PHARMACEUTICAL INDUSTRY

Prepared by

A.Erenşah KayaHande KartalMerve MaçinZüleyha Atlay

OUTLINE

Description of Pharmaceutical Industry

- Hıstory of Pharmaceutical Industry in Turkey

- Acts and Standards

Description of Industry

The Pharmaceutical Industry provides medicines to be used as medications for humans and animals.

The Pharmaceutical Industry includes:

Manufacture Extraction Processing Purification Packaging of chemicals to be used as medications.

Description of Industry

The Main Pharmeceutical Groups

The main groups that are manufactured are:

Proprietary ethical products ( prescription-only medicines POM)

General ethical products Over-the counter (OTC) products

The Major Manufactured Groups

The products are available as :

tablets capsules liquids ointments aerosols

The Major Manufactured Groups

The groups include: Antibiotics such as

penicillin Other synthetic drugs Vitamins Synthetic hormons Glandular products Vaccines and sera Drugs of vegatable origin

History of Pharmaceutical Industry In Turkey

1928-1950: Production of Pharmaceutical preparations done at laboratories

1952: The start of fabrication period of the Turkish Pharmaceuticals industry

1984-1990: Investments of foreign capital companies increased. Foreign Capitals entered into Turkish Market

Today: There are 300 entities operating in Turkey. 43 manufacturing facilities, 14 of them are multinational firms.

History of Pharmaceutical Industry In Turkey

The most important international pharmaceutical companies are:

Bayer (Germany) GlaxoSmithKline (UK) Aventis (US) Roche(Switzerland) Sanofi (France) Novartis( Switzerland)

History of Pharmaceutical Industry In Turkey

Turkish Manufacturers:

EIS Eczacıbaşı Abdi İbrahim Fako İlsan İltaş Mustafa Nevzat İbrahim Ethem Bilim

The Principal Manufacturing Step

Steps are: Preparation of process intermediates Introduction of functional groups Coupling and esterification Seperation processes such as washing and

stripping Purifications of the final product

Additional Product Preparation

Steps are:

Granulation Drying Tablet pressing Printing Coating Filling and packaging

Industrial Pollution

According to manufacturing steps, air emissions, liquid effluents ( wastewater) and solid wastes may be generated.

To reduce the wastes, we should reuse and recycle. Remaning wastes should be treated according to characteristic.

ACTS & STANDARDS

The Production and marketing of medicines must be authorized by The Health Ministry.

Treated wastewater should be discharged; According to The Control of Water Pollution Management ( 04.09.1998)

ACTS & STANDARDS

The Control of Water Pollution Management

Discharge Standards For Pharmaceutical

TABLES FROM EPA

Processes In Pharmaceutical Industry

Goods Receiving Laboratory Preparation Formulation Finishing Packaging Warehouse & Distrubituon

Goods receiving

pharmaceuticals are stored, either in the form of raw materials or

packaging. It’s vital to optimally manage these materials,

protect them from end to end, and systematically document them.

Goods receiving

Laboratory

laboratory management means proven solutions for access control,

building automation, and risk management to ensure constant and secure environmental conditions in lab.

Laboratory

Research & Development

Including several fields;

chemical research, microbiological research, pharmacological research

Produces different waste types

Preparation

The production process, for example, depends on being able to process the correct

amounts of the right raw materials at the right time

Preparation

Chemical Synthesis

Most drugs production

Chemical synthesis process

manufacturing pharmaceuticals using

organic and inorganic chemical reactions

Typical manufacturing plant,

one or more batch reactor vessels series of reaction,

separation and purification steps desired end product

In drug manufacturing plant,

reaction vessels Equipments arranged into separate

Solvents to dissolve Gaseous Solid Viscous reactants

To bring all the reactants close molecular

also serve to transmit heat to or from the reacting molecules.

Some solvents also control the reaction temperature.

common practice in a batch-type synthesis

Natural Product Extraction

Many materials as pharmaceuticals derived from such natural sources; the roots, leaves of plants, animal glands, and parasitic fungi

numerous and diverse pharmaceutical applications, ranging from

Tranquilizers and allergy-relief medications Insulin and Morphine Blood fractionation plasma and its

derivatives.

Despite diversity, all extractive pharmaceuticals common

characteristic: Too complex to synthesize commercially either very large molecules to synthesize

Extraction expensive manufacturing process

requires collecting and processing large volumes of specialized plant animal matter to produce small quantities of products.

