an outcome of a five (5)-day retreat for senior staff of the Liberia Medicines and Health Products Regulatory Authority (LMHRA). We herein acknowledge the ingenuity, far-sightedness and leadership role of Hon. Luke Bawo, Managing Director of LMHRA. We also acknowledge the organizational skills and guidance of the 2025 QMS Working Sessions led by Dr. Thomas B.L. Kokulo who is the Manager of the Quality Management System. Much recognition is given to the Guideline Drafting Team which includes Dr. Teedoh E. Beyslow, Deputy Director of Pharmacovigilance and Clinical Trials; Dr. Thomas B. L. Kokulo, Manager Quality Management System; Dr. Paul D. Y. Higgins, Director, Director, Inspectorate and Post Market Surveillance; Dr. F. Kwo- A-Kpeh Dolo; Dr. Jonathan J. Luciny, and Dr. Esau Davies. Our heartfelt thanks also go to Dr. Flomoku G. Miller, Training Coordinator, for his encouragement, technical and moral support to the Guideline Drafting Team. We also acknowledge and give recognition to the World Health Organization (WHO) and the International Committee on Harmonization (ICH) for making available documents which were used as resource materials in the compilation of this guideline. Most importantly and above all else, we sincerely give thanks and praises to the Almighty God for endowing us with the insight, resourcefulness and strength to draft these Guidelines. These Guidelines, along with other quality documents, shall constitute the legal basis for Post Market Surveillance of medicines and health products in Liberia (Premise Registration & Licensing, Local Manufacturing of Pharmaceuticals, Import & Export Procedures of Pharmaceuticals, Post Market Surveillance, as well as Waste Management Procedures). The LMHRA’s Inspectorate and Post-Market Surveillance Department shall welcome comments/suggestions for improvement of these Guidelines during its implementation. Dr. Paul D. Y. Higgins Sr Head of the Inspectorate/PMS Department Guidelines on Inspectorate and Post Market Surveillance (PMS) vii
Overview The Inspectorate and Post Market Surveillance Department is one of the four technical departments of the LMHRA with the responsibility to inspect all medicines and health products in line with LMHRA’s regulations and guidelines with the responsibilities to conduct: Post Market Surveillance activities, manage pharmaceutical wastes through incineration, and register and license Premises (Whole sale Pharmacies/Cosmetics shops). These guidelines have been developed in line with the LMHRA’s Act of 2010 Part IV, Section 2-g, which empowers the Liberia Medicines and Health Products Regulatory Authority (LMHRA) to carry out post market surveillance programs, including inspection. Thus, these Guidelines are of five (5) parts: Guidelines for Licensing of Premises for Importers/Wholesalers; Guidelines on Import and Export Procedures for Pharmaceutical Products; Guidelines on Post Marketing Surveillance, Guidelines for Local Manufacturing of Pharmaceutical Products; and Guidelines on Waste Management of Pharmaceutical Products. Any dealer engaged in pharmaceutical business should note that, the requirements stipulated in these guidelines are of minimum requirements and thus all dealers are expected to adhere to these requirements. Guidelines on Inspectorate and Post Market Surveillance (PMS) viii
GLOSSARY For the purpose of this document, the following definitions (adapted from the World Health Organization) are used. Active implantable medical device Any active medical device that is totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and that is intended to remain after the procedure. Active medical device Any medical device relying for its functioning ona source of electrical energy or any source of power other than that directly generated by the human body or gravity. Active pharmaceutical ingredient an active substance or ingredient that is produced through physical, chemical or biotechnological processes for use in the manufacture of a pharmaceutical, biopharmaceutical or biotechnological product. Advisory notice Supplementary information or advice issued by the manufacturer upon delivery of a medical device, regarding the use, modification, return or destruction of said device, for the purpose of taking corrective or preventive action or complying with regulatory requirements. Authority The Liberia Medicines and Health Products Regulatory Authority (LMHRA) established under Part II, Section 1.1 of the Act. Authorized exporter An individual or company or similar legal entity exporting or seeking to export a pharmaceutical or veterinary product. A "licensed" or "registered" exporter is one who has been granted a license or registration status for the purpose. Authorized importer An individual or company or similar legal entity importing or seeking to import a pharmaceutical or veterinary product. A "licensed" or "registered" importer is one who has been granted a license or registration status for the purpose. Batch A specific amount of pharmaceutical or other substance produced under a single set of manufacturing instructions, and that is consistent in character and quality. Hence, under conditions of continuous production, a batch refers to a specific amount of pharmaceutical or other substance produced within a specific time period, or that, within specific parameters, is consistent in character and quality. Batch Certificate Means Certificate of Analysis. Batch number Refers to any definite combination of letters, numbers or other symbols that can be used to look up comprehensive information on a batch of products or other substances. Guidelines on Inspectorate and Post Market Surveillance (PMS) ix
Biopharmaceuticals Biotechnology product Business Clinical trial drug Content Controlled substances Cosmetics Counterfeit Medicine Counterfeit product Customer complaint Dispense Substances such as blood serum, antitoxins, vaccines, or toxoids that are manufactured using microbiological and immunological methods. Any product that has been produced by means of gene recombination or cell fusion, or microorganisms obtained through cell culturing, fermentation, tissue extraction, proliferation of embryos or active animal or plant substances, or any other biotechnology method. Includes professional practice and any activity carried on by a person or a body of persons in relation to Medicines and Health Products regulated under LMHRA. A pharmaceutical or placebo that is undergoing clinical trials, and has not yet obtained approval. Refers to one of the following: a) The unit quantity of the components of a pharmaceutical: b) The potency or efficacy of a pharmaceutical; that is, the treatment efficacy as determined through testing or sufficient clinical data. Narcotic drugs and psychotropic substances under international control. Any preparation intended to be applied to the human body for cleansing, beautifying, promoting attractiveness or altering the appearance without affecting the body’s structure or functions. A medicine that is deliberately and fraudulently mislabeled with respect to identity or source. Counterfeit products may be branded or generic medicines, and may include products with the correct ingredients, with the wrong ingredient, without ingredients, with insufficient active ingredient, or with fake packaging material. A pharmaceutical product that is fraudulently mislabeled with respect to identity and/or source. Both branded and generic products can be counterfeited, and counterfeit products may include products with correct ingredients, with the wrong ingredients, without active ingredients, with insufficient quantity of active ingredients or with fake packaging. Any written, electronic or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety or performance of a medical device that has been placed on the market; Means supply of a Medicines and Health Products on and in accordance with a prescription lawfully given by a medical practitioner, dentist or veterinary surgeon. Guidelines on Inspectorate and Post Market Surveillance (PMS) x
Dispenser End products Exportation Falsified Fiber Good Storage is an individual that supplies Medicines and Health Products, Medicines and Health Products in accordance with a prescription lawfully given by a medical practitioner, dentist or veterinary surgeon. Refer to pharmaceutical products that have been packaged, and whose outer packaging clearly indicates the contents therein. The act of sending out or causing any goods to be taken out of a national territory. Medical products that deliberately/fraudulently misrepresent their identity, composition, or source. A substance whose length is at least three times its width. Is the proper cleaning of premises and warehouses; and preservation of medicines and health products to ensure their high qualities and efficacies at optimal temperature until they are dispensed to the end users. Implantable medical device Any medical device that is totally or partially introduced by surgical Importation Inspector In-vitro diagnostic device Labeling LMHRA or Authority Manufacture means into the human body or a natural orifice, or to replace an epithelial surface or the surface of the eye, that is intended to remain after the procedure for at least 30 days, and that can only be removed by medical or surgical intervention; The act of bringing or causing any goods to be brought into a national territory. Means an individual who is appointed, authorized or recognized by the Authority to inspect and examine for compliance with regulations and standards. Any medical device that is a reagent, instrument, or system used for the collection, preparation and examination of specimens from the human body for use in the diagnosis of disease or other conditions (including determination of the state of health); Refers to all text and graphics that appear on labels, instruction sheets or packages, or that come with products. Is used interchangeably to mean the national agency responsible for the registration of medicines, and other regulatory activities concerning, pharmaceutical, veterinary and biological products. Includes all operations of purchase of materials and products, production, quality control, release, storage, shipment of finished products, and related controls Guidelines on Inspectorate and Post Market Surveillance (PMS) xi
Medical Device Medical Supply Medicine Narcotic Drug Non-fiber releasing filter Packaging materials Permit Pharmaceutical Importer Means an instrument that is not a medicine, as defined herein, that is intended for use in the diagnosis, treatment, prevention of disease, disorder, abnormal physical or mental state, or symptoms thereof, in human or animal. Means any article that is intended for diagnosis, treatment, prevention of disease, disorder, abnormal physical or mental state, or symptoms thereof, in human or animal or restoring, correcting or beneficial modification of organic or mental functions in human or animal. This includes suturing materials, syringes, needles, bandages, gauze, cotton, artificial teeth, chemicals, and X-ray film and other similar articles. Means any substance or mixture of substances intended for use in: (i) the diagnosis, treatment, prevention of disease, disorder, abnormal physical or mental state, or the symptoms thereof, in man or animal; (ii) restoring, correcting or beneficial modification of organic or mental functions in man or animal; (iii) medicine shall include traditional medicine, narcotic drugs, psychotropic substances, blood and blood products, vaccines, sera, and radiopharmaceuticals, but not health products as defined herein. Means any substance subject to control according to the single Narcotic Drugs Conventions, 1962, adopted by the United Nations and ratified by the Republic of Liberia. This shall also include any substance categorized by the Authority as a narcotic drug. A filter which after any appropriate pretreatment, such as washing or flushing, will not release fibers into the filtrate of the product that is being filtered. Include product containers, caps, and any materials used in the outer packages of products. Means competency certification issued by the authority to a registered importer and/or wholesaler to handle and distribute/sell a medicine in a registered premise. Means a registered entity and licensed by LMHRA to procure and import medicines and health products from foreign countries and/or distribution in the commerce of Liberia. Pharmaceutical product (medicine) Any medicine intended for human or veterinary use, presented in its finished dosage form that is subject to control by pharmaceutical legislation. Pharmaceutical Wholesaler Means a dealer or trader duly registered and licensed by LMHRA for Pharmacy the purchase and distribution of medicine and health products from manufacturer and/or importer to the retail pharmacy and pharmacist in the commerce of Liberia. Is a registered place or department in a hospital, clinic or health center Guidelines on Inspectorate and Post Market Surveillance (PMS) xii
or a community pharmacy where medicines and other pharmaceuticals are stored and dispensed. Post-marketing surveillance Surveillance activities that occur following market approval of a Premise Products Product information medicine, including maintenance of product authorization and/or registration of variations or renewals; regular inspections of manufacturers, wholesalers, distributors, and retailers; quality control testing; pharmacovigilance; promotion control; public reporting of poor- quality products; handling of market complaints; and removal and disposal of non-compliant products. Includes land, building, basements and vessels and in relation to any building includes a part of a building and any cartilage, forecourt, yard or places of storage used in connection with building or part of that building, and in relation to vessel means ship, boat, and aircraft and includes a carriage or receptacle of any kind. Active pharmaceutical ingredients, or preparations that contain active pharmaceutical ingredients and may contain other non-active ingredients, for which all manufacturing processes have been completed. The approved product information for health professionals and the public as approved in the exporting country. Product license (registration certificate) An official document issued by the competent drug regulatory authority for the purpose of the marketing or free distribution of a product Psychotropic substance Also referred to as a controlled substance is any substance whether natural or synthetic listed in Schedules I, Il, III or IV of the 1971 Convention on psychotropic substances Psychotropic Substances Means any substance subject to control according to the conventions on Quality assurance Raw materials Registration psychotropic substances, 1971, adopted by the United Nations and ratified by the Republic of Liberia. This shall include any substance categorized by the Authority as a Psychotropic Substance. An integrated system of activities involving planning, quality control, quality assessment, reporting, and quality improvement to ensure that a product or service meets defined standards of quality with a stated level of confidence. Any materials used in the manufacture of pharmaceuticals, including those that do not remain in the end product. Any statutory system of approval required at national level as a precondition for introducing a pharmaceutical product on the market. Guidelines on Inspectorate and Post Market Surveillance (PMS) xiii
“Registered, licensed, authorized” These words are used in these guidelines interchangeable Regulations An official rule, law, or order stating what may or may not be done or how something must be done. Retail Pharmacy business Means a business, which consists of or includes the retail sale of medicine and health products but does not include professional practice carried on by Medical practitioner, dentist or veterinary surgeon. Risk analysis The investigation of available information to identify hazards and assess risks. Screening tests The qualitative and/or quantitative tests that could rapidly acquire preliminary analytical information or data on the quality of medical products in the field. Sell Means sell by wholesale or retail and include import, offer, advertise, keep, expose display, transmit, consign, convey or deliver for sale or authorize, direct or allow a sale or prepare or possess for the purpose of sale and barter or exchange supply or dispose of to any person whether for a consideration or otherwise. Semi-finished or intermediate products Any products that are obtained during the manufacturing process, and that, with further processing, can become finished products. Simple Random Sampling Random sampling is a probability-based sampling technique whereby a group of subjects is selected (a sample) for study from a larger group (a population). Each subject is chosen entirely by chance, and each has an equal (or non-zero in the case of complex random sampling) chance of being included in the sample. Substandard Also called “out of specification,” refers to authorized medical products that fail to meet either their quality standards or specifications, or both. Substandard Medicines These are products whose composition and ingredients do not meet the correct scientific specification and which are consequently ineffective and often dangerous to patients. Substandard products may occur as a result of negligence, human error, and insufficient human and financial resource of counterfeiting. Superintendent Pharmacist Means a pharmacist who is a technical manager and controls the business of a pharmaceutical outlet. Tamper-proof packaging Packaging with an identifying mark or barrier that enables consumers to clearly identify the contained product. Validation Written documentation attesting that any procedure, manufacturing process, mechanical device, raw material, action or system is capable of Guidelines on Inspectorate and Post Market Surveillance (PMS) xiv
achieving its anticipated effect. WHO Stands for World Health Organization. ACRONYMS LMHRA - Liberia Medicines and Health Products Regulatory Authority PBL- Pharmacy Board of Liberia CMHPI - County Medicines and Health Products Inspector RMHPI - Regional Medicines and Health Products Inspector NPS - Narcotic and Psychotropic Substances PQM - Promoting Quality of Medicine USP - United States Pharmacopeia WHO - World Health Organization PMS - Post Market Surveillance TFDA - Tanzania Food and Drug Authority PSI - Pharmaceutical Society of Ireland GMP - Good Manufacture Practices Guidelines on Inspectorate and Post Market Surveillance (PMS) xv
STATEMENT FROM THE MANAGING DIRECTOR Asa National Regulatory Agency for medicines and health products, the Liberia Medicines and Health Products Regulatory Authority is responsible to ensure the efficacy, quality and safety of all medicines and health products that circulate on the Liberian market. Additionally, it is incumbent upon the Authority to adequately disseminate relevant information for public consumption, and create a working tool for utilization by the public. Against this background, these guidelines have been developed to provide guidance for all Pharmaceutical entities in Liberia. | appreciate the contribution of the Inspectorate & Post-Market Surveillance Department and the team of validators for their guidance in the development of these Guidelines. Hon. Luke L. Bawo Managing Director Liberia Medicines and Health Products Regulatory Authority (LMHRA) Guidelines on Inspectorate and Post Market Surveillance (PMS) xvi
1.0 PROCEDURES FOR REGISTRATION & LICENSING OF PREMISES FOR IMPORTERS AND WHOLESALERS 1.1. INTRODUCTION The purpose of these Guidelines is to facilitate compliance with the requirements of the LMHRA Act 2010 and the Regulation of Importers and Wholesalers of Pharmaceuticals Businesses in relation to the premises that are engaged in import, distribution, storage, and sale of medicines and health products (i.e. pharmacies) under the Act. These guidelines are intended to assist pharmacy owners, applicants to open new pharmacy and superintendent pharmacists, in ensuring that their premises meet required standards. In that respect, pharmacy owners must ensure that the premises are fit for purpose and appropriately equipped and staffed and that the required governance arrangements are in place at all times so as to adequately protect the health, safety and convenience of patients, the public and staff. Pharmacy owners must recognize and facilitate compliance with their own legal obligations and with those of the superintendent pharmacist, all decisions and processes pertaining to the sale and supply of medicinal products are under the personal control of the superintendent pharmacist. In the discharge of their responsibilities for the appropriate management and administration of the respective pharmacies for which they are responsible, the superintendent pharmacist must be satisfied that the staff, premises, equipment and procedures are adequate for their purpose. These guidelines outline the minimum requirements relating to the premises of all existing pharmacies as well as for planned new pharmacy openings. Pharmacy owners and their superintendent pharmacists are required to conduct the wholesale pharmacy business in compliance with these guidelines and shall ensure that the minimum standards are met. Pharmacy premises should provide an environment which facilitates the adherence of pharmacists to the core principles set out in the Code of Conduct for Pharmacists. All registered pharmacists have an obligation to ensure that the pharmacy is operated in accordance with all legislations and guidance, promoting the highest professional standards in the delivery of pharmacy care, treatment and service. They must ensure that the premises and facilities are fit for purpose for the provision of pharmacy services and are well maintained, facilitating a safe and effective working environment and reflecting the professional nature of a healthcare facility. According to the LMHRA Act of 2010 Part II, Section 2.1(b) prohibits the use of any premise for the manufacture, sale, supply or storage of pharmaceuticals unless the premise has been registered by the Liberia Medicines and Health Products Regulatory Authority (LMHRA), excluding retail Pharmaceutical outlets. Registration of premises and licensing of pharmaceutical businesses shall not be considered as the sole Guidelines on Inspectorate and Post Market Surveillance (PMS) I
means of controlling operations of these premises. However, there are other valuable means of aid in enforcing relevant legislations, such as adherence to good hygienic and pharmacy practices, Good Distribution Practices that ensure day-to -day operations of these premises are in line with the laws and regulations. According to the LMHRA Act of 2010, Part II Section 2.1(c), The Authority has the power to suspend, cancel, or revoke the registration certificate, permit and license of any premise found to operate contrary to the law. The guidelines have also stipulated sizes for Import and wholesale pharmacies. The requirement is intended to set uniformity of size for establishments dealing with pharmaceutical business namely importation and wholesale. The Guidelines consist of the basic requirement for registration of premises as well as permit for pharmaceutical business and annexes. The Guidelines give detail procedure for application for registration of premises and pharmaceutical business permit. It also gives guidance on location, premise design and layout, personnel requirements, storage facilities, sanitation and hygiene; stock control and handling, records and documentation, recalls, rejection and withdrawal, cessation of business, validity of premises registration and pharmaceutical business permit, payment of fees, notification for change of any or alteration of registered premises. Any dealer engaged in pharmaceutical business should note that, the requirements stipulated in these guidelines are of minimum requirements and thus all dealers are expected to adhere to these requirements. Guidelines on Inspectorate and Post Market Surveillance (PMS) 2
