parenteral sro a
TRANSCRIPT
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PARENTERAL DRUG
DELIVERY
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Definitions related to the topic: Parenteral Products
Sterilization & Sterile Product
Pyrogen
SVP
LVP Light Resistant Containers
Well closed containers
Tightly closed containers
Single dose container
Multiple dose container
Hermetically sealed container
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PARENTERALS
para: outsideenteron: intestine (i.e. beside the intestine)
These are the preparations which are given other than
oral routes.
Injections:
These are
Sterile,
Pyrogen free preparations intended to be
administered parenterally (outside alimentary tract).
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Why Parenteral?
Parenteral Route Is Used bcoz
1) Rapid action
2) Oral route can not be used
3) Not effective except as injection4) Many new drugs particularly those derived from new
development in biotechnologically can only be givenby parenteral coz they are inactivated in GIT if given
orally.5) New drugs require to maintain potency & specificity
so that they are given by parenteral.
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Advantages:
Quick onset of action
Suitable for the drugs which are not
administered by oral route
Useful for unconscious or vomiting patients.Duration of action can be prolonged by
modifying formulation.
Suitable for nutritive like glucose & electrolyte.
Suitable for the drugs which are inactivated in
GIT or HCl (GI fluid)
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Disadvantages:
Once injected cannot be controlled (retreat)Injections may cause pain at the site of injection
Only trained person is required
If given by wrong route, difficult to control
adverse effect
Difficult to save patient if overdose
Sensitivity or allergic reaction at the site of
injectionRequires strict control of sterility & nonpyrogenicity than other formulation.
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Necessities of Parenteral preparations:
Sterility(must)
Pyrogen(must)
Free from particulate matter(must)
Clarity(must)
Stability(must)
Isotonicity(should)
Solvents or vehicles used must meet special purity and other standards.
Restrictions on buffers, stabilizers, antimicrobial preservative. Do not
use coloring agents.
Must be prepared under aseptic conditions.
Specific and high quality packaging.
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Routes of Parenteral Administration
Intradermal (23)Intramuscular (20)
Intravenous (21)Subcutaneous (21)
Dermis
Intra arterial (20-22)
Vein
Artery
Muscle
Epidermis
Subcutaneous
tissue
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Parental Routes of Administration:
Most Common: 1. Subcutaneous (SC; SQ ;SubQ
)2. Intramuscular (IM)
3. Intravenous (IV)
Others: 4. Intra-arterial (IA)5. Intrathecal
6. Intraarticular
7. Intrapleural8. Intracardial
9. Intradermal (Diagnostic)
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Subcutaneous (SC; SQ ;SubQ):
The injection is given under the skin
Need to be isotonic
Upto 2 ml is given
Using to 1 inch 23 gauge needle or smaller
needle
Given:
Vaccines
InsulinScopolamine
Epinephrine
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Intramuscular (IM): Striated muscle fibre
0.5 to 2 ml sometimes upto 4 ml 1 to 1.5 inch & 19 to 22 gauge needle is used
Preferably isotonic
Principle sites:
Gluteal (buttocks)
Deltoid (upper arms)
Vastus lateralis (lateral thigh)
Given:
Solutions
Emulsions Oils
Suspension
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Intravenous(IV):
Into the vein
1 to 1000 ml
1 inch ,19 to 20 gauge needle with injection rate 1ml/
10 sec. for volume upto 5 ml & 1 ml/ 20 sec. for
volume more than 5 ml.
Given:
Aqueous solutions
Hydro alcoholic solutions Emulsions
Liposome
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IV infusion of large volume fluids (100- 1000 ml)has become increasingly popular. This technique is
called as Venoclysis. This is used to supply electrolytes & nutrients to
restore blood volume & toprevent tissuedehydration.
Combination of parenteral dosage forms foradministration as a unit product is known as an IVadmixture.
Lactated Ringer Injection USP
NaCl Injection USP (0.9 %)(replenish fluid &electrolyte)
Dextrose Injection USP (fluid & electrolyte)
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Intra-arterial (IA):
Direct into the artery2 to 20 ml
20 to 22 gauge
Solutions & emulsions can be administered
Given:
Radio opaque media
Antineoplastic
Antibiotics
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Intrathecal:
Also called intra-spinalDirectly given into the spinal cord
1 to 4 ml
24 to 28 gaugeMust be isotonic
Given:
LA
Analgesics
Neuroleptics
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Intraarticular:
Given directly into the joints
2 to 20 ml5 inch 22 gauge
Must be isotonic
Given:Morphine
LA
Steroids
NSAIDs
Antibiotics
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Intrapleural:
Given directly into the pleural cavity or lung
Used for fluid withdrawal
2 to 30 ml
2 to 5 inch, 16 to 22 gauge needle
Given:
LA
Narcotics
Chemotherapeutic agents
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Intracardial:
Directly given into the heart
0.2 to 1 ml
5 inch , 22 gauge needle
Given:
Cadiotonics
Calcium salts as a calcium channel blockers
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Intradermal:
Also called as diagnostic testing0.05 ml
inch, 25 to 26 gauge needle
Should be isotonic Given:
Diagnostic agents
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Official Types of Injections:
1. Solutions of Medicinal
Example: Codeine Phosphate InjectionInsulin Injection
2. Dry solids or liquid concentrate does not
contain diluents etc.Example: Sterile Ampicillin Sodium
3. If diluents present, referred to as.....for
injectionExample: Methicillin Sodium for injection
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4. Suspensions
"Sterile....Suspension"
Example: Sterile Dexamethasone AcetateSuspension
5.Dry solids, which upon the addition of
suitable vehicles yield preparationscontaining in all respects to therequirements for sterile suspensions.
