chapter 16 - biologics

8/10/2019 Chapter 16 - Biologics

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CHAPTER 16

BIOLOGICS

13 GO,

14 GO

15 GRANDE,


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WHAT ARE BIOLOGICS?

A biologicis a substance produced by a living source; it comm

includes the following:

Antibiotics

Hormones

Vitamins

Others

Provision of immunity through the use of biologic is immuniza

Vaccination, a term which refers to the use of a biologic prod

vaccine) to develop active immunity in the patient.


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WHAT ARE BIOLOGICS?

The Food and Drug Administration (FDA) refers to immunizingas biologics.

TheAdvisory Committee on Immunization Practices (ACIP) refeimmunizing agents as immunobiologics.

According to the Code of Federal Regulations, a biologic produvirus, therapeutic serum, toxin, antitoxin, or analogous producemployed for prevention, treatment, or cure of diseases in hum


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DEFINITION OF TERMS

Antigen Antibody

Immunogen

Immunological

Interleukin

Serum/Sera

Virion


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PART ITYPES OF

IMMUNITY


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THERE ARE TWO MAIN CATEGORIES OF

IMMUNITY:

Natural Immunity

Species Immunity

Racial Immunity

IndividualImmunity

Acquired Immun

Active Immuni naturally acquired a

artificially acquired a

Passive Immu naturally acquired p

immunity

artificially acquired p

immunity


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1.1 NATURAL IMMUNITY

Natural, innate, or native immunity depends on factors th

inborn.

It can be classified as:

Species immunity Racial immunity

Individual immunity


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1.1.1 SPECIES IMMUNITY

In general, cold-blooded animals are not susceptible to d

common to warm-blooded animals.

Humans are not at all susceptible to certain diseases of lo

animals and correspondingly, many human diseases do n

naturally occur in animals.


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1.1.2 RACIAL IMMUNITY

Human races differ in susceptibility to common infect

Factors that determine racial immunity are elusive anwell known.


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1.1.3 INDIVIDUAL IMMUNITY

Individuals vary in the ability to resist common microbiolo

diseases.

The natural resistance of the same individual may vary fro

to time.

Health plays a vital role in resisting invasion by other spec

microorganisms capable of producing infection.


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1.2 ACQUIRED IMMUNITY

T lymphocytes regulate cell-mediated immunity and are

responsible for controlling certain bacterial and viral infec

They are responsible for mediating:

Graft vs Host disease

Allograft rejection

Delayed hypersensitivity reactions


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1.2.1 ACTIVE IMMUNITY

Active immunity develops in response to antigenic subs

in the body.

This may occur by natural means, as by infection, in which

is termed naturally acquired active immunity.

It may also develop in response to administration of a spe

vaccine or toxoid, in which case it is artificially acquired

immunity.


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Vaccines are administered primarily forprophylactic action

develop acquired active immunity. These may contain livi

attenuated (weakened) or killed microorganisms or fractio

these microorganism.

Toxoidsare bacterial toxins modified and detoxified with

moderate heat and chemical treatment so that the antige

properties remain while the substance is rendered nontox


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A problem with toxoids is that they produce inadequate

immunologic responses when administered alone. Theref

they are often combined with adjuvantssuch as alum, al

phosphate, and aluminum hydroxide that enhance their

antigenicity,

The insoluble property of these adjuvants help in prolong

immune response.


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A vaccine composed of killed whole microorganisms is known

inactivated vaccine.

Vaccine that contain live but significantly weakened microorga

are attenuated vaccines.

Both types are capable of producing immunity. However, the

attenuated vaccines typically have more antigenicity so are mo

to confer permanent immunity. Inactivated vaccines, however,

administered again over time for maintenance.


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With live vaccines, caution must be exercise withimmunocompromised patients. This group of patients include

with:

HIV infection

Thymic Abnormalities

Lymphoma

Leukemia

Generalized Malignancy

Advanced debilitating diseases

Or those receiving corticosteroids, alkylating agents, antimetabolites, o

radiation chemotherapy.