Fermentation

Most antibiotics ,steroids and vitamin B fermentation process,

two major steps: inoculum and seed preparation fermentation, followed by crude product

recovery and purification

Sterile inoculum preparation begins in the lab with carefully maintained population of a microbial

strain. A few cells this culture matured into a dense

suspension through a series of test tubes, agar slants, and shaker flasks.

For further propagation, the cells are then transferred to

Seed tanklike a full scale fermenter and is Designed for maximum cell growth Final seed tank volume occupies from 1 to 20% of the volume used in full

scale production.

Formulation

Formulation

Pharmaceutical formulation is the preparation of dosage forms such as

Tablets Capsules Liquids Parenterals Creams Ointments

Finishing

Finishing

The best way to reliably drug finishing efficiency, quality and transparency is through consistent, end-to-end automation solutions can seamlessly integrate components from a wide range of manufacturers.

Packaging

Warehouse & Distribution

Warehouse & Distribution

They’re efficient way stations on the road from manufacturer to consumer,

using the most precise and up-to-date climate control, automation, and building security.

Typical Waste Streams

The pharmaceutical industry is also highly diverse.

With this diversity of processes comes a similarly diverse set of waste streams.

spent fermentation broths, process liquors, solvents, equipment washwaters, spilled materials, off-spec products, used processing aids.

Potential Environmental Issues

Air emissions Wastewater Solid and hazardous wastes

Air emissions

Volatile organic compounds(VOCs) Acid gases Particulates Greenhouse gas emissions (Combustion

Source Emissions) Odors

emitted during manufacturing facilities

Volatile Organic Compounds

significant emissions of VOCs come from

1) Mostly in chemical synthesis and extraction phases

2) In primary pharmaceutical manufacturing ; reactor vents filtering systems in the separation process Solvent vapors from purification tanks and

dryers (including loading and unloading operations)

fugitive emissions from valves, tanks, pumps, and other equipment

prefermentation and fermentation solvents wastewater collection and treatment units.

3) In secondary pharmaceutical manufacturing;

mixing, compounding, granulation, and formulation

operations involving the use of solvents (e.g. granulation)

alcoholic solutions (e.g. tablet coating)

aerosol manufacturing processes.

How can we control the VOCs emissions?

1) Venting of emissions from sterilization chambers into control devices such as

carbon adsorption

OR

catalytic converters;

2) Condensation and distillation of solvents emitted from reactors or distillation units.

Possible installation of cryogenic condensersthat can reduce the gas stream temperaturebelow dew point to achieve higher VOC recovery efficiencies. Cryogenic condensers have higher removalefficiency (up to 99 percent) but they have higher energy requirements.

3) Installation of wet scrubbers (or gas absorbers), which may remove VOCs as well as other gaseous pollutants from a gas stream.

Also, addition of hypochlorite to the scrubber inorder to reduce emissions of nuisance odors; WHAT IS SCRUBBER? Water, caustic, and acidic scrubbers are widely used for

organic and inorganic gas emission reduction. Acid gas emissions are controlled through water and caustic scrubbing systems (often several scrubbersin series). Scrubbers create a wastewater stream requiring further treatment.

Particulate Matter

Particulates consisting of manufactured or in-process product can be emitted from

bulk (e.g. fermentation) secondary manufacturing. The most common sources of particulates include milling,

mixing,compounding,formulation, tableting, and packaging.

Recommended particulate matter management :

Collection of particulates through air filtration units, typicallybaghouse / fabric filters.

Depending on the volume of emissions and size of particulate matter, additional particulate emissions control methods should be considered,

such as Wet scrubbing and wet electrostatic precipitators, especiallyafter combustion / thermal oxidation treatments.

Combustion Source Emissions

Exhaust gas emissions produced by the

combustion of gas or diesel in turbines, boilers, compressors, pumps and other engines for power and heat generation, are a significant source of air emissions from pharmaceuticals manufacturing facilities.

Odors

The main source of odor emissions is typically associated with fermentation activities.

Recommended odor management strategies include: Post-combustion of venting gases; Use of exhaust stack heights that are consistent withpractices as described in the regulations. Use of wet scrubbers to remove odors with a high

affinity to water;

Solid and Hazardous Wastes

The principal solid wastes of concern include

process and effluent treatment sludges,

raw materials packaging waste

container residues

used air filter media

Offspec and expired products

laboratory wastes

Approximately 200 kg wastes per ton of product of waste are generated.

Hazardous and non-hazardous industrial wastes should be stored, transported, and managed as described in the regulations.

Treatment of solid wastes

Contaminated solid wastes are generally incinerated,and the flue gases are scrubbed.

Combustion devices should be operated at temperaturesabove 1,000° C, with a residence time of at least 1 second,to achieve acceptable destruction efficiency(over 99.99%) of toxics.

