3 3 Local medicine manufacture Content Political side: different levels of local medicine manufacture may exist – the country should choose its best Regulatory side: regulation and control of local medicine manufacture
5 5 Local drug manufacture, 1 WHO: different levels may exist a) most advanced: research and development of new APIs Active Pharmaceutical Ingredients also manufacture of APIs + dosage-form production isolation of herbal principles b) less advanced: manufacture of established APIs + intermediates, + their dosage-forms
6 6 Local drug manufacture, 2 (Different levels) c) only finished products (every kind of dosage-forms, including sterile) from purchased APIs and excipients d) only some simpler finished products (dosage forms simple difficult: e.g. solution/ointment tablets sterile vaccines ) e) the least advanced manufacture: only (re)packaging of purchased bulk finished products
7 To make the right choice… …is a political issue! Principles: Meeting the local needs should be the first Organising lower level, but working manufacture is better than aiming higher level that can not operate But drug export, if possible, ensures profit and power… 7
8 Achieving this political will… …needs various means depending on the situation! Is the pharma industry public or private? –Public (Government owned/subsidized): direct interference and decision-making –Private: only indirect measures (taxes, drug reimbursement system, etc.) –PPP (public-private-partnership): in between 8
9 9 If public The regulation is easier – the state „orders” Different levels –Factories belong to Ministry of Health (MoH) or Ministry of Industry, under their supervision, ministerial decisions on what is produced –State-owned industry (as a rule, organised into a Trust), the Sates specifies (kinds and quantities) of medicines to be provided –Factories are individual profit-centers, the State only nominates management and receives part of the profit
10 If private Fully domestic? Bought/shared by multis? between these two: „Domestic” but it is on the share-market How to regulate them? By legislation, taxation? Local management? More direct ways? Profit remains – repatrioted? (remains in the country or taken away by the foreign owner?)
11 Which level does meet the local needs? 1. API manufacture Not an aim in itself! To decide: are there chemical/biological traditions, is expertise available? study of international market for raw materials for local API manufacture (are they available?) or better rely on API import?
12 Established APIs manufactured What is the standard? Does the country have its own Pharmacopoeia? Or regional or well-known (e.g. USP, BP) Pharmacopoeias accepted or WHO International Pharmacopoeia? Is there a policy which quality to manufacture?
13 „Is there a policy which quality to manufacture?” Certain manufacturers apply more than one standard After a batch is manufactured, the QC analyses will decide which standard (e.g. which Pharmacopoeia) has been met This is a wrong approach!This is a wrong approach!
14 Which level does meet the local needs? 2. Finished drug product manufacture Human resources + supporting infrastructure (water and energy supplies) available? Ingredients purchased - price vs. quality offered often products meeting the requirements of only outdated Pharmacopoeias offered
15 Which level does meet the local needs? 2. Finished drug product manufacture Complete self-reliance (i.e. local manufacture of every medicine needed) should not be an aim! No country in 100%. –Thus, local manufacture + import Aiming also export? But is there a market? Quality could be provided? But local medicine manufacture creates new jobs, decreases prices...