Title: Sterile....for Suspension
Example: Sterile Ampicillin for Suspension
6. Injectable Emulsions:
Example: Propofol injection
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Formulation of Parenteral:1. Therapeutic agents
2. Vehiclesi. Water
ii. Water miscible vehicles
iii. Non- aqueous vehicles
3. Added substances (Additives)
i. Antimicrobialsii. Antioxidants
iii. Buffers
iv. Bulking agents
v. Chelating agents
vi. Protectantsvii. Solubilizing agents
viii. Surfactants
ix. Tonicity- adjusting agents
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General steps involved
1. Cleaning
2. Preparation of bulk products
3. Filtration
4. Filling of solution in or product in ampoule or vial
7. Tests for Quality control
5.Sealing
6. Sterilization
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Formulation of Parenteral
1.Therapeutic ingredients: Insulin
Antibiotics Anticancer
Steroids
Vaccines
Antipyretic
Analgesics
Anti- inflammatory
LVPs like Dextrose, NaCl or combination etc.
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2.Solvents:
o Water
o Should meet compendial requirements
o Water miscible vehicleso Ethyl alcohol
o PEG
o PG
o Non aqueous vehicles
o Fixed oils
Formulation of Parenteral
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Formulation of Parenteral
SolventsSolvents used must be:
Non-irritating
Non-toxic
Non-sensitizing
No pharmacological activity of its own
Not affect activity of medicinal
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3. Added substances (Additives) Antimicrobials:
Added for fungistatic or bacteriostat action orconcentration
Used to prevent the multiplication of micro-organisms
Ex..
Benzyl alcohol ------ 0.510 %
Benzethonium chloride -- 0.01 %
Methyl paraben ---- 0.010.18 %
Propyl paraben --- 0.0050.035 %
Phenol --- 0.0650.5 %
Formulation of Parenteral
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Preservatives: Multidose containers must
have preservatives unless prohibited by
monograph.
Large volume parenteral must not contain
preservative becoz it may be dangerous to
human body if it contain in high doses.
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Antioxidants: Used to protect product from oxidation
Acts as reducing agent or prevents oxidation
Ex:
A) Reducing agent:
Ascorbic acid -- 0.020.1 %
Sodium bisulphite-- 0.10.15 %
Sodium metabisulphite-- 0.10.15 %
Thiourea - 0.005 %
B) Blocking agents:
Ascorbic acid esters- 0.010.015%
BHT- 0.0050.02 %
C) Synergistic: Ascorbic acid , Citric acid , Tartaric acid
D) Chelating agent:
EDTA- 0.01- 0.075 %
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Buffers: Added to maintain pH,
Change in pH may causes degradation of the products
Acetates, citrates, phosphates are generally used.
Factors affecting selection of buffers: Effective range,
Concentration
Chemical effect on the total product
EXAMPLES:
Acetic acid ,adipic acid, benzoic acid, citric acid,
lactic acid
Used in the conc. of 0.1 to 5.0 %
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Chelating agents:
Used to form the complex with the metallicions present in the formulation so that the
ions will not interfere during mfg. of
formulation.
They form a complex which gets dissolved inthe solvents.
Examples:
Disodium edetate0.00368 - .05 % Disodium calcium edetate - 0.04 %
Tetrasodium edetate0.01 %
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Stabilizers:
As parenterals are available in solution form
they are most prone to unstabilize
Used to stabilize the formulation
Maintain stable
Examples:Creatinine0.5- 0.8 %
Glycerin1.52.25 %
Niacinamide1.25 -2.5 %
Sodium saccharin0.03 %
Sodium caprylate0.4 %
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Solubilizing agents:
Used to increase solubility of slightly soluble drugs
they acts by any one of the following: solubilizers,
emulsifiers or
wetting agents.
Examples: Dimethylacetamide,
Ethyl alcohol
Glycerin
Lecithin
PEG40 castor oil
PEG300
Polysorbate 20, 40, 80
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Tonicity- adjusting agents: Used to reduce the pain of injection.