12. PROCEDURES FOR LICENSING OF PREMISES FOR IMPORTERS AND WHOLESALERS 1.2.1 Applicants (Pharmacists) are required to get a copy of the Guidelines and read carefully before engaging in construction of intended premise. 1.2.2 The applicant (Pharmacist) shall continue with the process of construction/renovation of the premise. Upon completion he/she the applicant shall inform the Authority for inspection. 1.2.3. The applicant (Pharmacist) shall be made to sign a contract agreement with the owner of the business and submit the true copy of the original contract to LMHRA for record purposes and attach a copy of registration certificate of the pharmacist as issued by the Pharmacy Board of Liberia. 1.2.4 Neither the Pharmacist nor his/her proxy shall terminate such contractual agreement without a prior notice to the Authority. 1.2.5 Application for Premise licensing to operate a new pharmaceutical business shall be done with a letter written to the Authority by the Pharmacist in charge. 1.2.6 Application form shall be obtained from LMHRA office for a new or renewal of Pharmaceutical business. 1.2.7 Applicant shall be required to fill accurately all the required information in the application form. Applicants shall submit their applications to the LMHRA. 1.2.8 Applicant shall attach a sketch design of the proposed premise. Whereby, the Authority through the authorized inspector shall go through the sketch design to verify if it suits the intended purpose. The proposed business name shall be subject to further review by the Authority before the applicant forwards it to the registrar of business. The Authority shall approve or reject the submitted sketch design and the applicant will be informed accordingly. 1.2.9 The inspector shall make sure that the premise is inspected to verify if all the requirements have been met. Guidelines on Inspectorate and Post Market Surveillance (PMS) 3
1.3. LOCATION OF PHARMACEUTICAL BUSINESS 1.3.1 The premise shall be located away from sites or activities that emit obnoxious materials like fumes and contaminants, open sewerage, offensive trade etc. 1.3.2 Premise located within or near petrol station shall be furnished in such a way that the activities including fuel fumes does not affect in any way the quality of medicines and dispensation process in the premise. The premise shall be required to address among other issues, the fire prevention facilities. 1.3.3. Premise located within shopping centers, e.g. shopping malls, supermarkets etc. shall be confined and restricted from other activities that pose threat. 1.3.4 The premise shall be designed such that, it shall have no direct link to building with bar and restaurant. 1.3.5 The premise shall be designed such that, it shall have no direct link to building with bar and Restaurant 1.3.6 The premise shall have telephone number(s), e-mail addresses(s) and postal addresses(s) of County, District and Region where the business is to be carried out. This should be clearly indicated in the application form for easy communication and location during supervision and inspection. 1.3.7. The premise shall have a signboard conspicuously displayed at the main entrance. 1.3.8 Registration of premise shall be approved if the new premise is at least 150 meters away or as deemed necessary by LMHRA from an existing wholesale pharmacy. However, the Authority shall have power to review this requirement from time to time basing on the service need by the community and population increase. Guidelines on Inspectorate and Post Market Surveillance (PMS) 4
1.4. PREMISE DESIGN AND LAYOUT (IMPORTATION AND WHOLESALE) 1.4.1 The premise shall have a minimum total size/area of 8m (27 ft) long, 5m (17 ft) wide and 3m (10 ft) high; the wholesale section should be separated from retail. Both sections should have two different doors. 1.4.2 The front view of the premises should have a metal door with the Company’s name printed above. Glass door should be placed after the metal door; 1.4.3. The Premise shall have aluminum shelves and counter before being licensed. 1.4.4 The entire building shall be painted green and white. The name and logo of the Pharmacy shall be printed in green with white background. 1.4.5 The premise shall be durable, safe and made of permanent building materials so as to protect pharmaceuticals from potential harmful influences. 1.4.6 The surrounding shall be maintained so as to avoid dust, soil and other contaminants from entering the premise. 1.4.7. Sufficient lighting and ventilation shall be provided to enable all operation carried out. 1.4.8 “NO SMOKING?” sign shall be conspicuously displayed at the entrance. 1.4.9 The premise shall have air condition to maintain an optimal temperature of 259C for proper storage, safe keeping and handling of pharmaceuticals. 1.4.10 All biologicals shall be stored at temperature range of 2°C to8'C. 1.4.11 The premise that contains both human and veterinary medicines and health products, shall have separate displaying shelves and storage cabinets. 1.4.12 The premise dealing in pharmaceutical products shall not be stocked in the same registered premise with chemicals or pesticides used exclusively for plant protection. 1.4.13 The premise shall have separate secured cabinets with lock and key for controlled drugs such as Narcotic and Psychotropic substances. Guidelines on Inspectorate and Post Market Surveillance (PMS) 5
1.5. GOOD STORAGE AND WAREHOUSING FACILITIES 1.5.1 The minimum size/area of the warehouse shall be 16m (53 ft) long, 10m (33 ft) wide and 3m (10 ft) high to be of sufficient capacity to allow for the orderly storage of various categories of materials and products, including finished, rejected, returned, or recalled, expired and damage products. The maximum size/area of the shall be 18.28m (60 ft) long, 13.71m (45 ft) wide and 4.26m (14 ft) high. Any warehouse exceeding the maximum shall be charged additional fee. 1.5.2. There shall be a clearly demarcated area for storing damaged, expired, recall, quarantine, falsified and substandard products. 1.5.3. It shall be kept clean and dry at acceptable temperature of 20 to 25 Degree Celsius. 1.5.4 The storage area shall be furnished with shelves and pallets which must be kept in a good state of cleanliness and repairs; 1.5.5 All pharmaceutical products and/or medicines shall be stored off the floor and well- fitted on shelves or pallets and suitably spaced to permit cleaning and inspection; 1.5.6 Cartons shall be stocked at minimum 10cm (4 inches) off the floor, 30cm (1 ft) away from the walls and no more than 2.5m (8 ft) high. 1.5.7. Arrange cartons so that arrows point upward and identification labels, expiry and manufacture dates are clearly visible and in a manner accessible for First to expire and First out (FEFO). 1.5.8 Appropriate storage facilities for biological products shall include: Y Arefrigerator with a temperature range of 0 to 8 Degree Celsius. ¥Y There shall be uninterrupted supply of electricity. Y Cold chain products shall be monitored using suitable temperature recording devices. 1.5.9 The floor shall be durable to withstand heavy traffic and loads; the premise shall be provided with well-fitted shelves or pallets. Both the premise and warehouse shall be equipped with temperature and humidity control monitors and fire extinguishers. 1.5.10 A residential home shall not be used as a warehouse. 1.5.11 Warehouses shall be designed and constructed to ensure good storage conditions, sufficient lighting and ventilation. 1.5.12 Warehouse shall only be used for storage purposes and no sales shall be conducted in the warehouse. Guidelines on Inspectorate and Post Market Surveillance (PMS) 6
1.6. SANITATION AND HYGIENE OF PREMISES 1.6.1 There shall be a written sanitation procedure specifying the frequency and the methods to be used in cleaning the storage areas in the premise. 1.6.2 There shall be clean toilet facility available in the premise. 1.6.3 To maintain hygienic working conditions, the premise shall have good supply of portable water and proper sink for hand washing. 1.6.4. Only healthy Personnel shall be allowed to serve in the premise. 1.7. RESPONSIBILITY OF THE PHARMACIST 1.7.1 The Pharmacist shall be responsible to coordinate between the Authority and the Premise. 1.8. INSPECTION 1.8.1 There shall be current Good Manufacturing Practices (CGMP) Inspection carried out regularly. The inspection shall enable the LMHRA to confirm that license holders are in compliance with the conditions of their licenses with the provision of the Act. The LMHRA inspectors shall: v Enter and inspect any premise that is engaged in Pharmaceuticals activities. 1.9. STOCK CONTROL AND HANDLING 1.9.1 All pharmaceutical outlets shall have proper stock control and handling procedure for receiving, keeping, selling, dispensing and compounding of pharmaceuticals, which shall be properly labelled and stored in suitable and secured places. 1.9.2 Repackaging and re-labeling of pharmaceuticals are prohibited. 1.9.3. Storage, supply, distribution and recording of controlled drugs (Narcotic and Psychotropic substances) shall be done in accordance with the LMHRA Premise guidelines. 1.10. RECORDS AND DOCUMENTATION All importers and wholesalers shall have the following in their premise: Premise registration License Recording books for distribution Ledger book or an appropriate inventory control system Receipt book ASK Guidelines on Inspectorate and Post Market Surveillance (PMS) 7
v Complaints book for inspectors v Expired medicine Register book v Controlled medicine (Narcotic and Psychotropic) Register v Final invoices with corresponding certificate of importation and copy of purchase order and/or invoices. v Copies of delivery notes. 1.11. RECALLS AND WITHDRAWALS 1.11.1 The LMHRA inspectors shall recall all medicines and health products confirmed to be falsified, substandard, expired and damaged from the market 1.12. TERMINATION OF BUSINESS 1.12.1 According to the LMHRA Act of 2010, Part II Section 2.1(c), The Authority shall at any time suspend, cancel, or revoke the registration certificate, permits and license of any premise found not in compliance with the guidelines. 1.13. VALIDITY OF PREMISE REGISTRATION CERTIFICATE 1.13.1 The premise shall be maintained in the condition as at the time of its initial registration 1.13.2 There shall be no change of ownership, business name, location and closure without notification to the Authority. 1.13.2 The premise license shall be renewed annually [after every twelve (12) months] unless suspended, cancelled or revoked by the Authority. Guidelines on Inspectorate and Post Market Surveillance (PMS) 8
2.0 GUIDELINES ON IMPORT & EXPORT PROCEDURES 2.1 INTRODUCTION Public health concerns demand that the manufacture of pharmaceutical products and their subsequent handling within the distribution chain both nationally and internationally must conform to prescribed standards and be rigorously controlled in order to ensure their quality, safety and efficacy. The LMHRA has a responsibility of assuring the quality, safety and efficacy of medicinal products moving nationally and internationally. These Guideline documents are intended to summarize and to explain the basic requirements for exporting and importing medicinal products in the Country. However, the need for the effective use of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce - a Scheme which constitutes a formal agreement between countries to provide information on any product under consideration for export, notably on its registration status in the country of origin and whether or not the manufacturer complies with WHO's guidelines on Good Manufacturing Practices (GMP) for pharmaceutical products cannot be overemphasized. It is important to note that importers and exporters of medicinal products may be subjected to additional statutory or regulatory requirements beyond those inscribed in these guideline documents. Guidelines on Inspectorate and Post Market Surveillance (PMS) 9
2.2 LEGAL CONSIDERATIONS All transactions concerning the importation of consignments of pharmaceutical products should be conducted through Liberia Medicines and Health Products Regulatory Authority (LMHRA). Unless otherwise specified, only licensed/approved medicinal products shall be permitted to be imported (or exported) within the country. The importation of all consignments of pharmaceutical products should be channeled exclusively through the designated ports of entry (sea and Air port) and will be cleared by customs in consultation with the Inspectors of the LMHRA. Medicines and their documentation shall not be allowed through the Land borders unless otherwise approved by the LMHRA when deem necessary. All applicants must be in possession of a current Importers’ License issued by LMHRA. The Pharmaceutical Import License shall be subject to annual renewal upon expiry. An application for the issue of an import or export permit shall be made by an authorized importer to the LMHRA in a prescribed form/application to the Managing Director. The period of validity of the import and export permits shall be six (6) months unless otherwise deem necessary by LMHRA to exceed said period. 2.3. IMPLEMENTATION OF CONTROLS Liberia Medicines and Health Products Regulatory Authority (LMHRA) shall provide comprehensive and frequently updated lists of licensed or notified medicinal products and authorized dealers/importers which should be easily accessible to designated ports of entry and authorized dealers. Notifications on any product license that have been withdrawn on grounds of safety or quality and confirmed cases of imported counterfeit products and other illicit activities; shall immediately be communicated to all the LMHRA staff at the port of entry. LMHRA inspectors in collaboration with Custom officials shall carry out physical examination of all imported consignment of medicinal products and their documentation. The LMHRA inspectors shall carry out random sampling of pharmaceutical products in accordance with laid down guidelines on sampling of medicinal products imported into the country for product analysis. Consignments of any falsified and substandard products shall be forfeited and incinerated as per provisions in the LMHRA Guidelines. Liberia Medicines and Health Products Regulatory Authority (LMHRA) shall immediately be notified of these confirmed cases of counterfeit products. Consignments of pharmaceutical products shall be accorded high priority for clearance through ports of entry. Since pharmaceutical products tend to degrade on storage and some need to be kept in cold storage, ports of entry need to be provided with secure storage facilities including refrigerated compartments. Guidelines on Inspectorate and Post Market Surveillance (PMS) 10
The authorized importer shall alert LMHRA Inspectors and customs officials in advance of the anticipated arrival of consignments in order that they can be transferred to the designated storage facilities without breaking the cold chain. 2.4 EXEMPTIONS FROM REQUIREMENTS OF A PHARMACEUTICAL IMPORT/EXPORT LICENCES 2.4.1 2.4.2 2.4.2 2.4.3 2.4.4 Importation of Donated Pharmaceutical Products Importation of donated pharmaceutical products shall be dealt with in accordance with the donation guidelines of Liberia on donated drugs. Importation of Donated Pharmaceutical Products in Emergency The LMHRA reserve discretionary powers to waive product licensing requirements in respect of consignments of pharmaceutical products imported in response to emergency situations and, exceptionally, in response to requests from clinicians for limited supplies of unlicensed medicines needed for treatment of specific named patients. Importation of Pharmaceutical Products for Personal Use Importation of pharmaceutical products for personal use or for use by a member of a family shall be limited to one month, unless otherwise deem necessary by the Authority after which approval from LMHRA shall be required. It must be emphasized that the intent of the ‘personal use importation’ guidance is to generally permit the LMHRA exercise its enforcement discretion for medicines that may not otherwise be available in the country. Importation of Medicines to be used for Clinical Trials Authorization shall be sought from LMHRA for the purposes. Importation of Bio-Technological/Biological/Blood Products, SERA & Vaccines Authorization shall be sought from LMHRA for these purposes. Guidelines on Inspectorate and Post Market Surveillance (PMS) Il
2.5 DOCUMENTATION The authorized importer shall be required to furnish LMHRA and customs officials with: 1. Certified copies of documents issued by the LMHRA attesting that the importer is: (a) An authorized importer (produce a valid Pharmaceutical Imports’ License) (b) Importing a medicine that is duly authorized/certified (produce a valid product registration Certificate). 2. Batch certificate issued by the manufacturer in conformity with the requirements of WHO Certification Scheme. 3. Relevant invoice for product intended for importation or bill together with an import permit or export permit. 2.6 IMPORTATION AND EXPORTATION OF CONTROLLED SUBSTANCES Most of the requirements specified in these guidelines on import and export procedures for medicines also apply to the control of controlled substances in addition to the requirements of relevant legislation and in accordance with international conventions. Each member country shall be required to comply with the Treaty Obligations as enshrined in the “United Nations International Narcotics Control Board's (INCB) 1961 Single Convention on Narcotic Drugs” and the “1971 Convention on Psychotropic Substances”. The authorized importer shall present to the LMHRA and customs authorities a copy of the respective Import License issued by LMHRA and other relevant documents issued by the competent authorities of the exporting country, a copy of which must accompany each consignment. Import authorizations are required for psychotropic substances in Schedules I, II, II] and IV of the 1971 Convention so as to prevent attempts to divert psychotropic substances such as stimulants, sedative-hypnotics and tranquillizers into illicit trade. These Import authorizations shall only be issued to authorized importers with valid pharmaceutical import and wholesale dealer's licenses and appropriate premises. The import and export authorizations shall contain at least the following information: a) Name of controlled substance(s) (if available, the International Nonproprietary Name) b) Quantity to be imported / exported expressed in terms of anhydrous base content c) Name & address of the importer and exporter d) Period of validity of the authorization e) Route of entry/exit through which importation/exportation shall take effect. Guidelines on Inspectorate and Post Market Surveillance (PMS) 2
f) Number and date of the corresponding import/export authorization and the name of the competent authorities of the importing/exporting countries by whom it was issued g) Strength and dosage form An application for a license to import/export controlled substances will be made to LMHRA in the prescribed form/Application backed by legislation. 2.6.1 CRITERIA FOR ISSUE OF AUTHORISATION TO IMPORT The criteria for issue of a pharmaceutical import license should ensure that: a) b) c) d) 2.6.2 The applicant must be a Pharmacist There are suitable premises, facilities and equipment for proper pharmaceutical warehousing There are suitably qualified pharmaceutical personnel that shall oversee the quality assurance i.e. pharmacist. There are suitable arrangements, programmers and systems for procurement, storage, documentation, stock surveillance and distribution. APPLICATION FOR ISSUE OF AN IMPORT PERMIT An application accompanied by a prescribed fee for issue of an import permit shall be made on the prescribed form backed by legislation. An application for issue of an import permit shall state for each medicine to be imported; at least the following: a) b) c) d) e) f) g) h) i) ij) k) 1) Generic name or International Non-proprietary Name (INN) Strength and dosage form Name and strength of each ingredient; in case of a product containing more than one ingredient Trade name or proprietary name; if any Pharmacopoeia specification of the medicine, where applicable Total quantity to be imported Name and address of the supplier Name and address of the manufacturer Country of origin Route of entry License/ registration number Cost, insurance, freight (CIF) value m) Expected date of arrival n) Batch certificate issued by the manufacturer in conformity with the requirements of WHO Certification Scheme A separate import permit for controlled substances shall be applied as prescribed by the national legislation and applicable treaty obligations. The application shall be accompanied by copies of the pro-forma invoices. Guidelines on Inspectorate and Post Market Surveillance (PMS) 13
2.6.3 APPLICATION FOR ISSUE OF AN EXPORT PERMIT An application accompanied by a prescribed fee for issue of an export permit shall be made on the prescribed form backed by legislation. An application for issue of an export permit shall state, for each medicine to be exported at least the following: a) b) c) d) e) f) g) h) i) j k) )) Generic name or International Non-proprietary Name (INN) Strength and dosage form Name and strength of each ingredient; in case of a product containing more than one ingredient Trade name or proprietary name; if any Pharmacopoeia specification of the medicine, where applicable Total quantity to be exported Name and address of the exporter Name and address of the manufacturer Name and address of consignee Country of consignee Route of dispatch License/registration number m) Cost, insurance, freight (CIF) value n) ) Expected date of dispatch Batch certificate issued by the manufacturer in conformity with the requirements of WHO Certification Scheme The application shall be accompanied by copies of the purchase orders. In conclusion, importation of drugs that lack approval and are not in line with these guidelines whether for personal use or otherwise will be considered as illegal importation and could be refused entry into the country or seized by LMHRA Inspectors. In cases where LMHRA Inspectors are not present, collaborating partners (custom officials, DEA, LIS, LNP, etc.) shall seize said products and have it turned over to LMHRA. Guidelines on Inspectorate and Post Market Surveillance (PMS) 14
License No: Registration No. Pharmaceutical Import License Mr. /Madam. (Name of Importer) ........0.ssssssssecsssssssssssecesssssssssesscesessereesescesescs, Are hereby authorized to Import Pharmaceutical Products (Medicines, herbal medicines and allied substances) into the Country during the calendar Conditions imposed by the Pharmaceutical Regulatory Authority (refer to notes overleaf). This license is valid from........... Registrar of medicines Date stamp Date Issued ............0c.ccceeeeceeeceees Guidelines on Inspectorate and Post Market Surveillance (PMS) 15
2.6.4 Conditions of issue / renewal for import license Consideration of an application for issue / renewal may take advantage to impose any new conditions or insist on any aspects that had been overlooked previously or are brought about due to new or amended legislation or policy. 2.6.5 Conditions for Premises * Compliance with minimum requirements ¢ Valid local authority license * No adverse report since the previous issue regarding e.g. wrongful dealing in medicines, lack of proper management and control of the pharmaceutical business, ete. * Appropriately registered pharmacist with practicing license from Liberia Pharmacy Board (LPB) and with no recorded acts of professional misconduct over the previous year (those that may or may not warrant revocation of practicing license). * Appropriate renewal forms and fees submitted well before previous license lapsed * No changes to the previous conditions under which license was issued. 2.6.6 Conditions for Amendments All amendments to conditions under which an import license was issued must be formally applied for and approved. Annual importers’ license fee must be paid. An applicant must not affect any changes without prior approval except for situations where e.g. a registered pharmacist leaves without notice and is in attendance for a period less than four weeks, changes of directorship in a company without changes in the effective supervision of the business. Changes of ownership, effective directorship of a company, structural changes to the premises, changes in effective supervision of business, relocation to other premises require prior and written approval. 2.6.7 Validity Certificates are valid for one calendar year from time of issue or until formally cancelled by LMHRA. An annual renewal must be applied for each time an applicant wishes its license to be renewed. Once a license has lapsed due to failure to renew by the licensee, there shall not be a requirement for a formal notification of intent by LMHRA to consider the license invalid. 2.6.8 Suspension or cancellation of licenses A license may be cancelled under the following situations: ¢ Failure to comply with specific conditions of licensing. ¢ Wrongful dealing in medicines, herbal medicines and allied substances. Guidelines on Inspectorate and Post Market Surveillance (PMS) 16
Unauthorized change of premises. Failure to comply with other legislation e.g. local authority licensing, health requirements that were part of the conditions of initial approval. A formal and legislated appeal process must be conducted prior to cancellation of a license. Guidelines on Inspectorate and Post Market Surveillance (PMS) 17
