This document discusses sterile products and parenteral admixtures. It begins by defining parenteral as referring to injectable routes of drug administration other than oral. The primary parenteral routes are described as subcutaneous, intramuscular, intravenous, and venoclysis. Containers, closures, and the intravenous admixture system are then outlined. The document summarizes the processing of parenterals including cleaning, preparation, filtration, filling, sealing, and sterilization. Methods for evaluating parenteral preparations such as sterility testing, clarity testing, leakage testing, pyrogen testing, and assay are also summarized.

1. Sterile
products and
admixtures
Presented by:
Rameshwar madharia
PE/2013/313

2. Parenteral
Parenteral refers injectable route of
administration.
It derived from Greek words Para (Outside)
and enteron (Intestine).
So it is a route of administration other than
the oral route. This route of administration
bypasses the alimentary canal

3. PRIMARY PARENTERAL
ROUTES
Routes Usual volume
(mL)
Needle
commonly used
Formulation
constraints
Types of
medication
administered
SVP
Sub cutaneous 0.5-2 5/8 in. ,
23 gauge
Need to be isotonic Insulin, vaccines
Intra muscular 0.5-2 1.5 in. ,
23 gauge
Can be solutions,
emulsions, oils or
suspensions
Isotonic preferably
Nearly all drug
classes
Intra venous 1-100 Vein puncture
1.5 in. ,
20-22 gauge
Solutions, emulsions
and liposomes
Nearly all drug
classes
LVP 101 and larger
(infusion unit)
Venoclysis
1.5 in. ,
18-19 gauge
Solutions and some
emulsions
Nearly all drug
classes

4. S. No. ADVANTAGES DISVANTAGES
1. Quick onset Wrong dose or over dose can
be fatal
2. Vomiting and
unconscious patients can
take
Pain at site
3. Prolonged action by
modified formulation
( Depot)
Trained person required
4. Nutritive fluids (glucose,
electrolytes) can be given
Expensive
5. Drugs with poor
absorption or instability
from GIT
NECESSITY OF ASEPTIC
CONDITIONS IN
PRODUCTION,
COMPOUNDING AND
ADMINISTRATION

5. Containers:
1. Glass:
• Highly Resistant Borosilicate Glass
• Treated Soda lime Glass
• Regular Soda Lime Glass
• N.P (Non-parenteral) Glass
Type 4 is not used for parenteral packaging,
others all are used for parenteral packaging.

6. 2. Plastic:
Plastic containers are used but they face following problems
• Permeation
• Sorption
• Leaching
• Softening
3. Rubber:
To provide closure for multiple dose vials, IV fluid bottles, plugs for
disposable syringes and bulbs for ophthalmic pipettes, rubber is the
material of choice.
Problems associated with rubber closures are
• Incompatibility
• Chemical instability
• Physical instability

7. Closure:
• Characteristics of Good Pharmaceutical rubbers
• Good ageing qualities
• Satisfactory hardness and elasticity
• Resistance to sterilization conditions
• Impermeable to moisture and air
• Examples:
• Butyl Rubbers
• Natural Rubbers
• Neoprene Rubbers
• Polyisoprene rubbers
• Silicone Rubbers

8. Intravenous Admixture System
• “Admixture system” refers to sterile IV
solutions that are prepared by using one or
more medications or electrolytes and will be
administered via the parenteral route.
• It requires the measured addition of a
medication to a 50 ml or larger bag or bottle
of IV fluid.
• It can be provided to the patient in his/her
home.
• Many hospitals involved in compounding IV
solutions and medications to outpatient
settings.

9. Methods for safe & effective
use of IV admixture
• Proper training to nurses & pharmacist
• Instruction regarding labeling Information
for stability & compatibility to the hospital
pharmacy dept.
• Information for the formulation skills to the
pharmacist.

