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SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.

)

REGISTARTION DOSSIER

OF CEFOTAXIME FOR INJECTION USP 1 GM

Submitted by: SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, PHASE-I, JHARMAJRI BADDI, DISTT.SOLAN 173205 HIMACHAL PRADESH

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

CEFOTAXIME FOR INJECTION USP 1 GM DOSSIER CONTENT
S. NO. PARTICULARS

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Unit Dose and batch Formulation Technical Specification Of Active Raw Materials Analytical Method of Analysis of Active Raw Materials Manufacturing Procedure and Flow Chart In –Process Quality control Technical Specification of Finished Product Analytical Method Analysis Of Finished Product COA of Finished Product Accelerated Stability Study Report Long Term Stability Study Report Technical Specification of Packing Material Standard Test Procedure of Packing Material Clinical Pharmacology Draft Label

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

UNIT DOSE AND BATCH FORMULATION FOR CEFOTAXIME FOR INJECTION USP 1 GM

UNIT DOSE FORMULA

COMPOSITION:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Each Vial Contains: Cefotaxime Sodium USP Eq. to Cefotaxime

1000 mg

BATCH FORMULATION
Active Raw materials
Sr. No. Ingredients Specification Unit Dose Formula Standard Batch Formula Batch Size: 100000 Vials

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
1 Cefotaxime Sodium eq. to Cefotaxime USP 1.126gm* 112.55 Kg.*

*Material has been taken equivalent to its 100% potency on as dried basis considering The Minimum Assay =NLT 91.6% & Loss on drying = NMT 3.0% Calculation:
Required quantity of Cefotaxime Sodium USP = Label claim X 100X X 100 X Batch Size P X (100 – Q) 1000X1000 i.e. Label Claim: 1000 mg, Assay-NLT: 91.6%, Loss on drying-NMT: 3%. = = Where, 1000 X 100 X100 X 100000 91.6 X 97 X1000X1000 112.55 Kg/Standard Batch Size

‘P’ indicates the assay of raw material on anhydrous basis. ‘Q’ indicates the moisture content present in raw material.

Characteristic of active substances: Name: Empirical formula: Molecular Weight: Cefotaxime Sodium Cefotaxime : 477.45 454.45 Cefotaxime Sodium C16H16N5NaO7S2

Primary Packing Materials
Sr. No. Ingredients Specification Qty. / Batch

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
1 2 3 Clear Glass Vial - 10ml Rubber Stopper 20 mm Grey Butyl Aluminium Seal F/O – 20mm USP IHS IHS 10200 10200 10300

INPUT MATERIAL CONTROL
1. Check the manufacturing area for total cleanliness and removal of remainders if any from earlier processed batch, of raw material in process semi-finished goods and finished goods. 2. Transfer the raw material issued for the batch to be manufactured from R.M. quarantine and confirm that the issued materials are as per master formula indicated. Check that every ingredient is issued in proper container bearing tag label. Check that tag label of each ingredient gives following particulars - Name of the material with specification, quantity in Kg, Quality control Release No., and Name and Batch No. of the product for which it is intended to be used. 3. Check that the weighing balances are properly calibrated and clean. Check the weight of every ingredient and confirm that it is as per specified quantity. 4. If at all there is any variation then it should be reported immediately to the Head of Production as well as Stores. Corrective steps should be taken to eliminate the variation and then only further process is to be started. After checking, the concerned Chemist should sign under column “Weighed by” against each ingredient to indicate that all quantities are confirmed under his personal supervision. The net quantity should also be recorded in Standard Manufacturing Procedure along with corresponding Analytical Report No. (A. R. No.). Where two lot nos. are used to make up the required quantity, then amount of each lot should be recorded separately.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

TECHNICAL SPECIFICATION OF RAW MATERIALS FOR CEFOTAXIME FOR INJECTION USP 1 GM

RAW MATERIAL SPECIFICATIONS
CEFOTAXIME SODIUM (STERILE) TESTS Material Name SPECIFICATIONS Cefotaxime Sodium

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Molecular Structure C16H16N5NaO7S2 Molecular Weight Protocol of test Description Solubility Identification By IR By HPLC By Chemical Test Specific rotation pH Loss on drying Chromatographic purity Bacterial endotoxins Sterility ASSAY: Cefotaxime Sodium USP (Sterile) Additional Test Tapped density The infrared absorption spectrum is concordant with the reference spectrum of cefotaxime sodium WS. To be comply by HPLC (as per assay). It gives the reactions of sodium salts. Between +58° and + 64°. Between 4.5 and 6.5, determined in a 10% w/v solution. Not more than 3% w/w Not more than 1.0% of any individual impurity and the sum of all impurities is not more than 3.0% No more than 0.20EU/mg of cefotaxime. Test to be comply Not less than 916µg and not more than 964µg of C16H17N5O7S2 (ODB) Not less than 0.5gm/ml 477.45 USP Off white to pale yellow, crystalline powder. Freely soluble in water; practically insoluble in organic solvents.

Prepared By Name Designation Signature Date Tapan Kumar Rana Offier-Q.C

Checked By Prafulla Kumar Behera Officer-Q.C

Approved By S.K Das Manager-Q.C

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

METHOD OF ANALYSIS OF RAW MATERIAL FOR CEFOTAXIME FOR INJECTION USP 1 GM

QUALITY CONTROL DEPARTMENT Name of Raw Material STANDARD TEST PROCEDURE CEFOTAXIME SODIUM USP

For Authorized Person Only

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

1.0 Description: Take 1.0 gm sample in a clean and dry Petridish ,observe visually and record the
observation. 2.0 Solubility: Freely soluble in water, Practically insoluble in organic solvents. Descriptive term Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Insoluble or practically insoluble Part of solvent required for 1 part of solute less than 1 from 1 to 10 from 10 to 30 from 30 to 100 from 100 to 1000 from 1000 to 10,000 more than 10,000

3.0 Clarity and color of solution:
Take 2.5 gm of sample to a 25 ml volumetric flask, dissolve in carbon dioxide-free water to volume and mix. Examine immediately: the solution is clear, measure the absorbance of this solution at 430 nm,using carbon dioxide-free water as blank. Observed absorbance not more than 0.20.Transfer 10.0 ml of the solution to a glass test tube, add 1.0 ml of glacial acetic acid, mix and examine immediately: the solution is clear.

4.0 Identification:
(a) By IR: The infrared absorption spectrum is concordant with the reference spectrum of Cefotaxime sodium working standard. (b) By HPLC : The chromatogram of the assay preparation obtained as directed in the assay exhibits a major peak of cefotaxime, the retention time of which corresponds to that exhibited in the chromatogram of the standard preparation obtained as directed in the assay. (c) By chemical test: Dissolve 0.1 g of the substance add 2 ml of water And 2 ml of a 15% w/v solution of potassium carbonate and heat to boiling; no precipitate is produced. Add 4 ml of a freshly prepared potassium antimonite solution and heat to boiling. Allow cooling in ice and scratch. The inside of the test-tube with a glass rod; a dense, white precipitate is formed. Sodium compound impart an intense yellow color to a nonluminous flame after adding of potassium pyroantimonate TS.

5.0

Specific rotation:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Dissolve 0.5 gm of sample in 50.0 ml of volumetric flask and dissolve with Milli-Q water and dilute to 20 ml with the same solvent and measure the optical rotation at the wavelength of 589 nm against water blank , using a suitable Polarimeter at 25 +0.5°C. 100 × a × 100 Specific optical rotation = ----------------------------l × C × (100-LOD ) Where, a = Corrected observed rotation, at 250C.

l = Length of the polarimeter tube (dm). C = Concenration of substances (% w/v). 6.0 pH:
Determined in a solution prepared by shaking 2.5 gm with 25 ml of carbon dioxide-free water & measure the pH of the solution, at 250 C on Suitable calibrated pH meter.

7.0

Loss on drying:
Weigh a glass-stopper, shallow weighing bottle that has been dried for 30 minutes at 110 0C. Put about 1.0 g of the sample in the bottle, cover it , accurately weigh the bottle and its content and record the observed weight . By gentle, sidewise shaking, distribute the sample evenly. Place the loaded bottle in the drying chamber, remove the stopper and leave it also in the chamber, Dry the sample at 100 to 1050C for three hours. Upon opening the chamber, close the bottle promptly and allow it to attain room temperature in a dessiccator before weighing. Repeat the operation until two successive weighing do not differ by more than 0.5mg. Calculation: % loss on drying = Loss in wt of the sample (g) ------------------------------------ X 100 Wt of the sample (g)

8.0

Chromatography purity:
Using the chromatogram of the assay, calculate the percentage of each impurity By the formula; 100r i

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
---------------------(r is+rc) in which ri is the peak area response of a given impurity. ris is the sum of all of the impurity peak area responses. and rc is the peak area response for the main cefotaxime peak.

9.0 Bacterial Endotoxins: Carry out the procedure as per finished product standard test procedure.

10.0 Sterility: Carry out the procedure as per finished product standard test procedure. 11.0 Assay:
Chemical and reagents: 0.05M Phosphate buffer: Dissolve 7.1 gm of anhydrous dibasic sodium phosphate in 1000 ml of water and adjust with phosphoric acid to a pH of 6.25. Solution A: A mixture of 0.05 M phosphate buffer and methanol (86:14). Pass through a filter having a porosity of 0.05 µm and degas.

Solution B: A mixture of 0.05 M phosphate buffer and methanol (60:40) and Pass through a filter having a porosity of 0.05 µm and degas.

Mobile Phase:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
As shown in Table. Time (min.) 0 to 7 to 9 to 16 to 46 to 51 to A(%) 7 9 16 46 51 56 100 100 to 80 80 80 to 0 0 0 to 100 Solution B(%) 0 0 to 20 20 20 to 100 100 100 to 0 Solution

Standard Preparation: Weight accurately 40 mg working standard of Cefotaxime sodium in 50ml. Volumetric flask, add 40.0 ml of solution A and dissolved, dilute with solution A to volume and mix. in 50.0 ml. mobile phase. Test Preparation: Weight accurately 40 mg sample of Cefotaxime sodium in 50ml. Volumetric flask, add 40.0 ml of solution A and dissolved, dilute with solution A to volume and mix. in 50.0 ml. mobile phase. Column: 3.9mm x 15-cm, contains 5µm packing L1 Column Temp. 30° C

Detection wavelength: 235 nm Flow rate: 1.0 ml/Minute Injection volume: 10 µL

System suitability parameter: - Inject the standard preparation and record the chromatograph. The tailing factor is not more than 2 and the relative standard deviation for replicate injection is not more than 1.5 %. Separately inject 10 micro liters of the standard preparation and the assay preparation into the chromatograph, record the chromatograms, and measure the responses for major peaks.

Calculation: Calculate the % of Cefotaxime (C16H17N5O7S2) on dried basis using the formula. Au WStd 100 P 100 =---------×-------×-------×-------×---------------- × 100 As 100 WSpl 100 (100 - LOD)

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Where, Au As WStd WSpl P = Area of peak of Cefotaxime in test preparation. = Area of peak of Cefotaxime in standard preparation. = Weight of Cefotaxime working standard (in mg). = Weight of sample (in mg). = Potency of Cefotaxime sodium working standard on as such basis.

12.0 Additional test Tapped Density:
Transfer a known quantity of material in to a graduated measuring cylinder and note the weight, Fix the cylinder in tap density apparatus and start the tapping as per SOP After completion the tapping notes the volume of measuring cylinder. Density = Weight of sample (in gm ) Volume

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

MANUFACTURING PROCEDURE & FLOW CHART FOR CEFOTAXIME FOR INJECTION USP 1 GM

PREPARATORY WORK 1. CLEANING

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) a) Ensure cleanness of machinery, equipment and area before commencing manufacturing operation. b) Intimate the quality control department for sampling of washed water. Manufacturing should be started on the receipt of green card from the Department of Control and Quality (DCQ). 2. PRECAUTIONS a) Production personnel should wear sterile garments during weighing and filling operations. b) Premises should be cleaned thoroughly with antiseptic solution previously and also during lunch break. 3. SPECIAL PRECAUTIONS IF ANY a) The batch should be started after Q/C dept issues green card for cleaning of equipments. b) Humidity and temperature should be maintained strictly, i.e., temperature should not be more than 25°C and relative humidity less than 40%. (c) Positive pressure should be maintained in the filling and adjoining rooms of sterile area.

MANUFACTURING INSTRUCTIONS GOOD MANUFACTURING PRACTICES: To ensure a quality product, all current good manufacturing practices should

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) be followed such as: 1. AREA AND EQUIPMENTS: The area should be free from unwanted material as well materiel from the last batch. The equipments to be used be labelled for product, batch no and date prior to use. The equipments to be used bear a “clean equipment bag and wash water analysis report releasing the equipment is available in case of product change over. 2. PERSONNEL: All personnel should be of good health and should practice good sanitation habits. Persons engaged in the manufacture, processing, packing or holding of drug product should wear protective apron such as head, face, hand and arm covering, necessary to protect the product from contamination. 3. RAW MATERIAL AND PACKING MATERIAL: All ingredients and packing material must be tested for conformance to written specifications. Weight of the ingredient should be checked by the authorised persons. 4. PRODUCTION AND PROCESS CONTROL: Production record must be complete and accurate reflecting all the procedure and process adopted during production. Batch should be fabricated strictly as per the written procedure.

PERSONNEL HYGIENE:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) 1. 2. 3. 4. 5. 6. 7. Personnel working in Aseptic Area section should observe strict Good Manufacturing Practices. Personnel working in Aseptic Area should avoid talk, un-necessary movement and wear sterile dresses property and follow strict personnel hygiene. Personnel working in Aseptic Area should apply I.P.A. on Gloves after every half hour. Personnel working in Aseptic Area should spray (I.P.A. + Dettol) of critical points after every one hour, care should be taken to avoid spray on filling nozzles, solution manufacturing and into eyes. Personnel working in Aseptic Area should take out sterile dresses while coming out for lunch. Keep in shelves or bins marked for he purpose. After lunch, they should wear another sterilized dress. After the operation of filling is over, they should take out dresses and keep them in bins marked for the purpose. Dresses meant for Aseptic Area will be washed daily and sterilized.

CLEANING OF AREA: 1. 2. 3. 4. 5. 6. 7. Carry out the cleaning operation every 2 hours. Remove any broken glass pieces of containers. Mop up any spoilage of material immediately. Damp-mop the surfaces with 0.1% solution of Teepol. Damp-mop the surfaces with D.M. Water. Mop the surfaces with disinfectant solution, assigned for the day. Garments/gowns may be re-used after cleaning and sterilization. Wipe the window glasses with a cloth dipped in the disinfectants.

MANUFACTURING PROCEDURE

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) 1. Checking of weight: Check the weight of sterile Cefotaxime Sodium, the quantity of sterile Cefotaxime Sodium is checked and counter checked by approved technical staff. The weight of sterile Cefotaxime Sodium is noted down on flow sheet. Tally the weight with those in flow sheet and the pharmacist in charge initials it.

2.

Processing of Vials and Sterilization: Wash and sterilize the vials as per the procedure described in SOP in detail. Vials are first washed with filtered de-mineralized water and then finally with distilled water with the help of filtered de-mineralized water and then finally with distilled water with the help of filtered compressed air. Set the temperature of heater banks as per validated set parameters and sterile the vials through vial sterilization Tunnel, in order to sterilize & Depyrogenate the vials at minimum 300°C for 3 minutes and record the in process results periodically.

3.

