GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JA NUARY 2009– SINGAPORE QUA LITY OVERA LL SUMMARY FOR B IOLOGICSHEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP Ap pend ix 9 - Page 1 of 24 APPENDIX 9 SINGAPORE QUAL ITY OVERALL SUMMARY New 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 and fields that are not applicable should be indicated with “NA”. An explanatory no te must accompany all “NA” entries. INTRODUCTION Proprietary Name of Drug Product VaccafluNon-Propri etary or Common Name ofDrug 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 antigen with Aluminium phosphate adjuvant (solution). Strength(s) Influenza Virus A/Wisconsin/67/2005 (H3N2)-like strain (15 mcg hemagglutinin / 0.5 ml) Route of Administration Intramuscular Proposed Indication(s) Indicated for active immunization against Influenza caused by influenza H3N2 virusOther intr oductory infor mation: 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 are controlled 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 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).
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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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
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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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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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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):
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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):
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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,
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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
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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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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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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.