10. SYSTEM
COMPONE
NT
Preparatio
n
Area
Storage
Area
Personnel
Policies
and
Procedures
Admixture
system

11. PROCESSING OF
PARENTERALS
S.No. STEPS
1. Cleaning of containers, closures and equipments
2. Collection of materials
3. Preparation of parenteral products
4. Filtration
5. Filling the preparation in final containers
6. Sealing the containers
7. Sterilization
8. Evaluation of parenteral preparation
9. Labeling and packaging

12. Formulation of parenteral
products
• In the preparation of parenteral products, the following
substances are added to make a stable preparation:
 The active drug
 Vehicles
 Aqueous vehicle (e.g. water for injection, water for injection free
from CO2 )
 Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)
 Adjuvants
 Solubilizing agents (e.g. Tweens & polysorbates)
 Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)
 Buffering agents (e.g. citric acid, sodium citrate)
 Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)
 Chelating agents (e.g. EDTA)
 Suspending, emulsifying & wetting agents (e.g. MC, CMC)
 Tonicity factor (e.g. sodium chloride, dextrose)

13. Production facilities of
parenterals
• The production area where the parenteral
preparation are manufactured can be
divided into five sections:
Clean-up area
Preparation area
Aseptic area
Quarantine area
Finishing & packaging area

14. Clean-up area:
 It is not aseptic area.
 All the parenteral products must be free from foreign particles
& microorganism.
 Clean-up area should be withstand moisture, dust &
detergent.
 This area should be kept clean so that contaminants may not
be carried out into aseptic area.
Preparation area:
 In this area the ingredients of the parenteral preparation are
mixed & preparation is made for filling operation.
 It is not essentially aseptic area but strict precautions are
required to prevent any contamination from outside.

15. Aseptic area:
 The parenteral preparations are filtered, filled into final container
& sealed should be in aseptic area.
 The entry of personnel into aseptic area should be limited &
through an air lock.
 Ceiling, wall & floor of that area should be sealed & painted.
 The air in the aseptic area should be free from fibers, dust and
microorganism.
 The High efficiency particulate air filters (HEPA) is used for air.
 UV lamps are fitted in order to maintain sterility.

16. Quarantine area:
 After filling, sealing & sterilization the parenteral product
are held up in quarantine area.
 Randomly samples were kept foe evaluation.
 The batch or product pass the evaluation tests are transfer
in to finishing or packaging area.
 Finishing & packaging area:
 Parenteral products are properly labelled and packed.
 Properly packing is essential to provide protection against
physical damage.
 The labelled container should be packed in cardboard or
plastic container.
 Ampoules should be packed in partitioned boxes

17. EVALUATION OF
PARENTERAL PREPARATIONS
• The finished parenteral products are
subjected to the following tests, in order to
maintain quality control:
• A) sterility test
• B)clarity test
• C)leakage test
• D)pyrogen test
• E)assay

18. A) sterility test
• It is a procedure carried out to detect and
conform absence of any viable form of
microbes in or on pharmacopeia preparation
or product.
1) Method of sterility testing
i ) METHOD 1 Membrane filtration method
ii) METHOD 2 Direct inoculation method

19. Membrane filtration method
(METHOD 1):
 Membrane filtration Appropriate for : (advantage)
• Filterable aqueous preparations
• Alcoholic preparations
• Oily preparations
• Preparations miscible with or soluble in aqueous or
oily (solvents with no antimicrobial effect)
 All steps of this procedure are performed aseptically
in a Class 100 Laminar Flow Hood

20. Membrane filter 0.45μ porosity
Filter the test solution
After filtration remove the filter
Cut the filter in to two halves
First halves (For Bacteria) Second halves (For Fungi)
Transfer in 100 ml culture media
(Fluid Thioglycollate medium)
Incubate at 30-350 C for not less then 7
days
Transfer in 100 ml culture media
(Soyabeans-Casein Digest medium)
Incubate at 20-250 C for not less then 7
days
Observe the growth in the media Observe the growth in the media

21. Direct inoculation method
(METHOD 2):
 Suitable for samples with small volumes
 volume of the product is not more than 10%
of the volume of the medium
 suitable method for aqueous solutions, oily
liquids, ointments and creams
 Direct inoculation of the culture medium
suitable quantity of the preparation to be
examined is transferred directly into the
appropriate culture medium & incubate for
not less than 14 days.