Processing and Sterilization of Rubber bungs: Process the rubber bungs as per SOP in detail. Firstly bungs are washed with Teepol solution in bung processing machine and then washed with several times demineralized water and finally with distilled water. Bungs are siliconised and again washed with filtered distilled water. Bungs are autoclaved at 121°C for ½ hour and then dried at 120°C for 2 hrs in SS Stainless Steel Sterilizer.

4. Processing of flip off aluminium seals:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) Process the aluminium seals as per SOP in detail. Seals are washed, dried and then rinsed with I.P.A. and again dried.

5. Equipments and machines used for processing and filling: For Environmental control of Manufacturing, Filling, Air Locks and Transfer Areas: Centrally Air Conditioners - 7.5 tons capacity. U.V. Lights (not more than 1000 burning hours) Pressure Manometers Fumigation Equipments Liquid Antiseptic Solutions (Fairgenol, Dettol, Savlon, Lysol) Vacuum Cleaner Lint Free Synthetic Moppers and other cleaning and washing aids. Sterile garments.

6.

Checking of Temp., humidity & Pressure

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) The temperature of the Filling Area is maintained at 23°C ± 2°C and the Relative Humidity is NMT 30%, and checked & recorded after every 2 hours. The whole process of manufacturing and filling is done in an Aseptic Area. The microbial count of the area is checked everyday by Settle plate method as well as by Active air sampling method. All vessels used are previously sterilised 7. Aseptic Filling Machine used- Automatic filling line with S.S. conveyer belt, capacity 100 vials/min. attached with automatic rubber stoppering machine. High Speed Automatic Vials Sealing Machine - Capacity 100 vials/minute. Filling- Check and weigh of powder and feed it into the hopper of the filling machine aseptically. Average fill weight: + 2% Capping- Fill and plug the vials with gray butyl rubber aseptically on the filling machine, as per the procedure described in SOP. Sealing- Seal the stoppered vial with aluminium flip off seal & transfer the filled and sealed vials into plastic crates, previously cleaned with antiseptic solution. 8. In-process control checks Draw samples at regular intervals and check for Average Fill As calculated Uniformity of Fill + 2% Sealing Should not rotate Visual Inspection Visual checking tables with adequate provision of light in right direction of inspection position, with black and white backgrounds. Each vial is visually checked for foreign particle and also for less and more weight.

9.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) 10. Labeling & Packing Labelling and packing operations should be started on receipt of approval from Quality Control Department. 11. Withdrawal of control sample: Sample for two complete testing or one pack whichever is more is to be drawn for control samples and sent to control sample room after allotting the Ref. No. by Q.C. Dept. 12. Release order for sale: After the receipt of release order from Q.C. Dept., release the batch to the finished goods store.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Process Flow Chart
RM/PM Requisition cum Issue Slip

Issuance of BMR/BPR from QA Dispensing / Issuance of RM/PM in stores Check Materials as per Requisition cum Issue Slip for both RM/PM

Materials from Stores to Production with BMR/BPR file

Raw Materials transfer to Blending Area

Blend the Raw Material (if Required)

Sample is withdrawn by QA & Send to QC for Analysis
OK

Not OK

Initiate corrective Action

Bulk Release for Filling & other Processing

Continued

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

PROCESS FLOW CHART OF DRY POWDER FOR INJECTION
Glass Vial from Packing Material Store Vial Washing & De-pyrogenation (by Tunnel) Filling & Bunging Bulk Material Rubber Bungs from Packing Material Store Bung Processing (by Bung Processor)

Seals from Packing Material Store (by Tunnel)

Sterilization of Seals

Sealing

Visual Inspection
OK

Not OK

Rejected

Labeling and Packing Microbiological Analysis Finished Product Analysis
OK OK

IPQA Inspection
Not OK

Review / Corrective Action

Finished Product Release

Terminal Inspection
OK

Not OK

Initiate corrective Action

BMR/BPR Review / Collection of Control Sample / Release Report

Packed Goods to FG Quarantine

Finished Goods to FG Store

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

LIST OF EQUIPMENTS

Sr. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Name of Equipment Mesh Conveyor Vial Washing Machine Vial Sterilisation Tunnel Bung Washing Moist Heat Sterilizer (DD Autoclave) Powder Filling Machine Sealing Machine 8 Head Laminar Air Flow (LAF) Laminar Air Flow (LAF) Movable Laminar Air Flow (LAF) Laminar Air Flow (LAF) Sticker labeling machine Packing Conveyor Weighing Balance

Manufacturer / Supplier Pharma M/C Pharma M/C Febtech Technologies Indo German Indo German Pharma M/C Pharma M/C Thermodyne Thermodyne Thermodyne Thermodyne Pharma M/C Fababaia Metteler

I.D. Number DPI-002 DPI-003 DPI-004 DPI-005 DPI-006 DPI-007 DPI-009 DPI-010 DPI-011 DPI-012 DPI-013 DPI-015 DPI-016 DPI-022

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

IN-PROCESS QUALITY CONTROL FOR CEFOTAXIME FOR INJECTION USP 1 GM

IN –PROCESS CHECKS AND QUALITY CONTROL

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
1.0
1.1 1.2 1.3 1.4

Procedure
Material Dispensing Line clearance procedure as per SOP must be followed before starting of dispensing activity. Materials should be dispensed in controlled area. Quantity of material should be dispensed accurately by using weighing and measuring device of Suitable accuracy as per Material requisition Sheet.

1.5 Material Identification slip of dispensed material will be attached for individual pack. 1.5 1.6 1.7 Any dispensing activity will be done only in presence of person individually from Stores, Production and QA. Non sterile Material will be dispensed in double layer Poly bags, Closed air tightly and Kept in Dispensed Material Cage and will be transferred to production area only through Pass box / hatch. Sterile Materials will be dispensed in full pack to avoid any unnecessary contamination due to repeated exposure. It will be opened only in the area provided for dispensing & blending in Production section and the container having remaining sterile materials will be closed air-tightly and returned to Stores along with Excess Material Return Memo. Production Operation Line clearance procedure must be followed as per SOP before starting of Production activity. After completion of individual step of processing it should be assured that yield obtained is under acceptance criteria. Time limits for critical steps specified in the BMR should met. Time limits may deviate due to not getting exact specification e.g. Sterilization and De-Pyrogenation, drying up to limit, homogenisation, homogeneous mixing etc. because completion of processing steps are determined for in process sampling and testing. In case of deviation it should be noted in deviation sheet by QA personnel and intimated to head of QAD for further amendments in future and release of the said batch under deviation (If required). Production personnel will intimate QA to collect the sample for Q.C. testing and release. QA personnel will collect the sample for respective step as per sampling plan and sent it to QC for analysis of the same. QC personnel will analyse the sample and send analytical report to QA on the basis of which in process material will be released by HOD QA for further processing step. No further processing will be done without line clearance given for the next processing stage.

1.0 1.1.1 1.1.2 1.1.3

1.1.4 1.1.5 1.1.6 1.1.7

1.1.8

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

1.1.9

During filling/ filling & sealing/ forming filling & sealing process Production and QA personnel will do their periodic IPQA check related with specific parameters as per product specification for that stage.

1.1.10 SOP for intermediate product’s sampling plan as well as check-points will be followed and it will be recorded in the format provided for the same. 1.1.11 Production operation will be conducted in manner that will prevent contamination during in process for finished products in all aspects. 2.0 2.1.1 2.1.2 2.1.3 Visual Inspection, Packaging and labelling operation : Check and ensure that exact qty. of approved packing materials are dispensed. Filled and sealed containers/ampoules/vials will be subjected for visual inspection and the said operation will be carefully supervised periodically by production as well as QA personnel. In visual inspection filled packs will be subjected for visual inspection to check and ensure that it is intact, free from any leakages, de-shaping, denting, foreign coloured or white substances, turbidity, any precipitation, broken seal or cap. Labeling operation will be designed to prevent mix-ups. There will be physical and spatial separation from operation involving other batch or product. Label pasting and coding devices used for operation will be controlled to ensure that all imprinting conforms to the print specified in BPR. A printed label representative of those to be used should be checked by production, approved by QA before starting of Labeling & Coding. Specimen of coded packing material will be attached in the BPR. Labeled and coded pack will be examined carefully for proper identification and confirmity with respect to it’s Product name, Composition, Batch number, Manufacture date, Expiry date and M.R.P/Physician sample not to be sold. No labeled and coded pack having Cross label, Dirty label, Un-pasted label, Torned or Mutilated label, Label with Smudged over printed matter, label with invisible or incorrect pre printed text matter will be allowed for further packing. It will be sorted out and kept in the cage specified for rejected in process material. Labels of all the sorted problematic pack will be removed properly and it will be re-labeled and coded.

2.1.4 2.1.5 2.1.6

2.1.7

2.1.8

2.1.9

2.1.10 All the rejected labels will be destroyed and the same will be recorded at specified column in BPR.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

2.1.11 Labeling & Coding facility will be inspected as both Pre & Post labelling Operation to ensure that after completion or before start up neither previous nor in future planned probable Batch / product’s Packing materials are available inside the production area. 2.1.12 Reconciliation of all the Packing Materials after completion of Packing Operation is must and QA personnel have to verify it.

3.0 ENVIRONMENTAL CONTROL CHECKS
• Room temperature, relative humidity and differential pressure should be checked and it’s observation shall be noted after every two hours and ensured that it is within the specified limit : Following details shall be noted: 1. Date 2. Time 3. Name of area: blending room, Buffer room, Filling & Sealing room. 4. Observed Temperature 5. Observed Differential Pressure 6. Name of Operator 7. Name of Production personnel checking the aforesaid details.

4.0 VIAL WASHING: During washing of Vials following parameters shall be checked, recorded and ensured that it is within the specified limits. Following details shall be recorded: 1. Date 2. Washing Start time 3. Washing Completion Time. 4. Pressure of filtered air 5. Pressure of Reprocessed Water. 6. Pressure of Filtered WFI 7. Particulate Matter Test (on 20 Washed Vials ) 8. Machine ID No. 9. Operators signature 10. Checker’s signature Frequency: Initially & after 1 hour by Production and QA Personnel

5.0 VIAL STERILIZATION & DEPYROGENATION: During Sterilisation and Depyrogenation of Vial Set Temperature of different Heaters shall be checked and

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
ensured that it is as per the manufacturer’s manual. Temperature control Chart shall be checked for all the information and ensured that all the reading is within the specified relevant specification. Following parameters shall be checked: * Speed of Conveyor * Observed Temperature of Sterilising Zone at entry and exit points. * Differential Pressure of Drying Zone as well as Sterilising Zone. Differential Pressure of Sterilising Zone shall be more than the Drying Zone. Date Time and Checker’s Signature (production & QA) shall be put in the record.
Frequency: Initially & after every 1 hour by Production & QA Personnel.

6.0 STEAM STERILIZATION RECORD FOR FILLING EQUIPMENT: During Sterilisation of Filling Equipment following details shall be checked, recorded and ensured that it is within the specified limit. • Cycle No. • Cycle Start Time • Sterilisation Hold Time attained at (Time) • Sterilisation Hold completed at (Time) • Total Sterilisation Time • Temperature during hold • Cycle Completion Time. • Signature of Loading Personnel • Signature of Unloading Personnel. • Checker’s Signature Frequency: During each Sterilisation cycle.
7.0 VISUAL INSPECTION EMPTY VIALS:

Take 20 Empty vials before filling and pour membrane Filtered WFI (should free from foreign particles) in all vials. Check Individual vials for any rejection, Collect rinsed water from all the vials in a 100 ml. beaker, Observe it for below mentioned checks and compare its clarity with the filtered WFI used, record the observation and ensure that it is clear, free from visible particles.

Frequency: Initially & after every 1 hour by QA & Production Personnel 8.0 FILLING & WEIGHT VARIATION RECORD: Set the Filling machine to deliver below mentioned Set Standard Weight Continuously Std. Fill Weight: mg Limit: ± 2% of Standard fill wt. i.e Between-------- mg &------- mg Collect individual Vial from all the head, record the data and ensure that all the observed filled Weight is under acceptance limit. Following details shall be also recorded: • Machine Identification No. • Technician’s Name. • Filling Start Time

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
• •
9.0

Filling Completion Time. Checker’s Signature (Prod. & QA) Frequency: Initially & after every 1 hour by QA & Production Personnel.

VISUAL INSPECTION OF FILLED VIALS:

Filled and sealed Vials shall be on line collected and checked for followings: • Clarity & weight Variations • Sealing deformity • Absence of visible Particulate Contamination Frequency: Initially & after every 1 hour by QA & Production Personnel 10.0 VISUAL INSPECTION OF ON LINE LABELED VIALS: Online labeled vials shall be collected and checked for followings: * Cleanliness * Uniform labelling & proper pasting of Labels. * Clarity & correctness of Coded Matter: e.g. Product Name , Composition , B. No, Mfg. Date, Exp Date, M.R.P. Frequency: Initially & after every 1 hour by Production & QA Personnel. 11.0 VISUAL INSPECTION OF ON LINE PACKED VIALS: Online Vial Pack per monocarton carton shall be collected and checked for followings: * Cleanliness * Number of vial Pack per mono Carton. * Intactness of the Packed m mono cartoon. * Physical Conditions of the monocarton. 12.0 VISUAL INSPECTION OF ON LINE SHRINK PACK Online shrink pack shall be collected and checked for followings: * Cleanliness * Shrink Quality * Number of vial per shrink * Clarity & correctness of Coded Matter: e.g. Product Name , Composition , B. No, Mfg. Date, Exp Date, M.R.P. Frequency: Initially & after every 1 hour by Production & QA Personnel.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
13.0 VISUAL INSPECTION OF ON LINE PACKED VIALS: Online Shrink Pack per Shipper shall be collected and checked for followings: * Cleanliness * Number of Shrink Pack per Shipper. * Intactness of the Shipper. * Physical Conditions of the shipper * Gum Taps Properly Fixed. * Printed Label Pasted on the carton /shipper. * Check availability of packing slip. * Check and ensure that packing slip is duly signed by packing Supervisor or the section In- Charge. * Check and ensure that exact quantity of filled inner carton is packed in outer carton. * Check and ensure that exact quantity of filled outer carton is packed in Corrugated BOX. Frequency: Initially & after every 1 hour by Production & QA Personnel 14.0 UNIFORMITY OF CONTENTS IN FINAL PACK / SHIPPER * Check and ensure uniformity of content in final pack. Frequency: Initially & after every 1 hour by Production & QA Personnel

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

TECHNICAL SPECIFICATION FINISHED PRODUCT FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
FINISHED PRODUCT SPECIFICATIONS Quality Control Department Sr.No. 1. 2. a. b. c. Description Identification By IR By Chemical Test By HPLC The infrared spectrum of test is concordant with infrared spectrum of cefotaxime sodium WS. A dense white precipitate is formed. In the assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the 3. 4. 5. a. Average Weight Uniformity of Weights Constituted solution Completeness and clarity of solution chromatogram obtained with the standard solution. Theoretical ±2% Theoretical ±5% A: The solid dissolve completely, leaving no visible residue as undissolved matter. B: The constituted solution is not significantly less clear than a diluent or purified water contained in a similar vessel and examined similarly. The solution is essentially free from particles of foreign matter that can be seen on visual inspection. Between 4.50 and 6.50. Not more than 6000/container Not more than 600/container Between 85.0% to 115.0% Not more than 3% Any individual impurity not more than 6.0% and the sum of total impurities not more than 10% Sterile Not more than 0.20 USP EU/mg of cefotaxime. 90.0 % to 115.0 % of labeled amount of Cefotaxime. Name of Tests Specifications Off-White to Pale yellow crystalline powder.

b. 6. 7. a. b. 8. 9. 10. 11. 12. 13. 14.