Buffers may acts as tonicity contributor as well as
stabilizers for the pH. Isotonicity depends on permeability of a living
semipermaeable membrane Hypotonic : swelling of cells (enlargement)
Hypertonic: shrinking of cells (reduction)
Example: Glycerin
Lactose
Mannitol
Dextrose Sodium chloride
Sorbitol
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LABELING:
Name of product
Quantity of the product % of drug or amount of drug in specified volume of
amount of drug and volume of liquid to be added
Name and quantity of all added substances
Mfg. license no.
Batch no.
Manufacturer/Distributor
Mfg. & Expiration date
Retail price (incl. of all taxes)
Mfger. address
Veterinary product should be so labeled
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Must check each individual monogram for:
Type of container: Glass
Plastic
Rubber closure
Type of glass Type I
Type II Type III
NP
Tests for glass containers Powdered Glass test
Water Attack test Package size
Special storage instructions
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Production facilities
Types :
Emulsion
Suspension
Solutions
Preparation of IV fluids
IV admixtures
TPN
Dialysis fluids
QC tests for parenteral
Sterile area
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Production facilities:
Clean- up area
Preparation area
Aseptic area
Quarantine area
Finishing and packaging area
Sterile area
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S
T
O
C
K
R
O
O
M
COMPOUNDING
AREA
CLEAN UP
AREA
ASEPTIC
AREA
QUARANTINE
AREA
STERILIZATION
STORAGE
AND
TRANSPORT
PACKING
AND
LABELLING
LAY OUT OF PARENTERAL MANUFACTURING AREA
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Clean- up area:
Non aseptic area
Free from dust ,fibres & micro-organisms
Constructed in such a way that should withstand
moisture, steam & detergent
Ceiling & walls are coated with material to preventaccumulation of dust & micro-organisms
Exhaust fans are fitted to remove heat & humidity
The area should be kept clean so that to avoid
contamination to aseptic area
The containers & closures are washed & dried in this
area.
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Preparation area:
The ingredients are mixed & preparation is prepared forfilling
Not essential that the area is aseptic
Strict precaution is taken to prevent contamination fromoutside
Cabinets & counters: SS
Ceiling & walls : sealed & painted
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Aseptic area: Filtration & filling into final containers & sealing is
done The entry of outside person is strictly prohibited
To maintain sterility, special trained persons are only
allowed to enter & work
Person who worked should wear sterile cloths
Should be subjected for physical examination to ensure
the fitness
Minimum movement should be there in this area
Ceiling & walls & floors : sealed & painted or treated
with aseptic solution and there should not be any toxic
effect of this treatment
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Cabinets & counters: SS
Mechanical equipments : SS
AIR:
Free from fibres, dust & micro organisms
HEPA filters are used which removes particles upto
0.3 micron Fitted in laminar air flow system, in which air is free
from dust & micro organisms flows with uniform
velocity
Air supplied is under positive pressure which
prevents particulate contamination from sweeping
UV lamps are fitted to maintain sterility
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Quarantine area:
After filling, sealing & sterilization the
products or batch is kept in this area
The random samples are chosen and given for
analysis to QC dept.The batch is send to packing after issuing
satisfactory reports of analysis from QC
If any problem is observed in above analysisthe decision is to be taken for reprocessing or
others..
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Finishing and packaging area:
After proper label, the product is given for
packingPacking is done to protect the product from
external environment
The ideal Packing is that which protects theproduct during transportation, storage, shipping& handling.
The labeled container should be packed incardboard or plastic containers
Ampoules should be packed in partitionedboxes.
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Preparations for IV Fluids:
LVPs which are administered by IV routeare commonly called as IV fluids.
Purposes :
Body fluids,Electrolyte replenisher
Volume supplied:
100 to 1000 ml
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Precautions / necessities in mfg.:
Free from foreign particles
Free from micro organisms
Isotonic with body fluids
As they are in LVP no bacteriostatic agents areadded
Free from pyrogens
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Examples:
Dextrose injection IP : available in 2 , 5 , 10 , 25 & 50
% w/v solution. Used for
Fluids replenisher,
Electrolyte replenisher
Sodium chloride & Dextrose injection IP: (DNS) Contains
0.11 to 0.9 % Sodium chloride
2.5 to 5.0 % Dextrose
Used for
Fluids replenisher, Electrolyte replenisher
Nutrient replenisher
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Sodium chloride injection IP:
0.9 % conc. Also known as normal saline solution
Used as
Isotonic vehicle
Fluids replenisher, Electrolyte replenisher
Sodium lactate injection IP:
Contains 1.75 to 1.95 % w/v of sodium lactate
Used as Fluids replenisher,
Electrolyte replenisher
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Mannitol injection IP:
Contains 5, 10 , 15, 20 % of mannitolUsed as :
Diagnostic aid
Renal function determination
As a diuretic Mannitol & Sodium chloride injection IP:
Contains 5, 10 , 15, 20 % of mannitol & 0.45% of Sodium chloride
Used as :
As a diuretic
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Other solutions:
Ringer injection IPRinger lactate solution for injection IP
Common uses :
Used in surgery patientsIn replacement therapy
Providing basic nutrition
For providing TPNAs a vehicle for other drug subs.
