WORLD HEALTH ORGANIZATION . ORGANISATION MONDIALE DE LA SANTE Se GUIDELINES AND RECOMMENDATIONS FOR THE ESTABLISHMENT OF A LARGE VOLUME PARENTERAL SOLUTIONS PRODUCTION PLANT (L.V.P.5.P.P.) IN DEVELOPING COUNTRIES ‘The issue of this document does not constitute formal publication. It should not be reviewed, abstracted, quoted or tanslated withou the soreement of the World Health Organization. Authors alone te responsible for views expressed in signed articies, Co document ne constitue pss une publication. 1 ne doit faire objet d’aucun compre rendu ov résumé ni d’aucune citation ou traduetion sane Vautorisation de ‘Organisation mondiale dela Santé, Les opinions exprieées dans les articles signés n’engegent que leurs auteurspae/85.11 page 2 TABLE OF CONtUNTS 1 Revreseceints st naiters See eee cae Gt Once ecpernmen OU esse cece eee ret restr TEL. Description of Large Voluae Parontersl Solutions Type. 0 eres Tv. tmportance of WP Solutions in aodera medicine ss. ese eee Bis Ye Aim of the Proposal (Scope of work). - ee 5 VL. the LP folutons Production Plant CTSPA) o.oo eee eee 6 ce at eat tanete feer fiscal Grader west ect sees B. Selections of formulas and kind of packeging - 2. eee eee 6 et nee eeeeetag eer eset ees D. Recomended eciterie for the pleasing, design, construction, 2 Operation and waiatenance of the proposed LESPP ss v= + + - cae Hconowic and feasibility considerations sss e reece eee 8 gael cll tlpne upepdeay oie vane oust Treat 1s hoaex TL, ~The tndustrial Plant (Wodel 8) oes ea es Serer, Aonex 111, = Production equipment and Quality Control Instrumente s+ ++ 32 hanex TW. = Personnel qualifications, training of personnel 6 es + + 37 anaex V. = WD Deavings Schedule... aerate es Biren I. INTRODUCTION ‘the concept of essential drugs and vaccines, conceived and developed in WHO over the test tive years, fora one of the basic conponents of prinary health care. the Declaration CH Ains Aen mighLighes ene Inporeance of he availability af essential drage and vaccines nd the regular supply of @ Limited susber of essential drags is one of the indicators of the tuccent of the Clebal Strategy for Tealth for All by tne Year 2000, The WWD Seventh General Progranse of Wowk clearly indicates the objectives and targets for the WI Action Progcane on Fesencial. Drugs and Vaccines in support of the primary healeh care strateay- Resolutions EB61.R17, FBG3.R20, WHASL.32, WHA32.41 and WHAIS.27 Laid the basis for the establishment in 1981 of the WH) Secion Programe on Bssential Drugs and Vaccines. Im ut same yest, the UNICRF/WHD Joint Conmittee on Ilealth Policy adopted a joint wH0/UNzCE programe for support to the provision of essential druge for primary nealeh care in developing countries. Je is within the above resolutions and the spirit of che Action Progrumme on Essential ge and Vaccines that the following guidelines for the establishment of @ Large Parenteral Solution Production Plant for the local production of the most widely vsed infusions, in Aeveloping countries is presented. The guidelines for the establishment of Large Volume Parenteral Solution Production Plants (LvPSPP) in developing countries consists of: (a) buildings, (b) equipmeat, (c) insteusente, (¢) infrastructures, and (e) outline of training prograumes for operative personnel. It alse includes health and vafety standards, G¥P guidelines and ecologicalDAP/85. 11 page 3 considerations at the least possible investment cost and greatest reliability to enable aanufacture, support and control of manufacture of essential infusions in developing countries. The above LVPSPP attempts to provide alternative solutions for the problems faced by the developing countries in the £ielé of local formulation of essential drugs. This model gives consideration to pre-fabricated materials to facilitate developing countries to overcone some local technical constraints. However, it is strongly recommended that during the feasibility studies, local availability of adequate buildiag materials should be thoroughly investigated. In addition, the LVPSPP includes coneiderations of manpower and adequately trained personnel requirements, the use of selected formalas and packaging. ‘Two alternative plants are presented: Hospital plant with an annual manufacturing capability of 250,000 infusions (500 ml cap. each), this aodel can be sufficient for s comunity of 2-3 million population; and a second one, with a yearly capacity of 1,350,000 Litres infusions, vnich can supply the needs of a comunity of 10-15 million people. Since these guidelines are a preliminary approach to the establishment of LVPSPP in developing countries, both modelo require a couplere feasibiliry study, taking into account local climatic conditions, infrastructures, availability of qualified personnel, ete. before a decision ig made about their establishment. WHO should continue to provide assistance in obtaining the necessary technology for the operation of the plant, vhich includes master formulae, operating procedures, in-process control, etc, This specific feature would substantially accelerate the transfer of technology needed by the developing countries. ‘Training progrannes for production and quality coatrol personel needs to be developed and WHO could provide the necessary input for implementing countries. It is considered that chose countries with a population of less than 10 million might Like to consider joint projects to implenent LVPSPP with neighbouring countries through the Technical Cooperation enong Developing Countries (TCDC) approach. Return of investment of plant can be scheduled in 4-5 years. ‘These guidelines are provided in order to allow Menber States, interested in ‘establishing production plants for Large Volume Parenteral Fluids to quickly apprai nagaitude of the project and adjust the bacic guidelines to their national realities also expected that these guidelines will assist in the preparation of concrete feasibility studies for local production of the most used parenteral flui. TL. ACKNOWLEDGEMENTS ‘The author would Like to express his gratitude for help received from various knowledgeable professionals who have contributed to the development of these guidelines. Specist mention should be made to Dr E. Lauridsen, World Health Organization, Geneva, Switzerland; Dr F.S. Antezana, World Health Organization, Geneva, Switzerland; Mr J. Hedges, ASTRA, United States of America; Dr C, Battaglino, Ministry of Health, Rome, Italy and Mr A. Bertuzzi, OLSA, Milan, Italy for their valuable contribution. The content of this document remains the author's responsibility. ‘The author would also Like to give recogaition to WO for its support and for providing the opportunity to develop these guidelines within che Action Programe on Essential Drugs.DAP/B5. 1 page IIL, DESCRIPTION OF THE LARGE VOLUME PARENTERAL SOLUTIONS TYPES Even if well known, we take the opportunity co recapitulate in the following pages the description of parenteral solucions, their fields of use, and the importance in modera medicine. The Large Volume Parenteral Solutions are fundanentally simple formulas: made up of salts or sugars, or mixtures of both, dissolved in water. Wowever, the final product shall meet requirements of the highest standard of quality, due to its specific application and In Table 1, briefly deseribed below, the different types of psreateral solutions sppear. LARGE VOLUME PARENTERAL ILVPS) Infusion | Dialysis solutions solutions Tecesve | [Reve] [ Pipeenon | | age Gsm’ || Sac || Pevcigee | | Mir TABLE 1. Incigation fluide Thay are used in surgical procedures, such as for rinsing of body cavities with antibiotic solutions. fon sotuttor They might be given either intravenously (most common) or subcutaneously, There are several types of such solutions depending on the wedical needs, and their uses are varied. 1. Plagna expanders: This kind of solution, e.g., Dextran, substitutes the blood lost dye eo accident or ducing a surgical operation, etc. 2, Rehydeation fluids: They are mainly used to restore severe loss of Liquids in patients due to dfarehoea, when the general conditions of the patient ere ao bad that he cannot take rehydration fluids by mouth (e-g-, NaCl solution). 3, Nutritional solucions: They sre normally sugar solutions, given to patients not able to be fed normally, eg, after serious abdominal surgery or when the patient is in cona (a.g- Dextrose solutions, aminoacié solutions). 4. Blectrolyte solutioas: These solutions serve to restore the proper electrolyte balance'oF the patient Cerg., Darrow solutions). Dialysis solutions These solutions are absolutely necessary when the kidney functions are diminished; and, as @ consequence, they cannot eliminate the toxic waste products from the body.