Particulate matter pH Particulate matter For 10 micron For 25 micron Uniformity of dosage units Loss on drying Chromatographic purity Sterility Bacterial Endotoxins Assay: Each vial contains: Cefotaxime Sodium USP (Sterile) eq. to Cefotaxime 1 gm Prepared By

Checked By
Prafulla Kumar Behera Officer-Q.C

Approved By
S.K Das Manager-Q.C

Name Designation Signature Date

Tapan Kumar Rana Offier-Q.C

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

METHOD OF ANALYSIS OF FINISHED PRODUCT FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
QUALITY CONTROL DEPARTMENT STANDARD TEST PROCEDURE Generic Name 1.0 Description:
Open the vial, transfer 2.0 gm sample in a clean and dry Petri-dish and observe visually and record the observation.

For Authorized Person Only

Cefotaxime Sodium For Injection USP

2.0

Identification:
By IR: Take 2-3 mg of sample and 100mg of previously dried potassium bromide and titurate thoroughly. Open the lid of sample compartment set the diffuse reflectant assessory with instrument and remove the sampler from diffuse reflectant assessory by pulling. Set the both cup in sampler. Fill the outer cup with blank and inner cup with sample and put the sampler in diffuse reflactant assessory Examine the sample and compare the spectrum so obtained with the reference spectrum of cefotaxime sodium or with the spectrum obtained with cefotaxime sodium WS treated in the same manner.

By chemical: Dissolve 0.5 g of the sample in 2 ml of water, add 2 ml of a 15% w/v solution of potassium carbonate and heat to boiling; no precipitate is produced. Add 4 ml of a freshly prepared potassium antimonate solution and heat to boiling. Allow cool in ice and if necessary rub the inside of the test-tube with a glass rod; a dense, white precipitate is formed. Sodium compounds impart an intense yellow color to a nonluminous flame.
By HPLC: In the assay, the chromatogram obtained with the test solution corresponds to that the peak in the chromatogram obtained with the standard solution.

3.0

Constituted Solution:
A: Completeness and clarity of solution: Open the vial, constitute the solution with sterile water for injection as directed in labeling, check visually, the solid dissolve completely, leaving no visible residue as undissolved matter and vessel and examined similarly. the constituted solution is not significantly less clear than diluent or purified water contained in a similar

B: Particulate matter:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Constitute the solution as directed in labeling, the solution is essentially free from particles of foreign matter that can seen on visual inspection.

4.0

Uniformity of dosage units:
Remove any adherent labels from a container, wash and dry its outside. Open the container and immediately weigh the container and its contents. Empty the container as completely as possible by gentle tapping, rinse with water and then with ethanol (95%) and dry at 100o to 105o for 1 hour. Allow to cool in desiccators and weigh. The difference between the weights represents the weight of the contents. Repeat the procedure with a further 9 containers and Calculate the drug content expressed as % of label claim of each vial from the net weight of the individual content and the result of the assay. Calculate the acceptance value. Calculation of Acceptance Value: Calculate the acceptance value as shown in Content Uniformity, except that the individual contents of the units are replaced with the individual estimated contents defined below. X1, X2, ………., X n = W1, W2, ………., Wn A = W= individual estimated contents of the units tested, where Xi = Wi x A/W, = individual weights of the units tested, content of drug substance (% of label claim ) determined as described in the Assay and mean of individual weights (W1, W2, ………., W n)

5.0

Uniformity of weight:
Remove any adherent labels from a container and wash and dry the outside. Open the container and immediately weigh the container and its contents. Empty the container as completely as possible by gentle tapping, rinse if necessary with water and then with ethanol (95%) and dry at 100o to 105o for 1 hour or, if the nature of the container precludes such treatment, dry at a lower temperature to constant weight. Allow to cool in a dessiccator and weigh. The difference between the weights represents the weight of the contents. Repeat the procedure with a further 19 containers and determine the average weight. Not more than two of the individual weights deviate from the average weight by more than 10% and none deviates by more than 20%.

6.0 Particulate matter:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Constitute the solution with sterile water for injection (10%w/v) and check the particulate matter by lesser particle counter in per gram.

7.0

pH:
Weigh accurately 5.0 gm of sample, transfer in a beaker and add 50 ml of water. Measure the pH of the solution with calibrated pH meter.

8.0

Loss on Drying:
Procedure: Mix and accurately weigh 1.0 gm of this sample & transfer in to a glass-stoppered, shallow weighing bottle that has been dried for 30 minutes at 105° C. Cool, put the sample in the bottle, replace the cover, and accurately weigh the bottle and the contents. By gentle, sidewise shaking, distribute the sample evenly. Place the loaded bottle in the drying chamber, removing the stopper and leaving it also in the chamber. Dry the sample at 100°C to 105°C for 2 hours. After opening the chamber, close the bottle promptly, and before weighing it to attain room temperature in desiccators. Calculation: (%) Loss on drying = Loss in wt. of sample (in gm) ----------------------------------- x 100 Wt. of sample (in gm) = %w/w

9.0

Chromatographic purity:
Procedure: Use the chromatogram of the test preparation obtained in the assay. Run the test preparation injection 3 times of the retention time of cefotaxime sodium. Calculation: Impurity area ------------------------------------------------ x 100 (Total impurities area + main peak area)

10.0

Assay of Cefotaxime Sodium eq. to Cefotaxime:
Phosphate Buffer: Dissolve 7.1 gm of anhydrous dibasic sodium phosphate in 1000 ml of water and adjust with phosphoric acid to a pH of 6.25. Solution A: Prepare a mixure of phosphate buffer and methanol (86 : 14). Solution B: Prepare a mixture of phosphate buffer and methanol (60 : 40). Filter the both above solution through 0.45 µm membrane filter. Mobile Phase: Use both above solutions in gradient system as per procedure.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Standard Preparation: Weigh accurately about 40 mg Cefotaxime sodium WS in to a 50 ml volumetric flask, add 40 ml solution A, shake and make up the volume 50 ml with same solvent. Resolution preparation: Mix 1.0 ml of standard preparation, 7.0 ml of water and 2.0 ml of methanol. Add 25 mg of sodium carbonate, mix and allow to stand at room temperature for 10 minutes, with occasional swirling, Add 3 drops of glacial acetic acid and 1.0 ml of standard preparation and mix. Sample Preparation: Transfer accurately about 40 mg sample in to a 50 ml volumetric flask, add 40 ml solution A, shake and make up the volume 50 ml with same solvent. Chromatographic conditions: Column Detection wavelength Flow rate Inject volume Column temperature : 150 mm × 3.9 mm, 5 µm, L1. : 235 nm : 1.0ml/minute : 10 µl : 300C

The system is equilibrated with 100% solution A. Seven minutes after sample solution injection, the proportion of solution B is increased linearly from 0% to 20% at a rate of 10% per minute and is maintained at that composition for 7 minutes. The proportion of solution B is then increased linearly at a rate of 2.7% per minute until the proportion solution B is 100% and is held at that composition for 5 minutes, after which the proportion of solution A is increased linearly to 100% at a rate of 20% per minute. Procedure: Separately inject equal volumes (10 µl) of blank, six replicate standard preparation and sample preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. System suitability: For resolution solution: Retention time For desacetyl cefotaxime For cefotaxime sodium Resolution For standard solution: Retention time For cefotaxime sodium Tailing factor : : between 15 and 18 minutes : Not more than 2.0 : : about 3.5 minutes : about 14 minutes : Not less than 20

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Relative standard deviation : Not more than 1.5%

Calculation: Calculate the quantity, in µg of cefotaxime (C16H17N5O7S2) in each mg of the cefotaxime for injection taken by the formula:

Area of sample

Standard wt

50

P
mg/vial

------------------------×--------------------×-----------------x---------x average wt=

Area of standard 50 Sample wt P= Potency of cefotaxime sodium as cefotaxime. 11.0 Bacterial Endotoxins Test:

100

LIMIT: Not more than 0.20 Endotoxin Unit per mg of cefotaxime sodium. Procedure: 1. Clean and depyrogenate the glassware . 2. Enter into the BET room. 3. Operate the LAF and transfer all the depyrogenated glassware’s on LAF bench. 4. Switch “ON” the heating block and operate. Reconstitute of Lysate: 1. Now reconstitute the lysate by opening the aluminium seal of lysate vial with the help of depyrogenated blade. 2. Collect lysate powder into the bottom of the vial by tapping on a hard surface. And then open the cork slowly. 3. Add LRW as per manufacturer’s instruction and mix slowly. 4. Store reconstitutes lysate in refrigerator at 2-8 0C for 24 hrs and -200C for 28 days or as per manufacturer’s instruction. Preparation of Control Standard (CSE): 1. Reconstitute CSE in LRW as per manufacturer’s instruction and vortex for 15-20 minutes. 2. Use Reconstituted CSE within 4 weeks or as per manufacturer instruction. Store reconstituted CSE at 20C to 80C temperature. 3. Prepare a CSE dilution with LRW to yield 1EU/ml, vortex for 5 min before preceding the each dilution. 4. Prepare a 4λ dilution from 1 EU/ml in LRW.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Calculation of MVD: Prepare a solution of 100 mg cefotaxime and put the value in the below given formula Calculation of MVD for sample specimen by following formula – MVD = MVD = Endotoxin Limit X Potency of Product Lysate Sensitivity 0.20EU/ml X 100mg/ml * 0.125EU/ml

MVD = 160 MVD/2 = 80 MVD/4 = 40 *Note:If reconstituted volume mentioned on vial is different then potency will be change. Product Dilution
S.No. Sample LRW Product dilution 1 0.1 ml 0.9 ml 1:10 2 0.1 ml 0.3 ml 1:4 Note: If the Sensitivity of lysate is other than 0.125EU/ml than will  be change. Product diluted 1:40

1. Take 8 depyrogenated assay tubes and label the tubes by numbering and arrange in a stand one opposite to each other. i.e. 1 & 2 for NPC, 3 & 4 for PPC, 5 & 6 for PWC, 7 & 8 for Negative water control. 2. Add 50µl of LRW in NPC and PWC, and 100 µl in NWC. Immediately add 50 µl of product sample, which is diluted at MVD/4 in a NPC and PPC, and then add 50 µl of CSE that is diluted to 4 λ in a PPC and PWC. 3. Finally add 100µl of Lysate in all tubes and next, mix the assay tubes by hand and incubate in heating block, where the temperature is maintained at 37 ± 1 0C for 60 ± 2 minutes. Solution A B C D Solution description Negative product control (NPC) Positive Product control (PPC) Positive water control (PWC) Negative water control (NWC) LRW 4λ (CSE) in µ l in µ l 50 50 100 50 50 Product at Lysate in No. of Replica MVD/4 in µ l µl tes 50 100 2 50 100 2 100 2 100 2

After adding of lysate never vortex the tube.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Result: 1. Each tube in the gel clot method is interpreted as either positive or negative, Positive test indicates the formation of firm gel capable of maintaining its integrity when the test tube is inverted 180 0. 2. A negative test is characterized by the absence of gel or by the formation of a viscous mass, which does not hold when the tube is inverted at 1800. 3. The test is not valid unless both replicates of the two positive control solutions B and C are positive and those of the negative control solution D are negative. 4. The preparation being examined complies with the test when a negative result is found for both replicates of solution A. 5. When a positive result is found for both replicates of solution A, it does not comply with the test. 6. Repeat the test if a positive result is found for one replicate of solution A and a negative result is found for the other. The preparation being examined complies with the test if a negative result is found for both replicates of solution A in the repeat test.

12.0 12.1 12.2

Sterility
Prepare FTGM and SCDM for the Preparation of culture media. After sterilization label the tubes with media Ref. no., date of pre incubation and date of observation. Preincubate the FTGM tubes at 32.5° ± 2.5°C and SCDM tubes at 22.5° ± 2.5°C for 72 hrs before subjecting them for sterility purpose. After preincubation check the tubes for contamination if any contamination occurs discard the tubes.

12.3

Prepare fluid A by weighing 1 gm of bacteriological peptone in 1 liter of WFI and adjust pH to 7.1 ± 0.2 and dispense 100 ml in conical flasks and sterilize at 121°C for 20 minutes. If the test sample contains lecithin or oil, use fluid A with 1 ml of polysorbate 80, adjust pH to 7.1 ± 0.2, dispense into flasks and sterilize at 121° for 20 minutes and treat as fluid B.

12.4

Sterilize filtration unit with membrane filter of pore size 0.45µm with diameter of 47 mm, scissors and forceps at 121°C for 30 min..

12.5 Wipe the sample individually with filtered 70% IPA / other approved disinfectant and keep in clean SS
tray label with product name, batch no., and lot no. Transfer samples, preincubated SCDA plates, contact plates, FTGM, SCDM and other accessories tubes to pass box of sterility room.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
12.6 Enter in sterility room for Entry/ Exit and gowning procedure for sterility room. After sterilization
transfer materials from autoclave to cooling zone and from cooling zone to LAF of sterility room through pass box.

12.7 Also transfer the SCDA plates, contact plates, FTGM, SCDM tubes, other accessories and sample from
pass box to LAF of sterility room for performing the sterility.

12.8 Start LAF for operation of LAF. 12.9 Before starting sterility test expose the SCDA plates at specified locations throughout the testing.
Personnel monitoring must be carried out by finger dab and contact plates method. Surface monitoring also carried out.

12.10 Assemble the filtration unit and connect the manifold assembly with reservoir properly with rubber pipe
and reservoir to vacuum pump with rubber pipe. Under LAF place 0.45µm membrane filter with sterile forcep between filtration cup and receptacle with grided portion should be in upside position.

12.11 In case of water soluble product wet the membrane filter by adding 15-20 ml of fluid A (0.1 % peptone
water) and filter the fluid by employing vacuum. Cut the tip of bottle/vial and ampoule with sterile SS cutter / scissor in front of gas burner and immediately transfer the sample to membrane filter as per table given below. Immediately filter the solution with the help of vacuum and wash the membrane filter with 3 X 100 ml fluid A or fluid B as per sample.

12.12 In case of dry powder open the vial with sterile cutter and transfer the quantity according to table-1 given
below in 100 ml of fluid A or fluid B as per sample. Wet the membrane filter with approx. approx. 15-20 ml of fluid A (0.1 % peptone water) and filter the fluid by employing vacuum. Filter the sample with the help of vacuum and wash the membrane filter with 3 X 100 ml fluid A

12.13 For raw material prepared the pooled sample in to the total number of container and performed the
sterility test, dissolved the sample into the 100 ml of fluid A or fluid B as per sample. Wet the membrane filter with approx. approx. 15-20 ml of fluid A (0.1 % peptone water) and filter the fluid by employing vacuum. Filter the sample with the help of vacuum and wash the membrane filter with 3 X 100 ml fluid A or fluid B as per sample

12.14 For rubber bung and empty vial / ampoule take 25 nos. of each and transfer aseptically in to the conical
having 0.9% normal saline solution rinse the vial, ampoule and bung, after rinsing aseptically filter the

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
sample with sterile filtration assembly the help of vacuum and wash the membrane filter with 3 X 100 ml fluid A.

12.15 After complete filtration, stop the vacuum and lift the SS cup carefully. Aseptically cut the membrane
filter into two halves with sterile SS scissor and transfer one half to SCDM tube and other half to FTGM tube. Label the tubes with product name, batch no., lot no., date of testing, date of release and tested by.

