DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

CERTIFICATE OF ANALYSIS

Product trade name: CINRYZE 500

Batch Number Finished Product: C4V005
Batch Number (labelled): C4V005AS
Filling Size: 500 IU
Date of Manufacture: 06 2020
Number of Final
Containers for Release: 7305 pieces
Expiry Date: 05 2022
Storage Temperature: at room temperature (≤ 25 °C)
Destination country/countries: ROMANIA

PLASMA CERTIFICATE
This is to certify that each single plasma donation used for the manufacture of the product has been tested
f or HBs-antigen, HIV-1/2-antibody and HCV-antibody by Immunoassay. Only plasma found non-reactive for
HBs-antigen, HIV-1/2-antibody and HCV-antibody has been used for the manufacture of the product.
In addition, each plasma pool derived from plasma donations tested as described above, has been tested
f or HBs-antigen and HIV-1/2-antibody by Immunoassay and for viral nucleic acids of HAV, HBV, HCV, HIV-
1/2 and B19V by NAT. Only plasma pools found non-reactive for HBs-antigen, HIV-1/2-antibody, HAV
RNA, HBV DNA, HCV RNA, HIV-1/2 RNA and containing not more than 104 I.U. B19V DNA/ml are used for
the manuf acture of the product.

The f ollowing plasma pools were used for the manufacture of the product:
1305181, 1405181, 1505181, 1705181
(see enclosed Official Control Authority Batch Release certificates)

Takeda Manufacturing Austria AG

Industriestraße 67, 1221 Wien, AT
Handelsgericht Wien, FN: 491521 a, UID: ATU74323029
UniCredit Bank Austria, Kto.-Nr.: 10023 475 402, BLZ:12000, IBAN: AT261200010023475402, Swift Code: BKAUATWW
C4-Standard-V01.03 page 1 of 3
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735
Dept. BAMA
Possingergasse 38, AT-1160 Wien
Dieter Pullirsch; email: dieter.pullirsch@ages.at
Phone:+43(0)5 0555 36361 ; Fax: +43(0)5 0555 36309

EU/EEA CERTIFICATE OF APPROVAL FOR PLASMA POOLS FOR USE IN THE MANUFACTURE OF
MEDICINAL PRODUCTS
Examined in the context of Official Control Authority Batch Release of medicinal products derived from human blood or plasma in application of
Article 114 of Directive 2001/83/EC and amended by Directive 2004/27/EC.

Name and address of manufacturer of plasma pools (site of Qualified Person

signing summary protocol unless otherwise indicated):
Baxter Spa
Via della Chimica 5
IT-02010 S. Rufina, Cittaducale Rieti

Code numbers of Date of Volume Country PMF reference

sample No: plasma pools: manufacture of pools (l): of origin: (+certification):

20007242 1203181_10 12.03.2018 2425,448 US EMEA/H/PMF/000003/2004

20007243 1203181_20 12.03.2018 2425,448 US EMEA/H/PMF/000003/2004
20007230 1305181_10 13.05.2018 2453,486 US EMEA/H/PMF/000003/2004
20007231 1305181_20 13.05.2018 2453,486 US EMEA/H/PMF/000003/2004
20007265 1405181_10 14.05.2018 2416,396 US EMEA/H/PMF/000003/2004
20007264 1405181_20 14.05.2018 2416,396 US EMEA/H/PMF/000003/2004
20007246 1503181_10 15.03.2018 2410,687 US EMEA/H/PMF/000003/2004
20007247 1503181_20 15.03.2018 2410,687 US EMEA/H/PMF/000003/2004
20007228 1505181_10 15.05.2018 2417,647 US EMEA/H/PMF/000003/2004
20007229 1505181_20 15.05.2018 2417,647 US EMEA/H/PMF/000003/2004

These plasma pools have been examined using documented procedures, which form part of a quality system which is in accordance with the EN ISO/IEC 17025
standard. This examination is based on the current EU OCABR guideline 'Official Control Authority Protocol for Approval of Plasma Pools': review of the plasma pool
protocol and the following testing: The samples of these plasma pools (received: 22.01.2020) have been tested and found negative for the following virological
markers: anti HIV 1+2 (EIA), HBsAg (EIA) and HCV RNA (NAT).
These plasma pools are in compliance with the approved specifications laid down in the relevant European Pharmacopoeia monograph(s) and are approved.

