1 Revision History

Version Change Type

Revision Summary Justification
No. (New, Revise, or Admin)

1. Step 6.5.11 updated to include figure 5

7.0 Revise and reference to retentate line on vessel 1. As per PR127421
VE-101723
8.0 Revise 1. Added step 6.1.9, 6.1.10 and 6.1.11 1. Alignment

2 Objectivea
The objective of this work instruction is to detail the setup and Steam In Place (SIP) of
the Ultrafiltration/Diafiltration (UF/DF) 3 Retentate vessel (VE-101713 or VE-101723)in
the Bulk Drug Substance (BDS) at Alexion Dublin Manufacturing Facility (ADMF). This
includes set-up for SIP, the pressure hold test and the SIP operation.

3 Training Requirements/ Prerequisites

The following competencies, and associated training, must be complete prior to
performance of the task outlined in the instructions below.

ALXN-SOP-0005603 ADMF BDS Filter Handling and Installation Competency

ALXN-SOP-0005582 ADMF BDS Steam In Place (SIP) Competency

ALXN-SOP-0005850 ADMF BDS Use of Clamp Connections, O-rings and Gaskets

Competency

ALXN-SOP-0005605 ADMF BDS Sampling Device Assembly and Use Competency

ALXN-SOP-0005639 ADMF BDS Inspection of Process Disposables Competency

ALXN-SOP-0005906 ADMF BDS Parts Management Competency

ALXN-SOP-0005598 ADMF Aseptic Connections Competency in BDS manufacturing area

ALXN-SOP-0005452 ADMF Use of Transfer Panel Competency for BDS Manufacturing

ALXN-WI-0004616, ADMF BDS UF/DF Processing of Ravulizumab 100 mg/ml Work

Instruction
4 Equipment & Materials
Chrom 3 Pool Vessel, VE-101614

Viral Filtration Pool Vessel, VE-101616

UF/DF-3 Retentate Vessel, VE-101713 or VE-101723

UF/DF-3 Skid, UF-101710 or UF-101720

BDS Pool Vessel, VE-101716

SUM (Single Use Mixer), SUM-101710

Vent Filters as per applicable pBR

Processing Filters as per applicable pBR

Steam-thru Manifold (00008) (Part #101103)

Small steam to Manifold (00063) (Part #101177)

Novaseptum Sampling Bag 50mL (Part#101166)

Novaseptum Sampling Device

Novaseptum port plugs

Filter Housing FL-101713-01, FL-101716-01, FL-101716-02, FL-101716-03, FL-101723-01, FL-

101723-02

Equipment parts totes

3/8IN 5-Way Lynx Manifold (Part #101250)

½ IN 11M tubing Lynx (Part#101296)

KHGEG3TTT1H Filtration Manifolds

1/2 IN Short Cross Manifold

3/8 IN Tubing (00012)

¼ IN 3M Tubing (00010)

Aseptic Y-piece (00036)

Bag 500L SUM

Bag 1L 2D (Part #101109)

Novaseptum Leur Lines (Part#101167)

Novaseptum sampling bag 5 x 50 mL (Part#101165)

1.5” – ¾” Reducer

5 Environmental Health & Safety Information

Refer to Safety Signals referenced in the Work Instruction. Training on task associated
risks is completed through the relevant competencies on the job training (OJT)

6 Work Instruction Steps

6.1 Preparation for the SIP of UF/DF-3 Retentate Vessel (VE-101713 or VE-101723)
Signals Step Instruction Guide

Confirm the hygienic Ensure hygienic status is “Clean”.

