Introduction to Pharmaceutical Manufacturing and Pharmacology

Posted on May 12, 2024 in Biology

CGMP in Pharmaceutical Industries

21 CFR 210 & 211 are applicable for pharmaceutical manufacturing.

Subparts of 21 CFR

① Sub Part A – General Provisions: For prescribing drug and OTC (over-the-counter) drugs.

2) Sub Part B – Organization & Personnel: Qualification and personnel responsibilities.

3) Sub Part C – Buildings and Facilities: Design & construction of the buildings, lightning.

4) Sub Part D – Equipment: Design and construction of equipment, cleaning & maintenance.

⑤ Sub Part E – Control of Components and Drug Products Containers and Closures: Receipt & storage of components, component testing, use and rejection.

⑥ Sub Part F – Production and Process Control: Written procedures.

7) Sub Part G – Packaging & Labeling Control: Examination, labeling, inspection.

8) Sub Part H – Holding and Distribution: Warehousing & distribution procedure.

⑨ Sub Part I – Laboratory Control: Test and release for distribution, stability and contamination.

10) Sub Part J – Records and Reports: Equipment cleaning log, production record, testing records.

Definitions

CGMP Full Form – Current Good Manufacturing Practice

FDA – Food and Drug Administration

Basic Requirement Layout of Pharmaceutical Manufacturing Premises

Location, Surrounding & General Requirement: Any building used in the manufacturing, processing, or packaging of a drug product shall be of a suitable size, construction, and location to facilitate cleaning, maintenance, and manufacturing of the drug product. The factory building used for the manufacturing of drug products shall be situated to avoid the risk of contamination from open sewage, drain systems, or any other factory producing harmful fumes or dust.

Drug Formulations

Toxoids

Definition: A toxoid is an inactivated toxin whose toxicity is suppressed either by chemical (formalin) or heat treatment, but other properties, typically immunogenicity, are maintained. Toxins are secreted by bacteria, whereas toxoids are altered forms of toxins and those used in vaccines.

Preparation of Toxins: A suitable strain of Corynebacterium diphtheriae is grown on a liquid medium. After incubation, when toxin production has reached its peak, the bulk of the liquid is filtered through a bacterial-proof filter. The filtrate, which is the toxin, is then sterilized.

Ear Drops

Definition: Ear drops are liquid medications that you put inside your ear canal. Ear drops can help to treat pain, inflammation, infection, and ear blockage.

Types of Ear Drops:

• Ear Drops for Ear Infection: Recommended for fungal infections. They include acidic acid, fluconazole, ofloxacin in aluminum acetate.
• Ear Drops for Pain: Over-the-counter ear drops are used to relieve pain. Pain relievers like acetaminophen are usually the most common agents against ear pain.
• Ear Wax Removal Drops: There are three types of softening drops for ear wax: water-based, non-water-based, and a mixture of both. Examples include carbamide peroxide, glycerin, and sodium bicarbonate.
• Ear Drops for Itchy Ears: Dexamethasone

Eye Preparations

Definition: Preparations used for the eye are referred to as ophthalmic preparations. They may be sterile solutions free from microorganisms, suspensions, and ointments. These may be instilled in the eye either in the form of drops or sprays, or also applied as an ointment.

Classifications:

1. Eye Drops
2. Eye Ointments
3. Contact Lens Solutions

Factors Affecting Formulation of Eye Drops:

• Sterility
• Pain and irritation
• Antimicrobial activity
• pH adjustment
• Viscosity
• Adjustment to isotonicity with tears
• Volume

Eye Ointments

Definition: These are sterile ointments meant for application to the eye.

Characteristics:

• It should be sterile by a heating method.
• It should be free from infection or irritation.
• It should diffuse the drugs uniformly.
• It should melt close to body temperature.

Preparation Methods:

1. Trituration Method: Used when the drug is not stable at sterilization temperature.
2. Fusion Method: Used when the drug is stable at sterilization temperature.

Vaccines

Definition: A vaccine is defined as a live attenuated (weakened) or killed microorganism, or parts of the product of the antigen, that reduce the immune response.

Advantages:

• Vaccines can be safely used in immunocompromised individuals and in pregnant women.
• These vaccines are less expensive.
• These vaccines don’t have much demand for storage facilities.

Disadvantages:

• Due to sterile preparation, it affects the vaccine dose.
• Since antigens do not retain only in one part of the body, the antibodies produced against the antigen fail to recognize the same protein.

Types of Vaccines:

1. Live Attenuated Vaccine (Ex: Mumps, Rubella)
2. Inactivated Vaccine (Ex: Hepatitis A)
3. Recombinant Subunit Vaccine (Ex: Hepatitis B)
4. Toxoids Vaccine (Ex: Diphtheria)

Review on Production of Vaccines: Vaccines are used for providing good health to a large number of the population. Vaccine production includes:

1. Generation of Antigen: In the first step, the antigen is generated by growing and harvesting the proteins or DNA of the pathogen.
2. Release and Isolation of Antigen: In the second step, the virus or bacteria are released by separating the antigens from the cells and isolating the proteins.
3. Purification Process: In the third step, membrane separation and chromatography separation are used for separating the inactivated antigen.
4. Addition of Other Components: In the fourth step, the vaccine is formulated by adding excipients which enhance the immune response.
5. Packaging: In the final step, the vials or syringes containing the vaccines are sealed with sterile stoppers.

