QUALITY CONTROL1

PRESENTED BY:

2

QUALITY CONTROL OF PARENTERALS

Faculty Of Pharmacy

University Of Sindh

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Term derived from Greek words “Para” outside & “Enteron” intestine.

Parenterals are sterile solution/suspension of drug in aqueous or oily vehicle.

Parenteral drugs are administered directly into the veins, muscles or under the skin,

or more specialized tissues such as the spinal cord.

Term parenetral used for any drug/fluid whose delivery doesn’t utilize the alimentary

canal for entering into the body tissues.

Although it denotes routes of administration route other than oral route.

Medical & Pharmaceutical health care deliveries generally limit the definition to those

drugs ‘injected’ or ‘infused’ directly into the tissues, tissue spaces, vessels or body

compartments.

Circumvented the highly efficient first line body defense that is skin & mucus

membrane. They should be free from microbial contamination & should have high

purity.

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1657: First recorded injection

Christopher Wren

1855: First cutaneous injection of drugs using hypodermic needles.

Dr. Alexander Wood

1920s: Proof microbial growth resulting in infections.

Dr. Florence Seibert

1926: Inclusion in the national formulary.

1931: Commercial intravenous solution (Baxter).

1946: Organization of parenteral drugs association.

1961: Development of laminar flow concept.

1965: Development of total parenteral nutrition (TPN).

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Para enteron: beside the intestine

Circumvents

GI enzymatic activity

GI instability

Low absorption

Variable absorption

Provides

Rapid and accurate dosage

Alternative to other routes of delivery

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Small Volume Parenterals (25-50 ml)

Requires little or no manipulation

Extended stability

Little wastage

Do not offer flexibility in quantity/concentration\

Primary uses of SVP

Therapeutic injections

Ophthalmic products

Diagnostic agents including

Diagnostic radiopharmaceuticals

Allergenic extracts classification

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Large Volume Parenterals

Flexible but requires manipulation

Used for maintenance or replacement therapy

Free of Preservatives

Volume must not exceed 1L (except irrigation sols)

Clinical Utilization of LVP

Basic nutrition

Restoration of electrolyte balance

Fluid replacement

Blood and blood products drug carriers

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METHOD METHOD(A) (B)

Visual Control Coulter Counter Light Blockage

HIAC Counter*

LIMITS LIMITS

Partically free from

visible particles

≥ 2µm

max. 1000/ml

≥ 5µm

max.100/ml

≥ 2µm

max. 500/ml

≥ 5µm

max.80/ml

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SMALL VOLUME INJECTIONS (SVP) LARGE VOLUME INJECTIONS (LVP)

Valid as of 01.07.85

(Supplement 1)

METHOD METHOD

Light Blockage

HIAC Counter

Microscopic counter after membrane

filtration

LIMITS LIMITS

≥10µm: max. 10,000/container

≥25µm: max. 1000/container

≥10µm: max. 50/ml

≥25µm: max. 5/ml

Essentially free from viable particles.

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Intradermal (I/D)

Subcutaneous (S/C S/Q Sub-Q, Hypo)

Intramuscular (I/M)

Intravenous (I/V)

Intra-arterial

Intra cardiac

Intra articular (Joint)

Intra synovial (Joint fluid area)

Intra spinal, Intrat hecal (Spinal fluid)

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Useful for patients who cannot take drugs orally

Useful for drugs that require a rapid onset of action (primarily i/v admin)

Useful for emergency situations

Useful for providing sustained drug delivery (implants, im depot injections)

Can be used for self-delivery of drugs (subcutaneous)

Useful for drugs that are inactivated in the GIT or susceptible to first-pass

Useful for injection of drugs directly into a tissue (targeted drug delivery)

Useful for delivering fluids, electrolytes, or nutrients (TPN)

Useful for providing precise drug delivery by iv injection or infusion utilizing

pharmacokinetic techniques

Can be done in hospitals, ambulatory infusion centers, and home health care

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More expensive and costly to produce.

Potential for infection at the site of injection, thrombophlebitis, fluid overload, air embolism, extravasation, sepsis

Psychological distress by the patient

Require specialized equipment, devices, and techniques to prepare and administer drugs.

Potential for pain upon injection

Potential for tissue damage upon injection

Risk of needle stick injuries and exposure to blood-borne pathogens by health care worker.

Increased morbidity associated with long-term vascular access devices.

Disposal of needles, syringes, and other infusion devices requires special consideration.

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ASEPTIC: “Without Sepsis” Used to deisgante a practical level of sterility.

ALERT LEVEL: An established microbial or airborne particle level giving early warning of potential drift from normal opening conditions.

ACTION LEVEL: An established microbial or airborne particle level that when exceeded should trigger appropriate investigation & corrective action based on investigation.