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IV ADMIXTURES
Definition:
When two or more sterile products are added to
an IV fluid for their administration, theresulting combination is known as IVadmixture.
In hospitals, prepared by nurses by combining
or mixing drugs to the transfusion fluids.The drugs are incorporated in to bottles of LV
transfusion fluids.
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Care :
Microbial contamination
Incompatibility Physical : change in color
Chemical : hydrolysis, oxidation, reduction etc..
Therapeutic: undesirable antagonistic or synergistic
effect
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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.
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TPN stands for Total Parenteral Nutrition. Thisis a complete form of nutrition, containing
protein, sugar, fat and added vitamins andminerals as needed for each individual.
Total Parenteral Nutrition (TPN) may be
defined as provision of nutrition for metabolic
requirements and growth through the parenteralroute.
Total Parenteral Nutrition
Total Parenteral Nutrition (TPN)
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Total Parenteral Nutrition (TPN)
(Intravenous Nutrition)
TPN refers to the provision
of all required nutrients,
exclusively by the
Intravenous route.
Parenteral Nutrition (PN)can be used to
supplement ordinary or tube feeding.
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Components of TPN solutions:
(1) Protein as crystalline amino acids.
(2) Fats as lipids.
(3) Carbohydrate as glucose.
(4) ElectrolytesSodium, potassium, chloride,
calcium and magnesium.(5) Metals/Trace elementsZinc, copper,
manganese, chromium, selenium.
(6) Vitamins A, C, D, E, K, thiamine, riboflavin,niacin, pantothenic acid, pyridoxine, biotin,
choline and folic acid.
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TPN might be necessary if:
a patient is severely undernourished, and needs
to have surgery, radiotherapy or chemotherapy;a patient suffers from chronic diarrhea and
vomiting;
a baby's gut is too immature;
a patient's (their "gastrointestinal tract") is
paralysed, for example after major surgery.
Why it is necessary?
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Normal Diet TPN
ProteinAmino Acids
CarbohydratesDextrose Fat..Lipid Emulsion
VitaminsMultivitamin Infusion
MineralsElectrolytes & Trace Elements
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Nutritional Requirements
Amino acids
Glucose
Lipid
Minerals
Vitamins
Water and electrolytes
Trace elements
Total Parenteral Nutrition
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Total Parenteral Nutrition
Electrolytes
Electrolyt
e.
Daily Requirement Standard Concentration
Na 60-150 meq 35-50 meq/L
K 40-240 meq 30-40 meq/L
Ca 3-30 meq 5 meq/L
Mg 10-45 meq 5-10 meq/L
Phos. 30-50 mM 12-15 mM/L
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TPN is normally used following surgery,when feeding by mouth or using the gut is
not possible,
When a person's digestive system cannot
absorb nutrients due to chronic disease, or,
alternatively, if a person's nutrient
requirement cannot be met by enteral
feeding (tube feeding) and supplementation.
When is it necessary?
http://en.wikipedia.org/wiki/Guthttp://en.wikipedia.org/wiki/Chronic_%28medicine%29http://en.wikipedia.org/wiki/Enteral_feedinghttp://en.wikipedia.org/wiki/Enteral_feedinghttp://en.wikipedia.org/wiki/Enteral_feedinghttp://en.wikipedia.org/wiki/Enteral_feedinghttp://en.wikipedia.org/wiki/Chronic_%28medicine%29http://en.wikipedia.org/wiki/Gut -
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Short-term TPN may be used if a person's
digestive system has shut down (for instance by
Peritonitis), and they are at a low enough weight
to cause concerns about nutrition during an
extended hospital stay.
Long-term TPN is occasionally used to treat
people suffering the extended consequences of an
accident or surgery.
Most controversially, TPN has extended the life ofa small number of children born with nonexistent
or severely birth-deformed guts.
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GENERAL INDICATIONS Patient who cant eat
Patient who wont eat
Patient who shouldnt eat
Patient who cant eat enough
If the gut works, use it.
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NOMENCLATURE
TPN: Total Parenteral Nutrition
IVH: Intravenous Hyperalimentation
TNA: Total Nutrient Admixture
TPN: Total Parenteral Nutrition3-In-1 Admixture
All-In-One Admixture
PPN: Peripheral Parenteral Admixture
I di ti f TPN
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Indications for TPNShort-term use
Bowel injury /surgery
Bowel disease
Severe malnutrition
Nutritional preparation prior to surgery.
Malabsorption - bowel cancer
Long-term use
Prolonged Intestinal Failure
Crohns Disease
Bowel resection
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The preferred method of delivering TPN is with a
medical infusion pump.
A sterile bag of nutrient solution, between 500 mLand 4 L is provided.
The pump infuses a small amount (0.1 to 10
mL/hr) continuously in order to keep the vein
open.
