Parent MSA Final (1)

7/29/2019 Parent MSA Final (1)

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Formulations intended for use by injection under or

through one or more layers of the skin or mucous

membrane

From the Greek word pare-enteren means toavoid the intestines


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Parenteral products must be:

Sterile.

Free from pyrogenic (endotoxin) contamination.

Free from visible particulate matter.

Isotonic although strictness of isotonicity depends onthe route of administration.

Stable (chemically, physically, and microbiologically).

Compatible with I.V diluents, delivery systems, andother drug products co-administered.


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Advantages of Parenterals:

Immediate physiological action (emergency). Controlled therapeutic response of drug. Accurate dose administration. Useful in case of unconscious or uncooperative state.

To achieve a biological effect that is not possible from oraladministration: e.g. Insulin, certain penicillins To achieve local effect: e.g. local anaesthetics (dentist), local anti-

inflammatory (joints)

Slow onset and prolonged drug action can be obtainedby: Modifying the formulation. Using a route of injection other than I.V.


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Disadvantages of Parenterals

Difficult to administer (restriction to use in hospitals orwith specialized personnel)

Painful.

Require asepsis (absence of microorganisms) atadministration.

Impossible to correct an error unless a direct

pharamacological antagonist is immediately available. Risk of tissue toxicity from local irritation.


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Classification of Parenterals

I) Ready for injections

1-Solutions

2- Suspensions

3-Emulsions

II) Ready to becombined with a

vehicle

1- Dry solubleproducts

III) Ready for dilution

1- Liquidconcentrate

2- Dry insolubleproducts


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1. Solutions:

Are the most common of all parenteral products.

Are usually aqueous but may be also found asmixtures of ether with glycols, alcohol, or other non-aqueous solvents.

Most solutions have a viscosity and surface tensionsimilar to water.


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2. Suspensions:

Are dispersed, multi-phased, heterogeneous system ofinsoluble solid particles intended principally for I.Mand S.C injections.

Must not cake during shipping and storage and shouldbe easy to suspend and inject throughout its shelf life.

Must not be administered directly to the bloodstreambecause of the danger of insoluble particles blockingthe capillaries.


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Parenteral suspensions differ than other

suspensions in the following:

Microbiological purity.

Ingredients allowed. Mechanical flow properties


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The formula for injectable suspension consists of:

Active ingredient.

Aqueous vehicle.

Antimicrobial preservative. Surfactant for wetting.

Dispersing or suspending agent.

Buffer or salt.


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There are two methods to prepare parenteralsuspensions:

1-Sterile vehicle and powder combined aseptically.

2-Sterile solutions are combined and the crystalsformed in situ.


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The flow properties of parenteral suspensions

are characterized on the basis of:

Syringeability

It refers to the handling characteristics of suspension while

drawing it into a syringe i.e. the ease of withdrawal fromcontainer into the syringe, clogging and foamingtendencies, and accuracy of dose measurement.

Injectability

It refers to the properties of the suspension duringinjection. It includes factors such as pressure or force required for

injection, aspiration qualities and freedom from clogging.


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3-EmulsionsAre heterogeneous dispersions of one immiscible

liquid in another.

This inherently unstable system is made possible by

the use of an emulsifying agent.Are rare because it is difficult to achieve stable droplets

of less than 1m to prevent emboli in blood vessels.


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Parenteral emulsions have been used for thefollowing purposes:

Water-oil emulsions of allergenic extracts

(given subcutaneously).

Oil-in-water sustained release depot preparations(given intramuscularly).

Oil-in-water nutrient emulsions

(given intravenously).


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Fat emulsions is a popular class of intravenous

emulsion in which fat is transported in the bloodstream as small droplets called chylomicra.

-Chylomicra are 0.5 to 1.0m spheres consisting of acentral core of triglycerides and an outer layer ofphospholipids.


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Intravenous fat emulsions usually contain 10% oil,

although they may range up to 20%.

These emulsions yield triglycerides which provideessential fatty acids and calories during totalparenteral nutrition through the gastrointestinaltract.


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4-Dry Powders:

Parenteral drug products are usually prepared as drypowder because it is unstable in solution.

A disadvantage of this parenteral form is the need toreconstitute the product with the correct diluent prior to

use. Dry powders may be intended to be reconstituted as a

solution or as a suspension.


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Dry powders

Reconstituted assolution

e.g:Thiopental Sodium for

Injection [USP].

Reconstituted assuspension

e.g:Sterile Ampicillin for

Suspension [USP].


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1. Sterile crystallization.

2. Lyophilization (freeze-drying).

3. Spray drying.

Dry powder is produced by several

methods:


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Routes of Administration

Intravenous (I.V)

Subcutaneous (S.C)

Intramuscular (I.M)

Intra dermal (I.D)

Other parenteral routes.


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1. Intravenous RouteIntravenous medication is injected directly into vein to

Only drugs in aqueous or hydro-alcoholic solutions canbe given by the I.V route.

The most commonly used veins for I.V. administration areproximal veins that are located in the forearm.

Intravenous injections range from 1 - 100 ml.

Obtain rapid and

predictable onset

Avoid irritation

of other tissues.


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Venoclysis Is a technique of using intravenous infusion of large

volumes of fluids (100-1000 ml) It utilizes productsknown as large volume parenterals

(LVPs).LVPs are used to:a. Supply electrolytes and nutrients.b. Restore blood volume.c. Prevent tissue dehydration.

d. Dilute toxic materials already present in the body fluids.e.g. Sodium Chloride USP (0.9%)

Dextrose(5%) , Ringer.


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2.Subcutaneous Route

Slower onset of action than I.V or I.M routesLower absorption than I.V or I.M routes

Includes variety of drugs :

1.Vaccines

2.Insulin

3.Scopolamine

4.Epinephrine

S.C injections are administered in volumes up to 2 ml


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3. Intramuscular Route

It is the second route in rapidity of onset of systemicaction after the I.V. route.

Injections are made into the striated muscle fibers that

lie beneath the subcutaneous layer.

