463 PHT Parenteral Quality Control

8/3/2019 463 PHT Parenteral Quality Control

1/40

463 PHT

Compendia requirement for parenteral

dosage forms

Nahla S Barakat, PhD

Dept. of Pharmaceutics

College of Pharmacy

1430-2009

11--331 463 PHT


2/40

Parenteral quality Control

Parenteral articles are preparations intended for injection

through the skin or other external boundary tissue, rather than

through the alimentary canal.

They are prepared by methods designed to ensure that theymeet the pharmacopeial requirements for sterility, Pyrogens,

Particulate matter and other contaminants

11--332 463 PHT


3/40

Nomenclature

[DRUG] injection

[DRUG] for Injection

[DRUG] Injectable emulsion

[DRUG] Injectable suspension

[DRUG ] for Injectable suspension

11--333 463 PHT


4/40

Large-volume intravenous solution: is a single

dose injection that is intended for iv use and ispackaged in container labeled as containing

more than 100 ml

Small-volume intravenous injection: is applied

to an injection that is packaged in containers

labeled as containing 100 ml or less.

11--334 463 PHT


5/40

Ingredients Vehicles and added substances

Aqueous vehicles:

Types of water: Purified water

Sterile Purified water

Sterile water for injection

Bacteriostatic water for Injection Sterile water for inhalation

Sterile water for Irrigation

11--335 463 PHT


6/40

Drinking water: may be used in the early stage of chemical

synthesis and in the early stages of the cleaning of

pharmaceutical manufacturing equipments.

Purified water: (USP monograph), is used in the preparation of

some bulk pharmaceutical chemicals, do not use purified

water in preparations intended for parenteral administration.

Must be protected from microbial proliferation.

Sterile purified water: Is purified water that is packaged and

rendered sterile, contains no antimicrobial agent.

It is not for parenteral administration

11--336 463 PHT


7/40

Water for injection: is intended for use in the preparation of

parenteral solutions and in the preparation of some bulkpharmaceutical chemicals. It must be protected from

microbial contamination.

It meets the requirements of all of the tests under purified

water + Bacterial Endotoxin Test.

Sterile water for injection: It is prepared from water for

injection that is sterilized and suitably packaged. It contains no

antimicrobial agent. It is used as diluents for parenteral

products.

It is packaged in single dose container not larger than 1-Litresize.

Bacterial Endotoxin Test + Particulate Matter Test.

11--337 463 PHT


8/40

Bacteriostatic water for injection: is sterile water for injection

which contain on or more suitable antimicrobial agents. It is

intended to be used as diluent for parenteral products.

It is packaged in single or multiple-dose containers, not larger

than 30 mL size.

NOT FOR USE IN NEWBORNS

+ Antimicrobial Preservatives-effectiveness

Sterile water for irrigation: It contains no antimicrobial agent.

It is intended to delivered rapidly.

For irrigation only, Not for injection.

Packaged in single-dose containers of larger than 1-liter size.

- Particulate Matter Test.

11--338 463 PHT


9/40

Sterile water for inhalation: Is intended for use in inhalators

and in the preparation of inhalation solutions.

Not use for parenteral administration.

+ Bacterial Endotoxin Test.

11--339 463 PHT


10/40

Other vehicles:

Fixed oil used in non- aqueous injection are of vegetable

origin, have no taste, no odour suggesting rancidity,

Have a saponification value 185-200,

Have an Iodine value between 79-141.

Test for:

Unsaponifiable matter

Free Fatty acid

11--3310 463 PHT


11/40

Added substances:

Suitable substances may be added to preparations intended

for injection to increase stability or usefulness.Observe special care in the choice and use of added

substances in preparations for injection that areadministered in a volume exceeding 5 ml.

The following maximum limit

For agents containing mercury and cationic SAA, 0.01%

For those of the types of chlorobutanol, cresol, phenol,0.5%

For sulfur dioxide, sulfite, bisulfite, metabisulfite, 0.2%

11--3311 463 PHT


12/40

Substances to prevent the growth of microorganisms must be

added to preparations intended for injection that are packagedin multiple-dose containers, except the active ingredients are

themselves antimicrobial.

Such substances also meet the requirements of Antimicrobial

preservatives-effectiveness, and Antimicrobial Agents-

Content.