Table-1
Quantity in each container of injectable preparation For liquids Less than 1 ml 1 ml or more but less than 40 ml 40 ml or more but less than 100 ml 100ml or more Quantity in each container of injectable preparation For solids Less than 50 mg 50 mg or more but less than 300 mg 300 mg or more Minimum quantity to be used for each culture medium Total contents of a container Half the contents of a container 20 ml 10% of the contents of a container but not less than 20ml Minimum quantity to be used for each culture medium Total contents of a container Half the contents of a container 100 mg

12.16 Simultaneously prepare negative control by filtering 100 ml of sterile fluid A. Aseptically cut the
membrane filter into two halves and transfer one half to SCDM tube and other half to FTGM tube.

12.17 After completion of work transfer all inoculated media and other materials to pass box and exit from
sterility room for Entry/ exit and gowning procedure for sterility room.

12.18 Collect the FTGM, SCDM tubes from pass box and incubate FTGM tubes at 32.5° ± 2.5°C and SCDM
tubes at 22.5° ± 2.5°C for 14 days. Incubate SCDA and contact plates for environmental and personal monitoring at 32.5° ± 2.5°C for 48 hrs and followed by 22.5° ± 2.5°C for 72 hrs.

12.19 Start LAF of microbial assay room . Prepare positive control by inoculating aseptically FTGM by using
10-100 cfu of alternative following microorganism Bacillus subtilis ATCC no. 6633, NCIM No. 2063, Pseudomonas aeruginosa ATCC no. 9027, NCIM No. 2200, Staphylococcous aureus ATCC no.

6538, NCIM No. 2079, Clostridium sporogenes ATCC no. 11437, NCIM No. 5113, and inhouse culture (Micrococcus sp.). Similarly inoculate SCDM tubes by using 10-100 cfu of

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
alternative following microorganism Candida albicans ATCC no. 10231, NCIM No. 3471 or Aspergillus niger ATCC no. 16404, NCIM No. 1196 or in-house culture (Micrococcus sp.). 12.20 After completion of 14days incubation check the fertility of medium. Prepare positive control by
inoculating aseptically FTGM by using 10-100 cfu of alternative following microorganism Bacillus subtilis ATCC no. 6633, NCIM No. 2063, Pseudomonas aeruginosa ATCC no. 9027, NCIM

No. 2200, Staphylococcous aureus ATCC no. 6538, NCIM No. 2079, Clostridium sporogenes ATCC
no. 11437, NCIM No. 5113, and in-house culture (Micrococcus sp.). Similarly inoculate SCDM tubes by using 10-100 cfu of alternative following microorganism Candida albicans ATCC no. 10231, NCIM

No. 3471 or Aspergillus niger ATCC no. 16404, NCIM No. 1196 or in-house culture (Micrococcus
sp.).

12.21 Incubate FTGM tubes at 30°C -35°C and SCDM tubes at 20°C - 25°C for not more than 5 days. 12.22 Record the observations of sterility test in “Sterility test report”.
Results /Acceptance Criteria.

12.22.1 During the incubation period examine the medium for macroscopic evidence of microbial growth. If
no evidence of growth is found, sample being examined complies with the test for sterility. If the material being tested render the medium turbid so that the presence or absence of microbial growth can not be determined easily by visual examination, 14 days after the beginning of incubation, transfer the portion of the medium (not less than 1 ml), to the fresh vessel of the same medium and then incubate the original and transfer vessel for not less than 4 days. If the no evidence of growth is found, sample being examined comply with the test for sterility

12.22.2

If the evidence of growth is found, sample being examined does not comply with the test for

sterility, unless it can be clearly demonstrated that the test was invalid for causes unrelated to the product to be examined. The test may be considered invalid under the following conditions: 1. 2. 3. 4. The data of the microbiological monitoring of the sterility testing facility show a fault. Review the testing procedure of sterility. Microbial growth is found in the negative controls. After identification of the microorganisms isolated from the test, the growth of this species may be ascribed unequivocally to faults with respect to the material and or the technique used in conducting the sterility test. 5. If the test is declared to be invalid, it is repeated with the same number of units as in the original test. If no evidence of microbial growth is found in the repeat test, the product complies with sterility test.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
6. If microbial growth is found in the repeat test, the product examined does not comply with the test for sterility.

CERTIFICATE OF ANALYSIS FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Scott-Edil Pharmacia Ltd. 56, E.P.I.P., Phase-I, Jharmajri,Baddi (H.P.) QUALITY CONTROL DEPARTMENT
FINISHED PRODUCT CERTIFICATE OF ANALYSIS

PRODUCT NAME BATCH NO MFG. DATE BATCH SIZE SAMPLE QTY.
TEST

: Cefotaxime for Injection USP 1000mg : CFO-01 : 04/06 : 1,825 Vials : 25 Vials
OBSERVATION

REC. DATE : 03/04/06 EXP. DATE : 03/08 REPORT DATE : 17/04/06 A.R. NO. : F- CFO-01
SPECIFICATION

Description Identification (A,B & C) Average Fill Uniformity of Weights pH Loss on Drying Uniformity of Dosage Units Constituted Solution Chromatographic Purity Particulate Matter 1.Particles ≥ 10 µm 2. Particles ≥ 25 µm Bacterial Endotoxins Test Sterility Test Assay: Each vials contains: Cefotaxime sodium USP (Sterile) eq. to Cefotaxime 1000 mg.

Off-White Crystalline Powder filled in transparent glass Vials. Complies 1095.4mg Min: 1076.2mg Max: 1110.5mg 6.09 2.20%w/w 95.28% to 105.50% (RSD: 2.05%) Complies Complies 261 07 Less than 0.20 EU/Mg Sterile 999.0 mg 99.90%

Off-White to Pale yellow crystalline powder filled in transparent glass Vials. As per Specification (1073.4-1117.3)mg (1040.5-1150.0)mg Between 4.5 & 6.5 NMT 3.0%w/w 85.0% to 115.0% (RSD: NMT 6.0%) As Per Specification Individual Impurity NMT 6% Sum of all Impurity NMT 10% NMT 6000 particles per container. NMT 600 particles per container. NMT 0.20 EU/Mg Sterile NLT 900 mg and NMT 1150 mg (NLT 90% and NMT 115% of label claimed)

Remarks: The Sample complies / Does not comply as per IP. / BP. / USP./ IH. Specification. The sample referred to above is of standard quality. Analyst: Checked By: Approved By:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Q.C. Chemist Date: 17/04/06 Q.C. Officer Date: 17/04/06 Q.C. Incharge Date: 17/04/06

Scott-Edil Pharmacia Ltd. 56, E.P.I.P., Phase-I, Jharmajri,Baddi (H.P.) QUALITY CONTROL DEPARTMENT
FINISHED PRODUCT CERTIFICATE OF ANALYSIS

PRODUCT NAME BATCH NO MFG. DATE BATCH SIZE SAMPLE QTY.
TEST

: Cefotaxime for Injection USP 1000mg : CFO-02 : 04/06 : 1,825 Vials : 25 Vials
OBSERVATION

REC. DATE : 05/04/06 EXP. DATE : 03/08 REPORT DATE : 19/04/06 A.R. NO. : F- CFO-02
SPECIFICATION

Description Identification (A,B & C) Average Fill Uniformity of Weights pH Loss on Drying Uniformity of Dosage Units Constituted Solution Chromatographic Purity Particulate Matter 1.Particles ≥ 10 µm 2. Particles ≥ 25 µm Bacterial Endotoxins Test Sterility Test Assay: Each vials contains: Cefotaxime sodium USP (Sterile) eq. to Cefotaxime 1000 mg.

Off-White Crystalline Powder filled in transparent glass Vials. Complies 1092.7mg Min: 1075.1mg Max: 1108.3mg 6.17 2.25%w/w 94.77% to 105.14% (RSD: 2.27%) Complies Complies 243 03 Less than 0.20 EU/Mg Sterile 1011.2 mg 101.12%

Off-White to Pale yellow crystalline powder filled in transparent glass Vials. As per Specification (1073.4-1117.3)mg (1040.5-1150.0)mg Between 4.5 & 6.5 NMT 3.0%w/w 85.0% to 115.0% (RSD: NMT 6.0%) As Per Specification Individual Impurity NMT 6% Sum of all Impurity NMT 10% NMT 6000 particles per container. NMT 600 particles per container. NMT 0.20 EU/Mg Sterile NLT 900 mg and NMT 1150 mg (NLT 90% and NMT 115% of label claimed)

Remarks: The Sample complies / Does not comply as per IP. / BP. / USP./ IH. Specification. The sample referred to

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
above is of standard quality. Analyst: Q.C. Chemist Date: 19/04/06

Checked By: Q.C. Officer Date: 19/04/06

Approved By: Q.C. Incharge Date: 19/04/06

Scott-Edil Pharmacia Ltd. 56, E.P.I.P., Phase-I, Jharmajri,Baddi (H.P.) QUALITY CONTROL DEPARTMENT
FINISHED PRODUCT CERTIFICATE OF ANALYSIS

PRODUCT NAME BATCH NO MFG. DATE BATCH SIZE SAMPLE QTY.
TEST

: Cefotaxime for Injection USP 1000mg : CFO-03 : 04/06 : 1,825 Vials : 25 Vials
OBSERVATION

REC. DATE : 07/04/06 EXP. DATE : 03/08 REPORT DATE : 21/04/06 A.R. NO. : F- CFO-03
SPECIFICATION

Description Identification (A,B & C) Average Fill Uniformity of Weights pH Loss on Drying Uniformity of Dosage Units Constituted Solution Chromatographic Purity Particulate Matter 1.Particles ≥ 10 µm 2. Particles ≥ 25 µm Bacterial Endotoxins Test Sterility Test Assay: Each vials contains: Cefotaxime sodium USP (Sterile) eq. to Cefotaxime 1000 mg.

Off-White Crystalline Powder filled in transparent glass Vials. Complies 1090.8mg Min: 1075.1mg Max: 1108.3mg 6.14 2.33%w/w 96.04% to 106.22% (RSD: 2.41%) Complies Complies 228 11 Less than 0.20 EU/Mg Sterile 1002.5 mg 100.25%

Off-White to Pale yellow crystalline powder filled in transparent glass Vials. As per Specification (1073.4-1117.3)mg (1040.5-1150.0)mg Between 4.5 & 6.5 NMT 3.0%w/w 85.0% to 115.0% (RSD: NMT 6.0%) As Per Specification Individual Impurity NMT 6% Sum of all Impurity NMT 10% NMT 6000 particles per container. NMT 600 particles per container. NMT 0.20 EU/Mg Sterile NLT 900 mg and NMT 1150 mg (NLT 90% and NMT 115% of label claimed)

Remarks: The Sample complies / Does not comply as per IP. / BP. / USP./ IH. Specification. The sample referred to

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
above is of standard quality. Analyst: Q.C. Chemist Date: 21/04/06

Checked By: Q.C. Officer Date: 21/04/06

Approved By: Q.C. Incharge Date: 21/04/06

ACCELARTED STABILITY STUDY DATA FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

1.0 GENERIC NAME Cefotaxime for Injection USP 1 gm 2.0 SHELF - LIFE Cefotaxime for injection USP 1 gm is supposed to be stable at least 2 Years from the date of manufacture. 3.0 PROPOSED EXPIRY 2 years. 4.0 STORAGE Store in a cool, dry & dark place. 5.0 STABILITY STUDIES Accelerated Stability Study at 40ºC ± 2ºC & RH: 75% ± 5% are carried out and stability data are attached. 6.0 TYPE OF PACKING Dry injection packed in clear transparent USP Type-III Vial. 7.0 METHOD OF STUDY Conditions for Accelerated Stability Studies For Accelerated Stability Studies the products are kept in humidity chamber: At 40° ± 2 °C & RH 75% ± 5% Testing intervals for Accelerated Stability Studies:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) The stored samples are withdrawn at predetermined intervals the intervals are as follows: Initial, 1 month, 2 months 3 months & 6 months.

8.0 TESTING SPECIFICATIONS Physical Tests • Description • Identification • pH • Average fill weight • Water Chemical Tests & Microbiological Test • Sterility • BET (Bacterial Endotoxins Test ) • Assay of Active Ingredients Specification of Product for stability study: As per finish product specifications METHODS OF EVALUATION Description of methods of assay: 3 batches of Cefotaxime for Injection USP 1 gm has been subjected for accelerated stability studies as per specification.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

GENERIC NAME Batch No. Mfg. Date Pack Size Periodic interval Test PHYSICAL TEST

QUALITY CONTROL DEPARTMENT ACCELERATED STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-01 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type Initial 17/04/06 After 1M After 2M

1825 vials 03/2008 USP Type-III Vials After 3M After 6M

Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.09 2.20%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.06 2.28%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.02 2.34%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 5.98 2.40%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 5.92 2.45%w/w

Identification Average fill weight pH LOD

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 99.90% 98.82% 97.75 % 97.03% 96.48%

Conclusion : On the basis of aforesaid analytical data summary report. The product mentioned above is of standard quality through out the 6 month’s accelerated stability period. Opinion : Hence in the opinion of undersigned the product mentioned above may be stable till it’s proposed shelf life.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

GENERIC NAME Batch No. Mfg. Date Pack Size Periodic interval Test PHYSICAL TEST

QUALITY CONTROL DEPARTMENT ACCELERATED STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-02 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type Initial 19/04/06 After 1M After 2M

1825 vials 03/2008 USP Type-III Vials After 3M After 6M

Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.17 2.25%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.15 2.27%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.12 2.35%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.08 2.45%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.02 2.50%w/w

Identification Average fill weight pH LOD

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 101.12% 100.96% 99.94 % 99.12% 98.43%

Conclusion : On the basis of aforesaid analytical data summary report. The product mentioned above is of standard quality through out the 6 month’s accelerated stability period. Opinion : Hence in the opinion of undersigned the product mentioned above may be stable till it’s proposed shelf life.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

GENERIC NAME Batch No. Mfg. Date Pack Size Periodic interval Test PHYSICAL TEST

QUALITY CONTROL DEPARTMENT ACCELERATED STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-03 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type Initial 21/04/06 After 1M After 2M

1825 vials 03/2008 USP Type-III Vials After 3M After 6M

Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.14 2.33%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.10 2.36%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.07 2.39%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.01 2.44%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 5.92 2.52%w/w

Identification Average fill weight pH LOD

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 100.25% 99.96% 98.85 % 97.81% 96.57%

Conclusion : On the basis of aforesaid analytical data summary report. The product mentioned above is of standard quality through out the 6 month’s accelerated stability period. Opinion : Hence in the opinion of undersigned the product mentioned above may be stable till it’s proposed shelf life.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
REMARKS •

The finished packs were kept at 40°C ± 2°C & 75% ± 5%. The observation was made for changes in physical, chemical characteristics and sterility compliance for 6 months.

• •

No change in physical characteristics, i.e. colour & appearance of solution. There is no indication of the interaction of glass vial with the filled solution i.e. no change in pH.

Chemical characteristics of the Dry injection have been found to be within specification limits, i.e. no significant change in assay content of active ingredients.

The Dry injection confirmed to the standard sterility limits.