12 License No. Registration No. Pharmaceutical Export License Mr/Madam: (Name of Exporter) ..........0..c:ccscscesscsssesseeeseeseesse sesecssevsceaseeseeeecees Cate ying Oni BUSINESS AS) escseseccosseusxszereayacsts0%< 4 .2osasoesesnyesnebe voeenedesuectuevesnaavsusesteeoneoe Are hereby authorized to export Pharmaceutical Products (Medicines, herbal medicines and allied Substances) during the calendar year.. Name of Supervising Pharmacist ... HOttivessstseses, LOS so eranssio im mera Sneltamesslon sete fThsatny pe crate Rate eee Pe a Ree nna Registrar of medicines DatCUSSUBU cc sttossvescscrrcescenn ements en aoe ore te | oak ia, NOP erealiles Date stamp Overleaf notes Guidelines on Inspectorate and Post Market Surveillance (PMS) 18
2.6.9 Conditions of issue / renewal for export license Consideration of an application for issue / renewal may take advantage to impose any new conditions or insist on any aspects that had been overlooked previously or are brought about due to new or amended legislation or policy. 2.6.10 Conditions for Premises * Compliance with minimum requirements * Valid local authority license * No adverse report since the previous issue regarding e.g. wrongful dealing in medicines, lack of proper management and control of the pharmaceutical business, etc. * Appropriately registered pharmacist with practicing license from Liberia Pharmacy Board (LPB) and with no recorded acts of professional misconduct over the previous year (those that may or may not warrant revocation of practicing license). * Appropriate renewal forms and fees submitted well before previous license lapsed ° No changes to the previous conditions under which license was issued. 2.6.11 Conditions for Amendments All amendments to conditions under which an export license was issued must be formally applied for and approved. A processing fee must be paid. An applicant must not affect any changes without prior approval except for situations where e.g. a registered pharmacist leaves without notice and a locum tenens is in attendance for a period less than four weeks, changes of directorship in a company without changes in the effective supervision of the business. Changes of ownership, effective directorship of a company, structural changes to the premises, changes in effective supervision of business, relocation to another premises require prior and written approval. 2.6.12 Validity Licenses are valid for one calendar year from time of issue or until formally cancelled by the issuing authority. An annual renewal must be applied for each time an applicant wishes its license to be renewed. Once a license has lapsed due to failure to renew by the licensee, there should not be a requirement for a formal notification of intent by the licensing authority to consider the license invalid. 2.6.13 Suspension or cancellation of licenses A license may be cancelled under the following situations: e Failure to comply with specific conditions of licensing. e Wrongful dealing in medicines, herbal medicines and allied substances. Guidelines on Inspectorate and Post Market Surveillance (PMS) 19
Unauthorized change of premises Failure to comply with other legislation e.g. local authority licensing, health requirements that were part of the conditions of initial approval A formal and legislated appeal process must be conducted prior to cancellation of a license. Guidelines on Inspectorate and Post Market Surveillance (PMS) 20
3.0 | GUIDELINES ON POST MARKETING SURVEILLANCE 3.1 INTRODUCTION The Liberia Medicines and Health Products Regulatory Authority’s Act of 2010 Part IV, Section 2 empowers the Liberia Medicines and Health Products Regulatory Authority (LMHRA) to carry out post market surveillance programs. Post-market surveillance is a key standard regulatory function of the LMHRA with a legal basis in the national laws and regulations. Strong national post-market surveillance programs are focused on quality, safety and efficacy of medical products and responding to public health risks can help protect citizens from the threats posed by substandard and falsified (SF) medicines. This guideline defines the regular sampling and surveying of both the regulated and unregulated supply chains to identify SF medical products and. Different methodologies are used to sample the products market and range from random sampling through targeted sampling of particular products and outlets. Risk-based approaches are used to determine the types of medicines that will be sampled, the sampling locations, the sample size, and the appropriate analytical tests to perform. This guideline will assist the Quality Control Laboratory (QCL), Pharmacovigilance Division as well as Authorized Officers in Inspectorate division including those working in the periphery to effectively carry out relevant duties. 3.2. PURPOSE This guideline provides information for LMHRA to begin executing post-marketing surveillance as a core regulatory function. 3.3. OBJECTIVES 3.3.1 To monitor safety, quality and efficacy of medicines available in the market in different areas/region at various levels of distribution/supply chain with the aim to assess the exposure of the public to poor-quality medicines and propose appropriate actions. 3.3.2 To identify possible causes of inferior quality of specific products to which the public is exposed. 3.3.3. To test quality of medicines in order to support the LMHRA in identification of manufacturers non-compliant with quality standards and in adoption of regulatory measures. 3.3.4 To detect and report any SF product which penetrates through the market and what may be the health outcome/ impact. 3.3.5 To identify SF medical products that have reached consumers. 3.3.6 For raising awareness concerning the importance of reporting an unusual lack of efficacy of medicinal products. Guidelines on Inspectorate and Post Market Surveillance (PMS) 21
3.4 Procedures for Post-Marketing Surveillance 3.4.1 Inspection plan is prepared according to the requirements of LMHRA. 3.4.2. Initial planning under the LMHRA is coordinated with other stakeholders. 3.4.3. LMHRA Inspectors carry out Inspection according to an established and approved plan. 3.4.4 The PMS Unit shall carry out inspections according to SOP. 3.4.5 After inspection, samples collected from the field are sent to the QC Lab for analysis. Data are analyzed by the QCL of LMHRA and feedbacks are shared with all relevant stakeholders. 3.4.6 The Inspectorate Department carries out follow-up actions as appropriate. 3.5 Inspection and Testing Priorities The QCL involvement in the planning stage of any inspection and testing activity is to provide all technical information about the tests to be used, the specifications of the products, the number of units per sample to collect for each medicine and key information related to the stability and proper handling of medicines during inspection. The inspections and specifications for each medicine that are used are as following: a) Monitoring medicines that are new to the market. b) Monitoring medicines based on the risks associated with manufacturing complexity, dosage form, stability (e.g., temperature sensitivity), safety/efficacy (e.g., narrow therapeutic window), demand (e.g., high-burden diseases), therapeutic indication (e.g., infectious diseases), or other factors. C) Monitoring the quality of medicines at key ports of entry (visual inspection). This type of monitoring which serves as a first-line intervention, has been shown to deter the trading of poor-quality medicines, and requires close collaboration among the regulatory, customs, and law enforcement authorities. d) In active post-marketing surveillance programs, drug monitoring is also essential. 3.6 Sampling Plan The quantity of the sample required for testing is prepare by QCL and the amount of pharmaceutical dosage units required for the testing and Quantity of Samples required for Analysis. PMS Unit prepares a sampling plan which contains detailed identification of sites where samples shall be collected, medicines to be sampled, minimum number of dosage units to be collected per sample, number of samples to be collected per medicine, and total number of samples to be collected in the area for which the sampling plan is prepared. It contains also detailed instructions for sample collectors. Guidelines on Inspectorate and Post Market Surveillance (PMS) 22
3.7 Handling, storage, and transportation of samples LMHRA officers, other relevant authorized officers and healthcare institutions who are involve in sending samples to laboratory should observe the following best practices throughout the chain of custody of the products: 3.7.1 3.7.2 3.7.3 3.7.4 3.7.5 3.7.6 3.8 3.8.1 3.8.2 Shall avoid excessive mechanical vibration during transportation. Shall store products in original container, where available, and label accordingly Products shall be stored away from sunlight and excessive humidity. Collect all the information required for each sample with the location of collection, number of samples collected, name of the sample and any observation at the time of collection on the sample collection form. Samples that are light or heat sensitive shall require special handling, transportation, and storage conditions. If cold storage is indicated, store in an appropriate container and monitor the temperature during transportation. In the case that collectors are not transporting samples directly to the laboratory, samples with the accompanying documents shall be sent by a courier service with required storage conditions. For each shipment it shall be clearly indicated that samples are sent for laboratory testing purposes only. Testing QCL shall perform medicines quality testing to comply with international standards (ISO 17025:2017). These tests are conducted with reliability and accuracy according to the pharmacopoeia/validated tests procedure submitted in market authorization document, The following tests are conducted at QCL: visual inspection, identity, assay for APIs declared on the label, test for related substances and impurities, microbial load, disintegration and dissolution performance, uniformity of dosage units, pH value and volume in containers/extractable deliverable volume, for parenteral products — sterility and bacterial endotoxins, etc. Guidelines on Inspectorate and Post Market Surveillance (PMS) 23
4.0 | GUIDELINES FOR LICENSING LOCAL MANUFACTURE OF PHARMACEUTICAL FACTORY IN LIBERIA Standards for the Establishment of Pharmaceutical Factories 4.1 Introduction The Act of 2010 that established the LMHRA states the following: Part V Section 4 — 1 & 2 - No person/organization shall manufacture any medicine or health product, unless the person/organization has been issued a license or permit by the Authority; and the conditions of issuance of a license or permit for the manufacture of medicines or health products shall be stipulated in regulations promulgated by the Authority that shall provide for the issuance, renewal, suspension, cancellation and revocation of such licenses or permits. This set of Standards is formulated in accordance with LMHRA Act of 2010. Facilities and sanitary conditions of local pharmaceutical factories or sites shall comply with the Standards. Matters not provided for herein shall be governed by other relevant laws and regulations. When local pharmaceutical manufacturers of medicines establish new factories, relocate, expand, re-open for business, or add raw medicinal materials, dosage forms, items of processing or products, and are in compliance with LMHRA approval; said factory shall be certificated or licensed for operation. Local Pharmaceutical manufacturers of medicines shall be inspected by LMHRA inspectors for cGMP compliance before the issuance of license. 4.2 Procedure for Licensing of Local Manufacturer a) Applicants are required to get a copy of the local manufacturer’s guidelines and read carefully before engaging in construction of intended premises. b) Ifthe applicant is not a registered pharmacist, he/she shall be required to secure the services of a registered pharmacist to be in-charge of the business. C) Write a letter of application to the Authority. d) The applicant shall inform LMHRA and wait for approval before engaging in any process of construction/ renovation of premise. €) Applicant shall attach a sketch design of the proposed premises, annex or any adjustment to the approved premise as part of the application of request for approval. The Authority shall review application, inspect site and make a determination. The applicant shall be notified accordingly by the Authority as to the determination reached in regards to status of the application’s application filed in. f) The LMHRA Team of Inspectors shall ensure that the premises applied for to be licensed are inspected to conform to all the requirements. Guidelines on Inspectorate and Post Market Surveillance (PMS) 24
9) h) i) 4.3 When conducting inspection of the premises, the Inspectors shall use the GMP inspection checklist and give their observation and recommendation on the suitability of the factory. The Inspectors shall make sure that the necessary applicant information is accurately provided as requested in the application form and all information required in the GMP checklist are properly filled. Upon receipt of the duly filled application forms, premise inspection report and all other necessary documents from the Inspectors. The Inspectorate Head shall evaluate all the documents and if satisfied that all of the requirements have been met shall compiled and give its recommendation for the licensing of the factory. The Managing Director of the Authority with advice from the Internal Technical Committee on inspection for licensing of local manufacturers, may approve, withhold, or reject any application by providing reason(s) for its decision. Basic Requirements for the Establishment of Local Pharmaceutical Factory 4.3.1 Environmental Sanitation 1. Pharmaceutical factory sites shall be situated in sanitary locations with fresh air. Factory production, processing and packaging areas shall be constructed in accordance with relevant building codes, and located at a sufficient distance from factory boundaries to prevent pollution and fires. 2. In treating hazardous waste materials, toxic containers, hazardous gases, dust, wastewater, biological components and other hazardous components or materials; pharmaceutical factories shall act not only in accordance with relevant laws, but also with the following principles: a) For Pharmaceutical waste materials, storage facilities shall be established and LMHRA shall be informed to conduct the disposal. b) For hazardous gases and dust, airtight facilities, local exhaust ventilation systems and negative pressure procedures shall be established. These substances shall, in accordance with their properties, be scrubbed, collected, oxidized, reduced, combusted, or otherwise appropriately treated. If exhaust gas contains dust, it shall first be subjected to centrifuging, filtering, scrubbing, or some other form of dust-removal processing. The emission of such gases must comply with air pollutant emission standards. c) For the processing of wastewater, impermeable storage pools shall be established, and acidification, alkalization, neutralization, active carbon adsorption, or other effective methods shall be used to break down or remove wastewater toxins; the release of wastewater must comply with water release standards. Guidelines on Inspectorate and Post Market Surveillance (PMS) 25
4.3.2 Factory Buildings and Facilities 4.3.2.1 4.3.2.2 Factory buildings shall be well constructed and safe. Manufacturing, processing and packaging areas shall be completely separated from offices, reception rooms, laboratories, restaurants and their associated lavatories; the use of asbestos shall be avoided. The buildings shall be designed to prevent the entry of rodents, insects and dust. Interior ceilings, walls and floors shall be smooth and free of cracks and crevices, easy to clean, and non-conducive to the collection of dust. Where necessary, materials that are easily cleaned and disinfected, such as epoxy resins shall be used. Interior ducts shall be constructed of materials that do not easily collect dust, and shall be hidden where possible; drainage facilities and drainage exit shall be equipped to prevent wastewater backflow. Areas at pharmaceutical factories used for the storage of raw materials, product containers, caps, and labeling and packaging materials, and for the manufacturing, processing, re- packaging, packaging and storage of products, shall be appropriately sized and located. These areas shall be suitably arranged, with operation areas clearly delineated by production type. Moreover, appropriate work space and levels of insulation and cleanliness shall be established as needed. Levels of cleanliness shall be established in accordance with the type of product being manufactured. Operation areas requiring the same level of cleanliness shall be grouped together; buffer zones or entry rooms shall be established between areas with different levels of cleanliness, and different colors or types of work clothes may be used to indicate the cleanliness levels of the various operation areas. No operation area may be used as a passageway by personnel from other operation areas; passageways for people and for the transport of goods shall be separate, and shall not cross to avoid contamination. Facilities for the storage of raw materials, product containers, caps, labeling and packaging materials, semi-finished or intermediate products, and products shall be given “pre- inspection,” “approved for use” and “not approved for use” designations; if items are present that need to be kept frozen or are toxic, appropriate storage facilities shall be established. Semi-finished or intermediate products shall be stored separately; if they are not stored separately, special care shall be taken to prevent contamination and degradation of quality. Where biopharmaceutical and pharmaceutical factories use biotechnological methods to manufacture pharmacologically active substances or active pharmaceutical ingredients, they shall establish independent or separate factory buildings for this purpose; the air processing system for these buildings shall be Guidelines on Inspectorate and Post Market Surveillance (PMS) 26
4.3.2.3 4.3.2.4 independent from the systems of other drug production areas. However, where said factories manufacture non-contaminating biotechnology products, independent factory buildings and air processing systems shall not be necessary. Where pharmaceutical factories manufacture environmental sanitation agents, environmental sanitation agent, manufacturing processing and re-packaging areas, as well as raw material storage facilities; shall be separated from pharmaceutical manufacturing, processing and re-packaging areas by a distance of no less than eight (8) meters. Where pharmaceutical factories manufacture pharmaceutical feed additives, the pharmaceutical feed additive operation area shall be independent from other operation areas. Where pharmaceutical factories use their pharmaceutical production facilities to manufacture food products, cosmetics or general goods, care shall be taken to prevent cross-contamination, and validation procedures shall be carried out. All operation areas in pharmaceutical factories shall be equipped with appropriate illumination and ventilation facilities; where necessary, said areas shall also be equipped with appropriate facilities for the regulation of temperature and humidity. Each production and processing area shall, in accordance with its air purity requirements, be equipped with appropriate air filtration systems, including pre- filters and particulate filters. In areas for the storage of raw materials, products, semi-finished or intermediate products, and areas where products are manufactured, processed, re-packaged or packaged, conditions conducive to the prevention of quality degradation shall be maintained. Factories shall locate manufacturing, processing, re-packaging, packaging and other areas used in the production of penicillin products, as well as related facilities, in a completely separate building; the air processing system for this building shall be independent from the systems of other drug production areas. Factories shall establish independent operation areas for highly sensitizing substances such as antibiotics (cephalosporins, etc.), hormone drugs, cytotoxic drugs (including anticancer drugs), and drug and non-drug products that are highly physiologically active. If a special need arises to use said production areas and facilities for the manufacture of other products, special measures shall be established to prevent cross-contamination, and validation procedures shall be carried out. The implementation date for the requirements mentioned in the preceding Paragraph shall be determined by the LMHRA. Guidelines on Inspectorate and Post Market Surveillance (PMS) 27
4.3.2.5 4.3.2.6 4.3.2.7 4.3.2.8 4.3.2.9 For pharmaceutical factory production areas involving hazardous or flammable raw materials, solvents, semi-finished or intermediate products, or products, appropriate protective, first-aid and segregation facilities shall be established. Facilities used in the manufacturing, processing and re-packaging process shall be airtight from start to finish; where facilities are not airtight and dust or hazardous gases are produced, local exhaust ventilation systems and negative pressure procedures shall be established. Lighting, switches, sockets, motors and other electric devices for operation areas that produce dust, where organic solvents are used, or where hazardous substances are present, shall, as needed, be explosion-proof, airtight, or isolated from operation area. Boilers, pressure vessels, cranes and other types of dangerous equipment and facilities shall be inspected and approved in accordance with relevant regulations before use. Pharmaceutical factories shall, as needed, establish employee lounges and shower rooms outside of work areas. Manufacturing and processing areas shall be installed with appropriate lavatory facilities, and wastewater, garbage and other waste materials produced in said areas shall be treated in a safe and sanitary manner. Lavatory facilities shall be separated from work areas. Pharmaceutical factories shall, as needed, install facilities for the processing of general use and wastewater, and facilities for the production of boiler water or distilled water. Water supply facilities shall be kept from contaminating products. Container washing facilities shall be installed: where container washing facilities are used to wash containers for eye drops, injectables, or biopharmaceutical or biotechnology products, special care shall be taken to prevent contamination, and said facilities shall be installed away from other container washing facilities, Pharmaceutical factories shall carry out the manufacturing, processing and re- packaging of sterile products in aseptic room areas. The aseptic room areas shall, as needed, be installed with the following facilities: a) Floors, walls and ceilings that are easily cleaned and disinfected; b) Temperature and humidity control systems; c) High performance air filtration systems capable of maintaining positive pressure; d) Work area surveillance systems; e) Cleaning, disinfection, and other systems for maintaining sterile conditions. Operation areas for sterile products that cannot be sterilized during the final stage of production must be installed with high performance air filters and laminar flow Guidelines on Inspectorate and Post Market Surveillance (PMS) 28
