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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009 SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendi x 8 - Page 1 of 25
APPENDIX 8 SINGAPORE QUALITY OVERALL SUMMARYNew Drug Applications and Generic Drug Applications (Chemicals)
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) or a Generic Drug
Application (GDA) for a chemical drug product. Both hard copy and electronic copy of the Singapore QOSshall be submitted for review.
The applicant is responsible for completing all sections and fields as much as possible. Sections and fieldsthat are not applicable should be indicated with NA. An explanatory note must immediately follow all NAentries.
INTRODUCTION
Proprietary Name of Drug Product HSA Paracetamol
INN Common Name of DrugSubstance
Acetaminophen
Product Owner Name Somewhere Pte Ltd
Licence Holder Name HSA
Dosage Form Tablets
Strength(s) 100mg
Route of Administration Oral
Proposed Indication(s) Common analgesic and antipyretic drug that is used for therelief of fever and headaches and minor aches and painsand for the treatment of cancer.
Other int roductory information:
Approved in Singapore, Australia and USA.
HSA Paracetamol Tablets 100mg are round, white flat, plain tablets packaged in Alu Alu blisters. The
presentation is 10 tablets per blister strip and 2 strips per carton container box. The indication is forpain and cancer therapy and all appropriate and relevant information has been submitted inaccordance with the current HSA guidelines. A shelf life of 2 years when stored at or below 300C isproposed.
The Singapore Reference Product is Initial Paracetamol, Singapore (SIN01234) which is approved in1999.
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S DRUG SUBSTANCE
S 1 GENERAL INFORMATION
Check appropriate box.
DMF (open) part is attached.
DMF (open and restricted) and Letter of Access to be submi tted by 01/01/2009 (within onemonth of PRISM submission),
OR
Letter of Access to the DMF filed with HSA (015:________) is provided.
* CEP (Certificate of Suitability from EDQM) for Drug Substance is attached.
CEP Number:
CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients i s attached.
Drug Substance meets the current USP/PhEur/BP/JP (delete as appropriate)requirements.
Drug Substance meets other pharmacopoeia standards.
Drug Substance meets in-house specifications .
Drug Substance meets other pharmacopoeia standards. Analytical methods andappropriate analytical method validation data are included in the dossier.
Drug Substance meets in-house specifications. Analytical methods and appropr iateanalytical method validation data are included in the dossier.
* If CEP is provided and Ph.Eur standard is claimed for drug substance, please fill in S1, S2.1, S4.4 and #S7If CEP is provided and other standards are claimed for drug substance, please fill in S1, S2.1, S4.1 to S4.5 and #S7(#To be provided if re-test period/shelf life is not stated on CEP)
S 1.1 Nomenclature
Hard Copy Location/Pages: Module 3 Pg 1-5
E-Copy Location/File Name: CD 03 / S1.pdf
Chemical Name: para-acetylaminophenol
Other names: (e.g. INN, BAN, USAN, common name) Paracetamol
Company or laboratory code: APAP - 1234
Chemical Abstracts Service (CAS) registry number: 103-90-2
S 1.2 Structure
Hard Copy Location/Pages: Module 3 Pg 6-10
E-Copy Location/File Name: CD 03 / S1.pdf
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Structural formula (including stereochemistry):
Molecular formula: C8H9NO2
Molecular Mass: 151.169 g/mol
S 1.3 General Properties
Hard Copy Location/Pages: Module 3 Pg11-15
E-Copy Location/File Name: CD 03 / S1.pdf
Physical description (e.g., appearance, colour, physical state): White to off-white powder
Physical form (e.g., polymorphic form, solvate, hydrate):
Two other known crystallineanhydrous polymorphs denoted as
Form A and Form B. The XRPDpatterns for all crystalline forms aredifferent and XRPD has been usedto routinely differentiate the multiplecrystalline forms.
