PHARMACEUTICAL PRODUCTION TECHNIQUES · pharmaceutical or a drug is classified on the basis of their origin. 1) Drug from natural origin: Herbal or plant or mineral origin, some drug

PHARMACEUTICAL PRODUCTIONTECHNIQUES

OYA IRMAK CEBECİ

ASSIST. PROF. DR.

2019-2020

NOTE-1

HISTORY OF PHARMACEUTICS

PRESENT

OSMOTIC RELEASE ORAL TABLET

HALVING OF TABLETS

3D PRINTING TECHNOLOGY IN THE PHARMACEUTICS

Entry of Biotechnology - 1978

Introduction to the pharmaceutical terminology

Introduction to the pharmaceutical technology

WHAT IS PHARMACEUTICAL?

Pharmaceutical is a drug or finished form of a drug used to treat, cure,diagnose or prevent of a disease or to alter the physiological body functionsfor well being.

A pharmaceutical drug (also referred to as medicine, medication, or simply asdrug) is a drug used to diagnose, cure, treat, or prevent disease.

Pharmaceutical products – more commonly known as medicines or drugs –are a fundamental component of both modern and traditional medicine.

It is essential that such products are safe, effective, and of good quality, andare prescribed and used rationally.

DRUGS ARE CLASSIFIED IN VARIOUS WAYS

One of the key divisions is by level of control, which distinguishes prescriptiondrugs (those that a pharmacist dispenses only on the order of a physician, physicianassistant, or qualified nurse) from over-the-counter drugs (those that consumerscan order for themselves).

Another key distinction is between traditional small-molecule drugs, usually derivedfrom chemical synthesis, and biopharmaceuticals, which include recombinantproteins, vaccines, blood products used therapeutically (such as IVIG), gene therapy,monoclonal antibodies and cell therapy (for instance, stem-cell therapies).

Other ways to classify medicines are by mode of action, route of administration,biological system affected, or therapeutic effects.

In Europe, the term is "medicinal product", and it is defined by EU lawas: "Any substance or combination of substances presented as havingproperties for treating or preventing disease in human beings; or

Any substance or combination of substances which may be used in oradministered to human beings either with a view to restoring, correcting ormodifying physiological functions by exerting a pharmacological,immunological or metabolic action, or to making a medical diagnosis.

In the US, a "drug" is:

I. A substance recognized by an official pharmacopoeia or formulary.

II. A substance intended for use in the diagnosis, cure, mitigation, treatment, orprevention of disease.

III. A substance (other than food) intended to affect the structure or any function of thebody.

IV. A substance intended for use as a component of a medicine but not a device or acomponent, part or accessory of a device.

V. Biological products are included within this definition and are generally covered bythe same laws and regulations, but differences exist regarding their manufacturingprocesses (chemical process versus biological process

CLASSIFICATION-Ipharmaceutical or a drug is classified on the basis of their origin.

1) Drug from natural origin: Herbal or plant or mineral origin, some drug substancesare of marine origin.

2) Drug from chemical as well as natural origin: Derived from partial herbal andpartial chemical synthesis Chemical, example steroidal drugs

3) Drug derived from chemical synthesis.

4) Drug derived from animal origin: For example, hormones, and enzymes.

5) Drug derived from microbial origin: Antibiotics

6) Drug derived by biotechnology genetic-engineering, hybridoma technique forexample

7) Drug derived from radioactive substances.

CLASSIFICATION-II on the basis of pharmacological properties

1) Antipyretics: reducing fever (pyrexia/pyresis)

2) Analgesics: reducing pain (painkillers)

3) Antimalarial drugs: treating malaria

4) Antibiotics: inhibiting germ growth

5) Antiseptics: prevention of germ growth near burns, cuts and wounds

6) Mood stabilizers: lithium and valpromide

7) Hormone replacements: Premarin

8) Oral contraceptives: Enovid, "biphasic" pill, and "triphasic" pill

9) Stimulants: methylphenidate, amphetamine

10) Tranquilizers: meprobamate, chlorpromazine, reserpine, chlordiazepoxide, diazepam, and alprazolam

11) Statins: lovastatin, pravastatin, and simvastatin

Pharmaceuticals may also be described as "specialty", independent of otherclassifications, which is an ill defined class of drugs that might be difficult toadminister, require special handling during administration, require patientmonitoring during and immediately after administration, have particular regulatoryrequirements restricting their use, and are generally expensive relative to otherdrugs.