+ Normally, they are very concentrated salt solutions and are used With an artificial kidney, diluted with dewineralized water. solutions: These are similar golutions to the above, but Kidney, it is possible to use the peritoneum of the patient as a membrane, Two litres of solution ave given directly from the container into the peritoneum. After the necessary time in the body of the patient, the solution is drained off again into the container with the waste products, which have passed from the body through the peritoneum. IV, IMPORTANGE OF PARENTERAL SOLUTIONS IN MODERN MEDICINE The importance of the use of parenteral solutions ia modern therapy is today very well known. Not only in case of epidemic (e.g., cholera), but also in the daily hospital practice, the use of parenteral solutions is spreading wore and more; and the need for them is growing every day. Large volume intravenous fluids are vitel in the treatment of craumatic shocks of with consequence of dehydration, The use of parenteral solutions permits not only to correct organic disfunctions, as the acid-base or saline balance in the organism, but also to administer sone drugs patient and to feed him a¢ well. This enables a considerable reduction of the hospitalization time of the patient. It is estimated today that most developed countries! consumption of LVPS is about 500 mi to 1 litre por capita per year. Tn some developing countries the consumption per capita is estimated at 100 ml; and in others, especially the less developed countries, the consumption is even lower than that, ‘This seas to be directly related co the availability of health services. Due to the importance of parenteral solutions for the delivery of health services, the io Expert Comittee on the Selection of Easeatial Drugs had selected 8 types of parenteral solutions in the WHO model list of essential drugs (see TRS 722, 1985). Tn addition the use of saline solutions for peritoneal dialysis and heamodialysis will increase enornously the pattern of consumption of parenteral solutions. In fact, for peritoneal dialysis, each patient uses 2 1t. of sterile saline solution every 6 hours; and in case of extra body dialysis, the need is 5 It. of saline solution 3 cimey per week per patient. B.S. = Closely related to the production and use of parenteral solucions in today's health Gervices, is the availability of ORS, therefore full consideration should be given to the possibility of producing ORS within the frame of this project. Furthermore the WO publication “Guidelines and Recommendations for the Sstablishnent of a Large Volume Parenteral Solutions Production Plant (L.V.P.8.P.P.) in Developing Countries" can serve as a basis for the above suggestion of producing jointly LVPS and ORS. In addition the LPS Plant could easily supply drinkable water for the ORS mixture. ATL OF THE PROPOSAL. The aim of this guideline is: (i) to provide technical information for the establishaent of a Production Unit for Parenteral Solutions (LUPSPP), (ii) to discuss the production programme and the selection of different kinds of materials for containers, and (iii) to give criteria for construction, economic feasibility, qualifications, and training of personnel eequired in the manufacturing and quality control of pérenteral solutions.Dav/ 85,11 page 6 In the following pages we will describe two models of manufacturing units, one hospital pize and che other for industrial scale, Thie description includes estimated investment figures for the carrying out of the project. Bach specific project should rake into consideration the actual conditions of the countey concerned. Therefore, feasibility studies are recommended before further decisions are taken, This document provides the reader with enough technical and financial information, in # preliminary phase, Co make some decision toward the possibility of undertaking predvetion of LVPS. VI. THE LVP SOLUTIONS PRODUCTION PLANT (LVPSPP) The LWP solutions plant described in ehie document consiete of: (a) buildings, (b) equipment, (c) instruments, (d) factory infrastructure, and (e) personngl, which all fogether fulfili the technical requirements, keeping in mind sufety and wiO"s GMP recomendations. ‘The folloving guiding principles should be taken into account in the actual establishment of the pro, - the lowest possible operation cost; ~ the production programme planned according to the most suitable and economically feasible schedule; - due to the neture of the LWPS, selection of its containers according to the local situation; - when considering the feasibility of chis project and health needs, the concept of self-reliance and stratezical nature of LVPS. A vationgle for local formulation of LVS ‘The establishment of local production generally vill: (a) permit regular and sufficient availability of infusions (LVPS) of internationally-accepted qualitys (b) allow flexibility of infusions supply, according to the local needs, especially in emergency conditions, such a9 epidemics and natural disasters; (c) save hard currency: (8) develop technical and other national capabilities; (e) promote the developnent of velated industries; (£) acquire an advanced technology which could be the basi for a more diversified pharmaceutical industry. Selection of formulas and cont, 1, Selection of formulas: In considering the feasibilicy of establishing a LVPS plant in developing countries, it is recommended that the planning be based on the estimated national requirements made by che Ministry of Health, Although there is no statistical data available on the consumption of infusions in developing countries, it is estimated that within the population with access to health services, 300 ml per capita might be the average vequirement compared to 500 ml to 1,000 ml in the developed countries per year, With the above assumption, it ie easy coDAP/95.11 page 7 calculate the quantity of infusions needed for an area, country, or region. In addition, solutions for peritoneal dialysis and haemodialysis can algo be produced in the sase unit, The production of infusions has different levels of complexity. Therefore, che inplomentation of the production unit should be initiated step by step, caking into account the following factors: (i) technology, (i) erained personnel, (Ai) factory infrastructures. The following stages of complexity have deen identified: Stage I - production of the simple LVPS + dextrose 5% and 10% + sodium chloride 0.9% + dextrose 5% in normal saline (sodium chloride 0.9%) Staze TX - production of more complicated solutions + Ringer solutions + Ringer lactate + Darrow solutions Stage III ~ production oft + plasma expander + aminoacid solutions + solutions for dialysis (peritoneal or extrabody). Note = At the initial stage of production it is advisable to consider the inportacion of eontsiners in order to reduce the technical problens connected with the local production of containers. In this cage the use of imported printed PVC bage could be recomended. Where local capabilities are available, consideration should be given to produce the containers locally. TABLE 2 - Proposed Schedule to Set Up an Industrial Plant (Model 8) OBJECTIVE. approval of the feasivility etudy and final decision to realize the plant factory construction running test and s: rt up of the production stage T completed starting stage If and local production of plastic containers starting etage ItpaAP/85.11 page 8 Selection of containers ‘The selection of suitable containers for infusions requires serious analysis of the various factors to be taken into account: aw cost of material, (i) sources amd availabiliry, Gii)—stabiliey, (iv) transportation, ro) quality. ‘There are three different types of containers used for infusion: «a Blase bottles, Gi) rigid or semi-rigid plastic containers, Git) collapsible plastic bags. ALL three types have advantages and disadvantages. Glass bottles are fragile, heavy and bulky, and must be made of a cpeciai glass quality; but they prevent water evaporation, which can be a serious problem in hot climatic countries. Plastic containers of polypropylene prevent evaporation, are transparent enough to allow visual inspection; but, on the other hand, they are brittle. Plastic containers of polythene are not very transparent and, thus, do not allow a good visual inspection. While polythene has problens withstanding sterilization temperatures, it docs prevent evaporation. Both these types of plastic containers could be produced on the spot (importation implies the high cost of freight). Plastic PVC bags have che advantage of not being fragile and, therefore, being easy to handle compared with glass bottles. PVC bags can alvo be imported flat, uhicn saves freight costs. They withstand sterilization tenperatures and allow easy visual inspection. Disadvantages of PVG bags inclade their allowance of water evaporation and their containing softening ingredient, The presence of traces of thie softening ingedient in simple solutions containing salt and/or sugar does not represent a major problem; however, this could be a major problem for blood and fat emulsions, The table below sumoarizes the characteristics of the different containers: Glass bottles Polypropylene Polythene Plastic plastic bottles plastic bottles PVC bags Sterilization Prevente eveporation Allows visual inepection Fragility Bolkiness (shen imported) - - - ” As 2 conclusion, the most suitable alcernative in selecting containers for infusions should be decided considering technical inpur as shown in the above table, along with the national conditions and feasibilicy in each country. Note - A new material has been recently introduced in the market; it is a combination of ealendered PVC coupled with polyethylene or other polymere. Despite the expectation that these containers have created, ir is considered too early to inelude then in the document, until they are sufficiently tested.aP/85. 11 page 9 Introduction of 1,000 al containers along with the ordinary 500 ml, might result in 2 reduction of production costs and increase the output in litres. C. Ray Materials ‘The quality of a product is strongly related to and influenced by the raw materials used in the manufacture and processing of the final dosage form. Materials to be controlled are those raw materials that appear as a physical part of the final dosage form including the package, Thus, the drug substance, excipients and the primary packaging materials (euch ac, containers, closures or plastic resins) make up this group. An adequate system should be established for the proper receipt, testing and storage of raw materials, Standard operating procedures aust provide for proper segregation, and storage of all raw materials, and for their orderly and accurate transfer from one location to another. Provisions should be made for proper rotation of these materiale (Fif0 system), and 4 suitable quarantine procedure should exist for all ray materials that fail to conform fo a given specification or standard, ‘The raw materials used in the manufacture and processing of drugs, regardless of whether they appear in the finished product, chould be identified, stored, examined, tested, inventoried, and controlled as to their proper use. Appropriate records should be maintained as to their origin, receipt, testing, and disposition, and as to the assurance of their conformance to standards of identity, purity, quality, strength, potency, and freedow fron contaminants at the time of use. A resample and retest date should be eeteblished for stored rew materials, especially active and inactive drug substances, to assure the desired quality after extended storage. The product is affected by the presence of extraneous substances in the drug, contaminants in the excipients as purchased, and contaminants entering the product during manufacturing or packaging operations. The contro} of raw materials, active or inactive, begins before the purchase and is maintained by careful handling procedures cicoughout the manufacture of the packaged dosage form. D, Recommended criteria for the planning, design, construction, operation and aaintenance of the proposed Large Volume Paceateral Solution Production Plant We have considered two sires of plants: 1, The hospital size plant (Model A), is designed to enable the production of the most coamonly used LVPS formulas. The production ourput, one shift based, is 500 iferes of LWPS daily, equivalent to 1,000 units of 500 al, The capacity of the hospital size plant hae been calculated to be suitable for countries with approximately 2-3 million people, and an extension can be easily made. (See drawings Nos. 1 aad 2.) 