batch manufacturing record … manufacturing record controlled document ... material reconciliation...

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BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT

Department Name Filling Building # __ Page No of 27 Document No MBR-xxxxxx Title Blending, Filling, Lyophilization and

Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx

Officer Incharge: Date: (Checked by)

Issued By (Q.A ) : Date : Production Manager : Date :

INDEX No Description Page No

Summary of Process Summary of Activities Batch Formulation Thawing of Bulk Antigen Lyophilizer Trays Processing Rubber Stopper Processing Processing Product contact Material for Pooling & Filling Vial Processing Room Pressure Recording Preparation of Lyophilizer Verification of Bulk Antigen Container Weights. Pooling & Clarification of Thawed Bulk and Preparation of Final Bulk Integrity Testing of Product Filter Filling Integrity Test of Vent Filters Loading of Lyophilizer Lyophilization Aluminum cap processing Sealing of vials Material Reconciliation record Bulk reconciliation record BMR Certification






The entire activity has the following major steps: Activity Day No 1 2 3 4 5 1. Thawing of Bulk Antigen 2. Cleaning and Sterilization of Lyophilizer Trays 3. Sterilization and Drying of Rubber Stoppers

4. Cleaning, Preparation and Sterilization of Material Required for Filling and Pooling

5. Cleaning and Sterilization / Disinfection of Lyophilizer 6. Washing and Sterilization of Vials 7. Pooling and Clarification to Prepare ‘Final Bulk’ 8. Filling of Vaccine into Vials

9. Loading of Filled Vials in the Lyophilizer and Lyophilization

10. Sterilization and Drying of Aluminium Caps 11. Sealing

Day 1 Day 2 Day 3 Day 4 Day 5 Day before filling Day of filling Day after filling 2nd day after filling 3rd day after filling Sealed vials with lyophilized vaccine are handed over to Screening Dept. for visual inspection. Pages 5 and 6 to be issued to Bulk section who will fill the details and send it back. Pages 25 To 27 to be issued to Lyophilization section who will fill the details and send it back.






SUMMARY OF ACTIVITIES Target Lyophilizer Number XXXX Lyophilizer Batch Capacity VialsVolume per vial mL (23) Batch Volume as Dispensed by Bulk Mfg Dept L (24)Date of Filling dd/mm/yyyyFill volume per vial (xx x xx) (Overfill mid point at +X %) mL (25) Batch Volume as Rechecked by Filling Dept LTheoretical Batch Size Vials (28) Approx Filling Yield. [Quantity loaded in Lyophilizer] Vials (22) Approx Sealing Yield. [Quantity transferred to screening] Vials (19) Note: Acceptable variation between 24 and 26 which is caused by removal of outer packaging / double bagging should not be more than ± X % Activity: BATCH FORMULATION Ref SOP No: ______ Select the bulks for the batch on the basis of bulk Ag titre, volume, filling volume per vial, and batch size. Filling personnel* to cross check in terms of Weights on receipt.

Component Bulk Ag No. Antigen Titre Vol. ‘L’ *Gr Wt ‘kg’

Tare Wt ‘kg’

Limit XX L ± X% Actual Vol. L kg kgSet Ag Titre / vial Formulation: Dt: ___ Weighing: Dt: _____

Product X Volume /

vial Done by Checked by Done by Checked by X mL

Remarks:-






Activity : THAWING OF BULKS Ref SOP NO: ________________ The Bulks should be removed for thawing not more than xx Hours prior to estimated time of start of filling.

THAWING DETAILS Particulars Product #12 Diluent

Removed for thawing on (date) Location of cold room Bldg No

CR No Bldg No CR No

Removed for thawing at h h Incubator set temp (Range xx to xx °C)

ºC ºC

Thawing completed on (date) Thawing completed at h h

No Handling of Bulk Antigen Containers Done By Date Name Initials 1 2 3 4 Bulk Antigen Containers Received By: Remarks if any:






Activity : LYOPHILIZER TRAY PROCESSING Ref SOP No : ______________ 1. Clean the trays to be used for collecting filled vials using a clean lint free mop wetted with WFI/xx %