16 Right local manufacture and standards are extremely important! The sad mebendazole tablet story! It happened a few years ago 16
17 Mebendazol is an agent used to kill different worms (e.g. pinworms) that infected the human organism The infection rate is high in countries with limited hygienic conditions, e.g. soma parts of Africa UN organizations decided to finance free of charge mebendazole-medication to children in some African countries 17
18 The WHO International Pharmaceopoeia had a monograph for mebendazole syrup only The decision was –To prefer tablet dosage-form (to avoid distributing „water” to countryside) –Sucking tablet, for longer action –To find a local manufacturer (to avoid long- distance distibution) Local producer was found. It was ready to develop mebendazole sucking tablets 18
19 But it could produce only big tablets Decision: for the tablets would disintegrate after the mebendazole was dissolved and „sucked-out”, no problem Until now, everything does seem to be logcal, does not? However, mebendazol has various crystal modifications! The metastabil modification can be dissolved from tablets, the stable form can not! The metastable form is manufactured, but, if moisture is present, it is transformed to the stable modification! 19
20 This previous information was not taken into consideration/known by the decision-makers Locally manufactured sucking tablets were packed in a non-water-resistant material Mebendazole transformed to its stable crystal form, the tablets were sucked by children in vein. They got tired of sucking and swallowed the big tablet Six children suffocated and died before the issue was identified! 20
21 Thus, Everybody was benevolent, but The overall knowledge in the product was lacking The product development and control were not done according to international standards Six children were killed by a drug product distributed free of charge by UN bodies! (end of the story) 21
22 If mostly import –done by the Government? Or –encouraged (or forced) by the Government? Bulk purchasing? (Cheaper!) –If API is imported, bulk purchasing may ensure quality-safety-efficacy, but more acceptable price, then the API can be sold to private or „distributed” to public factories –If finished products imported in bulk, a local re-packaging factory is needed
23 Even import of finished drug products… …needs some preparedness! It is very dangerous to buy drugs if you have no local quality control facilities: –Counterfeit (fake) products –Low-quality or adulterated APIs For countries that have no local control facilities the WHO offered a solution 23
24 WHO Certification Scheme for products moving in international commerce for medicinal products: certified by the exporting authority to the importing one, when the latter has limited possibilities to control: –it has been registered in the country of origin –it is subject of GMP inspection –possibility of attaching approved information material
25 WHO Certification Scheme for APIs info about API manufacturer against brokers who –sell everything by repackaging and relabelling as if it were newly produced –providing no information on, e.g. potentially harmful solvent residues EU: either own manufacture or Drug Master File or European Pharmacopoeia Certificate of Suitability
26 Most advanced (EU) requirements for data on API manufacture when submitting applications for medicinal product marketing authorisation The product manufacturer is also the API manufacturer: submits also API manufacture basic data The product manufacturer is different from the API manufacturer: –the latter has European Pharmacopoeia Certificate of Suitability –the product manufacturer requests the API manufacturer to send the basic API manufacturing data („Drug Master File”) to the authority where the marketing authorisation request for the medicinal product has been submitted
27 European Pharmacopoeia (EP) Certificate of Suitability The API manufacturer initiates it by sending the synthesis route and basic data together with normal impurity (intermediers + decomposition products) samples to the European Department of Quality of Medicines (EDQM) EDQM checks whether the EP monograph methods are suitable to detect/quantify impurities If yes, the Certificate (referred to as Certificat of European Pharmacopoeia, CEP) issued, specific to the given API (manufacturer, synthesis)
28 Purchase of drug (and excipient) substances only from reliable sources is extremely important! As indicated by the „Glycerol story” In the 1960s years, in Haiti, about 50 children died Although the reason was identified, still there are children deaths in the developing World, every year! Why? 28
29 Glycerol is used as cheap sweetening agent in cough syrups for children The cheapest „drug quality” glycerol can be purchased from brokers (who buy it, re-labels and sells. Often „technical quality” glycerol is purchased and re- labeled as „pharmacopoeial”) However, diethylene glycol (toxic!) has the trade name „Glycol” 29
30 You already see, what happens Brokers, by mistake, purchase also GLYCOL, mix it to GLYCEROL and sell it as glycerol Poor country manufacturers do not have access to GLC analyses for every purchased batch, use them as purchased = toxic symptoms and deaths – in vein! 30
32 Regulation of local medicine manufacture The three regulatory issues Is manufacturing authorisation needed? By whom? (MoH, Min.of Industry…) If so, are minimum standards issued (GMP)? (If yes: which GMP?) Inspected? By whom?
33 Manufacturing authorisation 1 In the majority of the countries, drug manufacture needs prior authorisation By whom? –Ministry of Health –Drug Regulatory Authority (if independent from the MoH) –Other Ministry (Industry) –?