The air in the container may be evacuated or be displaced by a

chemically inert gas, when specified in the monograph,

information regarding sensitivity of the article to oxygen.

11--3312 463 PHT


13/40

Volume in container

An injection container is filled with a volume in slight excess of

the labeled size

Determination of filled volume:

10 mL or more 1 container

3-10 mL 3 containers

Less than 3 mL 5 containers11--33463 PHT13

Viscous liquidMobile liquidLabeled size

0.12 mL0.1 mL0.5 mL

0.15 mL0.1 mL1 mL

0.25 mL0.15 mL2 mL0.5 mL0.3 mL5 mL

0.7 mL0.5 mL10 mL

0.9 mL0.6 mL20 mL

3%2%50 mL or more


14/40

Take up individually the content of each container into a dry

hypodermic syringe fitted with 21-guage needle, 2.5 cm

length.

Discharge the contents of the syringe into a dry cylinder or in

dry tared beaker, weigh the solution.

The content of two or three containers (each 1 or 2-mL) may

be pooled for the measurement using separate dry syringe.

The volume is not less than the labeled volume in the case of

containers examined individually,

or in the case of pooled samples, is not less than the sum of the

labeled volumes of the containers taken collectively.

For injections containing oil, warm the containers and shake

them thoroughly and remove the content. Cool to 25 C before

measuring the volume.

11--33463 PHT14


15/40

PARTICULATE MATTER IN INJECTIONS

Particulate matter in injections and parenteral infusions

consists of mobile undissolved particles, other than gas

bubbles, unintentionally present in the solutions.

For the determination of particulate matter, two procedures,

Method 1 (Light Obscuration Particle Count Test) and Method2 (Microscopic Particle Count Test), are specified hereinafter.

When examining injections and parenteral infusions for sub-

visible particles Method 1 is preferably applied. However, it

may be necessary to test some preparations by the lightobscuration particle count test followed by the microscopic

particle count test to reach a conclusion on conformance to

the requirements.

11--33463 PHT15


16/40

When Method 1 is not applicable, e.g. in case of preparations

having reduced clarity or increased viscosity, the test should

be carried out according to Method 2, Emulsions, colloids, andliposomal preparations are examples.

Similarly, products that produce air or gas bubbles when

drawn into the sensor may also require microscopic particlecount testing.

If the viscosity of the preparation to be tested is sufficiently

high so as to preclude its examination by either test method, a

quantitative dilution with an appropriate diluents may be made

to decrease viscosity, as necessary, to allow the analysis to be

performed

11--33463 PHT16


17/40

METHOD 1. LIGHT OBSCURATION PARTICLE COUNT TEST

Use a suitable apparatus based on the principle of light

blockage which allows an automatic determination of the size

of particles and the number of particles according to size.

11--33463 PHT17


18/40

11--33463 PHT18

General precautions

The test is carried out under conditions limiting particulate

matter, preferably in a laminar-flow cabinet.

Very carefully wash the glassware and filtration equipment

used, with a warm detergent solution and rinse with abundant

amounts of water to remove all traces of detergent.

Immediately before use, rinse the equipment from top tobottom, outside and then inside, with particle-free water.

Take care not to introduce air bubbles into the preparation to

be examined, especially when fractions of the preparation are

being transferred to the container in which the determination is

to be carried out.


19/40

Method

Mix the contents of the sample by slowly inverting the

container 20 times successively. If necessary, cautiouslyremove the sealing closure. Clean the outer surfaces of the

container opening using a jet of particle-free water and

remove the closure, avoiding any contamination of the

contents. Eliminate gas bubbles by appropriate measures such

as allowing to stand for 2 min or sonicating.

For large-volume parenterals, single units are tested.

For small-volume parenterals less than 25 ml in volume, the

contents of 10 or more units is combined in a cleaned

container to obtain a volume of not less than 25 ml;

11--33463 PHT19


20/40

the test solution may be prepared by mixing the contents of a

suitable number of vials and diluting to 25 ml with particle-

free water or with an appropriate particle-free solvent when

particle-free water is not suitable.

Small volume parenterals having a volume of 25 ml or more

may be tested individually. Remove four portions, each of not less than 5 ml, and count

the number of particles equal to or greater than 10 m and 25

m.

