sample sqos biologics

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009 – SINGAPORE QUALITY OVERA LL SUMMARY FOR BIOLOGICS

HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP Append ix 9 - of 24

APPENDIX 9 SINGAPORE QUALITY OVERALL SUMMARYNew Drug Applications (Biologics)

The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e., Chemistry,Manufacturing and Controls) portion of a New Drug Application (NDA) for a biologic drug product.

Both hard copy and electronic copy of the Singapore QOS shall be submitted for review.

The applicant is responsible for completing all sections and fields as much as possible. Sections andfields that are not applicable should be indicated with “NA”. An explanatory note must accompany all“NA” entries.

INTRODUCTION

Proprietary Name of Drug Product Vaccaflu

Non-Proprietary or Common Name of Drug Substance

Hemagglutinin, Influenza Vaccine

Product Owner Name Company OW Inc.

License Holder Name Company LH (Singapore) Pte. Co.

Dosage Form Solution for injection. The vaccine contains antigenwith Aluminium phosphate adjuvant (solution).

Strength(s) Influenza Virus A/Wisconsin/67/2005 (H3N2)-likestrain (15 mcg hemagglutinin / 0.5 ml)

Route of Administration Intramuscular

Proposed Indication(s)Indicated for active immunization against Influenzacaused by influenza H3N2 virus

Other introductory information: Approved in USA, Canada, Japan, Mexico

Vaccaflu is a sterile liquid with 0.02% thimerosal (50μg of mercury per dose) as a preservative,and trace residual amounts of egg proteins, formaldehyde (≤25μg per dose) and sodium

deoxycholate (≤45μg per dose). Antibiotics are used in the manufacture of this vaccine and arecontrolled at ≤ 1 ng/mL. Vaccaflu is presented as a 10mL vial containing the antigen and the Aluminium phosphate adjuvant for a total of 20 doses of 0.5mL.





S DRUG SUBSTANCE

S 1 GENERAL INFORMATION

Check appropriate box.

CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients i s attached.

Plasma Master File (PMF)

Site Master File (SMF)

Drug Substance meets in-house specifications. Analytical methods and appropr iateanalytical method validation data are included in the dossier.

S 1.1 Nomenclature

Hard Copy Location/Pages: Tab C/ p. 7 – 10OR Tab C/ Module 3 Section S1 p. 7 – 10OR Volume 3/ p. 7 - 10OR Volume 3/ Module 3 Section S1 p. 7 – 10

E-Copy Location/File Name: CD 03 / FluS1.pdf OR PRISM/ FluS1.pdf

Substance Name: Hemagglutinin

Other names:(e.g. INN, BAN, USAN, common name)

Haemagglutinin

Company or laboratory code: OW AG Flu-068

S 1.2 Structure

Hard Copy Location/Pages: Tab C/ p. 11 - 87

E-Copy Location/File Name: CD 03 / FluS1.pdf

Schematic amino acid sequence indicatingglycosylation sites or other post-translationalmodifications and relative molecular massshould be provided, as appropriate:

Influenza virions are enveloped particles of spherical or elongated shape, measuring 80-120 nm in diameter and containing a

segmented, single-stranded, negative-senseRNA genome. Influenzavirus A is divided intosubtypes on the basis of the two antigenicglycoproteins, haemagglutinin (HA) andneuraminidase (NA). HA is responsible for attachment of the virus to specific receptors onthe host cell surface and mediates a fusionreaction between the viral envelope and the cellmembrane through which the viral genomegains access to the interior of the cell. NA isresponsible for cleaving the host cell receptor,releasing progeny virus from the infected cell

surface.

• Electron microscopy of the drug substance





demonstrates that greater than 98% of the virusin drug substance preparations is disrupted(split) by treatment with sodium deoxycholate.• Analysis of the protein content of the split-virion preparation by SDS-PAGE and Westernblot demonstrates the presence of a smallnumber of major protein bands (including HA)characteristic of each strain, with other lessprevalent protein bands that may be of viral or egg origin.• Dynamic Light Scattering analysis of themonovalent drug substances confirm a particlesize distribution with a mean diameter of 150-175nm, and >90% population less than 200nm.