2, the industeial plant (Model 8) has a production capacity for a country vith 10-15 million people, with the general technical characteristics described afterwards, but designed co combine efficiently semi-automatic and manual processes. The production output, one shift based, is 6,000 litres of LVPS equivalent to 6,000 units of 1,000 ml daily. (See drawings Nos, 3, 4, 5, 6 and 7.) Economics and feasibility considerations Consideration of the following matters is recomended to any interested country before implenentation of the proposed hospital size plant. 1, Feasibility estimates, for each project. A simplified method of a feasibility study is shown below, In this method only two criteria are required: the cost of investment and the estimated saving due to local production,DaP/85.11 page 10 The plant necessary to support the needs of @ community of 2-3 million people is based on the layout of a plant with « total area of 38 equare metres (276 of chen designed for LVPS production), utilizing Model A, the estimated investment for the proposed plant is showa below: TABLE 3 - Eotinated cost of investment for hospital size LVPS plant (Model A) in 1,000 Us $ in 1,000 US $ from to. Site work and surroundings 20 40 Buildings and structure (for production and quality control Laboratories) Services and auxiliary equipment Production equipment and in Line control Installation ané engineering Total cost AVERAGE: Approximately US $550,000.00 (1985 price) Specific figures Building cost including assesbly, air conditioning, sanitary, electrical site work and surroundings (first three of the above list), average = US $160,000. Specific building cost: us $ 160,000 2B aq. w * US: $580/0q. ‘This plant has an average capacity of: 250,000 (500 wl each) units per shift/year. The building cost will vary from country €0 country, therefore adjustments are necessary to artive at reasonable estinates of actual investnents. The estimate ic Dased on providing complete infrastructure services and no provisions were made for duties, delivery charges, insurance and other associated expenses. 2, availability of infrastructure ouch a9 energy, water, personnel, distribution network, 3. Financial and technical support could be provided for national projects by UNDP, WO, UNIDO, UNICEF, World Bank and others. 4. Increase of need for Large Volume Parenteral Solutions, resulting from the extension of any heaith care programnes, particularly PHC. 5. The possibility of Technical Cooperation among Developing Countries (TCbC), in order to improve the cost effectiveness in the operation of the plant. In order to determine the feasibility of the project, the following basic information is Projected forecast requirement in estimated quantiry and value units for the next 5-10 years;DAP /85.11 page lL (b) Working capital, financial costs; (c) Investment (direct and indirect), production cost amortization and depreciation; (a) Gost of raw material and other imported inputs. Considering the hospital size based on the following assumption: ant (Model A), the feasibility of the project may be (a) Initial production output (first year: 500 mi cap. each = 100,000 units); (b) An incre: je of 150,000 standard packs per year; (c) An estimate of 0,5 million standard packs can ve achieved after 5 years of operation without additional investment (by adding a 2nd shift); (a) Capitel investment: US $550,000.00; (e) Estimated price of inported standard pack: 500 ml, US $0.85 1000 wi, US $1.00; (#) Estimated saving due to local production based on the author's calculation, around 40x of imported cost (local production cost US $0.538/pee.)- ‘The above assumptions will result in che estimates appearing below. They show that payback may be accomplished within a period of about five years after the start of operation (see Tables 4 ond 5). The above estinates indicate a highly viable project with resulting economies on hard currency and probably real financial profits efter che fifth year of operation. In addition, the technical and managerial experience gained by the personnel aud cite -country from having auccessfully implenented this project is of great valve. Of course the production cost of the LVPS manufactured in a larger plant as the case of Model B is drastically reduced, particularly when the local production of plastic containers starts with higher economic savings. For example a polythene bottle i litre capacity will cost about US $0,035 against US $0,148 for a PYC bag of the cane capacity, The industrial plant of LVPS, ae per Model B, will require an investuent for building, equipment, apparatuses, technical services, of abou US $4.0 = 4.5 million, Naturally in this case a feasibility study will be necessary taking into consideration rhe Local conditions of the country under evaluation. For the pceliminary evaluation of the f¢ plant refer to Tables 6, 7, 8 and 9. ibility and rentability of the industrial sizeDAP/85.11 page 12 TABLE 4 ~ Production cost of 500 mi Dextrose S¥ packed in PYG bag. hoepital size Tuodel a Production per year, pes, 100,000 250,000 300,009 500,000 Incidence in US$ per unie PUC ompty-printed bage Tajectable Dextrose Depreciation in 10 years Polyethylene sachet Carton box, 1/29 Quality controt Salary and wages General services (partly Total cost in US$ per unit 0.978 0.538 0.518 0.398 = The inflation wes not evaluated in the calculation, as well as the unavoidable \crease of price for the LPS imported. TABLE 5 - Simplified estimated payback time period of the capital investment ‘Giopital size blest = Model A= WPS $00 aT Cap Production Quantity of Estimated cost etinated cost Saving due to Total eotina trandar ineateof incase of local local foreu” tion of cunules pecke in fepore in formalation ia lation in tive saving in @ 1000/year ‘US $1000/year US $1000/year US $1000/year US $1000 100 35 98 -3 “1 250 212 134 78 65 300 235 155 100 165 4th 500 425 199 226 301 Sen 500 425 199 226 67 6th 300 425 19 226 843 Teh 300 42s 199 226 065 Ben 300 425 199 226 295 oth 500 425 199 226 saa loth year 300 425 199 226 747 % Start oF the secad GhLEt which will attain the Gull production after two years. 4 Payback time after five years,AP /85.11 page 13 TABLE 6 ~ Production cost of 500 ml Dextrose 5% packed in PYC bags Fxgduction cost of 500 ml Dextrose 5% packed in PVC bags (industcial plant ~ Model 3) Production per year, pes. 600,000 1,200,000 1,800,000 2,500,000 3,600,000 Incidence in US$ per unie PVC empty=printed bags 0.130 0,130 Injectable Dextrose 0.022 0.022 Depreciation in 10 years 0.222 0.160 Polyeehylene sachet 0,033, 0.013, Carton box, 1/20 0.030 0.030 Quality control 0,010 0.008 Salary and vages 9.072 0.063 General expenses 0.025 0.030 Total cost in US$ per unit 1.167 0.685 0.526 0.456 0.376 ALB. = The inflation was not evaluated in the calculation, as well as the unavoidable Increase of price for the LVPS imported. TABLE 7 ~ Simplified estinated payback tise period of the ca (Cadustrial plane ~ Hodel ; LVPS 500 al vol.) Production Quantity of Eetimated cost Eotinated cost Saving due to Total estin year standard in case of in case of local local formu- tion of cumula- packs in iaport in formulation in lation ia tive saving in 1000/year US $1000/year US $1000/year US $1000/year JS $1000 Toe year 600 510 700 190 ~ 190 2nd year 1.800 1.530 943 587 397 3rd year* 2.500 2.125 1.140 985 1.382 4th year 3,600 3.060 1.354 1.706 3.088, Sth year 3.600 3.060 1.356 1.708 4.79% 6th year 3.600 3.060 1.354 1.706 6.500 Teh year 3.600 3-080 1,354 1.708 8.206 Beh year 3.600 3.060 1.355 1.708 9.912 Sth year 3.600 3.060 1.354 1.706 11,618 10th year 3,600 3.060 1.354, 1.708 13,326 * Start of the second shift which will attain the full production after two years. %* Payback time after four and half years.aP/85-11 page 14 TABLE 8 ~ Production cost of 1 litre Nextrose 5% packed in PVC ba Unietel Panes Wedel Production per year, peo, 600,000 1,350,000 1,900,000 2,700,000 Incidence in US $ per unit PVC empty-printed bags Injectable Dextrose Depreciation in 10 years Polyethylene sachet carton box, 1/10 Quality control Salary and wages General expenses Total cost in US$ per unit 1.220 0.683 9.587 0.487 N.B. ~ The inflation was not evalusted in the calculation, a5 well as the unavoidable Therease of price for the LVPS imported. TABLE 9 ~ Simplified eatimaced k time period of the capital investment Cindusteiat Plant = Wedel # > LV8S 1,000 al vol.) Production Quantity Estimated cost. Estimated cost Saving due Tora estima~ year of standard in case of in case of to local tion of, packs, in import in Jocal formu- formulation cumulative YO00/jear ‘U8 $1000/year ation in in US §1000/ saving in US $1000/year year us $1000, lst year 600 732 = 12 - a2 2nd year 1,350 922 428 296 3rd year 1.900 Lis 785 1.081 4th years* 2,700 L315 1.385 2,465 Sth year 2.700 1.315, 1.385 3.851 6th year 2.700 : 1315 1.385 5.236 7th year 2.700 1.315 1.385 6.621 8th year 2.700 2 1315 1,385 8.006 Ben year 2.700 Las 1.385 9.391 Och year 22300 1315 1,385 10.776 Start of the second shift which will attain the full production after two years. 