Signed:

Name and Function of Signatory: Dr. Dieter Pullirsch

Date of Issue: 28.01.2020
Release Certificate Number: ZAT-200326

BASG - Austrian Federal Office for Safety in Health Care

Traisengasse 5 l 1200 Vienna l AUSTRIA l www.basg.gv.at
DVR: 2112611 Page 1 of 1
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735
Dept. BAMA
Possingergasse 38, AT-1160 Wien
Dieter Pullirsch; email: dieter.pullirsch@ages.at
Phone:+43(0)5 0555 36361 ; Fax: +43(0)5 0555 36309

EU/EEA CERTIFICATE OF APPROVAL FOR PLASMA POOLS FOR USE IN THE MANUFACTURE OF
MEDICINAL PRODUCTS
Examined in the context of Official Control Authority Batch Release of medicinal products derived from human blood or plasma in application of
Article 114 of Directive 2001/83/EC and amended by Directive 2004/27/EC.

Name and address of manufacturer of plasma pools (site of Qualified Person

signing summary protocol unless otherwise indicated):
Baxter Spa
Via della Chimica 5
IT-02010 S. Rufina, Cittaducale Rieti

Code numbers of Date of Volume Country PMF reference

sample No: plasma pools: manufacture of pools (l): of origin: (+certification):

20007232 1605181_10 16.05.2018 2443,195 US EMEA/H/PMF/000003/2004

20007233 1605181_20 16.05.2018 2443,195 US EMEA/H/PMF/000003/2004
20007234 1705181_10 17.05.2018 2428,683 US EMEA/H/PMF/000003/2004
20007235 1705181_20 17.05.2018 2428,683 US EMEA/H/PMF/000003/2004
20007236 1805181_10 18.05.2018 2422,931 US EMEA/H/PMF/000003/2004
20007237 1805181_20 18.05.2018 2422,931 US EMEA/H/PMF/000003/2004
20007238 2005181_10 20.05.2018 2426,636 US EMEA/H/PMF/000003/2004
20007239 2005181_20 20.05.2018 2426,636 US EMEA/H/PMF/000003/2004
20007240 2105181_10 21.05.2018 2435,001 US EMEA/H/PMF/000003/2004
20007241 2105181_20 21.05.2018 2435,001 US EMEA/H/PMF/000003/2004

These plasma pools have been examined using documented procedures, which form part of a quality system which is in accordance with the EN ISO/IEC 17025
standard. This examination is based on the current EU OCABR guideline 'Official Control Authority Protocol for Approval of Plasma Pools': review of the plasma pool
protocol and the following testing: The samples of these plasma pools (received: 22.01.2020) have been tested and found negative for the following virological
markers: anti HIV 1+2 (EIA), HBsAg (EIA) and HCV RNA (NAT).
These plasma pools are in compliance with the approved specifications laid down in the relevant European Pharmacopoeia monograph(s) and are approved.

Signed:

Name and Function of Signatory: Dr. Dieter Pullirsch

Date of Issue: 28.01.2020
Release Certificate Number: ZAT-200327

BASG - Austrian Federal Office for Safety in Health Care

Traisengasse 5 l 1200 Vienna l AUSTRIA l www.basg.gv.at
DVR: 2112611 Page 1 of 1
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