CONCLUSION

The above accelerated stability shows that the product is stable for two years and found to comply with the standards.
Prepared By Name Designation Signature Date Tapan Kumar Rana Offier-Q.C Checked By Prafulla Kumar Behera Officer-Q.C Approved By S.K Das Manager-Q.C

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

LONG TERM STABILITY STUDY DATA FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

1.0 GENERIC NAME Cefotaxime for Injection USP 1gm 2.0 SHELF - LIFE Cefotaxime for Injection USP 1gm is supposed to be stable at least 2 years from the date of manufacture. 3.0 PROPOSED EXPIRY 2 years. 4.0 STORAGE Store in a cool, dry & dark place. 5.0 STABILITY STUDIES Long Term Stability Study at 30ºC ± 2ºC & RH: 65% ± 5% are carried out and Stability data are attached. 6.0 TYPE OF PACKING Dry injection packed in clear transparent USP Type-III Vial. 7.0 METHOD OF STUDY Conditions for Long Term Stability Studies For Long Term Stability Studies the products are kept in humidity chamber: At 30° ± 2 °C & RH 65% ± 5% Testing intervals for Long Term Stability Studies: The stored samples are withdrawn at predetermined intervals the intervals are as follows: Initial, 3 month, 6 months, 9 months , 12 months, 18 months, 24 months & 30 months.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

8.0 TESTING SPECIFICATIONS Physical Tests • Description • Identification • pH • Average fill weight • Water Chemical Tests & Microbiological Test • Sterility • BET (Bacterial Endotoxins) • Assay of Active Ingredients Specification of Product for stability study: As per finish product specifications METHODS OF EVALUATION Description of methods of assay: 3 batches of Cefotaxime for Injection USP 1gm has been subjected for Long term stability studies as per specification.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

GENERIC NAME Batch No. Mfg. Date Pack Size

QUALITY CONTROL DEPARTMENT LONG TERM STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-01 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type

1825 vials 03/2008 USP Type-III Vials

Periodic interval Test PHYSICAL TEST

Initial 17/04/06

After 3M

After 6M

After 9M

After 12 M

Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.09 2.20%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.07 2.24%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.07 2.30%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.00 2.33%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 5.97 2.36%w/w -----------

Identification Average fill weight pH LOD

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 99.90% 99.84% 99.22% 98.72% 97.46%

Continue…………..

QUALITY CONTROL DEPARTMENT

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
LONG TERM STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-01 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type

GENERIC NAME Batch No. Mfg. Date Pack Size

1825 vials 03/2008 USP Type-III Vials

Periodic interval Test PHYSICAL TEST

Initial 17/04/06

After 18 M

After 24 M

After 30 M

Remarks

Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.09 2.20%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.07 2.40%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.07 2.45%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1095.4 mg 6.00 2.50%w/w -----------

OK

Identification Average fill weight pH LOD

OK OK OK OK OK OK

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 99.90% 97.02% 96.88% 95.72% OK

Conclusion : On the basis of aforesaid analytical data summary report. The product mentioned above is of standard quality through out the 30 month’s Long term stability period.

GENERIC NAME Batch No. Mfg. Date Pack Size

QUALITY CONTROL DEPARTMENT LONG TERM STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-02 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type

1825 vials 03/2008 USP Type-III Vials

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Periodic interval Test PHYSICAL TEST

Initial 19/04/06

After 3M

After 6M

After 9M

After 12 M

Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.17 2.25%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.13 2.27%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.08 2.30%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.05 2.33%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.02 2.35%w/w -----------

Identification Average fill weight pH LOD

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 101.12% 100.08% 100.14% 99.94% 99.12%

Continue…………..

GENERIC NAME Batch No. Mfg. Date Pack Size

QUALITY CONTROL DEPARTMENT LONG TERM STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-02 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type

1825 vials 03/2008 USP Type-III Vials

Periodic interval Test

Initial 19/04/06

After 18 M

After 24 M

After 30 M

Remarks

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
PHYSICAL TEST Specification

Description

Off-White to Pale yellow crystalline powder filled in transparent glass Vials.
Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 6.17 2.25%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 5.97 2.40%w/w -----------

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 5.95 2.45%w/w

Off-White crystalline powder filled in transparent glass Vials.
Positive as FP Specification 1092.7 mg 5.80 2.50%w/w -----------

OK

Identification Average fill weight pH LOD

OK OK OK OK OK OK

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 101.12% 98.85% 98.65% 97.82% OK

Conclusion : On the basis of aforesaid analytical data summary report. The product mentioned above is of standard quality through out the 30 month’s Long term stability period.

GENERIC NAME Batch No. Mfg. Date Pack Size

QUALITY CONTROL DEPARTMENT LONG TERM STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-03 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type

1825 vials 03/2008 USP Type-III Vials

Periodic interval Test PHYSICAL TEST Description

Initial 21/04/06

After 3M

After 6M

After 9M

After 12 M

Specification

Off-White to

Off-White crystalline

Off-White crystalline

Off-White crystalline

Off-White crystalline

Off-White crystalline

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Pale yellow crystalline powder filled in transparent glass Vials.
Identification Average fill weight pH LOD Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5

powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.14 2.33%w/w

powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.10 2.37%w/w -----------

powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.05 2.41%w/w -----------

powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 6.00 2.45%w/w -----------

powder filled in transparent glass Vials.
Positive as FP Specification 1090.8 mg 5.97 2.49%w/w -----------

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 100.25% 99.93% 99.24% 98.85% 97.83%

Continue…………..

GENERIC NAME Batch No. Mfg. Date Pack Size

QUALITY CONTROL DEPARTMENT LONG TERM STABILITY STUDY DATA Cefotaxime for Injection USP 1gm CFO-03 Batch Size 04/2006 Exp. Date 1 gm /10 mL VIAL Pack Type

1825 vials 03/2008 USP Type-III Vials

Periodic interval Test PHYSICAL TEST Description

Initial 21/04/06

After 18 M

After 24 M

After 30 M

Remarks

Specification

Off-White to Pale yellow crystalline powder filled in transparent

Off-White crystalline powder filled in transparent glass Vials.

Off-White crystalline powder filled in transparent glass

Off-White crystalline powder filled in transparent glass Vials.

Off-White crystalline powder filled in transparent glass Vials.

OK

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
glass Vials.
Identification Average fill weight pH LOD Positive as FP Specification (1073.4-1117.3)mg 4.5 to 6.5 Positive as FP Specification 1090.8 mg 6.14 2.33%w/w

Vials.
Positive as FP Specification 1090.8 mg 5.94 2.51%w/w ----------Positive as FP Specification 1090.8 mg 5.90 2.52%w/w Positive as FP Specification 1090.8 mg 5.85 2.50%w/w ----------OK OK OK OK OK OK

Bacterial Endotoxins Sterility Cefotaxime sodium USP eq. to Cefotaxime 1gm

NMT 3%w/w Not more than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Less than 0.20 EU/mg Sterile

Assay: Each Vials contains: 90%-115% 100.25% 97.13% 96.89% 95.82% OK

Conclusion : On the basis of aforesaid analytical data summary report. The product mentioned above is of standard quality through out the 30 month’s Long term stability period.

PACKING MATERIAL SPECIFICATION FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

PACKING MATERIAL SPECIFICATION

TESTS

SPECIFICATIONS

Material Name: Description Glass Type Dimension Outer body diameter Total Height Average weight Neck Inner neck diameter

10 ML GLASS VIAL Transparent colourless glass vial free from any physical defects, Cracks, air bubbles, & dust. USP Type-III 25.0+1.0 mm 51.0 mm + 2 mm 19.0 gm + 1 gm 12.0 mm + 2.0 mm

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.) Outer neck diameter Over flow capacity Performance Hydrolic Resistance Test 16.0 mm + 2.0 mm NLT 10.0 ml To Pass ( It Should be 100 % breakless.) NMT 8.1ml of 0.01M HCl required.

PACKING MATERIAL SPECIFICATION TESTS
Material Name: Description
Total height of plug Diameter of Rim Diameter of plunger Thickness of Rim Average Weight Sterilization Test Fragmentation test Appearance of solution pH of aqueous extract

SPECIFICATIONS
Rubber Plug A simple thick top 20 mm Rubber Stopper made of Natural Grey Rubber.
Between 13.40 and 13.80 mm Between 18.90 and 19.20 mm Between 13.30 and 13.70 mm Between 3.10 and 3.50 mm Between 2.10 and 2.50 gm The plug should not soften or become tacky and there should not be any visual change in the plug. Not more than 15.0 Solution A should not be more opalescent than opalescence standard OS3 and not more intensely colored than reference solution BYS6 Not more than 0.3 ml of 0.01M NaOH or 0.8 ml 0.01 M HCl should be required to change the color of solution to

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
blue or yellow. The absorbance is not more than 2.0at 220 to 360 nm. The differences between titration volume should not be more than 7.0 ml The color produced in test solution is not darker than that produced on the standard solution. Not more than 4.0 mg as compared with blank Black stain on the paper should not be more intense than that of standard. The vials should not contain any traces of colored solution of methylene blue

Light absorption Reducing Substances Heavy metals Residue on evaporation Volatile Sulphide Self sealability

PACKING MATERIAL SPECIFICATION

TESTS
Material Name: Description
Total Height Height of aluminum portion Inner diameter of aluminum seal Diameter of Flip-off disc Thickness of aluminum seal Average weight Autoclave test

SPECIFICATIONS
Flip off Seal A closure with Aluminium base & Plastic Flip Off.
Between 8.50 and 9.50 mm Between 8.20 and 8.80 mm Between 19.50 and 20.50 mm Between 21.70 and 22.70 mm Between 0.23 and 0.27 mm Between 0.600gm and 0.800gm There should not be any discolouration and peeling off in seals.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

STANDARD TEST PROCEDURE OF PACKING MATERIAL FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

QUALITY CONTROL DEPARTMENT STANDARD TEST PROCEDURE Name of Packing Material 1.0 Description:
Procedure: Should comply with the specification.

For Authorized Person Only

Glass Vial

2.0
2.1

Dimensions:
Height: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier caliper, measure the height of the vial ensuring that one edge of the vial coincides with the zero on the Vernier caliper. Repeat the same for further four times and calculate the average height.

2.2

Body diameter: Apparatus: Calibrated Vernier caliper Procedure:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Using a calibrated Vernier caliper, measure the body diameter of the vials ensuring that one edge of the vial coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average body diameter. 2.3 Neck inner diameter: Apparatus: Calibrated Vernier caliper Procedure: Using a calibrated Vernier caliper, measure the inner diameter of neck ensuring that one edge of the vial coincides with the zero on the Vernier caliper. Repeat the same for further four times and calculate the average inner diameter of neck of the vials.

2.4

Neck Outer diameter: Apparatus: Calibrated Vernier caliper Procedure: Using a calibrated Vernier caliper, measure the outer diameter of the neck of the vial ensuring that one edge of the vial coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average neck outer diameter.

2.5

Height of Neck Ring: Apparatus: Calibrated Vernier caliper Procedure: Using a calibrated Vernier caliper, measure the outer diameter of the vial that one edge of the vial coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average height of neck ring.

2.6

Height base to shoulder: (Only applicable for tubular vials) Apparatus: Calibrated Vernier caliper Procedure:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Using Vernier caliper, measure the height of the vial from base to shoulder that one edge of the vial coincides with the zero on the Vernier caliper. Repeat the same for further four times and calculate the average height from base to shoulder.

3.0

Over flow capacity:
Apparatus: Burette Procedure: Take 5 vials for testing, fill each glass vial with water by burette to it’s over flow capacity and note down the reading of burette. Repeat the same for further four times and calculate the average overflow capacity.

4.0

Average weight:
Apparatus: Calibrated Weighing Balance Procedure: Weights of at least five vials are taken.

5.0

Hydrolytic Resistance:
Instrument: Autoclave

Reagent:
0.01 M Hydrochloric acid Preparation of Reagent: 0.01M hydrochloric acid Dilute 0.85 ml of concentrated hydrochloric acid to 100ml with purified water. Further dilute 10 ml of above solution to 100 ml with purified water. Procedure:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Carry out the determination on the unused containers. The number of containers to be examined and the volumes of test solution to be used are given in Table 1.Take no. of vials as described in table 1 for testing. Rinse each container with freshly prepared distilled water at least 5 times then fill vials to 90% of their overflow and cover them with aluminium foil previously rinsed with freshly prepared distilled water. Table-1 Nominal capacity of container(ml) Up to 3 5 or less 6 to 30 More than 30 Number of containers to be used At least 20 At least 10 At least 5 At least 3 Volume of test solution to be used for titration (ml) 25.0 50.0 50.0 100.0

Place the containers in an autoclave containing water so that they remain clear of the water. Close the autoclave and release the air by passage of steam for 10 minutes raise the temperature from 100° to 121° C over 20 minutes, maintain a temperature of 121°C for 60 minutes and reduce the temperature from 121° to 100° over 40 minutes, venting to prevent vacuum. Remove the containers from the autoclave and cool them in bath of running tap water. Carry out the following titration within 1 hour of removing the containers from the autoclave. Combine the liquids from the containers being examined; measure the volume of test solution specified in table each 50 ml of liquid into a conical flask and adds 0.15 ml of methyl red solution for each 50 ml of liquid, and titrates with 0.01 M hydrochloric acid. Repeat this operation using the same volume of freshly prepared distilled water as blank. The difference between the titrations represents the volume of 0.01 M hydrochloric acid required by the test solution. Calculate the volume of 0.01M hydrochloric acid required for each 100 ml of test solution, if necessary. The result is not greater than the value stated in Table 2. Table-2 TABLE REVISION CARD

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Capacity of container [corresponding to 90% average overflow volume(ml)]

Volume of 0.01M hydrochloric acid per 100 ml of test solution Type I or II glass (ml) 2.0 1.8 1.3 1.0 0.80 0.60 0.50 0.40 0.30 0.20 Type III glass (ml) 20.0 17.6 13.2 10.2 8.1 6.1 4.8 3.8 2.9 2.2

Not more than 1 More than 1 but not more than 2 More than 2 but not more than 5 More than 5 but not more than 10 More than 10 but not more than 20 More than 20 but not more than 50 More than 50 but not more than 100 More than 100 but not more than 200 More than 200 but not more than 500 More than 500

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
6.0
Arsenic : (Only applicable for type-I vials) Glass vials should comply with the following test. Carry out the test on vials, the inner and outer surfaces of which are washed five times with purified water. Preparation of reagent: Hydrazine-Molybdate Reagent: Dissolve 0.1 g of ammonium molybdate in 10 ml of water containing 1.5 ml of sulphuric acid, dilute to about 90 ml with water and add 1 ml of a 0.15% w/v solution of hydrazine sulphate and sufficient water to produce 100 ml. Procedure: Prepare a test solution as described in the test for Hydrolytic resistance for an adequate number of vials to produce 50 ml. Pipette 10 ml of the test solution from the combined contents of all the vials into a flask, add 10 ml of nitric acid and evaporate to dryness on a water-bath. Dry the residue in an oven at 130° for 30 minutes. Cool, add to the residue 10.0 ml of hydrazine-molybdate reagent, swirl to dissolve and heat under reflux on a water bath for 20 minutes. Cool to room temperature. Determine the absorbance of the resulting solution at the maximum at about 840 nm, using 10.0 ml of hydrazinemolybdate reagent as the blank. The absorbance of the test solution does not exceed the absorbance obtained by repeating the determination using 0.1 ml of arsenic standard solution (10 ppm As) in place of the test solution (0.1 ppm).

QUALITY CONTROL DEPARTMENT

For Authorized Person Only

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
STANDARD TEST PROCEDURE Name of Packing Material

Rubber Plug.

1.0 2.0
2.1

Description: A simple thick top 20 mm Rubber Stopper made of Natural Grey Rubber.
Dimensions: Total Height of Plug: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier Caliper, measure the total height of the rubber plug ensuring that one edge of the rubber plug coincides with the zero on the Vernier Caliper. Repeat the same for further four times and calculate the average height of plug.

2.2

Diameter of Rim: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier Caliper, measure the diameter of rim ensuring that one edge of the rim coincides with the zero on the Vernier Caliper. Repeat the same for further four times and calculate the average diameter of rim.