The sites of injections are:

Gluteal muscle (buttocks). Deltiod muscle (upper arm).

Vastus laterals muscle (lateral thigh).


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3.Intramuscular Route

The usual volumes injected are from 1-10 ml.

The major clinical problem is muscle or neural damage.

There are numerous dosage forms available for this route

which includes:a. Solutionsb. Emulsions (Oil in water (o/w) and water in oil (w/o).c. Colloidal suspensions.d. Reconstitutable powders.


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4.Intradermal Route

It involves injection of the drug into the skin layer.

Given for diagnostic purposes.e.g. Allergy test materials.

Injected volumes are given at 0.05 ml per dose.


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5. Other ParenteralRoutes

Intra-arterial route1-Injecting a drug directly into anartery

2-Used to administer radio-opaquecontract media for reviewing anorgan such as the heart or kidney or

perfuse an antineoplastic agent athighest possible concentration totarget organ.

Intrathecal route1-Used to administer a drug directly intothe cerebrospinal fluid.

2-It is not the same route as spinalanesthesia where the drug is injectedwithin the dural membrane surrounding

the spinal cord,or in extraduralor epiduralanesthesia where the drug is depositedouside the dural membrane.


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General manufacturing process

1-Procurementand

accumulation2-Processing

3-Packagingand labelling

4-QualityControl


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1-Procurement and accumulation:

It encompasses selecting and testing of the raw materials ingredientsand the containers and closures for the primary and secondarypackages.

2-Processing: It includes;

A- Cleaning of containers and equipment.B- Compounding the solution.C- Filtering the solution.D- Sterilizing the containers and equipments.

E- Filling measured quantities of product into sterile containers.F- Sealing the containers.


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3-Packaging:

It consists of labeling and cartooning filled and sealedprimary containers.

4-Quality control:

All specifications have to be met.

Reviewing the batch history.

Perform the release testing required to clear the

product for shipment to users.


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Vehicles

Definition:A vehicle should have no therapeuticactivity and it should be nontoxic.

Importance in formulation: Drug carrier.

Rapid and complete absorption especially when thedrug is presented in aqueous solution.


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Types of Vehicles

1-Aqueous

vehicles

2-Water

miscibleVehicles

3-Non-

aqueousVehicles


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1-Aqueous vehicles

They are used as isotonic vehicles to which a drug may be added at thetime of administration.

Examples:Sodium chloride injection, Ringer's injection and Dextrose

injection.

2-Water miscible vehicles They consist of a number of solvents that are miscible with water.

These solvents are used to:a-enhance solubility of drugs. b- Reducehydrolysis.

Examples: Ethyl alcohol (used in the preparation of solution of cardiacglycosides and certain I.M. antibiotics) and propylene glycol.


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3-Non-aqueous vehicles

The most important are fixed oils.The USP specifications of fixed oils are:

Must be of vegetable origin

Liquid at room temperature.

Do not rancid readily.

Unsaturation should be within specific limits.

Fatty acid content should be within specific limits.

Examples: corn oil, cotton seed oil and sesameoil (usually used in hormone preparation).

N.B. Non aqueous vehicles cannot be used I.V.


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Preparation of water for injection(WFI):The source of water can be contaminated with:o Natural suspended mineral and organic substances.o Dissolved mineral salts.o Colloidal silicates.o Industrial or agricultural chemicals.

The source of water must be pretreated by:o Chemical softening.o Filtration.o Deionization.o Carbon adsorption.o Distillation and reverse osmosis are the methods

used for preparation of WFI that meets the USPspecifications.


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Storage and distribution WFI is collected in a holding tank for subsequent use. WFI should be held at a temperature too high for microbial

growth (normally 80C).

The USP permits the WFI to be stored at room temperature

but for a maximum of 24 hours.

Purity Biological requirements for WFI not more than ten colony-

forming units per mL and 0.25 USP endotoxin units per ml.

A final product must pass the USP sterility test.

Bacteriostatic WFI may contain one or more suitableantimicrobial agents in containers of 30 ml or less.


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Solutes

I-

AddedSubstances

II-

AntimicrobialAgents

III-

Buffers

IV-

Antioxidants


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I-Added substance:

Affect solubilitye.g. sodium benzoate in caffeine.

Provide patient comfort, or make a solution isotonicor near physiological pH.

Enhance the chemical stability of a solution

e.g. antioxidants, chelating agents and buffers

Protect a preparation against the growth of

microorganisms (preservatives).


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II- Antimicrobial Agents:

They must be present in adequate concentration at the time of use toprevent the multiplication of microorganisms.

E.g. Phenylmercuric Nitrate 0.01%, Phenol or Cresol 0.5%,Chlorobutanol 0.5%.

E.g The binding and inactivation of esters of p-hydroxybenzoic acid bymacromolecules such as Polysorbate 80 or the reduction ofPhenylmercuric nitrate by sulfide residues in rubber closures.

Single dose containers and pharmacy bulk packs that do not containantimicrobial agents are expected to be used promptly after opening orto be discarded.

Refrigeration slows the growth of most microorganisms, but does notprevent their growth.


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III-Buffers: They are used primarily to stabilize a solution against pH changes.

Buffers used should have low buffering capacity so as not to disturb thebodies buffering system.

E.g. Acid salts of citrates, acetates, and phosphates.

IV- Antioxidants: They are required frequently to preserve products from oxidation.E.g. Sodium bisulfite 0.1%. Displacing the air (oxygen) in and above the solution by purging with

an inert gas, such as nitrogen, also can be used to control oxidation ofsensitive drugs.

They are used in many parenteral and ophthalmic products to adjustthe tonicity.

E.g. Electrolytes and mono- or disaccharides.


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Pyrogens(endotoxins)

Pyrogens are products of metabolism ofmicroorganisms.

The most potent pyrogenic substances are constituents

of the cell wall of gram- negative bacteria. Pyrogens, when present in parenteral drug products

and injected into patients can cause fever, chills, painin the back and legs, and malaise.