Feeding schedules vary, but one common regimen
ramps up the nutrition over a few hours, levels off
the rate for a few hours, and then ramps it downover a few more hours, in order to simulate a
normal set of meal times.
The nutrient solution consists of water glucose salts
http://en.wikipedia.org/wiki/Infusion_pumphttp://en.wikipedia.org/wiki/Sterilization_%28microbiology%29http://en.wikipedia.org/wiki/Sterilization_%28microbiology%29http://en.wikipedia.org/wiki/Infusion_pumphttp://en.wikipedia.org/wiki/Waterhttp://en.wikipedia.org/wiki/Glucosehttp://en.wikipedia.org/wiki/Salthttp://en.wikipedia.org/wiki/Salthttp://en.wikipedia.org/wiki/Glucosehttp://en.wikipedia.org/wiki/Water -
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The nutrient solution consists ofwater, glucose, salts,
amino acids, vitamins and (more controversially)
sometimes emulsified fats.
Long term TPN patients sometimes suffer from lack
of trace nutrients orelectrolyte imbalances. Because
increasedblood sugarcommonly occurs with TPN,
insulin may also be added to the infusion. Often though, an insignificant amount of insulin is
added, sometimes 10 units or less in 2 liters of TPN.
In actuality, the patient will probably get less thanthat.
Occasionally, other drugs are added as well,
sometimes unnecessarily.
Complications of TPN
http://en.wikipedia.org/wiki/Waterhttp://en.wikipedia.org/wiki/Glucosehttp://en.wikipedia.org/wiki/Salthttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Vitaminhttp://en.wikipedia.org/wiki/Fathttp://en.wikipedia.org/wiki/Electrolytehttp://en.wikipedia.org/wiki/Blood_sugarhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Blood_sugarhttp://en.wikipedia.org/wiki/Electrolytehttp://en.wikipedia.org/wiki/Fathttp://en.wikipedia.org/wiki/Vitaminhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Salthttp://en.wikipedia.org/wiki/Glucosehttp://en.wikipedia.org/wiki/Water -
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Complications of TPN
Sepsis Air embolism
Clotted catheter line
Catheter displacement
Fluid overload
Hyperglycaemia
Rebound Hypoglycaemia
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Dialysis is the process in which
substances are separated from one
another due to their difference in
diffusibility (distribution) thr
membrane.
The fluids used in dialysis are known as
dialysis fluids.
DIALYSIS FLUIDS
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General uses :Renal failure waste product is removed
Maintain electrolytes
Also called as haemodialysis orintraperitonealdialysis
Transplantation of kidney
Poisoning cases
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Haemodialysis:
To remove toxins from blood
In haemodialysis, the blood from artery is
passed thr artificial dialysis membrane, bathed
in dialysis fluid.The dialysis membrane is permeable to urea,
electrolytes & dextrose but not to plasma
proteins & lipids
So excess of urea is passed out from blood thr
dialysis fluid.
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After dialysis blood is returned back to the
body circulation thr vein.
A kidney unit may require more than 1200
litres of solution / week.
So haemodialysis fluid is prepared in conc.
Form then it is diluted with deionised water or
dist. water before use.
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Composition of Concentrated Haemodialysis Fluid BPC
Dilute 1 liter of conc. solution with 39 liters of water to make 40 litres.
Storage: store in warm place as it is liable to convert into crystals onstorage.
COMPOSITION
Dextrose monohydrate -----------
Sodium acetate ---------------------
Lactic acid ---------------------------
Sodium chloride -------------------
Potassium chloride ---------------
Freshly boiled & cooled water -q.s.
8.0 gm
19.04 gm
0.4 ml
22.24 gm
0.4 gm
100 ml
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IntraperitonealDialysis:
Peritoneal cavity is irrigated with dialysis fluid.
Peritoneumacts as a semi permeable membrane
Toxic subs. excreted by kidney are removed.
Requirements:
Sterile
Pyrogen free
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Composition of Fluid I ntraper itonealDialysis IP 1985
Sterilize by autoclave immediately afterpreparation.
COMPOSITION
Sodium chloride -------------------
Sodium acetate ---------------------
Calcium chloride -------------------
Magnesium chloride --------------
Sodium metabisulphite ----------
Dextrose (anhydrous) -----------
Purified water -----------q.s.-----
5.56 gm
4.76 gm
0.22 gm
0.152 gm
0.15 gm
17.30 gm
1000 ml
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STERILITY TESTING FOR
PARENTERAL PRODUCTS
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1. Sterility testing - definition
Sterility testing attempts to reveal the
presence or absence of viable micro-
organisms in a sample number of containerstaken from batch of product. Based on
results obtained from testing the sample a
decision is made as to the sterility of the
batch.