4 Payback times about five years.ap /85.11 page 15 saiex_ 2 HOSPITAL SIZE PLANT (Wodel A) (See dravings Nos, 1 and 2) The production unit described in this paper is designed to serve the needs of @ larger hospital (ike a teaching hospital), as well as to supply infusions to smaller rural hospicaie, This approach is advisable when transportation is a problem in the area and there are long distances between the factory and the consumers. There ere other advantages of having a hospital size plant, such as utilizing existing infraseruccure as well as services of the hospital, e.g. - technical services (steam, raw water, electricity, ete.) = analytical control laboratories = storage facilities for packaging, raw materials, and finished products. ‘the proposed hospital size plaat will consist of one building, separated from the other hospital buildings, where all the production and in-process control facilities are accommodated ae illustrated in the WHO drawing No. 1. This model plant could be attached to large hospitals with adequate facilities and where Limited consumption of parenteral solutions are required. The necessary biological laboratory and animal house will be built far from the production premises to avoid any contamination. Ao described above, the proposed hospital size plant will have a production capacity of 1000 units of 500 al per day for one shift (about 10-12 persons) and will require guilding space on a total area of 384 m? if ORS production is included, otherwise 276 m? are sufficient for the LWPS production. ‘The following production and quality control equipment will be needed: PRODUCTION BQUIPMENT (one) ATER DEMINERALIZER, mixed bed type, hourly outputs 450 litres (one) DEMINERALIZED WATER STORAGE TANK, made of stainless steel AISE 316: 500 Litres cap. (one) WATER DISTILLER, in ec. at. AIST 316, hourly output: 100 litres (50 litres when heated by electricity) (one) DISTILLED WATER COLLECTION AND STORAGE TANK, 500 litres cap., with electric resistor auitable to keep the tenperature of water up to 80°C, made of » steel AISI 216 (two) ST. ST. CENTRIFUGAL FUMES (one) SCALE, counter type, cap. 20 kg (two) MIXERS, im st. st.,'250 litres useful cap. (ewo) STERILE FILTRATION SYSTEM, by membranes (one) SET OF PIPE FITTINGS (one) HEAT EXCHANGER for cooling the distilled water before feeding the mixers (one) FILLING AND SEALING machine, 2 st. st. syringes, 500 ml cap. each (one) TANK for filtered solution, 50 litres useful cap. (one) VERTICAL LAMINAR FLOM CABINET (one) STEAM AUTOCLAVE, I-door model, st. st, chanber, 1 cuem cap., equipped with built-in electeie steam generator, temperature chart recorder (three) IRON UNDERCARRTAGES (chree)ST. ST. PLATFORMS with st. et. trays (one) AIR COMPRESSOR, complete with 300 litres cap. tank, to compensate pressure during the cooling of the autoclave after sterilization (one) LIQUID VIEWER, polarized light (one) ELECTRIC WELDING MACHINE, for polyethylene outer sachets (one) Q8VIGE for printing batch number on the bagspaP/85.11 page 16 A) GWEMLCAL LABORATORY 1 Cone) 1 Cone) 1 Cone) 1 Cone) 1 Cone) 1 Cone) WATER BATH, in at. et., complete with Vertex and relay ANALYELCAL BALANCE ELECTRIC STIRRER POLARIMETER, complete with cubes and Sodium lamp LABORATORY VACUUM-PUMP pH-METER ASSORTED GLASSWARE, chemical reagents, etc. 8) MICROBLOLOGIGAL. LABORATORY (one) (one) (one) (one) (two) (one) fone) (four) (one) ©) Brow VORTEX~GENIE, for mixing reagents, ete. TEMPERATURE-BLOCK MODULE HEATER, maintaining 379¢ + 190 MIOROSCOPE, monocular body; eyepiece X10 objectives 4-10-40 and illuminator with support DUAL PENS TEMPERATURE CHART. RECORDER TNCUBATOR, forced air circulation; Two temperature ranges - slightly above ambient to 60°C and 0°C co 60°C. Temperature uniformity + 0.15°C, Audible or Visual temperature alarms desired DRY HEAT OVEN for glassware depyrogenation, capable of heating at 250°C or above. Should also have a temperature recording device. LAMINAR FLOW CASTHET, for sterility testings, 99.99% final filter efficiency, meeting class 100 conditions (Fed. Std. 209) MEMBRANE STLTRATION ASSEMBLIES, for sterility caste AUTOCLAVE, Lad. aodel, 80 1c. cap., electrical heating - complete with two st. st. backers ASSORTED CULTURE MEDIA: glassware, test tubes, racks, and baskets, sterilizable gloves, etc. Nore: Menbrane Filters may be purchased - Millipore, Sertorious, Gelman, Pall, ete. LOGICAL LABORATORY AND ANTMAL HOI 12 (twelv 1 (one) 2 (eight) 1 (one) 1 (one) 1 (one) je) GAGES, suitable for single rabbits, in st. st., each cage is complete wich feeder compartment and drinking tube TACK, made of iron, suitable for housing above-mentioned cages, having pan co collect droppings.” Should be easy to clean and sanitize RESTRAINING CAGES, with pan and light-fitting neck etocks for confort. ANTMAL BALANCE, with cage, for veighing rabbits ANIMAL TEMPERATURE RECORDER, complete with rectal probes. TEMPERATURE MEASURING DEVICE ~ needed to calibrate recorder and temperature neasuring probes Appropriate syringes, needles and glassware for test procedures Even though the Pycogen (Rabbit) test has been established for the Biological Laboratory it would be advisable to set up the LA.L. Test capabilities in the Microbiological Laboratory, This vould enaple Bacterial Endotoxins tests to be performed in accordance with current US test procedures. Lysate may be purchased from Mallinckrodt, Cape Cod Associates, Microbiological Associates and others who might be licensed.IHE_INDUSTRIAL, PLANE (Wodel B) (See dravings Nos. 3, 6, 5, 6 and 7.) The general design of planning is made on the assumption chat the plant vill be set-up, in most cases, in developing countries, situated in the tropical area. ‘This design wes always kept in mind for the selection of materials, technical planning solutions. Plant capacity (a) Efficiency/flexibilicy (b) Expansion possibility Safety/security GMP Consideration ~ the prevention of mix-up and contamination through: (a) Segregated areas: = quarantine; = released area: ~ clean zones (heating ~ ventilation and ai conditioning levels - HVAC). (>) Flow: aaterials, personnel, visitors (c) Cleanable surfaces: = Eloorss = walls ~ coitings = counter top. Ecology/elinate Infrastructure - as @ function of availeble energy, water, transportation, sewage, ete. Plant capacity The author has considered a production capacity of 6000 litres per day of parenteral solutions, because this is the quantity which allows che combination of economee profitability and dimensions of the plant suitable for a country of 10-15 million people, Im this way it ie possible to realize a very rational production plant which can solve the problem of LWPS in the majority of developing countries; as a single production ceatre, as a plant at the service of a pool of countries and as the first of several production centres for highly populated countries. LWPS capacity ‘The plant can produce: 1,350,000 Litres of parenteral solutions per year packed in containers of 1000 ml volune. N.B. if we consider packing WPS in 500 ml PVC bags, the production capacity will be: 6000 Litzes x 1.4 x 225 working days = 1,800,000 pes, in fact the same volume of the autoclave chanber can contain 1000 LVPS of 1000 al cap. oF approx. 1400 pes of 500 al cap. ‘The guidelines are based on che following assumptions: {225 effective working days per year ave available (5 days a week); 30 days for anqual leave and general factory overhaul; 6 days for public holidays, The working hours are 8 hours a day or 40 hours a week, ive., a total of 1,800 hours a year (one shift): effective machine hour is calculated at 6 hours a day or 1,350 hours @DAP/85. 11 page 18 Te ie important to know that the plant capacity can be doubled by introducing « second shift. ‘The average batch size of solution is as follows: = injectable solution: 2000 litres = standard pack sizes 1000 ml This voluse of mangfacturing capacity may be accomodated in a plant of avout 2600 square metres which may be broken down into the folloving areas: ( area for offices, Laboratories ( and services main building (area for production ( and packaging (area for warehousing rea for infrastructures The offices, quality control Laboratory, canteen, reception, lockers and toilets, are located in the management services area of the main building. The production and packaging area includes the quarantine area, maoufucturing of solutions, packaging and cupervision office. ‘The varehousing area includes areas for receipt and shipment, quarantine for incoming abipments and released goods, storage of raw materials, containers, Labels and finished products. The infrastructures would vary in composition from country to country, depending on the available services for energy, water, sewage, transportation and comunieation. In our proposal the infrastructure units include energy plant, fuel sterage, rav water reservoir and water treatment plant- (a) Sf Sieiency/feasibiticy. ‘The general dimension of the building, including roof heights, ceiling heights, room sizes, construction design and materials, have been considered to’ provide flexibility and efficiency in the activity programed for the plant. (%) Expansion poesibility (See draving No. 6.) A very common problem which arises in plant operations is the need for expansion after the plant has been in operation for sone tine. ‘The expansion is easy co realize, a2 it is possible to see from the WO drawing No. 6, in the east area simply dismantling the prefabricated walls and adding the required apace. These expansion plans can be implemented at any time without disrupting production activities or jeopardizing GMP guidelines in affected areas. 