34 Manufacturing authorisation 2 If authorisation needed, Are there exemptions? (E.g. drug compounding in pharmacies, as a rule, not „manufacture”; local „herbalists other kinds of traditional medicine?) What does it cover? („General drug manufacturing authorisation” - this does not exist in most of the cases, or according to dosage-forms, or sterile – non-sterile, or which other principle?)
35 Manufacturing authorisation 3 If authorisation needed, What are the prerequisites? In most of the cases: Good Manufacturing Prcatices (GMP, see later ) If so, which GMP? –ICH-based as in the developed World (ICH: see later) –the WHO GMP –local GMP?
36 ICH International Conference on Harmonisation Participants: –USA, Japan, European Union –both Drug Regulatory Authority and Pharma Industry Development of common rules, guidelines, methodology, etc. for drug registration/authorisation Definitely and admittedly to meet the needs of the msot developed countries (e.g., in the guide for drug stability studies no „hot and humid” conditions, that do not apply in these ICH countries)
37 GMP, 1 It is a quality assurance system dedicated to drug manufacture API chapter and Drug Product Chapter Both: basic principles, personnel (incl. hygiene), premises and equipment, documentation, production, quality control, contract production and analysis, complaint handling and recall, self- inspection parts + Annexes (e.g. sterile production, process validation, manufacture of medicinal gases, etc.)
38 GMP, 2 The ICH GMP and the WHO GMP differ only in the order of the chapters the ICH one contains more annexes –for the ICH one is intended for the most developed countries, the WHO one for less developed (e.g. no medicinal gas or radiomedicine manufacture expected „Local” GMPs can be regional (such as ASEAN GMP) or national. As a rule, they follow WHO GMP, sometimes its less updated versions
39 Manufacturing authorisation, 4 Are authorised manufacturers subjected to regular GMP inspections? (=on-the-spot visit and checking of personal and other – see GMP chapters – requirements) Inspectors are governmental officials, belonging to (MoH, Min. of Ind., DRA, etc.) Issues: –Where inspectors were trained in GMP? –Are there conditions (e.g. education, industrial experience, regular training)?
40 Manufacture and drug compounding A crucial issue: are the industrial mdrug manufacture and large-scale drug compounding in bigger pharmacies (that also sell some compounded drugs to other pharmacies) separated? If so, how is the borderline set?
42 Drug procurement The total of activities resulting in the availibility of medicines in a country: purchasing and distribution This term is used mostly in developing countries when the State is directly involved in the medicine supply for the interest of the inhabitants
43 Drug procurement Public or private sector prevails the medicine supply? (If the latter, as a rule drug wholesalers or „importers” or others?) Public sector: the MoH itself or (semi)autonomous State Procurement Agencies? If public sector in the procurement: systematic tendering needed
44 Procurement, important Import: WHO Certification Scheme (assurance of registration in the country of origin + GMP surveillance) Info on product inter-changeability („what can I buy instead of it, if not available”?)
45 Interchangeability, substitution, etc. The correct information is crucial Used in various meanings It should always be clarified!
46 Interchangeability, substitution, etc. 1 Same API, same strength, similar dosage-form (e.g. tablets and capsules), bioequivalence proven interchangeable, theoretically substitution without problems. But: ready-made and reconstituted syrups…
47 Interchangeability, substitution, etc. 2 Same API, same strength, similar dosage- form (e.g. tablets and capsules), bioequivalence not known is the liberation crucial (i.e. the rate-limiting step in the organism)? Individual action (e.g. pain-killer vs. steady-state – absorption in mouth or stomach or only from small intestine?