Solubilities (e.g., in common solvents, aqueous/non-aqueoussolubility profile):
Freely soluble in water at pH7.0.
pH and pKa values: pKa = 9.5
Other (e.g., partition coefficients, melting or boiling points,optical rotation, refractive index (for a liquid), hygroscopicity,UV absorption maxima and molar absorptivity):
Melting Point = 169C
Non-hygroscopic
S 2 MANUFACTURE
S 2.1 Manufacturer(s)
Name, address, and activity of each manufacturer, including contractors, and each proposedproduction site or facility involved in manufacture and testing:
Activi ty Name and Address *GMP Compliance (Please
indicate Approving Agency)
Site of ManufactureGo Get Chemicals22 Pine ValleyCaliforniaUSA
Yes, US FDA
Site of Release testingGood Testers23 Grove RoadUSA
No
Site of Batch ReleaseGo Get Chemicals22 Pine ValleyCaliforniaUSA
Yes, US FDA
* For information only.
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S 2.2 Descrip tion of Manufacturing Process and Process Controls
Hard Copy Location/Pages: Module 3 15-20 and DMF (Restricted)
E-Copy Location/File Name: CD 03 / S2.pdf and CD_DMF (Restricted)
Typical production batch size: 100kg
Flow diagram of the synthetic process (es):
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S 2.3 Control of Materials
Hard Copy Location/Pages: Module 3 15-20 and DMF (Restricted)
E-Copy Location/File Name: CD 03 / S2.pdf and CD_DMF (Restricted)
S 2.4 Controls of Crit ical Steps and Intermediates
Hard Copy Location/Pages: Module 3 15-20 and DMF (Restricted)
E-Copy Location/File Name: CD 03 / S2.pdf and CD_DMF (Restricted)
S 2.5 Process Validation and/or Evaluation
Hard Copy Location/Pages: Module 3 15-20 and DMF (Restricted)
E-Copy Location/File Name: CD 03 / S2.pdf and CD_DMF (Restricted)
S 2.6 Manufacturing Process Development
Hard Copy Location/Pages: Module 3 15-20 and DMF (Restricted)
E-Copy Location/File Name: CD 03 / S2.pdf and CD_DMF (Restricted)
S 3 CHARACTERISATION
S 3.1 Elucidation of Structure and other Characteristics
Hard Copy Location/Pages: Module 3 Pg 41-45
E-Copy Location/File Name: CD 03/S3.pdf
S 3.2 Impurities
Summary of potential and actual impurities arising from the synthesis, manufacture and/or degradation:
ChemicalName/Laboratory Code
Origin/Type of Impurity Structure
4 aminophenol Degradation Product Structure of impurity should be insertedhere, if available.
2 aminophenol Degradation ProductStructure of impurity should be inserted
here
1 aminophenol Synthetic impurityStructure of impurity should be inserted
here
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Process-related impurities (e.g., residual solvents):
Compound Name Step in Process
Methanol Crystallisation
Benzene Extraction
S 4 CONTROL OF THE DRUG SUBSTANCE
S 4.1 Specification
Standard Claimed for the Drug Substance (e.g., USP, BP,etc.):
USP
Test Method(e.g., HPLC)
Source (e.g.,USP, in-house)
Acceptance Criteria
Appearance Visual In-house White to off white powder againstmatt white background
Identity test by IR IR USP IR spectrum of the standard conformsto the IR spectrum of the sample
Identity test by HPLC HPLC USP The HPLC chromatogram of thestandard peak corresponds to thepeak obtained in the chromatogramfor the sample solution
pH pH meter USP 3.5-5.5
Loss on drying USP USP Dry at 1050C, weight loss NMT 0.5%of its weight
Residue on ignition USP USP NMT 0.1%
Impurities (%w/w)
4 Aminophenol3 Aminophenol2 AminophenolAny other unidentifiedTotal
HPLC In-house
NMT 0.2NMT 0.1NMT 0.2NMT 0.1NMT 0.5
Assay (%w/w) on a dried basis HPLC In-house 98.5-101.0
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S 4.2 Analytical Procedures
S 4.3 Validation of Analytical Procedures
For each test, please indicate yes or no as appropriate
Test Name MethodDescription