2. Safety/security considerations ‘The plant is designed to meet all safety standards including fire hazards, building ateength, ete. Fuel storage has been segregated from the main building: emergency exits, fire alarms and fire fighting equipment have been provided in different places of the buildings. A first aid room nas been provid A security fence and a gate are recomended for additional safety and security of personnel and operations.ap /85.11 page 19 OMP_Considerations In the realization of the building, ve have essentially considered the GuP, to prevent uixing of products and contaminations, including the contamination from different products, from the operative personnel and from the environment. ft yet controlled as, for exemple, rav materials, labels, containers, seui-finished materials, finished products, separated from those controlied and ready for use or shipment. Te flow of materials is realized so that crossings are avoided and the possibility of mixing is eliminated. ‘The way of the operative staff in the production area is also realized so that contaminations introduced from staff to the product and vice versa are prevented. Further precautions againet the possibility of contaminations are foreseen for the visitors. ‘The building materiale and the finishing have been chosen for their easiness to keep then clean and for their resistance to atmospheric agents of tropical countries, Heology/elimate ‘The planner of a pharmaceutical industry, which is at the service of the country's health, must take into consideration the environmental contamination. Even if a factory of infusional solutions does not produce toxic wastes, the problem of wastes has been thoroughly considered, 0 that the environmental pollution can be avoided as much as possible. A Line for induoteial wastes has beea foreseen (production department, Laboratories and technical services) and another one for sanitary wastes (toilets, showers, sinks, kitchen, ete.). Line A, which gathers the sanitary wastes, undergoes a treatueat to coagulate and separate ail solids for sedimentation. Line B, which gathere the production vastec, is treated a¢ line A, but previously the Liquids undergo a neutralization, before passing to the ‘The two Lines are connected far from the plant, with some precautions to avoid any returns, To drain the solid refuse and the sediment picked up by the discharging plant, it ic advisable to foresee the inratiacion of an incinerator. Since the climate conditions vhere the plant will be installed are generally heavy, the temperature and humidity are controlled through the air conditioning plant or by means of an efficient ventilation, according to the necessities. Infrastructures In the industrial plant presented, provisions are made for the following services: (2) Energy plant (i) Fuel storage Gili) Rav water reservoir (iv) Waste water treatment plant (¥)_ Incinerator (vi) SecurityDaP/85, 11 page 20 According to the specific case, the various problems will be analyzed in detail, considering the conditions of the site where the plant will be installed. Description of Buildings, Installations, Air conditioning, Air filtering and Control Laboratories 1, BULLDINGS The establishnent is composed of a principal building (prefabricated) vhich contains: (a) Production: (manufacturing and packing); in thie area the production, the packaging and the storage of the products waiting for analysis are placed. (b) Warehouse: in thic erea the rav sateriats are stored, as well as the packaging materials and the finished products; conventional storage with pallet racks, 4 pallets in height. : in this area there are offices, analysis laboratories, canteen, changing and a satellite building where the technical services are installed as: power central panel, boiler house, vater tank and treatment plant and animal house and biological Laboratory. The principal prefaricated* building proposed is fundamentally a steel structure, the walls are prefabricated elenento vhere doors and windows are inserted. (See drawing No. 4.) The insulating material of the roof and walls hae passed through the most severe controls in many countries with extreme climate conditions. ‘The prefabricated construction proposed has many advantages in comparison with a traditional construction in masonry. (G) Standardization of che building elements = planning and time costs reduction; = use of materials cested by qualified firma. (ii) Light construction = use of non-heavy means of Lifting; - more inner space available, keeping at minimum the thickness of the walls and division walls; = lesser charge of the foundations. iis) Pre€abricated construction dimension suitable to transport (container); only boited aad "put in place” connection during constructio the construction can be carried out by semi-skilled personne: easiness in realizing internal divisions and of varying the local’ industries cam carry out part of the works such as: foundations, Flooring, fencing, etc; extensions and alterations can be carried out without disturbing the production proces the steel structure can be used for fixing of pipes, ducts, installations and appliances of all kinds. * The greater or lesser convenience in the use of # prefabricated building has to be exanined according to the circumstances. Tt is evident that if locally it is possible to construct a building with traditional aysteme at ¢ good level of finisning, it is preferable.DaP/85.11 page 21 Since the construction costs change quite # lot frou one country to the other, depending on the local availability and therefore on the costs of the construction materials, inner teansport, ete., it is preferable, at the stage of preliminary study, Co make a comparison of the different types of alternative construction, so that it is possible to choose the most economical and convenient solution. AUILDING DESCRIPTIONS 1.1 GENERAL DESIGN CRITERIA The design criteria of the plant have been conditioned in most of the architectural choices by the peculiar needs of the pharmaceutical industry. A very high degree of cleanliness and hygiene, of the personnel and of the equipment and premises, and the absence of any contamination from outside, are factors of paramouat importance. Such factors have determined the choice of 2 very coupact, blacked-out building concentrating in a single block the production areas, the warehouses, the laboratories, the offices as well ae the lockers and the personnel services. A secondary goal has also been achieved, that of reducing the outside perimeter and surfaces. A satellite building has been deoigaed, in order to group the technical services of the Aifferont utilities: electrical power, water, steam, as well as the emergency generator, the maintenance workshop; the aninal house with the biological laboratory also will be separated from the main building. As far as the design of the production area and warehouses is concerned, the plan ha been studied with che aim of assuring an easy and one-way flow of raw materials and finished products, An important role has also been played by the possibility of expansion in the future. For this reason the offices and the personnel services areas have been situated on the front of the building. This front will not be affected by future expansion which might interest the warehouses (expanding the east wall) or the production areas (expanding in the warehouse area). 1.2 PREPABRIGATED MAIN BUELDING a2 ~ Distilled water 39.0 = Solutions preparation 37.0 = Clean ares eatry is = Bags filling and sealing 30.0 ~ Sterilization and packagiog 219.0 Sub-total for production: 336.5 = Quality control labs 72.0 = Rew and packaging materials warehouse 192.0 = Finished products and shipping 987.0 = Quarantine 294.0 Sub-total for warehouses 1,473.0 ~ Office n9.5 = Showers and toilece u0:0 = Canteen 79.0 = Lobby, reception, aisles 1840 Sub-total for misc. areas 492.5 TOTAL FOR PREFAB. BULLDING 2,380.0DAP/85.12 page 22 13 ARCHITECTURAL, 1.3.1 MAIN BUILDING STRUCTURE (See drawing No.5.) The main building frame is made in prefabricated steel components, hot zine plated. The bolts are in steel galvanized electrolytically. 1.3.2 FOUNDATTONS ‘The foundations are in reinforced concrete with a porimetral aocle of concrete 1,00 m in height. 1.3.3 ROOFING A treated galvanized steel insulated sandwich deck is used for the roof. The external sheet is protected by acrylic paint. In the roof some areas are made for natural lighting by means of sheets of trantlucent laminaced plastic. 1.3.4 MALLS ‘The external walle ere made fron prefabricated galvanized steel panels with double metallic support and internal insulation. The external sheer is protected by acrylic paint. 1.3.5. FLoors ‘The industrial floor aakes a single slab, it consists of cast reinforced concrete, with wear resistant, dust-proof sueface finish. Floors are normally smoothed. The £loor finishing will be with epoxydic resins. This wakes the surface resistant and washable. 1.3.6 WINDOWS AND DOORS ‘Two main doors, two-wing type, with iron frame and panels, as for the walls, are Foreseen for the store. ALL windows, doors and frames comply with high quality standards and assure a very good sealing. Along the perimeters of the main profabricated building are foreseen fixed frames with mosquito vire-nets and external sun-screen blades. Inside the main prefabricated building there are thi 1.3.7 OFFICES ~ PRODUCTION DEPT. 6 QUALITY CONTROL LAB. prefabricated! walls - framework in anodized aluminium ~ moulding 1.00 m height in plastic laminated sandwich panel = upper part with glass 5 am thickness. Hindows and doors the external windows of the offices are made of iron frame with glass 4 mm thickness and aosquito wire-nets. The internal windows and the door are in aluminium and laminated plastic. Ceilings - false ceiling in eluminium staves pre-painted, supported by a structure of galvanized iron eections.DAP/85.11 page 23 1.3.8 SHOWERS AND TorLers Internal walls: made in galvanized steel sandwich and partitions with equipped Ceiling: with corrugated sheet iron and false ceiling in aluniniua staves Drepainted. Doors: made in enamelled wood. Floor: of cast reinforced concrete, rutted down and painted with epoxy resins. 