WNSFEILD Pharmaceuticals

Title: Standard Operating Procedure for WFI Plant

 WNSFEILD Pharmaceuticals
Title: Standard Operating Procedure for WFI Plant
 WNSFEILD Pharmaceuticals
Title: Method of Manufacturing

DESCRIPTION OF MANUFACTURING METHOD

Mixing:
1. Take 50 Liters SS Container.
2. Purge the tank with filtered Sterile Nitrogen.
3. Collect 5L Water for Injection.
4. Dissolve Ethyleneiaminetetraacetic Acid Disodium Salt and mix till the material
completely dissolved.
5. In a separate 5 Liters container, prepare 1N Sodium hydroxide Solution by
dissolving 0.14Kg Sodium Hydroxide in 3.5 Liters purified water.
6. Add 1N Sodium Hydroxide solution in step 4 and mix for 5 minutes.
7. Make up the volume to 20 Liters with Purified Water. Cool the solution to 4-
8°C.
8. Add Pantoprazole Sodium Sesquhydrate and mix till the material dissolved and
the solution becomes clear.
9. Send the solution to Quality Control for pH. (9.0 – 10.5).
10. Filter this solution through 0.2µm membrane filter in Class 100 sterile Area.

Sampling & Testing:

Send sample to Quality Control for complete Physical, Chemical & Microbiological
Testing.

Filling & Sealing:

11. After the approval of quality control, purge the Vials with Pre-Sterilized
Nitrogen Gas.
12. Fill the Vials at the volume range given by the quality control on controlled
humidity and temperature conditions under aseptic class 100 conditions.
13. Immediately semi stopper the Vials

Lyophilization:
14. Put the semi stopper vials in Lyophilizer (Freeze Drier).
15. Cool the vial to -45°C.
16. Raised the temperature to -20 to -5°C under vacuum (0.1 to 0.5mbar) for freeze
drying for 45 to 1 hr.
17. After drying raised the temperature to 30°C under vacuum adjusted to 0.01mbar
for 3 hrs.
18. Check the moisture from time to time till <0.5% moisture content achieved.

Sampling & Testing:

 Send sample to Quality Control for complete Physical, Chemical & Microbiological
Testing.

Sealing:
19. Press the push to completely stopper button on Lyophilizer panel to completely
stopper the semi stopper vials.
20. Remove the stoppered vials from Lyophilizer.
21. Transfer to sealing room.
22. Place Aluminum Seal on vial and seal all vials.
23. Store in in-process quarantine with product Identification card pasted on each of
the box.
24. Send “Request for analysis” to QC for complete Physical, Chemical &
Microbiological testing of filled/sealed autoclaved Vials.
25. Check the filled / sealed Vials individually on optical checking lamp.
26. After getting “Analytical Report” of filled / sealed Vials transfer the batch to
packing section when required.

Note: Use Vials which were purged and inerted with nitrogen for 30 seconds.

Packing:
After the approval of quality control, start packing as per SOP under controlled
humidity and temperature conditions.

Note:
During filling, Lyophilization, labeling and packing, follow area protocols as per
below
attachment.
 STANDARD OPERATING PROCEDURE
MANUFACTURING OF PARENTERAL PREPARATIONS (INJECTIONS, LARGE
VOLUME PARENTERALS, SMALL VOLUME PARENTERALS)

Parenterals preparations are in two forms:

 Liquid Parenteral Preparations

 Dry Powder Parenteral Preparation

Both type of preparation follow different type of procedure for preparing Parenterals.

Types of Parenteral Preparations

 Single Dose Parenterals

 Multiple Dose Parenterals

Section Required:
For Dry Injection:

 Sterile Raw Material Section

 Washing Section
 Terminal Sterilization Section
 Autoclave Sterilization Section
 Filling Section
 Capping and Sealing Section
 Labeling and Packaging Section 

For Liquid Injections:

 Warehouse
 Washing Section
 General Production Section
 Weighing, mixing and Transfer Section
 Sterilization Section
 Filling Section & Autoclave of filled Vials/vials
 Capping and Sealing Section
 Labeling and Packaging Section

Ensure sterile pyrogen free atmosphere before preparation of Parenterals.

 Procedure Involved In Parenteral Manufacturing:

For Dry Injections:

 Dispensing of Raw Material, API and Packaging Material.

 Raw material and API ware-house should maintain aseptic area.
 Washing, drying and Sterilization of Vials, Rubber stoppers, cap and sealing material.
 Vials are sterilized and pyrogen free by means of Terminal at temperature more than
300 degree.
 Rubber cap and heat sensitive material to be sterilized through Autoclave.
 If raw material is not sterilized, material to be sterilized through Autoclave.
 After Sterilization, Vials are filling with sterilized raw material. Continuous inspection
and documentation is essential.
 After filling vials and release from Quality Control at each stage, go for capping and
sealing.
 Then labeling and Packaging is conducted.