They can rarely cause serious discomfort and shocklike symptoms that can be fatal.


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Pyrogens(endotoxins)

The intensity of the pyrogenic response and its degreeof hazard will be affected by:

1- medical condition of the patient.

2- Potency of the pyrogen.

3- Amount of the pyrogen.

4- Route of administration (intrathecal is most

hazardous followed by intravenous, intramuscular,and subcutaneous).


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Sources of Pyrogens

Water is the greatest potential source of pyrogeniccontamination; since water is essential for the growthof microorganisms (microorganisms metabolizeproducing pyrogen).

Pyrogenic materials adhere strongly to glass and othersurfaces.

Residues of solutions in used equipment often becomebacterial cultures, with subsequent pyrogeniccontamination.


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Sources of Pyrogens

Pyrogens may remain in equipment for long periods(since drying does not destroy pyrogens).

Solutes may be a source of pyrogen.

Bulk drug substances derived from fermentation willalmost be heavily pyrogenic; therefore, all lots ofsolutes used to prepare parenteral products should betested to ensure that they will not contribute

unacceptable quantities of endotoxins to the finishedproduct.


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Control of Pyrogens

It is impractical to remove pyrogens without adverselyaffecting the drug product.

Prevention of the introduction or development of

pyrogens in all aspects of the compounding andprocessing of the product.

Time for microbial growth to occur increases the riskfor elevated levels of pyrogens, therefore compounding

and manufacturing processes should be carried outwithin one work day.


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Control of Pyrogens Pyrogens can be destroyed by heating at high

temperatures.

Depyrogenation of glassware and equipment is done bymaintaining a dry heat temperature of 250C for 45

minutes. Heating with strong alkali or oxidizing solutions will

destroy pyrogens.

Adsorptive agents are used for the removal of pyrogens

from solutions; however this method has limitedapplication since it may cause selective removal ofchemical substances from the solution.


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Containers and Closures Containers are an integral part of the formulation of

an injection.

No container is totally insoluble or does not in some

way affect the liquid it contains, particularly if theliquid is aqueous.

The selection of a container for a particular injection

must be based on:1) The composition of the container.

2) The composition of the solution.

3) The treatment to which it will be subjected.


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Containertypes

1-Plastic 2-Glass


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Thermoplastic polymers have been established aspackaging materials for sterile preparations such as:

a) Large volume parenterals.

b) Ophthalmic solution.

c) Small volume parenterals.


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Principle problems exist in using these material

a-

Permeation

b-

Leaching

c-

Sorption


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a) Permeation: It is the movement of vapors and other

molecules in either direction through the wall of the plasticcontainer.

a) Leaching:Migration of constituents from the plastic into theproduct. Leaching may be a problem when certainconstituents in the plastic formulation such as plasticizers orantioxidants migrate into the product.

a) Sorption: (absorption and/or adsorption) of drug moleculesor ions on the plastic material. Sorption is a problem when

adsorption of a few drug molecules occurs on specificpolymers.

E.g.: Sorption of insulin, vitamin A acetate, and Warfarin sodiumhas been shown to occur on PVC bags and tubing when thesedrugs were present as additives in IV admixtures.


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1) Not breakable as glass

2) low weight

3) Flexible, e.g. the use of low density polyethylene

polymer for ophthalmic preparations makes it possibleto squeeze the side wall of the container and dischargeone or more drops without introducing contaminationinto the remainder of the product.

N.B. The flexible bags of polyvinyl chloride, currently inuse for large volume intravenous fluid, have the advantagethat no air interchange is required (the flexible wall simplycollapses as the solution flows out of the bag).


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1. They are not as clear as glass and thereforeinspection of the contents is impeded.

2. Many of the materials used will soften or melt underthe conditions of thermal sterilization.


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Glass is employed as the container material of choice formost SVIs.

It is composed of silicon dioxide with varying amounts ofother oxides such as sodium, potassium, calcium,

magnesium, aluminum, boron, and iron.

Classification of glass

Type I

borosilicateglass

Type II

soda-limetreated glass

Type III

soda-limeglass


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Type I glass is suitable for all products,although sulfur dioxide treatmentsometimes is used for a further increase inresistance.

Type II glass is suitable for e.g. for a solutionthat is buffered has a pH below 7 or is notreactive with glass.

Type III glass is suitable principally foranhydrous liquids or dry substances.


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The glass types are determined by the

following USP test

1-Powdered Glass Test:

It is performed on powdered glass, which exposesinternal surfaces of the glass compound.

2-Water Attack Test:

It is used only for type II glass and is performed on thewhole container, because of the dealkalinized surface.


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Physical characteristics :-

Glass containers must be:

1) Strong enough to withstand the physical shocks ofhandling and shipping.

2) Able to withstand the thermal shock resulting fromlarge temperature changes during processing.

3) Transparent to permit inspection of the content.

Commercially available containers vary in size from 0.5to 1000 ml


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Sizes up to 100 ml may be obtained as:

1) Ampoules

2) Vials

3) Bottles (larger sizes which is used for intravenousand irrigating solutions. Smaller sizes also are

available as cartridges). Easy opening ampoules that permit the user to break

off the tip at the neck constriction without the use of afile are weakened at the neck by scoring or applying a

ceramic paint with a different coefficient of thermalexpansion.


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Other examples are:

-Wide mouth ampoules with flat or roundedbottoms to facilitate filling with dry materials orsuspensions and various modifications of thecartridge for use with disposable dosage units.

Preparations that are light-sensitive must beprotected by:

1) Placing them in amber glass containers.

2) Enclosing f lint glass containers in opaquecartons and labeled to remain on thecontainer during the period of use.


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Silicone coatings are applied to containers to produce ahydrophobic surface e.g Means of reducing of thefriction of a rubber-tip of a syringe plunger.

The size of single dose containers is limited to 1000 ml

by the USP and multiple dose containers to 30 ml. Multiple dose vials are limited in size to reduce the

number of punctures for withdrawing doses thusreducing the risk of contamination.