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Immunization during pregnancy is another concern. Live

attenuated vaccines should be avoided for pregnant patie

because of the danger of transmission of the microorgan

the fetus.


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1.2.2 PASSIVE IMMUNITY

Passive acquired immunity occurs by introduction of th

immunoglobulin produced in another individual (human

animal) into the host, who is not involved in their product

It can also be classified as natural or artificial, just like act

immunity.


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1.2.2 PASSIVE IMMUNITY

Naturally acquired passive immunity occurs by placent

transmission of immunoglobulin gamma (IgG) from the m

to the fetus.

Artificially acquired passive immunityinclude several b

products containing immunoglobulins. These are limited

provision of temporary prophylaxis to susceptible individ

Notable in this category are the anti-venins for the treatm

snakebite and spiders.


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PART IIPRODUCTION OF

BIOLOGICS


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PRODUCTION OF BIOLOGICS

Biologics are produced by manufacturers licensed to do

accordance with the terms of the federal Public Health

Actapproved July 1, 1944, and;

Each product must meet specified standard as administ

the Center for Biologics Evaluation and Research of the F


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PRODUCTION OF BIOLOGICS The label of a biologic product must include:

Title or Proper Name (the name under which the product is licensed)

Name, address, and license number of the manufacturer

Expiration date

Recommended individual dose for multiple-dose containers

Preservative/s used and the amount

Number of containers (if more than one)

Amount of product in the container

Recommended storage temperature

Auxiliary statements (e.g. freezing is to be avoided)

Other information as FDA regulations may require to ensure safe and ef

of the product.


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PRODUCTION OF BIOLOGICS

Most biologics are stored in a refrigerator (2

C to8

C, or35

F

tofreezing is to be avoided.

Diluents packaged with biologics should not be frozen.

Beside the biologic substance that is harmed by freezing, the cont

be broken due to the expansion of an aqueous vehicle resulting in

product.

The expiration date for biologic products varies with the product a

storage temperature. Most biologic products have an expiration d

year or longer after the date of manufacture or issue.


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PART IIISTORAGE, HANDLINAND SHIPPING OF

BIOLOGICS


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STORAGE, HANDLING, AND SHIPPING OFBIOLOGICS

Biologics are sensitive to extreme temperatures, and exposure tfreezing can decrease their potency and dramatically reduce th

effectiveness.

Biologics are expensive and can add significantly to ones inven

costs.

A real danger is that if damaged products are administered, the

may get little or none of the intended benefit. Worse, the perso

not be able to build up immunity and may result in an infection

inadequate protection from the disease.


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The overriding theme for the pharmacist in storage, handling, a

shipping of biologic products is to maintain the cold chain.

This implies continuity from the manufacturers refrigerator to o

pharmacy, clinic, or office to the point of administration. If this cis to be maintained, the pharmacist can be assured that the qua

product will not be diminished.


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For small-volume biologics, a standard refrigerator-freezer should be usedfreezersshould be used because ice buildup interferes with the freezers abi

maintain very low temperatures. Also, defrosting requires that the product b

to temporary storage.

A separate refrigerator dedicated to biologics is preferable to minimize the t

refrigerator door is opened. The WHO recommends that the door not be o

more frequently that four times per day.

The door shelving can be used to store diluents or bottles of water. This hel

insulation and a thermal reserve.

Refrigerator temperatures should range between 2C and 8C, and freezers

well below 0C. Usually, an optimal temperature is 15C (5F).


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Store containers of the same vaccine together.

To avoid selecting the wrong product or one having a similar so

name or packaging, separate the product.

Look-alike packaging as well as sound-alike names can easily co

any conscientious practitioner. The use of a mishandled or poorly stored biologic could have

devastating consequences on the person who receives it.