Sera

Definition: Sera are the blood components which are neither blood cells nor clotting factors, but the blood plasma present in the blood. Sera contains all the electrolytes, antibodies, antigens, hormones, etc.

Pharmacological Concepts

Bioavailability

Definition: The ability of a drug or other substance to be absorbed and used by the body.

Immunity

Definition: It refers to the body’s ability to prevent the invasion of pathogens.

Methods of Extraction

Infusion, decoction, digestion, maceration, percolation

Infusion

Definition: Fresh infusions are prepared by macerating the crude drug for a short period of time with cold or boiling water. Example: Infusion of Quassia.

Decoction

Definition: In this process, the crude drug is boiled in a specified volume of water for a given period of time. It is then cooled and strained or filtered. Example: Extraction of neem, ginger, tea, and coffee.

Digestion

Definition: It is a form of maceration in which gentle heat is used during the process of extraction. In this, high temperature is not provided to the crude drug or the solvent. Example: Extraction of morphine.

Maceration

Definition: In this process, solid ingredients are placed in a stoppered container with the solvent and allowed to stand for at least 3 to 7 days with frequent agitation until the soluble matter is dissolved. The mixture is then filtered, and a clarified liquid is obtained. Example: Extraction of orange peel.

Percolation

Definition: It is a continuous downward displacement of solvent through the bed of crude drug to get the extract. In this, the extract which was used in the crude drug is used to separate the active constituents present in the ingredients.

Tablets

Definition: According to the Indian Pharmacopoeia (IP), pharmaceutical tablets are solid, flat, unit dosage forms which are prepared by compressing drugs or a mixture of drugs with or without excipients.

Types of Tablets

The tablets are classified as follows:

1. Oral Tablets: These are tablets that can be swallowed orally with the help of some suitable fluids. They are designed to disintegrate in the stomach or small intestine if they are coated.
2. Chewable Tablets: These are tablets that are designed to be chewed before ingestion of the chewed particles. They are meant for children and persons who may find difficulty in swallowing tablets.

Membrane Filter

Principle

It consists of a microporous plastic film of a specific pore size, which is known as a microporous filter. These membrane filters retain particles or microorganisms.

Construction

It consists of a membrane of cellulose acetate, cellulose nitrate, and cellulose ester. The pore size of the filter is 150 μm.

Working

It is used as a filter to remove particles. The particles are 5 mm pore size, which is used to remove the microbes or insoluble particles present in the liquid.

Uses

It is used for clarifying aqueous and organic solvents. It is suitable for the filtration of enzyme solutions.

Fluidized Bed Dryer

Principle

The equipment works on the principle of fluidization of the materials. In this process, hot air is introduced at high pressure through a perforated bed of moist solid particles. The wet solid is then lifted up by the process of air. The hot air surrounding the energy helps the granules to dry, thus the materials and granules are uniformly dried.

Construction

The dryer is made up of stainless steel. To this, a detachable bowl is placed at the bottom of the dryer. The bowl has a perforated bottom with a wire mesh for placing the material to dry. A fan is mounted in the upper part for circulating the hot air. Fresh air inlet and air heaters are connected to heat to the required temperature. The temperature of the hot air and exit air are monitored. Back filters are placed above the drying bowl for circulation of air.

Working

The wet granules to be dried are placed in a detachable bowl and inserted in the dryer. Fresh air is passed through the inlet by using air filters to convert it into hot air. Hot air flows through the bottom of the bowl. At the same time, fans start rotating, and the granules move up and down due to the high pressure of air. The gas surrounds each granule, dries them completely, and passes through the filter bags for removal of air.

Pharmaceutical Preparations

Gels

Definition: Gels are also known as jellies. They are semi-solid preparations having a suspension containing either small particles or large molecules interpenetrated by a liquid.

Ointments

Definition: An ointment is a homogenous, viscous, semi-solid preparation, most commonly a greasy, thick oil with high viscosity, that is intended for external application to the skin or mucous membrane.

Elixirs

Definition: They are hydroalcoholic solutions of medicinal substances that are sweet and flavored. They are used as an excellent solvent for many drugs and mask the odor as well as the taste of any substances dissolved in them. Typically, alcohol and water are used as solvents when the drug will not dissolve alone. Examples: Aromatic elixirs, orange elixirs, benzaldehyde elixirs, phenobarbital elixirs.

Powders

Definition: Powder is defined as a uniform and dry mixture of one or more finely divided materials. Examples: Dusting powder, tooth powder, aerosols.