(These may range in size from 1000 ml bottles to 1-ml or less ampoules, vials, or syringes)


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The USP requires that all multiple dose vials mustcontain an antimicrobial agent.

In spite of the advantageous flexibility of dosageprovided by multiple dose vials, single dose

disposable container units provide the clearadvantage of greater sterility assurance and patientsafety.


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Rubber Closures

They are used to permit introduction of a hypodermicsyringe into a multiple dose vial and provide forresealing as soon as the needle is withdrawn.

Each vial is sealed with a rubber closure held in placeby an aluminum cap.

They are composed of multiple ingredients that areplasticized and mixed together at an elevated

temperature on milling machines. The plasticized mixture is placed in molds and

vulcanized (cured) under high temperature andpressure.


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Physical properties to be considered in selection ofparticular formulation include

A-Elasticity B- Hardeness C-Tendencyto fragment

D-Permeability

to vapor

transfer.


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It is critical in establishing a seal with the lip and neckof a vial or other opening and in resealing afterwithdrawal of a hypodermic needle from a vial closure.

It should provide firmness but not excessive resistance

to the insertion of a needle through the closure.


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It should be minimal.

It is controlled by appropriate selection of ingredients.


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The ingredients dispersed throughout the rubbercompound may be subject to leaching into the productcontacting the closure.

To reduce the problem of leachable, coatings have

been applied to the product contact surfaces of closurewith various polymers, the most successful beingTEFLON.

Many disc closures are being used now, particularly in

the high speed packaging of antibiotics.


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Slotted closures are used on freeze-dried productsto permit the escape of water vapor since they areinserted only partway into the neck of the vial untilcompletion of the drying phase of the cycle.

Intravenous solution closures often have permanentholes for adapters of administration sets; irrigatingsolution closures usually are designed for pouring.


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Functional area:-

To achieve the goal of a manufactured sterile product ofhigh quality five functional production areas will be

involved:

1-Warehousing

orProcurement.

2-Compounding

.

3-Materials

support .

4-Aseptic

filling .

5-Packagingand

Quarantine.


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Contaminantsinclude:

1-

Dust

2-Lint

3-Microorganism


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The design and control of an aseptic area is directedtoward reducing the presence of these contaminants sothat they are no longer a hazard to aseptic

filling.

Although the aseptic area must be adjacent to supportareas so that an efficient flow of components may beachieved, barriers must be provided to minimize

ingress of contaminants to the critical aseptic area.


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Such barriers may consistof:

A- Sealedwalls.

B- Manual orAutomatic

doors.

C- Airlockpass- throughs.

D- Ports ofvarious types.

E- Plasticcurtains.

General Guidance for Developing


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p gFormulations ofParenteral Drugs

1. Pharmacokinetics of the drug: These include the rate of absorption (for routes other

than intravenous or intra arterial), distribution,metabolism and elimination. They will affect;

the dose of drug,

the dosage regimen,

the selected route of administration

the type of formulation.


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1. Pharmacokinetics of the drug:

For example:

If the dosage regimen requires frequent injections,then a multiple dose formulation must be developed.

If the drug is distributed quickly from the injection,complexing agents or viscosity enhancing agents maybe added to the formulation to retard drug dissolutionand transport.


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2. Drug solubility:

If the drug is insufficiently soluble in water, then a co-solvent or a solute that sufficiently maintains the drugin solution must be added.

3. Drug stability:

If the drug has significant degradation problems insolution, then a freeze-dried or other sterile soliddosage form must be developed. Stability might affectthe size and type of packaging system used. Stability

also dictates the expiration date of the product that inturn will determine the storage conditions.


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4. Compatibility of drug with potential formulationadditives:

Stabilizers such as buffers and anti oxidants, whilechemically stabilizing the drug may also catalyze otherchemical degradation reactions.

Excipients and certain drugs can form insolublecomplexes.

Peroxide impurities in polymers may catalyze oxidativedegradation reactions with some drugs such as

proteins. These problems are avoided by preformulation

screening studies.


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5. Desired type of packaging:

Knowing the type of final package early in thedevelopment process aids the formulation scientist inbeing sure that the product will be compatible and

elegant in the packaging system.


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Production

Procedures

A-

Cleaningcontainers

andequipment

B-

Product

preparation

C-Filtration

D-

Filling

E-

Sealing

F-

Sterilization


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A-Cleaning containers and equipment:

Residues from debris as dust, fibers, chemical filmsand other materials arising from atmosphere, cartons,the manufacturing process and human hands must beremoved from equipment before it will be suitable forreuse.

The selection of the cleaning machine type will bedetermined by:

The physical type of containers. The type of contamination.

The number to be processed in a given period of time.


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Characteristics of Machinery:

The liquid or air treatment must be introduced in amanner so that it will strike the bottom of the inside ofthe inverted container, spread in all directions, and

smoothly flow down the walls and out the openingwith a sweeping action.

The pressure of the jet stream should be such thatthere is minimal splashing and turbulence insidebecause splashing may prevent cleaning all areas andturbulence may redeposit loosened debris.


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Characteristics of Machinery:

The container must receive a concurrent outside rinse.

The cycle of treatment should provide a plannedsequence alternating very hot and cool treatments.

The final treatment should be an effective rinse withWFI.

All metal parts coming in contact with the containersand with the treatments should be constructed ofstainless steel or other non-corroding and non-contaminating material.


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Treatment cycle

The cycle of treatments to be employed will vary withthe condition of the containers to be cleaned.

Loose debris is generally removed by vigorous rinsingwith water. However, a thermal-shock sequence in thecycle is usually employed to aid, by expansion andcontraction, loosening of debris that may be adheringto the wall of the container.


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Treatment cycle

Surfaces should be scrubbed with a stiff brush usingan effective detergent and paying attention to joints,cervices, screw threads and other structures where

debris is accumulated.

Sometimes only an air rinse is used for new containersif only loose debris is present.