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Sterility testing -
is made after the product exposition to the
one of the possible sterilization procedures
can only provide partial answers to the stateof sterility of the product batch under test
is inadequate as an assurance of sterility for
a terminally sterilized product
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Major factors of importance in sterility
testing
The environment in which the test is conducted
The quality of the culture conditions provided
The test method The sample size
The sampling procedure
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1.1.Environmental conditions
avoid accidental contamination of the
product during the test
the test is carried out under asepticconditions
regular microbiological monitoring should
be carried out
1 2 C l di i
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1.2.Culture conditions
Appropriate conditions for the growth of
any surviving organism should be providedby the culture media selection.
1 2 C lt diti
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1.2. Culture conditions
Factors affecting growth of bacteria
Phases of bacterial growth
Culture media for sterility testing
1 2 1 Factors affecting growth of
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1.2.1. Factors affecting growth of
bacteria
Nutrition
Moisture
Air Temperature
pH
Light Osmotic pressure
Growth inhibitors
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1.2.2. Phases of bacterial growth
Lag phase (A)
Log (logarithmic or
exponential) phase (B) Stationary phase (C)
Decline (death) phase (D)
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1 2 3 C lt di f t ilit t ti
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1.2.3.Culture media for sterility testing
capable of initiating and maintaining the
vigorous growth of a small number of
organisms
sterile
Types of media:
Fluid thioglycollate medium
Soya-bean casein digest medium
other media
1 2 3 1 Fl id thi l ll t di
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1.2.3.1.Fluid thioglycollate medium
composition described in next slide.
specific role of some ingredients
primarily intended for the culture ofanaerobic bacteria
incubation of the media:
14 days at 30 -35C
Fluid thioglycollate medium
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Fluid thioglycollate medium
1 2 3 2 S b i di t di
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1.2.3.2.Soya-bean casein digest medium
primarily intended for the culture of both
fungi and aerobic bacteria
specific role of some ingredients incubation of the media:
14 days at 20 -25C
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Soya-bean casein digest medium
1 2 3 3 Fertility control of the media
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1.2.3.3.Fertility control of the media
are they suitable for growth of each micro-organism?
'Growth promotion test for aerobes,
anaerobes and fungi' ; inoculation of media tubes with a MO
incubation (T, t)
the media are suitable if a clearly visible growth of themicro-organisms occurs
1.2.3.4.Effectiveness of the media
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under test conditions
are culture conditions satisfactory in the
presence of the product being examined?
comparing the rate of onset and the density
of growth of inoculated MO in the presence
and absence of the material being examined
growth control;
1.3.The test method for sterility of
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y
the product
Membrane filtration
Direct inoculation of the culture medium
1 3 1 Membrane filtration
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1.3.1. Membrane filtration
Appropriate for : (advantage)filterable aqueous preparations
alcoholic preparations
oily preparationspreparations miscible with or soluble in aqueous
or oily (solvents with no antimicrobial effect)
solutions to be examined must be introduced and
filtered under aseptic conditions
All steps of this procedure are performed
aseptically in a Class 100 Laminar Flow Hood
1.3.1.1.Selection of filters for membrane
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filtration
pore size of 0.45 m
effectiveness established in the retention of
micro-organisms appropriate composition
the size of filter discs is about 50 mm in
diameter
1.3.1.2.The procedure of membrane
filt ti
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filtration sterilization of filtration system and membrane
filtration of examined solution under aseptic
conditions(suitable volume, dissolution of solid particleswith suitable solvents, dilution if necessary)
one of two possible following procedures:the membrane is removed, aseptically transferred
to container of appropriate culture medium
passing the culture media through closed systemto the membrane, incubation in situ in the
filtration apparatus (sartorius, millipore).
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1.3.2.Direct inoculation of the
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culture medium
suitable quantity of the preparation to be
examined is transferred directly into the
appropriate culture medium volume of the product is not more than 10%
of the volume of the medium
suitable method for aqueous solutions, oilyliquids, ointments an creams
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Scheme for sterility test by membrane filtration Scheme for sterility test by direct inoculation
Advantages of the filtration method
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g
wide applications
a large volume can be tested with one filter
smaller volume of culture media is required
applicable to substances for which nosatisfactory inactivators are known
neutralization is possible on the filter
subculturing is often eliminated shorter time of incubation compared with
direct inoculation
1.4. Observation and
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interpretation of the results
Examination at time intervals during the
incubation period and at its conclusion
When the sample passes the test and whenfails?
When the test may be considered as invalid?
There is low incidence of accidentalcontamination or false positive results
1 5 Sampling
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1.5. Sampling
Selection of the samples
Sample size
Minimum number of items to be tested
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Instead of the conclusion - Guidelines for
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using the test for sterility
Precautions against microbial contamination
The level of assurance provided by a
satisfactory result of a test for sterility asapplied to the quality of the batch is a
function of:
The homogeneity of the batchThe conditions of manufacture
Efficiency of the adopted sampling plan
Guidelines
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Gu de es
In the case of terminally sterilized products:physical proofs, biologically based and
automatically documented, showing correct
treatment through the batch during sterilization are
of greater assurance than the sterility test Products prepared under aseptic conditions:
sterility test is the only available analytical method
only analytical method available to theauthorities who have to examine a specimen
of a product for sterility.