2.3

Diameter of Plunger: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier Caliper, measure the diameter of Plunger ensuring that one edge of the plunger coincides with the zero on the Vernier Caliper. Repeat the same for further four times and calculate the average diameter of plunger.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
2.4 Thickness of Rim: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier Caliper, measure the thickness of the rim ensuring that one edge of the rim coincides with the zero on the Vernier Caliper. Repeat the same for further four times and calculate the average thickness of rim. 3.0 Average Weight: Apparatus: Calibrated Weighing Balance Procedure: Weight 10 samples of rubber plugs individually using calibrated weighing balance and determine the average weight. 4.0 Sterilization test: Apparatus: Instrument: 1000 ml Borosilicate glass beaker. Autoclave Calibrated Weighing Balance Reagent: 0.2% v/v solution of Tween -80 or suitable anionic surface-active agent.

Preparation of reagents: Dilute 1.0 ml of Tween -80 solution in 500 ml of purified water. Procedure: Wash the rubber plugs by agitation in a 0.2% v/v solution of Tween -80 or suitable anionic surface-active agent for 5 minutes at room temperature. Rinse 5 times with purified water. Weigh 20gm of rubber plugs, washed them and place in a 1000 ml borosilicate glass beaker, add 200 ml of purified water per 20gm of the closures and weight. Cover the mouth of the glass beaker with aluminium foil and heat in an autoclave so that a temperature of 121 0C is reached within 20 to 30 minutes and maintain at that temperature for 30 minutes. Cool to room temperature over about 30 minutes and make to the original weight with purified water if required. Shake and immediately separate the solution from the closures by decantation. The decanted solution is called Solution ‘A’. Dry the treated rubber plugs at 64 0 C to 660 C at a pressure not exceeding 0.7 kPa for 24 hours. The dry treated closures are called Prepared Closures. Prepare a Blank Solution by using the same method as for Solution ‘A’ but using 200 ml of purified water without the closures. Check the Prepared Closures for softening or tackness as per specification.

5.0

Fragmentation test:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Apparatus: 12 clean vials Hypodermic needle Procedure: Close 12 clean vials with the Prepared Closures. Using a lubricated, long-bevel hypodermic needle with an external diameter of 0.8 mm (21SWG) fitted to a clean syringe, inject 1ml of water into the vial and remove 1ml of air, carry out this operation 4 times for each closure, piercing each time at a different site. Use a new needle for each closure and check the needle is not blunted during the test. Pass the liquid in the vials through a filter with a nominal pore size of 0.45µm. Check the needle and count the number of fragments on the filter paper.

6.0

Appearance of solution:
The solution A is not more opalescent than opalescence standard OS3 and not more intensely coloured than reference solution BYS6. Method : Standard Suspension: Dissolve 1.0 gm of hydrazine sulphate in sufficient water to produce 100.0ml and set aside for about 6 hours. To 25 ml of this solution add 25.0ml of 10.0% w/v solution of hexamine, mix well and allow to stand for 24 hours. Keep in a glass container with a smooth internal surface in which the suspension does not adhere to the glass. Store in this manner that the suspension is stable for about 2 months. Prepare the standard suspension diluting 15 ml of the well-mixed suspension to 1000 ml with water. The standard suspension should be used within 24 hours of preparation. Opalescence Standard OS3: Take 30.0 ml of Standard suspension add 70.0 ml of water and mix. Procedure: Transfer to a flat-bottomed test tube of neutral glass, 15 to 25 mm in diameter, a suitable volume of the solution being examined such that test-tube is filled to a depth of 40mm. In to another matched test-tube add same volume of the freshly prepared opalescence standard. After 5 minutes, compare the contents of the test-tubes against a black background viewing under diffused light down the vertical axis of the tubes. Conclusion: The test solution is not more opalescent than the opalescence of standard OS3.

Colour of solution:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Special Reagents-:Ferric chloride Colorimetric Solution ( FCS) Dissolve about 55 gm of ferric chloride hexahydrate in enough of a mixture of 25 ml of hydrochloric acid and 975 ml of water to produce 1000ml. Pipette 10 ml of this solution into a 250-ml iodine flask, add 15 ml of water, 3 gm of potassium iodide and 5 ml of hydrochloric acid and allow the mixture to stand for 15 minutes. Dilute with 100 ml of water and titrate the liberated iodine with 0.1M sodium thiosulphate using 0.5ml of starch solution, added towards the end of the titration, as indicator. Perform a blank determination and make any necessary correction. Each ml of 0.1M sodium thiosulphate is equivalent to 0.02703 gm of FeCl3.6H2O. Adjust the final volume of the solution by adding of enough of the mixture of hydrochloric acid and water so that each ml contains 0.045gm of FeCl 3.6H2O. The solution should be stored protected from light and standardized before use. Cobaltous Chloride Colorimetric Solution ( CCS): Dissolve about 65 gm of cobaltous chloride in enough of a mixture of 25 ml of hydrochloric acid and 975 ml of water to produce 1000ml. Pipette 5 ml of this solution into a 250-ml iodine flask, add 5ml of hydrogen peroxide solution (10 volume) and 15 ml of sodium hydroxide solution, boil for 10 minutes, cool and add 2gm of potassium iodide and 60 ml of dilute sulphuric acid. Dissolve the precipitate by gentle shaking. If necessary, and titrate the liberated iodine with 0.1M sodium thiosulphate using 0.5ml of starch solution, add towards the pink end point, as indicator. Perform a blank determination and make any necessary correction. Each ml of 0.1M sodium thiosulphate is equivalent to 0.02379gm of COCl 2, 6H2O. Adjust the final volume of the solution by addition of enough of the mixture of hydrochloric acid and water so that each ml contains 0.0595gm of COCl 2, 6H2O. Cupric Sulphate Colorimetric Solution ( CSS) : Dissolve about 65gm of cupric sulphate in enough of a mixture of 25 ml of hydrochloric acid and 975 ml of water to produce 1000ml. Pipette 10 ml of this solution into a 250-ml iodine flask, add 40 ml of water, 4ml of acetic acid, 3gm of potassium iodide, and 5 ml of hydrochloric acid and titrate the liberated iodine with 0.1M sodium thiosulphate using 0.5ml of starch solution, added towards the pale brown end point, as indicator. Perform a blank determination and make any necessary correction. Each ml of 0.1M sodium thiosulphate is equivalent to 0.02497gm of CuSO 4,5H2O. Adjust the final volume of the solution by the addition of enough of the mixture of hydrochloric acid and water so that each ml contains 0.0624gm of CuSo4, 5H2O.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Reference Solution BYS6: Take 1.5 ml of FCS solution add 0.8 ml of CCS and 0.2 ml of CSS solution in 97.5 ml of 1%w/v hydrochloric acid and mix. NOTE- Reference solution must be prepared immediately before use from the colorimetric solutions which may be stored. Procedure: Transfer to a flat bottomed test-tube of neutral glass, 15 to 25 mm in diameter, a suitable volume of the liquid being examined such that the test-tube is filled to a depth of 40 mm. In to another matched testtube add the same volume of water or of the solvent used for preparing the solution being examined or of the reference solution stated individual monograph. Examine the columns of liquid in diffused light by viewing down the vertical-axis of the tubes against a white background. Conclusion: The test solution is not more intensely coloured than reference solution BYS6 . 7.0 pH of aqueous extract: Apparatus: Reagent: Conical flask Bromothymol blue solution 0.01 M Sodium hydroxide or 0.01 M Hydrochloric acid Preparation of reagent: Bromothymol blue solution: Dissolve 50 mg of bromothymol blue in 4 ml of 0.02 M sodium hydroxide and 20 ml of ethanol (95%). After solution is effected, add sufficient purified water to produce 100 ml. 0.02 M sodium hydroxide: Dissolve 0.8 g of sodium hydroxide in 100 ml of purified water. Dilute 10 ml. of this solution to 100ml with purified water. 0.01 M sodium hydroxide: Dissolve 0.4 g of sodium hydroxide in 100 ml of purified water. Dilute 10 ml of this solution to 100ml with purified water.

0.01M hydrochloric acid:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Dilute 0.85 ml of concentrated hydrochloric acid to 100 ml with purified water. Further dilute 10 ml of this solution to 100 ml with purified water. Procedure: To 20 ml of Solution A add 0.1 ml of bromothymol blue solution. Titrate with 0.01 M sodium hydroxide or 0.01 M hydrochloric acid till the colour is changed. Note the reading. 8.0 Light absorption: Apparatus: Instrument: 250 ml Borosilicate glass beaker UV-VIS Spectrophotometer

An ultra-violet and visible spectrophotometer suitable for measuring in the ultra-violet and visible range of the spectrum and consisting of an optical system capable of producing monochromatic light in the range 200 to 800 nm and a device for measuring the absorbance. Procedure: Filter Solution A through a membrane filter with a nominal pore size of 0.45µm & reject the first few ml of the filtrate. Measure the light absorption of the filtrate on the UV spectrophotometer in the range of 220 nm to 360 nm against the Blank Solution. Note: Carry out the test within 4 hours of preparing Solution A. 9.0 Reducing substances: Apparatus: Reagent: 1 M sulphuric acid 0.002 M Potassium permanganate Potassium iodide AR grade 0.01M Sodium thiosulphate Starch solution Preparation of reagents: 1M Sulphuric acid Dilute 0.6 ml of sulphuric acid with 10 ml of purified water. 0.002 M Potassium permanganate Dilute 5 ml of 0.02 M Potassium permanganate with 50 ml of purified water. Conical flask

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
0.02 M Potassium permanganate Dissolve 0.32 g of Potassium permanganate in 100 ml of water. 0.01M Sodium thiosulphate Dissolve 1.24 g of sodium thiosulphate and 0.01 g of sodium carbonate in 500 ml of purified water. Starch solution Triturate 1 g of soluble starch with 5 ml of purified water and adds, stirring continuously, to 100 ml of boiling water containing 10 mg of mercuric iodide. Procedure: To 20 ml of Solution A, add 1 ml of 1M sulphuric acid & 20 ml of 0.002 M potassium permanganate & boil for 3 minutes. Cool and add 1 g of potassium iodide and titrate immediately with 0.01 M sodium thiosulphate using 0.25 ml of starch solution, added toward the end point of titration, as indicator. Repeat the operation using 20 ml of the Blank solution. Note: Carry out the test with in 4 hours of preparing Solution A. 10.0 Heavy Metals: Apparatus: 50 ml Nessler cylinder pipette 500 ml Borosilicate glass beaker Instrument: Reagent: pH meter Lead standard solution (20ppm) Dilute acetic acid or dilute ammonia solution Hydrogen sulphide solution Preparation of reagents: Lead standard solution (20ppm Pb) Dilute 1 ml of lead standard solution (100 ppm Pb) to 5 ml with purified water. Lead standard solution (100ppm Pb) Dilute 1 ml of lead standard solution (0.1 % Pb) to 10 ml with purified water. Lead standard solution (0.1%Pb) Dissolve 0. 400g of lead nitrate in water containing 2ml of nitric acid add sufficient purified water to produce 250.0 ml.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Dilute acetic acid: Dilute 5.7 ml of glacial acetic acid with 100 ml purified water. Dilute ammonia solution: Dilute 4.25 ml of strong ammonia solution with 100 ml purified water. Hydrogen sulphide solution A freshly prepared saturated solution of hydrogen sulphide in purified water. Prepare the gas by the action of hydrochloric acid, diluted with an equal volume of purified water, on iron sulphide and collected in water. Standard solution: Into a 50 ml Nessler cylinder pipette take 1.0 ml of lead standard solution (20ppm Pb) & dilute with purified water to 25 ml. Adjust the pH with dilute acetic acid or dilute ammonia solution between 3.0 to 4.0, dilute with purified water to about 35 ml & mix. Test solution: Into a 50 ml Nessler cylinder pipette 25 ml of Solution A. Adjust with dilute ammonia solution to a pH between 3.0 to 4.0, dilute with water to about 35 ml & mix. Procedure: To each of the cylinders containing the standard solution & test solution respectively, add 10 ml of freshly prepared hydrogen sulphide solution, mix and dilute to 50 ml with purified water, allow to stand for 5 minutes & view downwards over a white surface. Check the colour difference of standard solution & test solution. 11.0 Residue on evaporation: Instrument: Water bath Thermostatic oven Apparatus: Evaporating dish 50 ml. measuring cylinder Procedure: Dry the evaporating dish in a oven at 100 0C at 1050C and cool it in desicator. Remove the dish and weigh (W1g). Take 50 ml of Solution A in dish, evaporate on a water bath and then dry in oven at 1000C to 1050C. Cool in desicator and weigh (W2 g). Calculate the weight of residue (W2 g - W1 g).

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
12.0 Volatile sulphide: Instrument: 250 ml conical flask Autoclave Procedure: Place closures, cut if necessary, with a total surface area of 20 + 2 cm2 in a 100-ml conical flask and add 50ml of a 2% w/v solution of citric acid. Place a piece of lead acetate paper over the mouth of the flask and maintain the paper in position by placing over it an inverted weighing bottle. Heat in an autoclave at 121+ 20 for 30 minutes. Any black stain on the paper is not more intense than that of a standard prepared at the same time in the same manner using 0.154mg of sodium sulphide and 50ml of a 2 % w/v solution of citric acid. 13.0 Self seal-ability: Instrument: Dessicator Procedure: This test is applicable to closures intended to be used with multidose containers. Fill 10 suitable vials with water to the nominal volume, close the vials with the ‘prepared closures’ and secure with the cap. For each closure, use a new hypodermic needle with an external diameter of 0.8mm (21SWG) and pierce the closures 10 times, piercing each time at a different site. Immerse the vials upright in a 0.1% w/v solution of methylene blue and reduce the external pressure by 27 KPa for 10 minutes in a dessicator. Restore the atmospheric pressure and leave the vials immersed for 30 minutes. Rinsed the outside of the vials. None of the vials contains any trace of coloured solution.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

QUALITY CONTROL DEPARTMENT STANDARD TEST PROCEDURE Name of Packing Material

For Authorized Person Only

Aluminium Seal

1.0

Description: A closure with Aluminium base & Plastic Flip Off.
Procedure: Should comply with the specification.

2.0 2.1

Dimensions:
Total Height: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier caliper, measure the total height of the aluminium seal ensuring that one edge of the aluminium seal coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average of total height.

2.2 Height of aluminium portion: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier Caliper, measure the height of the aluminium portion of the seal ensuring that one edge of the aluminium seal coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average of height of aluminium portion. 2.3 Inner diameter of aluminium seal: Apparatus: Calibrated Vernier Caliper

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Procedure: Using a calibrated Vernier Caliper, measure the inner diameter of the aluminium seal ensuring that one edge of the flip-off seal coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average of inner diameter of aluminium seal. 2.4 Diameter of flip off disc: Apparatus: Calibrated Vernier Caliper Procedure: Using a calibrated Vernier Caliper, measure the external diameter of flip-off disc ensuring that one edge of the aluminium seal coincides with the zero on the vernier caliper. Repeat the same for further four times and calculate the average of diameter of flip off disc. 2.5 Thickness of Aluminium seal: Apparatus: Calibrated screw gage. Procedure: Using a calibrated Screw Gage, measure the thickness of the aluminium seal. Repeat the same for further four times and calculate the average of thickness of aluminium seal. 3.0 Average weight: Apparatus: Calibrated Weighing Balance Procedure: Weigh 5 samples of aluminium flip off seal using weighing balance and determine their average weight.
Total weight of aluminium seal (in gram)

Average weight = ------------------------------------------------------5

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
4.0 Autoclave Test: Apparatus: 250 ml Borosilicate glass beaker. 250ml conical flask Instrument: Autoclave Procedure: Wash the aluminium seals with purified water for 5 times in a 250 ml borosilicate glass beaker. Place approximately 12-15 and 20-23 aluminium seals of 20mm and 13mm respectively in a 250ml conical flask. Add 200ml of purified water and cover the mouth of flask with aluminium foil. This is solution A. Prepare a blank solution by using the same method as for solution A, by using 200 ml of purified water without aluminium seal. Now heat in an autoclave at a temperature of 121 0c and maintain at that temperature for 30 minutes. Cool at room temperature for about 30 minutes and check them visually for any physical change. Conclusion: No discolouration, corrosion, peeling off are observed in treated sample

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
QUALITY CONTROL DEPARTMENT Name of Packing Material For Authorized Person Only

STANDARD TEST PROCEDURE LABEL

1.0

Description:
Check the samples against the approved standard for design, colour, finish, alignment, printing matter.

