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STERILE PRODUCTS:

Definition: are dosage forms of therapeutic agents that are free of viable micro-organisms. Examples include solutions, irrigating preparations, ophthalmic preparations. Sterile products are most frequently solutions or suspensions, but may even be solid pellets for tissue implantation. Parenterals Products: Parenteral preparations are sterile, pyrogen-free liquids (solutions, emulsions, or suspensions) or solid dosage forms containing one or more active ingredients, packaged in either single-dose or multi-dose containers. ADVANTAGES & DISADVANTAGES OF PARENTERALS PRODUCTS S. No. ADVANTAGES 1. 2. 3. Quick onset Vomiting and unconscious patients can take DISVANTAGES Wrong dose or over dose can be fatal Pain at site

Prolonged action by modified formulation Trained person required (Depot)

4.

Nutritive fluids (glucose, electrolytes) can be Expensive given

5.

Drugs with poor absorption or instability from Necessity of aseptic conditions GIT production, administration compounding

in and

Sterile area: is that area which is free from all viable micro-organisms. What is contamination? Presence of any unwanted substance in the product Two types of contaminants Viable Non-viable
Industrial Pharmacy PCU-608

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Semester 8th

Sources of Contamination: Water Air Surfaces People HEPA filtration and laminar flow serve as contamination control devices. HEPA (High Efficiency Particulate Air) filters are used to remove particulates and microorganisms from the air supply to the manufacturing/filling rooms, laminar flow hoods, bio-safety cabinets, etc. HEPA (HIGH EFFICIENCY PARTICULATE AIR) FILTER Remove at least 99.97% of airborne particles 0.3 m in diameter EFFICIENCY OF FILTER IS CHECKED BY DOP (DIOCTYL PTHALATE TEST) DOP vapor (particle size 0.3 m) is passed by HEPA filter and on opposite smoke detector is used to detect its vapor. FDA/ISO Particulate and Microbial Air Classifications a and Levels
Clean Area Classification (0.5 um particles/ft )
100 1000 10,000 100,000 5 6 7 8 3,520 35,200 352,000 3,520,000 1e 7 10 100 1e 3 5 50
3

ISO Designation b

> 0.5 m particles/m3

Microbiological Active Air Action Levels c (cfu/m3 )

Microbiological Settling Plates Action Levels c,d (diam. 90mm; cfu/4 hours)

Industrial Pharmacy

PCU-608

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Semester 8th

a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity. b- ISO 14644-1 designations provide uniform particle concentration values for clean rooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A. c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. d- The additional use of settling plates is optional. e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants. Air Cleaning: Since air is one of the greatest potential sources of contaminants in clean rooms, special attention must be given to air being drawn into clean rooms by the heating, ventilating, and air conditioning (HVAC) system. This may be done by a series of treatments that will vary somewhat from one installation to another. Definition of Ophthalmic ointments Ophthalmic ointments are sterile, homogeneous, semi-solid preparations intended for application to the conjunctiva or the eyelids. They are usually prepared from non-aqueous bases, e.g. soft paraffin (Vaseline), liquid paraffin, and wool fat. They may contain suitable additives, such as antimicrobial agents, antioxidants, and stabilizing agents. Organoleptic inspection Evidence of physical instability is demonstrated by: a noticeable change in consistency, such as excessive "bleeding" (separation of excessive amounts of liquid) or formation of agglomerates or grittiness; discoloration; crystal growth; shrinking due to evaporation of water; or Evidence of microbial growth.

Industrial Pharmacy

PCU-608

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Semester 8th

Uniform consistency Ophthalmic ointments should be of uniform consistency. When a sample is rubbed on the back of the hand, no solid components should be noticed. Containers Ophthalmic ointments are normally supplied in small, sterilized, collapsible tubes fitted with a tamper-evident applicator. The containers or the nozzles of the tubes are shaped so that the ointment can be applied without contaminating what remains in the tube. The content of such a container is limited to not more than 5 g of the preparation. Suitable single-dose containers may also be used. Preparation of parenterals (Building, Equipment): The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination. (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable; (ii) Temperature and humidity controls; (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or non-laminar; (iv) A system for monitoring environmental conditions; (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions; (vi) A system for maintaining any equipment used to control the aseptic conditions. Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product. Air filtration systems, including pre-filters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. Complete Sterility (Aseptic area): Aseptic - Free from microorganisms that produce septic or septic disease. Sterile Manufacturing Processes are of Two types Terminal Sterilization Aseptic Processing
Industrial Pharmacy PCU-608

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Semester 8th

Terminal Sterilization Sterilization done for the final product Product, Container, Closures will have the low Bio-Burden but Sterility is not guaranteed.
Drug Product Sterile Drug Product

+
Container

Sterilization Process

+
Closure

Aseptic Processing Sterile products, which cannot receive a post filling lethal treatment because the product, container cannot withstand terminal sterilization treatments. Aseptic processing of the drug product, container, and closure are subjected to sterilization processes separately and then brought together in clean room environment to create the finished product.

Aseptic Processing

Industrial Pharmacy

PCU-608

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Semester 8th

Contamination Control Personnel borne Contaminants Minimum number of personnel in clean areas Should not enter clean rooms if ill or with open wounds No shedding of particles, Head gear, over gowning, boots and gloves are to be worn. Movement Should be slow and controlled No watches, jewellery and cosmetics Maintenance of a hygienic laboratory Frequent disinfection of floors and surfaces Minimizing the traffic in and out of the area Use of laminar air flow Units Use of LAFS LAFS use 0.2 HEPA Filters HEPA Filter was designed and installed in 1940s Minimum particle collection efficiency: 99.97% for 0.3m diameter particles. Filter made of pleated borosilicate glass To achieve class 100 conditions HEPA filters are required LAFS are of 2 types Horizontal LAFS Vertical LAFS GENERALLY Use of Sticky Mats Use of Air Locks for every Clean Room
Industrial Pharmacy PCU-608

Airborne Contamination Control

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Semester 8th

Use of Air Curtains at the plant entry Environmental Monitoring Particulate Matter Particle Counter Differential Pressure Positive pressure differential of 10-15 Pascal should be maintained between adjacent rooms of different classification (with door closed). Most critical area should have the highest pressure Air Changes and Air flow patterns Air flow over critical areas should be uni-directional Temperature and Relative Humidity Ambient Temperature and RH. Microbiological Testing of Air Two types of Microbiological Air testing Methods Sedimentation method Impaction method 1. Sedimentation method: The principle involved is Gravitational fallout in a given time on a given area. Irregularities in counts due to wild air currents, physical movement of personnel etc. 2. Impaction Method Different types of air samplers use this principle The particles in air Impact onto the medium plates by the application of Electrical or mechanical forces. Slit Samplers Sieve Samplers Centrifugal Samplers Microbiological Testing of Water Membrane filtration technique Standard Plate Count technique Most Probable Number Test BOD Test
Industrial Pharmacy PCU-608

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Semester 8th

1. Membrane Filter Technique 100 ml water sample is passed through Membrane filter Filter pad is then transferred to a bacteriological growth medium Bacteria trapped in the filter grow on the medium and form colonies when incubated. By counting the colonies, an estimate can be made of the number of bacteria in the original 100-ml sample.

2. Standard Plate Count Technique Samples of water are diluted in jars containing 99-ml sterile water Samples are placed in Petri dishes with nutrient agar medium. After incubation, the colony count is taken and multiplied by the dilution factor to obtain the total number of bacteria per ml of sample.

Industrial Pharmacy

PCU-608

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Semester 8th

3. Most Probable Number Test (MPN TEST) Tubes of lactose broth are inoculated with water samples measuring 10 ml, 1 ml, and 0.1 ml. During incubation, coliform organisms produce gas Depending upon which tubes from which water samples display gas, an MPN table is consulted and a statistical range of the number of coliform bacteria is determined. The MPN test is easy to perform but is not exact as standard plate count method. 4. The Biochemical Oxygen Demand Test: The BOD is the amount of oxygen required by the microorganisms during their growth. The BOD test is begin by noting the oxygen concentration in a sample of water before incubation The water is then incubated in an air-tight, stoppered bottle for a period of about five days at a temperature between 5 and 20C The oxygen concentration in the water is then noted again, and the difference in the dissolved oxygen is the BOD A higher BOD indicates presence of a higher amount of organic matter

Industrial Pharmacy

PCU-608

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Semester

8th
Evaluation of aseptic operations Media Fill Tests (MFT): Most useful methods for evaluating SAL of an aseptic filling operation is Media Fill Tests (MFT). MFT is the exact simulation of an aseptic process except that a microbiologic growth medium is substituted for the active ingredients in a sterile product. MFT is used to identify the potential weakness in an aseptic processing operation that might contribute to microbiologic contamination of the drug product. Minimum of 3 MFTs should be performed for initial validation of Aseptic Processing Operations. Media and Incubation Conditions for MFT : Ideal Medium for MFT Soyabean Casein Digest Medium (SCD) also known as Triptic Soya Broth (TSB). Commercially available TSB is Tripticase Fluid Thioglycollate Medium (FTM) Incubation Conditions 14 days at ambient temperature (20 -25 C)

PARENTERAL FORMULATION VEHICLES Aqueous vehicles 1. Water for injection USP 2. Water for injection free from CO2 3. Sterile water for injection USP 4. Bacteriostatic water for injection USP 5. Sodium chloride injection USP 6. Bacteriostatic Sodium chloride injection USP 7. Ringers injection USP 8. Lactated Ringers injection USP Non aqueous vehicles 1. Fixed oils
Industrial Pharmacy PCU-608

(Barbiturates & Sulfonamides)

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Semester

8th
2. Ethyl alcohol, propylene glycol, PEG ADDED SUBSTANCES Solubilising agents Surfactants (polysorbate, tweens) Stabilizers Antioxidants (thiourea, ascorbic acid, sodium bisulphite, sodium metabisulphite) Buffering agents Acetates, citrates and phosphates Anti bacterial agents Phenol or cresol, chlorocresol, phenyl mercuric nitrate, bezalkonium chloride
Tonicity contributors

Sodium chloride, Dextrose, Boric acid Chelating agents EDTA Suspending agents Methyl cellulose, CMC, gelatin, acacia Emulsifying agents Lecithin Wetting agent tween 80 , sorbitan trioleate CONTAINERS AND CLOSURES Glass Glass containers Type I, are best for aqueous preparations (vials & ampoules). Siliconization inside surface is done to prevent interaction. Plastics polypropylene containers can withstand autoclaving.

Rubber closures permit needle into multiple-dose vial. It is held by aluminum band.

Industrial Pharmacy

PCU-608

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Semester

8th

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

STERILIZATION METHODS: Evaluation of Sterilization Method Sterile products possess several unique properties, such as freedom from microorganism, pyrogens, particulates and high standards of purity and quality. This ultimate goal in the manufacture of sterile products can be attained by evaluation of sterilization procedure. The sterilization processes are likely to be subjected to the most detailed and complex validation procedures. Evaluation of processing includes equipments, process, personnel, material etc. The principle involve in the evaluation of sterilization process are: i. To build sterility into product. ii. Perform a maximum level of probability. iii. Establish specification and performance characteristic. iv. To provide greater assurance of support of the result. v. Specific methodology, process and equipment. vi. Final product testing using validated analytical method and vii. Verification, calibration and maintenance of equipments used in the processes.
Industrial Pharmacy PCU-608

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Semester

8th
Definition: Killing or removing all forms of microbial life (including endospores) in a material or an object. Mainly due to: oxidation of cell component, denature proteins, nucleic acids, RNA and loss of membrane permeability. Disinfection Killing of most microorganisms on a substance (Inanimate Objects)

Antisepsis Reduction or Inhibition of microbes found on LIVING TISSUE

Other Terms: Bacteriostatic Agent: Agent that inhibits the growth of bacteria, but does not necessarily kill them. Suffix stasis: To stop or steady. Germicide: Agent that kills certain microorganisms. Bactericide: Agent that kills bacteria. Most do not kill endospores. Viricide: Agent that inactivates viruses. Fungicide: Agent that kills fungi. Sporicide: Agent that kills bacterial endospores or fungal spores. Microbial Control Methods Five sterilization processes are described in the U.S.P: 1. By Steam 2. By Dry heat 3. By Filtration 4. By Gas 5. By Ionizing Radiation All are commonly used for parenteral products, except gas and ionizing radiation, which are widely used for devices and surgical materials. For sterilization purposes, microorganisms can be categorized into three general categories: a) Easy to kill with either dry or moist heat
Industrial Pharmacy PCU-608