Isopropyl alcohol. 2. The trays can be processed in either of two ways

A) Load the cleaned trays on the dry heat sterilizer (DHS) trolley, as per validated max loading pattern in DHS No xxxx and sterilize at xxx°C, xxx minutes B) Load the trays in Autoclave and sterilize at xxx °C ± x °C for XX minutes

No of Trays Pattern No Pattern No

3. If option A above is selected, run the cycle to hold the trays at xxx°C for xxx minutes. Normal variation –x ° to + x °C

4. Write Product, B.No., Charge No & date on the sterilizer thermograph/printout (for Option A only) sign it and attach it to this BMR

No Description of Activity Done By Checked

By Date

1 No of trays cleaned _______ Quantity for batches: ____ 2 Loaded ______ cleaned trays onto the trolley . Loaded in Sterilizer Load pattern no Charge No # xxxxxx xxxx xx # xxxxxx xxxx xx

Checked Cycle parameters A) xxx °C, xxx minutes B) xxx °C ± x°C for xx minutes

3 Sterilization temperature xxx °C achieved at (applicable for option A above)

h

4 Sterilization temperature xxx°C maintained till (applicable for option A above)

h

Remarks:-






Activity : RUBBER STOPPERS PROCESSING Ref SOP No : ___________ 1. Verify that QC approved stoppers of correct type have been taken for de-cartoning. 2. For RFS stoppers, after de cartoning directly move to sterilization. 3. Load stoppers as per validated loading pattern given below

RFS Max No of stoppers / pouches xxxx Pattern No for Autoclave X xxxx Pattern No for Autoclave Y xxxx

4. The stoppers can be processed in either of the two ways: A) Sterilization in Autoclave X (xxx to xxx °C) and drying in dry heat sterilizer (DHS) No ___ B) Sterilization and drying in Autoclave Y.

In both the cases, carry out sterilization at 121°C for xxx minutes, Write Product, B.No., Charge No and date on the sterilizer printout / thermograph sign it and attach it to this BMR

5. If option A above is selected, then transfer the sterilized rubber stoppers from the autoclave to the DHS from clean room side for drying. Start drying cycle: xxx°C for xxx mins. Normal variation - x °C to + x °C/ ± x min. If option B above is selected then Sterilize stoppers at xxx °C ± x °C for xxx minutes followed by a drying cycle for xxx mins in the autoclave. In case of greater variation in temperature or time, the deciding factor will be the moisture content. Write Product, B.No., Charge No and date on the sterilizer thermograph /printout (for Option A only) sign it and attach it to this BMR.

6. Draw one sample for Moisture content analysis (Limit NMT xxx mg/stopper). In case stoppers of 2 batches are sterilized in 1 load, draw only 1 sample, record both batch nos on TRF, attach copies to both BMRs

A) Stopper input: xx mm, Lyo Grey Butyl Rubber 1) Unprocessed b/f: B.No________

2) Processed b/f: B.No__________

3) Fresh quantity issued

4) Fresh used from issue

5) Option for Process

A =1+2+4 B =1+4

Actually Loaded for Sterilization 9) No of stoppers Pouches

Unprocessed

Done by Checked by Date

Remarks:






Activity : RUBBER STOPPERS PROCESSING, cont'd Ref SOP No : ___________ 7. Load pouches on the Autoclave trolley as per validated loading pattern.

Autoclave No. / Equipment No.

Charge No. Load Pattern

No.

Program No.

Quantity for 1 / 2 batches

Done by

Checked by

Date

######## XX XX X ######### XX XX X DHS No / Equip No #################### Charge

No.: X

Drying temperature xxx °C for xxx minutes for drying in DHS Done by Checked by

Date

Achieved at : h Maintained till: h Sample for Moisture Content (11) Nos. NOTE: Filling activity should not be started before the result of moisture content estimation is received from Q.C. Remarks:






Activity : PROCESSING PRODUCT CONTACT MATERIAL FOR POOLING AND FILLING Ref SOP No : _______________________ 1. Use filters based on the following table for B.Size for Filtration> xx L 2. Carry out pre-filtration integrity test using the following data

INTEGRITY TESTING OF xx µm FILTER

Bubble Point Diffusion Make Name Part No Quantity/

batch A B Tst pr. Rate xx 1 xx 2

XXXX

xx 3 yy 1 YYYY yy 2

No bubbles at ‘A’, Bubbles should be seen <‘B’, Units: BP, Diffusion Pr: Bar, rate: mL/min A) Pre-Sterilization Integrity Testing Application Stage Method Equipment Equipment No Test Type Step A Presteriliz’n Manual