Selectivity
Linearity
Range
Accuracy
Precision
-
Repeatability
-
Intermediate
Precision
-
Reproducibility
LimitofDetection
LimitofQuantitation
Assay of Paracetamol Yes Yes Yes Yes Yes Yes Yes YeImpurities by HPLC Yes Yes Yes Yes Yes Yes Yes Ye
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S 4.4 Batch Analyses
Batch Number Batch SizeBatch Type
(production/pilot)Date of
ProductionSite of Production
CA001 100kg Production 1 Jan 2001Go Get Chemicals22 Pine ValleyCaliforniaUSA
CA002 100kg Production 15 Sept 2002
CA003 100kg Production 30 April 2003
S 4.5 Just ification of Specification
Hard Copy Location/Pages: Module 3 Pg 66-70
E-Copy Location/File Name: CD 03/ S4.pdf
Test Just ification of Specifications
Appearance Visual inspection allows for identification & detection of possibledefects
ImpuritiesThe acceptance criteria applied is based on: 1) the maximum contentof impurities found in the batches used during the development for
toxicology studies and in the intentionally degraded and spiked batchNo. FE 349 used to qualify the impurities (Information located in3.2.S.3.2.) 2) the qualification level of each impurity.
Assay The HPLC weight percent assay specification of 98.5-101.0% wasestablished from a review of the release data generated to date andfrom consideration of the assay variability. The weight percentrelease results ranged from 98.5% to 100.7% in the batch data. Thespecification of 98.5-101.0% by weight describes the consistentlyhigh quality of the drug substance and allows for typical analyticalvariability.
Other tests Comply with USP requirements.
S 5 REFERENCE STANDARDS OR MATERIALS
Hard Copy Location/Pages: Module 3 Pg 71-75
E-Copy Location/File Name: CD 03/ S5.pdf
Batch Number Source (e.g., USP, in-house)
Primary Reference Standard USP 1111 USPWorking Standard CA 0000 In-house
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S 6 CONTAINER CLOSURE SYSTEM
Description of the container closure system(s) for the storage of the drug substance:
Drug substance in polyethylene bags, double layered with a twist tie.
S 7 STABILITY
S 7.1 Stability Summary and Conclus ions
Stability study details:
Storage
Conditions(C, % RH, light)
Batch
Number
Batch Size Site of
Manufacture
Completed Test Intervals
(months)
30C/75%RH CA011 100kgGo Get Chemicals22 Pine ValleyCaliforniaUSA
0, 3, 6, 9, 12, 18, 24, 36 and 48
CA012 100kg 0, 3, 6, 9, 12, 18, 24, 36 and 48
CA013 100kg 0, 3, 6, 9, 12, 18, 24
40C/75%RH CA011 100kg
Go Get Chemicals
22 Pine ValleyCaliforniaUSA
0, 3 and 6
CA012 100kg 0, 3 and 6
CA013 100kg 0, 3 and 6
Summary and discussion of all stability study results:
Hard Copy Location/Pages: Module 3 Pg 80-85E-Copy Location/File Name: CD 03/ S7.pdf
Proposed storage conditions and re-test period (or shelf life, as appropriate):
Container ClosureSystem
Storage Condit ions Re-test Period (or Shelf Life, asappropriate)
Polyethylene bags Store at or below 30C Retest period of 24 months
S 7.2 Post-approval Stability Protocol and Stability Commitment
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Stability protocol for commitment batches (if applicable):
Protocol Parameter Descrip tion
Number of batches and batch sizes None
Tests and acceptance criteria None
Container closure system(s) None
Testing frequency None
Storage conditions (and tolerances) of samples None
Other None
S 7.3 Stability Data
Hard Copy Location/Pages: Module 3 Pg 86-90
E-Copy Location/File Name: CD 03/ S7.pdf
P DRUG PRODUCT
P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT
(1) Description of the dosage form:
The tablets are round, white, flat plain and contain 100mg of acetaminophen. The tablets are packaged intoAlu Alu blister strips. There are 2 blister strips per carton box.