PHARMACEUTICAL INDUSTRY

The pharmaceutical industry discovers, develops, produces, and marketsdrugs or pharmaceutical drugs for use as medications.

They are subject to a variety of laws and regulations that govern the patenting,testing, safety, efficacy and marketing of drugs.


These terms are used frequently in the pharmaceutical industry:

Biologics are bacterial and viral vaccines, antigens, antitoxins and analogous products,serums, plasmas and other blood derivatives for therapeutically protecting or treatinghumans and animals.

Bulks are active drug substances used to manufacture dosage- form products, processmedicated animal feeds or compound prescription medications.

Diagnostic agents assist the diagnosis of diseases and disorders in humans andanimals. Diagnostic agents may be inorganic chemicals for examining thegastrointestinal tract, organic chemicals for visualizing the circulatory system and liverand radioactive compounds for measuring the function of organ system


Drugs are substances with active pharmacological properties in humans and animals.Drugs are compounded with other materials, such as pharmaceutical necessities, toproduce a medicinal product.

Ethical pharmaceuticals are biological and chemicals agents for preventing,diagnosing or treating disease and disorders in humans or animals. These products aredispensed by prescription or approval of a medical, pharmacy or veterinaryprofessional.

Excipients are inert ingredients which are combined with drug substances to create adosage form product. Excipients may affect the rate of absorption, dissolution,metabolism and distribution in humans or animals.


Over-the-counter pharmaceuticals are drug products sold in a retail store orpharmacy which do not require a prescription or the approval of a medical, pharmacyor veterinary professional.

Pharmacy is the art and science of preparing and dispensing drugs for preventing,diagnosing or treating diseases or disorders in humans and animals.

Pharmacokinetics is the study of metabolic processes relating to the absorption,distribution, biotransformation, and elimination of a drug in humans or animals.

Pharmacodynamics is the study of drug action relating to its chemical structure, siteof action, and the biochemical and physiological consequences in humans andanimals.


The pharmaceutical industry is an important component of health care systemsthroughout the world; it is comprised of many public and private organizations thatdiscover, develop, manufacture and market medicines for human and animal health.

The pharmaceutical industry is based primarily upon the scientific research anddevelopment (R&D) of medicines that prevent or treat diseases and disorders. Drugsubstances exhibit a wide range of pharmacological activity and toxicological properties.

Modern scientific and technological advances are accelerating the discovery anddevelopment of innovative pharmaceuticals with improved therapeutic activity andreduced side effects.

WHAT IS PHARMACEUTICAL MANUFACTURING???

It is the process of industrial scale synthesis of pharmaceutical drug by pharmaceutical companies.

The process can be broken down into a series of unit operations such as milling, drying, compression and coating

WHAT IS DRUG?

(AGAIN)!!!!

Simply;

A Chemical Substance that Interacts with a Living System and Produces a Biological Response

A drug product consists of therapeutics (API) and excipients combined in a

delivery system.

A drug product’s success lies in its ability to deliver the drug at a certain rate

in a certain environment in the body.

The success of a drug product involves three main aspects:

1)Discovery of the molecule that has the right therapeutic effect.

2)Delivery of the API.

3)Manufacturing the drug in a consistent and reliable way.

Delivery in a most efficient manner.

In order to avoid drug degradation and target efficiently the agent, it is required that the API’s delivery vehicle is properly designed. For example drugs can be easily degraded in the stomach due to low pH (about 1).

REGULATIONS

Whether it's a new technology or a conventional technology. The role of regularity authorities is to ensure that the products are safe.

FDA: «Our role is not really to make a judgment about whether they should be placed in the marketplace or not. . . . We are here as the gatekeeper to close the gate if a product is not going to be safe for consumers. . . . «

GMP regulations address issues including record keeping, personnel

qualifications, sanitation, cleanliness, equipment verification, process

validation, and complaint handling.

NEW DRUGDISCOVERY

For EACH DRUG approved, an average of 7500 compounds will have been made

Of this 7500, an average of 21 will be tested for sub-acute toxicology, 6.5 will be

tested in humans and 2.5 will reach Phase 3 – 1 then gets to market………

Entire process takes on average 12 years $138M (1975); $800M (2000); $1.6Bn

Development costs do NOT include pre-launch marketing which can DOUBLE

costs

PRODUCT/PROCESS DEVELOPMENT PARADIGM

WHO DISCOVERS DRUGS? DOCTORS?