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PART IVBIOLOGICS FOR ACTIVE

IMMUNITY


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THERE ARE FOUR TYPES OF BIOLOGICS FOR

ACTIVE IMMUNITY:

Bacterial Vaccines

Viral Vaccines

Cancer Vaccines Autologous tumor vaccines

Allogeneic tumor vaccines Anti-iodotypic vaccines

Gene therapy derived vaccines

Toxoids


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4.1 BACTERIAL VACCINES

Originally, organisms are grown in a suitable broth mediumicontrolled environment of temperature, pH, and oxygen tension

Following a suitable amount of time for bacterial growth, the ce

is processed in two steps:

Step 1: If the vaccine is to be inactivated, the organisms are treated with

formaldehyde. (Heat and phenol or heat and acetone are employed for

fever vaccine).

Step 2: Next, the organisms are separated from the medium through ce

and suspended in sterile water or 0.9% sodium chloride for injection.


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4.1 BACTERIAL VACCINES A live attenuated vaccine can also be produced by genetic alteration of

pathogenic organisms. This allows the organism to survive and multiply

produce the disease.

Another way to create a vaccine is to employ purified antigen subunits

with the use of recombinant DNA. With subunit vaccines, the genes that

the desired antigen are introduced into the nonpathogenic organisms.

Subunit vaccines have had limited clinical utility because of the inability t

a sufficient, specific immune response.

Alternative biotechnologic strategies have been employed to produce su

vaccine immunogens and adjuvant-active compounds that can be added

enhance the immune response.


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4.1 BACTERIAL VACCINES

The final vaccine may contain one single immunogen (monovalentcontain multiple immunogens (polyvalent, trivalent) to promote i

against the same disease.

Thestrength of a bacterial vaccine may be expressed as:

total number of organisms

total protective units per milliliter or dose

micrograms of immunogen in each milliliter or in each dose of va


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4.2 VIRAL VACCINES Viruses cannot be grown on inanimate media employed to grow bacteria

are propagated on one of several types of animate media.

Embryonic egg

Cell cultures of chick embryo

Human diploid cell culture

Monkey cell culture

Skin of living calves

Intact mice

After the growth of the culture, various techniques are employed to sepa

virus from the host cell. Purification steps are taken to reduce incidence o

hypersensitivity reactions to animate media or host cells.


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4.2 VIRAL VACCINES

The final viral product may contain asingle immunogen (monovalemay contain multiple immunogens (polyvalent) to elicit immunity

same disease.

The vaccine may remain as the whole virion or be further chemically

to split into a subvirion vaccine.

To prolong stimulation of antibodies, the virion may be adsorbed ontaluminum phosphate, as is the case with rabies vaccine (adsorbed).

Typically, viral vaccines are available as lyophilized (freeze-dried) prod

required reconstitution prior to administration with the provided dilu


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4.2 VIRAL VACCINES

The strength of viral vaccines can be provided in: tissue culture infection doses, the quantity of virus estimated to in

of inoculated cultures

Micrograms of immunogen

International units

D-antigen units

Plaque-forming units for yellow fever vaccine


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4.3 CANCER VACCINES T cells, lymphokine-activated killer cells, and natural killer cells have antit

activity. Thus, tumor vaccine development is to stimulate these immune instead of antibody-producing cells, the operational model used to prot

from an infection.

Tumor-killing cells recognize tumor-associated antigens (TAAs) on the su

the tumor cells.

Four types of cancer vaccines are under investigation:

Autologous tumor vaccines

Allogeneic tumor vaccines

Anti-iodotypic vaccines

Gene therapy-derived vaccines


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4.3.2 ALLOGENEIC TUMOR VACCINES

Allogeneic tumor vaccines use the concept of shared or tumor-specifantigens.

These vaccines are produced from cell lines that express tumor-speci

shared TAAs.

To induce an immune response, either the fragment of the allogeneic

or the whole cell is injected.