22. Observation and results
Culture media is examined during and after at the end of incubation. The
following observations are possible:
1) No evidence of growth Pass the test for sterility.
2) There is evidence of growth Re-testing is performed same
no. of sample, volume & media as in original test No
evidence of growth Pass the test for sterility.
3) There is evidence of growth isolate & identify the organism.
Re-testing is performed with twice no. of sample if:
No evidence of growth Pass the test for sterility.

23. B)clarity test
• Particulate matter is defined as unwanted mobile
insoluble matter other than gas bubble present in the
product.
• If the particle size of foreign matter is larger than the
size of R.B.C.. It can block the blood vessel.
• The permit limits of particulate matter as per I.P. are
follows:

24. Methods for monitoring particulate
matter contamination:
1) Visual method
2) Coulter counter method
3) Filtration method
4) Light blockage method

25. C)leakage test
• The sealed ampoules are subjected to small cracks
which occur due to rapid temperature changes or due
to mechanical shocks.
Filled & sealed ampoules
Dipped in 1% Methylene blue solution
Under negative pressure in vacuum chamber
Vacuum released colored solution enter into the ampoule
Defective sealing
Vials & bottles are not suitable for this test because the
sealing material used is not rigid

26. D)pyrogen test
 Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek
= beginning).
 Fever producing, metabolic by-products of
microbial growth and death.
 Bacterial pyrogens are called “Endotoxins”.
Gram negative bacteria produce more potent
endotoxins than gram + bacteria and fungi.
 Endotoxins are heat stable lipopolysaccharides
(LPS) present in bacterial cell walls, not present
in cell-free bacterial filtrates

27. Method
 Dissolve the subs being examined in, or dilute it with a pyrogen free saline
solution
 Warm the liquid being examined to approx. 38.5o C temp before injection
 The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body weight
 Withhold water during test
 Clinical thermometer is inserted into the rectum of rabbit to record body temp
 2 normal reading of rectal temp are should be taken prior to the test injection
at an interval of half an hr & its mean is calculated- initial temp
 The solution under test is injected through an ear vein
 Record the temp of each rabbit in an interval of 30 min for 3 hrs
 The difference between initial temp & maximum temp is recorded- taken as
response

28. Interpretation of results

29. Limulus amebocyte lysate [LAL]
test
• Limulus amebocyte lysate [LAL] test another
method for the determination of pyrogenic
endotoxins
• In this method the test solution is combined
with a cell lysate from the ameabocyte [blood
celels] of horse shoe crab
• Any endo toxin that might be present will be
coagulated with protien fraction of the
ameabocytes and results in the formation of a
gel
• This consider to be simple,rapid and of greater
sensitivity that the rabbit test

30. E)assay
• Assay is performed according to method
given In the monograph of that parental
preperation in the pharmacopoeia
• Assay is done to check the quantity of
medicament present in the parenteral
preperation

31. References
• Encyclopedia of pharmaceutical technology by James
Swarbrick pg.no.1266-1299
• Pharmaceutical product development by N.K.JAIN
• Chemical Incompatibility of Parenteral Drug Admixtures; T.
J. Mccarthy; S.A. Medical journal 2
• The theory & pratice of “Industrial Pharmacy” Leon
Lachman ,Herbert A. Liberman.special Indian Edition 2009
Pg. No.693-680.
• Modern Pharmaceutics Fourth Edition, Revised and
Expanded, Edited By G.S.Banker & C.T.Rhodes, Marcel
Dekker pg387-389.
• The Science & practice of Pharmacy, By Remington, Vol-
01, Edi.21st, Lippincott Publication, pg-838-840.

32. Thank You……..