6.1.1
status of the system to
be steamed using the
hygienic status HSTAT
function on MCS.
Retrieve the materials Refer to batch record for quantities
6.1.2 required.
required for Setup and
SIP from the storage
location as per
applicable pBR
Retrieve the UF/DF-3 As per ALXN-SOP-0005582 Gaskets must
6.1.3 either have been cleaned in place or
clean parts tote from
the dedicated location. cleaned out of place in the parts washer
and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-0005850
Check the CEH label on If parts are outside CEH send them to
6.1.4 the washer to be cleaned as per ALXN-
the equipment tote to
confirm they are within SOP-0005906
expiry.
Record the CEH expiry
6.1.5
date of the equipment
clean pats tote into the
UF/DF-3 pBR.
Signals Step Instruction Guide

Navigate to VE-101713
6.1.6
or VE-101723 on MCS.

Ensure correct unit This is UP_UF_SETUP

6.1.7
procedure is running on
the Batch Operator
Interface.
Ensure MCS prompt is Prompt “ACKNOWLEDGE WHEN VE-
6.1.8 101713/VE-101723 IS SETUP AND
displayed, to confirm it
is safe to set-up vessel. READY TO START PRESSURE HOLD TEST”

Answer the following Prompt “ACKNOWLEDGE WHEN READY

6.1.9 TO PROCEED WITH MEMBRANE DRAIN”
prompt to initiate
membrane drain as per
ALXN-WI-0004906
AMDF BDS UF/DF
Processing of
Eculizumab Work
Instruction.
Perform WFI rinse on
6.1.10
UF-101710 prior to set
up.
Ensure MCS prompt is Prompt “PERFORM WFI RINSE ON UF-
6.1.11 101710/UF-101720 RETENTATE LINE
displayed, to confirm it
is safe to set-up vessel. PRIOR TO SET-UP ”

Ensure Vessel is at a Ensure the pressure in VE-101713 OR

6.1.12 VE-101723 is at 0 barg. If there is any
safe pressure level
before working on the pressure in the vessel ensure this is
system. vented before proceeding.

6.2 Installation of filters to UF/DF-3 Retentate Vessel (VE-101713 OR VE-101723),

UF/DF-3 Skid (UF-101710 or UF-101720) and BDS Pool Vessel (VE-101716)
Signals Step Instruction Guide

Confirm vent filter to be

6.2.1
installed (Part #100047)
is within expiry on MES.

Perform Visual As per ALXN-SOP-0005603

6.2.2
inspection of the vent
filter prior to
installation
Signals Step Instruction Guide

Charge vent filter

6.2.3
(Part#100047) to
process order.

Install (Part#100047) As per ALXN-SOP-0005603

6.2.4
Vent filter into UF/DF-3 Table 1: Retentate Vessel Filter Housing
Retentate Vessel filter
housing. Vessel Housing
VE-101713 FL-101713-01
VE-101723 FL-101723-01

As per ALXN-SOP-0005582

Gaskets must either have been cleaned

in place or cleaned out of place in the
parts washer and be within Clean expiry.

Inspect gaskets as per ALXN-SOP-

0005850
Confirm filter to be
6.2.5
installed (Part #100218)
is within expiry on MES.

Perform visual As per ALXN-SOP-0005603

6.2.6
inspection of filter prior
to installation
Charge filter (Part
6.2.7
#100218) to process
order.

Install filter (Part As per ALXN-SOP-0005603

6.2.8
#100218) into UF/DF-3
skid filter housing.
Table 2: UF/DF-3 Skid Filter Housing

UF/DF-3 SKID Housing

UF-101710 FL-101710-03
UF-101720 FL-101723-02
As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-0005850
Signals Step Instruction Guide

Confirm vent filter to be Note: Step 6.2.9-6.2.16 are applicable to

6.2.9
installed (Part #100047) UF3 for Eculizumab
is within expiry on MES.

Perform Visual As per ALXN-SOP-0005603

6.2.10
inspection of vent filter
prior to installation.
Charge vent filter
6.2.11
(Part#100047) to
process order.