1.4 SECONDARY BUILDING Satetlite (200 nt) ‘This building includes: - Animal house Rabbits breeding Biological laboratory Air compressor and air conditioning room - Raw water treatment plant ~ Boiler Pumps room Maintenance workshop Blectric toon Electric generator (uader shed) Tt is connected to the main building through a pipe rack. This building will be constructed locally ia masonry, Janitor's lodge ‘The janitor's lodge is located close to the main gate, constructed lecally in magonry. 1.5 SBHAGE ‘The toilets as well as the laboratories and production equipment discharges are executed in heavy PVC pipeline. Discharges are collected in a leaching trench properly designed for wnderground dispersion, Toilets discharge will be previously clarified ia a separate tank, unile kitchen discharge will be defatted in a proper trench, Production equipment discharge will get no treatment. Laboratories, with the exception of the sterile ones, will have cast iron floor drains. A PVG pipeline guarantees ventilation into the discharge branches. Ventilation columns have a PVC vent stack on the roof. 1,6 BeNoING ‘The area of the factory will be feneed by reinforced concrete fence posts and wire-net. The access to the factory area takes place through an iron gate. Parking areas and roads within the factory area are paved with a surface layer of gravel and asphatt binder (thickness: 8 cm). The unpaved area ie reserved for gardening. 1.7 RAIN UNDER DRAINAGE ‘The vain on paved and green areas is disposed of underground; che rain from the building roofs is conveyed to the main drain vhich carries the water to a dispersion pit.DaP/85. 11 page 24 2, INSTALLATION 2.1 BEEOTREG WORKS A transformation cabin is necessary if it is not possible to have energy directly at low tension. Main disteibutton board The distribution of low tension will be at 380/220 V - 3 phase + neutral 50 He. Every single phase will be connected in order to obtain the maximm balancing of the whole system. Hiring Cables with 4 copper wires, ineulated in Sintenax and tested at 4 KW, every single wire inoulated with thermoplastic material and tected at 3 KW will be install The cables from the main board to the distribution panels will be in metal pipes. ‘Tne cables from the secondary panels to the utilization points will be in raceways or in PUC pipes. Conteol bosrde They will be completed with main euicches and power svitches. Lighting The following itlumination levets will be guaranteed: production: 300 tux ator 150 lux laboratories: 300 tux offices 200 lux technical and auxiliary services: 150 lex Fluorescent Lemps 2 x 40 W (or 2 x 65 U) will be used. ‘The outside illumination will be effected with sodium lamps 400 W fixed in brackets projecting from the building. Lighte control The illumination circuit will be controlled as follows: 1) Offices, locker rooms, with auitches placed at the entry of the rooms. 2) Stores, working rooms and’ corridors, directly frow the central distribution panel. Light tape and energy In the rooms will be installed groups complete with: ~ three poles tap 3 x 164 + earth, complete with svitch and fuses ~ two poles tap 2 x 16A + earch, complete as above = light tap. Grounding systen A grounding aysten for the building is absolutely necessary. Telephonic eye! It is suggested with internal derivation and distribution lines to the different separcmenca.var/85.11 page 25 We recomend, a8 well, the ingtallation of time clocks with electric stamping and factory hooters. 2,2 SANITARY SYSTEMS AND PIPELINES ‘The disposable varer must be analyzed and, if nececcary, treated before admitting it in the industrial vater line, In order to have a sufficient reserve of water for the firy pump network, the production and sanitation, a water reservoir of sufficient capacity will be built with a distribution system under pressure, A false ceiling is planned to be constructed where necessary so that the piping can be brought in to position from above. For the pipes we propose the use of the following materials: cold water steel pipes, galvanized pipes, plastics warm water galvanized pipes demineralized wa stainless steel pipes chilled water steel pipes diseilled water stainless steel pipes > steam steel pipes condensate steel pipe: = clean steam stainless steel pipes compressed air galvanized pipes + vacuum steel pipes, polypropylene - gas steel pipes AIR CONDITIONING The offices, the laboratories, the working areas, with particular regard to the filling area, are air conditioned at a temperature of about 25°C. The conditioning is effected with fan coils fed with cold water from che chiller, 3,1 TEN FAN COILS, installed in the floor or walle, connected to cold water network to the chilfer, euleable to keep, incide the roome, a temperature of about 25°C, one air exchange every hour. Capacity 2/3000 refrigerating units/nour (each). The fan coils are mounted in a zine coated, painted cabinet. Regulation thermostat ie provided for each unit. 3.2 WATER CHILLER for cold water production, inlet 12°C - outlet 7°C. ‘The chiller is equipped with: = one refrigerating group with condeaser cooled with tower water, compressor, seni-hernetic type, copper condenser and tube nest copper evaporator and tube nest two pressure regulators for high and low pressures regulation thermostat for working at 100% - 75% - 50% - 0 safety thermostat anti-freese type thermometer for temperature control panel vith 3 manometers for high-low gas pressure and for oil electric panel operating and control panel safety devices fairing and frane in galvanized stecl, painted filter, solenoid valve, indicator of gas passage.paP/65.11 page 26 ‘The chiller is working also for cooling the distilled water, 3.3 CENTRIFUGAL PuMP for circulation of the chilled water to the fan coile, delivery cunm/h.25, head 20 m, coupled to electric motor. GOOLING WATER TOWERS With the aim of reducing remarkably the consumption of the cooling water for the water acill, the chiller and the autoclave, we suggest installing tuo towere for water cooling, on for the chiller and the water still, the second for the cooling water of the autoclave, ‘The two towers are independent, provided with by-pass for emergency and safety. Te is advisable to install two towers, and not one bigger, because the tower working with the cooling water of tha autoclave has great temperature variations, and this variation Of temperature affects negatively the working capacity of che chiller, which requires constant temperatures at inlet and outlet. 5. AIR PULTWRING, AIR DRUSTING, AIR STERILIZATION To the pharmaceutical industry very high standards are demanded concerning the cleanliness of air within the plant or facility. ‘The air supply, circulated by air conditioning or ventilation units, pot only has to be dedusted, but also sanitized and, in some cases, sterilized. 7 attain such clean air conditions, several filtering stages are required. (i) The fitst stage of air filtering is the rough filtering. These filters are manufactured from glass fibre mats. They are reusable and washable. The rough filter absorbs the dust and dirt particles from the normal road dust. Their efficiency lies between 50 and 70 per cent. (ii) The second stage of air filtering is the fine filtering. These filters are called pocket filters. The fitter medium ie manufactured from glass fibre mats. ‘To protect the filter medium against mechanical loads, the filter surface ie covered by a fibrous veb, The pocket filters are used because ~ with their very fine glass fibre medium mostly not self-supporting - they are stretched in a corresponding supporting structure which gives the filtere the necessary support even in very high operating conditions. The fine filter mats are chrown avay after 1 or 2 tines of regeneration. The pocket filter absorbs the very fine dust and dirt particles from normal road dust with an efficiency of 85 to 95 per cent. fine filters of syathetic materials are very resistant to humidity and chemical influences. (ii) The chird stage of air filtering involves high efficiency submicron particulate air filters, These absolute filters consist of a superfine glass fibre paper with a thickness from 0.8 to 1.5 um which ie erimpad to a papyraceous bonded fibre fabric and thickened with a casting compound in a frame, ‘The absolute filter is not reuseable. Ie will need replacement depending on the operating conditions after @ few nonths or a few years. The submicron air filters absord from the air fine dust, fungi and bacteri ‘These submicron air filters are installed where germfree air has to be provided co meet the highest requirements. Their efficiency Lies between 99.5 and 99.99 per cent, For sir conditioning and ventilating plants of this «ind, the air resistance will be unavoidably very high. For this reason, centrifugal fans are required to guarantee operating conditions.6, HEATING SYSTEMS COMBINED WITH AIR CONDITIONING AND VENTILATING PLANTS Hach single room air conditioner can be equipped with aa electric heating element, The heating output can be adjusted or individually changed by a multi-step switch on the unit co provide partial or full-load heating for any room, depending on the existing requirements. + GONTROL LABORATORIES ‘The Eactory is equipped with the following laboratories: - analytical cheaical laboratory; ~ physico-chemical Laboratory; - microbiological laboratory; ~ biological laboratory and animal house. Those laboratories are required for ceating the quality of active ingredients, excipients, materials in-process as well es finished products and packaging materials. 7.1 Analytical chanical laboratory The furnishings should consist of a work-bench with an acid-resistant surface located in the iddle of the room, cupboard and drawer space should aleo be made available. ‘The work bench contains a sink complete with drain. Shelves are provided on top of the bench. The following may be available: water, gas, vacuum, compressed air and possibly inert gas. Further laboratory furnishings consist of one or more wall benches, tables, chairs, a weighing teble, a fume hood with aspirator, a well a one ox more built-in cupboards. 