HVAC : Heating, Ventilation and Air-conditioning.

LAMINAR FLOW OF AIR: Air flows in a single direction and in parallel layers at constant velocity

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.

LVP: A liquid intended for infusion & hermetically sealed in a container of greater

than 100ml volume.

PARENTERAL: Not through the alimentary canal, but rather by injection

through some other route as intravenous, intramuscular, subcutaneous etc.

PYROGEN: Fever producing lipid associated with polysaccharide or

polypeptide of microbial origin.

STERILIZATION: A process designed to completely eliminate or destroy

all living microorganism.

SVP: A parenteral preparation hermetically sealed in a container of 100ml or less

volume.

ULPA FILTER: Ultra-Low Penetration Air Filter with minimum 0.3µm

particle retaining efficiency of 99.999 percent.

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The quality of finished product depends upon Quality Assurance and

Quality Control.

Quality Assurance: The planned and systematic activities

implemented in a quality system so that quality requirements for a product or service

will be fulfilled.

Quality Control: is a procedure or set of procedures intended to

ensure that a manufactured product or performed service adheres to a defined set of

quality criteria or meets the requirements of the client or customer.

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Three General Areas:

1. Incoming Stock

i. Routine work testing

2. Manufacturing

i. In-numerable tests

ii. Reading and observations through out the manufacturing process

3. Finished Proucts

i. Sterility test

ii. Pyrogen test

iii. Calrity test

iv. Leaker test

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Conductivity measurement

Volume filled

Temperature for heat sterilized product

Environmental control tests

Visual inspection

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There are mainly five quality control test for the parenterals are performed.

i. LEAKER TEST

ii. PYROGEN TEST

iii. PARTICULATE TEST

iv. STERILITY TEST

v. UNIFORMITY OF CONTENT

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Leakage occurs when a discontinuity exists in the wall of a package that can allow the

passage of gas under the action of a pressure or concentration differential existing

across the wall.

Presence of capillary pores or tiny cracks can cause microbes or other dangerous

contaminants to enter the ampoules or may lead to the leakage of contents to

outside. This may lead to contamination of the sterile contents and also spoilage of

appearance of the package.

Changes in temperature during storage can cause expansion and contraction of the

ampoule and its contents, thereby accentuating interchange if an opening exists.

Leaker test for ampoules is intended to detect incompletely sealed ampoules so that

they can be discarded in order to maintain the sterile conditions of the medicines.

Tip seals are more likely to be incompletely closed than pull seals.

Open capillaries or cracks at the point of seal result in leakers.

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PROCEDURE

Leakers are detected by this process in a visible manner.

Ampoules are placed in a vacuum chamber.

Completely submerged in a deeply colored dye solution of about 0.5 to 1% methylene blue.

A negative pressure is applied within the ampoule. Subsequent atmospheric pressure causes the dye to penetrate an opening thus making it visible after the ampoule has been washed.

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The vacuum, about 27 inches Hg, should be sharply released after 30 minutes.

Detection of leakers is prominent when ampoules are immersed in a bath of dye

during autoclaving cycle as this has the advantage of accomplishing both leaker

detection and sterilization in one operation.

The color from the dye will be visible within a leaker.

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Capillaries of 15 micron or smaller diameter cannot be detected by this test.

Vials and bottles are not subjected to such a leaker test as the rubber closer is not

rigid.

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1. LAL test 2. Rabbit test

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The LAL (limulus amebocyte lysate) Assay is an in vitro assay used to detect the

presence and concentration of bacterial endotoxins in drugs and biological products.

Endotoxins, which are a type of pyrogen, are lipopolysaccharides present in the cell

walls of gram-negative bacteria.

Pyrogens as a class are fever-inducing substances that can be harmful or even fatal if

administered to humans above certain concentrations.

Water can be a source of pyrogens, so it may be important to routinely monitor water

systems using the bacterial endotoxins test.

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The solution of endotoxins containing preparation is added to the lysate derived from

heamolymph cells of horseshoe crab (limulus polymhemus).

The result of the reaction is turbidity or precipitation or gelation of the mixture.

This is used as a quantitative measure to estimate the endotoxin content.

The rate of reaction depends upon conc. of endotoxins, pH, temperature and

presence of clotting enzyme system and clottable proteins from lysate.

The quantities of endotoxins are expressed in defined Endotoxin Units (EU). Also 1 EU

is equal to 1 IU.

The endotoxin limit for a given test preparation is calculated from the expression

K/M; where M is maximum dose administered to adult per kg per hour.

The value for K is 5.0 EU/Kg for parenteral preparations, and it is 0.2 EU/Kg for intra

thecal preparations.