Install vent filter As per ALXN-SOP-0005603

6.2.12
(Part#100047) into BDS Table 3: BDS Pool Vessel Filter Housing
Pool Vessel filter
housing. Vessel Housing
VE-101716 FL-101716-01

As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850
Confirm filters to be
6.2.13
installed (Part#100043)
are within expiry on
MES.
Perform visual As per ALXN-SOP-0005603
6.2.14
inspection of filters
prior to installation.
Charge filter
6.2.15
(Part#100043) to
process order.
Signals Step Instruction Guide

Install filter As per ALXN-SOP-0005603

6.2.16
(Part#100043) into BDS Table 4: BDS Pool Vessel Filter Housing
Pool Vessel filter
housing. Vessel Housing
VE-101716 FL-101716-02

As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850

6.3 Installation of Manifolds for Eculizumab (for BDS Pool Vessel)

Signals Step Instruction Guide

Confirm steam-thru
6.3.1
manifold (Part# 101103)
is within expiry on MES.

Perform visual As per ALXN-SOP-0005639

6.3.2
inspection of steam-
thru manifold prior to
installation.
Charge steam-thru
6.3.3
manifold to process
order on MES.

Install steam-thru As per ALXN-SOP-0005598

6.3.4
manifold to the BDS As per ALXN-SOP-0005582
Pool Vessel (VE-
101716). Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850
Confirm small steam to
6.3.5
manifold (Part# 101177)
are within expiry on
MES.
Signals Step Instruction Guide

Perform visual As per ALXN-SOP-0005639

6.3.6
inspection of small
steam to manifold
(101177) prior to
installation.
Charge small steam to
6.3.7
manifolds (101177) to
process order on MES.

Remove the spool piece As per ALXN-SOP-0005598

6.3.8
above hand valve HV-
101716-058. Install a
1.5” – ¾” clean reducer
and a small steam to
manifold (Part #101177)
to the BDS Pool Vessel
(VE-101716) as per
Fig.1.

Figure 1: Spool piece

As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850
Signals Step Instruction Guide

Install small steam to As per ALXN-SOP-0005598

6.3.9
manifold (Part #101177)
to port A2 on the BDS
Pool Vessel (VE-
101716), as per Fig.2.

Figure 2: Port A2
As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850
Signals Step Instruction Guide

Install small steam to As per ALXN-SOP-0005598

6.3.10
manifold (Part #101177)
to the port beside XV-
101716-100 on the BDS
Pool Vessel (VE-101716)
as per Fig.3.

Figure 3: Port beside XV-101716-100

As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850
Confirm 3/8IN 5-Way
6.3.11
Lynx Manifold (Part#
101250) is within expiry
on MES.
Perform visual As per ALXN-SOP-0005639
6.3.12
inspection of lynx
manifold prior to
installation.
Charge the lynx
6.3.13
manifold to process
order on MES.

Install lynx manifold to As per ALXN-SOP-0005598

6.3.14
the BDS Pool Vessel (VE- As per ALXN-SOP-0005582
101716).
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850
 6.4 Setup of Transfer Panel
Signals Step Instruction Guide

Set up transfer panel to As per ALXN-SOP-0005452.

6.4.1
the required
configuration shown in
table 5/6 and record in
pBR.

Additional Information
Table 5: Eculizumab Transfer Panel Configuration

Chrom 3 Transfer Panel Ports to UF/DF-3 Transfer Ports to BDS Pool

Pool Vessel (Purification) connect Retentate Panel connect Vessel
Vessel (Purification)
VE-101614 TP-101713-01 CD VE-101713 TP-101713-02 HL VE-101716

Table 6: Ravulizumab Transfer Panel Configuration

VF Pool Transfer Panel Ports to Transfer Panel Ports to UF/DF-3

Vessel (Purification) connect (Purification) connect Retentate
Vessel
VE-101616 TP-101613-01 AF TP-101713-01 BD VE-101723
 6.5 Installation of Novaseptum Sampling Bags
Signals Step Instruction Guide