(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis(including overages, if any):
Strength (Label claim): 100mg
Components Qual ity Standard Quanti ty per uni t % Function
Acetaminophen USP 100mg 50 Active
Microcrystalline cellulose BP 20mg 10 Diluent
Starch PhEur 20mg 10 Diluent
Polyvinvyl pyroolidone JP 20mg 10 Binder
Magnesium stearate USP 20mg 10 Lubricant
Sodium starch glycolate BP 18mg 9 Disintegrant
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(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis(including overages, if any):
Strength (Label claim): 100mg
Components Qual ity Standard Quanti ty per uni t % Function
Brilliant Colour Coating In-house 2mg 1 Coating
Total 200mg 100
(3) Composition, i.e., qualitative list of all components of proprietary materials (e.g., capsule shells,colouring blends, imprinting inks, etc.): Brilliant Colour Coating
Proprietary Material Qualitative Composition Quantitative Composition
Iron Oxide Red NF NF 40%w/w
Hydroxy propyl methyl cellulose USP 50%w/w
Glycol JP 10%w/w
(4) Description of accompanying reconstitution diluent(s), if applicable:
Not applicable.
P 2 PHARMACEUTICAL DEVELOPMENT
P 2.1 Components of the Drug Product
Hard Copy Location/Pages: Module 3 Pg 91-95
E-Copy Location/File Name: CD 03/ P2.pdf
P 2.2 Drug Product
P 2.2.1 Formulation Development
Hard Copy Location/Pages: Module 3 Pg 96-100
E-Copy Location/File Name: CD 03/ P2.pdf
P 2.2.2 Overages
Hard Copy Location/Pages: Module 3 Pg 101-105
E-Copy Location/File Name: CD 03/ P2.pdf
P 2.2.3 Physicochemical and Biological Properties
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Hard Copy Location/Pages: Module 3 Pg 106-110
E-Copy Location/File Name: CD 03/ P2.pdf
P 2.3 Manufacturing Process Development
Discussion of the development of the manufacturing process of the drug product (e.g., optimization ofthe process, selection of the method of sterilization, etc.):
Hard Copy Location/Pages: Module 3 Pg 111-115
E-Copy Location/File Name: CD 03/ P2.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 (e.g., physicochemical tests, biological reactivitytests, leaching, etc.):
Hard Copy Location/Pages: Module 3 Pg 115-120
E-Copy Location/File Name: CD 03/ P2.pdf
P 2.5 Microbiological Attr ibutes
Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies):
Hard Copy Location/Pages: Module 3 Pg 121-125
E-Copy Location/File Name: CD 03/ P2.pdf
P 2.6 Compatibility
Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g.,precipitation of drug substance in solution, sorption on injection vessels, etc.):
Hard Copy Location/Pages: Module 3 Pg 126-130
E-Copy Location/File Name: CD 03/ P2.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
Site of Fabrication, Manufacturing HSA11 Biopolis WaySingapore
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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
Site of Primary Packaging Good PackagersJohore BahruMalaysia
Site of Secondary PackagingExcellent PackingBintanIndonesia
Site of Release TestingTrust TestersBangkokThailand
Site of Batch ReleaseHSA11 Biopolis WaySingapore
P 3.2 Batch Formula
List of all components of the dosage form to be used in the manufacturing process, and their amountson a per batch basis (including overages, if any):
Strength (Label claim): 100mg
Batch Size (Number of dosage units): 200kg (1000 000 tablets)
Component and Quality Standard (and Grade, if applicable) Quantity per batch
Acetaminophen 100kg
Microcrystalline cellulose 20kg
Starch 20kg
Polyvinvyl pyroolidone 20kg
Magnesium stearate 20kg
Sodium starch glycolate 18kg
Brilliant Colour Coating 2kg
Total 200kg
P 3.3 Descrip tion of Manufacturing Process and Process Controls
Hard Copy Location/Pages: Module 3 Pg 141-145
E-Copy Location/File Name: CD 03/ P3.pdf
Flow diagram of the manufacturing process(es):
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P 3.4 Controls of Critical Steps and Intermediates
Hard Copy Location/Pages: Module 3 Pg 146-150
E-Copy Location/File Name: CD 03/ P3.pdf
P 3.5 Process Validation and/or Evaluation
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Hard Copy Location/Pages: Module 3 Pg 151-155
E-Copy Location/File Name: CD 03/ P3.pdf
Please check appropriate boxes.