BATCH NUMBER: C4V005

CONTROL TESTS ON FINISHED PRODUCT

Test Method Specification Result
1. C1-Inhibitor Activity Chromogenic Assay 80 – 125 IU/ml 92 IU/ml
2. Specific C1-inhibitor Calculation 4 – 9 IU/mg 6 IU/mg
activity
3. Total protein Kjeldahl Method 10 – 20 g/L 15 g/L
4. Solubility (at 20°C to Dissolution Time Dissolution time: < 5 min; 1 min
25°C) completely soluble
Clarity (af ter Visual Inspection of the Appearance of solution: clear clear
reconstitution) Solution
Color (af ter Visual Inspection of Solution Appearance of solution: colorless
dissolving); < BL1
Stability Visual Inspection of Solution Appearance of solution: clear; clear, no clotting
(appearance after no clotting
dissolving 3 hours at
room temperature)
5. Water content Karl Fischer Method < 0.04 g/g 0.01 g/g
(Residual moisture)
6. Osmolality Measurement of the 200 - 400 mOsmol/kg 297 mOsmol/kg
Depression of Freezing Point
7. Sodium ICP-OES 80 – 120 mmol/L 105 mmol/L
8. Sucrose HPLC-RI 40 - 80 mmol/L 57 mmol/L
9. Citrate Enzymatic UV-testing 5 – 15 mmol/L 10 mmol/L
10. Valine HPLC-UV 11 – 20 mmol/L 18 mmol/L
11. Alanine HPLC-UV 9 – 17 mmol/L 13 mmol/L
12. Threonine HPLC-UV 30 – 45 mmol/L 39 mmol/L
13. pH-Value (directly Potentiometry 6.8 – 7-2 7.0
measured in
solution)
14. Sterility (Ph. Eur.) Membran Filtration sterile sterile
15. Bacterial Endotoxins Chromogenic Kinetic Method ≤ 5.0 EU/ml <0.5 EU/ml
16. Appearance Visual inspection of solution Essentially free from visible complies
(af ter reconstitution) particles

17. Sub-visible particles Particle Count Test (Light ≥ 10 µm: ≤ 6000 particles/vial 55 particles/vial
Obscuration) ≥ 25µm: ≤ 600 particles/vial 2 particles/vial
18. Purity SE-HPLC C1-inhibitor Monomer (%): 83 %
≥ 65 %
Low molecular weight species 16 %
(incl. α1 ACT (%): ≤ 26 %
High molecular weights 1 %
species (%):≥ 0 % (report
results)

Takeda Manufacturing Austria AG

Industriestraße 67, 1221 Wien, AT
Handelsgericht Wien, FN: 491521 a, UID: ATU74323029
UniCredit Bank Austria, Kto.-Nr.: 10023 475 402, BLZ:12000, IBAN: AT261200010023475402, Swift Code: BKAUATWW
C4-Standard-V01.03 page 2 of 3
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

BATCH NUMBER: C4V005

I hereby certify that all the manufacturing stages of this batch of finished product have been carried out in full
compliance with the GMP requirements of the EU and with the requirements of the Marketing Authorisation(s) of
the destination country/countries.

SIGNATURE

Issued by: Approved by:

printing date: 04-Nov-2020 Qualif ied Person

Takeda Manufacturing Austria AG

Industriestraße 67, 1221 Wien, AT
Handelsgericht Wien, FN: 491521 a, UID: ATU74323029
UniCredit Bank Austria, Kto.-Nr.: 10023 475 402, BLZ:12000, IBAN: AT261200010023475402, Swift Code: BKAUATWW
C4-Standard-V01.03 page 3 of 3
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

CERTIFICATE OF ANALYSIS FOR SOLVENT

WATER FOR INJECTION 5 ml / 10 ml / 20 ml

used as diluent for

CINRYZE 500

Batch No.: C4V005

Batch No (labelled): C4V005AS

Manuf acturer: Siegfried Hameln GmbH, 31789 Hameln, Germany

Batch No.: G000065

Filling Size: 5 ml
Expiry Date: 05 2024

Test results see enclosed addendum.

Baxter
Aktiengesellschaft

Date: 04-NOV-2020/mm Qualif ied Person

WFI-Standard-V01.01 page 1 of 1
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