Disregard the result obtained for the first portion, and calculatethe mean number of particles for the preparation to be

examined.

11--33463 PHT20


21/40

Evaluation

For preparations supplied in containers with a nominalvolume of more than 100 ml, apply the criteria of test 1.A.

The preparation complies with the test if the average number

of particles present in the units tested does not exceed 25 per

mL equal to or greater than 10 m and does not exceed 3 per

mL equal to or greater than 25 m.

11--33463 PHT21


22/40

For preparations supplied in containers with a nominal

volume of less than 100 ml, apply the criteria of test 1.B. The preparation complies with the test if the average number

of particles present in the units tested does not exceed 6000

per container equal to or greater than 10 m and does not

exceed 600 per container equal to or greater than 25 m.

If the average number of particles exceeds the limits, test the

preparation by the Microscopic Particle Count Test.

11--33463 PHT22


23/40

METHOD 2. MICROSCOPIC PARTICLE COUNT TEST

The microscope is equipped with an ocular micrometer

calibrated with an objective micrometer, a mechanical stage

capable of holding and traversing the entire filtration area of

the membrane filter, two suitable illuminators to provide

episcopic illumination in addition to oblique illumination, andis adjusted to 100 10 magnifications.

11--33463 PHT23


24/40

Test 2.A Solutions for parenteral infusion or solutions for

injection supplied in containers with a nominal content of

more than 100 mL. The preparation complies with the test if the average number


mL equal to or greater than 10 m and does not exceed 2 per

mL equal to or greater than 25 m. Test 2.B Solutions for parenteral infusion or solutions for

injection supplied in containers with a nominal content of less

than 100 ml.

The preparation complies with the test if the average number


container equal to or greater than 10 m and does not exceed

300 per container equal to or greater than 25 m.

11--33463 PHT24


25/40

Pyrogen testing

11--33463 PHT25

Is designed to limit to a acceptable level the risks offebrile reaction in the patient to the injectable

administration of the product concerned.

It involves measuring the rise in temperature of

rabbits following i.v injection (into ear vein) of a test

solution in a dose 10 ml/kg within 10 min.


26/40

Use temperature-sensing probe to measure the rabbits

body temp. 30 min before the injection of the test dose.

(use three rabbits).

Do not use a rabbit for pyrogen test more frequently than

once every 48 hours, do not use any rabbit having a temp.

exceeding 39.8C.

Record the temp. at 30-min intervals between 1 and 3

hours subsequent to the injection.

11--33463 PHT26


27/40

Consider any temp. decrease as zero rise. If no rabbit show a

rise in temp. of 0.5 or more its respective control temp. i.e

the product is pyrogen-free.

If any rabbit show rise in temp. of 0.5 or more, continue the

test using 5 other rabbits.

If not more than 3 rabbits of the 8 rabbits show individual

rise in temp. of 0.5 or more and if the sum of the 8 individual

maximum temp. rises doesnt exceed 3.3C ; the material is

pyrogen-free

11--33463 PHT27


28/40

Packaging

containers for injections The container is made of material that permits

inspection of the contents.

Containers are closed by fusion or byapplication of suitable closures.

11--3328 463 PHT


29/40

Elastomeric closures for Injections are made of materials

obtained by vulcanization (cross-linking) polymerization,

polyaddition, or polycondensation of macromolecular organic

substances (elastomers).

Closure formulations contain natural or synthetic elastomers

and inorganic and organic additives to aid or control

vulcanization, impart physical and chemical properties orcolor, or stabilize the closure formulation.

Such closure are typically used as part of a vial, bottle, or pre-

fill syringe package system.

11--3329 463 PHT


30/40

Criteria for the selection of an elastomeric closure should alsoinclude a careful review of all the ingredients to assure that

no known or suspected carcinogens, or other toxic substances

are added.

DefinitionAn elastomeric closure is a packaging component

that is, or may be, in direct contact with the drug.

11--33463 PHT30


31/40

Functionality tests

Includes: penetrability, fragmentation, self-sealing capacity Functionality tests are performed on closures intended to be

pierced by a hypodermic needle.

The self-sealing capacity is required only for closures intendedfor multiple-dose containers.

The needle specified for each test is a lubricated long bevelhypodermic needle*.