facilities for the circulation of sterile air. Furthermore, excessive traffic (personnel and objects) into and out of said areas shall be avoided. 4.3.3 Facilities 4.3.3.1 4.3.3.2 4.3.3.3 4.3.3.4 Facilities at pharmaceutical factories used for the manufacture, processing, re- packaging, packaging and storage of products shall be appropriately designed, sized and located for ease of use, cleaning and maintenance. Facilities needed for the production of different dosage forms shall be positioned according to manufacturing process sequence. The surfaces of facilities at pharmaceutical factories that come into direct contact with raw materials, semi-finished products, intermediate products or products shall be made of non- reactive, non-releasing and non-adsorptive materials; where any process requires the use of lubricants, coolants or other similar substance, said substances may not come into contact with raw materials, product containers, caps, semi-finished products, intermediate products or products. Facilities and appliances at pharmaceutical factories used for the manufacture, processing, re-packaging, packaging and storage of products shall be regularly cleaned and maintained, and operational procedures shall be established in writing. Facilities and appliances in aseptic room areas shall be made of materials that are easily cleaned, dried and disinfected, and shall be regularly cleaned, disinfected and maintained. The production capacities of mechanical facilities used at pharmaceutical factories to produce a single product shall be carefully coordinated to ensure consistency of product quality. Automated machinery and electronic facilities used in the manufacturing process, as well as software and equipment related to computers or to the manufacture, processing, re- packaging, packaging or storage of pharmaceuticals, shall be regularly recalibrated, inspected, examined and maintained. Computer systems used to control production and production management records shall be properly maintained, and alterations may not be made to said systems without permission from the personnel in charge; all data that is input or printed shall be checked for accuracy, and its period of validity shall be determined based on the complexity and reliability of the computer system. Air used by drying facilities during the manufacturing process shall first be treated with a purification filter. Facilities used to manufacture pharmaceuticals for internal and external use shall be kept strictly separate, and may not be used interchangeably. Guidelines on Inspectorate and Post Market Surveillance (PMS) 29
4.3.3.4 4.3.3.5 4.3.3.6 4.3.3.7 Pharmaceutical factories shall install weighing facilities that comply with regulations, and shall recalibrate said facilities regularly. Where a pharmaceutical factory manufactures processes or packs injectables, and has not installed filtration facilities capable of filtering out fibers, said factory may not use liquid filtration facilities that can possibly release fibers. Pharmaceutical factories shall keep facilities and equipment for the production of pharmaceuticals for human and animal use separate, and these two types of production may not be carried out in the same structure unless the two areas are completely separated. However, pharmaceuticals for animal use that comply with the standards governing drugs for human use are not subject to this restriction. Pharmaceutical factories shall, in accordance with the requirements of the products being manufactured, install necessary manufacturing, processing, re-packaging and packaging facilities. Pharmaceutical factories shall, in accordance with their specification testing requirements for raw materials, semi-finished products, intermediate products and products, establish testing departments and appropriate testing facilities. However, if tests are conducted on a contract basis by an organization approved by the competent authority, in accordance with the Contract Drug Manufacturing and Testing Operating Principles, and clear documentation is provided, establishment of said facilities may be waived. Testing departments shall include testing and instrument laboratories. Instrument laboratories shall be separate from testing laboratories, and shall be kept at an appropriate temperature and level of humidity and air purity; testing laboratories shall be installed with sufficient and easy to use test benches, test stands, drug cabinets, fume hoods, water supply and washing facilities, as well as electric heating, thermostatic and drying facilities, and shall also be stocked with utensils and containers, chemical reagents and solutions, standard solutions and other necessary items. Where eye preparations, injectable drugs, biopharmaceutical or biotechnology products are produced, areas, facilities and equipment necessary for conducting plate count, sterility tests and other tests shall be installed as needed; said areas and facilities shall be equipped with necessary culture mediums and control strains. Where injectable drugs and biopharmaceutical or biotechnology products are produced, areas, facilities and equipment necessary for conducting pyrogen tests shall be installed as needed; said areas and facilities shall be equipped with necessary animals and breeding areas. Where antibiotics and biopharmaceutical or biotechnology products are produced, areas, facilities and equipment necessary for conducting safety tests shall be installed as needed; said areas and facilities shall be equipped with necessary animals and breeding and observation areas. Guidelines on Inspectorate and Post Market Surveillance (PMS) 30
Where antibiotics, hormones and biopharmaceutical or biotechnology products are produced, areas, facilities and equipment necessary for conducting assays shall be installed as needed. The specifications of aseptic rooms and dissection laboratories shall be determined in accordance with the requirements of the tasks to be performed; microorganism strains, culture mediums and animals necessary for conducting bioassays shall be adequately stocked and maintained. 4.3.4 Organization and Personnel 43.4.1 4.3.4.2 43.4.3 4.3.4.4 Quality control departments and manufacturing departments at pharmaceutical factories shall be established separately. A person shall be placed in charge of each pharmaceutical factory department, and sufficient personnel shall be assigned to carry out and supervise the manufacture, processing, re-packaging, packaging or storage of each product. The person in charge, supervisors and employees of each pharmaceutical factory department shall all possess suitable educational backgrounds, and shall all undergo practical training in implementing the rules; employees who work in aseptic room areas shall undergo specialized training in aseptic room operations. Pharmaceutical factories shall establish in writing sanitary standards for employees; said standards shall include the following items: a) Regular health examinations in accordance with the nature of the employee’s job; b) Measures to prevent employees with illnesses or open wounds from having a negative impact on pharmaceutical safety or quality; c) Rules requiring employees to wash or disinfect their hands when entering work areas, refrain from wearing jewelry, eating, drinking, smoking, or engaging in any other behavior that may impact sanitation in manufacturing areas; d) Standards for the types of work clothes, hoods, face masks, gloves, arm covers, and shoe covers for each job. 4.3.5 Management of Raw Materials and Product Containers and Caps 4.3.5.1 Pharmaceutical factories shall establish detailed quality specifications for raw materials and product containers and caps, as well as operational procedures for the acceptance, labeling, storage, handling, sampling, testing and inspection of these items. Guidelines on Inspectorate and Post Market Surveillance (PMS) 31
4.3.5.2 4.3.5.3 4.3.5.4 Containers that hold raw materials, product containers or caps shall be clearly labeled with batch numbers and status, pending-inspection, approved for use, not approved for use, or to be isolated; this information shall be entered into the disposition record of each batch. Container caps shall, as needed, be fitted with children safety devices to prevent accidental consumption. When pharmaceutical factories receive shipments of raw materials, product containers or caps, they shall collect representative samples from each batch for testing; a note of this action shall be made on the original container. Containers holding the samples described in the preceding Paragraph shall be appropriately labeled to facilitate tracking of sample names, batch numbers, sampling basis, original container and name of sampler. The samples referred to in these guidelines shall be tested in accordance with the following principles: a) Every raw material shall be tested to determine whether it is in compliance with documented specifications. However, aside from identification tests, other tests may be waived if the test reports provided by the supplier are evaluated and found to be reliable. b) Products containers and caps shall be tested to determine whether they are in compliance with established specifications. c) Where raw materials, product containers or caps are susceptible to contamination by filth, insects, foreign objects or microorganisms, thus affecting their intended uses, relevant test items and methods shall be included in the quality specifications for said items, and each batch shall be inspected for contamination. Where raw materials, product containers or caps are tested and found to be in compliance with documented specifications, pharmaceutical factories may approve them for use; where Said items are not in compliance, they shall not be approved for use. Raw materials, product containers or caps that are approved for use shall be used in the order of approval. However, where said items have been stored for long periods, exposed to the air or high temperatures, or subjected to other detrimental conditions, retesting shall be carried out. Raw materials, product containers or caps that are not approved for use shall be labeled to this effect, and kept isolated prior to their proper disposal. Guidelines on Inspectorate and Post Market Surveillance (PMS) 32
4.3.6 Manufacturing Process Control 4.3.6.1 4.3.6.2 4.3.6.3 To ensure that each product batch is of consistent quality, pharmaceutical factories shall have designated personnel establish process control standards for every product, and have said standards independently reviewed by other personnel. The process control standards mentioned in the preceding Paragraph shall include the following items: a) Product name, content and dosage form; b) Name and weight or volume of each active ingredient per product by unit weight, volume or dosage form, and total weight or volume of unit dosage form: c) Names and specifications of all raw materials; if a code name or number is used to Tepresent a raw material, said code shall be sufficient to determine the nature of the material; d) Quantity of each product batch: e) Weight or volume required by each raw material for each product batch. However, the quantities of raw materials used to produce a given dosage form may be increased or varied within a reasonable range; said range shall be explained in the manufacturing process control standards; f) Appropriate theoretical wei ights or volumes for each stage of the manufacturing process; g) Theoretical production quantity, including upper and lower production quantity limits expressed as percentage; h) Product container, cap and packaging material specifications (along with label signed and dated by inspector and samples or copies of all other labeling); i) Complete manufacturing and control manuals, sampling and test procedures, specifications and guidelines. Pharmaceutical factories shall establish in writing process control procedures; said procedures shall be approved by the quality control department. Where actual operations deviate from documented procedures, said deviation shall be recorded, a determination of how best to handle the deviation shall be made, and an explanation shall be given. To ensure that each product batch is of consistent quality and integrity, pharmaceutical factories shall take steps to evaluate and validate the consistency of process control operations, including related equipment and facilities, for each product; documented procedures for the validation of each manufacturing process shall also be established, and shall be complied with and validated on a regular basis. All original verification records and statistical analysis data related to evaluation and validation procedures shall be compiled and filed for future reference. Guidelines on Inspectorate and Post Market Surveillance (PMS) 33
4.3.6.4 4.3.6.5 4.3.6.6 Pharmaceutical factories shall clearly mark the contents and product batch manufacturing stage dates and times of mixing and storage containers, production lines and main manufacturing facilities used in the production and manufacture of each product batch, and enter said information into the batch manufacturing record. In regard to the quantities of raw materials used by pharmaceutical factories in the manufacture of products, the amounts of active ingredients in each product batch may not fall below the nominal quantity. Weighing, dividing and other procedures carried out on raw materials shall be performed in designated segregation areas, and shall be appropriately supervised and controlled. Documented operational procedures shall include detailed test and control procedures for representative samples from each batch of semi-finished or intermediate products. During the manufacturing and production process, the quality control departments of pharmaceutical factories shall carry out tests on semi-finished or intermediate products in accordance with established test procedures, thereby determining whether to approve said products for use; semi-finished or intermediate products that are not approved for use shall be labeled to this effect and kept isolated. Where pharmaceutical factories weigh, mix, pulverize, form tablets from, fill, re- package or carry out other related procedures on antibiotic powder, and said procedures are carried out in areas also used for the production of general pharmaceutical products, steps shall be taken to prevent cross-contamination, and validation procedures shall be carried out. Pharmaceutical factories shall include appropriate measures to prevent contamination by harmful microorganisms in the documented operational procedures for products that do not require sterilization; steps or other appropriate measures to ensure sterilization results shall be established for products that require sterilization. 4.3.7 Management of Packaging and Labeling 4.3.7.1 Pharmaceutical factories shall establish in writing management procedures for the acceptance, labeling, storage, handling, sampling and testing of packaging and labeling materials. Where over-the-counter drug products for human use are produced, packaging for said products shall be tamper-proof, and shall be kept intact during the manufacturing, shipping and retail display process; moreover, said packaging shall be designed in such a manner that tampering is easily detectable by consumers. Prior to the acceptance or use of labeling and packaging materials, representative samples shall be taken from each batch for testing; testing results shall be recorded Guidelines on Inspectorate and Post Market Surveillance (PMS) 34
4.3.7.2 4.3.7.3 4.3.7.4 4.3.7.5 and samples preserved. Where test results comply with established specifications, said materials may be approved for use; where said materials are not in compliance, they shall not be approved for use. Pharmaceutical factories shall, in accordance with product type, content and dosage form, separately store and appropriately mark labels and other labeling materials; storage areas for said materials may not be entered without the consent of the personnel in charge. Packaging or labeling materials that have expired or are not approved for use shall be returned or destroyed. The amounts of labeling materials received, used and returned shall be kept track of, and no discrepancies shall be allowed. Unused portions of labeling materials printed with batch numbers shall be destroyed; unused labeling materials that are not printed with batch numbers shall be appropriately identified and stored. Prior to packaging and labeling products, pharmaceutical factories shall first inspect packaging and labeling materials to ensure that they are correct and suitable for use; said inspection results shall be entered into the batch manufacturing record. Packaging and labeling facilities shall be inspected prior to use to ensure that all pharmaceuticals from the previous run and packaging and labeling materials not suited to the present run have been completely removed; said inspection results shall be entered into the batch manufacturing record. During the final stage of production, products that have already been packaged and labeled shall be inspected to ensure that every container or package is correctly labeled. To ensure that the ingredients, contents, quality and purity of products ready for use are in compliance with established specifications, pharmaceutical factories shall, unless other regulations apply, label said products with a usage period or expiration date as determined through stability testing; products that must be prepared before use shall be clearly labeled with the method of preparation and usage period following preparation. Standard (USP, BP, Int. Ph., etc.) for the Finished Pharmaceutical Product /product/drug product shall be place on the package right after product name. Guidelines on Inspectorate and Post Market Surveillance (PMS) 35
4.3.8 Storage, Shipping and Sales 4.3.8.1 4.3.8.2 Pharmaceutical factories shall establish in writing product storage procedures: said procedures shall include the following items: a) Segregation measures for products awaiting approval for use; b) Appropriate temperature, humidity and light exposure standards to ensure that product ingredients, contents, quality and purity are not adversely affected by storage. Pharmaceutical factories shall establish in writing shipping and sales procedures; said procedures shall include the following items: a) Measures to ensure that products are sold in the order of manufacture: b) Shipping and sales methods that ensure product ingredients, contents, quality and purity are not adversely affected by environmental factors; c) Systems to ensure prompt recycling. 4.3.9 Quality Control 4.3.9.1 4.3.9.2 Pharmaceutical factories shall establish in writing quality control department duties and operational procedures; said duties and procedures shall include the following items: a) Examination of approval, non-approval and manufacturing records for all raw materials, product containers, caps, semi-finished or intermediate products, packaging materials, labeling materials and products; b) Examination of operational procedures specifications that affect product ingredients, contents, quality and purity; c) Inspection of facilities used in the testing of raw materials, product containers, caps, semi-finished or intermediate products, packaging materials, labeling materials and products; d) Establishment in writing of operational procedures governing the calibration of instruments, devices, meters and recording apparatuses; said procedures shall clearly prescribe calibration methods, schedules, accuracy limits, as well as usage restrictions and remedial measures for items that do not comply with accuracy limits; e) Establishment in writing of operational procedures governing sample quantities, test intervals and test methods for product stability testing. Specifications, standards, sampling plans, test procedures, and test control measures established for the various departments of a pharmaceutical factory, and any alterations related to said items, shall be examined and approved by the quality control department of said factory prior to implementation. Guidelines on Inspectorate and Post Market Surveillance (PMS) 36
4.3.9.3 4.3.9.4 4.3.9.5 Pharmaceutical factories shall faithfully follow the operational guidelines that they have established and keep records of the implementation process; where a deviation from said guidelines occurs, said deviation shall be recorded, a determination of how best to handle the deviation shall be made, and an explanation shall be given. Pharmaceutical factories shall select senior specialist personnel from each department to establish a quality assurance system to regularly assess the status of factory operations; this process shall include establishment of self-assessment procedures for the production of records and reports for future reference. Pharmaceutical factories shall test every batch of products to ensure that they are in compliance with established specifications; each batch of products that must not contain harmful microorganisms shall, where necessary, be subjected to appropriate tests. Representative samples shall be removed from each batch of products or end products, and taken from the raw materials containing active ingredients used in making said products, and placed in reserve; said reserve samples shall be stored under indicated conditions, and shall be of at least twice the quantity needed for all required tests. However, the quantity of reserve samples for sterility and pyrogen tests shall be determined in accordance with requirements. Reserve samples shall be retained until one year after the expiration date of the product from which it was taken; reserve samples of products that do not require expiration dates shall be kept for at least three years after the date of dispatch of the last batch of said product. Pharmaceutical factories shall use appropriate methods to breed, maintain and dispose of animals required for the testing of raw materials, semi-finished or intermediate products, and products. Laboratory animals shall be marked; records sufficient to trace their usage history shall be kept. Pharmaceutical factories shall, where necessary, test non-penicillin antibiotics to ensure that they have not been contaminated by penicillin, hormone or cephalosporin products. Guidelines on Inspectorate and Post Market Surveillance (PMS) 37
4.3.10 Records and Reports 4.3.10.1 4.3.10.2 4.3.10.3 The manufacturing, control, shipping and sales records shall all be stored in suitable locations, made available for inspection, and used at least once a year in the assessment of product quality standards; said records shall be kept until one year after the expiration date of the batch of products or end products in question. However, records for products that do not require expiration dates shall be kept for three years after the date of dispatch of the batch of products or end products in question. Pharmaceutical factories shall keep batch manufacturing records for each batch of products produced; said records shall contain comprehensive manufacturing and quality control information on the product batch in question. Pharmaceutical factories shall produce accurate copies of manufacturing management standards, verify the accuracy of said copies, and sign and date them. Pharmaceutical factories shall make detailed records of the important steps in the manufacture, processing, re-packaging, packaging and storage of each batch of products; said records shall include the following items: a) Date and product batch number; b) Identification marks for each batch of raw materials and semi-finished or intermediate products; c) Identity of major facilities and production lines; d) Quantity and volume of raw materials used in product processing; e) Manufacturing process, testing and control results; f) Pre- and post-use inspection of labeling and packaging areas; g) Ratio of actual production output to theoretical output at appropriate stages of manufacturing process; h) Comprehensive labeling control records, including samples or copies of all labeling; i) Product container and cap identification marks and usage quantity; j) Sampling record; k) Dates and times of each major step in the production process, as well as signatures and dates for operation personnel, direct supervisors or inspectors involved in each step. The test records produced by pharmaceutical factories shall include all test data used in determining compliance with established specifications and standards; said data shall include the following items: a) Sampling location, quantity, batch number or other clear identifying code, sampling date, and date of test completion; b) Basis of all test methods; c) Weight or volume of all samples tested; d) Comprehensive records of all data generated during testing process, including Guidelines on Inspectorate and Post Market Surveillance (PMS) 38
