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Secretary General, Bangladesh Association of Pharmaceutical Industries (BAPI)

Managing Director, Incepta Pharmaceuticals Ltd

Abdul Muktadir

B.Pharm, University of Dhaka M.Pharm, University of Dhaka M.S. in Industrial Pharmacy, Long Island University, USA

Research on 1. Anti-tumor antibiotic, University of Dhaka & IPGMR (BSMMU) 2. Dosage Form Design, Long Island University, USA 3. Special research interest on Aerosol, Nanotechnology, Sustain release drug, Lyophilyzation, Design of Pharmaceutical Factory

Immunity A Brief History Types of Vaccines Antigen How vaccines differ from conventional pharmaceutical products Manufacturing techniques Inactivation of microorganism

Immunity is a biological defense to avoid infection, disease or other unwanted biological invasion.
Specific defenses Immunity

Active immunity natural

Passive immunity

Following clinical infection

Transfer of maternal Antibodies Through placenta Transfer of maternal Antibodies Through milk

Following subclinical infection

acquired
Following vaccination Following administration of Immunoglobulin or antiserum

Immunizing agents

vaccines

immunuglobulins

antisera

We don't vaccinate just to protect our children. We also vaccinate to protect our grandchildren and their grandchildren. With one disease, smallpox, we "stopped the leak" in the boat by eradicating the disease. Our children don't have to get smallpox shots any more because the disease no longer exists. If we keep vaccinating now, parents in the future may be able to trust that diseases like polio and meningitis won't infect, cripple, or kill children.

Successes of the Past

Possibilities for the Future

The term vaccine derives from Edward Jenner's 1796 use of the term Variola Vaccinae (Latin for cow pox), which, when administered to humans, provided them protection against smallpox.

A vaccine is a preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease causing microorganism and is often made from weakened or killed forms of the microbe or its toxins. The agent stimulates the bodys immune system to recognize the agent as foreign, destroy it and remember it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later invade.

According to WHO Safe Cheap Heat stable Good immune response after a single dose Immunity is long-lived Low potential for reversion to virulence Safe in immunocompromised individuals Applicable to a number of diseases Administered by a mucosal route Suitable for administration early in life

Inactivated or killed: Inactivated vaccines are composed of microorganisms that have been killed with chemicals and/or heat and are no longer infectious. Examples are Influenza vaccine Cholera vaccine Polio vaccine Hepatitis A vaccine Rabies vaccine

Attenuated: Live, attenuated vaccines are composed of microorganisms that have been cultivated under conditions which disable their ability to induce disease. Examples include Yellow fever Measles Rubella Mumps Typhoid

Toxoid: Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples include Tatanus Diphtheria

Subunit: Subunit vaccines are composed of small fragments (protein) rather than introducing an inactivated or attenuated microorganisms to an immune system (which would constitute a whole agent vaccine). This fragment can create an immune response. Examples Hepatitis B vaccine is a subunit vaccine that is composed of only the surface proteins of the virus

Conjugate: Certain bacteria have polysaccharide outer coats to proteins (e.g. toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in Haemophilus influenza type B vaccine

An antigen is any substance that causes your immune system to produce antibodies against it. An antigen may be a foreign substance from the environment such as chemicals, bacteria, viruses, or pollen. An antigen may also be formed within the body, as with bacterial toxins or tissue cells.

Comparison 1. Therapeutic use 2. Chemical nature

Vaccine

Conventional dosage form

1. Mainly used for prophylaxis 1. Mainly for treatment of purposes. various diseases. 2. The vast majority of antigens 2. Most of the drug molecules are proteins. They may be also have heterogeneous chemical polysaccharides, nucleic acids structures. and lipids. 3. Used to develop antibody 3. Used as agonist or antagonist against specific microorganisms. on receptor, enzyme or other Sometimes acts as antibody. substrates of the body.

3. Mechanism of action

4. Heat stability 4. Vaccines are thermolabile 4. Maximum products are products. thermostable, some products are thermolabile. 5. Foreignness 5. To serve as an immunogen a 5. A drug molecule may be molecule must be seen as non bodys self molecule or non-self self. molecule.

Comparison 6. Size 7. Route of administration

Vaccine

Conventional dosage form

6. The molecular weight should 6. There is no such size range for be between 1,000 to 100,000 Da. conventional drug molecules. 7. Generally the subcutaneous route is better than the intravenous or intragastric routes. 7. Conventional dosage form can be administered by so many routes. For example: Enteral route, Parenteral route, Inhalation, Topical etc.

8. Excipients

8. Adjuvants, suspending agents 8. Conventional dosage form can and preservatives are main be formulated by so many excipients of pharmaceutical excipients. products 9. During storage and 9. Maximum conventional distribution +2C to +8C should dosage form can be stored and be maintained. distributed at room temperature.