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PYROGENS AND PYROGEN TESTING
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I Love The Rabbit!
Pyrogens
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y g
Pyrogenic - means producing fever
Pyrogens - fever inducing substances
Having nature Endogenous (inside body)
Exogenous (outside body)
Exogenous pyrogens
mainly lipopolysaccharides
bacterial origin, but not necessary
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Generalized structure of endotoxins
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Generalized structure of Endotoxins
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Sources of pyrogen contamination
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Sources of pyrogen contamination
solvent - possibly the most important
source
the medicament the apparatus
the method of storage between preparation
and sterilization
The endotoxin characteristics
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The endotoxin characteristics
thermostable water-soluble
unaffected by the common bactericides
non-volatile
These are the reasons why pyrogens are
difficult to destroy once produced in a
product
Tests for pyrogenic activity
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Tests for pyrogenic activity
Test for pyrogens = Rabbit test
Bacterial endotoxins
Test for pyrogens = Rabbit test
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Test for pyrogens Rabbit test
the development of the test for pyrogens
reach in 1920
a pyrogen test was introduced into the USPXII (1942)
The test consists of measuring the rise in
body temperature in healthy rabbits by theintravenous injection of a sterile solution of
the substance under the test.
Why the Rabbit?
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Why the Rabbit?
Reproducible pyrogenic response Other species not predictable
Rabbit vs. dog as model?
Rabbits: false positives Dogs: false negatives
Similar threshold pyrogenic response to
humans
Rabbit Pyrogen Test
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Rabbit Pyrogen Test
Rabbits must be healthy and mature
New Zealand or Belgian Whites used
Either sex may be used Length of use
>48 hours within negative result
>2 weeks within a positive result
Must be individually housed between 20and 23C
Rabbit test -
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selection of animals (healthy, adult, not less than
1.5 kg,) housing of animals (environmental problems:
presence of strangers (unknown place), noise, T,
)
equipment and material used in test (glassware,
syringes, needles)
retaining boxes (comfortable for rabbits as
possible) thermometers (standardized position in rectum,
precision of 0.1C)
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Rabbit test
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Rabbit test
Preliminary test (Sham Test)
intravenous injection of sterile pyrogen-free
saline solution
to exclude any animal showing an unusual
response to the trauma (shock) of injection
any animal showing a temperature variation
greater than 0.6C is not used in the main test
Rabbit test -i
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main test:
group of 3 rabbits
preparation and injection of the product:
warming the product
dissolving or dilution
duration of injection: not more than 4 min the injected volume: not less than 0.5 ml per 1 kg
and not more than 10 ml per kg of body mass
determination of the initial and maximum temperature
all rabbits should have initial T: from 38.0 to 39.8C the differences in initial T should not differ from
one another by more than 1C
Rabbit test
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Interpretation of the results:
the test is carried out on the first group of 3 rabbits; ifnecessary on further groups of 3 rabbits to a total of 4
groups, depending on the results obtained
intervals of passing or failing of products are on the
basis of summed temperature response
The result of pyrogen test:
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The result of pyrogen test:
No.of Rabbits IndividualTempt. rise
(c)
Tempt.Rise in
group (c)
Test
3 rabbits 0.6 1.4 Passes
If above not passes
3+5 = 8 rabbits
0.6 3.7 Passes
If above test not passes perform the test again
If above test not passes, the sample is said to be pyrogenic
or go thr the sources of contamination of pyrogen.
Bacterial endotoxins
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Bacterial endotoxins
to detect or quantify endotoxins of gram-
negative bacterial origin
reagent: amoebocyte lysate from horseshoecrab (Limulus polyphemus or Tachypleus
tridentatus).
The name of the test is alsoLimulus amebocyte
lysate (LAL) test
Limulus polyphemus = horseshoe crab
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p yp
Mechanism of LAL
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the test is based on the primitive blood-
clotting mechanism of the horseshoe crab
enzymes located with the crab's amebocyte
blood cellsendotoxins
initiation of an enzymatic coagulation cascade
proteinaceous gel
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Test performance (short)
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avoid endotoxin contamination
Before the test: interfering factors should not be present
equipment should be depyrogenated
the sensitivity of the lysate should be known Test:
equal V of LAL reagent and test solution (usually 0.1 ml of
each) are mixed in a depyrogenated test-tube
incubation at 37C, 1 hour remove the tube - invert in one smooth motion (180) - read
(observe) the result
pass-fail test
LAL test
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Three different techniques: the gel-clot technique - gel formation
the turbidimetric technique - the development
of turbidity after cleavage of an endogenoussubstrate
the chromogenic technique - the development
of color after cleavage of a synthetic peptide-
chromogen complex
LAL test
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6 methods with different steps of accuracy of LAL test
results: Method A: gel-clot method: limit test
Method B: gel-clot method: semi-quantitative test
Method C: turbidimetric kinetic method
Method D: chromogenic kinetic method
Method E: chromogenic end-point method
Method F: turbidimetric end-point method
In the event of doubt or dispute, the final decision ismade upon Method A unless otherwise indicated in
the monograph.