4.3.10.4 4.3.10.5 4.3.10.6 4.3.10.7 charts, graphs and spectra produced by test instruments, and clearly listing all the raw materials, product containers, caps, semi-finished products, intermediate products or products tested, along with the batch numbers of said items; e) Record of all test-related calculations; f) Records of test results and comparison of said results with established specifications; g) Names and dates for all personnel involved in conducting tests; h) Signatures of inspectors testifying that the original records inspected are accurate, truthful and in compliance with established specifications. The manufacturing and quality control records (including packaging and labeling control records) for all products manufactured by pharmaceutical factories shall be examined by the quality control departments of said factories to ensure that all products are in compliance with all established documented operational procedures prior to release, shipment or sale. Where the theoretical production quantity exceeds the upper or lower production quantity limits prescribed by manufacturing control standards, or if any other similar discrepancy occurs, or if any batch or raw material does not conform to specifications, a thorough investigation shall be conducted even if said batch of products has already been shipped or sold; such investigations shall be extended to other batches of the product in which said discrepancy occurred, and to any other products that may be affected by said discrepancy. Written records shall be kept of the investigations described in the preceding Paragraph; said records shall include investigation conclusions and methods. Pharmaceutical factory’s shipping and sales records shall include products names, contents, dosage forms, recipient names and addresses and shipping dates and quantities. Pharmaceutical factories shall make written records of product complaints, and keep said records in product complaint files; said files shall be stored in a suitable location or in a facility where they can be easily accessed for inspection. All written records shall be kept until the expiration date of the product in question or for one year after the complaint was received. However, for products that do not require expiration dates, said records shall be kept for at least three years after the date of dispatch of the product in question. Records of returned products kept by pharmaceutical factories shall include product names, contents, batch numbers, reasons for return, quantities, disposition dates, final disposition methods; said records shall be kept. Guidelines on Inspectorate and Post Market Surveillance (PMS) 39
4.3.11 Handling of Complaints and Returned Products 4.3.11.1 4.3.11.2 Pharmaceutical factories shall establish in writing procedures for the handling of oral and written complaints from consumers; all oral and written complaints shall be investigated and assessed by the quality control departments of said factories. Where pharmaceutical factories discover serious and unanticipated product defects, they shall report said defects to the relevant competent authorities, and handle said defects in accordance with the stipulations of the Act. Written records shall be kept of the handling of all complaints; said records shall be properly collated and filed. Pharmaceutical factories shall properly identify and separately store returned products. If there are any doubts regarding a product’s safety, ingredients, contents, quality or purity due to storage or shipping conditions, the condition of the product, container, packaging or labeling, or any other relevant circumstances either before or after the product is returned, unless the product’s safety, ingredients, contents, quality and purity are confirmed to be in compliance with established specifications through testing or investigation, said product shall be destroyed. However, where said product can be brought into compliance with established specifications through remanufacturing, remanufacturing may be carried out. 4.3.12 Pharmaceuticals for Use in Clinical Trials 4.3.12.1 4.3.12.2 4.3.12.3 4.3.12.4 The production and manufacturing of pharmaceuticals for use in clinical trials by pharmaceutical factories shall, unless otherwise regulated by regulations of this Chapter, be governed by other relevant regulations. Where pharmaceutical factories have not yet established validated manufacturing processes for pharmaceuticals for use in clinical trials, or have not yet established comprehensive manufacturing control standards, said factories shall establish in writing operational procedures and keep detailed and accurate records for each batch of products manufactured and each batch of raw material used. Batch manufacturing records shall be kept until clinical trials are completed, or until at least two years after the product is completed, whichever period is longer. Where pharmaceutical factories produce biopharmaceuticals or biotechnology products for use in clinical trials, impurities caused by virus inactivation/removal or other organisms may not exceed the limits imposed on other similar products on the market. Where operational procedures for said products have not yet been validated, quality control tests shall be performed. Where pharmaceutical factories produce pharmaceuticals for use in clinical trials, said pharmaceuticals, in addition to complying with regulations governing labeling in the Act, must also be labeled “for use in clinical trials only,” and marked with the Guidelines on Inspectorate and Post Market Surveillance (PMS) 40
4.3.12.5 4.3.12.6 4.3.12.7 name of the party that commissioned the clinical trial and a trial code sufficient to identify the trial location and research personnel involved. However, where pharmaceuticals for use in clinical trials are tested in closed trials (double-blind trials), drug name, potency and efficacy may be replaced by product codes, serial numbers and packaging batch numbers. Pharmaceutical factories shall determine suitable expiration dates for pharmaceuticals for use in clinical trials based on the product properties, container characteristics and storage conditions; the expiration dates marked on said pharmaceuticals may not exceed the expiration dates marked on the original product packaging. Where clinical trials do not provide stability testing information, the usage period of a repackaged product may not exceed 25% of the remaining portion of the usage period of the original bulk product, or the six-month period following repackaging, whichever period is shorter. Where a pharmaceutical factory has a pharmaceutical for use in clinical trials manufactured or tested on a contract basis, said contract shall clearly state that the product in question is for use in clinical trials only. Where pharmaceutical factories in line with LMHRA shall destroy pharmaceuticals for use in clinical trials, destruction of said pharmaceuticals may not take place until all clinical trials and the final report are completed; detailed records shall be kept of the destruction process, and said records shall be preserved by the manufacturer. 4.3.13 Good Manufacturing Practices for Medical Devices 4.3.13.1 Manufacturers of medical devices (hereafter referred to as the manufacturers) shall comply with regulations of this Part. However, where the Medical Device Management Measures or other relevant laws or regulations apply, compliance with this Part may be waived. 4.3.14 Management Responsibility 4.3.14.1 Manufacturers shall clearly establish quality policies, including objectives for, and commitment to quality. The quality policies described in the preceding Paragraph shall be relevant to manufacturers’ organizational goals and the expectations and needs of their customers. Manufacturers shall ensure that these quality policies are understood, implemented and maintained at all levels of the organization. Guidelines on Inspectorate and Post Market Surveillance (PMS) 41
4.3.14.2 4.3.14.3 4.3.14.4 4.3.14.5 Manufacturers shall clearly define and document the responsibility, authority and interrelation of personnel who manage, perform and verify work affecting quality, particularly personnel who need the organizational authorization to perform the following tasks: a) Initiate action to prevent the oceurrence of any nonconformities relating to products, process or quality system; b) Identify and record any problems relating to products, process or quality system; c) Initiate, recommend or provide solutions through designated channels; d) Verify the implementation of solutions; e) Control further processing, delivery or installation of nonconforming product until the deficiency or unsatisfactory condition has been corrected. Manufacturers shall identify resource requirements and provide adequate resources, including the assignment of trained personnel for management, performance of work and verification activities including internal quality audits. Manufacturers shall appoint a member of their own management team who, irrespective of other responsibilities, shall define authority for the following tasks: a) Ensuring that a quality system is established, implemented and maintained in accordance with regulations of this Part; b) Reporting on the performance of the quality system to the management for review and as a basis for improvement of the quality system; c) Ensuring the safety and effectiveness of manufactured medical devices. Manufacturers shall review their quality systems at defined intervals sufficient to ensure its continuing suitability and effectiveness in satisfying the requirements of this Part and the manufacturer’s stated quality policies and objectives. Records of said reviews shall be kept and maintained. 4.3.15 Quality Systems 4.3.15.1 4.3.15.2 Manufacturers shall establish document and maintain quality systems as a means of ensuring that products conform to specified requirements. Manufacturers shall prepare a quality manual covering the requirements of this Part; said manual shall include or make reference to the quality system procedures and outline the structure of the documentation used. Manufacturers shall adhere to the following quality system procedures: a) Prepare documented procedures consistent with the quality policy and the requirements of this Part; b) Effectively implement the quality system and its documented procedures. Guidelines on Inspectorate and Post Market Surveillance (PMS) 42
4.3.15.3 The quality system procedures described in the preceding Paragraph shall be dependent upon the complexity of the work, the methods used, and the training required by the personnel involved. Manufacturers shall establish in writing a quality plan detailing how quality requirements are to be met. The quality plan described in the preceding Paragraph shall be consistent with the requirements of manufacturers’ quality systems, and shall be documented in a format to suit the supplier’s operation. Manufacturers shall give consideration to the following activities, as appropriate, in meeting specified requirements for products, projects or contracts: a) Preparation of quality plans; b) The identification and acquisition of any controls, processes, facilities, (including inspection and test facilities), fixtures, resources and skills that may be needed to achieve the required quality; c) Ensuring the compatibility of the design, the production processes, installation, servicing, inspection and test procedures and the applicable documentation; d) The updating, as necessary, of quality control, inspection and testing techniques, including the development of new instruments; e) The identification of any measurement requirement involving capability that exceeds the known state of the art, in sufficient time for the needed capability to be developed; f) The identification of suitable verification at appropriate stages in the realization of products; g) The clarification of standards of acceptability for all features and requirements, including those that contain a subjective element; h) The identification and preparation of quality records. Manufacturers shall establish and maintain medical device manufacturing procedure, installation and maintenance files, or a location where relevant information can be accessed. Said files or information shall include product specifications and quality system requirements (including process and quality assurance) for each product type or model. 4.3.16 Contract Review 4.3.16.1 4.3.16.2 Manufacturers shall establish in writing and maintain procedures for contract review and for the coordination of review activities. Before submitting a tender, or accepting a contract or order, manufacturers shall review said tender, contract or order to ensure that the following conditions are met: a) Requirements are adequately defined and documented; where an order is placed orally and there is no accompanying documentation, steps shall be taken to ensure that requirements have been met before said order is accepted. Guidelines on Inspectorate and Post Market Surveillance (PMS) 43
b) Any discrepancies between items in contact/order and tender have been resolved. c) Contract/order requirements are capable of being fulfilled. Manufacturers shall identify contract amendments and accurately communicate said amendments to relevant departments within the organization. Records of the review procedures described in the preceding two Paragraphs shall be kept and maintained. 4.3.17 Design Control 4.3.17.1 4.3.17.2 4.3.17.3 4.3.17.4 Manufacturers shall control and verify product design, and establish in writing and maintain procedures to ensure that specified requirements are met. However, products for which the Authority does not mandate the implementation of design control, are not required to comply with the provisions of this Chapter. Manufacturers shall, in the course of the design process, assess the need for risk analysis and keep and maintain records of any risk analysis performed. Manufacturers shall draft plans for each design and development activity; said plans shall comply with the following conditions: a) Each plan shall document or refer related activities. b) Implementation responsibility shall be defined. c) Design and development tasks shall be assigned to qualified personnel equipped with adequate resources. d) Plans shall be updated as designs evolve. Manufacturers shall define organizational and technical interfaces between the different groups involved in the design process; necessary information shall be documented, circulated and reviewed on a regular basis. Manufacturers shall identify, document and adequately review product design input requirements (including applicable statutory and regulatory requirements). Where said requirements are incomplete, ambiguous or conflicting, solutions shall be reached in consultation with those responsible for imposing said requirements. Design input shall take into consideration contract review results. Manufacturers shall document design output; said output shall comply with the following conditions: a) Design output shall comply with design input requirements, and expressed in terms that can be verified and validated against design input requirements. b) Design output shall contain or make reference to acceptance criteria. c) Design input shall identify the design characteristics that are crucial to the safe Guidelines on Inspectorate and Post Market Surveillance (PMS) 44
4.3.17.5 4.3.17.6 4.3.17.7 4.3.17.7 and proper functioning of the product (e.g. operation, storage, shipping, maintenance and handling requirements). d) Design output documentation shall be reviewed before release. Manufacturers shall, in the course of the design process, plan and conduct formal written reviews of design results. Participants in said reviews shall include representatives of all departments involved in review of the design stage; where necessary, other specialist personnel shall be asked to participate. Records of said reviews shall be kept and maintained. Manufacturers shall perform design verification at appropriate stages in the design process to ensure that design stage output complies with design stage input requirements. Records of the design verification measures referred to in the preceding Paragraph shall be kept and maintained. Manufacturers shall perform design validation and clinical evaluations to ensure that products comply with established user needs and specified requirements; records of these activities shall be kept and maintained as part of the design validation process. The clinical evaluations referred to in the preceding paragraph shall include relevant scientific literature and established evidence proving that similar designs and materials are clinically safe, or use clinical studies or experiments to ensure that said equipment conforms to specified functions. All design alterations and modifications made by manufacturers shall be identified, documented and reviewed, as well as approved by authorized personnel, prior to implementation. 4.3.18 Document and Data Control 4.3.18.1 Manufacturers shall establish in writing and maintain procedures for the control of all documents and data governed by the provisions of this Part; where feasible, said procedures shall include original documents of external origin (such as standards and client drawings) Document and data control by manufacturers shall comply with the following conditions: a) Documents and data shall be reviewed and approved for adequacy by authorized personnel prior to issue. b) A master list or equivalent document control procedure identifying the current Guidelines on Inspectorate and Post Market Surveillance (PMS) 45
4.3.18.2 revision status of documents shall be established and be readily available to prevent the use of obsolete or invalid documents. c) Valid versions of appropriate documents shall be made available at all locations where operations essential to the effective functioning of the quality system are performed. d) Obsolete or invalid documents shall be promptly removed from all points of issue or use, or other steps shall be taken to ensure that inadvertent use does not occur. e) Obsolete documents retained for legal or information purposes shall be appropriately identified. f) Manufacturers shall retain at least one copy of obsolete control documents, and shall determine the period of retention. Said period shall be sufficient to ensure that the specifications to which medical devices have been manufactured are available for at least the specified usage period of said products. Alterations to documents shall, unless otherwise designated, be reviewed and approved by the same functional units/organizations that performed the original review and approval. If other functional units/organizations are assigned to review said alterations, said units/organizations shall have access to background information used in the original review upon which to base their review and approval. Where feasible, the nature of the alteration shall be indicated in the document or an appropriate attachment. 4.3.19 Purchasing 4.3.19.1 Manufacturers shall establish in writing and maintain purchasing procedures to ensure that all products purchased comply with specified requirements. Purchasing documents shall clearly describe the products being purchased; where feasible, said documents shall include the following items: a) Product type, class, grade or other precise identifying information; b) Product name or other proper identification and applicable versions of specifications, graphics, process requirements, inspection instructions and other relevant technical data, including items required for product, procedure, process equipment and personnel approval or validation; c) Name, serial number and version of the quality system standard used. Where it is necessary to verify a purchased product on the subcontractor’s premises, verification arrangements and the method of product release shall be specified in the purchasing documents. Manufacturers shall review and approve purchasing documents for adequacy of specified requirements prior to release. Additionally, manufacturers shall retain copies of all relevant purchasing documents. Guidelines on Inspectorate and Post Market Surveillance (PMS) 46
4.2.19.2 Manufacturers shall adopt the following measures in regard to subcontractors: a) Evaluate and select subcontractors based on their ability to meet subcontracting requirements, including quality system and specific quality assurance requirements. b) Define the method and extent of control exercised over subcontractors based on product type and impact of subcontracted product on quality of end product; where applicable, the subcontractor’s quality audit reports or quality records demonstrating the subcontractor’s capabilities and performance shall be consulted. c) Establish and maintain subcontractor quality records. Manufacturers shall not take testimonials from clients regarding subcontractors as evidence for use in effective subcontractor quality control. 4.3.20 Control of Customer-supplied Products 4.3.21 Manufacturers shall establish in writing and maintain procedures for control of the verification, storage and maintenance of customer-supplied products. Customer-supplied products are supplies provided by customers that are incorporated into products or used in related activities. Where customer-supplied products are lost, damaged or otherwise unsuitable for use, the manufacturer shall record the problem and report it to the customer. Product Identification and Traceability Where appropriate, manufacturers shall establish in writing and maintain procedures detailing suitable means for identifying their products at the various stages of receiving, production, delivery and installation. The procedures shall include instructions ensuring that where returned medical devices are reprocessed due to special requirements, said products are properly identified and differentiated at all times. For products where traceability is required, manufacturers shall establish in writing and maintain procedures to ensure unique identification of individual products or product batches. Records shall be kept of said identification. Manufacturers shall establish and maintain traceability procedures; said procedures shall define the extent of traceability and facilitate corrective and preventive measures. The extent of traceability for active implantable medical devices and implantable medical devices shall include records of all components, materials and environmental conditions that could possibly prevent said devices from complying with specified requirements. Guidelines on Inspectorate and Post Market Surveillance (PMS) 47
4.3.22 4.3.22.1 4,3.22.2 4.3.22.3 Manufacturers shall require that their agents or distributors maintain and retain medical device sales records for inspection purposes. Production Process Control Manufacturers shall identify and plan the production, installation and service processes that directly affect quality, and shall ensure that these processes are implemented under controlled conditions. These controlled conditions shall include the following: a) Where the absence of certain production, installation or service procedures would adversely affect quality, said procedures shall be established in writing. b) Suitable production, installation and service facilities shall be used in a suitable work environment. c) Relevant laws, standards, and quality plans or documented procedures shall be complied with. d) Suitable process parameters and product characteristics shall be monitored and controlled. e) Where necessary, processes and facilities shall be approved. f) Workmanship criteria (e.g. documented standards, representative samples or illustrations) shall be stipulated in a clear and practical manner. g) Facilities shall be suitably maintained to ensure continuing process capabilities. Where process results cannot be fully verified through subsequent product inspection and testing (including manufacturing deficiencies that only become apparent with product use), said process shall be carried out by qualified operators, or the parameters of said process shall be continuously monitored and controlled, to ensure that specified requirements are met. Conditions required for process operation, including relevant facilities and personnel, shall be stipulated. Where contact between personnel and products or the production environment could adversely affect product quality, manufacturers shall establish in writing and maintain regulations governing personnel health, cleanliness and attire. Manufacturers shall ensure that all temporary personnel required to work under special conditions receive necessary training or work under the supervision of trained personnel. Where medical devices meet the following conditions, manufacturers shall establish in writing requirements for the environments to which said devices are exposed: a) Said devices are sterile at time of supply. b) Said devices are not sterile at time of supply, but require sterilization prior to use. c) Removal of microorganisms or dust, or other environmental conditions are Guidelines on Inspectorate and Post Market Surveillance (PMS) 48