2.0 3.0

Printed text matter.
Check printed text of labels by comparing with approved standard.

Grammage:
Determine on same 5 labels used for dimensions. Weigh the entire label accurately (A) gm. Remove the glue coating with the help of piece of cotton dipped in acetone by rubbing the glued side of the label. Dry it at room temperature for 5 minutes and reweigh (B) gm. B X 100 X 100 ------------------------------------Length (cm) X Width (cm)

A] Grammage of paper (without adhesive) =

(A-B) X 100 X 100 B] Grammage of adhesive = ---------------------------------------Length (cm) X Width (cm) Weight (in gm ) X 100 X 100 C] Grammage of silicon liner = ---------------------------------------Length (cm) X Width (cm)

4.0 5.0 6.0 7.0

Inner diameter of core:
Measure the inner diameter of core with calibrated vernier caliper.

Maximum outer diameter of roll:
Measure the outer diameter of role with calibrated scale.

Dimensions:
Determine on 5 labels. Determine length and width of label using calibrated measuring scale .

Width of release paper :( Silicon Linear)
Measure with calibrated measuring scale.

8.0

Rub test:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Take a clean white cloth and rub the printed matter for two minutes so as to avoid the broking or torning of label observe for any migration of printed text matter’s ink.

9.0

Functional Test:
Paste the label on glass /LDPE container and remove. Label should be pasted properly and firmly on container, it should not flagger after sticking.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
QUALITY CONTROL DEPARTMENT Name of Packing Material 1.0 STANDARD TEST PROCEDURE CARTONS For Authorized Person Only

Description: Printed ITC board monocarton with tuck-in flap opening on both the sides
Check the samples against the approved standard for design finish. Colour, alignment, Printing and printed matter.

2.0

Printed text matter: The printed text matter should be as per approved text, design and colour scheme. There should not be any ink stain and letter submerging

3.0

Dimension:
Determine on 5 samples. Check the dimensions of all the 5 individual samples with calibrated scale. Dimension should be within the specified limit.

4.0

Grammage:
Cut a piece of 10cm X 10cm or any other suitable size & weigh it on balance up to the minimum accuracy of 2 decimal points. Calculate the Grammage as follows. Weight in gram x 100 x 100

Grammage=

--------------------------------- = XYZ GSM (Gram per square meter)
Length in cm. x Width in cm.

The GSM value should be within the specified limits. 5.0 Overprinting : Batch No., Mfg. Dt., Exp. Dt. to be overprinted in the space provided Height of tuck in flap: The flaps should be properly check height of cartons.

6.0 7.0

Folding and pasting of flaps:
The flaps should be properly folded and cartons should be pasted properly and the forcible separation of these flaps should be free from fiber tearing. The adhesive used for flap pasting should not come out and it should be completely dry.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
QUALITY CONTROL DEPARTMENT Name of Packing Material 1.0 STANDARD TEST PROCEDURE Package Insert For Authorized Person Only

Description: White Paper Printed with Black colour on both side Check the samples against the approved standard for design, finish, alignment, printing and printed matter.

3.0

Printed text matter: The printed text matter should be as per approved text, design and colour scheme. There should not be any ink stain and letter submerging.

3.0

Dimension: Apparatus: Calibrated stainless steel scale Length: Procedure: Using calibrated stainless steel scale determines the length of 5 inserts. Width: Procedure: Using calibrated stainless steel scale determines the width of 5 inserts. Grammage: Apparatus: Calibrated weighing balance Procedure: Determine on 1 sample, weigh the sample on balance and calculate the GSM as follow: Weight in gram x 100 x 100 Grammage: -----------------------------------Length in cm. x Width in cm.

3.1

3.2

4.0

5.0

Weight of 10 inserts: Apparatus: Calibrated weighing balance Procedure: Using Calibrated weighing balance, determine weight of 10 inserts.
Cleanness Check: Insert should be clean, without torn and stain

6.0

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

CLINICAL PHARMACOLOGY FOR CEFOTAXIME FOR INJECTION USP 1 GM

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

CLINICAL PHARMACOLOGY
INTRODUCTION: Cefotaxime for injection is to reduce the development of drug-resistant bacteria and maintain the effectiveness and other antibacterial drugs, Cefotaxime for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Sterile cefotaxime sodium is a semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration. It is the sodium salt of 7-[2-(2-amino-4-thiazolyl) glyoxylamido]-3-(hydroxymethyl)-8oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 72 (Z)-(o-methyloxime), acetate (ester). Cefotaxime sodium contains approximately 50.5 mg (2.2 mEq) of sodium per gram of cefotaxime activity.

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INDICATIONS: Treatment CEFOTAXIME FOR INJECTION is indicated for the treatment of patients with serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below. 1. Lower respiratory tract infections, including pneumonia, caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes* (Group A streptococci) and other streptococci (excluding enterococci, e.g., Enterococcus faecalis), Staphylococcus aureus (penicillinase and non-penicillinase producing), Escherichia coli, Klebsiella species, Haemophilus influenzae (including ampicillin resistant strains), Haemophilus parainfluenzae, Proteus mirabilis, Serratia marcescens*, Enterobacter species, indole positive Proteus and Pseudomonas species (including P. aeruginosa). 2. Genitourinary infections.Urinary tract infections caused by Enterococcus species, Staphylococcus epidermidis, Staphylococcus aureus*, (penicillinase and non-penicillinase producing), Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Proteus mirabilis, Proteus vulgaris*, Providencia stuartii, Morganella morganii*, Providencia rettgeri*, Serratia marcescens and Pseudomonas species (including P. aeruginosa). Also, uncomplicated gonorrhea (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including penicillinase producing strains. 3. Gynecologic infections, including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by Staphylococcus epidermidis, Streptococcus species, Enterococcus species, Enterobacter species*, Klebsiella species*, Escherichia coli, Proteus mirabilis, Bacteroides species (including Bacteroides fragilis*), Clostridium species, and anaerobic cocci (including Peptostreptococcus species and Peptococcus species) and Fusobacterium species (including F. nucleatum*). CEFOTAXIME FOR INJECTION, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.

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4. Bacteremia/Septicemia caused by Escherichia coli, Klebsiella species, and Serratia marcescens, Staphylococcus aureus and Streptococcus species (including S. pneumonia). 5. Skin and skin structure infections caused by Staphylococcus aureus (penicillinase and nonpenicillinase producing), Staphylococcus epidermidis, Streptococcus pyogenes (Group A streptococci) and other streptococci, Enterococcus species, Acinetobacter species*, Escherichia coli, Citrobacter species (including C. freundii*), Enterobacter species, Klebsiella species, Proteus mirabilis, Proteus vulgaris*, Morganella morganii, Providencia rettgeri*, Pseudomonas species, Serratia marcescens, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus species). 6. Intra-abdominal infections including peritonitis caused by Streptococcus species*, Escherichia coli, Klebsiella species, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus* species) Proteus mirabilis*, and Clostridium species*. 7. Bone and/or joint infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing strains), Streptococcus species (including S. pyogenes*), Pseudomonas species (including P. aeruginosa*), and Proteus mirabilis*. 8. Central nervous system infections, e.g., meningitis and ventriculitis, caused by Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae* and Escherichia coli*. Although many strains of enterococci (e.g., S. faecalis) and Pseudomonas species are resistant to cefotaxime sodium in vitro, CEFOTAXIME FOR INJECTION has been used successfully in treating patients with infections caused by susceptible organisms. Specimens for bacteriologic culture should be obtained prior to therapy in order to isolate and identify causative organisms and to determine their susceptibilities to CEFOTAXIME FOR INJECTION. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly. In certain cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, CEFOTAXIME FOR INJECTION may be used concomitantly with an aminoglycoside.

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The dosage recommended in the labeling of both antibiotics may be given and depends on the severity of the infection and the patient's condition. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. It is possible that nephrotoxicity may be potentiated if CEFOTAXIME FOR INJECTION is used concomitantly with an aminoglycoside. Prevention The administration of CEFOTAXIME FOR INJECTION preoperatively reduces the incidence of certain infections in patients undergoing surgical procedures (e.g., abdominal or vaginal hysterectomy, gastrointestinal and genitourinary tract surgery) that may be classified as contaminated or potentially contaminated. In patients undergoing cesarean section, intraoperative (after clamping the umbilical cord) and postoperative use of CEFOTAXIME FOR INJECTION may also reduce the incidence of certain postoperative infections. Effective use for elective surgery depends on the time of administration. To achieve effective tissue levels, CEFOTAXIME FOR INJECTION should be given 1/2 or 1 1/2 hours before surgery. For patients undergoing gastrointestinal surgery, preoperative bowel preparation by mechanical cleansing as well as with a non-absorbable antibiotic (e.g., neomycin) is recommended. If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapy may be instituted. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CEFOTAXIME FOR INJECTION and other antibacterial drugs, CEFOTAXIME FOR INJECTION should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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DOSAGE AND ADMINISTRATION:

Adults Dosage and route of administration should be determined by susceptibility of the causative organisms, severity of the infection, and the condition of the patient (see table for dosage guideline). Cefotaxime injection may be administered IM or IV after reconstitution. Premixed Cefotaxime Injection is intended for IV administration after thawing. The maximum daily dosage should not exceed 12 grams.
GUIDELINES FOR DOSAGE OF CEFOTAXIME FOR INJECTION

Type of Infection

Daily Dose (grams)

Frequency and Route

Gonococcal urethritis/cervicitis in males and females Rectal gonorrhea in females Rectal gonorrhea in males

0.5

0.5 gram IM (single dose)

0.5 1

0.5 gram IM (single dose) 1 gram IM (single dose) 1 gram every 12 hours IM or IV 1-2 grams every 8 hours IM or IV

Uncomplicated infections

2

Moderate to severe infections

3-6

Infections commonly needing antibiotics in higher dosage (e.g., septicemia) Life-threatening infections

6-8

2 grams every 6-8 hours IV

up to 12

2 grams every 4 hours IV

If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefotaxime sodium has no activity against this organism.

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To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended dose is a single 1 gram IM or IV administered 30 to 90 minutes prior to start of surgery. Cesarean Section Patients The first dose of 1 gram is administered intravenously as soon as the umbilical cord is clamped. The second and third doses should be given as 1 gram intravenously or intramuscularly at 6 and 12 hours after the first dose. Neonates, Infants, and Children The following dosage schedule is recommended: Neonates (birth to 1 month): 0-1 week of age 50 mg/kg per dose every 12 hours IV 1-4 weeks of age 50 mg/kg per dose every 8 hours IV It is not necessary to differentiate between premature and normal-gestational age infants. Infants and Children (1 month to 12 years): For body weights less than 50 kg, the recommended daily dose is 50 to 180 mg/kg IM or IV body weight divided into four to six equal doses. The higher dosages should be used for more severe or serious infections, including meningitis. For body weights 50 kg or more, the usual adult dosage should be used; the maximum daily dosage should not exceed 12 grams. Geriatric Use This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. NOTE: As with antibiotic therapy in general, administration of Cefotaxime injection should be continued for a minimum of 48 to 72 hours after the patient defervesces or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended for infections caused by Group A beta-hemolytic streptococci in order to guard against the risk of rheumatic fever or

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glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment of several weeks and doses smaller than those indicated above should not be used. Preparation of Cefotaxime Sterile Cefotaxime for injection for IM or IV administration should be reconstituted as follows:
Strength Diluent (mL) Withdrawable Volume (mL) Approximate Concentration (mg/mL) 230 300 330 50 95 180 20-10 40-20

500 mg vial* (IM) 1g vial* (IM) 2g vial* (IM) 500 mg vial* (IV) 1g vial* (IV) 2g vial* (IV) 1g infusion 2g infusion
(*) in conventional vials

2 3 5 10 10 10 50-100 50-100

2.2 3.4 6.0 10.2 10.4 11.0 50-100 50-100

Shake to dissolve; inspect for particulate matter and discoloration prior to use. Solutions of CEFOTAXIME FOR INJECTION range from very pale yellow to light amber, depending on concentration, diluent used, and length and condition of storage. For intramuscular use: Reconstitute VIALS with Sterile Water for Injection or Bacteriostatic Water for Injection as described above.

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For intravenous use: Reconstitute VIALS with at least 10 mL of Sterile Water for Injection. Reconstitute INFUSION BOTTLES with 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. For other diluents, see Compatibility And Stability section. NOTE: Solutions of CEFOTAXIME FOR INJECTION must not be admixed with aminoglycoside solutions. If CEFOTAXIME FOR INJECTION and aminoglycosides are to be administered to the same patient, they must be administered separately and not as mixed injection. A SOLUTION OF 1 G CEFOTAXIME FOR INJECTION IN 14 ML OF STERILE WATER FOR INJECTION IS ISOTONIC. IM Administration: As with all IM preparations, CEFOTAXIME FOR INJECTION should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel. Individual IM doses of 2 grams may be given if the dose is divided and is administered in different intramuscular sites. IV Administration: The IV route is preferable for patients with bacteremia, bacterial septicemia, peritonitis, meningitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

SIDE EFFECTS: CEFOTAXIME FOR INJECTION is generally well tolerated. The most common adverse reactions have been local reactions following IM or IV injection. Other adverse reactions have been encountered infrequently. The most frequent adverse reactions (greater than 1%) are: Local (4.3%) - Injection site inflammation with IV administration. Pain, induration, and tenderness after IM injection.

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Hypersensitivity (2.4%) - Rash, pruritus, fever, eosinophilia and less frequently urticaria and anaphylaxis. Gastrointestinal (1.4%) - Colitis, diarrhea, nausea, and vomiting. Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely. Less frequent adverse reactions (less than 1%) are: Cardiovascular System - Potentially life-threatening arrhythmias following rapid (less than 60 seconds) bolus administration via central venous catheter have been observed. Hematologic System - Neutropenia, transient leukopenia, eosinophilia, thrombocytopenia and agranulocytosis have been reported. Some individuals have developed positive direct Coombs Tests during treatment with CEFOTAXIME FOR INJECTION and other cephalosporin antibiotics. Rare cases of hemolytic anemia have been reported. Genitourinary System - Moniliasis, vaginitis. Central Nervous System - Headache. Liver- Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase levels have been reported. Increase in liver enzymes (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase) and/or bilirubin. These laboratory abnormalities, which may also be explained by the infection, may rarely exceed twice the upper limit of the normal range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic. Hepatitis, sometimes with jaundice, has been reported. Kidney - As with some other cephalosporins, interstitial nephritis and transient elevations of BUN and creatinine have been occasionally observed with CEFOTAXIME FOR INJECTION. Cutaneous - As with other cephalosporins, isolated cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported.

