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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 - Page 1 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.
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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 - Page 2 of 24
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
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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 - Page 3 of 24
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
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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 - Page 4 of 24
Name and address, of each production site or facility involved in different manufacture and testingactivities:
Activi ty Name and Address
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
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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 - Page 5 of 24
S 2.2 Descrip tion of Manufacturing Process and Process Controls
Hard Copy Location/Pages: Tab C/ p. 201 – 550
(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
Hard Copy Location/Pages: Tab C/ p. 551 – 630
E-Copy Location/File Name:CD 03/ FluS2.pdf
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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 - Page 6 of 24
S 2.4 Controls of Critical Steps and Intermediates
Hard Copy Location/Pages: Tab C/ p. 631 – 800
E-Copy Location/File Name: CD 03/ FluS2.pdf
S 2.5 Process Validation and/or Evaluation
Hard Copy Location/Pages: Tab C/ p. 801 – 1150
E-Copy Location/File Name: CD 03/ FluS2.pdf
S 2.6 Manufacturing Process Development
Hard Copy Location/Pages: Tab C/ p.1151 - 1200
E-Copy Location/File Name: CD 03/ FluS2.pdf
S 3 CHARACTERISATION
S 3.1 Elucidation of Structure and other Characteristics
Hard Copy Location/Pages: Tab C/ p.1201 - 1300
E-Copy Location/File Name: CD 03/ FluS3.pdf
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
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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 - Page 7 of 24
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
Hard Copy Location/Pages: Tab C/ p.1301 - 1305
E-Copy Location/File Name: CD 03/ FluDS.pdf
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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
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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 - Page 9 of 24
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
Hard Copy Location/Pages: Tab C/ p.2000 - 2007
E-Copy Location/File Name: CD 03/ FluS4.pdf
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
Hard Copy Location/Pages: Tab C/ p.2008 - 2012
E-Copy Location/File Name: CD 03/ FluS5.pdf
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
Hard Copy Location/Pages: Tab C/ p.2013 - 2024
E-Copy Location/File Name: CD 03/ FluS6.pdf
Description of the container closure system(s) for the storage of the drug substance:
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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 - Page 10 of 24
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
2°C to 8°C, protectfrom light
FVIXS004 50LCompany SA AGSwitzerland
0, 1, 3, 6, 9, 12, 18, 24
2°C to 8°C, protectfrom light
FVIXS005 50LCompany SA AGSwitzerland
0, 1, 3, 6, 9, 12, 18, 24
(2) Summary and Discussion of All Stability Study Results:
Hard Copy Location/Pages: Tab C/ p.2013 - 2024
E-Copy Location/File Name: CD 03/ FluS7.pdf
(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
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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 - Page 11 of 24
Other NA
S 7.3 Stabilit y Data
Hard Copy Location/Pages: Tab C/ p.2101 - 2200
E-Copy Location/File Name: CD 03/ FluS7.pdf
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
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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 - Page 12 of 24
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
Hard Copy Location/Pages: Tab C/ 2601 – 2610
E-Copy Location/File Name: CD 03/ FluP2.pdf
P 2.2.2 Overages
Hard Copy Location/Pages: Tab C/ 2601 – 2610
E-Copy Location/File Name: CD 03/ FluP2.pdf
P 2.2.3 Physicochemical and Biological Properties
Hard Copy Location/Pages: Tab C/ 2611 – 2650
E-Copy Location/File Name: CD 03/ FluP2.pdf
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.):
Hard Copy Location/Pages: Tab C/ 2651 – 2700
E-Copy Location/File Name: CD 03/ FluP2.pdf
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.):
Hard Copy Location/Pages: Tab C/ 2701 – 2750
E-Copy Location/File Name: CD 03/ FluP2.pdf
P 2.5 Microbiological Att ributes
Discussion of microbiological attributes of the dosage form where applicable (e.g., preservativeeffectiveness studies):
Hard Copy Location/Pages: Tab C/ 2751 – 2800
E-Copy Location/File Name: CD 03/ FluP2.pdf
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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 - Page 13 of 24
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
E-Copy Location/File Name: CD 03/ FluP2.pdf
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:
Activi ty Name and Address
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