Development Pharmaceutics Report Starting page #:Ending page#:
91130
Validation Scheme Starting page #:Ending page#:
151155
3 (e.g. 2) Pilot batches were used in the validationstudy
Starting page #:Ending page#:
151155
_____ (e.g. 3) full production batches were used inthe validation study
Starting page #:Ending page#:
Type of Validation
Retrospective
Prospective
Concurrent*
Others; please specify:
* Prior consultation with HSA is required.
Manufacturing site at which the validation is carried out: HSA, Singapore
Batch Number (Batches must be consecutive) Batch SizeBatch Type
(production/pilot/experimental)
SQ1100 150kg Pilot
SQ2200 150kg Pilot
SQ3300 150kg Pilot
Post-Approval Commitment
(1) Validation protocol for commitment batches:
Protocol Parameter Descrip tion
Number of batches per strength 3 batches
Batch Size 200kg
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) may be found in:
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Hard Copy Location/Pages: Module 3 Pg 156-160
E-Copy Location/File Name: CD 03/ P4.pdf
P 4.2 Analytical Procedures
Hard Copy Location/Pages: Module 3 Pg 161-165
E-Copy Location/File Name: CD 03/ P4.pdf
P 4.3 Validation of Analytical Procedures
Hard Copy Location/Pages: Module 3 Pg 166-170
E-Copy Location/File Name: CD 03/ P4.pdf
P 4.4 Just ification of Specifications
Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria,exclusion of certain tests, differences from compendial standard, etc.):
Hard Copy Location/Pages: Module 3 Pg 171-175
E-Copy Location/File Name: CD 03/ P4.pdf
P 4.5 Excipients of Human or Animal Origin
Hard Copy Location/Pages: Module 3 Pg 176
E-Copy Location/File Name: CD 03/ P4.pdf
P 4.6 Novel Excipients
Hard Copy Location/Pages: Module 3 Pg 176
E-Copy Location/File Name: CD 03/ P4.pdf
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P 5 CONTROL OF DRUG PRODUCT
P 5.1 Specification(s)
Standard Claimed for the Drug Product(e.g., USP, Ph.Eur, BP, JP etc.):
In-house
Test Method (e.g.,HPLC)
Source (e.g.,USP, In-house)
ReleaseSpecification
Shelf LifeSpecification
Appearance Visual In-house Round, white, flat plain tablets
Identification by IR IR In-house The IR spectrum of the sampleconforms to the reference IR
Identification by HPLC HPLC In-house The HPLC peak in the referencestandard conforms to the peak in theHPLC chromatogram of the sample
Weight Variation BP Method BP Complies to BP -
Dissolution Time (Q at 30min)
USP Method USP 80 70
Assay (% of label claim) HPLC In-house 95.0-105.0 90.0-110.0
Impurities (%w/w)
4 Aminophenol3 Aminophenol2 AminophenolAny other unspecifiedTotal
HPLC In-house
NMT 0.5NMT 0.3NMT 0.2NMT 0.1NMT 1.0
NMT 0.8NMT 0.5NMT 0.4NMT 0.1NMT 4.0
Microbial Limit Test USP USP - Complies
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P 5.2 Analytical Procedures
P 5.3 Validation of Analytical Procedures
For each test, please indicate yes or no as appropriate
Test Name MethodDescription
Selectivity
Linearity
Range
Accuracy
Precision
-
Repeatability
-
Intermediate
Precision
-
Reproducibility
LimitofDetection
Assay of Paracetamol Yes Yes Yes Yes Yes Yes Yes
Impurities Method Yes Yes Yes Yes Yes Yes Yes
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P 5.4 Batch Analyses
Batch Number Batch SizeBatch Type
(production/pilot)Date of
ProductionSite of
ProductionSite of Batch
Release
SQ55 200kg Production 1 Mar 2000 HSA 11Biopolis WaySingapore
HSA 11 BiopolisWay Singapore
SQ66 200kg Production 2 Apr 2001
SQ77 200kg Production 5 July 2004
P 5.5 Characterisation of Impurities
Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary ofactual and potential degradation products, basis for setting the acceptance criteria, etc):
Chemical Name/LaboratoryCode
Origin/Type of Impurity
4 Aminophenol Degradation product
P 5.6 Just ification of Specification(s)
Hard Copy Location/Pages: Module 3 Pg 196-200
E-Copy Location/File Name: CD 03/ P5.pdf
Test Just ification of Specifications
Appearance Visual inspection allows for identification & detection of possibledefects
IdentificationTwo identification tests carried out routinely: HPLC and infraredspectrum. Although the retention times obtained from HPLC may notbe regarded as being specific, the combination of infrared spectrumwith it is sufficient and acceptable to identify the drug substancewithout ambiguity.
