Waste generation in pharmaceutical manufacturing industry

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


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


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) …

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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


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


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 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 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

Waste generation in pharmaceutical manufacturing industry

Environment

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