Auto XXXX XXXX

Bubble Pt Diffusion

Filter Details Mfg/ Brand Part No Pore Size Wetting Liq. Test Parameter XXXX XXXX

xx um WFI

Filter Lot No Filter S.No Observation Result Done by

Check by

Date

Bubbles seen at _____bar

Printout attached

Remarks:-






Activity : PROCESSING PRODUCT CONTACT MATERIAL FOR POOLING AND FILLING Ref SOP No : _______________________ 1. Inactivation: Inactivate the Material used for Pooling and Filling in the Autoclave by heating it to

xxx°C for x minutes. Record in the autoclave Log Book. (Variation xx°C to xx°C) 2. Preparation: Unload the inactivated material from the Autoclave on the Washing room side; Wash

inactivated material by passing Cooled WFI. Draw a sample from the tanks & check conductivity. Draw samples from Tanks, Silicon tube to header, Header, Syringes, needles & screen for particulates. In case the previous product is Media fill, draw additional samples submit to QC with Product Changeover TRF. On clearance wrap in sterilization pouches.

3. In case the vent filters on BV2 are new, carry out WIT and attach the results on opposite page. In case they continue from the previous day, the Post use integrity test of the previous batch will be treated as the pre-use integrity test of this batch.

4. Check the plan for the next day & select the loading pattern. Load the wrapped material on the autoclave trolley as per validated loading pattern. Attach a list of material sterilized, to this BMR. Write Product, B.No., Charge No and date on the sterilizer printout / thermograph (for Autoclave XX only) sign it and attach it to this BMR.

Conductivity check on product tank rinse sample NMT 1 mS/cm

Check xx mS/cm

BV1 BV2 Product C/O Done by Checked by

Date

_____ mS/cm ____ mS/cm ____ mS/cm NA TRF attached

Visual Inspection of Product Contact material rinse sample Item BV 1 BV 2 Silicon tube Header Syringe Needle Fibres Particles Sampled by: Screened by: Date:

STERILIZATION OF MATERIAL FOR POOLING AND FILLING

1 Autoclave No / Equip No ######### / ######## Done by Checked by Date 2 Load Pattern number XXX XXX 3 Charge No XX XX 4 Program No XXXXX XXXXX

Remarks:-






Activity : VIAL PROCESSING – WASHING Ref SOP No : _________ 1. Verify that QC approved vials of correct type have been taken for de-cartoning. 2. De-carton the Vials, transfer them into clean SS trays and pass them to the washing area. 3. Ensure WFI cooling assembly is sanitized before commencing Washing of xst batch. Ensure pressure

of Fresh and Recycled WFI and compressed air, conductivity of Fresh WFI are within limits. Ensure area is free of previous product vials

4. Perform Test for Adequacy using X washed vials. 5. After operation is completed, drain the WFI assembly and clean the machine A) Vial input: x mL, xx mm X xx mm height, (Amber, tubular, USP type-1) 1) Unprocessed b/f: B.No________

2) Processed b/f: B.No________

3) Fresh qty issued

4) Fresh used from issue

Done By

Checked by

Date

5) Option for Process

A=1+2+4 B=1+4

6) Taken for washing: -

B Pre-washing and Washing operation checks: Done By

Checked by

Date

WFI cooling ass’ly sanitized

Line Clearance Checked

WFI Conductivity (NMT X mS/cm)

WFI Temp (xx to xx°C)

Yes / No Yes / No mS/cm °C

Washing Media Outlet Pressure (Range ‘Bar’)

Fresh WFI Recycled WFI

Comp. Air

Set –XXXXXXX ##########

xx - xx xx - xx xx-xx

Observed (Bar)

Washing Started at : h Completed at: h Adequacy Sampled by Results Time Pass / Fail h

C Vial Output Remarks (7) Sampled (8) Rejected For Sterilization

6 - (7+ 8) = 9 Unprocessed

18 = 3 - 4






Activity : VIAL PROCESSING – STERILIZATION Ref SOP No : _________ 1. At the start of washing activity, ensure there is enough paper in the printer and a fresh circular chart is

placed in the recorder. Ensure that the set points of the Heater Banks of the Tunnel Sterilizer are as per the following chart.