S 1.3 General Propert ies

Hard Copy Location/Pages: Tab C/ p. 88 – 200

E-Copy Location/File Name: CD 03 / FluS1.pdf

Physicochemical and other relevant propertiesof the drug substance, including biologicalactivity

Each monovalent drug substance is a sterile,suspension prepared from influenza virus type A or B, which is propagated in the allantoiccavity of embryonated chicken eggs. After harvesting, the influenza virus is inactivated,purified, detergent-split, and sterile-filtered. Thecontent of each drug substance is standardized

on the basis of hemagglutinin (HA) antigen. Inaddition to the HA proteins, other influenza andegg-derived proteins are present. The drugsubstance is stored in pre-sterilized, single-usefluid handling bags at 2-8°C until formulation of the trivalent vaccine drug product. The specificstrains of influenza virus that are included in thevaccine are selected annually by the U.S. FDA,in collaboration with other Public Health Serviceagencies and the WHO.

S 2 MANUFACTURE

S 2.1 Manufacturer(s)

Name and address, of each production site or facility involved in different manufacture and testingactivities:

Activi ty Name and Address

2.1.1 Drug Substance Manufacture Company SA AGXxxstrasse 123, CH-4567 Basel, Switzerland

Company SU Inc (for US Market only) 123 Technology Park, Cambridge, MA6789, USA





Name and address, of each production site or facility involved in different manufacture and testingactivities:


2.1.2Process Intermediates Manufacture(e.g. Master Cell Bank, Working CellBank)

Same as 2.1.1 except

MCB manufacturer:Company SB Ltd8 Technology Drive, Biotech Industrial Estate, London

XX9 YY0, UK

2.1.3 Pilot/ Development BatchesManufacture

Company SC GmbH

Yyystrasse 89, D-0123 Frankfurt, Germany

2.1.4 Testing of Process Intermediates andDrug Substance Release

Same as 2.1.1 except Additional testing site:Company SD B. V.

Postbus 34567, NL-8910, Netherlands

2.1.5 Stability Study Company SE Pty Ltd1234 Science Avenue, AUS-Melbourne, Victoria 2234,

Australia

2.1.6 Others (if applicable, please specify) Additional storage site for DS:

Company SE Pty Ltd1234 Science Avenue, AUS-Melbourne, Victoria 2234,

Australia





S 2.2 Descrip tion of Manufacturing Process and Process Controls


(Tab C/ Module 3 Section S2 p.1 – 350)

E-Copy Location/File Name: CD 03/ FluS2.pdf

Typical production batch size: 50L

Flow diagram of the manufacturing process:

S 2.3 Control of Materials


E-Copy Location/File Name:CD 03/ FluS2.pdf





S 2.4 Controls of Critical Steps and Intermediates



S 2.5 Process Validation and/or Evaluation



S 2.6 Manufacturing Process Development

Hard Copy Location/Pages: Tab C/ p.1151 - 1200


S 3 CHARACTERISATION

S 3.1 Elucidation of Structure and other Characteristics



S 3.2 Impurities

(1) Product-Related Impurities:

Name Description Control Method* & Acceptance Level

Influenza-DerivedProteins

Non-HA and non-NAproteins

Removed during purification. ≤500μg/mL

* Please indicate if it is controlled by in-process control test, product release test, or by validatedpurification method.

(2) Process-Related Impurities:

Human plasma derived materials

Name Origin / Point of Entry Control Method* & Acceptance Level

NA NA NA (no human plasma derived materials are

used in the DS manufacturing process)

NA NA NA

Animal derived materials

Name Origin / Point of Entry Control Method* & Acceptance LevelOvalbumin Eggs Product release test, ≤ 1.0 μg/mL (Final Bulk





Vaccine Only)

Sodiumtaurodeoxycholate

Detergent disruption In-process control test, ≤ 75 ppm

Other materials

Name Origin / Point of Entry Control Method* & Acceptance Level

Neomycin Neomycin stock solutionused in the preparation of influenza monovalent bulks

Absence of Neomycin was assessed byFluorescence Polarization ImmunoAssay.