Identify biological target - biology

Prioritise/ validate target – pharmacology and chemistry

Identify and optimise lead molecules – chemistry/pharmacology

Preclinical studies – chemistry/pharmacology/ toxicology

Formulation - pharmaceutical sciences

Clinical evaluation – medicine

Manufacture - chemical engineering

Drugs are chemical entities. One needs pharmacologists (biologists) to elucidate the metabolic pathways associated with a disease- ie find the way to attack the disease. This might be a receptor, an enzyme, or an aspect of metabolism that is unique to say, a bacterium rather than a mammal. Designing, making and understanding the way a drug works is a multidisciplinary exercise and involves both chemistry and pharmacology.

Many other science based disciplines involved as well as all of the other business skills.

Increasing information handling and mining is critical Human genome project will generate many new biological targets and methods for both making and screening many more compounds (potential NCEs) are on stream. This means more and more information must be dealt with, analysed and put to use.


Many different biological and chemical agents are discovered, developed and usedin the pharmaceutical industry.

Some manufacturing processes in the pharmaceutical, biochemical and syntheticorganic chemical industries are similar; however, the greater diversity, smallerscale and specific applications in the pharmaceutical industry are unique.

Since the primary purpose is to produce medicinal substances with pharmacologicalactivity, many agents in pharmaceutical R&D and manufacturing are hazardous toworkers. Proper control measures must be implemented to protect workers fromindustrial chemicals and drug substances during many R&D, manufacturing andquality control operations.

PHARMACEUTICAL ENGINEERING

PHARMACEUTICAL ENGINEERING

Improvement in organic synthesis allow us to make larger and larger molecules. Trends in today's pharmaceutical industry are towards producing bigger and bigger molecules.

Today larger molecules are discovered at an increasing rate due to the development of combinatorial chemistry, and organic synthesis is getting better.

Nevertheless, large molecules have less solubility.

LIST OF THE PRINCIPAL PHARMACEUTICAL AGENTS

Central nervous system

• Analgesics; Acetaminophen , Salicylates

• Anaesthetics; General and local

• Anticonvulsants; Barbituates, Benzodiazepine

• Migraine preparations; Beta adrenergic blocking agents,Serotonin receptor antagonists

• Narcotics; Opates

• Psychotherapeutics; Antianxiety agents, Antidepressants

• Sedatives and hypnotics; Barbituates, Benzodiazepine


2) Renal and cardiovascular system

a) Antidiabetics; Biguanides, Glycosidase inhibitors, Insulins,

b) Cardioprotective agents; Adrenergic blockers, Stimulants, Angiotensin inhibitors, Antiarrhythmics, Calcium channelblockers, Diuretics, Vasodilators, Vasodepressors

3) Gastrointestinal system

a) Gastrointestinal agents; Antacids, Antiflatulents, Antidiarrhoeals, Antiemetics, Antispasmodics, Laxatives, Prostaglandins


4) Anti-infectives and target organs

a) Systemic anti-infectives; AIDS therapies, Amebicides, Anthelmintics, Antibiotics, Antifungals, Antimalarials, Sulphonamides, Cephalosporins, penicillins, tetracyclines, etc.

b) Respiratory agents;

c) Skin and mucous membrane agents; Acne preparations, Allergans, Anti-infectives, Burn preparations

d) Urinary tract agents; Anti-inflectives, Antispasmodics

e) Vaginal preparations; Antifungals


5) Immune system

a) Analgesics; Non-steroidal anti-inflammatory agents·(NSAIDs)

b) Biological response modifiers; Alpha proteinase inhibitors, Antitoxins, Immune serums, Toxoids

c) Antifibrosis therapy

d) Immunodilators and immuno-suppressives

e) Multiple sclerosis management


6) Chemotherapy; Antineoplastics

7) Blood and blood-formingorgans; Blood modifiers

8) Endocrine system; Diagnostics, Hormones, Prostaglandins

Pharmaceutical manufacturing operations

may be categorized as basic production of bulk

drug substances and pharmaceutical

manufacturing of dosage form products

PROCESS TYPES

Basic production of bulk drug substances may employ three major types of processes: fermentation,organic chemical synthesis, and biological and natural extraction.

These manufacturing operations may be discrete batch, continuous or a combination of theseprocesses.

Antibiotics, steroids and vitamins are produced by fermentation, whereas many new drugsubstances are produced by organic synthesis.

Historically, most drug substances were derived from natural sources such as plants, animals, fungiand other organisms. Natural medicines are pharmacologically diverse and difficult to producecommercially due to their complex chemistry and limited potency.

1. FERMENTATION

Fermentation is a biochemical process employing selected micro-organisms and microbiological technologies to produce a chemical product.