Siegfried

Certificate of Analysis
To whom it may concern
Printout date
06/27/2019

Page
1 of 2

Material: 7906600 Wfl, STER, 5ml, EP/USP/JP, UNLBLD

Customer Material: 3500044

Techn. quality agreement: current Version

Batch: GQ00065
Batch Siegfried: 1923HMF045

Manufacturing date: 06/06/2019 Exp. date: 05/2024

Test specification: 7906000 Version: 12/03/2018

Specification
Lower Upper
Characteristics Unit Result Limit Limit

Analysis on finished producfs

Appearance - complies clear solution
Clarity and Opalescence (Ph.Eur./USP)
Appearance - complies colouriess solution
Colour (Ph.Eur./USP)
Appearance (JP) complies clear and
colouriess
solution, odourless
Foreign Insoluble Matter (JP) - complies complies
Extractable volume ml 5.3 5.0
(Ph.Eur./USP/JP)
Acidity or Alkalinity - complies complies
(Ph.Eur.)
Oxidisable substances (Ph.Eur./USP) - complies complies
Potassium Permanganate- “ complies complies
reducing substances (JP)
Ammonium (Ph.Eur.) - complies max. 0.6 ppm
Calcium and Magnesium (Ph.Eur.) - complies complies

Our Companies terms and conditions are applicable and to be read on our website www.siegfried-hameln.de
Siegfried Hameln GmbH, Langes Feld 13, 31789 Hameln, Geschäftsführer: Torsten Förster, Dr. Rene Imwinkelried,
Amtsgericht Hannover HRB 100015, USt.-ID Nr. DE 811165138

www.siegfried.ch
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

Siegfried

Paae
2 of 2

Material: 7906600 Wfl, STER, 5ml, EP/USP/JP, UNLBLD

Customer Material: 3500044

Techn. quality agreement: current Version

Batch: G0Q0Q65
Batch Siegfried: 1923HMFQ45

Manufacturing date: 06/06/2019 Exp. date: 05/2024

Specification
Lower Upper
Characteristics Unit Result Limit Limit

Sulfates (Ph.Eur.) - complies complies

Chlorides (Ph.Eur.) - complies max. 0.5 ppm
Nitrates (Ph.Eur.) - complies max. 0.2 ppm
Aluminium (Ph.Eur./AAS) - complies max. 50 ppb
0/
Residue on Evaporation (Ph.Eur.) /o < 0.001 0.004
Conductivity (Ph.Eur.) pS/crri 2 25
Conductivity (USP/JP) pS/crri 2 25
Insoluble Particulate Matter /cont. 8 6000
(sub-visible particles)
(>/= 10 pm/s.v.)
(Ph.Eur./USP/JP)
Insoluble Particulate Matter /cont. 0 600
(sub-visible particles)
(>/= 25 pm/s.v.)
(Ph.Eur./USP/JP)
Sterility (Ph.Eur./USP/JP) - complies complies
Endotoxins (Ph.Eur./USP/JP) EU/ml < 0.12 0.24

Siegfried Hameln GmbH (formerly hameln pharmaceuticals gmbh untii 01/2018)

Siegfried
Siegfried Hameln GmbH
PostfäoKTq OS 63, Langes Feld 13
31 /£9\Hairiein
wvww.siaßfried.ch
Hameln, 06/27/2019
Dr. Olaf Schagon
Qualified Person

*** End ***

Our Companies terms and conditions are applicable and to be read on our website www.siegfried-hameln.de
Siegfried Hameln GmbH, Langes Feld 13, 31789 Hameln, Geschäftsführer: Torsten Förster, Dr. Rene Imwinkelried,
Amtsgericht Hannover HRB 100015, USt.-ID Nr. DE 811165138
www.siegfried.ch
DocuSign Envelope ID: F0494BC1-3CAA-407E-8F4C-AFC9F9A00735

Dept. BAMA
Possingergasse 38, AT-1160 Wien
Dipl.Ing. (FH) Christoph Kefeder; e-mail: christoph.kefeder@ages.at
Phone: +43(0)5 0555 36331; Fax: +43(0)5 0555 36309
To: Baxter AG, AT

EU/EEA OFFICIAL CONTROL AUTHORITY BATCH RELEASE CERTIFICATE - Finished Product

Examined under Article 114 of Directives 2001/83/EC as amended by Directive 2004/27/EC (Medicinal
Products derived from Human Blood or Plasma) and in accordance with the Administrative Procedure
for Official Control Authority Batch Release.