SucroseSucrose gradient /concentration andpurification of virus

< 20 μg/mL

Beta-propiolactone Viral inactivation ≤ 4 ng/mL

S 4 CONTROL OF THE DRUG SUBSTANCE

S 4.1 Specification

Standard Claimed for the Drug Substance (e.g., USP, BP, in-house etc.):

Ph. Eur

Test Method (e.g.,HPLC)

Source/Ref #or SOP #

Acceptance Criteria

Hemagglutinin content SRD (Single

RadialDiffusion)

Ph. Eur. 2.7.1 Report result in μg HA/mL

Sterility test FTM(30 - 35°C)SCDM(20 - 25°C)

Ph. Eur., USP<71> Absence of growth

Absence of growth

Residual sodiumdeoxycholate

HPLC-MSmethodGC-MS

In-houseSOP FLU 004

≤ 150 μg/ml

Appearance VisualInspection

In-house

SOP FLU 007Colourless to pale yellow liquid

Copy of o ffic ial Drug Substance Release Specifications


E-Copy Location/File Name: CD 03/ FluDS.pdf



GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE – SINGAPORE QUALITY OVERA LL SUMMARY FOR BIOLOGICS

HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP

S 4.2 Analytical Procedures

S 4.3 Validation of Analytical Procedures

For each test, please indicate “ yes” or “ no” as appropriate

Test Name M e t h o d D e s c r i p t i on

S el e c t i v i t y

L i n e ar i t y

R an g e

A c c ur a c y

P r e c i s i on

-

R e p e a t a b i l i t y

-

I n t er m e d i a t e

P r e c i s i on

-

R e pr o d u c i b i l i t y

L i mi t of D e t e c t i on

Hemagglutinincontent

Single RadialImmunodiffusion

yes no no no yes no

SterilityMembraneFiltration

no no no no no no

Residual sodiumdeoxycholate

HPLC andSpectrometry

yes yes yes yes yes yes





S 4.4 Batch Analyses

Batch Number Batch SizeBatch Type

(production/pilot)Date of

ProductionSite of Production

FVIXS009 50L Production 06 Apr 07Company SA AGSwitzerland

FVIXS010 50L Production 27 Nov 07Company SA AGSwitzerland

FVIXS011 50L Production 15 Apr 08Company SA AGSwitzerland

S 4.5 Justi fication of Specification



Test Just ification of Specifications

Hemagglutinin contentNo specification for this parameter as the product formulationprocess can accommodate a wide range of HAconcentration.

Sterility test No growth as DS must be absent of microbial contamination.

Residual sodium deoxycholateSet to ensure DP will be below EP specification of sodiumdeoxycholate.

Appearance Specification is from known properties of DS.

S 5 REFERENCE STANDARDS OR MATERIALS



Batch Number

Source (e.g., USP, in-

house)

Primary Reference StandardNIBSC A/Wisconsin/67/2005(H3N2)-like strain 002

National Institute of BiologicalStandards and Control

Working Standard NA (Same as above) NA (Same as above)

S 6 CONTAINER CLOSURE SYSTEM



Description of the container closure system(s) for the storage of the drug substance:





The Monovalent Pooled Harvest is stored in 10L glass bottles, which is made from Class ABorosilicate with Polypropylene screw cap that meets the European Pharmacopoeial specificationsfor Type I Borosilicate Glass and Polypropylene closures.