Dusting Powders: Pharmaceutical powders that contain a single medicinal agent applied as a dusting agent.

Drying

Definition: Drying is the process of removing the presence of solvents in a formulation with the presence of heat.

Test for Identification of Emulsions

Dilution Test

The emulsion is diluted with water. If the emulsion remains stable after dilution, it is an oil-in-water emulsion. A water-in-oil emulsion breaks on dilution with water but remains stable when diluted with oil.

Dye Test

Red dye is mixed with animals, and a drop of emulsion is placed on a microscopic slide and covered with a cover slip. It is then examined under a microscope. If the dispersed globules appear red and the background is colorless, the emulsion is of the oil-in-water type. The reverse condition occurs in the water-in-oil type of emulsion.

Conductivity Test

Water is a good conductor of electricity, while oil is a non-conductor of electricity. The conductivity test can be performed by dipping a pair of electrodes connected through a low-voltage bulb in the emulsion. If the bulb glows on passing an electric current, the emulsion is of the oil-in-water type. If the bulb doesn’t glow, it is a water-in-oil type of emulsion.

Salient Features of IP 7th Edition

1. It contains a total number of 2500 monographs, out of which 577 are newly added.
2. 19 monographs and a general chapter were related to radiopharmaceuticals.
3. It contains four volumes which are hardbound, along with a DVD.
4. Many monographs are related to herbs.
5. A certificate of IP 7th edition is provided to prove its authenticity.
6. It also contains the use of chromatographic methods.

Indian Pharmacopoeia

Definition: The Indian Pharmacopoeia is an official document meant for overall quality control and assurance of pharmaceutical products marketed in India, with their safety, efficacy, and affordability.

Editions of the Indian Pharmacopoeia

Pharmacopoeia

Definition: A pharmacopoeia is an official book that lists all the drugs that are used to treat people in a particular country and describes how to use them.

United States Pharmacopoeia

Definition: The USP is a pharmacopoeia that was published annually by the United States Pharmacopeian Convention. It is a book for standards of chemicals and biological drug substances, dosage forms, their preparation, excipients, etc.

Extra Pharmacopoeia (Martindale)

Definition: The Extra Pharmacopoeia is a complete drug reference book that was published by Pharmaceutical Press, listing about 6000 drugs and medicines used worldwide.

Monograph

Definition: Monographs are descriptions of pharmaceutical products.

Pharmaceutical Aids

Definition: Substances that are of little or no therapeutic value but are necessary in the manufacturing, compounding, and storage of pharmaceutical products or drug dosage forms. Examples: Solvents, diluents, antioxidants, preservatives.

Coloring Agents

Definition: Coloring agents impart an appropriate color to pharmaceutical preparations.

Selection of Colors

• It should be checked for its quality.
• It should not modify the physical and chemical properties.
• It should be unaffected by light.

Classification of Coloring Agents

• Mineral Colors: Also called pigments. These are used in the preparation of lotions, cosmetics, and other topical preparations. Examples: Red and yellow ferric oxide, carbon black.
• Plant Colors: These colors are obtained by extracting plant material. Examples: Chlorophyll, indigo.
• Animal Colors: These colors are obtained by extracting colors from animals. Example: Carminic acid.

Preservatives

Definition: A preservative is a substance that is added to a formulation to prevent bacterial growth and avoid spoilage of the formulation.

Classification of Preservatives

• Acids: Example: Benzoic acid.
• Alcohols: Example: Ethyl alcohol, benzyl alcohol.
• Phenols: Example: Phenol and cresol.
• Hydroxybenzoates: Example: Ethyl hydroxybenzoate, methyl hydroxybenzoate.

Unit Operation

Definition: Any chemical process may be a combination of a series of unit operations, which involve physical changes, while unit processes involve chemical changes.

Filtration

Definition: It is defined as the process of separation of solids from liquids by passing the mixture through a medium that retains the solids but allows the liquid to pass through it.

Factors Affecting Filtration

• Viscosity
• Particle size
• Temperature
• Surface area of filter medium
• Microbial contamination

Pharmacy

Definition: It is a branch of science that deals with the study of drugs, starting from manufacturing to packaging of materials, to ensure the safety and efficacy of pharmaceutical drugs.

Scope of D. Pharm

• Retail and wholesale shops
• Government pharmacist
• Pharmacist in hospitals
• Higher education (lateral entry in B. Pharm)
• Lab assistant in degree teaching institutes

United States Pharmacopoeia (USP)

The first edition of the United States Pharmacopoeia was published on December 15, 1820, in both Latin and English. From 1822 to 1942, it was published at 10-year intervals. From 1942 to 2000, it was published at 5-year intervals. The first National Formulary of the United States Pharmacopoeia appeared in 1888. USP 21 NF 16 had 8 supplements and was published in January 1985.

USP-NF

Definition: It is a book of public pharmacopeial standards for chemical and biological drug substances, dosage forms, excipients, APIs, and dietary supplements.

British Pharmacopoeia