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PharmaceuticalManufacturing

PharmaceuticalManufacturing

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Multilateral Investment Guarantee Agency
Environmental Guidelines for
Pharmaceutical Manufacturing 
Industry Description and Practices
The pharmaceutical industry includes themanufacture, extraction, processing,purification, and packaging of chemicalmaterials to be used as medication for humansor animals. Pharmaceutical manufacturing isdivided into two major stages. The first stage,which is typically referred to as primaryprocessing or manufacture, is the production ofthe active ingredient or drug. The second stage,secondary processing, is the conversion of theactive drugs into products suitable foradministration. This document addresses thesynthesis of the active ingredients and theirusage in the drug formulations to deliver theprescribed dosage. Formulation is also referredto as galenical production.Major pharmaceutical groups manufacturedinclude:
proprietary ethical products orprescription only medicines (POM) and usuallyare patented products;
general ethical products which arebasically standard prescription only medicinesmade to a recognized formula, which may bespecified in standard industry reference books;and
over-the counter (OTC) or non-prescription products.The products are available as tablets;capsules; liquids (which may be in the form ofsolutions, suspensions, emulsions, gels, orinjectables); creams and ointments (whichusually consist of an oil-in-water emulsion(cream) or water-in-oil emulsion (ointment));and aerosols (which contain inhalable productsor products suitable for external use).Propellants used in aerosols includechlorofluorocarbons—CFCs—(which are beingphased out) and more recently butane has beenused in externally applied products.Major manufactured groups include: (a)antibiotics (such as penicillin, streptomycin,tetracyclines, chloramphenicol, andantifungals); (b) other synthetic drugs includingsulfa drugs, anti-tuberculosis drugs, antileproticdrugs, analgesics, anaesthetics, andantimalarials; (c) vitamins; (d) synthetichormones; (e) glandular products; (f) drugs ofvegetable origin such as quinine, strychnine andbrucine, emetine, and
digitalis
glycosides:; (g)vaccines and sera; (h) other pharmaceuticalchemicals such as calcium gluconate, ferroussalts, nikethamide, glycerophosphates, chloralhydrate, saccharine, antihistamines ( includingmeclozine, and buclozine), tranquilizers(including meprobamate andchloropromoazine), antifilarials, diethylcarbamazine citrate, and oral antidiabetics(including tolbutamide and chloropropamide);and (i) surgical sutures and dressings.The principal manufacturing steps are: (a)preparation of process intermediates; (b)introduction of functional groups; (c) couplingand esterification; (d) separation processes(such as washing and stripping); and (e)purification of the final product. In addition,other product preparation steps includegranulation; drying; tablet pressing, printing,and coating; filling; and packaging. Each ofthese steps may generate air emissions, liquideffluents, and solid wastes.The manufacture of penicillin, for example,involves the batch fermentation—100 to 200cubic meter (m
3
) batches—of maize steep liquor
475
 
 
Pollution Prevention and Abatement
Fruit and Vegetable Processing
January 31, 1996Page 476
or a similar base with organic precursors addedto control the yield. Specific mold culture suchas
Penicillium chrysogenum
for Type II isinoculated to the fermentation medium.Separation of penicillin from fermentation brothis accomplished using solvent extraction andthe product is further purified using acidicextraction. This is followed by treatment withpyrogen-free distilled water solution containingthe alkaline salt of the desired element. Thepurified aqueous concentrate is separated fromthe solvent in a supercentrifuge and thenpressurized through a biological filter toremove the final traces of bacteria andpyrogens. The solution can be concentrated byfreeze drying or vacuum spray drying. The oil-soluble procaine penicillin is made by reacting apenicillin concentrate (20 to 30 percent) with a50 percent aqueous solution of procainehydrochloride. Procaine penicillin crystallizesfrom this mixture.The manufacture of pharmaceuticals iscontrolled by Good Management Practices(GMP) in some countries (for example, refer toHer Majesty's Inspectorate of Pollution, 1993)and some countries require an environmentalassessment (EA) report addressing the fate andtoxicity of drugs and their metabolized by-products. The EA data relate to the parent drug,not all metabolites, and includes: (a) physicaland chemical properties; (b) biodegradability;(c) photolysis propensity; (d) aqueous toxicity tofish; (e) prediction of existing or plannedtreatment plant to treat wastes andwastewaters; and (f) treatment sequences thatare capable of treating wastes and wastewaters.
 Waste Characteristics
The principal air pollutants are volatile organiccompounds (VOCs) and particulate matter(PM).Liquid effluents resulting from equipmentcleaning after batch operation contain toxicorganic residues and are variable in theircomposition depending on the productmanufactured, materials used in the process,and other process details. Cooling waters arenormally recirculated. Some wastewaters maycontain mercury—0.1 to 4 milligrams per liter(mg/L), cadmium (10-600 mg/L), isomers ofhexachlorocyclohexane, 1,2-dichloroethane, andsolvents. Typically 25 kilograms kg ofbiochemical oxygen demand (BOD
5
)
 