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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 - Page 14 of 24
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
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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 - Page 15 of 24
P 3.3 Description of Manufacturing Process and Process Controls
Hard Copy Location/Pages: Tab C/ 3001 – 3050
E-Copy Location/File Name: CD 03/ FluP3.pdf
Flow diagram of the manufacturing process(es):
P 3.4 Controls of Critical Steps and Intermediates
Hard Copy Location/Pages: Tab C/ 3051 – 3100
E-Copy Location/File Name: CD 03/ FluP3.pdf
P 3.5 Process Validation and/or Evaluation
Hard Copy Location/Pages: Tab C/ 3101 – 3200
E-Copy Location/File Name: CD 03/ FluP3.pdf
Manufacturing site at which the validation is carried out: Company PA
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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 - Page 16 of 24
Batch Number (Batches must be consecutive) Batch SizeBatch Type
(production/pilot/experimental)
FVIXP001150,000vials
Production
FVIXP002150,000
vials
Production
FVIXP003150,000vials
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):
Hard Copy Location/Pages: Tab C/ 3201 – 3250
E-Copy Location/File Name: CD 03/ FluP4.pdf
P 4.2 Analytical Procedures
Hard Copy Location/Pages: Tab C/ 3251 – 3300
E-Copy Location/File Name: CD 03/ FluP4.pdf
P 4.3 Validation of Analytical Procedures
Hard Copy Location/Pages: Tab C/ 3301 – 3400
E-Copy Location/File Name: CD 03/ FluP4.pdf
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.):
Hard Copy Location/Pages: Tab C/ 3401 – 3450
E-Copy Location/File Name: CD 03/ FluP4.pdf
Specifications for non-compendial excipients and for compendial excipients which includesupplementary tests not required by the monograph(s).
Hard Copy Location/Pages: Tab C/ 3451 – 3500
E-Copy Location/File Name: CD 03/ FluP4.pdf
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):
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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009 – SINGAPORE QUALITY OVERA LL SUMMARY FOR BIOLOGICS
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Hard Copy Location/Pages: Tab C/ 3501 – 3550
E-Copy Location/File Name: CD 03/ FluP4.pdf
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:
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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 - Page 18 of 24
Hard Copy Location/Pages: Tab C/ 3551 – 3600
E-Copy Location/File Name: CD 03/ FluDP-spec.pdf
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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
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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 - Page 20 of 24
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
E-Copy Location/File Name: CD 03/ FluP5.pdf
P 5.6 Justi fication of Specification(s)
Hard Copy Location/Pages: Tab C/ 3651 – 3660
E-Copy Location/File Name: CD 03/ FluP5.pdf
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.
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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 - Page 21 of 24
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.
Hard Copy Location/Pages: Tab C/ 3662 – 3666
E-Copy Location/File Name: CD 03/ FluP6.pdf
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:
Hard Copy Location/Pages: Tab C/ 3667 – 3700
E-Copy Location/File Name: CD 03/ FluP7.pdf
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
E-Copy Location/File Name: CD 03/ FluP8.pdf
(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
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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 - Page 22 of 24
BatchNumber
Batch Size Date of Manufacture
Site of Manufacture
Source of DrugSubstance andBatch number
Container ClosureSystem
FVIXP002 150,000vials
16 May 07 Company PA Company SA AGFVIXS009
Type I uncoloured
glass 15ml vial withrubber stopper andflip-off cap
FVIXP003150,000vials
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
FVIXP002 at 30±2°C 9 months 24 hours
FVIXP003 at 30±2°C 6 months 24 hours
(3) Proposed Storage Conditions and Shelf Life:
Container ClosureSystem
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)
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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 - Page 23 of 24
stopper and flip-off cap
P 8.2 Post-Approval Stability Protocol and Stability Commitment
(1) Stability Protocol for Commitment Batches:
Protocol Parameter Descrip tion
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:
Protocol Parameter Descrip tion
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
Hard Copy Location/Pages: Tab C/ 4100 - 4200
E-Copy Location/File Name: CD 03/ FluP8.pdf
A APPENDICES
A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)
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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009 – SINGAPORE QUALITY OVERA LL SUMMARY FOR BIOLOGICS
Hard Copy Location/Pages: Tab C/ 4201 - 4300
E-Copy Location/File Name: CD 03/ FluPA.pdf
A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM,MANUFACTURER)
Hard Copy Location/Pages: Tab C/ 4301 - 4433
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: