REGISTRATION OF PHARMACEUTICAL PRODUCT - …infar.cl/infar.cl/baraya/Registro Colisan-1/COLISAN -...

COLISAN - 1

Colistimethate Sodium for Injection BP 1 MIU

(Lyophilized )

REGISTRATION OF PHARMACEUTICAL PRODUCT

TO

MINISTRY OF HEALTH

OF CHILE

COLISAN - 1

Colistimethate Sodium For Injection BP 1 MIU

(Lyophilized)

SUBMITTED BY

Immacule Life sciences (P) LTD.

At: Vill. Thanthewal, Ropar Road, Nalagarh, Dist .Solan (H.P.)

COLISAN - 1


(Lyophilized )

INDEX

SR.NO DESCRIPTION

01. License or Contract Manufacturing

02. Certificate of Pharmaceutical Product

03. WHO GMP Certificate

04. TSE/BSE Certificate & EDQM Certificate

05.

Formula & Pharmaceutical Form

a) Manufacturing Formula

b) Final Formula of product

06. Specifications of Active and Inactive Raw Materials

07. Active Raw Material COA from Manufacturer & Supplier

08. Specification and Certificate of analysis of Finished Product

09. Control of the Finished Product

10. Method Validation of Finished Product

11. Manufacturing procedure

12. Stability study of the finished product

13. Packaging Material

14. Graphic Labeling Project

15. Presentation

16. Samples

17. Standard of active with certificate of analysis

18. Pharmacological Clinical Monograph

19. Professional Brochure

20. Patient Information Leaflet

21. Scientific Information ( Only for new product , not for similar )

22. Bibliography References

23.

Additional Information

a) Manufacturing Diagram

b) Allocation system lot number

COLISAN - 1


(Lyophilized )

1. LICENSE OR CONTRACT

MANUFACTURING

COLISAN - 1


(Lyophilized )

LICENSE OR CONTRACT MANUFACTURING

Attached hereafter

COLISAN - 1


(Lyophilized )

2. CERTIFICATE OF

PHARMACEUTICAL PRODUCT

COLISAN - 1


(Lyophilized )

CERTIFICATE OF PHARMACEUTICAL PRODUCT (COPP)

Attached Hereafter

COLISAN - 1


(Lyophilized )

3. WHO-GMP CERTIFICATE

COLISAN - 1


(Lyophilized )

WHO-GMP CEFTIFICATE

Attached Hereafter

COLISAN - 1


(Lyophilized )

3. TSE/BSE CERTIFICATE & EDQM

CERTIFICATE

COLISAN - 1


(Lyophilized )

TSE/BSE CERTIFICATE & EDQM CERTIFICATE

(If applicable)

Not applicable

COLISAN - 1


(Lyophilized )

5. FORMULA & PHARMACEUTICAL

FORM

COLISAN - 1


(Lyophilized )

FORMULA & PHARMACEUTICAL FORM

(A) Manufacturing Formula

(B) Final formula of the product

Attached Hereafter

COLISAN - 1


(Lyophilized )

(A) MANUFACTURING FORMULA

PRODUCT NAME : COLISAN - 1

GENERIC NAME : Colistimethate Sodium For Injection BP 1 MIU (Lyophilized).

COMPOSITION : Each vial contains:

Colistimethate Sodium BP ............... 1.0 MIU

Excipients......................................... q.s.

EXPIRY : 2 Years

BATCH SIZE : 50 Liters (10,000 Vials).

Sr.

No Ingredients

Specifi-

cation

Label claim

(in IU)

Std Qty /vial in

mg

Qty./Batch

(in kg)

1. Colistimethate Sodium BP 10,00,000 78.74 *0.7874

2. Water for Injection BP - q.s. to 5.0 ml q.s. to

50.0 liters

* Quantity may vary as per assay and LOD.

Colistimethate Sodium contains 12700 units/mg of colistimethate.

COLISAN - 1


(Lyophilized )

(B) FINAL FORMULA OF THE PRODUCT

Not applicable

COLISAN - 1


(Lyophilized )

6. SPECIFICATION OF ACTIVE &

INACTIVE RAW MATERIAL

COLISAN - 1


(Lyophilized )

SPECIFICATION OF RAW MATERIAL

Attached Hereafter

COLISAN - 1


(Lyophilized )

QUALITY CONTROL TESTING

COLISTIMETHATE SODIUM BP

BP 2015 Monograph attached Hereafter

Search:Colistimethate Sodium

Colistimethate SodiumGeneral Notices

(Ph. Eur. monograph 0319)

8068-28-8

Action and use

Antibacterial.

Preparations

Colistimethate Injection

Colistimethate Sodium Powder for Nebuliser Solution

Ph Eur DEFINITION

Colistimethate sodium is prepared from colistin by the action of formaldehyde and sodium hydrogen sulfite.

Semi-synthetic product derived from a fermentation product.

Content

Minimum 11 500 IU/mg (dried substance).

CHARACTERS Appearance

White or almost white, hygroscopic powder.

Solubility

Very soluble in water, slightly soluble in ethanol (96 per cent), practically insoluble in acetone.

IDENTIFICATION

A. Thin-layer chromatography (2.2.27).

Test solution Dissolve 5 mg of the substance to be examined in 1 mL of a mixture of equal volumes of hydrochloric acid R and water R. Heat at 135 °C in a sealed tube for 5 h. Evaporate to dryness on a water-bath and continue the heating until the hydrochloric acid has evaporated. Dissolve the residue in 0.5 mL of water R.

Reference solution (a) Dissolve 20 mg of leucine R in water R and dilute to 10 mL with the same solvent.

Reference solution (b) Dissolve 20 mg of threonine R in water R and dilute to 10 mL with the same solvent.

Reference solution (c) Dissolve 20 mg of phenylalanine R in water R and dilute to 10 mL with the same solvent.

©Crown Copyright 2014 1

Reference solution (d) Dissolve 20 mg of serine R in water R and dilute to 10 mL with the same solvent.

Plate TLC silica gel G plate R.

Carry out the following procedures protected from light.

Mobile phase water R, phenol R (25:75 V/V).

Application 5 µL as bands of 10 mm, then place the plate in the chromatographic tank so that it is not in contact with the mobile phase, and allow it to become impregnated with the vapour of the mobile phase for at least 12 h.

Development Over a path of 12 cm using the same mobile phase.

Drying At 100-105 °C.

Detection Spray with ninhydrin solution R1 and heat at 110 °C for 5 min.

Results The chromatogram obtained with the test solution shows zones corresponding to those in the chromatograms obtained with reference solutions (a) and (b), but shows no zones corresponding to those in the chromatograms obtained with reference solutions (c) and (d); the chromatogram obtained with the test solution also shows a zone with a very low RF value (2,4-diaminobutyric acid).

B. Dissolve about 5 mg in 3 mL of water R. Add 3 mL of dilute sodium hydroxide solution R. Shake and add 0.5 mL of a 10 g/L solution of copper sulfate R. A violet colour is produced.

C. Dissolve about 50 mg in 1 mL of 1 M hydrochloric acid and add 0.5 mL of 0.01 M iodine. The solution is decolourised and gives reaction (a) of sulfates (2.3.1).

D. It gives reaction (b) of sodium (2.3.1).

TESTS Appearance of solution

The solution is clear (2.2.1).

Dissolve 0.16 g in 10 mL of water R.

pH (2.2.3)

6.5 to 8.5.

Dissolve 0.1 g in carbon dioxide-free water R and dilute to 10 mL with the same solvent. Measure after 30 min.

Specific optical rotation (2.2.7)

-46 to -51 (dried substance).

Dissolve 1.25 g in water R and dilute to 25.0 mL with the same solvent.

Free colistin

Dissolve 80 mg in 3 mL of water R. Add 0.1 mL of a 100 g/L solution of silicotungstic acid R; 10-20 s after addition of the reagent, the solution is not more opalescent than reference suspension II (2.2.1).

Total sulfite


Work in a fume cupboard. Dissolve 0.100 g in 50 mL of water R and add 5 mL of a 100 g/L solution of sodium hydroxide R and 0.3 g of potassium cyanide R. Boil gently for 3 min and then cool. Neutralise with 0.5 M sulfuric acid using 0.2 mL of methyl orange solution R as indicator. Add an excess of 0.5 mL of the acid and 0.2 g of potassium iodide R. Titrate with 0.05 M iodine using 1 mL of starch solution R as indicator. The volume of 0.05 M iodine used in the titration is 5.5 mL to 7.0 mL.

Loss on drying (2.2.32)

Maximum 5.0 per cent, determined on 1.000 g by drying at 60 °C over diphosphorus pentoxide R at a pressure not exceeding 670 Pa for 3 h.

Sulfated ash (2.4.14)

16 per cent to 21 per cent, determined on 0.50 g.

Pyrogens (2.6.8)

If intended for use in the manufacture of parenteral preparations without a further appropriate procedure for removal of pyrogens, it complies with the test. Inject, per kilogram of the rabbit′s mass, 1 mL of a solution in water for injections R containing 2.5 mg of the substance to be examined per millilitre.

ASSAY

Carry out the microbiological assay of antibiotics (2.7.2).

STORAGE

In an airtight container, protected from light. If the substance is sterile, store in a sterile, airtight, tamper-proof container.

Ph Eur


COLISAN - 1


(Lyophilized )

QUALITY CONTROL TESTING

OF

WATER FOR INJECTION BP (IN BULK)

BP 2015 monograph attached Hereafter

Search:water for injections

Water for InjectionsGeneral Notices

(Ph. Eur. monograph 0169)

H2O��18.02��7732-18-5

Ph Eur DEFINITION

Water for the preparation of medicines for parenteral administration when water is used as vehicle (water for injections in bulk) and for dissolving or diluting substances or preparations for parenteral administration (sterilised water for injections).

WATER FOR INJECTIONS IN BULK PRODUCTION

Water for injections in bulk is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority or from purified water by distillation in an apparatus of which the parts in contact with the water are of neutral glass, quartz or a suitable metal and which is fitted with an effective device to prevent the entrainment of droplets. The correct maintenance of the apparatus is essential. The first portion of the distillate obtained when the apparatus begins to function is discarded and the distillate is collected.

In order to ensure the appropriate quality of the water, validated procedures and in-process-monitoring of the electrical conductivity and regular microbial monitoring are applied.

Water for injections in bulk is stored and distributed in conditions designed to prevent growth of micro-organisms and to avoid any other contamination. Microbiological monitoring

During production and subsequent storage, appropriate measures are taken to ensure that the microbial count is adequately controlled and monitored. Appropriate alert and action levels are set so as to detect adverse trends. Under normal conditions, an appropriate action level is a microbial count of 10 CFU per 100 ml when determined by filtration through a membrane with a nominal pore size not greater than 0.45 µm, using R2A agar, using at least 200 ml of water for injections in bulk and incubating at 30-35 °C for not less than 5 days. For aseptic processing, stricter alert levels may need to be applied.

R2A agar

Yeast extract

0.5 g

Proteose peptone

0.5 g

Casein hydrolysate

0.5 g

Glucose

0.5 g


Starch 0.5 g

Dipotassium hydrogen phosphate

0.3 g

Magnesium sulphate, anhydrous

0.024 g

Sodium pyruvate

0.3 g

Agar

15.0 g

Purified water

to 1000 ml

Adjust the pH so that after sterilisation it is 7.2 ± 0.2. Sterilise by heating in an autoclave at 121 °C for 15 min.

Growth promotion of R2A agar��— Preparation of test strains. Use standardised stable suspensions of test strains or prepare

them as stated in Table 0169.-1. Seed lot culture maintenance techniques (seed-lot systems) are used so that the viable micro-organisms used for inoculation are not more than 5 passages removed from the original master seed-lot. Grow each of the bacterial strains separately as described in Table 0169.-1. Use buffered sodium chloride-peptone solution pH 7.0 or phosphate buffer solution pH 7.2 to make test suspensions. Use the suspensions within 2 h, or within 24 h if stored at 2-8 °C. As an alternative to preparing and then diluting a fresh suspension of vegetative cells of Bacillus subtilis, a stable spore suspension is prepared and then an appropriate volume of the spore suspension is used for test inoculation. The stable spore suspension may be maintained at 2-8 °C for a validated period of time.

�— Growth promotion. Test each batch of ready-prepared medium and each batch of medium, prepared either from dehydrated medium or from the ingredients described. Inoculate plates of R2A agar separately with a small number (not more than 100 CFU) of the micro-organisms indicated in Table 0169.-1. Incubate under the conditions described in the table. Growth obtained must not differ by a factor greater than 2 from the calculated value for a standardised inoculum. For a freshly prepared inoculum, growth of the micro-organisms must be comparable to that obtained with a previously tested and approved batch of medium.


Total organic carbon (2.2.44)

Maximum 0.5 mg/l. Conductivity

Determine the conductivity off-line or in-line under the following conditions.

EQUIPMENT

Conductivity cell:��— electrodes of a suitable material such as stainless steel; �— cell constant: the cell constant is generally certified by the supplier and is subsequently

verified at suitable intervals using a certified reference solution with a conductivity less than 1500 µS·cm-1 or by comparison with a cell having a certified cell constant. The cell constant is confirmed if the value found is within 2 per cent of the certified value, otherwise re-calibration must be performed.

Conductometer�Accuracy of 0.1 µS·cm-1 or better at the lowest range.

System calibration (conductivity cell and conductometer):�— against one or more suitable certified reference solutions; �— accuracy: within 3 per cent of the measured conductivity plus 0.1 µS·cm-1.

Conductometer calibration�Calibration is carried out for each range of measurement to be used, after disconnection of the conductivity cell, using certified precision resistors or equivalent devices with an uncertainty not greater than 0.1 per cent of the certified value.

If in-line conductivity cells cannot be dismantled, system calibration may be performed against a calibrated conductivity-measuring instrument with a conductivity cell placed close to the cell to be calibrated in the water flow.

Temperature measurement�Tolerance ± 2 °C.

PROCEDURE


Stage 1

�1. Measure the conductivity without temperature compensation, recording simultaneously the temperature. Temperature-compensated measurement may be performed after suitable validation.

�2. Using Table 0169.-2, find the closest temperature value that is not greater than the measured temperature. The corresponding conductivity value is the limit at that temperature.

�3. If the measured conductivity is not greater than the value in Table 0169.-2, the water to be examined meets the requirements of the test for conductivity. If the conductivity is higher than the value in Table 0169.-2, proceed with stage 2.

Stage 2


�4. Transfer a sufficient amount of the water to be examined (100 ml or more) to a suitable container, and stir the test sample. Adjust the temperature, if necessary, and while maintaining it at 25 ± 1 °C, begin vigorously agitating the test sample while periodically observing the conductivity. When the change in conductivity (due to uptake of atmospheric carbon dioxide) is less than 0.1 µS.cm-1 per 5 min, note the conductivity.

�5. If the conductivity is not greater than 2.1 µS.cm-1, the water to be examined meets the requirements of the test for conductivity. If the conductivity is greater than 2.1 µS.cm-1, proceed with stage 3.

Stage 3

�6. Perform this test within approximately 5 min of the conductivity determination in step 5 under stage 2, while maintaining the sample temperature at 25 ± 1 °C. Add a recently prepared saturated solution of potassium chloride R to the test sample (0.3 ml per 100 ml of the test sample), and determine the pH (2.2.3) to the nearest 0.1 pH unit.

�7. Using Table 0169.-3, determine the conductivity limit at the measured pH value in step 6. If the measured conductivity in step 4 under stage 2 is not greater than the conductivity requirements for the pH determined, the water to be examined meets the requirements of the test for conductivity. If either the measured conductivity is greater than this value or the pH is outside the range of 5.0-7.0, the water to be examined does not meet the requirements of the test for conductivity.


CHARACTERS Appearance

Clear and colourless liquid. TESTS Nitrates

Maximum 0.2 ppm.

Place 5 ml in a test-tube immersed in iced water, add 0.4 ml of a 100 g/l solution of potassium chloride R, 0.1 ml of diphenylamine solution R and, dropwise with shaking, 5 ml of nitrogen-free sulphuric acid R. Transfer the tube to a water-bath at 50 °C. After 15 min, any blue colour


in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate-free water R and 0.5 ml of nitrate standard solution (2 ppm NO3) R.

Aluminium (2.4.17)

Maximum 10 ppb, if intended for use in the manufacture of dialysis solutions.

Prescribed solution�To 400 ml of the water to be examined add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution�Mix 2 ml of aluminium standard solution (2 ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution�Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Bacterial endotoxins (2.6.14)

Less than 0.25 IU/ml.

STERILISED WATER FOR INJECTIONS DEFINITION

Water for injections in bulk that has been distributed into suitable containers, closed and sterilised by heat in conditions which ensure that the product still complies with the test for bacterial endotoxins. Sterilised water for injections is free from any added substances.

Examined in suitable conditions of visibility, it is clear and colourless.

Each container contains a sufficient quantity of water for injections to permit the nominal volume to be withdrawn.

TESTS Acidity or alkalinity

To 20 ml add 0.05 ml of phenol red solution R. If the solution is yellow, it becomes red on the addition of 0.1 ml of 0.01 M sodium hydroxide; if red, it becomes yellow on the addition of 0.15 ml of 0.01 M hydrochloric acid .

Conductivity

Maximum 25 µS·cm-1 for containers with a nominal volume of 10 ml or less; maximum 5 µS·cm-1 for containers with a nominal volume greater than 10 ml.

Use equipment and the calibration procedure as defined under Water for injections in bulk, maintaining the sample temperature at 25 ± 1 °C.

Oxidisable substances

For containers with a nominal volume less than 50 ml: heat 100 ml to boiling with 10 ml of dilute sulphuric acid R, add 0.4 ml of 0.02 M potassium permanganate and boil for 5 min; the solution remains faintly pink.

For containers with a nominal volume equal to or greater than 50 ml: heat 100 ml to boiling with 10 ml of dilute sulphuric acid R, add 0.2 ml of 0.02 M potassium permanganate and boil for 5 min; the solution remains faintly pink.


Chlorides (2.4.4)

Maximum 0.5 ppm for containers with a nominal volume of 100 ml or less.

15 ml complies with the limit test for chlorides. Prepare the standard using a mixture of 1.5 ml of chloride standard solution (5 ppm Cl) R and 13.5 ml of water R. Examine the solutions down the vertical axes of the tubes.

For containers with a nominal volume greater than 100 ml, use the following test: to 10 ml add 1 ml of dilute nitric acid R and 0.2 ml of silver nitrate solution R2. The solution shows no change in appearance for at least 15 min.

Nitrates

Maximum 0.2 ppm.

Place 5 ml in a test-tube immersed in iced water, add 0.4 ml of a 100 g/l solution of potassium chloride R, 0.1 ml of diphenylamine solution R and, dropwise with shaking, 5 ml of nitrogen-free sulphuric acid R. Transfer the tube to a water-bath at 50 °C. After 15 min, any blue colour in the solution is not more intense than that in a reference solution prepared at the same time in the same manner using a mixture of 4.5 ml of nitrate-free water R and 0.5 ml of nitrate standard solution (2 ppm NO3) R.

Sulphates

To 10 ml add 0.1 ml of dilute hydrochloric acid R and 0.1 ml of barium chloride solution R1. The solution shows no change in appearance for at least 1 h. Aluminium (2.4.17)

Maximum 10 ppb, if intended for use in the manufacture of dialysis solutions.

Prescribed solution�To 400 ml of the water to be examined add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Reference solution�Mix 2 ml of aluminium standard solution (2 ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R.

Blank solution�Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Ammonium

For containers with a nominal volume less than 50 ml: maximum 0.6 ppm; for containers with a nominal volume equal to or greater than 50 ml: maximum 0.2 ppm.

Containers with a nominal volume less than 50 ml: to 20 ml add 1 ml of alkaline potassium tetraiodomercurate solution R; after 5 min, examine the solution down the vertical axis of the tube; the solution is not more intensely coloured than a standard prepared at the same time by adding 1 ml of alkaline potassium tetraiodomercurate solution R to a mixture of 4 ml of ammonium standard solution (3 ppm NH4) R and 16 ml of ammonium-free water R.

Containers with a nominal volume equal to or greater than 50 ml: to 20 ml add 1 ml of alkaline potassium tetraiodomercurate solution R; after 5 min, examine the solution down the vertical axis of the tube; the solution is not more intensely coloured than a standard prepared at the same time by adding 1 ml of alkaline potassium tetraiodomercurate solution R to a mixture of 4 ml of ammonium standard solution (1 ppm NH4) R and 16 ml of ammonium-free water R.

Calcium and magnesium

To 100 ml add 2 ml of ammonium chloride buffer solution pH 10.0 R, 50 mg of mordant black


11 triturate R and 0.5 ml of 0.01 M sodium edetate. A pure blue colour is produced. Residue on evaporation

Maximum 4 mg (0.004 per cent) for containers with a nominal volume of 10 ml or less; maximum 3 mg (0.003 per cent ) for containers with a nominal volume greater than 10 ml.

Evaporate 100 ml to dryness on a water-bath and dry in an oven at 100-105 °C.

Particulate contamination: Sub-visible particles (2.9.19)

It complies with test A or test B, as appropriate. Sterility (2.6.1)

It complies with the test for sterility. Bacterial endotoxins (2.6.14)

Less than 0.25 IU/ml.

Ph Eur


COLISAN - 1


(Lyophilized )

7. ACTIVE RAW MATERIAL COA

FROM MANUFACTURER & SUPPLIER

COLISAN - 1


(Lyophilized )

ACTIVE RAW MATERIAL COA FROM MANUFACTURER

Attached Hereafter

COLISAN - 1


(Lyophilized )

Raw Data Calculation

1. ASSAY: (By Microbial Assay Cylinder plate method):

Solvent Used for Dilution: Monobasic potassium phosphate pH 6.0 (Buffer pH 6.0).

Potency: 13728.75 IU/mg

Standard Dilution (Soln B):

100.2 mg to 100 ml (with water), (Solution A, 1mg/ml).

Dilute 10 ml of Solution A to 100 ml with 6.0 pH Buffer. (Solution B,100 IU/ml)

1) S1 1.0 ml of solution B to 10 ml with Buffer pH 6.0 = ( i.e.10 mcg/ml)

2) S2 1.2 ml of solution B to 10 ml with Buffer pH 6.0 = (i.e.12 mcg /ml)




S1 to S5 are the standard dilutions, where S3 is the median dose.

Sample Dilution:

100.1 mg to 100 ml with water solution A, 1 mg/ml

From solution A take 10 ml and dilute to 100 ml with Buffer pH 6.0 (Soln B, 100 mcg/ml)

From solution B take 1.4 ml and dilute to 10 ml with Buffer. pH 6.0(Test Soln

14 mcg/ml)

Medium Used: Medium No 10 (Hi-Media)

Microbial Culture Used: Bordentella Brcnchiseptica ATCC 4617.

Incubation Temperature: 35°-37°C.

Zone of inhibition in mm.


Plate No. 10 mcg/ml 12 mcg/ml 16 mcg/ml 18 mcg/ml Test

S3 S1 S3 S2 S3 S4 S3 S5 S3 R1

1

23.40 18.60 23.60 20.90 23.50 24.0 23.70 24.80 23.50 22.30

23.60 18.80 23.40 20.70 23.60 23.80 23.60 24.60 23.60 22.20

23.60 18.70 23.60 20.60 23.70 24.20 23.60 24.90 23.30 22.30

2

23.40 18.60 23.60 20.90 23.50 24.00 23.70 24.80 23.50 22.30

23.60 18.80 23.40 20.70 23.60 23.80 23.60 24.60 23.60 22.20

23.60 18.70 23.60 20.60 23.70 24.20 23.60 24.90 23.30 22.30

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3

23.40 18.60 23.60 20.90 23.50 24.00 23.70 24.80 23.50 22.30

23.60 18.80 23.40 20.70 23.60 23.80 23.60 24.60 23.60 22.20

23.60 18.70 23.60 20.60 23.70 24.20 23.60 24.90 23.30 22.30

Average 23.53 18.7 23.53 20.73 23.60 24.00 23.63. 24.77 23.47 22.27

Corrected

value in

18.74 20.78 23.98 24.71 22.38

a b d e

Average of S3 (36 Readings) 23.58 (c= Correction point for the curve).

Corrected average value : (Combined avg- Individual avg)+ Average zone diameter.

L= (3a+ 2b+ c-e)/5

L=19.33 (The calculated zone diameter for the lowest concentration of the standard)

H= (3e+ 2d +c-a )/5

H= 25.38 (The calculated zone diameter for the highest concentration of the standard )

c= 23.58 (Average of S3)

Corrected value for sample : c+(uk- S3UK)

C= 14.5 mcg/ml obtained from graph

uK= 22.27 Average of test zone diameter.

S3UK= 23.47 Average zone diameter for 10 mcg/ml of standard read in the same plate.

Calculation :

Potency of Standard on a such basis = 13728.75 mcg/ ml

Content of Colistimethate IU/mg

Sample graph reading = 14.5 IU/ml

Weight of Standard= 100.2 mg

Weight of Sample= 100.1 mg

Potency of standard on as such basis=13728.75 IU/ mg

Loss on drying of Sample= 1.96 %

Test Conc:

100.1 mg 100 ml

10.0 ml 100 ml

1.4 ml 10 ml : Test Conc : 14.014 mcg / ml

Std Conc:

100.2 mg 100 ml

10.0 ml 100 ml

1.4 ml 10 ml : Std Conc : 14.028 mcg/ ml

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Formula:

Sample graph reading std conc. Std. Potency

= ------------------------------ x -------------- x ---------------------

Median dose test conc. 1000

14.5 14.028 13728.75

= -------- x ----------- x --------------

14 14.014 1000

= 14.23327 mg/vial

Content of Colistimethate IU/mg = 14233.27 IU/ mg

Content of Colistimethate on dry basis:

14233.27 IU/ mg

=----------------------- X 100

(100- LOD)

14233.27 IU/ mg

=----------------------- X 100

98.04

= 14517.82 IU/ mg

COLISAN - 1


(Lyophilized )

ACTIVE RAW MATERIAL COA FROM SUPPLIER

Attached hereafter

COLISAN - 1


(Lyophilized )

8. SPECIFICATION AND CERTIFICATE

OF ANALYSIS OF FINISHED PRODUCT

COLISAN - 1


(Lyophilized )

SPECIFICATION OF FINISHED PRODUCT

Attached Hereafter

COLISAN - 1


(Lyophilized )

CERTIFICATE OF ANALYSIS OF FINISHED PRODUCT

Attached Hereafter

COLISAN - 1


(Lyophilized )

RAW DATA CALCULATION

1. ASSAY: (By Microbial Assay Cylinder plate method):

Slovent Used for Dilution: Monobasic potassium phosphate pH 6.0 (Buffer pH 6.0 ).

Potency : 13728.75 IU/mg

Standard Dilution (Soln B):

74.8 mg to 100 ml (with water), (Solution A, 10,000 IU/ml).

Dilute 10 ml of Solution A to 100 ml with 6.0 pH Buffer. (Solution B,1000 IU/ml)



3) S3 1.40 ml of solution B to 10 ml with Buffer pH 6.0 = (i.e.140 mcg/ml)

4) S4 1.60 ml of solution B to 10 ml with Buffer pH 6.0 = (i.e.160 mcg/ml)



Sample Dilution:

Content of 10 vials to 1000 ml with water solution A, 10,000 IU/ml

From solution A take 10 ml and dilute to 100 ml with Buffer pH 6(Soln B, 1000 mcg/ml)

From solution B take 1.4 ml and dilute to 10 ml with Buffer. pH 6(Test Soln

140 mcg/ml)

Medium Used: Medium No 10 (Hi-Media)

Microbial Culture Used: Bordentella Brcnchiseptica ATCC 4617.

Incubation Temperature: 35°-37°C.

Zone of inhibition in mm.

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Plate No. 100 IU/ml 120 IU/ml 160 IU/ml 180 IU/ml Test

S3 S1 S3 S2 S3 S4 S3 S5 S3 R1

1

17.4 15.6 17.6 16.4 17.2 18.4 17.6 19.2 17.4 16.8

17.2 15.4 17.6 16.4 17.6 18.8 17.4 19.4 17.6 17.2

17.4 15.4 17.4 16.6 17.4 18.6 17.2 19.6 17.6 16.6

2

17.6 15.6 17.4 16.4 17.6 18.4 17.4 19.4 17.4 17.6

17.8 15.4 17.2 16.6 17.4 18.4 17.6 19.6 17.8 17.2

17.2 15.6 17.6 16.8 17.6 18.6 17.4 19.4 17.4 17.4

3

17.6 15.4 17.2 16.2 17.4 18.4 17.6 19.6 17.6 16.8

17.4 15.4 17.6 16.4 17.6 18.6 17.8 19.4 17.8 17.4

17.4 15.2 17.8 17.0 17.4 18.2 17.4 19.6 17.6 17.2

Av. Zone

Dia. In mm

17.44

15.4

17.489

16.5

17.47

18.5

17.47

19.47

17.58

17.13

Corrected

value in mm

15.47

16.52

18.49

19.45

17.03

a b d e

Average of S3 (36 Readings) 17.47 (c= Correction point for the curve)

Corrected average value: (Combined avg- Individual avg)+ Average zone diameter.

L= (3a+ 2b+ c-e)/5

L=15.49 (The calculated zone diameter for the lowest concentration of the standard)

H= (3e+ 2d +c-a )/5

H= 19.47 (The calculated zone diameter for the highest concentration of the standard)

c= 17.47 (Average of S3)

Corrected value for sample:

C= 132 mcg/ml obtained from graph

UK=17.13 Average of test zone diameter.

S3UK= 17.58 Average zone diameter for 10 mcg/ml of standard read in the same plate.

Calculation:

Content of Colistimethate IU

Sample graph reading = 132 IU/ml

Weight of Standard= 74.8 mg

Potency of standard on as such basis=13728.75 IU/ mg

Loss on drying of Sample= 1.43%

Weight of sample= 70.0 mg.

COLISAN - 1


(Lyophilized )

Test Conc:

700 mg 1000 ml

10.0 ml 100 ml

1.4 ml 10 ml: Test Conc : 9.8 mcg / ml

Std Conc:

74.8 mg 100 ml

10.0 ml 100 ml

1.4 ml 10 ml : Std Conc : 10.472 mcg/ ml

Formula:

Sample graph reading std conc. Std. Potency

=------------------------------ x -------------- x ---------------------

Median dose test conc. 1000

132 10.472 13728.75

=-------- x----------- x---------------

140 9.8 1000

= 13.83185 mg/vial

= 13831.85 IU/ mg

Content of Colistimethate in % =

13728.75 IU/mg of Colistimethate sodium 100 % Content of Colistimethate

13829.2 IU/mg of Colistimethate sodium ‘X’ Colistimethate

13831.85 x 100

Content of Colistimethate in % = ---------------------------

13728.75

= 100.75 %

COLISAN - 1


(Lyophilized )

9. CONTROL OF THE FINISHED

PRODUCT

COLISAN - 1


(Lyophilized )

METHOD OF ANALYSIS

COLISAN-1


(Lyophilized)

1. DESCRIPTION (By Visual observation):

White to slightly yellow coloured fluffy mass after reconstitution becomes clear colourless to

slightly yellowish coloured clear solution filled in 10ml clear colourless glass vial USP Type

I sealed with white colour flip off seal.

2. IDENTIFICATION:

A. By thin-layer chromatography:

Carry out the method for protected from light, using the following solutions in water.

(1) Dissolve a quantity containing 62,500 IU in 1 ml of a mixture of equal volumes of

hydrochloric acid and water, heat at 135° in a sealed tube for 5 hours, evaporate to dryness on

a water-bath, continue the heating until any residual hydrochloric acid has evaporated and

dissolve the residue in 0.5 ml of water.

(2) 0.2% w/v of leucine.

(3) 0.2% w/v of threonine.

(4) 0.2% w/v of phenylalanine.

(5) 0.2% w/v of serine solution.

CHROMATOGRAPHIC CONDITIONS

(a) Use as the coating silica gel G.

(b) Use the mobile phase as described below.

(c) Apply 5 µl of each solution, as 10-mm bands.

(d) Place the plate in the chromatographic tank so that it is not in contact with the mobile

phase. Allow the plate to become impregnated with the vapour of the solvent for at least 12

hours and develop over a path of 12 cm using the same mobile phase.

(e) After removal of the plate, dry at 100° to 105°, spray with ninhydrin solution R1 and heat

at 110° for 5 minutes.

MOBILE PHASE: 25 parts of water and 75 parts of phenol.

COLISAN - 1


(Lyophilized )

CONFIRMATION

The chromatogram obtained with solution (1) shows zones corresponding to those in the

chromatograms obtained with solutions (2) and (3) but shows no zones corresponding to

those in the chromatograms obtained with solutions (4) and (5). The chromatogram obtained

with solution (1) also shows a zone with a very low Rf value (2,4-diaminobutyric acid).

B. Dissolve a quantity containing 125,000 IU in 5 ml of water. Heat 0.5 ml of the solution

with 0.5 ml of chromotropic acid–sulphuric acid solution at 100° for 30 minutes. A purple

colour is produced (distinction from colistin sulphate).

C. Dissolve a quantity containing 625,000 IU in 1 ml of 1M hydrochloric acid and add 0.5 ml

of 0.01M iodine. The colour is discharged (distinction from colistin sulphate) and the

resulting solution yields reaction-A characteristic of sulphates.

(*Reaction A.- Dissolve about 45 mg of the substance to be examined in 5 ml of water R or

use 5 ml of the prescribed solution. Add 1 ml of dilute hydrochloric acid R and 1 ml of

barium chloride solution R1. A white precipitate is formed.)

D. Dissolve a quantity of the substance to be examined equivalent to about 2 mg of sodium

(Na+) in 0.5 ml of water R or use 0.5 ml of the prescribed solution. Add 1.5 ml of

methoxyphenylacetic reagent R and cool in ice-water for 30 min. A voluminous, white,

crystalline precipitate is formed. Place in water at 20 °C and stir for 5 min. The precipitate

does not disappear. Add 1 ml of dilute ammonia R1. The precipitate dissolves completely.

Add 1 ml of ammonium carbonate solution R. No precipitate is formed.)

3. UNIFORMITY OF WEIGHT:

Procedure: Take 20 vials from the sample for analysis. Remove any paper labels from a

container and wash and dry the outside. Open the container and without delay weigh the

container and its contents. Empty the container as completely as possible by gentle tapping,

rinse it if necessary with water R and then with alcohol R and dry at 100-105 °C for 1 h, or,

if the nature of the container precludes heating at this temperature, dry at a lower

temperature to constant mass. Allow to cool in a desiccator and weigh. The mass of the

contents is the difference between the weighings. Repeat the procedure with another 19

containers. Determine the average mass.

Acceptance criteria: Not more than 2 of the individual masses deviate from the average

mass of 20 units by more than 10 % and none deviates by more than 20%.

COLISAN - 1


(Lyophilized )

4. ACIDITY OR ALKALINITY:

Test solution:

Dissolve a quantity in sufficient carbon dioxide-free water in a beaker to produce a solution

containing 125,000 IU per ml.

Procedure:

Measure the pH of test solution after 30 minutes of preparation.

1 Wash the electrode and wipe with the tissue paper.

2 Dip the electrode in the test solution.

3 Measure the pH previously calibrated pH meter.

4 Note down the reading.

5 Remove the electrode from test solution.

Acceptance criteria: The pH of solution containing 125,000 IU colistimethate per ml of

cabon dioxide –free water, measured 30 minutes after preparation, is 6.5 to 8.5

5. CLARITY OF CONSTITUTED SOLUTION (By visual observation) :

Procedure:

Reconstitute one vial with 10 ml of water for injection.

a) The solid dissolves completely, leaving no visual residue as undissolved matter.

b) The constituted solution is not significantly less clear than an equal volume of the

diluents or of Purified water contained in a similar vessel and examined in same

manner.

Acceptance criteria: Constituted solution should be clear.

6. FREE COLISTIN (By visual method)

Test solution: Dissolve a quantity containing 1,000,000 IU in 3 ml of water, add 0.1 ml of a

10% w/v solution of silicotungstic acid and allow standing for 10 to 20 seconds.

Reference suspension II preparation:

Hydrazine sulphate solution: Dissolve 1.0 g of hydrazine sulphate R in water R and dilute to

100.0 ml with the same solvent. Allow to stand for 4-6 h.

Hexamethylenetetramine solution: In a 100 ml ground-glass-stoppered flask, dissolve 2.5 g

of hexamethylenetetramine R in 25.0 ml of water R.

Primary opalescent suspension (formazin suspension): To the hexamethylenetetramine

solution in the flask add 25.0 ml of the hydrazine sulphate solution. Mix and allow standing

COLISAN - 1


(Lyophilized )

for 24 h. This suspension is stable for 2 months, provided it is stored in a glass container free

from surface defects. The suspension must not adhere to the glass and must be well mixed

before use.

Standard of opalescence: Dilute 15.0 ml of the primary opalescent suspension to 1000.0 ml

with water R. This suspension is freshly prepared and may be stored for up to 24 h.

Reference suspension II: Dilute 10.0 ml of standard of opalescence with 90 ml of water R.

Procedure: Using identical test-tubes of colourless, transparent, neutral glass with a flat base

and an internal diameter of 15-25 mm, compare the test solution with reference suspension

freshly prepared, the depth of the layer being 40 mm. Compare the solutions in diffused

daylight 5 min after preparation of the reference suspension, viewing vertically against a

black background.

Acceptance criteria: The resulting solution is not more opalescent than reference suspension

II.

7. LOSS ON DRYING:

Place the 1g of sample in a previously weighed bottle (W1) previously dried under the

conditions the same conditions to be employed in the determination (W2). Dry the sample

over phosphorus pentoxide at 60°C (± 2ºC) at a pressure not exceeding 0.7 kPa for 3 hours.

At the end of the heating period, lose not more than 5.0% of their weight (W3).

W2-W3

Loss on drying: ------------- X 100

W2-W1

Acceptance criteria: Not more than 5.0% W/W

8. STERILITY:

Test carried out as per BP method of Appendix XVI A.

Limit: To be sterile.

9. BACTERIAL ENDOTOXINS:

Test carried out as per BP method of Appendix XIV C.

Acceptance criteria: The endotoxin limit of solution containing 250,000 IU

Colistimetahte per ml of water BET is 43.75 IU of endotoxin per ml.

COLISAN - 1


(Lyophilized )

10.PARTICULATE MATTER :

Test carried out as per BP method of Appendix XIII.

a) By Visual Inspection:

It should be visibly clear & free from any residual particles.

b) By Light Obscuration particles count test:

Limit: The preparation complies with the test if the average number of particles present in

the units tested does not exceed 6000 per container equal to or greater than 10 µm and does

not exceed 600 per container equal to or greater than 25µm.

11. ASSAY: (By Microbial Assay)

Sample preparation:

Take 10 vials from the sample for analysis. Remove any paper labels from a container and

wash and dry the outside. Open the container and without delay weigh the container and its

contents. Empty the container as completely as possible by gentle tapping, rinse it if

necessary with water R and then with alcohol R and dry at 100-105 °C for 1 h, or, if the

nature of the container precludes heating at this temperature, dry at a lower temperature to

constant mass. Allow to cool in desiccators and weigh. The mass of the contents is the

difference between the weighings. Repeat the procedure with another 9 containers. Determine

the average mass. Mix the contents of the 10 containers.

Proceudre (By Cylinder plate method):

Liquefy a medium suitable for the conditions of the assay and inoculate it at a suitable

temperature, for example 48 °C to 50 °C for vegetative forms, with a known quantity of a

suspension of micro-organisms sensitive to the antibiotic to be examined, such that clearly

defined zones of inhibition of suitable diameter are produced with the concentrations of the

antibiotic used for the assay. Immediately pour into Petri dishes or large rectangular dishes a

quantity of the inoculated medium to form a uniform layer 2-5 mm thick. Alternatively, the

medium may consist of 2 layers, only the upper layer being inoculated. Store the dishes so

that no appreciable growth or death of the micro-organisms occurs before the dishes are used

and so that the surface of the medium is dry at the time of use.

Using the solvent and the buffer solution indicated in Table 2.7.2.-1, prepare solutions of the

reference substance and of the antibiotic to be examined having known concentrations and

COLISAN - 1


(Lyophilized )

presumed to be of equal activity. Apply the solutions to the surface of the medium, for

example, in sterile cylinders of porcelain, stainless steel or other suitable material, or in

cavities prepared in the agar. The same volume of solution must be added to each cylinder or

cavity. Alternatively, use sterile absorbent paper discs of suitable quality; impregnate the

discs with the solutions of the reference substance or the solutions of the antibiotic to be

examined and place on the surface of the agar.

In order to assess the validity of the assay, use not fewer than 3 doses of the reference

substance and 3 doses of the antibiotic to be examined having the same presumed activity as

the doses of the reference substance. It is preferable to use a series of doses in geometric

progression. In routine assays when the linearity of the system has been demonstrated over an

adequate number of experiments using a three-point assay, a two-point assay may be

sufficient, subject to agreement by the competent authority. However, in all cases of dispute,

a three-point assay as described above must be applied.

Arrange the solutions on each Petri dish or on each rectangular dish according to a

statistically suitable design, except for small Petri dishes that cannot accommodate more than

6 solutions, arrange the solutions of the antibiotic to be examined and the solutions of the

reference substance in an alternate manner to avoid interaction of the more concentrated

solutions.

Incubate at a suitable temperature for about 18 h. A period of diffusion prior to incubation,

usually 1-4 h, at room temperature or at about 4 °C, as appropriate, may be used to minimize

the effects of the variation in time between the application of the solutions and to improve

the regression slope. Measure the diameters with a precision of at least 0.1 mm or the areas

of the circular inhibition zones with a corresponding precision and calculate the potency

using appropriate statistical methods. Use in each assay the number of replications per dose

sufficient to ensure the required precision. The assay may be repeated and the results

combined statistically to obtain the required precision and to ascertain whether the potency of

the antibiotic to be examined is not less than the minimum required.

COLISAN - 1


(Lyophilized )

Table 1: Diffusion Assay

Antibiotic Reference

Substance

Solvent to

be used in

preparing

the stock

solution

Buffer

solution

(pH)

Micro-

Organism

Medium

& Final

pH(±0.1

pH unit

)

Incubation

temperatur

e

Colistimethate

Sodium

Colistimethate

Sodium CRS

Water R pH 6.0

(0.05M)

Bordetella

bronchiseptica

NCTC 8344

CIP 53.157

ATCC 4617

Escherichia coli

NCIB 8879

CIP 54.127

ATCC 10636

B-

pH 7.3

35-39 °C

Acceptance Criteria:

For a container of average content weight, the upper fiducially limit of error is not less than

95.0% and the lower fiducially limit of error is not more than 115.0% of the stated number of

IU.

COLISAN - 1


(Lyophilized )

10. METHOD VALIDATION OF THE

FINISHED PRODUCT

COLISAN - 1


(Lyophilized )

METHOD VALIDATION OF THE FINISHED PRODUCT

Not required it is official in BP

COLISAN - 1


(Lyophilized )

11. STABILITY STUDY OF THE

FINISHED PRODUCT

COLISAN - 1


(Lyophilized )

STABILITY STUDY OF THE FINISHED PRODUCT

Attached Hereafter

COLISAN - 1


(Lyophilized )

STABILITY PROTOCOL

1. Name of the product : COLISAN – 1

(Colistimethate Sodium for Injection BP 1 MIU)

2. Description of the container : Box of 10ml clear colourless glass vial USP Type I

sealed with white colour flip off seal.

3. Parameters monitored and test method employed :

Description : White to slightly yellow coloured fluffy mass after

reconstitution becomes clear colourless to slightly

yellowish coloured clear solution filled in 10ml clear

colourless glass vial USP Type I sealed with white

colour flip off seal.

Identification

: A.By TLC- The chromatogram obtained with solution

(1) shows zones corresponding to those in the

chromatograms obtained with solutions (2) and (3) but

shows no zones corresponding to those in the

chromatograms obtained with solutions (4) and (5). The

chromatogram obtained with solution (1) also shows a

zone with a very low Rf value (2,4-diaminobutyric acid )

B. A purple colour is produced.

C. Positive for sulphates test.

D. Positive for Sodium salts test.

Uniformity of weight : Not more than 2 of the individual masses deviate from

the average mass of 20 units by more than 10 % and

none deviates by more than 20%.

Acidity or Alkalinity : pH of solution containing 125,000 IU colistimethate per

ml of carbon dioxide –free water , measured 30 minutes

after preparation, is 6.5 to 8.5

Clarity of constituted solution

(By visual observation)

: Should be Clear solution

Free colistin (By visual method) : The resulting solution should not be more opalescent

than reference suspension II.

Loss on drying : Not more than 5.0% w/w

Sterility : To be sterile

Bacterial Endotoxins

(By Kinetic -Chromogenic

technique)

:

The endotoxin limit of solution containing 250,000 IU

colistimetahte per ml of water BET is 43.75 IU of

endotoxin per ml.

Particulate matter

a)By Visible inspection

b)By Light Obscuration particles

count

≥ 10µm

≥25µm

It should be visibly clear & free from any residual

particles

NMT 6000 particles/container

NMT 600 particles/container

Assay

(By Microbial Assay ) NLT 95.0% and NMT 115.0% of the stated number of IU.

COLISAN - 1


(Lyophilized )

4. Product formula

Sr.

No Ingredients

Specifi-

cation

Label claim

(in IU)

Std Qty /vial in

mg

Qty./Batch

(in kg)

1. Colistimethate Sodium BP 10,00,000 78.74 *0.7874

2. Water for Injection BP - q.s. to 5.0 ml q.s. to

50.0 liters

* Quantity may vary as per assay and LOD.

Colistimethate Sodium contains 12700 units/mg of colistimethate.

5. Batches Studied:

Batch No. Mfg. Date Exp. Date Batch Size

COL0211301 09/2013 08/2015 10000Vials (50 Liters)

COL0221301 09/2013 08/2015 10000Vials (50 Liters)

COL0231301 09/2013 08/2015 10000Vials (50 Liters)

6. Testing conditions:

Storage Time Storage Condition (Temperature/RH) Results

24 Months Store at temperature 25

oC (± 2

0C).

Relative humidity 60 % (± 5 %) Complies

6 Months Store at temperature 40

oC (± 2

0C) and

Relative humidity 75 % (± 5 %)

Complies

7. Discussion:

Storage under accelerated testing conditions causes insignificant change of assay results of

COLISAN – 1 (Colistimethate For Injection BP 1 MIU). Significant changes in physical

and chemical stabilities were not observed.

COLISAN - 1


(Lyophilized )

STABILITY DATA

Attached hereafter

COLISAN - 1


(Lyophilized )

12. GRAPHIC LABELLING PROJECT

COLISAN - 1


(Lyophilized )

GRAPHIC LABELLING PROJECT

Carton, Label & Insert attached here after.

COLISAN - 1


(Lyophilized )

13. PRESENTATION

COLISAN - 1


(Lyophilized )

PRESENTATION

Presentation: Box of One 10ml Vial USP Type I sealed with white colour flip off seal.

COLISAN - 1


(Lyophilized )

14. SAMPLES

COLISAN - 1


(Lyophilized )

SAMPLES

Attached Hereafter

COLISAN - 1


(Lyophilized )

15. STANDARD OF ACTIVE WITH

CERTIFICATE OF ANALYSIS

COLISAN - 1


(Lyophilized )

STANDARD OF ACTIVE WITH CERTIFICATE OF ANALYSIS

Attached Hereafter

COLISAN - 1


(Lyophilized )

16. PHARMACOLOGICAL CLINICAL

MONOGRAPH

COLISAN - 1


(Lyophilized )

PHARMACOLOGICAL CLINICAL MONOGRAPH

Attached Hereafter

COLISAN - 1


(Lyophilized )

PHARMACODYNAMICS:

Pharmacology

Polymyxins are selective cationic agents acting on certain bacteria. The bacterial cell

membrane is composed principally of phospholipid and provides the target site for polymyxin

activity. Disruption of the membrane results in profound physiological effects which are

lethal to the bacterium. The cell is no longer capable of controlling the influx and efflux of

cations, e.g. potassium and sodium. The selectivity of polymyxins for gram- negative bacteria

is a result of the presence of a hydrophobic outer membrane. Polymyxins bind to the lipid A

moiety of endotoxin causing disorganization of the outer membrane altering the cell’s

permeability to various hydrophobic substances including antibiotics, e.g. erythromycin,

trimethoprim

PHARMACOKINETICS:

Absorption from the gastrointestinal tract does not occur appreciably in the normal individual

though patients with disturbed gut mucosa, e.g.patients given cytotoxic drugs, may behave

differently.

Colistimethate is converted to the base in vivo, has a plasma half-life of 4-8 h, and is bound

slightly to plasma protein. Half-life values of colistimethate sodium after intramuscular or

intravenous administration to be 2.75-3 h and 1.5h. Colistin crosses the placental barrier.

The route of excertion is via kidney with about 40% of the dose being excreted in the first 8

h. Only 80% of the dose can be recovered unchanged in the urine, and no biliary excretion

has been demonstrated.

COLISAN - 1


(Lyophilized )

17. PROFESSIONAL BROCHURE

COLISAN - 1


(Lyophilized )

PROFESSIONAL BROCHURE

Attached Hereafter

COLISAN - 1


(Lyophilized )

PROFESSIONAL BROCHURE

COMPOSITION

Each vial contains:

Colistimethate Sodium BP ............... 1 MIU

Excipients......................................... q.s.

INDICATIONS:

Colistimethate Sodium is used for:

1. Respiratory tract infection

2. Systemic infections

3. Bladder irrigation

DOSAGE AND ADMINISTRATION:

Colistin is a polymyxin antibacterial that has been used in the treatment of severe Gram-

negative infections, especially those due to Pseudomonas aeruginosa, although other drugs

are usually preferred.Colistimethate sodium is used by inhalation in the management of

respiratory infections, especially in patients with cystic fibrosis.

Colistin is given parenterally, as colistimethate sodium, by intramuscular injection or slow

intravenous injection or infusion.

In the UK, usual doses are 1 to 2million units given 3 times daily (maximum dose 6 million

units in 24 hours) for patients weighing more than 60 kg; those weighing up to 60 kg may be

given 50 000 units/kg daily in 3 divided doses up to a maximum of 75000 units/kg daily. In

the USA, the usual dose is equivalent to colistin base 2.5 to 5 mg/kg daily in 2 to 4 divided

doses. Monitoring of plasma concentrations is required in some patients.

Colistimethate sodium may also be given by inhalation in respiratory infections as an adjunct

to systemic antibacterial therapy.

The usual dose is 1 to 2 million units given 2 or 3 times daily. A 3-week course of 2 million

units twice daily may be given initially, increased to a maximum of 2 million units given 3

times daily for up to 3 months in frequent recurrent infections; 1 to 2 million units twice daily

may be given for long-term therapy. Solutions for inhalation should be freshly prepared

COLISAN - 1


(Lyophilized )

Colistimethate sodium has also been given by subcon-junctival injection and as a bladder

instillation. Both colistin sulfate and colistimethate sodium have been applied topically, often

with other antibacterials, in the management of ear, eye, and skin infections.

Directions for reconstitution

Colistimethate sodium is reconstituted with water for injections or 0.9% Sodium chloride.

The reconstituted solution should be used immediately.

The reconstituted solution is stored for 24 hours in the refrigeration at 20C to 8

0 C or up to 8

hours when stored at temperatures not exceeding 250 C.

CONTRAINDICATIONS:

Patients known to be sensitive to Colistimethate Sodium.

Dosage must be modified in patients with impaired renal function.

Curariform muscle relaxants must be used with extreme caution

WARNINGS AND PRECAUTIONS:

Cough and bronchospasm may occur during inhalation; cases of sore throat or sore mouth,

possibly due to Hypersensitivity or superinfection with Candida spp., have also been reported.

Neurotoxic reactions such as dizziness, confusion, and visual disturbances can occur during

parenteral therapy and patients so affected should not drive or operate machinery.

Pain and local irritation are reported to be less troublesome after intramuscular injection of

colistimethate sodium than with Colistin sulfate or polymyxin B.

Overgrowth of nonsusceptible organisms, particularly Proteus spp., may occur after prolonged

use.

Plasma-concentration monitoring during systemic treatment is recommended in neonates,

patients with renal impairment, and those with cystic fibrosis. Peak plasma-colistin

concentrations of 10 to 15 mg/litre (about 125 to 200 units/mL) are recommended.

INTERACTIONS WITH OTHER MEDICINE:

It may enhance the action of neuromuscular blockers possibly resulting in respiratory

depression and apnoea, and concurrent use should be avoided. Additive neurotoxicity and/or

COLISAN - 1


(Lyophilized )

nephrotoxicity may occur if polymyxins are given with other potentially neurotoxic and/or

nephrotoxic. Drugs including aminoglycosides and cefaloridine; concurrent use should also

be avoided.

OVERDOSE AND TREATMENT:

Overdose can results in renal insufficiency, muscle weakness and apnea.

There is no specific antidote. In cases of overdosage, treatment should be supportive, and

forced diuresis, prolonged hemodialysis, or peritoneal dialysis used to increase the rate of

elimination.

PREGNANCY AND LACTATION:

Pregnancy: There is no evidence to suggest that the drug is teratogenic when used during

pregnancy.

Lactation: A small amount of the drug appears in breast milk and , as the drug may be

absorbed from the gut in the newborn, mothers being treated with it should not breast- feed.

COLISAN - 1


(Lyophilized )

18. PATIENT INFORMATION LEAFLET

COLISAN - 1


(Lyophilized )

PATIENT INFORMATION LEAFLET

Attached Hereafter

COLISAN - 1


(Lyophilized )

PATIENT INFORMATION LEAFLET

INDICATIONS:

Colistimethate Sodium is used for:

1. Respiratory tract infection

2. Systemic infections

3. Bladder irrigation

DOSAGE AND ADMINISTRATION:

Colistin is a polymyxin antibacterial that has been used in the treatment of severe Gram-

negative infections, especially those due to Pseudomonas aeruginosa, although other drugs

are usually preferred.Colistimethate sodium is used by inhalation in the management of

respiratory infections, especially in patients with cystic fibrosis.

Colistin is given parenterally, as colistimethate sodium, by intramuscular injection or slow

intravenous injection or infusion.

In the UK, usual doses are 1 to 2million units given 3 times daily (maximum dose 6 million

units in 24 hours) for patients weighing more than 60 kg; those weighing up to 60 kg may be

given 50 000 units/kg daily in 3 divided doses up to a maximum of 75000 units/kg daily. In

the USA, the usual dose is equivalent to colistin base 2.5 to 5 mg/kg daily in 2 to 4 divided

doses. Monitoring of plasma concentrations is required in some patients.

Colistimethate sodium may also be given by inhalation in respiratory infections as an adjunct

to systemic antibacterial therapy.

The usual dose is 1 to 2 million units given 2 or 3 times daily. A 3-week course of 2 million

units twice daily may be given initially, increased to a maximum of 2 million units given 3

times daily for up to 3 months in frequent recurrent infections; 1 to 2 million units twice daily

may be given for long-term therapy. Solutions for inhalation should be freshly prepared

Colistimethate sodium has also been given by subcon-junctival injection and as a bladder

instillation. Both colistin sulfate and colistimethate sodium have been applied topically, often

with other antibacterials, in the management of ear, eye, and skin infections.

COLISAN - 1


(Lyophilized )

Directions for reconstitution

Colistimethate sodium is reconstituted with water for injections or 0.9% Sodium chloride.

The reconstituted solution should be used immediately.

The reconstituted solution is stored for 24 hours in the refrigeration at 20C to 8

0 C or up to 8

hours when stored at temperatures not exceeding 250 C.

CONTRAINDICATIONS:

Patients known to be sensitive to Colistimethate Sodium.

Dosage must be modified in patients with impaired renal function.

Curariform muscle relaxants must be used with extreme caution

WARNINGS AND PRECAUTIONS:

Cough and bronchospasm may occur during inhalation; cases of sore throat or sore mouth,

possibly due to Hypersensitivity or superinfection with Candida spp., have also been reported.

Neurotoxic reactions such as dizziness, confusion, and visual disturbances can occur during

parenteral therapy and patients so affected should not drive or operate machinery.

Pain and local irritation are reported to be less troublesome after intramuscular injection of

colistimethate sodium than with Colistin sulfate or polymyxin B.

Overgrowth of nonsusceptible organisms, particularly Proteus spp., may occur after prolonged

use.

Plasma-concentration monitoring during systemic treatment is recommended in neonates,

patients with renal impairment, and those with cystic fibrosis. Peak plasma-colistin

concentrations of 10 to 15 mg/litre (about 125 to 200 units/mL) are recommended.

INTERACTIONS WITH OTHER MEDICINE:

It may enhance the action of neuromuscular blockers possibly resulting in respiratory

depression and apnoea, and concurrent use should be avoided. Additive neurotoxicity and/or

nephrotoxicity may occur if polymyxins are given with other potentially neurotoxic and/or

nephrotoxic. Drugs including aminoglycosides and cefaloridine; concurrent use should also

be avoided.