48 Interchangeability, substitution, etc. 3 Same API, different strength, similar dosage-form (e.g. tablets and capsules)… e.g. double strength – can it be broken to two equal parts? Not for capsules…
49 Interchangeability, substitution, etc. 4 Different API, same therapeutic group… e.g. ACE inhibitors – selectivity – patient’s reaction may be different…
50 Interchangeability, substitution, etc. 5 Different API, different therapeutic groups, similar therapeutic application… e.g. antihypertensives: duiretics – ACE inhibitors – Ca-channel inhibitors – beta- blockers – alpha-blockers… Questionable, but may be a must in some Third World countries
51 Procurement, premises Warehouses needed to store the medicines (controlled temperature, cold rooms…) If central storage: distribution means (trucks, cars – more frequently to the countryside – suitable roads?) If regional storage: suitable regional warehouses
52 Procurement, process Estimates (quarterly/annually) But no “planned economy!” Lead-time Based on health status, morbidity, past period, etc. Buying Public: aggregation of national needs large quantitites but climate, warehousing, shelf- life in bulk and re-package but stability, liability
53 If possible, avoid brokers! Broker: (mostly international) company purchasing cheap medicines (mostly APIs, sometimes also products) „on the world market” (the manufacturer, as a rule, not known), analyses until a Pharmacopoeia found that the delivery complies with, then re-packaging, re-labeling and offered for sale as „newly manufactured” according to this Pharmacopoeia
54 Special procurement: donations WHO guidelines: >6 months to expiry date, known and needed by the recipient country Regulatory authority and pharmaceutical expertise involved Otherwise: only export of environmental/waste problems from donor countries
55 Donations Info: what are the drugs that are really needed in the acceptor country vs. drugs that not needed in donor country… Not those collected back from patients or to be wasted!
57 Distribution/Wholesaling Only authorised wholesalers? By whom? GMP? Inspections? Storage conditions also during transport Interim storage (airport, freeports), even cold chains for vaccines
58 Storage conditions also during transport „TempTags” in the deliveries (devices registering temperature) – the requirement is contained in the contract with transport companies? Is it specified who will be in charge of checking TempTags?
59 Standard for drug manufacture Also for drug wholesaling (some parts) Good Manufacturing Practice (GMP) General Principles Special Annexes (sterile production, medicinal gases, clinical trial samples, etc.)
60 Our recent special probleme: counterfeit drugs = intentional falsification for profit WHO: up to 50% in some Third World countries!
61 Counterfeit drugs, types 1 Good quality, mislabelled using a manufacturer’s name and brand, well-known in the region The same with bad quality: ingredients with more impurities, less stable, API outside (mostly below) the limits
63 Counterfeit drugs, types 2 Bad quality: much less API 50% to 10% (some API contained to be identified by spot tests or basic tests) No API at all! Life-threatening e.g. antibiotics, vaccines, antimalaria medicines
65 Counterfeit drugs and the supply chain, 1 Different vulnerability! Drugs pharmacy-only, pharmacy owned by pharmacists, mostly drugs sold in pharmacies, drugs bought from licensed wholesalers
66 Counterfeit drugs and the supply chain, 2 Drugs pharmacy-only, pharmacy owned by pharmacists, not only drugs sold in pharmacies, products bought from different sources Drugs pharmacy-only, pharmacy owned by laymen/chains, not only drugs sold in pharmacies, products bought from different sources
67 Counterfeit drugs and the supply chain, 3 Drugs sold in ordinary shops, fuel- stations, even markets Distant and Internet-selling…
68 Complexity of the supply chain Earlier: manufacturer wholesale distributor pharmacy
69 Complexity of the supply chain API manufacturer international transport Co product manufacturer broker wholesaler international transport Co global wholesaler distributors central warehous
71 Drug manufacture, procurement and wholesale distribution Manufacture –Discuss the different levels of local manufacture. Self-reliance?Export? –State-owned or public factories versus regulation of the private pharma industry –Is authorisation needed? By whom? GMP and inspection –Importance of WHO Certification Scheme Procurement –Definition –Possibilities of private or public procurement –Semi-autonomous Procurment Agencies, tendering –The interchangeability issue –How to make procurement estimates? –WHO rules on donations Wholesale distribution –Authorisation? –Storage and transport –Final and interim storage –The counterfeit issue