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Semester

8th
b) Susceptible to moist heat, but resistant to dry heat (e.g. Bacillus subtilis) c) Resistant to moist heat, but susceptible to dry heat (e.g. Clostridium sporogenes) 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 A) Sterility test: It is done by detecting the presence of viable forms of bacteria, fungi and yeast in parenteral products. The test for Sterility must be carried out under strict aseptic conditions in order to avoid accidental contamination of the product during test. All glass-wares required for the test must be Sterile. The test for Sterility may be carried out either by: a) membrane filteration method b) Direct inoculation method 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. 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 Environmental conditions: a. Environmental conditions avoid accidental contamination of the product during the test.

Industrial Pharmacy

PCU-608

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Semester

8th
b. The test is carried out under aseptic conditions regular microbiological monitoring should be carried out. Culture conditions: Appropriate conditions for the growth of any surviving organism should be provided by the culture media selection. Factors affecting growth of bacteria: Nutrition Moisture Air Temperature pH Light Osmotic pressure Growth inhibitors Culture media for sterility testing: Culture media for sterility testing capable of initiating and maintaining the vigorous growth of a small number of organisms sterile Types of media: 1. Fluid thioglycollate medium, 2. Soya-bean casein digest medium 1. Fluid thioglycollate medium: specific role of some ingredients primarily intended for the culture of anaerobic bacteria. incubation of the media: 14 days at 30 -35C

Industrial Pharmacy

PCU-608

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Semester

8th

2. Soya-bean casein digest medium : 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

Industrial Pharmacy

PCU-608

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Semester

8th

Membrane filtration method In this method, the test sample of parenteral preparation are transferred (aspetically) into sterile nutrient media, suitable pH and incubated for suitable period of time at optimum temperature. Evaluated in the presence of turbidity. 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) 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

Industrial Pharmacy

PCU-608

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Semester

8th
Selection of filters for membrane filtration: pore size of 0.45 mm effectiveness established in the retention of micro-organisms appropriate composition the size of filter discs is about 50 mm in diameter The procedure of membrane filtration: Sterilization of filtration system and membrane filtration of examined solution under aseptic conditions (suitable volume, dissolution of solid particles with suitable solvents, dilution if necessary). The membrane is removed, aseptically transferred to container of appropriate culture medium passing the culture media through closed system to the membrane, incubation in situ in the filtration apparatus (sartorius, millipore). Direct inoculation of the 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, oily liquids, ointments an creams CLARITY TEST It is performed to ensure that the parenterals are free from visible foreign particles. Each parenteral preparation in its final container is subjected individually to a visual inspection to exclude the possibility of foreign particles. The un labeled containers are held by the neck against strongly illuminated black (for dark particles) & white screen(for light colour particles). The contents of the container are slowly inverted & rotated, then examined. . It may be dangerous when the particle size is larger than R.B.C. & may block the blood vessel. This type of products is immediately rejected from the batch. 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: Multi-dose injections Single dose SVP injectable solutions constituted from sterile solids.

Industrial Pharmacy

PCU-608

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Semester

8th
PARTICULATE MATTER: Definition: 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 is immediately rejected from the batch.

Sources of particulate matter: 1. Intrinsic contamination: Originally present in products e.g. Barium ions may react or leach with Sulphur ion which is already present in formulation may produce barium sulphate crystals. 2. 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: Methods of monitoring particulate matter contamination are: Visual method, Coulter counter method, Filtration method, Light blockage method Visual method: Simple method is filled container is 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 electrodes & if particle found the resistance of electrode is increased. Filtration method: It is used for counting the particles in hydraulic fluids. Sample passed through 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 & photo-iodide sensor.