Charge no:

SET TEMPERATURES OF HEATER BANKS

Heater Bank No S1 S2 S3 S4 S5 S6 S7 S8 Done by Checked

by Date

Temperature ºC 2. At the start of washing for the day, after the vials have reached the exit gate of the sterilization

zone, the conveyor of the Tunnel shall automatically stop for ten minutes. This event shall be printed by the controller.

3. The conveyor speed at the start of the washing i.e. till the vials reach the infeed of the filling machine should be xx Hz. Thereafter it will automatically switch to xx Hz. This event shall be printed by the controller.

No Description of Activity Time Done By Checked by Date 1 Tunnel sterilizer started at h

2 Minimum set temperature (xxx oC) achieved at h

3 xx Minute hold ____ h to ____ h*

4 Tunnel Set to Night operation (Process End) h

4. Attach the printout and circular chart to the BMR. Operators – Washing and Sterilization:-

Remarks:- * xst / xnd batch of the day.






Activity : VIAL PROCESSING – STERILIZATION, continued Ref SOP No : _________ 1. Check the pressures of the three zones of the tunnel, at least once, preferably at start of washing. If

the pressures are not within the range given below, immediately stop washing activity and inform the Officer in charge

2. At the end of washing, perform sanitization of the bulk WFI cooling assembly 3. Write the Product, B.No., Charge no and date on the sterilizer printout / graph ,sign it and attach it

with this page of BMR.

CHART SHOWING THE PRESSURES OF THE VARIOUS ZONES OF THE TUNNEL #XXX Drying Zone (P1) mm wg

Sterilization Zone (P2)

mm wg

Cooling Zone (P3)

mm wg

Done by Checked by

Time Pressure Range

xx --xx xx --xx xx --xx Observed Observed

Remarks:- Activity : ROOM PRESSURE RECORDING Ref SOP No. ____________ 1. Record ‘Room differential pressure’ before entering the clean area for pooling and filling.

No Room & range

Observed value (Pa)

Done by Checked by

Date Time

1. PAL 1 (xx-xx) 2. PAL 2 (xx-xx) 3. PAL 3 (xx-xx) 4. Filling (xx-xx) 5. Tunnel Room (xx-xx) 6. Sealing (xx-xx) 7. Pooling (xx-xx)

Remarks:






Activity: PREPARATION OF LYOPHILIZER Ref SOP No.: ________ 1. After Unloading, Carry out cleaning of Lyophilizer and record in the BMR 2. Carry out Sterilization / Disinfection as below:

A week1 denotes 6 working days with the day the Lyophilizer gets Steam Sterilized/Steamed being declared the 1st day of the week and the batch filled after steam sterilization/ steaming the 1st batch. If the third batch is to be loaded later than the 6th day of the week, it is treated as the first batch of the next week. The gap between Sterilization/disinfection step and loading should not be more than xx hours.

For Lyophilizer No. A, B, C Batch Before Loading /week1 1st batch of week 2nd batch of week 3rd batch of week Lyo A Lyo B, C Lyo A, B, C Lyo A, B, C 3 Steam Exposure xxx

mins Steam Exposure xxx°C, xx mins

Disinfection with XXX


2 Steam Exposure xxx mins

Steam Exposure xxx°C, xx mins


1 Steam Exposure xxx mins

Steam Exposure xxx°C, xx mins

In case there is a change of product, with the virus of the current product not in the present product, the lyophilizer should be sterilized. Display boards: ‘Cleaned, ready for Steam Exposure’, and ‘Disinfected with XXX ready for evacuation’ after Steam Sterilization, Steaming and treatment with XXX respectively. No Description of Activity Done

By Checked by

Date

1 Lyophilizer No: _____ - Cleaning done after unloading of Product

______________ /Batch.No: ____________________

Strike out what is not used 2 □ Steam Exposure xxx mins

□ Steam Exposure xxx°C, xx mins

□ XX disinfection

Remarks:-






Activity : VERIFICATION OF BULK ANTIGEN CONTAINER WEIGHTS Ref SOP No.: _____ 1. Unwrap the outer packing of the thawed bulk antigen containers 2. Check the Bulk antigen container numbers and record their gross Weights in the Batch Formulation

Sheet. 3. Carry out surface disinfection and transfer them to clean room, through hatch.