Water Supply

Water is generally needed both for the process (e.g., dilution) and for other uses including cooling water, deionized water, equipment and piping cleaning water, etc.

Water for injection is used for manufacture of injectable products and in any process where sterile conditions are needed.

Water purity is obtained by deionized water distillation or by double reverse osmosis.

The storage tank is blanketed with pure nitrogen or air.

Piping and storage are maintained at a temperature higher than 80°C, and water is continuously recycled to avoid contamination.

WastewaterIndustrial Process Wastewater

Wastewater streams in pharmaceuticals manufacturing come from;

chemical reactions streams product wash water spent acid and caustic streams condensed steam from sterilization and strippers air pollution control scrubber release equipment and facility wash water clean-in-place wastewater.

The main pollutants of concern in these wastewater streams from primary manufacturing (e.g.fermentation, chemical synthesis, crystallization, purification, and biological / natural extraction) parameters are

biochemical oxygen demand (BOD) chemical oxygen demand(COD) total suspended solids (TSS) Ammonia Toxicity Biodegradability pH.

Typical Wastewater Characteristic

Typical amounts released with the wastewater are:

25 kg/t (BOD) 50 kg/t (COD) 3 kg/t (TSS) 0.8 kg/t phenol

Wastewaters produced from pharmaceutical industry may contain :

mercury, in a range of 0.1–4 (mg/l), cadmium (10–600 mg/l), isomers of hexachlorocyclohexane, 1,2-dichloroethane,

Typical wastewater treatment steps

grease traps, skimmers, dissolved air floatation or oil water separators for separation of oils and floatable solids;

filtration for separation of filterable solids; flow and load equalization; sedimentation for suspended solids reduction using clarifiers; biological treatment, typically aerobic

treatment for reduction of soluble organic matter (BOD)

biological nutrient removal for reduction in nitrogen and phosphorus

biological nutrient removal for reduction in nitrogen and phosphorus

using clarifiers; biological treatment, typically aerobic treatment for reduction of soluble organic matter (BOD)

biological nutrient removal for reduction in nitrogen and phosphorus

chlorination of effluent when disinfection is required

dewatering and disposal of residuals in designated hazardous waste landfills.

Additional engineering controls may be required for

advanced metals removal using membrane filtration or

other physical/chemical treatment technologies removal of recalcitrant organics and active ingredients

using activated carbon or advanced chemical oxidation residual color removal using adsorption or chemical

oxidation reduction in effluent toxicity using appropriate technology

(such as reverse osmosis, ion exchange, activated carbon, etc.)

reduction in TDS in the effluent using reverse osmosis or evaporation

Pollution Prevention and Control

Recommended pollution prevention and control measures include:

Waste reduction by material substitution (e.g. use of water based solvents),

Process modifications (e.g. continuous rather than batch operations to reduce spillage and other material losses),

Spent solvent recycling and reuse, through distillation,evaporation, decantation, centrifugation and filtration,

Potentially pathogenic waste from biotechnology manufacturing should be inactivated through sterilization or chemical treatment before final disposal.

Use automated filling to minimize spillage, Use “closed” feed systems into batch

reactors, Use equipment washdown waters and other

process waters (such as leakages from pump seals) as makeup solutions for subsequent batches,

Recirculate cooling water, Use dedicated dust collectors to recycle

recovered materials, Vent equipment through a vapor recovery

system, Use loss-free vacuum pumps,

Return toxic materials packaging to the supplier for reuse, or incinerate it in an environmentally acceptable manner,

Minimize storage time of off-specification products through regular reprocessing,

Find productive uses for off-specification products to avoid disposal problems,

Use high-pressure hoses for equipment cleaning to reduce wastewater,

Provide stormwater drainage and avoid contamination of stormwater from process areas,

Label and store toxic and hazardous materials in secure, bunded areas. Spillage should be collected and reused.

References

http://www.cygm.gov.tr/mevzuat/yonetmelik/DKYD5.doc http://www.epa.gov/waterscience/guide/pharm/techdev/

ch5.pdf http://209.85.129.132/search?

q=cache:oY_mrWym7BUJ:en.wikipedia.org/wiki/Validation_(drug_manufacture)+drug+production+process&cd=4&hl=tr&ct=clnk&gl=tr

http://www.automation.siemens.com/pharma/html_76/process/pro_manu_07.htm

http://www.ifc.org/ifcext/enviro.nsf/AttachmentsByTitle/gui_pharmmfg_WB/$FILE/pharma_PPAH.pdf