Industrial Pharmacy

PCU-608

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Semester

8th
Identification of Particulate Matter: Identification of Particulate Matter Microscopy Xray powder diffraction Mass microscopy Micro-chemical tests Electron microscopy etc. Significance of Particulate Matter monitoring: Its presence may causes: Septicemia Fever & blockage of blood vessels Quality of product may affect As per USP LVP: NMT 50 particles/ ml (size 10 or more than 10 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. C. LEAKAGE TEST: This test is performed only for ampoules which have been sealed by fusion to ensure that there should not be any leakage in them. Ampoules are dipped in 1% methylene blue solution. It is performed in vacuum chamber. Vials & bottles not subjected to this test because of flexibility of rubber. D) PYROGEN TEST PYROGENS: 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 Structure of endotoxins : Produced mostly by gram-negative bacteria Endotoxin - complex of pyrogenic lipopolysaccharide, a protein and inert lipid; lipid part of the lipopolysaccharide is the main pyrogenic agent; polysaccharide part increases solubility 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: The endotoxin characteristics include: thermostable, watersoluble, unaffected by the common bactericides non-volatile These are the reasons why pyrogens are difficult to destroy once produced in a product To check the presence or absence of pyrogens in all aqueous parenterals.

The test involves the measurement of rise in body temperature of rabbits following intravenous injection of a sterile solution of a parental preparation being examined
Industrial Pharmacy PCU-608

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8th
Rabbits are used for this test because their body temperature increases when pyrogens are introduced into their bodies through parental route Test for pyrogens - Rabbit test: The development of the test for pyrogens reach in 1920 a pyrogen test was introduced into the USP XII (1942) The test consists of measuring the rise in body temperature in healthy rabbits by the intravenous injection of a sterile solution of the substance under the test. Temperature elevation in rabbits under test, is seen for three (03) hours.

No. of Rabbits

Individual Temperature rise (C)

Temperature Rise in group (C) 1.4 3.7

Test Result

3 rabbits If above not passes 3+5 = 8 rabbits

0.6 0.6

Passes Passes

If above test not passes perform the test again or go through the sources of contamination of pyrogen. TABLE FOR INTERPREATATION OF RESULT OF PYROGEN TEST

Result: If above test not passes, the sample is said to be pyrogenic. 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 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 endotoxin that might be present will be

Industrial Pharmacy

PCU-608

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Semester

8th
coagulated with protien fraction of the amebocytes and results in the formation of a gel. This consider to be simple, rapid and of greater sensitivity that the rabbit test.

Limulus polyphemus = horseshoe crab

Mechanism of LAL: Mechanism of LAL the test is based on the primitive blood-clotting mechanism of the horseshoe crab enzymes located with the crab's amebocyte blood cells endotoxins initiation of an enzymatic coagulation cascade proteinaceous gel. Commercially derived LAL reagents: Bleeding adult crabs into an anticlotting solution washing and centrifuging to collect the amebocyte lysing in 3% NaCl lysate is washed and lyophilized for storage activity varies on a seasonal basis and standardization is necessary. Test performance (short): Test performance (short) 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 volume of LAL reagent and test solution (usually 0.1 ml of each) are mixed in a depyrogenated test-tube incubation at
Industrial Pharmacy PCU-608

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37C, 1 hour remove the tube - invert in one smooth motion (180) - read (observe) the result pass-fail test LAL TEST: Three different techniques: The gel-clot technique gel formation the turbidimetric technique - the development of turbidity after cleavage of an endogenous substrate the chromogenic technique - the development of color after cleavage of a synthetic peptide-chromogen complex LAL test: LAL test 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 is made upon Method A unless otherwise indicated in the monograph. Advantages of LAL test: Fast - 60 minutes vs. 180 minutes 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 activity in the rabbit (e.g. insulin) Blood products which sometime give misleading results in the rabbit Water for injection where LAL test is potentially more stringent and readily applied E. ASSAY Assay is performed according to method given in the monograph of that parental preparation in the pharmacopoeia. Assay is done to check the quantity of medicament present in the parenteral preparation.
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Semester

8th

Bibliography 1) Lachman, liebermann the parenteral preparations, Volume 3. 2) Avis, Lachman, Liebermann Pharmaceutical dosage forms, parenteral preparations, Marcel dekkar 3) Turcos and King r.e sterile dosage forms 4) Grooves M j sterile dosage forms manfacturing 5) Olson W P sterile dosage forms manfacturing

Industrial Pharmacy

PCU-608