Net Weight of Formulation

(Gross – Tare on Page 5)

Weight in g /mL (B) (From Page 20) (Same as kg /L)

Net Volume of formulation

(Net Wt / kg/L)

Done by Checked by

Date

___________ kg ___________ kg/L (26) _______ L Remarks:- Activity : POOLING & CLARIFICATION OF THAWED BULK AND PREPARATION OF FINAL BULK Ref SOP No : ________ 1. The contents of the Bulk antigen containers are pooled in a sterilized, SS blending vessel, with the jacket

at a temperature NMT XX°C. Start the magnetic stirrer (xxx to xxx rpm) after the level of bulk antigen inside the tank has gone above the impeller. If the temperature of the pool exceeds xxoC, immediately shut off the heating immersion circulator and the magnetic stirrer.

2. The pool of bulk antigens is clarified using a sterilized xx µm filter capsule/s. The outlet of the xx µm filter/s is connected to a 2nd sterilized SS blending vessel with the jacket at a temperature of XX – XX°C. Clarification should be started only after the temperature of the pool is in the range of XX –XX°C for xx minutes. The contents of the second SS blending vessel will be the final bulk for the batch.

No Particulars Done by Checked by Date Bath temp before Pooling Pooling: xx-xx°C Start End Blending

vessel

1

°C ______ h ______ h A B

2 Temperature of

Stirrer

Clarification: A, B

Pool Final Bulk RPM Start time End time xx - xx°C xx - xx°C xxx-xxx °C °C ______ h ______ h 3 Filtration Residue (29) Sampled Bulk (30) mL XX mL x X bottles = XX mL Remarks:-






Activity : POOLING & CLARIFICATION OF THAWED BULK AND PREPARATION OF FINAL BULK Ref SOP No : _________________________ 1. Check the integrity of xx µm filter capsule by bubble point method. Connect the SS blending vessel

with the final bulk to the glass header only after the integrity test is done and the filter capsule has passed the test.

2. Inactivation: Inactivate the Material used for Pooling in the Autoclave by heating it to XXX °C for X minutes. (Variation permitted XX °C to XX °C)

3. Perform the environmental monitoring activities as per SOP No _______. This includes exposing settle plates, contact plates and Air sampling as per location map, Swabs of critical surfaces, Finger dabs of operators involved in pooling & filling operation

FILTER INTEGRITY TESTING

Application Stage Method Equipment Equipment No Test Type Clarification Post-Clarific’n XXXXX XXXXX ######## Bubble Pt

Filter Details Mfg/ Brand Part No Pore Size Wetting Liq. Test Parameter Filter Lot No Filter S.No Observation: bubbles

@ Result Done by Checked

by Date

_______________ bar

Done by Checked by

Date Pooling material

Inactivation

Autoclave No: Charge no:

Remarks:-






Activity : FILLING Ref SOP No.: _________________ 1. Volume per vial (23) is indicated on page 5 of this BMR. The Volume per vial is the lower limit of

the permitted volume range. The upper range is calculated by adding X % of the Volume per vial. The weight range is derived from this volume range by multiplying it with weight/mL of the bulk. Calibrate the balance to be used for verifying the Fill volume.

2. Check for absence of previous product components. Carry out the priming of the header and the pumps, collect the priming liquid and send as sample of final bulk to Q.C.

No Description of Activity Done

by Checked

by Date

1 Volume / vial (23), Pg 5

XX mL

Balance Calibrated YES / NO

Line Clearance:

2 Weight per mL Calculation Volume Wt (Bulk WFI)

(C) Wt (Final bulk) (D)

Wt/mL (D/C) = (B)

XX mL g

g

3 Volume Range to weight range setting Lower Vol.

Limit (23) Upper Vol. Limit (23) x XXX=(E)

Lower Wt Limit (23) x (B)

Upper Wt. Limit (E) x (B)

XX mL

XX mL

g

g

Sampling for Visual Inspection (Sample size: XX vials) Fibre Black Part. White Part. Glass Total (%)

4

5 Filling activity : Filling machine XXXXXXXXX Room Started at Room Completed at

Temp °C Temp °C Rh %

h Rh %

h

Remarks:






Activity : FILLING Ref SOP No.: _________________ Rejection Quantity Sample

to QC Total Loaded in Lyophilizer Done

By Checked

by Date

Vials (12A)

Stopper (12B)

(13)

Filled Vials (F)

Appr. Vials F-

(12A+13)=22

Trays (G)

XX

Stoppers rejection details (12B=R1+R2) Balance processed (17) During filling (R1) Balance in hopper (R2) Vials Nos Stoppers Nos


by Date

6 Rejection Inactivation details Autoclave No:

Charge No:

Operators: I Shift II Shift III Shift

STATION NUMBER 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

ID numbers of syringes used for filling

Remark :






Activity : FILLING Ref SOP No.: _____________________

1. At the start of filling, reject the vials used for checking the centering of filling needles, volume setting etc. (Reject Not less than first xx vials)

Attach Fill Volume Print or record manually, on weight basis, every xx Minutes

Time (h) Syringe Number

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

Water bath temp xx-xx 0C

Done by *Checked

by

* Fill in case no printout is available, otherwise sign on printout Remarks:-






Activity : INTEGRITY TESTING VENT FILTERS Ref SOP No.: ________________ 1. On completion of the Filling activity, carry out integrity testing of the two vent filters (XXXX) of the

Blending vessel tank attached to the filling machine by WIT method. 2. Fill the upstream side with WFI at xx-xx oC. A hold at xxxx mbar should not produce an intrusion

rate greater than xxx mL/min 3. Attach printouts below:-

Remarks:-






Activity : LOADING OF LYOPHILIZER Ref SOP No.: _________________ 1. Ensure that the Lyophilizer to be loaded has been cleaned and Sterilized/disinfected, the date of

loading should not be later than the date on the board (Pg.no 16) 2. The trays containing filled and half stoppered vials are to be transported to the Lyophilizer in a

mobile class 100 trolley 3. Ensure that the temperature of the Lyophilizer shelves is –xx ºC before loading of trays containing

filled and half-stoppered vials. 4. After all the trays have been loaded in the lyophilizer, inform lyophilizer operator on duty. He will

check the loading of the lyophilizer, insert product temperature probes and close the door of the lyophilizer.


by Date

1. Checked, that Lyophilizer is □ Sterilized / □ Disinfected

2. Checked that Class 100 trolley is Switched “ON”

3. Vials Loaded in Lyophilizer No: _______ Remarks:-

Vol. Per Vial (23) xx mL Lyo. No:- Loading

date Recipe No.

Sterilization Details (see page 15)

□ Lyophilizer B, C: 1st Batch Steam Steriliz’n.

□ Lyophilizer A: 1st Batch Steaming.

□ 2nd Batch / 3rd Batch All Lyophililzers XX disinfection

For Filling Dept:






LYOPHILIZER CHAMBER CLEANING, DISINFECTION AND STERILIZATION: 1. For Lyophilizers B and C, If Status board ‘Cleaned, Ready for Steam exposure’ is displayed on clean

room side, evacuate chamber to xxx mbar (Water ring vac pump: WP), followed by steam exposure at xxx - xxx °C for xx minutes.

2. For Lyophilizer A, If Status board ‘Cleaned, Ready for Steam exposure’ is displayed on clean room side, evacuate chamber to xxx mbar (WP), followed by steaming for xx mins.

3. Above steps are followed by drying of chamber with WP for minimum xx mins. 4. For all Lyophilizers, If status board ‘Disinfected with XXX, Start evacuation’ is displayed on clean

room side, carry out evacuation as per SOP _____ (XXX cycle: xx min evacuation by vacuum pump with shelf at xx °C)

No Description of Activity Done By Date 1. Status board: Lyo B and C:'Cleaned, Ready for Steam Exposure’ Process xxx - xxx °C maintained Process Start Start End End h h h h

2 Status board: Lyo A:Cleaned, Ready for Steam Exposure’ Vacuum Pull down Started xxx min Exposure Drying Start End Steam Start End End h h h h h h

Drain temperature at the end of Steaming: _______°C 3 Status board: ‘Disinfected with XXX, Start evacuation’ Shelf temp. +xx°C Evacuation with vac pump attained at Start End h h h