4.3.22.4 4.3.22.5 4.3.22.6 4.3.22.7 4.3.22.8 critical to the use of said devices. d) Environmental conditions during the production process are critical to said devices. Where necessary, environmental conditions shall be controlled or monitored. Where products meet the following conditions, manufacturers shall establish in writing product cleanliness requirements: a) Said products are cleaned by the manufacturer prior to sterilization or use. b) Said products are not sterile at time of supply, but require cleaning prior to sterilization or use. c) Said products need not be sterile at time of use, but their level of cleanliness is critical to usage results. d) Agents used in the manufacture of said products require removal. Where necessary, products cleaned in accordance with regulations of Subparagraph ‘a’ and Subparagraph ‘b’ of the preceding Paragraph, may be waived from the special requirements regarding control of personnel and production environment. Manufacturers shall establish in writing and maintain requirements for maintenance and repair activities where said activities may affect product quality. Maintenance and repair records shall be kept and maintained. Where necessary, manufacturers shall establish operational guidance documents and acceptance criteria regarding the installation and inspection of medical devices. Installation and inspection records made by manufacturers or their authorized representatives shall be retained. Where contracts do not require manufacturers or their authorized representatives to take responsibility for product installation, those who purchase said products shall be provided with documented installation and inspection instructions. Where computer software is applied in process control, manufacturers shall establish in writing and maintain procedures for the validation of said software application. Records shall be kept of validation results. Where medical devices require sterilization, manufacturers shall subject said devices to a validated sterilization process; records shall be kept of all control parameters involved in said sterilization process. Guidelines on Inspectorate and Post Market Surveillance (PMS) 49
4.3.23 Inspection and Testing 4.3.23.1 4.3.23.2 4.3.23.3 4.3.23.4 Manufacturers shall establish in writing and maintain procedures for inspection and testing activities in order to verify that products meet specified requirements. The inspection and testing as well as the records to be established of said activities, shall be detailed in the quality plan or in documented procedures. Manufacturers shall apply the following control measures to incoming products: a) Manufacturers shall ensure that incoming products are not used or processed until said products have been inspected or otherwise verified as complying with specified requirements. Verification of compliance with specified requirements shall be carried out in accordance with the quality plan or documented procedures. b) In determining the nature and amount of receiving inspection, consideration shall be given to the amount of control implemented at the subcontractor’s premises and the records of conformance provided. c) Where incoming products are released for urgent production purposes prior to verification, said products shall be clearly identified and a record kept in order facilitating immediate recall and replacement in the event of noncompliance with specified requirements. Manufacturers shall implement the following in-process inspection and testing measures: a) Inspect and test products in accordance with quality plan or documented procedural requirements. b) Hold products until required inspection and tests have been completed or necessary reports have been received and verified; however, this requirement does not apply to products that are released under positive-recall procedures. Products released under positive-recall procedures must still be inspected and tested. Manufacturers shall carry out final inspection and testing, and create a record of said activities, in accordance with the quality plan or documented procedures, to ensure that end products are in compliance with specified requirements. The quality plan or documented procedures for final inspection and testing shall require that all specified inspection and tests (including those specified either on receipt of product or in-process) have been carried out and that results meet specified requirements. No product shall be dispatched until all the activities specified in the quality plan or documented procedures have been satisfactorily completed and the associated data and documentation is available and authorized. Guidelines on Inspectorate and Post Market Surveillance (PMS) 50
4.3.23.5 Manufacturers shall establish and maintain records that give evidence that products have been inspected and/or tested. The records described in the preceding Paragraph shall meet the following conditions: a) Said records shall show clearly whether products have passed or failed the inspection or tests performed according to acceptance criteria; where products fail to pass any inspection or test, the procedures for control of nonconforming products shall apply. b) Records shall identify the inspection authority responsible for the release of products. c) Manufacturers shall record the identity of personnel performing any inspection or testing of active implantable medical devices or implantable medical devices. 4.3.24 Control of Inspection, Measuring and Test Facilities 4.3.24.1 4.3.24.2 4.3.24.3 Manufacturers shall establish in writing and maintain procedures to control, calibrate and maintain inspection, measuring and test facilities (including test software) used by the manufacturer to demonstrate the conformance of product to the specified requirements. The inspection, measuring and test facilities shall be used in a manner that ensures that the measurement uncertainty is known and is consistent with the required measurement capability. Where test software or comparative references (such as test hardware) are used as suitable forms of inspection, they shall be checked to prove that they are capable of verifying the acceptability of products, prior to release for production, installation or servicing, and shall be rechecked at prescribed intervals. Manufacturers shall establish the extent and frequency of such checks and shall maintain records as evidence of control. Where the availability of technical data pertaining to the inspection, measuring and test facilities is a specified requirement, such data shall be made available, when required by the customer or the customer’s representative, for verification that the inspection, measuring and test facilities is functionally adequate. Manufacturers shall apply the following control procedures to inspection, measuring and test facilities: a) Determine the measurements to be made and the accuracy required, and select the appropriate inspection, measuring and test facilities that are capable of the necessary accuracy and precision. b) Identify all inspection, measuring and test facilities that can affect product quality, and calibrate and adjust them at prescribed intervals or prior to use, against certified equipment having a known valid relationship to internationally or nationally recognized standards; where no such standards exist, the basis Guidelines on Inspectorate and Post Market Surveillance (PMS) 51
used for calibration shall be documented. c) Define the process employed for the calibration of inspection, measuring and test facilities including details of facility type, unique identification, location, frequency of checks, check method, acceptance criteria and action taken when results are unsatisfactory. d) Identify inspection, measuring and test facilities with a suitable indicator or approved identification record to show the calibration status. e) Produce and maintain calibration records for inspection, measuring and test facilities. f) Assess and document the validity of previous inspection and test results when inspection, measuring or test facilities are found to be out of calibration. g) Ensure that the environmental conditions are suitable for the calibrations, inspections, measurements and tests being carried out. h) Ensure that the handling, preservation and storage of inspection, measuring and test facilities are such that the accuracy and fitness for use are maintained. i) Safeguard inspection, measuring and test facilities, including both test hardware and test software, from adjustments that would invalidate the calibration setting. 4.3.25 Identification of Inspection and Test Status 4.3.25.1 Manufacturers shall identify the inspection and test status of products by suitable means to indicate the conformance or nonconformance of product with regard to inspection and tests performed. The identification of inspection and test status shall be maintained, as defined in the quality plan or documented procedures, throughout production, installation and servicing of products to ensure that only products that have passed the required inspection and tests, or released under an authorized concession, is dispatched, used or installed. 4.3.26 Control of Nonconforming Products 4.3.26.1 4.3.26.2 Manufacturers shall establish in writing and maintain control procedures to ensure that products that do not conform to specified requirements are prevented from unintentional use or installation. The control procedures referred to in the preceding Paragraph shall provide for identification, documentation, evaluation, segregation (when practical) and disposition of nonconforming products, and for notification of relevant authorities. Manufacturers shall define the responsibility for review and authority for disposition of nonconforming products. Nonconforming products shall be reviewed in accordance with documented procedures, and handled in one of the following manners: a) Reworked to meet the specified requirements; b) Accepted with or without repair by concession; c) Re-graded for alternative applications: Guidelines on Inspectorate and Post Market Surveillance (PMS) 52
4.3.26.3 d) Rejected or scrapped. Where required by contract, the proposed use or repair of products that do not conform to specified requirements shall be reported for concession to the customer or customer’s representative. The description of the nonconform ity that has been accepted, and of repairs, shall be recorded to denote the actual condition. Repaired or reworked products shall be re-inspected in accordance with the quality plan or documented procedures. Manufacturers shall ensure that nonconforming products are accepted by concession only if regulatory requirements are met. The identity of the person(s) authorizing the concession shall be recorded. If products need to be reworked, manufacturers shall document the rework in a work instruction that has undergone the same authorization and approval procedure as the original work instruction. Prior to authorization and approval, a determination of any adverse effect of the rework upon the product shall be made and documented. 4.3.27 Corrective and Preventive Action 4.3.27.1 Manufacturers shall establish in writing and maintain procedures for implementing corrective and preventive actions. Any corrective or preventive action taken to eliminate the causes of actual or potential nonconformities shall be to a degree appropriate to the magnitude of problems and commensurate with the risks encountered. Manufacturers shall implement and record any changes to the documented procedures resulting from corrective and preventive actions. Manufacturers shall establish in writing and maintain a feedback system to provide early warning of quality problems and for input into corrective and preventive action systems. Manufacturers shall gain experience through monitoring of post-production phase feedback data; the review of this experience shall form part of the feedback system. Manufacturers shall maintain records of all customer complaint investigations. When the investigation determines that the activities at remote premises contributed to the customer complaint, relevant information shall be communicated between the manufacturer and the remote premises. If any customer complaint is not followed by corrective and preventive action, the reason shall be recorded. Guidelines on Inspectorate and Post Market Surveillance (PMS) 53
4.3.27.2 4.3.27.3 4.3.28 4.3.28.1 Manufacturers shall establish reporting procedures governing notification to the LMHRA when injuries involving medical devices occur. Manufacturers shall establish, document and maintain procedures for the issuance of advisory notices for medical devices. These procedures shall be capable of being implemented at any time. The procedures for corrective action shall include the following: a) The effective handling of customer complaints and reports of product nonconformities; b) Investigation of the causes of nonconformities relating to product, process and quality system, and recording the results of the investigation; c) Determination of the corrective action needed to eliminate the cause of nonconformities; d) Application of controls to ensure that corrective action is taken and that it is effective. The procedures for preventive action shall include the following: a) The use of appropriate sources of information such as process and work operations which affect product quality, concessions, audit results, quality records, service reports and customer complaints to detect, analyze and eliminate potential causes of nonconformities; b) Determination of the steps needed to deal with any problems requiring preventive action; c) Initiation of preventive action and application of controls to ensure that it is effective; d) Ensuring that relevant information on actions taken is submitted for management review. Handling, Storage, Packaging, Preservation and Delivery Manufacturers shall establish in writing and maintain procedures for handling, storage, packaging, preservation and delivery of products. Manufacturers shall establish in writing and maintain procedures governing medical device shelf life or special storage conditions. Said conditions shall be controlled and recorded. If appropriate, special arrangements shall be established, documented and maintained for the control of used products in order to prevent contamination of other products, the manufacturing environment or personnel. Manufacturers shall carry out handling, storage, packaging, preservation, and delivery of products in accordance with the following rules: a) Handling: methods of handling products that prevent damage or deterioration shall be used. b) Storage: designated storage areas or stock rooms shall be used to prevent damage or deterioration of product, pending use or delivery; appropriate Guidelines on Inspectorate and Post Market Surveillance (PMS) 54
methods for authorizing receipt to and dispatch from said areas shall be stipulated; the condition of products in stock shall be assessed at appropriate intervals in order to detect deterioration. c) Packaging: packing, packaging and marking processes (including materials used) shall be controlled to the extent necessary to ensure conformance to specified requirements; the identity of persons who perform the final labeling operation for active implantable medical devices and implantable medical devices shall be recorded. d) Preservation: appropriate methods for preservation and segregation of products when said products are under the manufacturer’s control. e) Delivery: arrangements shall be made to protect the quality of products after final inspection and test; where contractually specified, this protection shall extend to include delivery to destination; the name and address of the shipping package consignee shall be included in the quality records for active implantable medical devices and implantable medical devices. 4.3.29 Control of Quality Records 4.3.29.1 4.3.29.2 Manufacturers shall establish in writing and maintain procedures for identification, collection, indexing, access, filing, storage, maintenance and disposition of quality records. Quality records and their control shall conform to the following rules: a) Quality records shall be maintained to demonstrate conformance to specified requirements and the effective operation of the quality system. b) Pertinent quality records from the subcontractor shall be an element of this data. c) Retention times of quality records shall be clearly defined, and shall be at least equivalent to the lifetime of the medical device, but not less than two years from the date of dispatch from the manufacturer. d) Quality records shall be legible and shall be stored and retained in such a way that they are readily retrievable in facilities that provide a suitable environment to prevent damage, deterioration and loss. e) Where agreed contractually, quality records shall be made available for evaluation by the customer for an agreed period. Manufacturers shall establish and maintain a record for each batch of medical devices that provides traceability and identifies the quantity manufactured and quantity approved for distribution. The batch record referred to in the preceding Paragraph shall be verified and authorized. Guidelines on Inspectorate and Post Market Surveillance (PMS) 55
4.3.30 4.3.31 4.3.32 4.3.33 Internal Quality Audits Manufacturers shall establish in writing and maintain procedures for planning and implementing internal quality audits to verify whether quality activities and related results comply with planned arrangements and to determine the effectiveness of the quality system. Internal quality audits shall be scheduled by manufacturers on the basis of the status and importance of the activity to be audited, and shall be carried out by personnel independent of those having direct responsibility for the activity being audited. The results of the audits shall be recorded and brought to the attention of the personnel having responsibility in the area audited. The management personnel responsible for the area shall take timely corrective action on the deficiencies found during the audit. Follow-up activities shall be carried out to verify and record the implementation and effectiveness of the corrective action taken. Training Manufacturers shall establish in writing and maintain procedures for identifying training needs and provide for the training of all personnel performing activities affecting quality; personnel performing specific assigned tasks shall be qualified on the basis of appropriate education, training or experience, as required. Appropriate records of the training referred to in the preceding Paragraph shall be maintained. Servicing Where servicing is a specified requirement, the manufacturer shall establish in writing and maintain procedures for performing, verifying and reporting that the servicing meets the specified requirements. Statistical Techniques Manufacturers shall identify the need for statistical techniques required for establishing, controlling and verifying process capability and product characteristics. Manufacturer shall establish in writing and maintain procedures to implement and control the application of the statistical techniques referred to in the preceding Paragraph. Guidelines on Inspectorate and Post Market Surveillance (PMS) 56
4.3.34 Basic Installation Requirements 4.3.34.1 4.3.34.2 Where foreign pharmaceutical manufacturers are found by inspections to be in compliance with regulations of this set of Standards, said manufacturers shall be issued certificates of pharmaceutical GMP compliance or medical device GMP compliance for the items qualified by inspections of the LMHRA. Pharmaceutical factories shall possess the following basic requirements and common facilities: a) Factory sites shall be situated in sanitary locations with fresh air; factory production, processing and packaging areas shall be constructed in accordance with relevant building codes, and located at a sufficient distance from factory boundaries to prevent pollution and fires; safety measures against pathogens implemented at factories and facilities that manufacture biopharmaceuticals or biotechnology products may not interfere with public health or safety; factory sewers shall be covered to prevent the entry and exit of animals to spread pathogens. b) Factory buildings shall be solid and safe, and designed to prevent rodents, insects and dust; interior ceilings, walls and floors shall be smooth and free of cracks and crevices, easy to clean, and non-conducive to the collection of dust; where necessary, materials that are easily cleaned and disinfected may be used; all operation areas shall be well illuminated and ventilated; where necessary, equipment for the regulation of temperature, humidity and air purity may be installed. c) Operation areas shall be clearly delineated (e.g. powder manufacturing room, liquid manufacturing room); in factories that environmental sanitation medicines are also manufactured, the operation areas shall be separated by an appropriate distance from manufacturing factories of other medicines; when necessary, separation walls may be installed. d) Warehouses for the storage of raw materials, supplies, semi-finished products and end products shall be established. e) There shall be facilities for the treatment of dust and powder, wastewater, hazardous wastes, toxic containers, hazardous gases, biological components and other hazardous components or materials. f) There shall be weighing facilities that comply with regulations, and they shall be rectified regularly. g) There shall be container washing facilities. Where container washing facilities are used in factories manufacturing eye drops, injectables and biopharmaceuticals or biotechnology products, special care shall be taken to prevent contamination, and said facilities shall be installed separately. h) There shall be hand-washing facilities for employees, and facilities for the washing or sterilization of work clothes, caps, face masks, gloves and shoes. Employee lounges and shower rooms shall be established, as needed, outside of the operation areas; appropriate lavatory facilities shall be established in manufacturing and processing areas, separated from operation areas. i) There shall be testing departments (laboratory and instrument room), and Guidelines on Inspectorate and Post Market Surveillance (PMS) 57
4.3.34.3 4.3.34.4 4.3.34.5 5D) k) appropriate testing equipment. However, if tests are conducted on a contract basis by an organization approved by the competent authority, in accordance with the Contract Drug Manufacturing and Testing Operating Principles, and clear document is provided, establishment of said facilities may be waived. For operation areas involving flammable or hazardous raw materials, solvents, semi- finished or intermediate products and finished products, appropriate protective, first- aid and segregation facilities shall be installed. Boilers, water pumps, vacuum pumps, compressors, general use water processing systems, purified water processing systems (ion exchange resin, etc.), water distillation systems, dust removal/exhaust systems, or air processing systems shall be installed as needed at pharmaceutical factories. The various types of facilities mentioned may be installed at medical device factories in accordance with actual needs. Facilities used to manufacture pharmaceuticals for internal use and intense toxic drugs for external use shall be kept strictly separate, and may not be used interchangeably. Sites and facilities for the manufacturing of pharmaceuticals for human and animal use shall be kept separate; they may not be operated in the same building without separation. However, pharmaceuticals for animal use that comply with the standards governing drugs for human use are not subject to this restriction. Factories that manufacture pharmaceutical powders shall, as needed, install the following facilities: a) b) c) d) e) f) Pulverizing facilities; Screening facilities; Mixing facilities; Drying facilities; Dust collection facilities; Other relevant facilities. Factories that manufacture hard/soft capsule pharmaceuticals shall, as needed, install the following facilities: a) b) c) d) e) f) g) h) i) Pulverizing facilities; Screening facilities; Mixing facilities; Drying facilities; Gelatin blending facilities; Soft gelatin processing facilities; Soft capsule filling and pressing facilities; Automatic or semi-automatic capsule filling facilities; Dust collection facilities. Guidelines on Inspectorate and Post Market Surveillance (PMS) 58
4.3.34.6 4.3.34.7 4.3.34.8 Facilities mentioned above in ‘e” through ‘h’ of the preceding Paragraph are commonly used in factories that produce soft capsules; areas where the facilities mentioned in ‘e’ and «f are installed shall be separate from other areas: areas where the facilities mentioned in “f and ‘g’ are installed must have equipment for the regulation of air temperature and humidity. Factories that manufacture pharmaceutical granules, tablets (including tablets for eye use), coated tablets, or pills shall, as needed, install the following facilities: a) Pulverizing facilities; b) Screening facilities; c) Mixing or annealing facilities; d) Drying facilities; e) Granulating facilities; f) Milling facilities; g) Tablet pressing or pill making facilities; h) Gelatin or coating, syrup blending, atomizing, coating, ventilation, drying, polishing facilities, etc.; i) Molding machines, buffing machines; j) Dust collection facilities. For factories manufacturing tablets for eye use, there shall be additionally as needed, sterilization, air purification, aseptic filling (packaging) and sterility test facilities. Factories that manufacture pharmaceutical emulsions shall, as needed, install the following facilities: a) Emulsion stirring facilities; b) Emulsion blending facilities; c) Emulsion filling (packaging) facilities. Factories that manufacture pharmaceutical suspensions, tinctures, extracts, fluid extracts or liquid preparations (including eye drops, hemodialysis solutions and lavage solutions) shall, as needed, install the following facilities: a) Facilities for the manufacturing of distilled water or purified water; b) Liquid blending containers, settling tanks or ceramic vats; c) Percolation facilities; d) Soaking facilities; e) Filtration facilities; f) Stirring facilities; g) Quantitative filling (packaging) and container sealing facilities; h) Heat compression (pressure-reduction) facilities; i) Sterilization facilities. Guidelines on Inspectorate and Post Market Surveillance (PMS) 59