.

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19. SCIENTIFIC INFORMATION

COLISAN - 1


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SCIENTIFIC INFORMATION

Attached hereafter

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PRECLINICAL TRIAL

Data on potential genotoxicity are limited and carcinogenicity data for colistimethate sodium

are lacking. Colistimethate sodium has been shown to induce chromosomal aberrations in

human lymphocytes in vitro. This effect may be related to a reduction in mitotic index, which

was also observed.

Reproductive toxicity studies in rats and mice do not indicate teratogenic properties.

However, colistimethate sodium given intramuscularly during organogenesis to rabbits at

4.15 and 9.3 mg/kg resulted in talipes varus in 2.6 and 2.9% of foetuses respectively. These

doses are 0.5 and 1.2 times the maximum daily human dose. In addition, increased

reabsorption occurred at 9.3mg/kg.

There are no other preclinical safety data of relevance to the prescriber that are additional to

safety data derived from patient exposure and already included in other sections of the SPC.

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CLINICAL TRIALS

Antimicrob Agents Chemother. 2001 Mar;45(3):781-5.

In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against

Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

Li J1, Turnidge J, Milne R, Nation RL, Coulthard K.

Author information

Abstract

The in vitro pharmacodynamic properties of colistin and colistin methanesulfonate were

investigated by studying the MICs, time-kill kinetics, and postantibiotic effect (PAE) against

mucoid and nonmucoid strains of Pseudomonas aeruginosa isolated from patients with cystic

fibrosis. Twenty-three clinical strains, including multiresistant strains, and one type strain

were selected for MIC determination. Eleven strains were resistant; MICs for these strains

were >128 mg/liter. For the susceptible strains, MICs of colistin ranged from 1 to 4 mg/liter,

while the MICs of colistin methanesulfonate were significantly higher and ranged from 4 to

16 mg/liter. The time-kill kinetics were investigated with three strains at drug concentrations

ranging from 0.5 to 64 times the MIC. Colistin showed extremely rapid killing, resulting in

complete elimination at the highest concentrations within 5 min, while colistin

methanesulfonate killed more slowly, requiring a concentration of 16 times the MIC to

achieve complete killing within 24 h. Colistin exhibited a significant PAE of 2 to 3 h at 16

times the MIC against the three strains after 15 min of exposure. For colistin

methanesulfonate, PAEs were shorter at the concentrations tested. Colistin methanesulfonate

had lower overall bactericidal and postantibiotic activities than colistin, even when adjusted

for differences in MICs. Our data suggest that doses of colistin methanesulfonate higher than

the recommended 2 to 3 mg/kg of body weight every 12 h may be required for the effective

treatment of P. aeruginosa infections in cystic fibrosis patients.

PMID:11181360

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Am J Physiol Cell Physiol. 2004 Apr; 286(4):C913-22. Epub 2003 Dec 10.

Colistin interactions with the mammalian urothelium.

Lewis JR1, Lewis SA.

Author information

Abstract

Here we describe the effect of colistin on the barrier function of the mammalian urinary

bladder epithelium. Addition of colistin to the mucosal solution of the rabbit urinary bladder

epithelium (urothelium) resulted in an increase in the transepithelial conductance. The

magnitude of the increase in transepithelial conductance was dependent on the membrane

voltage, concentration of colistin, and presence of divalent cations in the bath solution. The

initial site of action of colistin was at the apical membrane. Colistin increased the membrane

conductance only when the apical membrane potential was cell interior negative. The more

negative the membrane potential, the larger the conductance increase. The concentration

dependence of the conductance increase saturated, suggesting a membrane binding site.

Divalent cations decreased the magnitude of the conductance increase. This divalent cation

action occurred at two sites: one in competition with colistin for a membrane binding site,

and the other by rapidly blocking the induced conductance. At short exposure times, the

increase in conductance was reversed by either removing colistin from the bath or changing

the voltage so that the apical membrane was cell interior positive. At long exposure times, the

increase was only partially reversible by voltage or removal from the bath. This finding

suggests that at long exposure times, there is a toxic effect of colistin on the urothelium.

PMID: 14668261

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Clin Microbiol Infect. 2005 Feb;11(2):115-21.

Colistin treatment in patients with ICU-acquired infections caused by multiresistant

Gram-negative bacteria: the renaissance of an old antibiotic.

Michalopoulos AS1, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME.

Author information

Abstract

A retrospective case series study was performed in a 30-bed general intensive care unit (ICU)

of a tertiary care hospital to assess the effectiveness and safety of colistin in 43 critically ill

patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria.

Various ICU-acquired infections, mainly pneumonia and bacteraemia caused by

multiresistant strains of Pseudomonas aeruginosa and/or Acinetobacter baumannii, were

treated with colistin. Good clinical response (cure or improvement) was noted in 74.4% of

patients. Deterioration of renal function occurred in 18.6% of patients during colistin therapy.

Nephrotoxicity was elevated significantly in those patients with a history of renal failure

(62.5%). All-cause mortality amounted to 27.9%. In this group of critically ill patients, an age

of >50 years (OR, 5.4; 95% CI 1.3-24.9) and acute renal failure (OR, 8.2; 95% CI 2.9-23.8)

were independent predictors of mortality. Colistin should be considered as a treatment option

in critically ill patients with infection caused by multiresistant Gram-negative bacilli.

Comment in

Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii

infections: clinical outcome and adverse events. [Clin Microbiol Infect. 2005]

PMID: 15679485

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Clin Infect Dis. 2005 May 1;40(9):1333-41. Epub 2005 Mar 22.

Colistin: the revival of polymyxins for the management of multidrug-resistant gram-

negative bacterial infections.

Falagas ME1, Kasiakou SK.

Author information

Erratum in

Clin Infect Dis. 2006 Jun 15;42(12):1819. Dosage error in article text.

Abstract

The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics

to combat them have led to the revival of polymyxins, an old class of cationic, cyclic

polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used

in clinical practice. Most of the reintroduction of polymyxins during the last few years is

related to colistin. The polymyxins are active against selected gram-negative bacteria,

including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and

Enterobacter species. These drugs have been used extensively worldwide for decades for

local use. However, parenteral use of these drugs was abandoned approximately 20 years ago

in most countries, except for treatment of patients with cystic fibrosis, because of reports of

common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who

received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter

baumannii infections of various types, including pneumonia, bacteremia, and urinary tract

infections, have led to the conclusion that these antibiotics have acceptable effectiveness and

considerably less toxicity than was reported in old studies.

PMID: 15825037

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20. BIBLIOGRAPHY REFERENCES

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BIBLIOGRAPHY REFERENCES

1. Therapeutics Drugs second edition.

2. Handbook on Injectable Drugs 15th

edition.

3. The Complete Drug Reference-Martindale 36TH

Edition.

4. Pubmed

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21. ADDITIONAL INFORMATION

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ADDITIONAL INFORMATION

(A) MANUFACTURING DIAGRAM

(B) ALLOCATION SYSTEM LOT NUMBER

COLISAN - 1


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(A) MANUFACTURING DIAGRAM

Attached Hereafter

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Lyophilisation & Full Stoppering

Batch Filtration

Decartoned Vials, Rubber

stoppers & seals transfer to

Material staging area

Raw Material

Dispensing

Primary Packing Material

Dispensing

Batch Manufacturing

Primary Packing Material

Decarotining in WH

Sealing

Visual Inspection

Filling & Half Stoppering

Vial Washing &

Depyrogenation

Component Preparation

(Sterilization of m/c parts,

rubber stopper & seals)

Holding of the Filtrate

FLOW CHART OF PROCESS FLOW CHART

Process

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(B) ALLOCATION SYSTEM LOT NUMBER

Attached Hereafter

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ALLOCATION SYSTEM BATCH NUMBER

The firm manufactures various dosage forms hence the batch numbering system is followed.

Batch numbering is as per standard operating procedure.

Batch number is the given to the particular product as below:

Batch Numbering for COLISAN – 1 (Colistimethate For Injection BP 1 MIU).

Initial 3 letters for Product code – Serial number of the batch manufactured – two digit of the

current year of manufacturing - last two digit of strenth.

E.g. Batch No. COL0201501 indicates

- COL is initial 3 letters of Product code

- 020 is serial number of batch manufactured

- 15 is year of manufacturing

- 01 is last two digit of strength

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