per metricton of product (kg/t) (or 2000 mg/L); 50 kgchemical oxygen demand (COD) per metric tonof products (or 4,000 mg/L), together with 3 kgof suspended solids per metric ton, and up to0.8 kg of phenol per metric ton are released withthe wastewater. However, in some cases, BODis not to be considered when the pollutants aretoxic to the micro-organisms in the test.Major solid wastes of concern includeprocess and effluent treatment sludges, spentcatalysts, and container residues.Approximately 200 kg of waste is generated permetric ton of active ingredient manufactured.Some solid wastes contain spent solvents andother toxic organics at significantconcentrations.
Pollution Prevention and Control
Every effort should be made to substitute highlytoxic and persistent ingredients with degradableand less toxic ones. Recommended pollutionprevention measures are to:
Meter and control the quantities of activeingredients to minimize wastage.
Reuse by-products from the process asraw materials or as raw material substitutes inother processes.
Recover solvents used in the process bydistillation or other methods.
Give preference to the use of non-halogenated solvents.
Use automated filling to minimizespillage.
Use “closed” feed systems into batchreactors.
Use equipment washdown waters andother process waters (such as leakages frompump seals) as make-up solutions forsubsequent batches.
Recirculate cooling water.
Use dedicated dust collectors to recyclerecovered materials.
Vent equipment through a vapor recoverysystem.
Use loss free vacuum pumps.
476
 
Pollution Prevention and Abatement
Fruit and Vegetable Processing
January 31, 1996Page 477
Treatment Technologies
Return toxic materials packaging to thesupplier for reuse or incinerate/destroy in anenvironmentally acceptable manner.
 Air Emissions
Minimize storage time of off-specificationproducts through regular reprocessing. Stack gas scrubbing, carbon adsorption, (fortoxic organics), and baghouses (for particulatematter removal) are applicable and effectivetechnologies for minimizing the release ofsignificant pollutants to air. In some cases,biological filters are also used to reduceemissions of organics. Combustion is used forthe destruction of toxic organics.
Find productive uses for off-specificationproducts to avoid disposal problems.
Minimize raw material and productinventory to avoid degradation and wastage.
Use high pressure hoses for equipmentcleaning to reduce wastewater.
Provide storm water drainage and avoidits contamination from process areas.
Liquid Effluents
Label and store toxic and hazardousmaterials in secure bunded areas. Spillageshould be collected and re-used. Reverse osmosis or ultra-filtration is used torecover and concentrate active ingredients.Effluent treatment normally includesneutralization, flocculation, flotation,coagulation, filtration, settling, ion exchange,carbon adsorption, detoxification of activeingredients by oxidation (using ozone wet airoxidation ultraviolet systems, or peroxidesolutions), and biological treatment (usingtrickling filters, anaerobic, activated sludge, androtating biological contactors). Exhaustedcarbon from adsorption processes may be sentfor regeneration or combustion. In some cases,air or steam stripping is performed to removeorganics. Toxic metals are precipitated andfiltered out.Where appropriate, a pharmaceuticalmanufacturing plant should prepare a hazardassessment and operability study and alsoprepare and implement an Emergency Planwhich takes into account neighboring land usesand the potential consequences of anemergency. Measures to avoid the release ofharmful substances should be incorporated inthe design operation, maintenance, andmanagement of the plant.
 
Pollution Reduction Targets
Implementation of cleaner production processesand pollution prevention measures can provideboth economic and environmental benefits.
Solid Wastes
Specific reduction targets for the differentprocesses have not been determined. In theabsence of specific pollution reduction targets,new plants should always achieve better thanthe industry averages quoted in the section onWaste Characteristics and should approach theeffluent levels. The table in the EmissionsRequirements section presents the maximumeffluent levels after the addition of pollutioncontrol measures
.
Contaminated solid wastes are generallyincinerated and the flue gases are scrubbed.Combustion devices should be operated attemperatures above 1,000
0
C with a residencetime of at least one second to achieve acceptabledestruction efficiency (of over 99.99 percent) oftoxics. However, temperatures of around 900
0
Care acceptable provided at least 99.99 percentdestruction/removal efficiency of toxics isachieved.For controlling air emissions, install vaporrecovery systems. Recycle wastewaters andtreated effluents to the extent feasible.
Emissions Requirements
Emission levels for the design and operation ofeach project must be established through theEnvironmental Assessment (EA) process, basedon country legislation and the
Pollution
477

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