S 7 STABILITY

S 7.1 Stability Summary and Conclus ions

(1) Stability Study Details:

Storage Condit ions(°C, % RH, light)

BatchNumber

Batch Size Site of Manufacture

Completed Test Intervals(months)

2°C to 8°C, protectfrom light

FVIXS003 50LCompany SA

AGSwitzerland

0, 1, 3, 6, 9, 12, 18, 24


FVIXS004 50LCompany SA AGSwitzerland

0, 1, 3, 6, 9, 12, 18, 24


FVIXS005 50LCompany SA AGSwitzerland

0, 1, 3, 6, 9, 12, 18, 24

(2) Summary and Discussion of All Stability Study Results:



(3) Proposed Storage Conditions and Shelf Life:

Container Closure System Storage Conditions Shelf Life

10L Type I Borosilicate GlassBottle with Polypropylenescrew cap

2°C to 8°C, protect from light 24 months

S 7.2 Post-approval Stability Protocol and Stability Commitment

Stability protocol for commitment batches (if applicable):

Protocol Parameter Descrip tion

Number of batches and batch sizes 1 batch per year

Tests and acceptance criteria Same as indicated in S7.1

Container closure system(s) Same as indicated in S7.1

Testing frequency Same as indicated in S7.1

Storage conditions (and tolerances) of samples Same as indicated in S7.1





Other NA

S 7.3 Stabilit y Data



P DRUG PRODUCT

P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

(1) Description of the Dosage Form (Type of container closure system used for the dosage

form and accompanying reconstitution diluent, if applicable):Vaccaflu is presented as a 10mL vial containing the 15 mcg hemagglutinin / 0.5 ml of InfluenzaVirus A/Wisconsin/67/2005 (H3N2)-like strain and the Aluminium phosphate adjuvant for a totalof 20 doses of 0.5mL. The formulation contains thiomersal as a preservative.

(2) Composition (i.e., list of all components of the dosage form, and their amounts on a per unitbasis including overages):

Component Quality Standard Quantity per unit

(incl. overages)

Function

Drug Substance

Influenza Virus A/Wisconsin/67/2005 (H3N2)-like strain

Ph Eur. 15mcghemagglutinin / 0.5ml dose

Immunogen

Excipients (Human Plasma Derived)

NA NA NA NA

Excipients (Animal Derived)

NA NA NA NA

Excipients (Others)

Aluminium phosphate In house 0.5 mg Aluminiumper 0.5mL dose Adjuvant

Sodium chloride Ph. Eur. 2.82 mg per 0.5mLdose

Buffer

Thiomersal Ph. Eur. 50 mcg / 0.5ml dose Preservative

Potassium dihydrogenphosphate

Ph. Eur. 0.203 mg per 0.5mLdose

Buffer

Water for injection Ph. Eur. q.s 0.5 ml Solvent

Residuals

Neomycin NA ≤2ng per 0.5mL dose NAReconstitution Diluents





NA NA NA NA

P 2 PHARMACEUTICAL DEVELOPMENT

P 2.1 Components of the Drug Product

Hard Copy Location/Pages: Tab C/ 2551 – 2600

E-Copy Location/File Name: CD 03/ FluP2.pdf

P 2.2 Drug Product

P 2.2.1 Formulation Development



P 2.2.2 Overages



P 2.2.3 Physicochemical and Biological Properties



P 2.3 Manufacturing Process Development

Discussion of the development of the manufacturing process of the drug product(e.g., optimization of the process, selection of the method of sterilization, etc.):



P 2.4 Container Closure System

Discussion of the suitability of the container closure system (described in P 7) used for the

storage, transportation (shipping), and use of the drug product and reconstitution diluent (e.g.,physicochemical tests, biological reactivity tests, leaching, etc.):



P 2.5 Microbiological Att ributes

Discussion of microbiological attributes of the dosage form where applicable (e.g., preservativeeffectiveness studies):







P 2.6 Compatibility

Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosagedevices (e.g., precipitation of drug substance in solution, sorption on injection vessels, etc.):

Hard Copy Location/Pages:Tab C/ 2801 – 2850


P 3 MANUFACTURE

P 3.1 Manufacturer(s)