4. Display Board: ‘Ready for Loading up to: _________’

5. SHELF PRE-COOLING: (Set Shelf temperature: -xx °C). – yy °C attained: ______ h. Inform production dept. the achievement of – yy °C by displaying the status board indicating time of attaining temperature

6. CHECK LOADING OF VIALS ON SHELVES (SOP No.________) No of shelves

Loaded Loading end Time

No. of product temp. Probes

Door closing time

h h






LYOPHILIZATION CYCLE DETAILS

Step Freezing Condenser cooling

Chamber Evacuation

Primary drying

Sec. Drying

Shelf Temp - xx °C NA NA -xx to xx °C xx °C

Time Start

Date

Time End

Date

Duration

X / X x ± x h ≤ x h ≤ x h xx ± x h x ± x h

7.

Nor

m

X x ± x h ≤ x h ≤ x h xx h xx min ± x h x ± x h

8 BATCH STOPPERING AND UNLOADING Ensure the following parameters before stoppering the vials.

Done / Checked By

Date

Avg. Product Temp Spec: xx ± x °C

Vacuum Spec: xx ± xx µbar

Condenser Temp. Spec: ≤ - xx °C

°C µbar °C

Stop the cycle and stopper the vials as per SOP No. __________. Time of Stoppering: ____________ h.

9 Chamber vacuum released by sterile air at _______ h. Instruct production department to unload the vials after breaking the vacuum by air.

DEVIATIONS DURING LYOPHILIZATION (if any) :____________






Activity : ALUMINUM CAPS PROCESSING Ref SOP No : __________________________

1. Verify that QC approved Aluminum Caps of correct colour have been taken for decartoning. 2. Remove the outer package and transfer the inner plastic bag to the sterilizer loading area. 3. The caps can be processed in either of the two ways: A) Sterilization in Autoclave X and drying in

dry heat sterilizer (DHS) XX; B) Sterilization and drying in Autoclave Y. If option A is selected, then transfer the caps into clean SS trays, load into the autoclave as per validated loading pattern and Sterilize it at XXX °C to XXX °C for xx minutes.

Pattern No 1 II No of Caps/trays

4. After sterilization, transfer the trays containing the Aluminium caps from the autoclave to the DHS via clean room side for drying at xxx °C for xx mins Normal variation – x °C to + x °C

5. If option B is selected then process the caps at xxx °C ± x °C for xx minutes in the autoclave. 5. Write /verify Product, B.No., Charge No and date on the sterilizer thermograph / printout (for Option

A only) sign it and attach it to this BMR A) Aluminum Cap input: 13 mm, Colour ______ Done

by Checked

by Date

1) Unprocessed b/f: B.No_____________

2) Processed b/f: B.No___________

3) Fresh quantity issued

4) Fresh used from issued

Nos Nos Nos Nos

Unprocessed quantity from this batch (18) (3 - 4)

6) Taken for Sterility = 9

(For 1 / 2 batch/es)

5) Option of Process

A =1+ 2 + 4

B =1+ 4 Nos

No Description of Activity

B) Loaded in Autoclave No. ################ Charge No. Load Pattern No Prog No.

C) Aluminum Cap Drying at xxx °C in DHS No: ########### Charge No. xxx °C Achieved at xxx °C Held till h h Remarks:- .






Activity : SEALING OF VIALS Ref SOP No : ____________ Lyophilizer Unloading: 1. After the lyophilization operator on duty has informed you about completion of lyophilization cycle,

open the door of the Lyophilizer &unload the trays containing the lyophilized vaccine 2. Clean and Sterilize/disinfect the lyophilizer. Record the same in the BMR of the batch to be loaded . Sealing Operation: 1. Carry out sealing operation on the vials unloaded from the Lyophilizer. 2. The trays containing the good sealed vials should be transferred to visual inspection department

through the material transfer hatch. 3. The sealing rejection should be loaded in autoclave and heated at xxx ºC (xx to xxxoC) for x minutes

and then unloaded from the autoclave from the washing room side.

