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8/10/2019 orjalo phardose ppt

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Pyrogens and Pyrogen Testing

USP EU- a bacterial endotoxin limit stated by USP injection

monographs.

Injections are not pyrogen or endotoxin free but are only limited. Examples from USP32-NF27(12)

Dextrose Injection: Contains not more than 0.5 USP EU per mL for

injections not containing less than 5% dextrose and not more than

10.0 USP EU per mL for injection containing between 5% and 70%

dextrose. Digoxin Injection: contains not more than 200.0 USP EU per mg of

digoxin.

Gentamicin Injection: contains not more than 0.71 USP EU per mg

of gentamicin.


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common method used to remove pyrogens. Done to convert them to easily eliminated gases or nonvolatile

solids which are both separated by fractional distillation.

Potassium Permanganate - oxidizing agent

- efficiency increased by addition of

Barium Hydroxideto impart alkalinity

and make nonvolatile barium salts to

any present acidic compounds.

Oxidation


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These two reagents + water distilled several times collect under

strict aseptic conditions chemical free distillate with highly pure,

sterile, and pyrogen free water test with official pyrogen test.

Pyrogen test

Uses healthy rabbits that have been properly maintained in terms of

environment and diet before the test. Normal, or control, temperatures

are taken for each animal to be used in the test. These are used as abase to determine any rise in temperature after injection of sample.

The test uses rabbits whose temperatures do not differ by more

than1C from each other and whose body temperatures are considered

not to be elevated.


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Some parenterals cannot be tested with LAL due to interference of the

active ingredient. This products use the pyrogen test.

These are: meperidine HCL, promethazine HCL, oxacillin sodium, sulfisoxazole,vancomycin HCL, etc.

Since the LAL test is sensitive, interference of an active ingredient can

be overwhelmed by diluting the product with more than twofold of

water.

Products tested in this manner: Diphenhydramine HCL, ephedrine HCL,meperidine HCL, promethazine HCL, thiamine HCL


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Industrial Preparation of Parenteral

Products

Some injections are packaged as dry powders due to being unstable in

the presence of a liquid.

Method of sterilization of the powder: Dry heat

Examples of sterile drugs packaged without pharmaceutical additives:o Ampicillin sodium

o Ceftizoxime sodium

o Ceftazidime sodiumo Cefuroxime sodium

o Kanamycin sulfate

o Nafcillin sodium

o Penicillin G Benzathine

o Streptomycin sulfate

o Tobramycin sulfate


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Products


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Products

Sterile drugs with pharmaceutical additives and intended to be

reconstituted:o Cyclophosphamide

o Dactinomycino Erythromycin lactobionate

o Hydrocortisone sodium succinate

o Mitomycin

o Nafcillin sodium

o Penicillin G potassium

o Vinblastine sulfate


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Products


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Products

Antibioticsprepared industrially in large fermentation tanks

Sometimes a liquid is packaged along with the dry powder for use at the

time of reconstitution.Mix-O-Vial

Dry ingredients in the bottom

compartment

Liquid diluent in the top

Separated by a specially

formulated center seal Offers stability of the product

until it is activated, convenient,

fast, and safe as long as the right

drug and proper diluent are in

correct proportions.

Manufactured by Pfizer


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Products Most commonly employed solvents to reconstitute dry-packaged injections:

Sodium chloride injection

Sterile water for injection

Dry powders packaged in large containers

- caking is prevented upon standing to facilitate dissolution

- uses lyophilization

Treated powders form a honey comb lattice structure that is rapidly

penetrated by liquid.

Solution is rapid due to the exposed powders large surface area.


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Products

Hospira ADD-Vantage System

Ready to mix sterile IV product

Designed for intermittent administration of

potent drugs that do not have long term

stability in solution

Antibiotics and other drugs do not have to

be mixed until prior to administration

Consists of two components:

Flexible plastic IV container

Partially filled with diluent

Glass vial of powdered or liquid drug


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Products

Monovial Safety Guard

Manufactured by Becton Dickinson Pharmaceutical

Systems

IV infusion system for use in preparing

extemporaneous small-volume infusions using plastic

minibags

More favorable, less time consuming, costs less than

traditional:

Transfer needle and vial (TFN) method

Syringe and vial (SYR) methods

Integrated drug transfer mechanism with a protective

shield surrounding the attached transfer needle

Reconstitution and transfer of the drug into an

infusion bag are accomplished safely, quickly, and with

few materials.


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Packaging, Labeling, and Storage of

Injections

Containers for injections must not interact physically or chemically with

the preparation

If container is made of glass, it must be clear and colorless, or light amberto permit inspection of its contents

Injections are placed either in: Single dose container- hermetic container intended for single dose of administration

wherein once opened, it cannot be resealed; may be in ampules or single dose vials

Multiple dose container-hermetic container that permits successive withdrawal of its

contents without changing the strength, quality, or purity of the remaining portion

Some products are packaged in pre-filled syringes, with or w/out special

administration devices


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Injections

TYPE GENERAL DESCRIPTION

I Highly resistant borosilicate glass

II Treated soda-lime glass

III Soda-lime glass

NP General purpose soda-lime glass

CONSTITUTION OF OFFICIAL GLASS TYPES

Type I, II, III are suitable for parenterals with type I being the most

resistant to chemical deterioration.


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Injections

Clarity- prime prerequisite; clear and free of all particulate matter

Precautions to be taken during manufacture, storage, and use of product:

Filter parental solution before transferring into the container Containers must be chemically resistant and of highest available quality

-prevents leaching

After selection, container must be carefully cleaned

Extreme care must be exercised during container filling

Personnel must wear monofilament fabric uniform, face hoods, caps, gloves, and

disposable shoe covers

After filling of container, it must be visually or automatically inspected

- Done by passing through a light source with black background- Particles 50 um are detected


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Injections

Methods to detect smaller particulate matter: Microscopic examination

Coulter Counterelectronically counts particles in samples

Particulate matter has the potential to induce thrombi and vesselblockage.

