Date post: | 16-Apr-2017 |
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WASTE GENERATION INPHARMACEUTICAL MANUFACTURING
INDUSTRYby
Vishal DuggalAlliance Engineers
7812/5, Passi Road, PATIALA (Punjab).Ph.: 98 140 059 33
email: [email protected]; [email protected]
forCESE, IITB
Powai, Mumbai (MS)
PHARMACEUTICAL INDUSTRY Medications/therapeutic products for humans and
animals Manufacture, extraction, processing, purification
and packaging of chemical materials (may include following);Medicinal chemicals and botanical productsPharmaceutical active ingredients – resulting from fermentation,
biological and natural extraction, chemical synthesis, and formulation products
Biological (and micro-biological) productsMultiple end-use products – components of formulations,
intermediates, final productsCosmetic preparations – containing pharmaceutically active
ingredients (typically intended for treatment of some skin condition)
PHARMACEUTICAL INDUSTRY Products or activities specifically excluded from
pharmaceutical manufacturing category are;Surgical and medical instruments and apparatusOrthopaedic, prosthetic, and surgical appliances and suppliesDental equipment and suppliesMedical/dental laboratory servicesDiagnostic devicesFood and beverage products fortified with vitamins or other
pharmaceutical active ingredients
Pharmaceutical Processes Fermentation Biological and natural extraction Chemical (organic) synthesis Physical methods
Pharmaceutical Processes (Fermentation)
Manufacturing of most antibiotics, steroids, enzymes, hormones, vitamins, etc.
Three basic stepsInoculum and seed preparationFermentation (including mycelia filteration) Product recovery
Fermentation is a large scale batch process Usually begins with a water wash and steam
sterilisation of fermenter vessel Usually an exothermic process and needs
temperature control Product recovery – solvent extraction, direct
precipitation, ion exchange, adsorption Sterilisation – steam is major medium, chemical also
Pharmaceutical Processes(Fermentation) ..
Fermentation waste off-gases – CO2 and odiferous substances (e.g., oxides of N and S)
Scrubbing water from APCE – absorbed chemicals, soluble organic compounds, insoluble organic oils and waxes
Solvents used – recovered and reused Small fraction of solvents left in aquous phase Direct precipitation – Cu and Zn are commonly used
priority pollutant metals Occassional infestation of fermentation batch by
“phage” – large amount of wastewaters in very short time (very high nutrient concentration)
Spent fermentation broth – sugars, starches, proteins, N, phosphates
Sterilizing/cleaning rejects
Pharmaceutical Processes (Fermentation) …
Commonly used solventsAcetone Acetonitrile Ammonia (aq.)
n-Amyl acetate Amyl alcohol n-butyl acetate
n-Butyl alcohol Chloroform N,N-Dimethylformaldehyde
Ethanol Ethyl acetate Formaldehyde
n-Heptane n-Hexane Isopropanol
Isopropyl acetate Methanol Methyl cellosolve
Methylene chloride
Methyl isobutyl ketone (MIBK)
Petroleum naptha
Phenol Toluene Triethylamine
Pharmaceutical Processes(Biological and Natural
Extraction) Products derived from natural sources – roots/leaves
of plants, animal glands, parasitic fungi, etc. Also include blood fractionation – production of
plasma and its derivatives These are too complex to synthesize commerically Usually requires collection and processing of large
quantities of specialised plant or animal matter to produce small quantities of products
Active ingredients extracted are generally present in raw materials at very low levels
Series of steps – volume of material in process reduces significantly after almost every step
Mostly, a unique assembly-line, small-scale batch processing
Pharmaceutical Processes(Biological and Natural
Extraction)… Residual wastes mostly equal to weight of raw
materials Solid wastes are greatest source of pollutant load Use of solvents in processing steps (sometimes used
to decontaminate material) Detergents and disinfectants used in equipment
cleaning – wastewater – use of phenols is prevalent Metals (Pb, Zn, etc.) used as precipitating agents Some extraction processes use ammonia where pH
control is necessary Principal sources of waste include;
Spent raw materialChemical wastesEquipment and floor cleaningCleanup of spills
Pharmaceutical Processes(Biological and Natural
Extraction)… Commonly used solventsAcetone Acetonitrile Ammonia (aq.)