Name, address, and activity of each manufacturer, including contractors, and each proposedproduction site or facility involved in manufacture and testing of product intended for Singapore:


3.1.1 Drug Product ManufactureCompany PA

Xxxstrasse 123, CH-4567 Basel, Switzerland

3.1.2 Process Intermediates (e.g. DrugProduct bulk) Manufacture (if differentfrom 3.1.1)

Same as 3.1.1 except Additional primary packaging site for USmarket only

Company PB

123 Packed Rd, Cambridge, MA6789, USA

3.1.3 Pilot/ Development BatchesManufacture (if different from 3.1.1)

Same as 3.1.1

3.1.4 Testing for Process Intermediates andDrug Product Release (if different from3.1.1)

Same as 3.1.1

3.1.5 Stability Study (if different from 3.1.1) Company PC1234 Science Avenue, AUS-Melbourne,

Victoria 2234, Australia

3.1.6 Others (if applicable, please specify) Sterility (Back up): ABS Biotec Services856 Michele-Blain, Bohecville, Quebec,Canada J7C 6J8





P 3.2 Batch Formula

List of all components of the dosage form to be used in the manufacturing process, and their amounts on a per batch basis (including overages, if any):

Strength (Label claim): 15μg H3N2/0.5mL dose

Batch/ Lot Size (Number of dosage units): 150,000 vials

Component and Quality Standard (and Grade, if applicable) Quantity per batch

Split-virion H3N2 Antigen ( aa μg/mL) 20L

Thiomersal stock solution ( bb mg/mL) 1.5L

Aluminium phosphate solution ( cc g/L) 20 L

Sodium chloride (dd g/L) 5 L

Potassium dihydrogen phosphate (ee g/L) 8.5L

Water for injection q.s

Total 1850L





P 3.3 Description of Manufacturing Process and Process Controls



Flow diagram of the manufacturing process(es):

P 3.4 Controls of Critical Steps and Intermediates



P 3.5 Process Validation and/or Evaluation



Manufacturing site at which the validation is carried out: Company PA





Batch Number (Batches must be consecutive) Batch SizeBatch Type

(production/pilot/experimental)

FVIXP001150,000vials

Production

FVIXP002150,000

vials

Production


Production

P 4 CONTROL OF EXCIPIENTS

P 4.1 Specifications

Specifications for non-compendial excipients and for compendial excipients which includesupplementary tests not required by the monograph(s):



P 4.2 Analytical Procedures



P 4.3 Validation of Analytical Procedures



P 4.4 Justi fication of Specifications

Justification of the specifications (e.g., evolution of tests, analytical procedures, andacceptance criteria, exclusion of certain tests, differences from compendial standard, etc.):



Specifications for non-compendial excipients and for compendial excipients which includesupplementary tests not required by the monograph(s).



P 4.5 Excipients of Human or Animal Origin

Information regarding adventitious agents for excipients of human or animal origin (e.g.,sources, specifications, description of the testing performed, viral safety data):







P 4.6 Novel Excipients

Hard Copy Location/Pages: NA (No novel excipient used in the manufacturing)

E-Copy Location/File Name: NA

P 5 CONTROL OF DRUG PRODUCT

P 5.1 Specification(s)

Standard Claimed for the Drug Product

(e.g., USP, Ph.Eur, BP, JP, In-house etc.):

In-house

Test Method (e.g.,HPLC)

Source/Ref #or SOP #

ReleaseSpecification

Shelf LifeSpecification

pH Potentiometric Ph.Eur.2.2.3 6.7 – 7.3 6.6 – 7.4

DescriptionVisualExamination

In-house

SOP FLU 010

Pass if consistentwith description

Pass if consistent withdescription

Extractable

Volume

Volume

calculated asmass per density

Ph.Eur 2.9.17

≥ 11.2mL to

≤ 11.4mL

≥ 11.2mL to

≤ 11.4mL

Strain identitySingle RadialImmunodiffusion (SRD)