Depending on chemical composition, it has potential to introduce to the

patient agents that are undesired and toxic.

Some single dose preparations are to be administered rapidly in smallvolumes, but others infuse slowly into the circulatory system over hours.


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Injections

Small volume parenteralsformulated so that a convenient amount of

solution contains the usual dose of the drug.

Larger volumes of more diluted solutionsare administered intravenouslyand intramuscularly.

Large- volume single-dose preparationsused to expand the blood

volume or to replenish nutrients or electrolytes

-given by slow IV infusion

-does not permit withdrawal of more than 1,000 mL

Intraspinal, intracisternal, or peridural administration must be packaged

only in single-dose containers.


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Injections

Multiple dose containers Affixed with rubber closures to permit penetration of a hypodermic needle

without removal or destruction of the closure.

As long as the needle at the time of entry is sterile, the injection will remainsterile

Required to contain antibacterial preservatives

Not permitted to allow withdrawal of more than 30mL

Usual container contains about 10 usual doses of the injection


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Injections Labels on containers of parenteral products must state the ff:

Name of preparation

For liquid preparation, the percentage content of drug or the amount of drug in a

specified volume

For a dry preparation, the amount of active ingredient present and the volume of liquid

to be added to prepare a solution or suspension

Route of administration

Statement of storage conditions and expiration date

Name of manufacturer and distributor

Identifying lot number capable of yielding complete manufacture history


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Injections

Preparations for dialysis, hemofiltration, or irrigation solutions should bear

a statement indicating that the solution is not intended for IV infusion.

Containers have an area free of label to permit inspection of the contents.

If inspection reveals presence of particulate matter, preparation should be

discarded.

Each individual monograph for the official injection states:

Type of container Type of glass preferred

Exemptions if any to usual package size limitations

Special storage instructions


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Injections

Injections prepared from chemically puremedicianal agents are: Stable at room temperature

Stored without special concern or conditions

Biologic products such as:

Insulin injection

Various vaccines

toxoids

Toxins

Should be stored under refrigeration.


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Environmental issues

Hospira, Baxter Healthcare, B. Braun, are shipping containers free from

PVC and di-2-ethylhexylpthalate (DEHP).

PVC or polyvinyl chloride- popular thermoplastic that contains high levels

of chlorine ; referred to as the "Poison Plastic" due to the toxic pollutants

it might release.

There is a huge concern regarding the effects of DEHP on male neonate

patients.

PVC bags can leach DEHP into the fluid of the container.

Another concern is the amount of plastic waste.

In response, Hospira launched its VISIV line of IV containers.


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Environmental issues

VISIV containers: Are PVC/DEHP free

Do not contain any overwrap

Has a sterile port

During emergency, does not have to sterilize the port prior to administration

Provides thermal stability

Moisture barrier properties

Inertness

Avoids leaching

Problems associated with PVC/DEHP: IV admixtures still need preparation in glass containers

Costly to manufacture than non-PVC/DEHP plastic bags


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Quality Assurance for Pharmacy-

Prepared Sterile Products USP

June 1, 2008revised USP Chapter , Pharmaceutical Compounding

Sterile Preparations became official.

USP - provides the minimum practice and quality standards for

compounded sterile preparations (CPSs).

- Applies at all times to those who compound sterile

preparations

Three risk levels of (CPCs): Low risk level

Medium risk level

High risk level


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Risk levelsbased on the potential of contaminating a low risk level or

medium risk level CSP or failure to sterilize a high risk level CSP which can

harm the patient and lead to death.

Low risk level and medium risk level CSPssterile ingredients and devices

are used and sterility is maintained

High risk level CSPsmust be sterilized before administration

Any CSP with a nonsterile component is always high risk level.


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Immediate use CSPs sectiononly for emergency or situation wherein

the patient immediately needs to receive a low risk level CSP

- May occur in a: Respiratory or cardiac arrest

Emergency room

Operating room

Combat zone

With the preparation of a diagnostic agent


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Compounding process cannot exceed one hour.

Compounding under immediate use conditions increases the likelihood

of microbial contamination and potential patient harm.

Facilities for compounding CSPs are designed and environmentally

controlled to minimize airborne contaminations.

PECS or sources of ISO class 5 air quality: Laminar airflow workbenches

Compounding aseptic isolators

Compounding aseptic containment isolators (CACI)

Biological safety cabinets (BSC)


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PECs should be recertified at least every 6 months or whenever the

device or room is relocated or altered or a major service to the facility is

performed.

Exposure to hazardous drugs may lead to adverse events which may

range fromskin rashes to effects on the respiratory system and cancer.

Preparation of such drug shall occur in an ISO Class 5 environment.

Closed system transfer devices (CSTDs) that prevent venting or exposureof the drug to the environment shall be used within the ISO Class 5

environment.


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For institutions that compound a low number of hazardous drugs, a

CSTD used within a BSC or CACI in a nonnegative pressure room is

acceptable.

Key components in minimizing the risk to patients are: Proper hand hygiene and garbing practices

Personnel aseptic technique

Disinfection of compounding practices


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Compounding personnel must be : completely trained in the theoretical and practical aspects of aseptic

manipulation

Must pass written examinations and media fill testing before being allowed to

prepare CSPs for patients Must take gloved fingertip sampling which assesses competency in performing

hand hygiene and garbing

USP also includes sections on: Establishing beyond use dates

Compounding radiopharmaceuticals and allergen extracts

Characteristics of a quality assurance program

Verification of compounding accuracy and sterility

Finished preparation release checks and test

Elements of quality control

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