Description of Activity Done By

Checked by

Date

Unloading & line Clearance:

Sealing Rejection in Lyo Sensor

(14)

Approx. Vial for sealing

(22)-(14) = (H)

Sealing machine used

Started

(h) Completed

(h) XXXXXX

Vials

XXXXXX

Rejection & inactivation details

Autoclave No: ______ Charge No:

Empty vial

(15A)

Bad seal

(15B)

Breakage (15C)

Vial, Stopper Rej 15A to 15C =(15D)

Cap rej (15E)

Processed Caps (17)

nos nos nos nos nos nos Approx No of Vials Handed Over To Visual Inspection Department H-15D= _____

Trays

Vials

Vials Received by screening: Name: ______________: ________________ (for Screening Dept)






Activity: MATERIAL RECONCILIATION RECORD No Description Vial Stopper Caps 1 Bal. Unprocessed Material b/f (18) Quantity Prod / Batch No 2 Bal. Processed Material b/f (19) Quantity Prod / Batch No 3 Fresh Material Issued Quantity

Res. Doc No. 4 Quantity used from Fresh material 5 Option for washing/sterilizing [A: 1+2+4, B: 1+4] A / B A / B A / B 6 Total Quantity for Washing or Transfer based on (5) 7 Sampled for Adequacy of Washing XX X X 8 Rejected during Washing or Transfer X X 8A Rejection in % [(8/6) x 100] Limit: 2% 9 Sterilized [6-(7+8)] 10 Quantity for Filling/Sealing (If 5: A, 10=9) (If 5: B, 10=9+2) 11 Sampled- Post Sterilization x x 12 Rejection- Filling stage x 13 Sampled- Filling stage xx xx xx 14 Rejection: Lyophilization stage x 15 Rejection: Sealing stage 16 Post Sterilization Sample and Rejection (Sum 11 to 15) 17 Bal. Processed Material Quantity c/f Prod/Batch No or ICN 18 Bal. Unprocessed Material Quantity [3-4] c/f Prod/Batch No or ICN 19 Quantity of vials for visual inspection 20 Variance* In No: [(1+2+3)-(7+8+16+17+18+19)] In percent: [(In no)/(10-17)] x 100, 21 Consumption (1+2+3)-(17+18) *Permissible variance ± X % Vial and Cap, ± X % Stoppers






Activity: BULK RECONCILIATION RECORD After the sealing activity is over, reconciliation on the basis of final bulk should be done to determine the percentage yield for the batch. No Description (A) (B)

22 Quantity of vials Loaded in Lyophilizer Vials

23 Volume per Vial as declared by Bulk Mfg Dept X mL

24 Batch Vol. dispensed by Bulk Mfg Dept L

25 Fill Volume X mL

26 Batch Vol. rechecked by Filling Dept L

27 Post Clarification Yield [26-(29/1000)] L

28 Theoretical yield [(26) x 1000]/ (25) Vials

29 Blending & Filtration residue (29A=26-27) 29B=29A/25 mL Vials

30 Sample in Liquid Form [Filling stage] XX mL

31 Excess Volume Balance in Tank after filling mL

32 Total Liq Samples /Losses [32A=29+30+31] 32B =32A/ 25 mL Vials

33 Total Loss/Samples as vials (32B+16) Vials

34 Expected Yield 28-33B Vials

35 Final yield [(19) / (28B) x 100] (not less than XX%) %

36 Percentage Reconciliation [(19) / (34B) x 100] % Stage: Post Clarific’n Filling Lyophiliz’n and Sealing Total Calc x 100 29B / 28 [(28-29B)-22]/(28-

29B) (22-19) / 22 Sum of all

Norm (NMT) x % x % x % x % Actual:

Remarks: DEVIATION: Yes / No. If yes, Report date/s:






BMR CERTIFICATION

01. MANUFACTURING DEPARTMENT : The contents of this Document have been checked and verified by me. The information contained herein is complete and true to the best of my Knowledge. Deviations if any are reported. Hence submitted to Quality Assurance department. Signature of Production Officer :____________________________ Date of Completion : ___________________________ Date of Submission :___________________________ 02. QUALITY ASSURANCE DEPARTMENT : I hereby certify that, this batch record is reviewed by me, to ensure that the above mentioned batch process has been carried out according to the Authorized Master formula and processing instructions. All operational steps have been scrutinized and approved according to the checklist (attached ) and have been found to be complete. Signature of Quality Assurance Review Officer :__________________________ Date of Receipt :__________________________ Date of Approval :__________________________

batch manufacturing record … manufacturing record controlled document ... material reconciliation...

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