"Quality Control Of Parenteral Preparations" class presentation.

1. QUALITY CONTROL1

2. PRESENTED BY:
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3. QUALITY CONTROL OF PARENTERALS
Faculty Of Pharmacy
University Of Sindh
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4.  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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5.  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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6. 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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7. 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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8. .
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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9. 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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10. 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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11.  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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12.  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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13.  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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14. 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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15. .
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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17.  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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18.  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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19.  Conductivity measurement
 Volume filled
 Temperature for heat sterilized
product
 Environmental control tests
 Visual inspection
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20.  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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21.  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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22. 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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23. .
 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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24.  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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25. 1. LAL test 2. Rabbit test
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26.  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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28.  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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29. 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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30. 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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31. 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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32.  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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33. 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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34. 1. Membrane Filtartion Method 2. Direct Inoculation Method
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35. 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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36. 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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37.  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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38. .
 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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39.  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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40.  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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41.  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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