Ph. Eur 2.7.1Pass if consistentwith expectedstrain

Pass if consistent withexpected strain

HA Content Single RadialImmunodiffusion (SRD)

Ph.Eur.2.7.1 ≥ 35 μg HA / mL ≥ 30 μg HA / mL

Sterility MembraneFiltration

Ph.Eur 2.6.1Pass if noContaminationdetected

Pass if noContaminationdetected

Endotoxin (LAL) Gel Clot Ph.Eur.2.6.14 ≤ 40 EU/mL ≤ 40 EU/mL

Thiomersal Atomicabsorptionspectroscopy

In-house

SOP FLU 012

0.0185% to0.0215% w/v

0.0180% to0.0210% w/v

Aluminium Atomicabsorptionspectroscopy

In-house

SOP FLU 015

0.35 to 0.40mg/mL

0.35 to 0.40mg/mL

Copy of Offic ial Drug Product Release Specifications:






E-Copy Location/File Name: CD 03/ FluDP-spec.pdf



GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE – SINGAPORE QUALITY OVERA LL SUMMARY FOR BIOLOGICS

HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP

P 5.2 Analytical Procedures

P 5.3 Validation of Analytical Procedures

For each test, please indicate “ yes” or “ no” as appropriate

Test Name M e t h o d D e s c r i p t i on

S el e c t i v i t y

L i n e ar i t y

R an g e

A c c ur a c y

P r e c i s i on

-

R e p e a t a b i l i t y

-

I n t er m e d i a t e

P r e c i s i on

-

R e pr o d u c i b i l i t y

L i mi t of D e t e c t i on

Thiomersal Atomic Absorption

Spectroscopy

Yes Yes Yes Yes Yes No

Aluminium Atomic Absorption

SpectroscopyYes Yes Yes Yes Yes No

Endotoxin Gel Clot Yes No Yes Yes Yes No

Hemagglutinin Antigen

ContentSingle Radial

ImmunoDiffusionYes No No No Yes No





P 5.4 Batch Analyses

Batch Number Batch SizeBatch Type

(production/pilot)Date of

ProductionSite of

ProductionSite of Batch

Release

FVIXP001 150,000 vials Production 01 Apr 06 Company PA Company PA

FVIXP002 150,000 vials Production 09 May 06 Company PA Company PA

FVIXP003 150,000 vials Production 04 Jun 06 Company PA Company PA

P 5.5 Characterisation of Impurities

Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary

of actual and potential degradation products, basis for setting the acceptance criteria, etc): Hard Copy Location/Pages: Tab C/ 3601 – 3650


P 5.6 Justi fication of Specification(s)



Test Justi fication of Specifications

pH This limit was chosen as it is specified for other aluminium-adjuvanted vaccines manufactured by Company PA

Description This is based on known properties of the drug product.

Extractable Volume

The target fill volume is 11.2 mL to ensure the ability towithdraw 20 x 0.5mL single doses per vial when using a 1mLsyringe. The end user withdraws each single dose with a newsyringe, thus some product loss occurs during this procedure,which necessitates the approximate 1.2mL overfill.

Strain identity This is to ensure that the correct strain is used.

HA Content This limit was chosen as it is specified for other influenzavaccines manufactured by Company PA

Sterility This is based on the sterile requirement for the product.

Endotoxin (LAL)The specifications and the limit is in compliance with the Ph.Eur.: 0158 monograph requirement.

Thiomersal The limit is in compliance with the Ph. Eur.: 0158 monographrequirement.

AluminiumThe specification is consistent with the limit used for other Company PA aluminium-adjuvanted vaccines.





P 6 REFERENCE STANDARDS OR MATERIALS

If the reference standard is a secondary standard (in house /working standard), evidence that the

secondary standard has been standardised against an official standard should be provided Dataof studies performed on working standard against primary standard should be included, together with a Certificate of Analysis.