7.2 Physicochemical laboratory ‘The furnishings of this unit are similar to the chemical laboratory. A large area for instruments and appliances is required in this Laboratory. 7.3 Wierodiological laboratory The independent air conditioning system of this Laboratory is of the high efficiency submicron particulate type for the sterility test room only. The laboratory is furnished with tables covered with synthetic resin. As an alternative to the separate air conditioning system and the Hepafilcers, it is possible to install laminar flow hoods, meeting or exceeding the specification requiremeats as outlined in Fed. Sed. 2095. 7.4 Biological 1aboratory* ‘The current U.S.P, provides, by the LeA.L. Test (85 Bacterial Endotoxins Test U.S.?. XXL) for assay of pyrogens in injectable producte. We suggest setting up a rabbite’ warren ‘and an animal house as soon as possible and to equip che biological laboratory with the insteuments necessary Co cacry out the pytogen test with the rabbits as described in all pharaacopocias. WET TE Te of utmost importance to have the Biological Laboratory under seperate W.VA.C. Systems. The rabbits should be maintained under controlled eavironaental conditions at all tines and especially under test conditions.DAP/85. 11 page 28 TECHNICAL DATA AND SPECIFICATIONS ‘TSCHNEGAL DATA Effective story heights (See drawing No.5.) Production building Warehouse Services Imposed toad on ground floor Production 1000 kg/m? Main warehouse 1500 kg/m? Laboratories and kitchen 800 ke/ mn? All other rooms 500 kg/a? Compressed air supply Pressure 6 bar for production and regulating appliances. Consumption approxinately 150 w/hour. Power supply The power requicement for the described industrial plant (vodel 8) is approximately 150 kw/h. ‘The capacity ef the connection must be 200 kw/h. Lighe intensity Production and control laboratories 300 lux Offices, canteen and kicchen 200 tux AML other rooms 150 lux Ady conditioning for the production unite ~ control labo ‘Temperature about 25°C Ay hwaidity 55% + 10x Aix ventilation of main varehous Temperature ax 28°C Hater requirements The water requirements for the described industrial plant amount to che following quantities: ~ cold water 150 «3 /day ~ de-ionized water 13 al/day = distilled water 7-8 wf aay The_aix-flow from the production process ‘The flow of the air from che production process is effected by overpressure and special air-outlet directly outside the process rooms.Floor covering. + Production: clinker slabs, arcigicial stone slabs, terrazzo or epoxy covering. ~ Packaging: artificial atone slabs, PVC tiles or epoxy covering. = Control Laboratories: clincer slabs, artificial stone slabs, terrazzo, or epoxy covering = Main warehouse: cement finish. = ALL other coons: glinker elads or artificial stone slabs (in the canteen, PVC tiles can be used). Stean For the nced of the plant a steam generator for the production of dry, filtered steas is recommended. e Pressure: 12 bar Capacity: 2000 kg/h ROOM PROGRAMME LIST (See drawing Wo.3.) The list containe the room peogeame for the industrial plant (Model 5). Warehousing, at/net No 101 Main warehouse - receiving and delivering 947.0 No 102 Raw materials warehouse 192.0 No 103 OfFice 10.0 No 14 Quarantine 295.0 Ho 105 Dispensing room 30,0 Processing and packaging No 201 Air-Lock No 202 Changing-room No 203 Sterile entry No 204 Distilled water production No 203 Solutions preparation Wo 206 Bage Filling & sealing No 207 Sterilization - Packaging & quarantineaP/B5. 11 page 30 Secretary office Plant & production manager office Quality control head office Toilet Toilet Toilet Telephone exchange room ting roon Locker male Locker fenale Janitor's room Chemical laboratory Physical leboratory 312 Microbiological Laboratory Sterility test roo 31é Airlock 315 Animal house 316 Biological Lab (pyrogen test coon) 10.0 317 Engineer office 16.0 318 Medical room 10.0 319 Administrative manager office 18.0 320 Cherks 18.0 321 Canteen 75.0 Infeasteucture a?/net Wo 41 Workshop. 42.0 No 402 Air compressor & waterchiller 2.0 No 403 Raw water demineralizer 21.0 Wo 404 Raw water pumps 2.0 No 40S Steam generator 42.0 No 406 Power central panel 21.0 No 407 Evmef, generator under shed No 408 O41 tank buried No 409 Raw water reservoir buried Total floor areas/gross Warehouse 1,474.0 m2 Production 338.0 Services (including corridors, aisles) 618.0 m? Infrastructure 168.0 m? Totsl gross area approx.RECOMMENDED ATR CONDICTONING SYSTEN Designation Main warehouse Raw material varehouse Office Quarant ine Dispensing room Aix-lock Changing zoom Sterile entry Distilled water production Solutions preparation Bags filling & sealing Sterilization Packaging Secretary office Plant & production manager office Quality control head office Toilet Telephone exchange room Waiting room Locker male Locker fenale Janitor's room Chemical laboratory Physical laboratory Microbiological laboratory Sterility test room Aix lock Animal house Biological lab. (pyrogen test roon) Hospital size plant Model & overpressure flow overpressure flow overpressure flow ventilation only x x ventilation only x exhaust only exhaust only exhaust only pap/85. 11 page 31 Ind. plant Model B overpressure flow overpressure flow overpressure flow ventilation only x x ventilation only x x x x exhaust only x x exhaust only exhaust onlyDAP/85, 11 page 32 ANNEX TIT PRODUCTION EQUTEMENT AND QUALITY CONTROL INSTRUMENTS A list of production equipment and quality control instruments (see below) was prepared, based on an eetimated production which would service « model population of avout 10-15 million consumers, The List of production equipnent was based solely om the capacity to produce che most cost-effactive batch ize. In the final selection of equipment for the purpose of procurement, each piece should de evaluated to ensure compliance with Good Manufacturing Practices standards, taking the following factors into consideration: (a) Contact surfaces should be non-reacting and non-addirive, e.g., stainless cteel dotosilicate glass, teflon-coated surfaces; they should not enit metal particles, ets (6) Manufacturing waterials such as lubricants should not contaminate the product; (2) Cleaning, maintenance and operation chould be simple; (a) the least infrastructure should be required; (e) Adequate safecy devices should be provided. PRODUCELON/ENGINEERING EQUEPMENT AND QUALUEY CONTROL INSTRUMENTS 1. PRODUCTION 1.1 DISPENSING RooM Quantity 1 1 1 1 1 Various Description of equipment Floor scale ‘Table seale Top-loading balance Fork lift Vacuum cleaner Accessories for weighing: WATER DEMINERALIZED ROOM Quantity Description of equipment Demineralizer Storage tank for dem, warer Pump Pump DISTELLED WATER ROOM Quantity Desceiption of equipneat Water atilt Storage tank for dist, water Pump Filtee for steam Distilled water cooler Chiller for cooling wacer GE necesnary) pacity 0-150. kg + TARE 0-20 ke 0-1200 g 1 ton 550 spoons, containers, dust mask, etc. Capacity 5.000 ter/n 6 cum 1,5 cuen/h 2,0 cara/n capaciey, 3000 It. /h 5000 1t./eap. 3000 Le./hdaP/85.11 page 33 1,4 SOWTION PREPARATION AND STERILIZING FILTRATION ROOM Quantity Description of equipment Gapaciey 2 Stainless steel vessels with stirrer 2000 It. (useful cap.) 2 Pumps 1500 Le./h 1 Muleiplate Filter 2 Stainless steel nenbrane filter holders for sterilicing fileration L Floor scale 0-200 kg 1 Table scale 0-20 kg. 1 Top loading balance 0-2 kg Various accessories, prefilter pads, membrane filter, stainless steel connection, silicone rubber tubes, ete, 1,5 BAGS FILLING AND SEALING Description of equipment Capacity Bags filling and seating machines 400-500 pee/h (500 ml cap.) Laminar flow hood Feeding tank for sterile solution Tablas for the machines Conveyor bele Various accessories Description of equipment Autoclave (2-door type) ‘Trays (stainless steel) ‘Trucke Sets of st. st. shelves 1.7 packacins Quantity Description of equipment Coding machine Liquid viewers Conveyor belt Roller belt. Electric welding aachines Sealing machine for boxes Traapallete 1000 kg, 1.8 stores Quantity Description of equipmenc Capacity Floor scate 0-200 kg Table scale 0-30 kg ‘Top Loading balance 09-1200" Electric fork lift 1 ton. 1 Washing ~ drying machine 650 w various Storage (racks and shelves) various Accessories for packing and sealing, pallets, ete.DaP/85.11 page 24 2. 2 1 ENGINEERING ANFRASTRUCTURE EQUIPMENT Quantity steaw Quantity. Description of aquipmont Deep well pump 5-7 44P. (if necessary) Storage tank 100-150 m? (depending on requicenents) Pressure pumps Fire pump (preferably diesel) Hot water generator, steamneated (if necessary) Description of equipment Boiler, until 2 ¢/h capacity + water-softening equipment Oil storage tank (size depends on delivery terms) Condensate return tank Fuel pumps Feed-water pumps AIR CONDITIONING (depends on system) wanciey. 