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Cephalosporin Class Labeling In addition to the adverse reactions listed above which have been observed in patients treated with cefotaxime sodium, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics: allergic reactions, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and false-positive test for urinary glucose. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. DRUG INTERACTION: Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics. Drug/Laboratory Test Interactions Cephalosporins, including cefotaxime sodium, are known to occasionally induce a positive direct Coombs' test. WARNINGS: BEFORE THERAPY WITH CEFOTAXIME FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTAXIME SODIUM, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN WITH CAUTION TO PATIENTS WITH TYPE I HYPERSENSITIVITY REACTIONS TO PENICILLIN. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN

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ALLERGIC REACTION TO CEFOTAXIME FOR INJECTION OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

During post-marketing surveillance, a potentially life-threatening arrhythmia was reported in each of six patients who received a rapid (less than 60 seconds) bolus injection of cefotaxime through a central venous catheter. Therefore, cefotaxime should only be administered as instructed in the DOSAGE AND ADMINISTRATION section. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CEFOTAXIME FOR INJECTION, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS:
General

Prescribing CEFOTAXIME FOR INJECTION in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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CEFOTAXIME FOR INJECTION should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when CEFOTAXIME FOR INJECTION is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organism. Although there is no clinical evidence supporting the necessity of changing the dosage of cefotaxime sodium in patients with even profound renal dysfunction, it is suggested that, until further data are obtained, the dose of cefotaxime sodium be halved in patients with estimated creatinine clearances of less than 20 mL/min/1.73 m2. When only serum creatinine is available, the following formula 5 (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Weight (kg) x (140 - age) Males: 72 x serum creatinine Females: 0.85 x above value As with other antibiotics, prolonged use of CEFOTAXIME FOR INJECTION may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. As with other beta-lactam antibiotics, granulocytopenia and, more rarely, agranulocytosis may develop during treatment with CEFOTAXIME FOR INJECTION, particularly if given over long periods. For courses of treatment lasting longer than 10 days, blood counts should therefore be monitored. CEFOTAXIME FOR INJECTION, like other parenteral anti-infective drugs, may be locally irritating to tissues. In most cases, perivascular extravasation of CEFOTAXIME FOR INJECTION responds to changing of the infusion site. In rare instances, extensive perivascular extravasation of CEFOTAXIME

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FOR INJECTION may result in tissue damage and require surgical treatment. To minimize the potential for tissue inflammation, infusion sites should be monitored regularly and changed when appropriate.

Carcinogenesis, Mutagenesis Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. CEFOTAXIME FOR INJECTION was not mutagenic in the mouse micronucleus test or in the Ames test. CEFOTAXIME FOR INJECTION did not impair fertility to rats when administered subcutaneously at doses up to 250 mg/kg/day (0.2 times the maximum recommended human dose based on mg/m 2) or in mice when administered intravenously at doses up to 2000 mg/kg/day (0.7 times the recommended human dose based on mg/m2). Pregnancy Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in pregnant mice given CEFOTAXIME FOR INJECTION intravenously at doses up to 1200 mg/kg/day (0.4 times the recommended human dose based on mg/m2) or in pregnant rats when administered intravenously at doses up to 1200 mg/kg/day (0.8 times the recommended human dose based on mg/m2). No evidence of embryotoxicity or teratogenicity was seen in these studies. There are no well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects Use of the drug in women of child-bearing potential requires that the anticipated benefit be weighed against the possible risks. In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of CEFOTAXIME FOR INJECTION were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.

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Nursing Mothers CEFOTAXIME FOR INJECTION is excreted in human milk in low concentrations. Caution should be exercised when CEFOTAXIME FOR INJECTION is administered to a nursing woman.

Pediatric Use See PRECAUTIONS above regarding perivascular extravasation. The potential for toxic effects in pediatric patients from chemicals that may leach from the plastic in single dose Galaxy® containers (premixed CEFOTAXIME FOR INJECTION) has not been determined. Geriatric Use Of the 1409 subjects in clinical studies of cefotaxime, 632 (45%) were 65 and over, while 258 (18%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. REFERENCES 5) Cockcroft, D.W. and Gault, M.H.: Prediction of Creatinine Clearance from Serum Creatinine, Nephron 16:31-41, 1976.

OVERDOSE:

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The acute toxicity of CEFOTAXIME FOR INJECTION was evaluated in neonatal and adult mice and rats. Significant mortality was seen at parenteral doses in excess of 6000 mg/kg/day in all groups. Common toxic signs in animals that died were a decrease in spontaneous activity, tonic and clonic convulsions, dyspnea, hypothermia, and cyanosis.

Cefotaxime sodium overdosage has occurred in patients. Most cases have shown no overt toxicity. The most frequent reactions were elevations of BUN and creatinine. Patients who receive an acute overdosage should be carefully observed and given supportive treatment.

CONTRAINDICATIONS: Cefotaxime for injection is contraindicated in patients who have shown hypersensitivity to cefotaxime sodium, any component of cefotaxime, or the cephalosporin group of antibiotics. CLINICAL PHARMACOLOGY: Following IM administration of a single 500 mg or 1 g dose of CEFOTAXIME FOR INJECTION to normal volunteers, mean peak serum concentrations of 11.7 and 20.5 mcg/mL respectively were attained within 30 minutes and declined with an elimination half-life of approximately 1 hour. There was a dosedependent increase in serum levels after the IV administration of 500 mg, 1 g, and 2 g of CEFOTAXIME FOR INJECTION (38.9, 101.7, and 214.4 mcg/mL respectively) without alteration in the elimination half-life. There is no evidence of accumulation following repetitive IV infusion of 1 g doses every 6 hours for 14 days as there are no alterations of serum or renal clearance. About 60% of the administered dose was recovered from urine during the first 6 hours following the start of the infusion. Approximately 20-36% of an intravenously administered dose of
14

C-cefotaxime is excreted by the

kidney as unchanged cefotaxime and 15-25% as the desacetyl derivative, the major metabolite. The

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desacetyl metabolite has been shown to contribute to the bactericidal activity. Two other urinary metabolites (M2 and M3) account for about 20-25%. They lack bactericidal activity. A single 50 mg/kg dose of CEFOTAXIME FOR INJECTION was administered as an intravenous infusion over a 10- to 15-minute period to 29 newborn infants grouped according to birth weight and age. The mean half-life of cefotaxime in infants with lower birth weights ( ≤ 1500 grams), regardless of age, was longer (4.6 hours) than the mean half-life (3.4 hours) in infants whose birth weight was greater than 1500 grams. Mean serum clearance was also smaller in the lower birth weight infants. Although the differences in mean half-life values are statistically significant for weight, they are not clinically important. Therefore, dosage should be based solely on age. Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered CEFOTAXIME FOR INJECTION and ethanol. Microbiology The bactericidal activity of cefotaxime sodium results from inhibition of cell wall synthesis. Cefotaxime sodium has in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime sodium has a high degree of stability in the presence of β-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. Cefotaxime sodium has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS section. Aerobes, Gram-positive: Enterococcus spp. Staphylococcus aureus*, including β-lactamase-positive and negative strains Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes (Group A beta-hemolytic streptococci) Streptococcus spp.

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*Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to cefotaxime sodium. Aerobes, Gram-negative: Acinetobacter spp. Citrobacter spp. Enterobacter spp. Escherichia coli Haemophilus influenzae (including ampicillin-resistant strains) Haemophilus parainfluenzae Klebsiella spp. (including Klebsiella pneumoniae) Morganella morganii Neisseria gonorrhoeae (including β-lactamase-positive and negative strains) Neisseria meningitidis Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marcescens NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics, e.g. penicillins, cephalosporins, and aminoglycosides, are susceptible to cefotaxime sodium. Cefotaxime sodium is active against some strains of Pseudomonas aeruginosa. Anaerobes: Bacteroides spp., including some strains of Bacteroides fragilis Clostridium spp. (Note: Most strains of Clostridium difficile are resistant.) Fusobacterium spp. (Including Fusobacterium nucleatum). Peptococcus spp. Peptostreptococcus spp.

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Cefotaxime sodium also demonstrates in vitro activity against the following microorganisms but the clinical significance is unknown. Cefotaxime sodium exhibits in vitro minimal inhibitory concentrations (MICs) of 8 mcg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefotaxime sodium in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:

Aerobes, Gram-negative: Providencia spp. Salmonella spp. (including Salmonella typhi) Shigella spp. Cefotaxime sodium is highly stable in vitro to four of the five major classes of 5-lactamases described by Richmond et al.1, including type IIIa (TEM) which is produced by many gram-negative bacteria. The drug is also stable to β-lactamase (penicillinase) produced by staphylococci. In addition, cefotaxime sodium shows high affinity for penicillin-binding proteins in the cell wall, including PBP: Ib and III. Cefotaxime sodium and aminoglycosides have been shown to be synergistic in vitro against some strains of Pseudomonas aeruginosa but the clinical significance is unknown.

Susceptibility Tests Dilution techniques

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Quantitative methods that are used to determine minimum inhibitory concentrations (MICs) provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method1 (broth or agar) or equivalent with cefotaxime sodium powder. The MIC values obtained should be interpreted according to the following criteria:

When testing organismsa other than Haemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp.
MIC (mcg/mL) ≤8 16-32 ≥ 64 When testing Haemophilus spp.b MIC (mcg/mL) ≤2 When testing Streptococcus d MIC (mcg/mL) ≤ 0.5 1 ≥2 When testing Neisseria gonorrhoeaee Interpretation Susceptible (S) Intermediate (I) Resistant (R) Interpretationc Susceptible (S) Interpretation Susceptible (S) Intermediate (I) Resistant (R)

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MIC (mcg/mL) ≤ 0.5
a.

Interpretationc Susceptible (S)

Staphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime despite apparent in vitro susceptibility. b. Interpretive criteria is applicable only to tests performed by broth microdilution method using Haemophilus Test Media.2 c. The absence of resistant strains precludes defining any interpretations other than susceptible. d. Streptococcus pneumoniae must be tested using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood. e. Interpretive criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.2

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically feasible drugs the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable, other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedure. Standard cefotaxime sodium powder should provide the following MIC values:
Microorganism Escherichia coli ATCC 25922 Staphylococcus aureus ATCC 29213 Pseudomonas aeruginosa ATCC 27853 Haemophilus influenzaea ATCC 49247 MIC (mcg/mL) 0.06-0.25 1-4 4-16 0.12-0.5

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Streptococcus pneumoniaeb ATCC 49619 Neisseria gonorrhoeaec ATCC 49226
a. b.

0.06-0.25 0.015-0.06

Ranges applicable only to tests performed by broth microdilution method using Haemophilus Test Media. 2 Ranges applicable only to tests performed by broth microdilution method using cation-adjusted MuellerHinton broth with 2-5% lysed horse blood.2 c. Ranges applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.2

Diffusion Techniques Quantitative methods that require measurements of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg cefotaxime sodium to test the susceptibility of microorganisms to cefotaxime sodium. Reports from the laboratory providing results of the standard single-disk susceptibility test using a 30 mcg cefotaxime sodium disk should be interpreted according to the following criteria:

When testing organismsa other than Haemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp.
MIC (mcg/mL) ≥ 23 15-22 ≤ 14 When testing Haemophilus spp.b Zone Diameter (mm) ≥ 26 Interpretationc Susceptible (S) Interpretation Susceptible (S) Intermediate (I) Resistant (R)

When testing Streptococcus other than Streptococcus pneumoniae Zone Diameter (mm) Interpretation

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
≥ 28 26-27 ≤ 25 When testing Neisseria gonorrhoeaed Zone Diameter (mm) ≥ 31
a.

Susceptible (S) Intermediate (I) Resistant (R)

Interpretationc Susceptible (S)

Staphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime despite apparent in vitro susceptibility. b. Interpretive criteria is applicable only to tests performed by disk diffusion method using Haemophilus Test Media.3 c. The absence of resistant strains precludes defining any interpretations other than susceptible. d. Interpretive criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement.3

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefotaxime sodium. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg cefotaxime sodium disk should provide the following zone diameters in these laboratory test quality control strains:
Microorganism Escherichia coli ATCC 25922 Staphylococcus aureus ATCC 25923 Pseudomonas aeruginosa ATCC 27853 Haemophilus influenzaea ATCC 49247 Neisseria gonorrhoeaeb ATCC 49226
a. b.

Zone Diameter (mm) 29-35 25-31 18-22 31-39 38-48

Ranges applicable only to tests performed by disk diffusion method using Haemophilus Test Media. 3 Ranges applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement.3

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

Anaerobic Techniques For anaerobic bacteria, the susceptibility to cefotaxime sodium as MICs can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria:
MIC (mcg/mL) ≤ 16 32 ≥ 64 Interpretation Susceptible (S) Intermediate (I) Resistant (R)

Interpretation is identical to that stated above for results using dilution techniques. As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized cefotaxime sodium powder should provide the following MIC values:

Microorganism Bacteroides fragilisa ATCC 25285 Bacteroides thetaiotaomicron ATCC 29741 Eubacterium lantem ATCC 43055
a.

MIC (mcg/mL) 8-32 16-64 64-256

Ranges applicable only to tests performed by agar dilution method.

REFERENCES

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
1) Richmond, M. H. and Sykes R. B.: The β-Lactamases of Gram-Negative Bacteria and their Possible Physiological Role, Advances in Microbial Physiology 9:31-88, 1973. 2) National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December, 1993. 3) National Committee for Clinical Laboratory Standards. Performance Standard for Antimicrobial Disk Susceptibility Tests - Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December, 1993. 4) National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria - Third Edition. Approved Standard NCCLS Document M11-A3, NCCLS, Villanova, PA, December, 1993.

Toxicology of cefotaxime in comparison to other cephalosporins B. I. Doerr*, R. Glomot , H. Kief , M. Kramer and T. Sakaguchi Department of Toxicology of Roussel Uclaf Paris, France * HoechstRoussel Pharmaceuticals Inc. Somerville, NJ., U.S.A Hoechst Japan Ltd. Tokyo, Japan Pharma Research Hoechst AG, Frankfurt/M. West Germany

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Cefotaxime is very well tolerated in animals, the LD 50 in rats and mice following intravenous administration is in the range of 9 to 10 g/kg. This is unusual for a chemotherapeutic agent Even the LD50 of penicillin G in the mouse is in the range of 2 g/kg, which means its toxicity is about 5 times higher compared to that of cefotaxime. Comparative nephrotoxicity studies revealed that cefotaxime is one of the best tolerated cephalosporins. Its kidney tolerance in the rat is ten times better than that of cephaloridine. Subacute and chronic toxicity studies in rats and dogs showed an extremely high tolerance of the compound in both species. Reproduction toxicological studies did not show any adverse effect, either on fertility or on fetal development Cefotaxime is a highly effective antibacterial agent with unusually high tolerance.

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)

DRAFT LABEL FOR CEFOTAXIME FOR INJECTION USP 1 GM

DRAFT LABEL
CEFOTAXIME FOR INJECTION 1 GM

COMPOSITION: Each vial contains:

SCOTT-EDIL PHARMACIA LIMITED 56, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan (H.P.)
Sterile Cefotaxime Sodium USP Eq. to Cefotaxime 1000 mg

Dosage Storage

: As directed by the Physician. : Store in cool dry and dark place below 25 ºC. Do not freeze. SCHEDULE ’H’ DRUG

Warning: to be sold by retail on the prescription of a Registered Medical Practitioner only. • • •
Single Dose vial. Keep out of reach of children Must be further diluted before use. : : : :

Batch No. Manufacturing Date Expiry Date Maximum Retail Price (Inclusive of All Taxes)

Manufactured By. SCOTT-EDIL PHARMACIA LTD. 56, EPIP, Phase-I, Jharmajri Baddi. Distt Solan 173205 Himachal Pradesh India