Trade name: Cinryze 500IU

International non-propriety name / Ph. Eur. name / Human C1 inhibitor
common name:
Batch numbers appearing on package and other C4V005
identification numbers associated with this batch:
Type of container: Vials of moulded glass, type I
Total number of containers in this batch: 7305
Nominal dose per container: 500 IU
Date of start of period of validity: 15.06.2020
Date of expiry: 31.05.2022
Marketing authorisation number (member state / EU) EU/1/11/688/001 (EMA)
issued by:
Name and address of manufacturer (site of Qualified Takeda Manufacturing Austria AG
Person signing summary protocol unless otherwise Industriestraße 67
indicated): AT-1221 Wien
Name and address of marketing authorisation holder: Shire Services BVBA
Rue Montoyer 47
BE-1000 Brussels

This batch has been examined using documented procedures which form part of a quality system which is
in accordance with the EN/ISO 17025 standard.
This examination is based on the relevant EU OCABR guideline for this product.
All constituent plasma pools have been tested by an OMCL for virological markers.

This batch is in compliance with the approved specifications laid down in the relevant
European Pharmacopoeia monographs and the above marketing authorisation and is released.

Signed:

Name and Function of Signatory: Dipl.Ing. (FH) Christoph Kefeder

Date of Issue: 13.07.2020
Release Certificate Number: ZAT-202916
20067136

BASG - Austrian Federal Office for Safety in Health Care Page 1 of 1

Traisengasse 5 l 1200 Vienna l AUSTRIA l www.basg.gv.at
DVR: 2112611
Abschlusszertifikat
Umschlag-ID: F0494BC13CAA407E8F4CAFC9F9A00735 Status: Abgeschlossen
Betreff: C4V005AS_COA.pdf
Quellumschlag:
Dokumentenseiten: 9 Signaturen: 3 Umschlagersteller:
Zertifikatsseiten: 2 Initialen: 0 Manuela Meixner
Signatur mit Anleitung: Aktiviert 40 Landsdowne Street
Umschlag-ID-Stempel: Aktiviert Cambridge, MA 02139
Zeitzone: (UTC+09:00) Osaka, Sapporo, Tokio manuela.meixner@takeda.com
IP-Adresse: 81.217.224.216

Eintragsverfolgung
Status: Original Inhaber: Manuela Meixner Standort: DocuSign
04-Nov-2020 | 21:56 manuela.meixner@takeda.com

Unterzeichnerereignisse Signatur Zeitstempel

Manuela Meixner Gesendet: 04-Nov-2020 | 21:57
manuela.meixner@takeda.com Eingesehen: 04-Nov-2020 | 21:57
Takeda - DocuSign GxP Signiert: 04-Nov-2020 | 21:57
Sicherheitsstufe: E-Mail, Kontoauthentifizierung
(erforderlich) Signaturübernahme: Vorgegebener Stil
Signatur-ID:
6DA3F14D-4986-42EE-B62B-A0A00519D573
Mit IP-Adresse: 81.217.224.216

Mit Signaturauthentifizierung über

DocuSign-Passwort
Mit Signiergrund (auf jeder Registerkarte):
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Vereinbarung bezüglich elektronischer Unterlagen und Signaturen:
Nicht über DocuSign möglich

Barbara Groh Gesendet: 04-Nov-2020 | 21:57

barbara.groh@takeda.com Eingesehen: 05-Nov-2020 | 01:26
Qualified Person, QA Assoc. Director Signiert: 05-Nov-2020 | 01:27
Takeda - DocuSign GxP
Signaturübernahme: Vorgegebener Stil
Sicherheitsstufe: E-Mail, Kontoauthentifizierung
(erforderlich) Signatur-ID:
8E8B7270-3358-4ED8-9336-E3742C4A986F
Mit IP-Adresse: 88.117.69.98

Mit Signaturauthentifizierung über

DocuSign-Passwort
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I approve this document
I approve this document
Vereinbarung bezüglich elektronischer Unterlagen und Signaturen:
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Umschlag gesendet Hash-codiert/verschlüsselt 04-Nov-2020 | 21:57
Zertifiziert zugestellt Sicherheitsprüfung ausgeführt 05-Nov-2020 | 01:26
Signiervorgang abgeschlossen Sicherheitsprüfung ausgeführt 05-Nov-2020 | 01:27
Abgeschlossen Sicherheitsprüfung ausgeführt 05-Nov-2020 | 01:27

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