The beneficial aspect of this vaccine is that it can be used in a wide p

of patients.


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4.3.3 ANTI-IODOTYPIC VACCINES

Anti-iodotypic vaccines are three-dimensional immunogenic regions antibody that binds antigen.

Antibodies that bind TAAs are isolated and injected into mice. The re

antibodies are harvested and used to vaccinate another mouse. The r

anti-bodies have a three-dimensional binding site that mimics the or

structure of the TAA. Because the anti-iodotypic antibody closely resembles the antigen, th

used to induce immune responses (cellular, antibody-antigen) to a gi

antigen.


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4.3.4 GENE THERAPY DERIVEDVACCINES

Gene therapy allows a DNA template to be placed within a cell, tra

into messenger RNA, and expressed as a costimulatory protein. O

then induce a cell to synthesize this proteins as part of its normal f

A gene that encodes interleukins or other costimulatory proteins cplaced in cells expressing TAAs. This stimulates the immune respo


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4.4 TOXOIDS Bacteria are propagated, and after the required growth is achieved, the cultu

through a sterilizing membrane filter. The filtrate that contains the toxin (exthen processed.

Processing involves addition of a concentrated salt solution to precipitate th

from the filtrate. After the precipitated toxin is washed and dialyzed to purify

toxin is detoxified with formaldehyde.

The detoxified toxin (toxoid) may be plain or contain an adjuvant. The proalso contain single, multiple, or mixed immunogens.

A mixed biologic has two toxoids and a vaccine in single dosage form for a

immunization against different toxicities and infection.

Their advantage is broad immunization coverage and minimum number of i


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4.4 TOXOIDS The strength of a toxoid is in flocculating (Lf)) units.

e.g. Tetanus toxoid, 4 to 5 Lf U/0.5 mL dose

A flocculating unit is the smallest amount of toxin that floccul

rapidly one unit of standard antitoxin in a series of mixtures con

fixed amounts of antitoxin and varying amounts of toxin.


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PART VBIOLOGICS FOR PASSIV

IMMUNITY


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5 1 HUMAN IMMUNE SERA AND


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5.1 HUMAN IMMUNE SERA ANDGLOBULINS

(HOMOLOGOUS SERA)

They include immunoglobulin and hyperimmunesera for specific d

These contain the specific antibodies obtained from the blood of h

and produced as a result of having had the specific disease or hav

immunized against it with a specific biologic product.

The source of homologous sera is the pooled plasma of adult don

General populationfor immunoglobulins

Hyperimmunized donorsfor immunoglobulins for specif

diseases

5 1 HUMAN IMMUNE SERA AND


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5.1 HUMAN IMMUNE SERA ANDGLOBULINS

(HOMOLOGOUS SERA)

The pooled plasma from adult donors must be free of hepatitis B antantibodies to HIV.

Processing steps include:

Fractional precipitation (e.g., with cold ethanol)

Maintaining rigorous control of pH; and

Ionic strength

Further purification takes place with a finished biologic product that c

n.l.t 15% and n.m.t 18% protein. There are exceptions such as the vari

immunoglobulins (VZIGs) which contain n.l.t 10% proteins.


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5 2 ANIMAL IMMUNE SERA


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5.2 ANIMAL IMMUNE SERA(HETEROLOGOUS SERA)

This category includes theantitoxins and antivenins.

Antitoxinsare produced by inoculating horses with increasing doses

toxoids and exotoxins.

Antiveninsare produced similarly, by inoculating horses with the ven

selected species and harvesting the plasma.

Before using these products, precautions must be taken to ensure the

the patient, who may be sensitive to horse protein. Sensitivity tests m

undertaken to detect any dangerous hypersensitivity.


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See TABLE 16.1 for

EXAMPLES OF OFFICIAL BIOLOGIC PROD

EXAMPLES OF OFFICIAL BIOLOGICPRODUCTS

chapter 16 - biologics

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