Ref: FHP/SOP/QAD/001/02

STANDARD OPERATING PROCEDURE

Title: CIP / SIP and Readiness of Product Manufacturing Lines

SOP NO. FHP/SOP/PRI/011 VERSION NO. 03
ISSUE DATE EFFECTIVE DATE

SUPERSEDES 02 REVIEW BEFORE

COPY NO. PAGE NUMBER Page 1 of 10

DISTRIBUTION LIST:

DISTRIBUTION Copy DISTRIBUTION Copy

No. No.
Quality Assurance Master copy - NA NA

Production (Infusion) 01 NA NA

DISPLAY LOCATION LIST:

DISPLAY LOCATION Copy DISPLAY LOCATION. Copy No
No.
Manufacturing Room for BP360 01 Manufacturing Room for 03
3peice
Manufacturing Room for STERIMAX 540 02 Manufacturing Room for 04
STERIMAX 816

1.0 PURPOSE: To describe the standard operating procedure for cleaning in place (CIP)
PREPARED BY REVIEWED BY REVIEWED BY APPROVED BY
Signature
Date

Name Seyi Samuel Isaac Bajulaye Boyejo Omolara Tijani Nmaka

Designation Production Head-Infusion Quality Head Quality &

Chemist Plant Assurance Regulatory
Manager Affairs
 STANDARD OPERATING PROCEDURE
SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 2 of 10
and sterilization in place (SIP) for production lines.
2.0 SCOPE: This procedure is applicable in Manufacturing Area in Block-C and Block F at
Fidson Healthcare Plc.
3.0 RESPONSIBILITY:
3.1 Officer : To perform all the functions as per this SOP.
3.2 Sr. Officer : To implement the SOP
3.3 Department Head : To ensure implementation of the SOP
4.0 GLOSSARY:
4.1 Abbreviations:
CIP Cleaning in Place
SIP Steaming in Place
L Liter
V Valve
BMR Batch Manufacturing Record
LVP Large Volume Parenteral
RM Raw Material
BP Bottle Pack
WFI Water For Injections
Prod. Production
5.0 PRECAUTION/ HSE:
5.1 Ensure the Mixing Tank Jacket is empty before SIP start.
5.2 Always follow manufacturing instruction according to the BMR
5.3 Production Officer must be present at the time of charging of materials and filtration of
product
6.0 PROCEDURE:
6.1 General Conditions:
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SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 3 of 10

6.1.1 Mixing tank jacket inlet and outlet should be closed and bypass valve open
during SIP.
6.1.2 Mixing tank jacket drain valve and air vent are open during SIP
6.1.3 The smooth working of the machine requires filtered solution flow rate at
pressure around 2.0 to 2.5 bar for 100ml & 3.0 to 4.5 bar for 500ml
6.1.4 The filter is to be changed If the pressure goes above 2.5 to 3.0 bar for
100ml and 4.5 to 5.5 bar for 500ml and outlet pressure goes below 1.5 bar
for 100ml & 2.0 bar for 500ml.
6.1. When solution transfer is required by air/N2 pressure, do not exceed
pressure beyond 3.0 bar to avoid any leakage solution of housing.
6.2 Equipment required
6.2.1 Mixing Tanks

6.2.2 Holding tanks

6.2.3 BP 360/ Sterimax 540/Sterimax 816

6.2.5 Filter Housing,

6.2.6 SS316 transfer pump with pipe line
6.3 Material Required:
6.3.1 Water for injections
6.3.2 Weighed ingredients (Raw Material)

6.4 Utility requirement:

6.4.1 Power supply
6.4.2 Pure Steam
6.4.3 0.2µ filter compressed air
6.5 Methodology:
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SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 4 of 10