Confirm Novaseptum
6.5.1
sampling bags and Leur
lines to be installed as
per applicable pBR are
within expiry on MES.
Perform Visual As per ALXN-SOP-0005639
6.5.2
inspection of Table 7: Installation of Novaseptum
Novaseptum sampling Sampling Bags and Leur lines for Eculizumab:
bags and Leur lines prior Novaseptum Sampling Vessel
to installation. Units
5x50mL 101165 VE-101713
VE-101716
50mL 101166 VE-101713
Leur Lines 101167 VE-101713
VE-101716

Table 8: : Installation of Novaseptum

Sampling Bags and Leur lines forRavulizumab
Novaseptum Sampling Vessel
Units

5x50mL 101165 VE-101723

Leur Lines 101167 VE-101723

Charge Novaseptum
6.5.3
sampling bags and Luer
lines to the process
order.

Populate 9 shot As per ALXN-SOP-0005605

6.5.4
Novaseptum sampling
device with
Novaseptum sampling
bags and Novaseptum
Leur Line as defined in
the UF/DF-3 pBR.
Ensure any remaining As per ALXN-SOP-0005605
6.5.5
open ports on the
Novaseptum sampling
device are populated
with Novaseptum port
plugs.
Signals Step Instruction Guide

Install the populated As per ALXN-SOP-0005605

6.5.6
Novaseptum sampling Table 9: Retentate vessel sample port
device onto UF/DF-3
Retentate Vessel Vessel Location
sample port.
VE-101713 S1 Port

VE-101723 S1 Port

As per ALXN-SOP-0005582
Gaskets must either have been cleaned
in place or cleaned out of place in the
parts washer and be within Clean expiry.
Inspect gaskets as per ALXN-SOP-
0005850

Populate 9 shot As per ALXN-SOP-0005605

6.5.7
Novaseptum sampling
device with
Novaseptum sampling
bags and Novaseptum
Leur Line as defined in
the UF/DF-3 pBR.
Ensure any remaining As per ALXN-SOP-0005605
6.5.8
open ports on the
Novaseptum sampling
device are populated
with Novaseptum port
plugs.

Perform Visual
6.5.9
Inspection of
Novaseptum Leur Lines
(Part#101167) prior to
installation

Charge Novaseptum
6.5.10
Leur Line (Part#101167)
to the process order
Signals Step Instruction Guide

Install novaseptum leur

6.5.11
line (Part#101167) onto
the UF/DF Retentate line
(VE-101713/VE-101723)

Figure 4: UF-3 Retentate For sampling

point VE-101713 beside flow meter (FIT-
101710-064)

Figure 5: UF-3 Retentate sampling point

For VE-101723
Install Novaseptum As per ALXN-SOP-0005605
6.5.12
sampling device onto Table 10: BDS pool vessel sample ports
BDS Pool Vessel.
Vessel Location

VE-101716 S1 Port

Note: Step 6.5.12-6.5.16 are applicable

to UF3 for Eculizumab
Signals Step Instruction Guide

Confirm Bag 1L 2D (Part

6.5.13
#101109) are within
expiry on MES.

Perform Visual As per ALXN-SOP-0005639

6.5.14
inspection of Bag 1L 2D
prior to installation.

Charge Bag 1L 2D (Part

6.5.15
#101109) to the process
order.
Install Bag 1L 2D (Part
6.5.16
#101109) on to the BDS
Pool Vessel.

6.6 Setup of the SUM (applicable to Ravulizumab)

Signals Step Instruction Guide

Ensure the SUM Vessel

6.6.1
is setup as per ALXN-WI-
0004616, ADMF BDS
UF/DF Processing of
Ravulizumab 100 mg/ml
Work Instruction

6.7 SIP of Feed Transfer Line and UF/DF-3 Retentate Vessel

Signals Step Instruction Guide

Position a safety barrier

6.7.1
at the equipment being
SIP’d.