For Liquid Parenteral Products:

 Dispensing of Raw, API and Packaging material.

 Raw material and API ware-house should maintain aseptic area.
 Washing, drying and Sterilization of Vials, Rubber stoppers, cap and sealing material.
 Vials to be sterilized and pyrogen free by means of Terminal at temperature more than
300 degree.
 Ensure that Rubber cap and heat sensitive material is sterilized through Autoclave.
 Preparation of Vehicle or solution.
 Mix API and other raw material in above prepared preparation.
 Filtration of whole solution for sterilization.
 Filling.
 Sealing.
 Packaging.
 Storage.

For Lyophilization Products:

 Dissolving the drug and excipients in a suitable solvent, generally water for injection
(WFI).
 Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
 Filling into individual sterile containers and partially stoppering the containers under
aseptic conditions.
 Transporting the partially stoppered containers to the lyophilizer and loading into the
chamber under aseptic conditions.
 Freezing the solution by placing the partially stoppered containers on cooled shelves in
a freeze-drying chamber or pre-freezing in another chamber.
 Applying a vacuum to the chamber and heating the shelves in order to evaporate the
water from the frozen state.
 Complete stoppering of the vials usually by hydraulic or screw rod stoppering
mechanisms installed in the lyophilizers.
Equipments and Machinery:

 Storage equipments for Vials, Vials and Closures

 Washing and Drying Equipments
 Dust proof storage equipment including cold storage and refrigerator
 Water Still
 Mixing and Preparation Containers and Tanks
 Mixing Equipments
 Filtration Equipments
 Hot air sterilizer
 Benches and tables
 Bacteriological Filters
 Laminar Flow work station

Essential Steps:

 Products to be released only after complete filling and testing. 

 Result of the tests relating to sterility, pyrogens, and Bacterial endotoxins to be
maintained in the analytical records. 
 Validation details and simulation trail records to be maintained separately,
 Maintain records of environmental monitoring like temperature, humidity,
microbiological data, etc. Maintain records of periodic servicing of HEPA filters,
sterilizers and other periodic maintenance of facilities and equipment carried out. 
 Separate facilities to be provided for filling-cum-sealing of Small Volume Parenterals in
glass containers and/or plastic containers. 

Specific Requirements in Brief:

 General Specifications: General Sterile products, being very critical and sensitive in

nature, a very high degree of precautions, prevention and preparations are needed.
Dampness, dirt and darkness to be avoided to ensure aseptic conditions in all areas. There
to be strict compliance in the prescribed standards especially in the matter of supply of
water, air, active materials and in the maintenance of hygienic environment.

2. Building and Civil Works:

 Building to be constructed to avoid any cracks.

 Location should avoid contamination and leakage.
 All sections and departments to be clearly separated from each other.
 Walls, floors and ceiling to be impervious, non-shedding, non-flaking and non-cracking.
Flooring to be unbroken and provided with a cove both at the junction between the wall
and the floor as well as the wall and ceiling. Walls to be flat, and ledges and recesses to be
avoided. Wherever other surfaces join the wall (e,g, sterilizers, electric sockets, gas points
etc.) these shall flush the walls. Walls to be provided with a cove at the joint between the
ceiling and floor.
 Change rooms with entrance shall have air locks and separate exit space from the
aseptic area.
 Material transfer between aseptic areas and outside to be through suitable airlocks or
pass-boxes. Doors of such airlocks and pass-boxes shall have suitable interlocking
arrangements.

3. Air Handling System (Central Air Conditioning): 

Air Handling Units for sterile product manufacturing areas to be different from those for
other areas. Critical areas, such as the aseptic filling area, sterilized components unloading
area and change room conforming to Grades B, C and D respectively shall have separate air
handling units. The filter configuration in the air handling system to be suitably designed to
achieve the

Grade of air which to be achieved by providing laminar air flow work stations with suitable
HEPA filters or isolator technology.

4. Environmental Monitoring: 

All environmental parameters listed to be verified and established at the time of installation
and thereafter monitored at periodic intervals.

5. Garments: 

This section covers garments required for use by personnel working only in aseptic area.
Outdoor clothing shall not be brought into the sterile areas. Only clean, sterilized and
protective garments to be used at each work session where aseptic filtration and filling
operations are undertaken and at each work shift for products intended to be sterilized, post-
filling. The mask and gloves to be changed at every work session in both instances.

6. Sanitation: 

There to be written procedures for the sanitation of sterile processing facilities. Employees
carrying out sanitation of aseptic areas to be trained specifically for this purpose.

7. Equipments: 

The special equipment required for manufacturing sterile products includes component
washing machines, steam sterilizers, dry heat sterilizers, membrane filter assemblies,
manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing
and labeling machines, vacuum testing chambers, inspection machines, lyophilisers, pressure
vessels etc. suitable and fully integrated washing sterilizing filling lines may be provided,
depending upon the type and volume of activity.
8. Water System: 

Potable water meeting microbiological specification of not more than 500 cfu/ml and
indicating absence of individual pathogenic microorganisms, Escherichia coli, Salmonella,
Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample to be used for the
preparation of purified water

9. Manufacturing Process: 

Manufacturing of sterile products shall required defined conditions and environment.

11. Product Container and Closures: 

All containers and closures intended for use shall comply with the pharmacopoeial and other
specified requirements.

12. Documentation: 

The manufacturing records must indicate the following details:-

 Serial number of the Batch Manufacturing Record. 

 Name of the product 
 Batch/Lot number 
 Batch/Lot size. 
 Date of commencement of manufacture and date of completion of manufacture. 
 Date of manufacture and assigned date of expiry. 
 Date of each step in manufacturing. 
 Names of all ingredients with the grade given by the quality control department. 
 Quality of all ingredients. 
 Quality Control reference numbers for all ingredients. 
 Time and duration of blending, mixing, etc. whenever applicable. 
 PH of solution whenever applicable. 
 Filter integrity testing records 
 Temperature and humidity records whenever applicable 
 Records of plate-counts whenever applicable. 
 Results of pyrogen and/or bacterial endotoxin & toxicity. 
 Results of weight or volume of drug filled in containers. 
 Bulk sterility in case of aseptically filled products. 
 Leak test records. 
 Inspection records. 
 Sterilization records including autoclave leakage test records, load details, date,
duration, temperature, pressure, etc. 
 Container washing records. 
 Total number of containers filled. 
 Total numbers of containers rejected at each stage 
 Theoretical yield, permissible yield, actual yield and variation thereof. 
 Clarification for variation in yield beyond permissible yield. 
 Reference numbers of relevant analytical reports. 
 Details of reprocessing, if any. 
 Name of all operators carrying out different activities. 
 Environmental monitoring records. 
 Specimens of printed packaging materials. 
 Records of destruction of rejected containers printed packaging and testing.
 Signature of competent technical staff responsible for manufacture and testing.
FLOW CHART OF METHOD OF MANUFACTURING
 FINISHED PRODUCT
SPECIFICATION
METHOD OF ANALYSIS
 ANNEXURE – 10
Full description of the specifications and analytical methods necessary to assure the
identity, strength, quality, purity and homogenicity throughout the shelf life of the drug
product including following.
1. Validation of Analytical Method
2. Stability Reports

FINISHED PRODUCT SPECIFICATION

PANTOPRAZOLE 40MG INJECTION

COMPOSITION:
Each Vial Contains:
Pantoprazole (as Sodium Sesquhydrate – USP) ……….. ..... 40mg
(Product Complies In-House Specs)

No Parameter Specification

1 Physical Description White to Off White Color Lyophilized

Sterile Powder free from foreign particles
liquid.
2 pH 9.0 – 10.5

3 Particulate Matters Meets USP Specs

4 Sterility Must be sterile

5 Assay 90 – 110%

METHOD OF ANALYSIS
 PANTOPRAZOLE 40MG INJECTION

Standard Solution:
Weigh accurately Working Standard equivalent to 100mg Pantoprazole into 100mL
volumetric flask. Add 15mL Water and shake well till all material dissolved. Sonicate for 5
minutes. Dilute with DI Water to prepare solution of 1mg/mL.
Transfer 5mL of above solution in 10mL volumetric flask and diluted with 5M HCl solution
to obtain solution of 0.5mg/mL.

Sample Solution:
Reconstitute the vial as per instruction and transfer amount of Sample and dilute with DI
Water to prepare solution of 1mg/mL.
Transfer 5mL of above solution in 10mL volumetric flask and diluted with 5M HCl solution
to obtain solution of 0.5mg/mL.

Chromatographic Condition:
Mobile Phase: 30% acetonitrile and 0.05 mol/L phosphate dibasic adjusted to pH 7.1
with phosphoric acid.
Column: 15 cm × 4.6 mm reverse-phase 3 µm column
Flow Rate: 1.0 mL/min.
Injection Volume: 2 µL each)
Wave Length: 280 nm.
Temperature: Ambient

Procedure:
Inject sample and standard in to HPLC and record the chromatogram.\

Calculation:

%age = Peak Area of Sample x 100

Peak Area of Standard

Limit:
NLT 90.0% and NMT 110.0% of the labeled amount of Pantoprazole.