9. Storage and distribution

Manufacturing Excipients Storage Distribution

Environmental factors (Temperature, light) Typical vaccine products contain up to 3 or more strains/ sub-units. Long lead times to manufacture all sub-components Long cycle times Significantly complex supply chain and manufacturing Packaging

Suspending fluids: The liquid that contains the chemicals used during production that kill or weaken the germ for use in vaccines. E.g.: sterile water, saline or fluids containing protein, egg protein. Preservatives and stabilizers: Stabilizers increase the storage life, and preservatives allow the use of multi dose vials. E.g.: albumin, phenols, antibiotics and glycine, MSG, 2-phenoxy-ethanol, thimerosal. Adjuvants or enhancers: Substances that enhance the immunogenicity of vaccines. E.g.: aluminum gels or salts.

Certain live vaccines must be stored in a continuously frozen state at -15C or colder until administration. Inactivated vaccines are sensitive to both excessive heat and freezing. They should be stored in a refrigerator at +2C to +8C, with a desired average temperature of +5C.

Temperature-sensitive vaccines have to be stored at a constant temperature of 2C-8C to not lose their effectiveness, and a stable temperature must be maintained from the laboratory to the point of administration to the patient.

Standard manufacture uses a bacterial or viral antigen, e.g. bacterium or virus, which may be killed or may be living but attenuated. To make a live attenuated vaccine, the disease-causing organism is grown under special laboratory conditions that cause it to lose its virulence or disease-causing properties. The attenuation can be obtained by heat or by passage of the virus in foreign host such as embryonated eggs or tissue culture cells. Cell cultures are required for viral vaccines since viruses can replicate only inside the living cells. For example, to produce the polio vaccine, attenuation was only achieved with high inocula and rapid passage in primary monkey kidney cells. Inactivated vaccines are produced by killing the disease-causing microorganism with chemicals or heat.

Pathogen(Seed or Clinical isolate)


Inactivation Culture Attenuation Cloning, GMO

VACCINE

Ag Purification

Seed (Live attenuated)

Seed

Purification
wP, HAV Inactivation Culture Culture

VACCINE
VACCINE VACCINE VACCINE

Rab, Flu

aP

MMR, OPV

HBV, HPV

Vaccines are currently produced by gene techniques, i.e. instead of using a virus or bacterium, a single gene (usually a surface glycoprotein of the virus) can be expressed in a foreign host by Cloning. Most used vectors for expression are Bacteria: Escherichia coli, Yeasts ,Baculovirus. This process induces the vector to produce an antigen, which is then purified. The purified antigen, when combined with an adjuvant results in a safe and very effective vaccine. Example: Gardasil, an anti-human papilloma virus vaccine that is very effective in preventing cervical cancer. The current Hepatitis B vaccine is also this type.

SELECTING THE STRAINS FOR VACCINE PRODUCTION


GROWING THE MICROORGANISMS

Upstream processing

ISOLATION & PURIFICATION OF MICROORGANISM Downstream processing

INACTIVATION OF ORGANISM

FORMULATION OF VACCINE

QUALITY CONTROL AND LOT RELEASE

Inactivation of microorganism

KILLED/INACTIVATED VACCINE:
VIRUS INACTIVATION:

Viruses can be lipid-coated (enveloped) or non-enveloped. Virus inactivation involves dismantling a viruss ability to infect cells without actually eliminating the virus. Virus inactivation works by one of the following two mechanisms:
i. ii.

By attacking the viral envelope or capsid and destroying its ability to infect or interact with cells. By disrupting the viral DNA or RNA and preventing replication.

1) 2) 3) 4)

Different techniques
Solvent/detergent (S/D) inactivation Pasteurization Acidic pH inactivation (Low pH Treatment) Ultraviolet (UV) inactivation

LIVE WHOLE VACCINES: Several methods have been used to attenuate viruses for vaccine production. a) Use of a related microorganism from another animal b) Administration of pathogenic or partially attenuated microorganism by an unnatural route c) Passage of the microorganism in an "unnatural host" or host cell d) Development of temperature sensitive mutants

centrifugation

virus cell
(production seed)

Cell culture Inoculation

Harvest

Bulk

filtering

Purification

Stabilizer

Add

Bulking agent Adjuvant

Packaging

Labeling

Inspection

Filling

Preservative Formulation

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Vaccine virus

Vaccine virus multiplied

Virus is spun to separate it from the egg white

The vaccine virus is injected into a 9 to 12 day old fertilized egg and incubated for 2 to 3 days (during this time the virus multiplies).

After incubation the egg white contains millions of vaccine viruses which are harvested and then separated from the egg white.

The vaccines are produced using recombinant DNA technology or genetic engineering. Recombinant vaccines are those in which genes for desired antigens of a microbe are inserted into a vector.

Different strategies are:


Using the engineered vector (e.g., Vaccinia virus) that is expressing desired antigen as a vaccine Introduction of a mutation by deleting a portion of DNA such that they are unlikely to revert can create an attenuated live vaccine.

Genetic approaches to vaccine development:


One or more genes encoding pathogenspecific antigens are isolated and -recombined with a harmless or disabled vector for delivery by injection, - or incorporated into food plants for ingestion, -or modified for injection as naked DNA. -subunit antigens can be produced by genetic engineering.

Unique antigen

Isolated gene coding for significant antigen Nonpathogenic bacterial plasmid DNA

Vector Recombinent vaccine

Vaccines are expensive to make Big pharma needs incentives Liability International, National and Foundation support (Public and private sector support)

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