43.34.10 43.34.11 4.3.34.12 4.3.34.13 43.34.14 Factories that manufacture pharmaceutical aerosols shall, as needed, install the following facilities: Stirring facilities; Filling facilities. Factories that manufacture pharmaceutical ointments (including eye ointments) or suppositories shall, as needed, install the following facilities: a) Powder grinding facilities; b) Screening facilities; c) Heating vat; d) Blending facilities; e) Filling (packaging) facilities; f) Ointment tube sealing facilities; g) Suppository molding facilities: h) Sterilization, air purification, aseptic filling (packaging) and sterility test facilities; i) Dust collection facilities. Factories that manufacture pharmaceutical sticks shall, as needed, install the following facilities: a) Mixing facilities; b) Filling facilities. Factories that manufacture pharmaceutical patches shall, as needed, install the following facilities: a) Heating facilities; b) Stirring and kneading facilities; c) Coating facilities; d) Cutting facilities. Factories that manufacture pharmaceutical implants shall, as needed, install the following facilities: a) Pressing or molding facilities; b) Sterilization facilities. Factories that manufacture Injectables (including dialysates) shall, as needed, install the following facilities: a) Facilities for the production of water for injectables; b) Ampoule cutting facilities; c) Container drying, sterilization, cooling and storage facilities, must effectively sterilize containers and prevent contamination; d) Injectable solution filtering facilities; must include cooling element and pathogen filter; for injectables in powder form, this requirement may be waived; Guidelines on Inspectorate and Post Market Surveillance (PMS) 60
e) Filling facilities with precise measuring capabilities; Guidelines on Inspectorate and Post Market Surveillance (PMS) 61
f) 8) h) i) AD) k) )) Injectables container sealing facilities; Sterilization facilities; Injectables container seal and leak testing facilities; Injectables foreign matter testing facilities; Distillation room (for employees’ washing and distillation); Changing room (for employees to changed into sterilized work clothes, caps, face masks, gloves and shoes); Drug solution preparation room; m) Drug solution filling and container sealing room; n) 0) Pp) Animal experiment area, facilities and equipment, equipped with necessary animals and breeding and observation areas; Area, facilities and equipment necessary for conducting plate count, sterility tests and other tests; Freeze-drying facilities. The rooms mentioned in ‘I’ and ‘m’ of the preceding Paragraph shall be strictly separated from other operation areas; they shall be equipped with double doors that seal tightly, air purification and sterilization facilities, and facilities for the regulation of temperature and humidity. 43.34.15 Factories that manufacture antibiotics shall install the following facilities: a) b) For injectable antibiotics i) For liquid form antibiotics, the facilities mentioned above in number 14 shall be installed; for powder form antibiotics, relevant facilities as mentioned below in #16 shall be installed in accordance with actual needs, and aseptic filling (packaging) facilities with appropriate temperature and humidity control capabilities, and automatic or semi-automatic precision scales shall also be installed additionally. ii) Doors/windows that open to the exterior shall be double doors/windows that seal tightly. iii) There shall be potency and safety testing facilities for antibiotic raw materials and products. iv) Preparation rooms (for drying, sterilization and storage of packaging materials and containers, and other preparatory tasks related to packaging) and packaging rooms (with appropriate temperature and humidity control capabilities, and automatic or semi-automatic precision scales) shall be installed in processing and packaging areas. For non-injectable antibiotics (including capsules, tablets, liquids, ointments, etc.): The various types of facilities described in the rules governing each dosage form shall be installed; in processing and packaging areas, air purification and sterilization equipment, and equipment for the regulation of temperature and humidity, shall be installed. Manufacturing, processing, re-packaging, packaging and other operation areas used in the manufacturing of penicillin products shall be located in a completely separate building; the air processing system for this building shall be Guidelines on Inspectorate and Post Market Surveillance (PMS) 62
43.34.16 43.34.17 independent from the systems of other drug production areas. Factories that manufacture biopharmaceuticals or biotechnology products shall have operation areas with interior ceilings, walls, doors, floors and other structural components that are easily cleaned and disinfected; and shall also, as needed, install the following facilities: a) Facilities for the breeding and segregation of animals used in manufacturing and testing, and animals that have been inoculated with microorganisms; b) Areas, facilities and equipment for safety testing and bioassaying; c) Factories that collect animal blood or use other animal products in the manufacturing of vaccines shall possess water sources and facilities sufficient for required rinsing. d) Waste water removal and disinfection facilities shall be installed in the operation areas. e) Microorganism culturing facilities; f) Microorganism filtering facilities; g) Microorganism inoculation and collection facilities; h) Freeze-drying facilities; i) Dilution facilities; j) Filling (packaging) and container sealing facilities; k) Microorganism storage facilities; 1) Intermediate and end product storage facilities; said facilities shall be kept at temperatures appropriate to each type of product stored. m) Blending solution and culture medium production facilities; n) Pre-use and post-use sterilization and disinfection facilities for containers, solutions and culture mediums used in manufacturing and testing: 0) Thermostats, _ sterilization facilities, refrigeration and freezing facilities, automatic regulators, thermometers and necessary recording instruments; p) Facilities for the incineration or destruction of animal remains and other waste materials; q) Employees’ changing and bathing facilities; r) Animal dissection and organ grinding facilities; s) Other relevant facilities. Areas where spores, bacteria or viruses are handled shall be completely separated from other areas. Factories that grind herbal medicines shall, as needed, install the following facilities: a) Pulverizing facilities; b) Screening facilities; c) Drying facilities; d) Dust collection facilities; e) Re-packaging and packaging facilities. Guidelines on Inspectorate and Post Market Surveillance (PMS) 63
43.34.18 43.34.19 43.34.20 43.34.21 43.34.22 Factories that concoct sliced herbal medicines shall, as needed, install the following facilities: a) Sorting and processing facilities; b) Slice processing facilities: c) Slicing facilities; d) Drying facilities; e) Concocting facilities; f) Re-packaging and packaging facilities; g) Other relevant facilities. Factories that manufacture herbal plasters/poultices and adhesive pads shall, as needed, install the following facilities: a) Pulverizing facilities; b) Mixing facilities; c) Paste boiling vat and stirring facilities; d) Plaster coating facilities; e) Cutting facilities. Factories that manufacture flaked herbal medicines shall, as needed, install the following facilities: a) Slicing (mincing) facilities; b) Screening facilities; c) Mixing facilities; d) Drying facilities. Factories that manufacture herbal liquids, essences, liquors, syrups, or jellies shall, as needed, install the following facilities: a) Cutting (mincing) facilities; b) Soaking facilities; c) Filtering facilities; d) Boiling or concentration facilities; e) Distillation facilities; f) Stirring facilities; g) Liquid filling (packaging) facilities; Factories that manufacture herbal concentrates shall, as needed, install the following facilities: a) Cutting (mincing) facilities; b) Extracting facilities; c) Filtering facilities; d) Pressure-reducing and concentration facilities; e) Thermostatic or vacuum drying facilities. Guidelines on Inspectorate and Post Market Surveillance (PMS) 64
4.3.34.23 4.3.34.24 43.34.25 Factories that manufacture hard gelatin capsule shells shall, as needed, install the following facilities: a) Gelatin dissolving facilities; b) Molding facilities; c) Drying facilities; d) Capsule cutting and joining facilities; e) Sterilization and distillation facilities; f) Microorganism testing facilities; g) Operation areas shall be installed with air purification facilities, and facilities for the regulation of temperature and humidity. Factories that manufacture medicinal gases shall, as needed, install the following facilities: a) Storage facilities; b) Vaporizing facilities; c) Air compression facilities; d) Purifying facilities; e) Filling facilities. In factories that manufacture medical materials, operation areas shall be separated based on the type of material produced; they shall also install the following facilities: a) Cotton fluffing, spreading or carding machines; where these procedures are contracted out to other factories, installation of said facilities may be waived. b) Pressure degreasing facilities; c) Rinsing facilities: d) Dehydration facilities; e) Drying facilities (drying room); f) Spinning machines, weaving machines and other textile facilities; where these procedures are contracted out to textile factories, installation of said facilities may be waived. g) Gauze cutting facilities; h) Bandage cutting facilities; i) Appropriate facilities to prevent recontamination of gauze and bandages after drying; j) Tape adhesive or medical material annealing facilities; k) Soaking and blending facilities; to be installed at factories using the solvent method; 1) Coating facilities; m) Drying and sterilizing facilities; n) Ground fabric processing facilities; 0) Fabric cutting and rolling facilities; p) Soaking and drying facilities for medicinal gauze; q) Aseptic testing facilities for semi-finished and end products shall be installed as needed. Guidelines on Inspectorate and Post Market Surveillance (PMS) 65
The facilities mentioned in ‘a’ through ‘f’ of the preceding paragraph are commonly used in the manufacturing of degreased cotton; the facilities mentioned in ‘b’ through ‘i’ are commonly used in the manufacturing of medicinal gauze and bandages; the facilities mentioned in ‘j’ through ‘o’ are commonly used in the manufacturing of adhesive tape; the facilities mentioned in ‘o’ and ‘p’ are commonly used in the manufacturing of first aid adhesive tape and medicinal gauze. 43.34.26 Factories that manufacture syringes shall, as needed, install the following facilities: a) Gas processing facilities; b) Grinding processing facilities; c) Graduation mark facilities; d) Syringe joint inspection facilities; e) Glass alkalinity testing facilities; f) Crack detecting facilities; g) Heat impact testing facilities; h) Standard volume testing facilities; i) Airtight testing facilities. 43.34.27 Factories that manufacture electric instruments for medical use shall, as needed, install the following facilities: a) Lathes; b) Drilling machines; c) Jacks; d) Grinding machines or grinding wheels; e) Electric facilities of 1/4 horsepower or greater; f) Punching machines; g) Power distribution panel for use in testing; h) Voltage detectors; i) Ohmmeters. 43.34.28 Factories that manufacture blood collection and blood transfusion devices (that incorporate plastic tubes) shall, as needed, install the following facilities: a) High-speed stirring facilities; b) Stir cooling facilities; c) Plastic pellet facilities; d) High-pressure steam sterilization facilities; e) High-frequency welding facilities; f) Water sterilization facilities; g) Aseptic operation rooms. 43.34.29 Factories that manufacture hypodermic needles shall, as needed, install the following facilities: a) Straight line facilities; b) Grinding facilities; Guidelines on Inspectorate and Post Market Surveillance (PMS) 66
c) Needle valve seat facilities: Guidelines on Inspectorate and Post Market Surveillance (PMS) 67
4.3.34.30 43.34.31 d) Tightening facilities; e) Bend testing facilities; f) Flexibility testing devices; g) Pull-out testing devices; h) Pinch meters; i) Microcalipers; j) Micrometers. Re-packaging, packaging and labeling areas shall, as needed, install the following facilities: a) Weighing instruments and other necessary re-packaging facilities (counting devices, automated re-packaging facilities, etc.) b) Damp-proof packaging facilities; c) Bottle sealing/stopping machines; d) Semi-automatic or automatic ampoule labeling facilities; e) Batch number printing facilities; f) Revolving or regular operation tables. Facilities at medical device factories shall be installed based on actual manufacturing needs; facilities used in the inspection and testing of products to ensure product compliance shall be appropriately monitored, managed, rectified and maintained. Guidelines on Inspectorate and Post Market Surveillance (PMS) 68
5.0 5.1 GUIDELINE FOR PHARMACEUTICAL WASTES MANAGEMENT INTRODUCTION The Liberia Medicines and Health Products Regulatory Authority (LMHRA) were established under the LMHRA 2010 Act. The LMHRA exist to implement the provision of LMHRA Act by employing good regulatory practices to ensure that medicines and health products used in Liberia conform to the highest standards of quality, safety, and efficacy. In order to achieve this mission, various measures are required to be put in place including proper means or strategies of managing unfit medicines and health products. LMHRA has developed these guidelines to provide guidance to medicines and health products dealers on how to dispose of medicines and health products safely. The guidelines have been developed based on the World Health Organization (WHO) guidelines for safe disposal of unwanted pharmaceuticals. The guidelines are divided into four sections which define unfit medicines and health products at a facility, procedure for application for disposal of unfit medicines and health products and the actual destruction exercise. The last parts provide formats of application, verification form disposal methods, and disposal form and disposal certificate. The Authority anticipates that good implementation of these guidelines shall help to present unnecessary accumulation of unfit medicines and health products. For quite a long time disposal of unfit medicines and health products in Liberia has not been done systematically and professionally due to lack of appropriate guidance. This has resulted to accumulation of unfit medicines and health products in pharmaceutical outlets and medical institutions in the country. The accumulation of these products has been mainly contributed to the lack of adequate knowledge on procedure for safe disposal of unfit medicines and health products among the dealers. Hazards associated with unfit medicines and health products may result from improper or non- disposal and handling activities carried out by all actors in the medicines and health products business. In view of the unique nature of these products, the LMHRA 2010 Act Part II] Count 2 states, “to protect the Liberian public from the harmful effects of unfit medicines and health products”. In general, improper disposal of unfit medicines and health products presents a serious threat to public health. Some of the health risks include: > Contamination of drinking water. > Non-biodegradable antibiotics, antineoplastics and disinfectants may kill bacteria necessary for the treatment of sewage. > Burning medicines and health products at low temperatures or in open containers results in release of toxic pollutants into the air which should ideally be avoided. Guidelines on Inspectorate and Post Market Surveillance (PMS) 69
> Inefficient and insecure sorting and disposal may allow medicines and health products beyond their expiry dates to be diverted for resale to the general public. > In the absence of suitable disposal sites, if stored in their original packing there is a risk of diversion. In order to protect the entire Liberian population, medicines and health products manufacturers, dealers, private health facilities and institutions, Local Authorities, Non-Governmental Organizations (NGOs), drug inspectors and the general public are required to adhere to set procedures as stipulated in these guidelines. Therefore, it is anticipated that these guidelines will help to overcome the problems, which the dealers have been facing for many years while dealing with unfit medicines and health products. Prevention of waste from Pharmaceutical donations, Sale, and/ or purchase a. Appropriate donations: this is ensured by adhering to the interagency or National Donation Guidelines. The key principles are that medicines and health products donated shall address the expressed needs of the recipients and that the date of expiration on arrival shall be no less than one year, unless there is clear evidence from the recipients that they have the logistic and managerial capacity to store, distribute and consume shorter-dated medicines efficiently. The blind donation of pharmaceuticals based on unsubstantiated assumptions of recipient needs and logistic capacities is a major factor in the production of pharmaceutical wastes. b. The commercial importers, wholesalers, and retailers shall ensure that medicines and health products with different expiration dates are sold, distributed, or used in accordance with the principle of First-Expired First-Out. Medicines that are not frequently used should not be imported in large quantities. Importers should avoid selling large quantities of medicines and health products with short expiration dates (three months to expiration) to their customers except justified that the medicine(s) shall be consumed before expiration. 5.3 Procedures for Handling and Disposal of Unfit Medicines and Health Products 5.3.1 Unfit medicines and health products Medicines and health products shall be considered unfit when they are: Expired Improperly sealed Damaged, unexpired but improperly stored Improperly labeled Falsified and substandard Prohibited Unauthorized Guidelines on Inspectorate and Post Market Surveillance (PMS) 70
5.3.2 Handling of unfit medicines and health products at facility level §.3.2.1 51322 533.213 5.3.2.4 5.3.2.5 5.3.2.6 5327 5.3.2.8 5.3.2.9 In order to manage properly unfit medicines and health products at a facility level, the following requirements shall be adhered to: Maintain a register book (Annex I) for unfit medicines and health products. Keep them into different categories by dosage form such as: a) Solids, semi-solids, powders, capsules, powders for injection, tablets, granules, creams, gels, suppositories etc. b) Liquids: Solutions, suspension, syrups, mixtures, lotions, aerosol, inhalers etc. Keep separately medicines which fall under controlled drugs, antineoplastics, antibiotics and any other hazardous medicines or health products. Keep in containers according to their dosage forms to facilitate verification exercise, sorting and selection of disposal method. Demarcate an area for keeping containers of unfit medicines and health products which shall be labeled conspicuously with words “Expired medicines/ health products — Not for Sale” or “Unfit medicines/health products — Not for sale”. Maintain safe custody of unfit pharmaceutical products in registered premises until they are disposed of to avoid pilferage. The request for disposal of unfit medicines and health products shall be made by county or hospital pharmacist, owners, person-in-charge of facility, dispensers, and inspectors (including inspectors at ports of entry) to avoid accumulation of such unfit products. Application for disposal of unfit medicines from Government institutions shall be accompanied by an approval from entity’s Pharmacist, with approval of the Head of the Institution declaring that the products have been written off and that they are subject to disposal as required by the pharmaceutical waste’s disposal as indicated herein. Guidelines on Inspectorate and Post Market Surveillance (PMS) 71
5.3.3 5.3331 5.3.3.2 $:3:3.3 5.3.3.4 Procedures for application to dispose of unfit medicines and health products Any person who intends to dispose of unfit medicines or health products shall adhere to the following procedures: Request in writing to the Managing Director of LMHRA by using application form (Annex II) which is available at LMHRA offices or LMHRA’s website: www.!|mhra.gov.Ir A request shall be accompanied by a list of products to be disposed of and should state clearly trade name, generic name and strength (where applicable), dosage form, pack size, quantity, manufacturer, batch number and market value of product. Once the request has been received by LMHRA, the Managing Director shall send the application to the Head of Inspectorate. The head of Inspectorate shall give the communication to the focal person on Wastes Management who shall acknowledge and inform the applicant through a letter that will be approved by the Head of Inspectorate that the Wastes Management Team conducts verification of the product quantity. In case of counties where there are no LMHRA offices, the applicant shall be informed to contact the County Pharmacist for same. LMHRA Head Offices shall send the focal person on Wastes Management to inspect the pharmaceutical wastes to verify and authenticate the information submitted. Guidelines on Inspectorate and Post Market Surveillance (PMS) 72
5.3.4 5.3.4.1 SORTING AND VERIFICATION EXERCISE During verification exercise, Pharmacists who are LMHRA inspectors shall supervise sorting exercise of unfit medicines and health products before determination of disposal method. Some of the examples of category of products and their recommended disposal methods are highlighted on the table below: Category Disposal methods _ Solids, semi-solids and Powders Landfill, incineration and waste Immobilization Liquids Sewer, high temperature incineration and treated waste Antineoplastics Treated waste and landfill, high temperature incineration and return to manufacturer Controlled drugs Treated waste and landfill, high temperature incineration Aerosols and inhalers Landfill without waste inertization Disinfectants Sewer or fast-flowing water course PVC plastics, glass (ampoules, bottles and Landfill and re-cycling vials) Paper, cardboard Recycle, burn, landfill 5.3.4.2 5.3.4.2. a) b) ¢) qd) Sorting should be done in an open or in a well-ventilated area/building as close as possible to the stock pile in an orderly manner. After verification exercise is completed, a verification form (Annex III) shall be filled and signed by both parties. Verification process shall involve the following stages: 1 Identification of the product. Separate medicines which fall under controlled drugs, antineoplastics, antibiotics and any other hazardous medicinal or cosmetic products. Sort according to Disposal/Destruction Method (Annex IV) Staff involved in sorting exercise shall be provided with protective gears such as gloves, boots, overalls and dust masks and shall be briefed on the sorting exercise, health and safety risks associated with handling the materials. Sorted medicines and health products shall be carefully packed into steel drums or cardboard boxes or jute bags and information to be indicated outside the container shall include; dosage form(s) and proposed mode of disposal/destruction. The materials should be kept in a dry secure and preferably separate room to avoid being confused with in—date medicines or health products until disposal is carried out. After verification the applicant shall be informed by either the Office of the Managing Director or the Inspectorate Department through the focal person on Pharmaceutical Wastes Management by means of a letter indicating the proposed mode of disposal/destruction and shall be directed to arrange with the Inspectorate to submit a bill request to Accounts where an invoice is issued for payment of cost of the disposal/destruction at the LMHRA disposal site approved by EPA. In cases where Guidelines on Inspectorate and Post Market Surveillance (PMS) 73
