WASTE GENERATION IN

PHARMACEUTICAL MANUFACTURING
INDUSTRY
by
Vishal Duggal
Alliance Engineers
7812/5, Passi Road, PATIALA (Punjab).
Ph.: 98 140 059 33
email: visduggal@gmail.com; mailto@allianceers.com

for
CESE, 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 products
 Pharmaceutical active ingredients – resulting from
fermentation, biological and natural extraction, chemical
synthesis, and formulation products
 Biological (and micro-biological) products
 Multiple end-use products – components of formulations,
intermediates, final products
 Cosmetic 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 apparatus
 Orthopaedic, prosthetic, and surgical appliances and supplies
 Dental equipment and supplies
 Medical/dental laboratory services
 Diagnostic devices
 Food 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 steps
 Inoculum and seed preparation
 Fermentation (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 solvents

Acetone 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 Methyl isobutyl Petroleum naptha
chloride ketone (MIBK)
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 material
 Chemical wastes
 Equipment and floor cleaning
 Cleanup of spills
 Pharmaceutical Processes
(Biological and Natural Extraction)…
 Commonly used solvents

Acetone Acetonitrile Ammonia (aq.)

n-Amyl acetate Amyl alcohol n-Butyl alcohol
1,2-Dichloroethane Chloroform Diethylamine
N,N-Dimethylformaldehyde Methyl isobutyl ketone 1,4-Dioxane
(MIBK)
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 medium
 Reflux condensation equipment
 Vacuum
 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
A Typical Reactor (Chemical Synthesis) …
 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 water
 Equipment and floor cleaning
 Spills
 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 cleaning
 Spills 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 variability
 Campaigning
 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 process
 Water 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 material
 Low to moderate in BOD
 Low TSS
 Around neutral pH
 Fermentation
 ~2-10 m5/kg of final product
 Mycellium cake – wet cake has 40-70 g/l of BOD and 30-50 g/l
of TSS
 BOD – 2500-1000 mg/l
 pH – 4-8
 Vaccination, microbial suspension, antitoxin preparation
 Wastes contain very high BOD/COD and bad odours
 Antiseptic and anti-bacterial agents contribute to toxicity
 Wastewater Characterization …
 Chemical synthesis
 General process liquor
 High strength process liquor
 Acidic and alkaline effluent
 Emulsified effluent
 Toxic effluent
 Composition of Pharmaceutical Process
Wastes
Waste Description Process Origin Composition
Process liquors Chemical synthesis Contaminated solvents
Spent fermentation Fermentation processes Contaminated waters
broth
Spent natural product, Natural product, Plant residues, tissues
raw materials extraction processes
Spent aqueous solutions Solvent extraction Contaminated water
processes
Leftover raw material, Unloading of materials Bags/drums (fibre,
containers into process equipment plastic, metal), plastic
bottles
Scrubber water from Dust or hazardous Contaminated water
APCE vapour generation
process
 Composition of Pharmaceutical Process
Wastes …
Waste Description Process Origin Composition
Volatile organic Chemical storage tanks, Solvents
compounds drums
Off-spec or out-dated Manufacturing Miscellaneous
products operations chemicals
Spillages Manufacturing and Miscellaneous
laboratory operations chemicals and heavy
metals
Wastewater Equipment cleaning, Contaminated water,
extraction residues phenol based
Spent solvents Solvent extraction or Contaminated solvents
wash practices
Used production Manufacturing Filters, tubing,
materials operations diatomaceous earth
 Composition of Pharmaceutical Process
Wastes …
Waste Description Process Origin Composition
Used chemical reagents R&D activities Miscellaneous
chemicals, solvents,
acid/alkaline wastes,
radio-isotopes,
formaldehyde
Spent ethylene oxide Sterilization operations Ethylene oxide
Miscellaneous 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 Composition
Used packaging Packaging operations Plastic, wood,
material cardboard, foam
products
Infectious/medical R&D, manufacturing Vials, biomass, blood
wastes operations, off-spec products, human/animal
products specimens
Incinerator exhaust On-site incinerators Metals, oxides
Combustion products Boilers, thermic fluid Carbon compounds,
heater oxides of N & S, boiler
blow-down, cooling
tower sludges, and
sediments
 Waste Management
Conventional approach;
 Waste collection
 Treatment for compliance (and to make the waste
compatible for disposal)
 Dispose
Alternative thoughts;
 Cheapest available solution just avoiding prosecution
 Best available solution not entailing excessive cost

Spend resources or face penalty

 Waste Management
(Waste Minimization)
Source Reduction
 Material substitution
 Process modification
 Good operating practices
 Waste Management
(Waste Minimization) …
Waste Waste Minimization Option
Containers Return empties to suppliers
Thoroughly empty and triple rinse with minimal water
Use containers with recyclable liners
Segregate solid waste
Collect and reuse plastic from in-house molding
Air Control bulk storage air emissions
emissions Use dedicated dust collectors & rework dust back into product
Optimize fossil fuel combustion
Use dedicated vent condensers & return condensate to source,
where possible
Maintain N2 purge rates at minimum through vapour space of
agitated reactors
 Waste Management
(Waste Minimization) …
Waste Waste Minimization Option
Equipment Maximize number of campaigns to reduce cleaning frequency
cleaning Use final rinse as pre-rinse on next cleaning cycle
wastes
Use wiper blades & squeezes and rework remainders into
products
Use low volume, high efficiency cleaning (e.g., spray heads)
Spills and Use dedicated vacuum systems
area Use dry-cleaning methods
washdown
Use recycled water

Off-spec Rework off-spec material

products Use automated processing systems
 Waste Management
(Waste Minimization) …
Waste Waste Minimization Option
Solvents Substitute with aqueous systems where possible
Reduce quantity of solvent used
Regenerate/recover spent solvent
Production Validate cleaning and reuse
materials
 Waste Management
(Good Operating Practices)
Plant Management Waste Management Material handling
Management incentives Waste/environmental Material tracking &
audits inventory control
Employee training Waste stream Spill prevention
segregation
Closer supervision Waste handling and Material handling &
storage procedures storage procedures
Production scheduling Preventive maintenance
Additional
documentation