The final rinse, whether air or WFI must be ultracleanby the end of the cycle.


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Treatment cycle

Only new containers are used for parenterals soimprovements have been made in maintaining theircleanliness during shipment from the manufacturer

through tight low shedding packaging, includingplastic blister packs.


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Machinery for

containers

I. The manualloading type

II. The large

conveyor vialwasher

III. The continuous

automatic lineoperation


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I. The manual loading type:

The jet tubes are arranged on arms like the spokes of awheel, which rotate around a center post throughwhich the treatments are introduced. An operator

places the unclean containers on the jet tubes as theypass the loading point and removes the cleancontainers as they complete one rotation.


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II. The large conveyor vial washer:

It uses a row of jet tubes across a conveyor belt. Thebelt moves the inverted containers and discharges theclean containers into a sterilizing oven which

discharges them through a wall into a clean room forfilling.


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III. The continuous automatic line operation:

It is capable of cleaning hundreds of containers an hour.The vials are shed into the rotary rinser in the foreground,transferred automatically to the covered sterilizing tunnel

in the center, conveyed through the wall in thebackground and discharged into the filling clean room.

H dli f l i


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Handling after cleaning

The wet rinsed containers must be protected fromrecontamination as wet surface will collectcontaminants more than a dry surface, this protectioncould be by a laminar flow of air within a stainless steel

box or within a sterilizing tunnel.

Microorganisms are more likely to grow in thepresence of moisture, therefore wet clean containersshould be dry-heat sterilized as soon as possible afterwashing, and doubling the heating period generally isadequate also to destroy pyrogens.


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Closures

The normal procedures for cleaning closures calls for agentle agitation in a hot solution of a mild water softener ordetergent, the closures are removed from the solution andrinsed (f lush rinsing) several times with filtered WFI.

The wet closures are carefully protected fromenvironmental contamination, sterilized (usually byautoclaving) and stored in closed containers until ready foruse.

The equipment used for washing large numbers of closuresis usually an agitator or horizontal basket type automatic

washing machine.


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Closures

This cleaning and sterilizing processes must bevalidated for rendering the closures free frompyrogens. Actually the WFI must remove pyrogenssince autoclaving does not destroy pyrogens.

Some freeze-dried products require extremely dryclosures to avoid desorption of moisture from the

closure into the moisture-sensitive powder so theclosures are subjected to vacuum drying at 100 0C forhours following the steam sterilization.


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B-Product Preparation:A master formula would have been developed and

be on file. Each batch formula sheet should beprepared from the master and confirmed foraccuracy.

The measurements of quantities of ingredients arecomputer controlled.

The order of mixing of ingredient affect theproduct, particularly those of large volume requiresconsiderable mixing time.


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B-Product Preparation:

Parenteral dispersions (colloids, emulsions andsuspensions) provide problems such as;

Achieving and maintaining proper reduction in particlesize under aseptic conditions.

Must be kept in a uniform state of suspension throughoutthe preparative transfer and subdividing operations.

Proteins are extremely sensitive to many environmentaland processing conditions as temperature, mixing time and

speed, pH and contact time with various surfaces sodevelopment studies must minimize the adverse effects ofthe process on the activity of the protein.


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C- Filtration:

If the product is a solution so it must be filtered after ithas been compounded.

The filtration clarifies the solution. A further step is toremove the particulate down to 0.2 m in size; this willeliminate microorganisms and will accomplish coldsterilization.


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C-Filtration

Filtration functions by one or more of the following: Sieving or screening.

Entrapment or impaction (when a particle smallerthan the dimensions of the passage way pore becomeslodged in a turn or impacted on the surface of thepassage way).

Electrostatic attraction (causes particles opposite in

charge to that of the surface of the filter pore to beheld on the surface).

b f l


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Membrane filtersThese filters are used exclusively for parenteral

products because they are;

Non-shedding

Non-reactive

Disposable

Particle-retention effectiveness


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Membrane filters

N.B. Non reactivity does not apply in all cases wherepolypeptide products may be adsorbed through somemembrane filters. So we use polysulfone and polyvinyldifluoride (PVDF) which are non-adsorptive for theseproducts.

The most common membrane filters are composed ofcellulose esters, nylon, polysulfone, polycarbonate,PVDF or Teflon.

There are reusable membrane filters made of sintered

glass or sintered stainless steel or sintered metal. Each filter should be tested for integrity before and

after use.


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The integrity tests performed are either;

a) The bubble point test or,

b) The diffusion (forward flow) test.

a)The bubble point test:

Used for small filters. It keeps raising pressure until a pressure is obtained

where air bubbles first appear downstream and this isthe bubble point (the bubble point pressure is

inversely proportional to the pore size).


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b)The diffusion (forward flow) test:

Used for large filters.

It raises pressure to some point below the knownbubble point pressure, and then diffusion flow (usually

in ml/min) is measured. For example a 0.2m cellulose ester filter will bubble at

about 50 psig or a diffusive flow rating of no greaterthan 13 ml/min at a pressure of 40 psig.


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If the filter is wetted with other liquids such as aproduct, the bubble point will differ and must be

determined experimentally.

If the bubble point is lower than the rated pressure sothe filter is defective (leakage), probably because of arupture or tear, and should not be used.

If the bubble point is higher than the rated pressure so

the filter is clogged.


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Today, clean, sterile, pretested, disposable assembliesfor small as well as large volumes of solutions areavailable commercially.

New evidence is being reported that 0.2 m filters do

not remove all possible microbial contaminationsnecessitating the need to use 0.1 m membrane filters.


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IV. Filling

During the filling operation, the product must betransferred from a bulk container and subdivided intodose containers.

This operation exposes the sterile product to theenvironment and equipment until it can be sealed inthe dose container. Therefore this operation is heldwith a minimum exposure time, even though

maximum protection is provided by filling under ablanket of HEPA-filtered laminar flow-air within anaseptic area.


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Filling of Liquids It is done by forcing a measured volume of the liquid

repetitively through an orifice in a delivery tube that isintroduced into the container.