Batch fermentation processes involve three basic steps: inoculum and seed preparation, fermentation, and product recovery or isolation.

Inoculum preparation begins with a spore sample from a microbial strain. The strain is selectively cultured, purified and grown using a battery of microbiological techniques to produce the desired product. The spores of the microbial strain are activated with water and nutrients in warm conditions. Cells from the culture are grown through a series of agar plates, test tubes and flasks under controlled environmental conditions to create a dense suspension.

The cells are transferred to a seed tank for further growth. The seed tank is a smallfermentation vessel designed to optimize the growth of the inoculum. The cells from theseed tank are charged to a steam sterilized production fermenter.

Sterilized nutrients and purified water are added to the vessel to begin the fermentation.During aerobic fermentation, the contents of the fermenter are heated, agitated andaerated by a perforated pipe, maintaining an optimum air flow rate and temperature.

After the biochemical reactions are complete, the fermentation broth is filtered to removethe micro-organisms, or mycelia. The drug product, which may be present in the filtrate orwithin the mycelia, is recovered by various steps, such as solvent extraction, precipitation,ion exchange and absorption.

Solvents used for extracting the product generally can be recovered; however, smallportions remain in the process wastewater, depending upon their solubility and the designof the process equipment.

Precipitation is a method to separate the drug product from the aqueous broth. The drugproduct is filtered from the broth and extracted from the solid residues. Copper and zinc arecommon precipitating agents in this process. Ion exchange or adsorption removes theproduct from the broth by chemical reaction with solid materials, such as resins or activatedcarbon. The drug product is recovered from the solid phase by a solvent which may berecovered by evaporation.

2. CHEMICALSYNTHESIS

Chemical synthesis processes use organic and inorganic chemicals in batch operations to produce drug substances with unique physical and pharmacological properties.

Typically, a series of chemical reactions are performed in multi-purpose reactors and the products are isolated by extraction, crystallization and filtration.

The finished products are usually dried, milled and blended.

Organic synthesis plants, process equipment and utilities are comparable in the pharmaceutical and fine chemical industries.

Pharmaceutical chemistry is complex with multi-step processing, where the product fromone step becomes a starting material for the next step, until the finished drug product issynthesized.

Bulk chemicals which are intermediates of the finished product may be transferred betweenorganic synthesis plants for various technical, financial and legal considerations. Mostintermediates and products are produced in a series of batch reactions on a campaign basis.

Manufacturing processes operate for discrete periods of time, before materials, equipmentand utilities are changed to prepare for a new process.

Many organic synthesis plants in the pharmaceutical industry are designed to maximize theiroperating flexibility, due to the diversity and complexity of modern medicinal chemistry. Thisis achieved by constructing facilities and installing process equipment that can be modifiedfor new manufacturing processes, in addition to their utility requirements.

Multi-purpose reactors are the primary processing equipment in chemical synthesisoperations. They are reinforced pressure vessels with stainless, glass or metal alloy linings.The nature of chemical reactions and physical properties of materials (e.g., reactive,corrosive, flammable) determine the design, features and construction of reactors. Multi-purpose reactors have external shells and internal coils which are filled with cooling water,steam or chemicals with special heat-transfer properties. The reactor shell is heated orcooled, based upon the requirements of the chemical reactions. Multi-purpose reactors haveagitators, baffles and many inlets and outlets connecting them to other process vessels,equipment and bulk chemical supplies. Temperature-, pressure- and weight-sensinginstruments are installed to measure and control the chemical process in the reactor.Reactors may be operated at high pressures or low vacuums, depending upon theirengineering design and features and the requirements of the process chemistry.

3. BIOLOGICAL AND NATURAL EXTRACTION

Large volumes of natural materials, such asplant and animal matter, may be processed toextract substances which arepharmacologically active. In each step of theprocess, the volumes of materials are reducedby a series of batch processes, until the finaldrug product is obtained. Typically, processesare performed in campaigns lasting a fewweeks, until the desired quantity of finishedproduct is obtained. Solvents are used toremove insoluble fats and oils, therebyextracting the finished drug substance. The pH(acidity) of the extraction solution and wasteproducts can be adjusted by neutralizing themwith strong acids and bases. Metal compoundsfrequently serve as precipitating agents, andphenol compounds as disinfectants.

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PHARMACEUTICAL PRODUCTION TECHNIQUES · pharmaceutical or a drug is classified on the basis of their origin. 1) Drug from natural origin: Herbal or plant or mineral origin, some drug