Label the safety barrier This will provide visibility to other

6.7.2 operators on the status of the vessel.
“SIP in progress”.
Signals Step Instruction Guide

Walk down vessel and Pay particular attention to clamps or

6.7.3 blanks that were removed and
confirm all clamps are
reinstalled during SIP setup.
hand tightened.
 Filters
 Blanks on ports
 Clamps
 Novaseptum port plugs
 Gaskets

Acknowledge Prompt Answer prompt “ACKNOWLEDGE TO

6.7.4 PROCEED WITH <THIS UNIT> PRESSURE
HOLD TEST”

If vessel fails to vent the Prompt “VESSEL VENTING FAILED.

6.7.5
following prompt will be CURRENT VESSEL PRESSURE IS <VESSEL
displayed PRESSURE> BARG. ACKNOWLEDGE TO
RETRY VENT”
Acknowledge prompt to continue
Confirm prompt is Prompt “ACKNOWLEDGE WHEN <THIS
6.7.6 UNIT> TRANSFER LINE FROM <SOURCE
available on MCS
UNIT> AND TRANSFER LINE TO
<DESTINATION UNIT> ARE SET UP AND
READY TO START PRESSURE HOLD TEST”
Answer Prompt Prompt “ACKNOWLEDGE WHEN <THIS
6.7.7 UNIT> TRANSFER LINE FROM <SOURCE
UNIT> AND TRANSFER LINE TO
<DESTINATION UNIT> ARE SET UP AND
READY TO START PRESSURE HOLD TEST”
Monitor MCS to confirm Monitor PHT as per ALXN-SOP-0005582.
6.7.8 Refer to section 8.3 of ALXN-SOP-
if Pressure Hold Test
passes. 0005582 if pressure hold test fails.

Ensure MCS prompt is

6.7.9 Prompt “CONFIRM UF RETENTATE
displayed, to confirm
VESSEL, TRANSFER LINE FROM <SOURCE
the PHT has passed.
UNIT> AND TRANSFER LINE TO
<DESTINATION UNIT> ARE READY FOR
SIP. ACKNOWLEDGE TO PROCEED”

Answer MCS prompt to

6.7.10 Prompt ““CONFIRM UF RETENTATE
begin SIP.
VESSEL, UF SKID, TRANSFER LINE FROM
<SOURCE UNIT> AND TRANSFER LINE TO
<DESTINATION UNIT> ARE READY FOR
SIP. ACKNOWLEDGE TO PROCEED”.”
Signals Step Instruction Guide

Monitor Temperature The SIP will heat to a minimum

6.7.11 temperature of ≥123oC during the Heat-
Transmitters as MCS
introduces High up period.
pressure Steam. During the SIP Dwell time, the SIP timer
will pause if the temperature drops
below 121.5oC.
If temperature transmitters fail to reach
≥123oC during Heat-up or fall below
121.5oC during the Dwell time refer to
the troubleshooting section 8.5 of ALXN-
SOP-0005582.

Ensure SIP is complete If SIP is successful MCS updates the

6.7.12 HSTAT to “STEAMED”, no further action
on MCS.
is required.

After SIP is complete Clamps that were opened and closed

6.7.13 during set-up.
walk steam route to
confirm all clamps are
hand tight.
Remove the safety
6.7.14
barriers and signage of
the equipment being
steamed and store
appropriately.
7 References
ALXN-SOP-0005603 ADMF BDS Filter Handling and Installation Competency

ALXN-SOP-0005582 ADMF BDS Steam In Place (SIP) Competency

ALXN-SOP-0005850 ADMF BDS Use of Clamp Connections, O-rings and Gaskets

Competency

ALXN-SOP-0005605 ADMF BDS Sampling Device Assembly and Use Competency

ALXN-SOP-0005639 ADMF BDS Inspection of process disposables Competency

ALXN-SOP-0005906 ADMF BDS Parts Management Competency

ALXN-SOP-0005452 ADMF Use of Transfer Panel Competency for BDS Manufacturing

ALXN-SOP-0005598 ADMF Aseptic Connections Competency in BDS manufacturing area

ALXN-WI-0004616 ADMF BDS UF/DF Processing of Ravulizumab 100 mg/ml Work

Instruction