* Sterile hypodermic needle with an external diameter of

0.8mm (21 Gauge).

11--3331 463 PHT


32/40

Penetrability

ProcedureFill 10 suitable vials to the nominal volume with

water, fit the closures to be examined, and secure with a cap.

Using a new hypodermic needle for each closure, pierce the

closure with the needle perpendicular to the surface.

RequirementThe force for piercing is no greater than 10 N (1

kgf) for each closure, determinedwith an accuracy of 0.25 N

(25 gf).

11--3332 463 PHT


33/40

Fragmentation

Closures for LiquidPreparationsFill 12 clean vials with water

to 4 mL less than the nominal capacity. Fit the closures to beexamined, secure with a cap, and allow to stand for 16 hours.

Closures for Dry PreparationsFit closures to be examined

into 12 clean vials, and secure each with a cap.

ProcedureUsing a hypodermic needle fitted to a cleansyringe, inject into each vial 1 mL of water while removing 1

mL of air. Repeat this procedure 4 times for each closure,

piercing each time at a different site.

Use a new needle for each closure, checking that it is not

blunted during the test.

11--3333 463 PHT


34/40

Filter the total volume of liquid in all the vials through a single

filter with a nominal pore size no greater than 0.5 m. Count the rubber fragments on the surface of the filter visible

to the naked eye.

Requirement:

there are no more than 5 fragments visible.

This limit is based on the assumption that fragments with adiameter 0.5 m are visible to the naked eye.

In case of doubt, the particles are examined microscopically to

verify the nature and size.

11--33463 PHT34


35/40

Self-Sealing Capacity

ProcedureFill 10 suitable vials with water to the nominal

volume. Fit the closures that are to be examined, and cap.

Using a new hypodermic needle as described above for each

closure, pierce each closure 10 times, piercing each time at a

different site.

Immerse the 10 vials in a solution of 0.1% (1 g per L)methylene blue, and reduce the external pressure by 27 kPa

for 10 minutes.

Restore to atmospheric pressure, and leave the vials

immersed for 30 minutes. Rinse the outside of the vials. RequirementNone of the vials contain any trace of blue

solution.

11--33463 PHT35


36/40

Type of glass containers:

Type I, II: Soda-lime glass is suitably dealkalized are usually

used for packaging neutral and acidic parenteral

preparations.

Type III is soda-lime glass containers are not used for

parenteral preparations.

Type NP glass: for packaging nonparenteral articles, for oral

and topical use.

11--33463 PHT36


37/40

Powdered glass Test:

Use crushed glass containers in 250-ml conical flask, add 50ml high purity water, cap the flask with borosilicate glass

beaker

Place the containers in the autoclave and close it securely hold

temperature at 1212rC for 30 min., counting from the time

this temperature is reached.

cool the flask, decant the water from the flask into a clean

vessel, and wash the residual powdered glass with high purity

water, add 5 drops methyl red solution, titrate immediately

with 0.02 N sulfuric acid . Record the volume of 0.02N Sulfuric acid used to neutralize

the extract from 10 g of the prepared specimen of glass.

11--33463 PHT37


38/40

Water attack at 121C

Rinse 3 or more containers with high purity water

Fill each container to 90% of its capacity with high purity

water

Cap all the flasks with borosilicate glass beaker, place in the

autoclave at 121 C for 60 min

11--33463 PHT38

mL of 0.02 N acidGeneral

description

Type

1.0High resistant

borosilicate glass

I

0.7

0.2

Treated soda lime

glass

II

8.5

Soda lime glassIII

15.0

All purpose glassNP


39/40

Labels and labeling

The label states the name of the preparation (in case of a liquid

preparation)

The percentage content of drug in a specified volume (in case

of dry preparation) The route of administration

Storage condition

Expiration date

Name of the manufacturer

The lot number

11--33463 PHT39


40/40

Containers for injection that are intended for use as dialysis, orirrigation solution are labeled to indicate that the contents are

not intended for use by iv infusion

Injection intended forveterinary use are labeled to that effect

The containers are so labeled that a sufficient area of thecontainer remains uncovered for its full length to permit

inspection of the contents

11--33463 PHT40

463 PHT Parenteral Quality Control

Documents

Transcript of 463 PHT Parenteral Quality Control