n-Amyl acetate Amyl alcohol n-Butyl alcohol
1,2-Dichloroethane Chloroform Diethylamine
N,N-Dimethylformaldehyde Methyl isobutyl ketone (MIBK)
1,4-Dioxane
Dimethyl sulfoxiide Diethyl ether Ethylene glycol
Ethanol Ethyl acetate Formaldehyde
n-Heptane n-Hexane Isopropanol
Isopropyl acetate Methanol Pyridine
Methylene chloride N-propanol Petroleum naptha
Phenol Toluene Tetrahydrofuran
Pharmaceutical Processes(Chemical Synthesis)
Use organic and inorganic chemical reactions Most of the active ingredients marketed/sold as drugs Conventional batch reaction vessel Reaction vessels may be fitted with different
attachments – depending on process needs Common modifications for additional uses;
Heating/refrigeration mediumReflux condensation equipmentVacuum Perform solvent extraction/crystallization operations
Common attachments – filter, centrifuge, solvent recovery header, etc.
Usually product is manufactured in a “campaign” Same equipment can be utilized for manufacturing
different products
Pharmaceutical Processes(Chemical Synthesis) …
A Ty
pica
l Rea
ctor
Pharmaceutical Processes(Chemical Synthesis) …
Most of the industries have solvent recovery units SRU operation result in aqueous wastes fully or
partially saturated with residual solvent Wastewater is generally produced with each chemical
modification – requiring filling and emptying of reactors
Wastewaters contain – unreacted raw materials, some solvents, along with number of compounds
The pollutants vary w.r.t. toxicity and biodegradability Principal sources of waste include;
Process wastes – spent solvents, filtrates, concentrates, etc.Pump seal waterEquipment and floor cleaningSpills APCE blowdown
Pharmaceutical Processes(Chemical Synthesis)…
Commonly used solvents (additional)Aniline Benzene 2-Butanone (MEK)
n-Butyl acetate Chlorobenzene Chloromethane
Cyclohexane 1,2-Dichlorobenzene 1,2-Dichloroethane
Diethylamine Diethyl ether N,N-Dimethyl acetamide
Dimethylamine N,N-Dimethylaniline Formamide
Furfural Isobutyraldehyde Methylamine
Methyl formate MIBK 2-Methylpyridine
Triethylamine Trichlorofluoromethane Polyethylene glycol 600
Xylenes
Pharmaceutical Processes(Mixing, Compounding &
Formulating) Converting pharmaceutical active ingredients (produced in
bulk) to dosage (usable) form for consumer use – tablets, capsules, liquids, and ointments
Tablets – need blending with filler and binder (lubricants also sometimes). Some tablets use solvent based coatings
Capsules use hard gelatine shell Liquid preparations are formulated for injection or oral use Need sterilization sometimes Principal sources of waste include;
Equipment and floor cleaningSpills and breakage
Broken tablets – reused in granulation Improper capsules – remelted and reused or sold for glue
manufacture
Pharmaceutical Manufacturing Process Variability
Waste generation (quantitatively and qualitatively) can be highly variable
Factors contributing to variabilityCampaigning Batch processing Waste commingling
Utilities in Pharmaceutical Manufacturing
Water treatment – RO, DM, EDI, etc. Compressed air Process heating – steam generation/distribution,
thermic fluid heater Process cooling – cooling water, chiller, brine-water Work environment conditioning Cleaning – including CIP Air pollution control equipment Vacuum system Solvent recovery Effluent treatment Thermal destruction – incineration, MEE, drier
Water Use and Wastewater generation in Pharmaceutical
Manufacturing As product – becomes a part of final product Water of reaction – water formed during chemical
reaction Process solvent – used to transport or support chemicals
involved in reaction processWater is usually removed – centrifugation, decanting, filtration, drying,
stripping, etc. Process stream wash Product wash Spent acid/caustic Condensed steam APCE blow-down Process cleaning, washing and housekeeping Pump seal water Non-contact cooling blow-down
Wastewater Characterization Mixing, compounding and formulation
May contain carbohydrates and inert formulating materialLow to moderate in BODLow TSSAround neutral pH
Fermentation~2-10 m5/kg of final productMycellium cake – wet cake has 40-70 g/l of BOD and 30-50 g/l
of TSSBOD – 2500-1000 mg/lpH – 4-8
Vaccination, microbial suspension, antitoxin preparationWastes contain very high BOD/COD and bad odoursAntiseptic and anti-bacterial agents contribute to toxicity
Wastewater Characterization … Chemical synthesis