6.5.1 CIP OF PRODUCT LINE AND MANUFACTURING TANK:

6.5.1.1 Immediately after emptying out of the bulk solution from the Manufacturing
tank, affix a status label on the tank "TANK UNDER CLEANING’’.
6.5.1.2 Open the WFI inlet valve completely (fitted with a spray ball) in the
manufacturing tank, collect approx. 500L for cleaning all the internal surface
and stirrer of the Manufacturing tank.
6.5.1.3 Close the WFI inlet valve and open flush bottom valve
6.5.1.4 Start circulation pump and circulate the WFI into the tank for 5 min by
opening the valves and keeping the other valves close. After 5 min, open
drain valve of the Manufacturing tank to drain the WFI.
6.5.1.5 Again repeat step 6.5.1.2 to 6.5.1.3
6.5.1.6 Open circulation line valves and keep closed the drain line valves and all
sampling points.
6.5.1.7 Start pump and allow passing WFI from the Manufacturing tank to the
product line along with filter housings with filters up to Holding tank drain
point Connect 316L SS flexible Hosepipe to Drain water
6.5.1.8 Repeat steps 6.5.1.5 & 6.5.1.7 twice
6.5.1.9 At the end, collect last rinse sample (100 ml) from sampling point & send to
Quality Control Unit for trace analysis of drug (main ingredient of previous
batch) and or as per WFI quality parameters, i.e. pH, Conductivity,
Oxidizable matter.
6.5.1.10 If the result passes, stop washing. If not, repeat the above steps till
clearance of rinse water by QC is satisfactory. Collect approval sheet from
QC Unit and attached to BMR. Affix a status label on the tank “TANK
READY FOR STERILIZATION".
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SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 5 of 10
6.5.2 SIP OF LVP AND STERIMAX MANUFACTURING TANK ALONG WITH
PRODUCT LINE
6.5.2.1 Drain the cooling water completely from the jacket of the manufacturing
tank.
6.5.2.2 Open both jacket valve and keeping closed other valve.
6.5.2.3 Vent valve must be closed during CIP/ SIP of manufacturing tank.
6.5.2.4 Open the pure steam valve of manufacturing tank slowly. When temperature
reaches121C then maintain temperature 121C and pressure 1.5kg/cm² for
30 min.
6.5.2.5 During sterilization hold time, observe temperature of all product line
temperature sensors on display. Keep track on the visual display, if any
probe shows less than 1210C, restart the sterilization cycle and maintain
temperature of all sensors  121C for minimum 30 minutes.
6.5.2.6 After 30 min, close the pure steam inlet valve.
6.5.2.7 After SIP, slowly open air vent valve of mixing tank and remove steam
through vent filter and allow the pressure to drop to zero.
6.5.2.8 After attaining zero pressure, drain all the WFI remaining in the system.
6.5.2.9 Closed jacket drain valve and open jacket outlet and inlet valve for jacket to
be filled with chilled water in mixing tank and slowly close jacket air vent
valve to remove all air from jacket and after all the air has been removed,
close the jacket air vent valve.
6.5.2.10 Close the bottom flush valves.
6.5.2.11 Check the temperature of all the probes on printed record. Sign and attach
printed record to the BMR.
6.5.2.12 Affix a status label on the tank “LVP MANUFACTURING TANK READY FOR
 STANDARD OPERATING PROCEDURE
SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 6 of 10
BATCH PREPARATION”.
6.5.3 LVP AND STERIMAX BATCH MANUFACTURING:
6.5.3.1 Open WFI user point valve to collect the WFI sample
6.5.3.2 Close WFI user point valve
6.5.3.3 Send the WFI sample collected from the user point to Quality Control for
testing along with the Water for Injection testing slip
6.5.3.4 With approval of WFI sample from QC Unit and receipt of WFI testing slip
6.5.3.5 Open WFI user point valve and close the Manufacturing flush bottom valve.
6.5.3.6 Collect WFI in the Manufacturing tank as per quantity mentioned in the
BMR, start the stirrer.
6.5.3.7 Recheck the tags and gross weight of all the ingredients to be used for batch
manufacturing and ensure the entries are as in the BMR on the weighing
sheet in day material store.
6.5.3.8 Add ingredients in the Mixing tank one by one through the manhole of the
tank as per Standard Procedure of particular product mentioned in the BMR.
6.5.3.9 Continue stirring according to the time specified in respective BMR
6.5.3.10 Stop the stirrer.
6.5.3.11 Make up the volume to the required batch size (Load cell value) with WFI
and close the WFI user point valve. Open the flush bottom valve, All drain
and stream trap valve close.
6.5.3.12 Start the stirring.
6.5.3.13 Start pump for circulation according to the time specified in BMR.
6.5.3.14 Stop stirrer and pump.
6.5.3.15 Withdraw bulk solution sample from sampling point in a SS container and
send it for testing in Q.C. Lab. along with the Bulk Intimation Slip.
6.5.3.16 After getting clearance of bulk analysis from Quality Control (Satisfactory
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SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 7 of 10
Result) on the intimation slip, pass the intimation slip and instruction to the
Production Officer.
6.5.4 CIP OF HOLDING TANK AND BP360 MACHINE/ STERIMAX:

6.5.4.1 After completion of BP360 machine last filling cycle, cross check buffer
tanks solution level zero on BP360 machine display and holding tank
manually.
6.5.4.2 Stop the BP360 machine and solution transfer pump of holding tank.
Remove scrap and all rejection bottles from BP360 machine room.
6.5.4.3 Fix the mandrel hoods filling units of BP360 machine.
6.5.4.4 Collect 500L WFI in holding tank by spray ball and close WFI inlet valve.
6.5.4.5 Open product line valves and keep sampling points closed.
6.5.4.6 Start circulation pump and circulate the WFI in the tank for 5 min.
After 5 min open drain valve for drain solution.
6.5.4.7 Again collect 500L WFI in holding tank by spray ball and close WFI inlet
valve.
6.5.4.8 Partially open by pass valve and keep drain valve closed.
6.5.4.9 Start circulation pump for cleaning cycle of BP360 machine/sterimax
machines
6.5.4.10 Repeat the step 6.5.4.7 to 6.5.4.9.
6.5.4.11 At the end, collect last rinse sample (250 ml) from sampling point & send to
QC Lab for trace analysis of drug (main ingredient of previous batch) and/ or
as per WFI quality parameters, i.e. pH, Conductivity, Oxidizable matter.
6.5.4.11 If the result passes, collect CIP approval sheet from QC and attached in
BMR. Affix a status label on the tank “TANK READY FOR STERILIZATION”
6.5.5 SIP HOLDING TANK AND BP360 MACHINE/STERIMAX MACHINES :
6.5.5.1 Open the pure steam valve of holding tank and BP360 machine, when the
 STANDARD OPERATING PROCEDURE
SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 8 of 10
temperature reaches 121C then maintain temperature 121C and pressure
2.0 kg/cm2 for 30 min.
6.5.5.2 During sterilization hold time observe temperature of temperature sensors
on holding and BP360machine display. Holding tank steam trap valve
should be open.
6.5.5.3 Keep track on the visual display. If any probe shows less than 121 0C, restart
the sterilization cycle and maintain temperature of all sensors  121C for
minimum 30 minutes
6.5.5.4 After 30 minutes, close the pure steam inlet valve.
6.5.5.5 Slowly open air vent valve of Holding tank and remove steam through vent
filter and allow the pressure to drop to zero.
6.5.5.6 After attaining zero pressure, drain all the WFI remaining in the system.
6.5.5.6 After attaining zero pressure by air vent valve, close the drain valve.
6.5.5.7 Check the temperatures of all probes on printed record of holding tank and
BP360 machine. Sign and attach printed record in BMR.
6.5.5.8 Affix a status label on the tank and BP360 machine/sterimax “HOLDING
TANK READY FOR FILTRATION” and BP360 MACHINE/ sterimax READY
FOR FILLING”
6.5.6 FILTRATION BULK SOLUTION FROM LVP MIXING TANK TO HOLDING
TANK to BP360/STERIMAX
6.5.6.1 Open product line valves and keep drain valve closed.
6.5.6.2 Start the filtration of the bulk solution mixing tank to holding tank
6.5.6.3 After complete transfer the solution, close the bottom flush valve of
manufacturing tank.
6.5.7 FILTRATION SOLUTION FROM HOLDING TANK TO BP360 / STERIMAX:
6.5.7.1 Open product line valves ( partially open for circulation valve)
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SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 9 of 10

6.5.7.2 Start the solution transfer pump from holding tank to Filling machine.
6.14.11 Frequency- As per Product

7.0 REFERENCE:
7.1 In-House & GMP Standards

8.0 Attachments:
8.1 Attachments -1 Sterilization Observation Record of Mixing Tank/Holding
Tank
8.2 Attachments -2 Bottle pack machine 360 Sterilization Observation Record
8.3 Attachments -3 Bottle pack machine Sterimax Sterilization Observation
Record

9.0 Revision History:

Sr. No. Version Effective Date Reason for Change.

No.
01 00 09/10/2017 Initial version
 STANDARD OPERATING PROCEDURE
SOP No. FHP/SOP/PRI/011 VERSION NO. 03 Page 10 of 10
02 01 26/01/2018 SOP was reviewed to be in line with the new
SOP for guidance, preparation and
management of SOPs.
03 02 06/02/2020 SOP was reviewed.
04 03 Periodic review of SOP