The size of the delivery tube will vary from that of about a20 gauge hypodermic needle to a tube half in or more indiameter.

The delivery tube should be as large in diameter as possibleto reduce the resistance and decrease the velocity of flow of

the liquid. Mobile liquids are easier to transfer and subdivide than

viscous, sticky liquids, which require heavy duty machineryfor rapid filling.


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For heavy, viscous liquids, a sliding piston valve, the turn

of an auger in the neck of a funnel, or the oscillation of arubber diaphragm may be used.

A drop of liquid normally hangs at the tip of the delivery

tube causing the neck of an ampoule to be wet as thetube is withdrawn, unless the drop is retracted.

Since the liquid will be in intimate contact with theparts of the machine, so these parts should beconstructed of non-reactive materials such as,borosilicate glass or stainless steel.


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Because of the concern for particulate matter in

injectable preparations, a final filter (usually amembrane filter) is inserted between the filter and thedelivery tube. This final membrane filter has a porosityof 1m and treated to have a hydrophobic edge (this isnecessary to reduce the risk of membrane rupture dueto filling pulsations).

N.B. The filter reduces the liquid flow and reduces the

efficiency of drop retraction; sometimes makes itdifficult to control delivery volume as precisely aswould be possible without the filter.


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Methods ofliquid filling

Volumetricfilling

Time -pressure(time-gravity)filling

Net weigh


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Stainless steel syringes are required with viscousliquids because glass syringes cant withstand the highpressure developed during delivery.

When high speed filling rates are desired, multiplefilling units are often joined together in anelectronically coordinate machine.

When the product is sensitive to metals, peristaltic-pump filler may be used because the product comes incontact only with silicone rubber tubing. However,there is some sacrifice of filling accuracy.

1-Volumetric Filling


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A product tank is connected to the filling system thatis equipped with a pressure sensor.

The sensor continuously measures pressure and sendvalues to the PLC system that controls the flow ofproduct from tank to filling manifold.

Product flow occurs when tubing is mechanically un-

pinched and stops when tubing is mechanicallypinched.

2-Time-pressure (time-gravity) filling


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The filling apparatuses do not contain mechanical

moving parts in the product stream (the product isdriven by pressure, mainly nitrogen) thus it ispreferable for proteins that are quite sensitive to shearforces.

Advantage of the time-pressure filling

operations


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Cornwall Pipet (Becton Dickinson)

Device It is a device for providing greater speed of filling.

It has a two-way valve between the syringe and theneedle and a means for setting the stroke of thesyringe so that the same volume will be delivered eachtime.

Clean, sterile, disposable assemblies operating on thesame principle are useful in hospital pharmacy orexperimental operations.


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Filling of solid

Filling of solids is more difficult than that ofliquids; this is because the rate of flow of solids is

slow and often irregular. Even though, a containerwith a large-diameter opening is used to facilitatefilling, the risk of spillage is ever present.

Methods for filling


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Some sterile solids are subdivided into containers byindividual weighing. The quantity filled into thecontainer finally is weighed on a balance (this is a slowprocess).

If the solid is in granular form, it will flow more freely.An adjustable cavity in the rim of a wheel is filled byvacuum and the contents held by vacuum until thecavity is inverted over the container. The solid material

is then discharged into the container by a puff ofsterile air.

Methods for filling

solids


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Filled containers should be sealed as soon as possibleto prevent the contents from being contaminated bythe environment.


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Types ofampoule

seals

Tip-seals(bead-seals)

Pull-seals

Tip seals (bead seals)


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Tip-seals (bead-seals)

Made by melting enough glass at the tip of the neck ofan ampoule to form a bead and close the opening.

It can be done rapidly in a high-temperature gas-

oxygen flame To produce a uniform bead, the ampoule neck must

be heated evenly on all sides, such as by burners onopposite sides of stationary ampoules or by rotating

the ampoule in a single flame.

Ti l (b d l )


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Tip-seals (bead-seals)

Excessive heating will cause expansion of the gaseswithin the ampoule against the soft bead and cause abubble to form.

Insufficient heating will leave an open capillary throughthe center of the bead. An incompletely sealedampoule is called a leaker.

Pull seals


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Pull-seals Made by heating the neck of the ampoule below the tip,

leaving enough of the tip for grasping with forceps orother mechanical device after the glass has beensoftened.

The ampoule is rotated in the f lame from a single burner.

Pull-sealing is slower but the seals are more accuratethan tip-sealing.

Powder ampoules or other types having a wide opening

must be sealed by pull-sealing.

Fracture of the neck of ampoule


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This may occur during sealing if wetting of the necks occurred

at the time of filling.Problems of wet necks

Fracture of the necks of ampoules during sealing.

Increase the frequency of bubble formation and unsightlycarbon deposits if the product is organic.

To prevent the decomposition of a product, it is sometimesnecessary to displace the air in the space above the product in

the ampoule with an inert gas (as nitrogen or carbon dioxide)during or after filling with the product. Then immediately theampoule is sealed before the gas can diffuse to the outside.

Vials and bottles


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These are sealed by closing the opening by a rubberclosure. The large opening makes the introduction ofcontaminants much easier than with ampoules.

Therefore, during the critical exposure time, the opencontainers should be protected from the ingress ofcontamination, preferably with a blanket of HEPA-filtered laminar airflow.

Vials and bottles


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Closures are preferably inserted mechanically using anautomated process especially with high speedprocessing. Closures surfaces are halogenated or treatedwith silicone to reduce the friction so that the closure

slide more easily through a chute and into the containeropening.

When small lots are encountered, manual stopperingwith forceps may be used, but this poses greater risk of

contamination than automated process.

Container-closure integrity test:


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It measures the ability of the seal between the glass orthe plastic containers opening and the rubber closureto remain tight fit and resist any entrance of microbialcontamination during product shelf life.