LMHRA does not have and approved disposal site, the LMHRA shall arrange with the respective local authority e.g. County Health Officer/Pharmacist to determine disposal site and date of destruction. 5.3.5 Cost of Waste Disposal The cost of disposal/destruction shall be borne by the owner of the product. 5.3.5.1 Pharmaceutical wastes disposal cost shall vary with the manner in which the wastes are accumulated; that is, Medicines and health products that are imported in good quality and are in circulation and subsequently gets expire or damage and are taken off shelves by owner, kept and reported; this category of wastes shall be charged US$3.00/Kg. 5352 Medicines and health products that are imported and immediately found to be falsified, damaged, substandard, unregistered, or prohibited, this category of wastes shall be charged US$3.00/Kg. 535.3 Medicines and health products that are imported in good quality and are in circulation and subsequently got expired or damaged but were intentionally kept on shelves and being willfully sold to the Liberian Public shall be un-shelved, quarantined and charged US$5.00/Kg. 5.3.6 DESTRUCTION OF UNFIT MEDICINES AND HEALTH PRODUCTS Disposal/destruction of unfit medicines and health products shall involve the following procedures: 5.3.6.1 The focal person on Pharmaceutical Wastes Management at LMHRA shall coordinate the entire exercise. Other LMHRA Inspectors, and the County Pharmacist of the county in which the destruction is taking place shall supervise various aspects of the disposal exercise. While the County Health Officer, Environmental Protection Agency Officer, shall serve as observers during the transport of consignment from the owner’s premises or temporary storage site to the disposal site as well as during the entire destruction exercise as deemed necessary. 5.3.6.2 Unfit medicines and health products shall be transported in a closed motor vehicle or if in opened vehicle, must be properly covered to avoid pilferage. 5.3.6.3 Supervisors and other workers shall wear protective gears such as overalls, gloves, masks, helmets and boots during the disposal/destruction exercise. 5.3.6.4 Upon completion of the exercise, a Drug Disposal Form (Annex V) shall be duly filled in and signed by the supervisors and owner/owner’s representative. 5.3.6.5 Drug Disposal Form shall be sent to LMHRA offices. Guidelines on Inspectorate and Post Market Surveillance (PMS) 74
5.3.6.6 Once LMHRA offices have received the form, a certificate of destruction of unfit medicines and health products (Annex V1) shall be prepared and sent to the consignee. 5.3.6.7 Particular care shall be taken while handling anticancer drugs, narcotic drugs and Penicillin to avoid associated hazards. Guidelines on Inspectorate and Post Market Surveillance (PMS) 75
5.4 ANNEXES Annex I: Format of Register Book of unfit Medicines/and health products S/N | Name of product Strength Dosage | Quantity | Batch Cost (where form Number | Value applicable) Trade Generic Name Name Signed: Date Manager/Proprietor/Designate Guidelines on Inspectorate and Post Market Surveillance (PMS) 76
Annex II Model of Application Form for Disposal of unfit Products To: Managing Director Liberia Medicines and Health Products Regulatory Authority (LMHRA) Adjacent Concern Worldwide Office VP Road, Old Road, Sinkor Monrovia, Liberia Name of Premise. bacenites Undertaking the business of (specify)... .... ..hereby apply for disposal of unfit (Medicines or Medical supplies) Premise license Number........--+-++++++ Issued OMvenennensdd tees Location of Business.......-.+++++ess+0++ veceacecceeceecsvcaasdaecsesceusessaescsesseasgesoessoosess .. Name of person in-charge of the DUSiNESSesesieyssserseswewossvensnnernennnn saan reseeeeeeeoe seen ro mee Contact Number ........-:2:eceeeeseeeeeees Reason for disposal.......:sssessecsssssessessneensseneseseeneennennes ey HUST Estimated value (in US$/LD$). Attached herewith is the list of products to be disposed of. Declaration: I certify that the information provided in the application form is true and correct. Date of application........ssssssecssessssseeessstesneesnsens Signature of Applicant........--ssrsssesssesssseeeeens Stamp.....cecceeeee cece sesesensenseneeneenes For official use only: Received by: ...... Guidelines on Inspectorate and Post Market Surveillance (PMS) Td
Annex Ii Model of Verification Form Form No.......++++++++ Liberia Medicines and Health Products Regulatory Authority (LMHRA) P.O. Box 1994 and g 3rd Floors, Sekou Toure Avenue Mamba Point Monrovia, Liberia Name of applicant. ......sccssessseessessesenesesensnsseresseensennennnsensssyss Contact undertaking the business of (specify).........+-2000+ Location of Business. . Weight (in Kg)....... USS/LDS) seszesssssssscsivccisessenssees Does the actual product(s) tally with the list of product(s) submitted to LMHRA? YES/NO Suggested mode of destruction. Name of Applicant........ccsssscsssecssssssssieeesneesersssesenesees Sigature.......esccsseeceeecessesseesesceneeeeesnets Date of verification. 4. Name of LMHRA Inspector. 2. Name of LMHRA Inspector: Guidelines on Inspectorate and Post Market Surveillance (PMS) 78
Annex IV Disposal Methods Landfill This is a disposal method, which involves placing unfit medicines and cosmetic products directly into a land disposal site without prior treatment. The method is used in disposing of solid waste. Small quantities of unfit medicines and health products produced on a daily basis may be land filled provided that they are dispersed in large quantities of general waste. Cytotoxic, narcotic drugs and cosmetic products containing heavy metals such as mercury should not be land filled, even in small quantities. Three types of landfill methods are recognized as outlined below: Landfill for untreated unfit medicines and Health products The method is applicable to small quantities of unfit medicine and cosmetic products. It involves placing untreated waste medicine and cosmetic into an uncontrolled, non- engineered open dump. The unfit medicine and health products should be covered immediately with large quantities of other type of waste or soil/sand to prevent scavenging by unscrupulous people. Discarding of untreated unfit medicine and cosmetics into such a site is not recommended except as a last resort. They should preferably be discharged after immobilization by encapsulation or inertization. It should be noted that discarding in open uncontrolled dump with insufficient isolation from the aquifer or other water courses can lead to pollution, with the risk of drinking water contamination in the worst cases. The disposal exercise should be done amid tightly security supervised by technical personnel. This method is applicable to solids, semi-solids, powders, medicines, waste dosage forms and health products. Guidelines on Inspectorate and Post Market Surveillance (PMS) 79
Engineered landfill Such landfill has some features to protect from loss of chemicals into the aquifer. Direct deposit of medicines and cosmetics is second best to discharging immobilized unfit medicines and cosmetic products into such a landfill. Highly engineered sanitary landfill Properly constructed and operated landfill sites offer relative safe disposal route for unfit medicines and cosmetic products. An appropriate landfill consists of an evacuated pit isolated from water courses and which is above water table. Once unfit medicine and cosmetic products are thrown into the pit, they are compacted and covered with soil to maintain sanitary environment. The term ‘safe sanitary landfill’ means a site that is adequately situated, constructed and managed. Limited quantities of untreated medicines and health products waste in form of solids, semi-solids and powders are disposed of by this method. Landfill for treated unfit medicines and health products waste immobilization Immobilization of unfit medicine and cosmetics can be done in the following ways: Encapsulation In this process waste medicines and cosmetics are immobilized in a solid block within a plastic or steel drum. The drum should be cleaned before using them and they should not have contained explosive or hazardous materials previously. The exercise starts by filling the drum to 75% of their capacity with solid and semi-solid waste medicines and cosmetics. The remaining space is filled by pouring in a medium such as cement or cement-lime mixture, plastic foam or bituminous sand. For ease and speed of filling, the drum lids should be cut open and bent back. Once the drums are filled to 75% capacity, the mixture of lime, cement and water in the proportions 15:15: 5 (by weight) is added and drum filled to capacity. Steel drum lids should then be bent back and sealed by seam or spot welding. The sealed drum lids should be placed at the base of a landfill site and covered with fresh municipal solid waste. The method is applicable to solids waste, semi-solids, powders, and liquids. Inertization The method involves removing the packaging materials (inner and outer container). The unfit medicines and cosmetics are then ground and a mix of water, cement and lime added to form a homogenous paste. The paste is then transported in liquid state by concrete mixer truck to a landfill site and decanted into a normal municipal waste. The paste then sets as a solid mass Dispersed within the municipal solid waste Guidelines on Inspectorate and Post Market Surveillance (PMS) 80
The main tools required for the operation are a grinder or road roller to crush the medicines/health products, lime and water. Medicines or cosmetics waste, lime, cement and water are mixed in the following ratios by weight 65%, 15%, 15% and 5% respectively. Water can be added more than the required amount when need arises to have satisfactory liquid consistency. The method is applicable to solids, semi-solids, powders, antineoplastics controlled drugs of that nature and cosmetics containing heavy metals (e.g. Mercury). Sewer This is a method used whereby waste medicines and cosmetic products in liquid form e.g. syrups, lotions and intravenous fluids are diluted with water and flushed into a proper functioning sewerage system/sewers in small quantities over a period of time without causing serious public health or environmental effect. Fast flowing water courses may likewise be used to flush small quantities of well-diluted liquid medicines/cosmetics or antiseptics. Medium temperature incineration This method involves the use of medium temperature incinerators. Unwanted solid pharmaceuticals may be destroyed by using a two-chamber incinerator that operates at the minimum temperature of 8500 degrees Celsius, with a combustion retention time of at least two seconds in the second chamber. It is recommended that prior to destruction; pharmaceutical waste should be diluted with large quantities of municipal waste (approximately 1:1000). Medium temperature furnaces may be used in absence of medium temperature incinerators. This type of incinerator is not suitable for incineration of halogenated compounds, as they need a higher temperature incinerator. The method is applicable to solids, semi-solids, powders and controlled drugs of that nature. High temperature incineration This involves the use of high temperature incinerator, which operates at a temperature well in excess of 8500 degrees Celsius. Cement kilns can reach temperatures of 14500 degrees centigrade — 20000 degrees Celsius that is suitable for total destruction of organic waste component. These have long combustion retention times and disperse exhaust gases via tall chimneys, often to high altitudes thus reducing the risk of environmental effect. It may be necessary prior to incineration to remove packaging materials to avoid clogging and blockage of incinerator or kiln. Burning in open containers Paper and cardboard packaging materials, if they are not to be recycled, may be burnt. Polyvinyl Chloride (PVC) plastic however must not be burnt, Unfit medicines and cosmetics should not be destroyed by burning at low temperatures in open containers, as toxic pollutants may be released into the air. It is strongly recommended that only very small quantities of unfit medicines and health products be disposed of in this way. Guidelines on Inspectorate and Post Market Surveillance (PMS) 81
Return to donor or manufacturer Wherever practical, the possibility of returning unfit medicines and health products for safe disposal by the manufacturer, this shall be explored by LMHRA; particularly medicines and cosmetics which present problems, such as antineoplastics and heavy metals. For unwanted, unrequested donations, especially that arrive with past or unreasonably expiry dates, it may be possible to return them to the donor for disposal. Guidelines on Inspectorate and Post Market Surveillance (PMS) 82
Annex V Model of Disposal Form (Pursuant to Liberia Medicines and Health Products Regulatory Authority Act of 2010) The Liberia Medicines and Health Products Regulatory Authority declares to have supervised the Disposal of unfit product (as per attached list) belonging to Mr./Mrs./Mss./Dr./Pharm .......0cceceseeeseeeeeeeeeeseeeeerseneees . The destruction exercise was conducted at (location, Site) .....sssesesssssssessssseseeenenesennecssssesnnnsccnnasennssenses® on this date by the following method(s) (state clearly): Biccccccecccncecccscceeeeccuecccnecensesceosesessaweneeeess The total weight of the products destroyed is .. and value iS...........cccsssseossoeeesessanonscersceneenensesenansseeeconees Name and signature of owner/in charge/representative of the organization: Names, title and signatures of LMHRA Inspector(s), other supervisor(s) and witness of the disposal exercise: - Name NAME Title/Position Signature Date Dl Nn} S] W/V) —| 7 fo} Guidelines on Inspectorate and Post Market Surveillance (PMS) 83
Annex VI Ref, No...Date: .........:.cseereseeeeeerees THE LIBERIA MEDICINES AND HEALTH PRODUCTS REGULATORY AUTHORITY ACT OF 2010 CERTIFICATE OF DISPOSAL I, being the person in-charge with the administration of the law relating to the control of Pharmaceutical Products to which the Liberia Medicines and Health Products Regulatory Authority Act of 2010 apply, hereby certify the destruction of expired, improperly sealed, damaged, unexpired but improperly stored, improperly labeled, counterfeit, substandard and adulterated, prohibited, and unauthorized pharmaceutical products belonging to savonugueonnesprenns isthe db eeeenyees .of (Address). wc wrseuuigecrovcdsescacassssonnuespuetennusssesuTvEetanereece RUC tOOK Place OM.....seeccssescerneseseesseesstesnnnsennnersnnnnacennensnsnesees The said consignment was destroyed by Ateccccccecescsssssscseseseseeesssseseneseeseneussenesenenseneness under the witness and supervision of LMHRA Inspectors, Environmental Officer, Health Officer and Police officer as specified in the attached disposal form With S. NO. cccsssssessesessessssseseeenensensereees The weight of the Pharmaceutical wastes disposed is actesrentiyeceaninensmuunes Kg and its value Fits eon heck Snitchin peer anet tee USIEDS sicisssnsscescisssencovoneeonsceseneneeneties Name: Signature.........-sseseeeeee DatSiuicsessscheteasiae MANAGING DIRECTOR Guidelines on Inspectorate and Post Market Surveillance (PMS) 84
Annex VII REPUBLIC OF LIBERIA LIBERIA MEDICINES & HEALTH PRODUCTS REGULATORY AUTHORITY 2nd and 3°4 Floors, Sekou Toure Avenue Mamba Point Monrovia, Liberia 5.6 Standard Operating Procedures (SOP) for Pharmaceutical and other hazardous medical Wastes Management in Liberia 1. PURPOSE: To provide a SOP establishing uniform policies, procedures and responsibilities for the receipt, labeling, management, storage, and disposal of pharmaceutical wastes, and to establish the requirements for environmental compliance. 2. SCOPE: This SOP applies to the management of pharmaceutical and other hazardous medical wastes within the healthcare delivery system. 3. GENERAL a. Pharmaceutical and other hazardous medicinal wastes and health products are those that can no longer be used for its intended purpose, because they have been contaminated, damaged or have gone beyond their shelf-life. They could be chemicals or other substances that are potentially dangerous to human health and safety or the environment when improperly treated, stored, transported, disposed of, or otherwise mismanaged. This SOP outlines how wastes management units within the LMHRA will care for both pharmaceutical and other hazardous medicinal wastes from receipt to disposal (otherwise identified as cradle to grave). 4. RESPONSIBLITIES. a. Pharmaceutical Wastes Management Unit o Has overall responsibility for the safe removal, handling, and disposal of all pharmaceutical and other hazardous medicinal wastes as well as environmental compliance management program o Ensure full awareness regarding the timely appropriate collection, storage, labeling, transporting, and disposal of these wastes. o Ensure all pharmaceutical and other hazardous medical wastes generators comply with their respective regulatory requirements. Guidelines on Inspectorate and Post Market Surveillance (PMS) 85
5.6.1 o Identify and develop wastes protectorate accumulation points within all pharmaceutical and health entities. Ensure that all entities have access to Wastes Management Guidelines and SOP. b. Entity’s Supply Technicians (pharmacist, dispenser, etc.) should: o Track products throughout the supply process cycle from receipt to disposal. © Minimize wastes generation whenever possible or feasible through rational requisition and appropriate information dissemination. o Conduct quarterly inspections of all targeted entities, through appropriate coordination. Procedures for the Application for Pharmaceutical Wastes Disposal Write a letter to the Managing Director informing the Authority that there are accumulations of unfit pharmaceutical products in your entities. Attach a list of the unfit products, which should include: trade name, generic name strength, dosage form, pack size, quantity, manufacturer, batch number, and market value of each. The Managing Director shall acknowledge the letter and send same to the head of inspectorate who will also acknowledge the application and send the communication to the Manager on Wastes Management. Upon receipt of the communication by the Manager for pharmaceutical waste management, s/he shall formerly inform the applicant on the date and time of verification and quantification with approval from the Head of Inspectorate. The Manager shall go with a team to the premise of the applicant on the date and time scheduled to verify and authenticate the information provided in order to quantify and appropriately charge the cost for the disposal exercise with regards to the type and nature of the unfit products. The cost will be approved by the Head of Inspectorate and formally communicated to the applicant. Before the date of the commencement of the disposal exercise, the applicant shall be instructed to do preliminary separation where infusions, injectable, and syrups will be separately placed at one location and tablets, capsules, and dry suspensions separately placed at another location, while health products are also placed at separate location inside the same storage facility. Based on the agreement reached, the applicant shall obtain an invoice from LMHRA Accounts and be requested to deposit the cost of the disposal into the LMHRA’s Accounts and the deposit slip be given to the Manager who will report same to the Accounts section of the Authority and obtained the official receipt and deliver it to the applicant. If there is space in the Authority’s Wastes Management temporary storage facility that can accommodate the volume of wastes that is available in the premise of the applicant, the wastes should be collected and transferred to said temporary storage site; but if the volume is wastes is large, it shall remain quarantine in the premise of the applicant and date of disposal shall be scheduled within 10 working days. Guidelines on Inspectorate and Post Market Surveillance (PMS) 86
9. Incase of any delay on the part of the Authority due to any unforeseen reason(s), the applicant shall be appropriately notified through written communication signed by the Manager and approved by the Head of Inspectorate. 5.6.2 Procedures for pharmaceutical wastes Disposal 4. Before the disposal exercise commencement, there shall be a disposal plan formulated by the Manager in relation to the volume of pharmaceutical wastes and presented to the head of Inspectorate. 2. The Head of Inspectorate shall review, modify, and finalize the plan with the Management of LMHRA for its approval for implementation. 3. The Manager shall go to the disposal site to meet with the local authorities on the ground and shall recruit locally base casual laborers. 4. All required materials for the disposal exercise shall be obtained at least one day ahead of the exercise. 5. During the disposal exercise, the collection and transfer shall be supervised by LMHRA’s pharmacists from storage sites to disposal site. 6. The entire wastes disposal team shall be given all needed outfits on the day of the disposal which shall include: safety boots, goggles, gloves, helmets, nose masks, and joint suits. 7. The Authority’s hired casual laborers shall be used to load the unfit products on available vehicles and offload same at the disposal site. 8. After offloading, there shall be complete professional separation of unfit products into various pharmaceutical dosage forms under the direct supervision of professional pharmacists. 9. If there is no temporary storage facility for the sorted wastes, there shall be immediate disposal of the separated wastes according to all the various available acceptable professional disposal methods. The crushing, for which there is currently no facility at along the disposal site will, for now be done at the Monrovia City Corporation at its Weine Town’s disposal Site in Paynesville. 10. During every stage of the disposal exercise, there shall be pictorial evidence by the display of action photos of activities. 44. All issued outfits shall be returned by all members of the wastes management team to the supervisors for onward reporting to the Manager. 12.A comprehensive report shall be written by the Manager in collaboration with the General Supervisor/Head of inspectorate and be submitted to the project officer within five working days after the completion of the disposal exercise. 13. The project officer along with the Head of Inspectorate shall review and finalize the report and subsequently submit same to the Management of LMHRA within three working days for onward submission to relevant stakeholders. Guidelines on Inspectorate and Post Market Surveillance (PMS) 87
5.6.3 Procedures for Wastes Management Team during Disposal Exercise There shall be no binding contract signed with any causal worker. The maintenance of the work to the end depends on one’s effective working habit. 4. With the exception of the drivers, no assignment shall be permanent; that is, any worker can be rotated to any location of the work by the Coordinator in consultation with the Head of Inspectorate. 2. Every assigned supervisor shall give summary report of every day’s activities during the next day early morning hours meeting, and such shall include: a. Observations b. Challenges c. Recommendations 3. Every supervisor shall be responsible for all outfits issued to workers assigned under him/her and fully account for same. 4. All workers shall strongly be advised to work with great care and be in their available outfits as there shall be no medical insurance provided for staff hired for the disposal exercise. 5. There shall be clear photos of all activities produced by assigned supervisors depicting the undertaking of these activities. 6. Payment of compensation to casual workers shall be made on the last day of work; even in the case of dropped out. 7. Every supervisor must ensure the safety of both personnel and equipment/materials assigned to him/her. 8. Supervisors assigned shall report all items issued to their supervisees after the completion of the disposal exercise to the Manager. 9. Full adherence to this SOP is the due obligation for all participants. Guidelines on Inspectorate and Post Market Surveillance (PMS) T
The guideli: gp pe i ef and Post Market Surveillance is Hereby Promulgated and A proved by the Man ing Directo or on Sabie 13 Day of April, A. D. 2026. eBawo sor LMHRA Guidelines on Inspectorate and Post Market Surveillance (PMS) 2