Batch Number Source (e.g., USP, in-house)

Primary Reference StandardNIBSC A/Wisconsin/67/2005(H3N2)-like strain 002

National Institute of BiologicalStandards and Control

Working Standard NA (Same as above) NA (Same as above)

P 7 CONTAINER CLOSURE SYSTEM

Description of the container closure systems:



Container Closure System Quantity per Container Pack Size

Type I uncoloured glass 15ml vial with rubber

stopper and flip-off cap

Fill volume of 12.1mL 1 vial / carton

P 8 STABILITY

P 8.1 Stabilit y Summary and Conclusions

(1) Summary and Conclusions:

Hard Copy Location/Pages: Tab C/ 4000 - 4050


(2) Stability Study Details:

Proposed Commercial Batch Size (e.g.kg, litres) :

150,000 vials (1850L)

BatchNumber

Batch Size Date of Manufacture

Site of Manufacture

Source of DrugSubstance andBatch number

Container ClosureSystem

FVIXP001 150,000vials 26 March 07 Company PA

Company SA AG

FVIXS008

Type I uncoloured

glass 15ml vial withrubber stopper andflip-off cap





BatchNumber

Batch Size Date of Manufacture

Site of Manufacture

Source of DrugSubstance andBatch number


FVIXP002 150,000vials

16 May 07 Company PA Company SA AGFVIXS009

Type I uncoloured

glass 15ml vial withrubber stopper andflip-off cap


07 Dec 07 Company PA Company SA AG

FVIXS010

Type I uncolouredglass 15ml vial withrubber stopper andflip-off cap

Storage Condi tions (°C, % RH,light) Completed Test Intervals

FVIXP001 at 5±3°C 0, 1, 2, 4, 6, 9, 12 (12 months)

FVIXP002 at 5±3°C 0, 1, 2, 4, 6, 9, 12 (12 months)

FVIXP003 at 5±3°C 0, 1, 2, 4, 6, 9, 12 (12 months)

FVIXP001 at 30±2°C 0, 1, 2, 4, 6 (6 months)

FVIXP002 at 30±2°C 0, 1, 2, 4, 6 (6 months)

FVIXP003 at 30±2°C 0, 1, 2, 4, 6 (6 months)

In-use stability testing (where applicable):

In-use Storage Conditions(°C, % RH, light)

Length of Storage prior toStart of In-use Stability

Testing

Completed In-use Test Intervals(e.g. minutes/ hours/ days)

FVIXP001 at 30±2°C 12 months 24 hours



(3) Proposed Storage Conditions and Shelf Life:


Storage Conditions (and In-useStorage Conditions, if applicable)

Shelf Life (and In-use Period, if applicable)

Type I uncoloured glass15ml vial with rubber

Store at 5±3°C. (30±2°C after opening)

12 months (24 hours after opening)





stopper and flip-off cap

P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1) Stability Protocol for Commitment Batches:


Number of batches per strength and batch sizes NA (No post-approval commitments)

Tests and acceptance criteria NA

Container closure system(s) NA

Testing frequency NA

Storage conditions (and tolerances) of samples NA

Other NA

(2) Stability Protocol for Continuing (i.e., ongoing) Batches:


Number of batches per strength per year andbatch sizes

Minimum of 1 batch per year

Tests and acceptance criteria Same as indicated in P8.1

Container closure system(s) Same as indicated in P8.1

Testing frequency Same as indicated in P8.1

Storage conditions (and tolerances) of samples Same as indicated in P8.1

Other NA

P 8.3 Stabilit y Data



A APPENDICES

A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)





E-Copy Location/File Name: CD 03/ FluPA.pdf

A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM,MANUFACTURER)


E-Copy Location/File Name: CD 03/ FluPA.pdf

A 3 NOVEL EXCIPIENTS

Hard Copy Location/Pages: NA (no novel excipients used in the manufacturing)

E-Copy Location/File Name: NA

Applicant’s Name: Date:

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