Gel-cloth technique (Methods A, B)
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allows detection or
quantification of
endotoxins
clotting of the lysate in the
presence of endotoxins.
1.Preparatory testing Confirmation of the
labeled lysate sensitivity
Tests for interfering
factors
Gel Clot
Invert Tube in Smooth
Motion
Gel-cloth technique (Methods A, B)-
t
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cont. 2. Limit test (method A)
procedure described on page. 24 a firm gel - positive result.
an intact gel is not formed - negative result.
the interpretation of the results
3. Semi-quantitative test (method B)
quantification of bacterial endotoxins in the test solution bytitration to an end-point.
procedure is similar as in the limit test
The results are expressed as concentration of endotoxin asless, equal or greater than (labeled lysate sensitivity).
Turbidimetric technique (Methods C,F)
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) photometric test to measure the increase in
turbidity
end-point test (Method F): quantitative relationshipbetween the endotoxin concentration and the turbidity
(absorbance or transmission) of the reaction mixture at theend of an incubation period.
kinetic test (Method C): a method to measure either thetime (onset time) needed for the reaction mixture to reach a
predetermined absorbance, or the rate of turbidity
development.
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Instead of the conclusion -Guidelines for test for bacterial
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endotoxins
the absence of bacterial endotoxins in a product
implies the absence of pyrogenic component
if you wish to replace rabbit test you should
prove that you dont have interfering factors
if rabbit pyrogen test is replaced by endotoxin
test, the last one should be validated
methods from C to F require moreinstrumentation, but they are easier to automate
test for bacterial endotoxins is preferred over
the test for pyrogens
Advantages of LAL test Fast - 60 minutes vs. 180 minutes
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Greater Sensitivity
Less Variability Much Less False Positives
Much Less Expensive
Alternative to Animal Model
cheaper,
more accurate than other is performed in the pharmaceutical laboratory
specific for endotoxins of gram-negative origin
particularly useful for:
Radiopharmaceuticals and cytotoxic agents
Products with marked pharmacological or toxicological activityin the rabbit (e.g. insulin)
Blood products which sometime give misleading results in therabbit
Water for injection where LAL test is potentially more stringent
and readily applied
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Particulate Matter Monitoring
Definition:
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Unwanted mobile insoluble matter other
than gas bubbles present in the given
product.
It may be dangerous when the particle size
is larger than R.B.C. & may block the blood
vessel.
This type of products are immediately
rejected from the batch.
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The limit test for particulate matter is prescribed in
I.P. 1996 (A- 125)
Applicable for:
100 ml or more volume containers of single dose LV given
by IV infusion Not applicable for:
Multidose injections
Single dose SVP
Injectable solutions constituted from sterile solids
Permitted limits of particulate matter
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Particle size in micrometer Max.No.of particles
(equal to or larger than) per ml
10 50
25 5
50 Nil
Sources of particulate matter
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Contamination
Contaminant
Intrinsic contamination:Originally present in products
e.g. Barium ions may react or leach with Sulphur
ion which are already present in formulation may
produce barium sulphate crystals.
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Extrinsic contamination:
Material comes from outside or environment
e.g. coming off the material from body & cloths of
person
Entry of particle from ceiling , walls & furniture
May be in the form of cotton, glass rubber, plastics,
tissues, insect fragments, bacterial contamination,
dust, papers etc
Methods of monitoring particulate matter
contamination
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contamination
Visual method
Coulter counter method
Filtration method Light blockage method
Visual method:
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Visual method:
Simple method
Filled container are examined against strong illuminated
screen by holding neck & rotating it slowly or inverted it to
keep out the foreign matter.
Coulter counter method:
It is used for detection of particles less than 0.1 micrometer
in diameter.
Based on electrode resistance.
Sample is evaluated between two electrode & if particlefound the resistance of electrode is increased.
Filtration method:
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It is used for counting the particles in hydraulic fluids.
Sample passed thr filter Material is collected on filter
Evaluated under microscope.
Disadvantage:
Skilled & trained person is required
Light blockage method:
Used for hydraulic oils
Allows stream of fluid under test to pass between a bright
white light source & photoiodide sensor.
Identification of Particulate Matter
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Microscopy
X- ray powder diffraction
Mass microscopy Microchemical tests
Electron microscopy etc
Significance of Particulate Matter monitoring
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Its presence may causes:
Septicemia
Fever & blockage of blood vessels Quality of product may affect
As per USP
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As per USP
LVP : NMT 50 particles/ ml (size 10 or more than10 micrometer) & 5 particles/ ml (size more than
25 micrometer)
SVP: 10,000 particles/ container of size 10
micrometer or greater & NMT 1000 particles/
container greater than 25 micrometer.