General process liquorHigh strength process liquorAcidic and alkaline effluentEmulsified effluentToxic effluent
Composition of Pharmaceutical Process Wastes
Waste Description Process Origin CompositionProcess liquors Chemical synthesis Contaminated solventsSpent fermentation broth
Fermentation processes Contaminated waters
Spent natural product, raw materials
Natural product, extraction processes
Plant residues, tissues
Spent aqueous solutions Solvent extraction processes
Contaminated water
Leftover raw material, containers
Unloading of materials into process equipment
Bags/drums (fibre, plastic, metal), plastic bottles
Scrubber water from APCE
Dust or hazardous vapour generation process
Contaminated water
Composition of Pharmaceutical Process Wastes …
Waste Description Process Origin CompositionVolatile organic compounds
Chemical storage tanks, drums
Solvents
Off-spec or out-dated products
Manufacturing operations
Miscellaneous chemicals
Spillages Manufacturing and laboratory operations
Miscellaneous chemicals and heavy metals
Wastewater Equipment cleaning, extraction residues
Contaminated water, phenol based
Spent solvents Solvent extraction or wash practices
Contaminated solvents
Used production materials
Manufacturing operations
Filters, tubing, diatomaceous earth
Composition of Pharmaceutical Process Wastes …
Waste Description Process Origin CompositionUsed chemical reagents R&D activities Miscellaneous
chemicals, solvents, acid/alkaline wastes, radio-isotopes, formaldehyde
Spent ethylene oxide Sterilization operations Ethylene oxideMiscellaneous wastes Maintenance operations Waste lube oils,
vacuum pump oils, cleaning solvents, paint stripping wastes, leftover paints and accessories, spent flourescent lamps, trash
Composition of Pharmaceutical Process Wastes …
Waste Description Process Origin CompositionUsed packaging material
Packaging operations Plastic, wood, cardboard, foam products
Infectious/medical wastes
R&D, manufacturing operations, off-spec products
Vials, biomass, blood products, human/animal specimens
Incinerator exhaust On-site incinerators Metals, oxidesCombustion products Boilers, thermic fluid
heaterCarbon compounds, oxides of N & S, boiler blow-down, cooling tower sludges, and sediments
Conventional approach; Waste collection Treatment for compliance (and to make the waste
compatible for disposal) DisposeAlternative thoughts; Cheapest available solution just avoiding prosecution Best available solution not entailing excessive cost
Waste Management
Spend resources or face penalty
Source Reduction Material substitution Process modification Good operating practices
Waste Management(Waste Minimization)
Waste Management(Waste Minimization) …
Waste Waste Minimization OptionContainers Return empties to suppliers
Thoroughly empty and triple rinse with minimal waterUse containers with recyclable linersSegregate solid wasteCollect and reuse plastic from in-house molding
Air emissions
Control bulk storage air emissionsUse dedicated dust collectors & rework dust back into productOptimize fossil fuel combustionUse dedicated vent condensers & return condensate to source, where possibleMaintain N2 purge rates at minimum through vapour space of agitated reactors
Waste Management(Waste Minimization) …
Waste Waste Minimization OptionEquipment cleaning wastes
Maximize number of campaigns to reduce cleaning frequencyUse final rinse as pre-rinse on next cleaning cycleUse wiper blades & squeezes and rework remainders into productsUse low volume, high efficiency cleaning (e.g., spray heads)
Spills and area washdown
Use dedicated vacuum systemsUse dry-cleaning methodsUse recycled water
Off-spec products
Rework off-spec materialUse automated processing systems
Waste Management(Waste Minimization) …
Waste Waste Minimization OptionSolvents Substitute with aqueous systems where possible
Reduce quantity of solvent usedRegenerate/recover spent solvent
Production materials
Validate cleaning and reuse
Waste Management(Good Operating Practices)
Plant Management Waste Management Material handlingManagement incentives Waste/environmental
auditsMaterial tracking & inventory control
Employee training Waste stream segregation
Spill prevention
Closer supervision Waste handling and storage procedures
Material handling & storage procedures
Production scheduling Preventive maintenanceAdditional documentation