1 COMPRESSED AIR Quantity 1 1 1 Blectricity Quantity Description of equipaent Chiller unit with compressor and air-cooled condensing costa Chilled water pumps Electric control panel for AC plant Description of equipneat Dil-free compressor 150 N m3/b Air dehydrator Compressed eir storage tank 3 cu-m cap. Description of equigseat Transformer 200-250 KVA Emergency generator 150/200 KVA Switchboard for low tension Transformer 60-90 KA (Light) Hater treatment plant Depends on local requirements. Horkshop equipment Quancity Description of equipment Pipe-bending machine Rircular saw for wood Wood planiag machine Pedestal grinder Benen grinder Pipe chreading machine Pedestal drilling machine Bench drilling machineap /85, 21 page 35, Power bench sav Bench vices (diverse) Gas welding and cutting set Rectifier welding set vith attachuent for argon welding Welding set, transformer type (general purpose) Welding set, transformer type (light-duty, portable) Contre Lathe Diverse tool sets 3. QUALETY CONTROL LASORATORIES 3.1 CHENTCAL, LABORATORY Central beach Fume cupboacd wall benches Cupboards Analytical balance, with 300 gr. capacity, weighing 200 gr. ~ reading precision 0,01 ge- Tables for balances Technical Balance: cap. 1 kg + 1 kg care, precision 0,2 gr. = Spectrophotoueter, for UV and visible Two digital laboratory pliva meters with: no. 2 glass electrodes, no. 2 PT=probes 100 Ohm. ar O°C for rhe automatic tenperacure adjusting, now 1 buffer solution pH 10,00 (500 ml), 2 electrode holding clamps. Polarimeter suitable for tubes with length up to 220 mn with single inclined focusable eyeplace, tube holder seat, the sodium vapour lanp, polarizer, analyzer Wanuat particle-eounter for counting particles included between 1:75 microns, coulter calculation system, reproductibilicy + 1. Conductivity meter Muffle oven, chasber mn 170 x 120 x 250, with electronic pyrometer for tenperature regulation up to 1,000%6 Flama-photoneter for detersination of Na and K + Wator-bach with three independent datas ~ Theemostatic oven, forced air ventilation model Range: + 35 + 30000 Inside dimensions 51 x 45 x 60 en Two electronagnetic stirrers, with heating plete, controlled by thermostat Various equipment and different amterial such as: conical flasks, beakers, funnels, filters, volunecric flasks, thermometers, evaporating dishes, porcelain crucibles, weighing bortles, chemical reagents, stanés, tripods, bunven burners, vacuua dessicators, etc, 3.2 MECROBTOLOGLCAL LABORATORY. = ORV heat oven for depyrogenation, 250°C - 300°C capability Two water circulation incubators, one with refrigerating group ~ Refrigerator, capacity 275 lt ~ Laminar flow hood “class 100" - board in stainless steel Vertical autoclave, in stainless steel, capacity about 140 it, hinged cover with fact central tightening, complete with two st. st,baskets holding the material to be sterilized Two stainless steel sinks, with wash basins and support shelves Two tables with stainless steel shelf, on trucks with rubber wheels Technical balance, capacity 5 kg, precision 0,1 gr- Microscope, binocular clear field, power 4 X~ 10 X~ 40 x ~ loo x Centrifuge with 30 positions for 15 cc., 5 adjustable speedspap/@5.11 page 36 ~ Sterility control system for 6 tests/day complete vith various = Various glass equipuent and different materials: filters, thermoneters, bottles for reagents, pyrex funnels, microbiological pyrex tase tudes, 38 «200, autoclavable CAP-O=TEST, etc. = Tenperature-Block Module Heater, 37°C + 19C (LsAvL. Testa), Vortex-Genie 3.3. BEOLOGTCAL LABORATORY AND PYROGEN TEST Shelving with 12 restraining cages for pyrogen control Shelving with 12 warrens in stainless steel for rabbits Shelving with 30 places for mice = Balance for rabbits with stainless steel tank Balance for mice with PYC tank Electric theraometer at high precision, digital reading for pyrogen test, complete with 9 probes Tank’ for cage washing = Two cables with stainless steel shelf = Two insecticide lamps - high voltage type 3.4 RARBTTS WARREN Boxes, arranged on batteries, complete with feed-box snd watering place with stainless steel valve, protection shelves, support structures hot dip galvanized Neste for delivery Gutters for evacuation Brackets with 2 buckets at 10 It. constant level for water distribution with flexible pipe Two insecticide laepa - high voltage typeDaP/85.11 page 37 NNEX IV PERSONNEL QUALIFICATIONS AND TRAINING OF PERSONNEL, 1. ORGANEZATION As reconmended by the WHO Guidelines on Good Manufacturing Practices (GMP), as well as to ensure efficient operation of the plant, the organizational chart shown in Table 10 is recommended, In order to achieve better quality drugs, che quality conteol department should report directly to the Plant Manager rather than to the Production Nanager= PERSONNEL REQUIRENENTS Depnnding on the degree of automation, the total personnel requirenent for the industrial plant is between 35-40 persons, Management, Control laboratory Plant Manager Manager (Pharmacist) Secretary University graduares in sciences Supervisors and Technicians Secretary Warehouse and Dispensing Operators Manager (Pharnecist) Engineering department Supervisors Clerks Manager (Engineer) Secrecary Technicians Workers Secretary Workers Personnel and administration department Manager (Pharmeise) Pharmacists Manager Supervisors Accountant. Secretary Clerks Operators and workers Secretaries 3. QUALIFLCATIONS Good Manufacturing Practices standards require that each percon engaged in the manufacture, processing, packaging or holding of a drug product should have the education, training and experience to enable that person co perforn the assigned tasks, vith the specific additional provision that those who are supervising such activities are able to function in such a manner 48 to provide assurance that the drug product has the safety, identity, strength, quality and purity it purports or is said £0 possess. Production Heads of departments such as production, quality control, engineering, ete., should de persons with university degrees in pharmacy, chenistry, engineering or in any other related scientific field. Tf possible, some operational units oe sections for preparation of solutions, bag filling, dispensing and packaging units or sections should also be filled by staff with university degrees, such as pharmaciste, Operators and first-level sugervisors are usually persons with a high school or equivalent education, Proficient and dependable operators are usually promted to first-level supervision. Occasionally, cecond-level supervision may be filled by such individuals, Whenever possible, other workers such as packers, storemen, those involved in production, cleaners, etc., should be able co read and write ptoperly.Dap /85.11 page 38 4, TRAINING (a) Production personne! Ie is important that the jobs in production activities are not labelled as purely manus) labour. The need for alertness and avarenecs in individuals employed, and especially understanding of the job to be performed, should be emphasized. Therefore, there is Little argument thet, for an industry vhose products demand personnel with 2 high sense of responsibility, motivation and training are crucial, The importance of job rotation, chances of further training for capable candidates in order co improve his/her capabilities or co open possibilities for promotion or some sort of incentive scheme should not be overlooked. On-the-spot training in Good Manufacturing Practices (GHP), especially on problem oriented teaching, e.g+, personal hygiene, health habits, quality, ete., is important. Key personnel in injectable drugs production could be given the following training programe: (i) Introduction ro relevant legislation with particular emphasis on GMP quality assurance, 6afety and health; (ii) Personal hygiene; Introduction to injectable dosage forms; Tatroduction to weighing and measuring; Information on available mixers and introduction to preparation of solutions, sterile filtration and different systems of sterilization; (vi) Procedures used to ensure required stenderds of cleanliness in equipment and retention of product integrity and purity; (vii) Introduction co and iaforsation on filling-sesling and in-process control during operation; (viii) Tatroduction to containers, batches, tooling, maintenance and packaging; (ix) Introduction co recording and reporting techniques. Quality control personnel The contents of a programme for quality control key personnel could be as follows: G2) Theoretical aspects of quality control methods and equipment, discussion of the products to be manufactured, methods of manufacturing and equipment required as well ao the necessary in-process quality control to be performed; Practical training on the several aethods of control, preparation of the reagents, completing protocol, ete; Sampling procedures and techniques; Supervision of the implementation of GMP, stability tests, ete; Senbility testings Bioavailability testing;pap/85,11 page 33, (vii) Tavestigation of manufacturing variances (viii) Management of field complaints; (ix) Periodic auditing of the plant. (c) Consubtants, Since the manufacturing of Large volume parenteral solutions i¢ a rather simple process bur requires highly skilled personnel and 2 high degree of quality standards, technical personnel with mich experience is recomended, Tt is suggested that at che initial acage, two years at least, to have the support of three experts in charge of ~ plant & production manager + quality conteol wanager = engineering & maintenance managor. During the stay on the spot the three experts will cooperate with the national staff in their work and they will continue the training progranme in order to complete, as soon as possible, the transfer of the management and cechnical responsabilities of the plant.DAP/85.11 page 40 TABLE 10 PROPOSED ORGANIZATIONAL CHART Ponce Lf sey Control Production Personnel & Laboratory Administration Manager (Ph) Manager (Ph) Manager Supervisors Secretary Clerk. Technicians Accountant Operators Workers Secretary Secretary InProc Control Planning & Purchasing Supervisor Supervisor ‘Staff Staff anal y Engineering Packaging Large volume Warehouse & Parenteral Dispensing Manager (Ena Manager (Ph) Manager (Ph) Manager (Ph) Technician ‘Supervisor Supervisor ‘Supervisor Workers Workers Operators Workers Secretary Secrevary Ph_ = Pharmacist wo Eng = EngineerANNEX V DAP A511 page 41 RHO DRAWINGS SCHEDULE Now Wo? No.3 Wo.d Wo.5, Ho.6 Wo.7 Hospitel size plant (Medel 4): Layout Hospital size plant (Model a): Side and front views Industrisl size plant (Hodel 3): Layout Industrial size plant (Yodel B): Side and front views Tadustrial size plant (Model B)s Section Industrial size plant (fodel 8): Master plan Industrial size plant (Model 8): Panoranic view4MMT MT iDAP/85.11 page 44 apt ase ap TERAL SOLUTIONS PRODUGTION. PLANT PLANT = LAY=OltDAP/B5.11 page 45DAP/@5..11 page 46 PRODUCTION PLANT (DAP/85.11 page 47 aDAP/85.11 page 49 Partial view of a prototype LYPSPP, especially designed for developing countries (reproduction of photograph courtesy of Gruppo Marcucei~Castelvechio, Toscana, Italy)