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LAL TUBE TEST SAMPLE/CONTROL RESULT

1

Negative control

(pyrogen free saline)Should be -ve

2 Positive control (pyrogen ) Should be +ve

3

Positive internal control

(test sample tainted with

exdotoxins)

Should be +ve

4 Test Sample May be +ve or -ve

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Sham test is performed to select the proper animals for the main tests.

Rabbit test Qualitative fever response test.

The Rabbit Pyrogen Test in an in vivo test to detect pyrogens qualitatively.

Rabbits have a similar pyrogen tolerance to humans, so by observing a change in

body temperature in rabbits it is possible to make a determination of the presence of

pyrogens.

This method can detect non-bacterial endotoxin pyrogens as well as bacterial

endotoxins.

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Withheld food in the day of

experiment.

Record the initial tempreture of the

rabbits, any rabbit show temp. more

than 39 0C, should be excluded.

Inject the sample into the ear vein of

each rabbit.

Check the temperature after

30minutes, 1, 2 and 3 hours.

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Biological variation

Expensive

Laborious

Dose dependent.

Not for anti pyretic drug.

The test is +ve when each rabbit show increase in temperature.

If only 2 of the three rabbits show increase in temperature, repeat the test using

group of five, and test will be positive if the four of the five rabbits show increase in

tempreture.

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Sterility testing attempts to reveal

the presence or absence of viable

micro-organisms in a sample

number of containers taken from

batch of product.

Based on results obtained from

testing the sample a decision is

made as to the sterility of the

batch.

The primary official test is

performed by means of filtration

but direct transfer is used if

membrane filtration is unsuitable.

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1. Membrane Filtartion Method 2. Direct Inoculation Method

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Media suitable for Sterility tests are:

i. Fluid Thioglycollate medium

ii. Soya-bean casein digest medium

Wash the filters with fluids to remove

inhibitory properties, cutting the

membranes aseptically into equal

parts and transferring one of the parts

to each type of culture medium used.

The media are then incubated under

prescribed conditions.

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This method is only used when

membrane filtration is not

possible the sample is

inoculated directly into the

media or the device is placed

directly into the media.

Result:

If no growth in the media then

test is positive.

Parenteral Preparation

Culture medium

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It has been shown that particles of lint, rubber, insoluble chemicals, and other foreign

matter can produce emboli in the vital organs of animals and human beings.

The USP specifies that good manufacturing practice (GMP) requires that each final

container of an injection be subjected individually to a visual inspection and that

containers in which visible particles can be seen should be discarded.

Therefore, all of the product units from a production line currently are being

inspected individually by human inspectors under a good light, baffled against

reflection into the eye and against a black-and-white background.

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.

The USP has identified two test methods.

The first test to be used is the light obscuration test, which uses an electronic

instrument designed to count and measure the size of particles by means of a

shadow cast by the particle as it passes through a high- intensity light beam.

If the injection formulation is not a clear,

colorless solution , it exceeds the limits specified

for the light obscuration test, it is to be subjected

to the microscopic count test.

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This test is intended for sterile solids used for parenteral preparation.

The weight of 10 individual sterile units is noted and the content is removed from

them and empty individual sterile unit is weighed intern.

Then net weight is calculated by subtracting

empty sterile unit weight form gross weight.

The content of active ingredient in

each sterile unit is calculated by performing the

assay according to the individual monographs.

The content in 10 sterile units is calculated by

performing the assy.

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The dose uniformity is met if the amount of active ingredient is within the range of

85-115.0% of label claim as determine by the content uniformity method or weight

variation method.

The dose uniformity is also met if the potency value is 100% in the individual

monograph or less of label claim multiplied by average of limits specified for potency

in individual monograph divided by 100 provided that the relative standard deviation

in both the cases is equal to or less than 6.0%.

If one unit is outside the range of 85-115.0%, and none of the sterile unit is outside

the range of 75-125.0% and if the relative standard deviation of the resultant is

greater than 6.0% then, the fore mentioned test is carried for 20 more sterile units.

The sterile units meet the requirements if not more than one unit is out side the

range of 85-115%, no unit is outside the range of 75-125.0% and the calculated

relative standard deviation is NMT 7.8%.

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http://www.fda.gov/

www.GMP.online.coms

www.pharmaceuticalonline.com

www.pharmamachines.com

Parenteral Quality Control – Sterility, Pyrogen, Particulate and Package Integrity

Test . Michael J. Akers and Daniel S. Larriemore 3rd edition

Pharmaceutical dosage forms (Parenteral Preparation) Kenneth E. Avis, Leon L.

Parenteral Medications Parenteral Quality Control. Michael J. Akers and Daniel S

The Theory & Practice Of Industrial Pharmacy Lieberman

Modern Pharmaceutics. Gilbert S. Banker, Christopher T. Rhodes.

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