Rubber closures for use with intravenousadministration sets often have a permanent holethrough the closure, so a thin rubber disk overlayed

with a solid aluminum disk is placed between an innerand outer aluminum cap, thereby providing a seal forthe hole in the closure.

N.B.Interaction among environmental conditions, the

tit t i th l d th d t lt


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constituents in the closure, and the product may resultin undesirable closure changes such as increased

brittleness or stickiness which may cause loss ofcontainer-closure seal integrity.

Thus shelf life integrity is an important consideration inclosure selection and evaluation.

Single-layered aluminum caps may be applied by means

of a hand crimper known as the Fermpress. Double ortriple-layered caps require greater force for crimping;therefore, heavy-duty mechanical crimpers are required.


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Whenever possible, the parenteral product should besterilized after being sealed in its final container(terminal sterilization).

Since this usually involves a thermal process (althoughthere is a trend in applying radiation sterilization tofinished products), due consideration must be given tothe effect of the elevated temperature on the stability

of the product.

diation sterilization:


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This is gaining some momentum as an alternativeterminal sterilization method.

There has been limited understanding of the molecularchanges that may occur in drug and excipientsmolecules under exposure to the high-energy gammaradiations.

Lower energy beta particles (electron beam) radiationhas seen some success.

The use of radiation for the sterilization of materialssuch as plastic medical devices is well established.


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May be used for a few dry solids that are not affectedadversely by the high temperatures and by therelatively long heating period required.

This is mostly applied to the sterilization of glasswareand metalware.

After sterilization, the equipment will be sterile, dry,and pyrogens-free (if the sterilization period is long

enough).


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It is the most commonly used and the most effectivemethod for the sterilization of aqueous liquids orsubstances that can be penetrated by steam.

A survival probability of at least is readily achievablewith terminal autoclaving of a thermally stableproduct.

Since the temperature employed in an autoclave is

lower than that for dry-heat sterilization, equipmentmade of rubber or polypropylene may be sterilized ifthe time and temperature are controlled carefully.


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For some products, such as dextrose injection, ashortened cycle using an autoclave designed to permit arapid temperature rise and rapid cooling with water

spray or other cooling methods will make it possible touse this method.

It is ineffective in anhydrous conditions, such as within

a sealed ampoule containing a dry solid or an anhydrousoil.


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Other products that will not withstand autoclavingtemperatures may withstand marginal thermal methodssuch as tyndallization or pasteurization, e.g. 10 to 12 hours at60C.

These methods maybe rendered more effective for someinjections by the inclusion of a bacteriostatic agent in theproduct.

Articles to be sterilized must be probably wrapped or placedin suitable containers as bags or sheets made of steam-penetrating paper or polymeric materials.


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Since the goal of sterilization is to kill microorganisms,the ideal indicator to prove the effectiveness of the

process is a resistant form of an appropriatemicroorganism, normally resistant spores (a biologicalindicator or BI).


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Therefore during validation of a sterilization process,BIs of known resistance and numbers are used inassociation with physical-parameter indicators, such

as recording thermocouples, color-change and meltingindicators.

The number of the spores and their resistance in BIsused for validation studies must be accurately known.

Additionally, the manner in which BIs are used invalidation is critical and must be controlled carefully

Freeze-drying (Lyophilization)


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y g y p

Many parenteral drugs, particularly

biopharmaceuticals, are too unstable in solution, sosuch drugs should be subjected to freeze drying.

Mechanism of freeze-drying

The unstable drugs in solution are placed in achamber where the combined effects of freezing anddrying under low pressure will remove the solvent andresidual moisture from the solute components,resulting in a dry powder that has sufficient long-termstability.

Stages of freeze-drying:


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Stages of freeze drying: Freezing stage

Primary drying stage

Secondary drying stage


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Factors affecting the process rate:


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g p

The direction of heat and mass transfer causes the topof the product to dry first with drying proceedingdownward to the bottom of the vial.

Therefore, as drying proceed; there is a three layersystem in each vial;

a) the upper dry product,

b) the middle sublimation frontc) the lower frozen liquid product.



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As the dried layer increases, it becomes the source ofgreatest resistance to the transfer of mass out of thevials.

The actual driving force for the process is the vaporpressure difference between the vapors at the surfacewhere drying of the product is occurring (the drying

boundary) and that at the surface of the ice on thecondenser.

Factors affecting formulation:


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The active constituent of many pharmaceuticalproducts is present in such a small amount that iffreeze-dried alone its presence would be hard to detect

visually. Therefore, bulking agents are used in freezedried formulations.

The most commonly used bulking agent in freeze-drying is mannitol.



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Also most freeze-dried formulations must containbuffering agents (e.g. Sodium or potassium

phosphate, sodium acetate and sodium citrate) in order

to buffer the product and/or to protect the activeingredient from the adverse effects of freezing and/ordrying.

Sucrose, trehalose, dextran and amino acids such asglycine are commonly used lyoprotectants.



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Each of these substances affect the appearancecharacteristics of the plug, such as whether dull andspongy or sparkling and crystalline, firm or friable,

expanded or shrunken, and uniform or striated.

Therefore the formulation of a product to be freeze-dried must include consideration to the characteristics

desired in the dried plug.

Modifications in the process and equipment:


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p q p

A product may be frozen in a bulk container or in traysrather than in the final container and then handled asa bulk solid; this requires continuation of the asepticprocessing as long as the product is exposed to theenvironment.

Available freeze-dryers range in size from small

laboratory units to large industrial models.

Modifications in the process and equipment:


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Their selection depends on the following factors: The tray area required

The volume of water to be removed

How the chamber will be sterilizedWhether internal stoppering is required

Whether separate freezers will be used for initialfreezing and condensation of the product

The degree of automatic operation desired

Advantages of freeze-drying: Product is stored in dry state (few stability problems)


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Product is stored in dry state (few stability problems)

Product is dried without elevated temperature

Good for oxygen and/or air-sensitive drugs

Rapid reconstitution time.

Constituents of the dried material remain

homogenously dispersed.

Advantages of freeze-drying:


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Sterility of the product can be achieved andmaintained.

Used now for the research in the preservation ofhuman tissues.

Used in food industry.

Used in recombinant DNA technology. Proteins andpeptides must be freeze dried.

Disadvantages of freeze-drying:


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Volatile compounds may be removed by high vacuum.

Single most expensive unit operation.

Stability problems associated with individual drugs.

Some issues associated with sterilization and sterility

assurance of the dryer chamber and aseptic loading ofvials into the chamber.

Desired characteristics of freeze-driedproducts:


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products:

Intact cake Sufficient strength

Uniform color

Sufficiently dry

Sufficiently porous

Sterile

Free of pyrogens

Free of particulates

Chemically stable

Quality Assurance and Control


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The responsibility for achieving this quality is divided

into:a) Quality Assurance (QA)

It relates to the studies made and the plans developedfor ensuring quality of a product prospectively, with a

final confirmation of achievement.b) Quality Control (QC)

It embodies the carrying out of these plans duringproduction and includes all of the tests and evaluationsperformed to be sure that quality exists in a specific lotof a product.

Sterility test


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Sterility test

The primary official test is performed by means offiltration.

To give greater assurance that viable microorganismswill grow, if present, the USP requires that all lots ofculture media be tested for their growth-promotioncapabilities.

Sterility test


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y

It is intended primarily as a check test on theprobability that a previously validated sterilizationprocedure has been repeated or to give assurance of itscontinued effectiveness.

In the event of a sterility-test failure, the immediateissue concerns whether the growth observed camefrom viable microorganisms in the product (true

contamination) or from adventitious contaminationduring the testing (false positive).

Pyrogen testing


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Pyrogen testing

a)Rabbit method

In vivo test where three healthy rabbits withtemperature not more than 39.8C are injected by the

test solution in the ear vein, if the temperature of thethree rabbits is raised so pyrogens present.

b)Limulus Amebocyte Lysate LAL or BacterialEndotoxins Test BET test

It is more sophisticated and rapid method

b)Limulus Amebocyte Lysate LAL or BacterialE d t i T t BET t t


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Endotoxins Test BET test

(LAL) test, is employed for the detection ofendotoxin-typepyrogens.

A test sample is incubated

with amebocyte lysate from the blood

of horseshoe crab, Limulus Polyphemus.

A pyrogenic substance will cause a gel to form. This is as aresult of clottable protein from the amebocyte cells reactingwith the endotoxins.

N.B:


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Alcoholic solvents cause precipitation of the lysate andtherefore must be avoided.

Several proteins at high concentrations tend to

produce gel even without endotoxin and should bediluted to appropriate concentrations before the test.

It is a more sensitive, rapid and easier method than the

rabbit method.

Particulate Evaluation


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It has been shown that particles of lint, rubber, insoluble

chemicals and other foreign matter can producephlebitis and/or emboli in the vital organs of animal andman.

The USP specifies that good manufacturing practicerequires each final container of an injection to beindividually subjected to visual inspection by humaninspectors under a good light baffled against reflection

into the eye and against a black and white background.


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Particulate Evaluation

Lightobscuration

test

Microscopic

test

Container/

closureintegrity test

Safety test

Light Obscuration test:


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g It uses an electronic instrument designed to count and

measure the size of particles by means of a shadowspread out by the particle as it passes through a highintensity light beam.

If the injection is not a clear, colorless solution (e.g.emulsion) or it exceeds the limits specified for the lightobscuration test, it is to be subjected to the microscopic

test.

The Microscopic test:


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The Microscopic test:

It consists of filtering a measured sample of solutionthrough a membrane filter under ultraclean conditionsand then counting the number of particles on the

surface of the filter, using a microscope and obliquelight at 100X magnification.

Container/Closure integrity test:


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g

This test is performed by applying a negative pressure

within an incompletely sealed ampoule which issubmerged entirely in a deeply colored dye solution(mostly 1% methylene blue solution is employed). Ifthe closure leaks, the color of the dye will be visible in

the ampoule. Leakers are of course discarded.

Vials and bottles are not subjected to such a leaker test

because the sealing material (rubber stopper) is notrigid, therefore results from this test will bemeaningless.

Safety test:


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Because it is entirely possible for a parenteral product topass the routine sterility test, pyrogens test andchemical analysis, and still causes unfavorable reactionswhen injected, a safety test in animals is essential,

particularly for biological products, to provideadditional assurance that the product does not haveunexpected toxic properties.

Packaging and Labeling


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a)Packaging The packaging should provide sample protection for the

product against physical damage from shipping,handling, and storage as well as protecting light-

sensitive materials from ultraviolet radiation.

The USP includes the following requirements for


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g qthe packaging and storage of injections;

1. The volume of injection in single-dose containers isdefined as that which is specified for parenteraladministration at one time and is limited to a volumeof 1L.

2. Parenterals intended for intraspinal, intracisternal, orperidural administrations are packaged only in single-dose containers.

3. No multiple-dose container shall contain a volume of

injection more than that sufficient to permit thewithdrawal and administration of 30 ml unless anindividual monograph specifies otherwise.

Containers for injections packaged for use in


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4. Containers for injections packaged for use in

hemofiltration or as irrigation solutions may bedesigned to empty rapidly and may contain a volumein excess of 1L.

5. Injections intended for veterinary use are excusedfrom the packaging and storage requirementsconcerning the limitation to single-dose containersand to volume of multiple-dose containers.

Labeling designates all labels, and other written,


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g g , ,printed, graphic matter upon an immediate container or

upon, or in, any package or wrapper in which it isenclosed, with the exception of the outer shippingcontainer.

Labeldesignates that part of the labeling upon theimmediate container.

The label states: The name of the preparation,


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p p

The proportion of each constituent,

The name of the vehicle,

The volume of liquid to be added to prepare an injectionor suspension from a dry preparation,

The route of administration,A statement of storage conditions,

The expiration date,

The name of the manufacturer or distributor,

An identifying lot number

Parent MSA Final (1)

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