ImpuritiesThe acceptance criteria applied is based on: 1) the maximum contentof impurities found in the batches used during the development fortoxicology studies and in the intentionally degraded and spiked batchNo. FE 250 used to qualify the impurities 2) the qualification level ofeach impurity.
Assay The HPLC weight percent assay specification was established froma review of the release and stability data generated to date and fromconsideration of the assay variability. The specification describes
the consistently high quality of the drug product and allows fortypical analytical variability.
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Test Just ification of Specifications
Other tests Comply with Pharmacopeia requirements.
P 6 REFERENCE STANDARDS OR MATERIALS
If the reference standard is a secondary standard (in house /working standard), evidence that thesecondary standard has been standardised against an official standard should be provided Data ofstudies performed on working standard against primary standard should be included, together withappropriate Certificate of Analysis.
Hard Copy Location/Pages: Module 3 Pg 201-205
E-Copy Location/File Name: CD 03/ P6.pdf
Batch Number Source (e.g., USP, in-house)Primary Reference Standard USP 1111 USP
Working Standard SQ 0000 In-house
P 7 CONTAINER CLOSURE SYSTEM
Description of the container closure systems:
Descrip tion of Container Closure Quantity Per Container Pack Size
Alu Alu Blisters 10 tablets per blister strip 2 strips per carton
P 8 STABILITY
P 8.1 Stability Summary and Conclusions
Hard Copy Location/Pages: Module 3 Pg 211-220
E-Copy Location/File Name: CD 03/ P8.pdf
Proposed Commercial Batch Size (kg): 200kg
BatchNumber
Batch Size Date of Manufacture
Site ofManufacture
Source of ActiveIngredient andBatch Number
ContainerClosureSystem
BA001 100kg 1 June 2003HSA11 Biopolis WaySingapore
Go Get Chemicals22 Pine ValleyCaliforniaUSA
Alu Alu blisters
BA002 100kg 2 June 2003 Alu Alu bisters
BA003 100kg 3 June 2003 Alu Alu bisters
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Storage Condi tions (C, % RH,light)
Completed Test Intervals
30C/75%RH 0, 3, 6, 9, 12, 18 and 24 months
40C/75%RH 0, 3 and 6
Light cabinet 1, 2 weeks
In-use stability testing (where applicable): Not applicable as no in-use shelf life is claimed
In-use Storage Conditions(C, % RH, light)
Length of Storage prior to Startof In-use Stability Testing
Completed In-use Test Intervals(e.g. minutes/ hours/ days)
Proposed storage conditions and shelf life:
Container ClosureSystem
Storage Condit ions (and In-useStorage Conditions, if
applicable)
Shelf Life (and In-use Period, ifapplicable)
Alu Alu Blisters Store at or below 300C 24 months
P 8.2 Post-Approval Stabilit y Protocol and Stability Commitment
(1) Stability protocol for commitment batches:
Protocol Parameter Descrip tion
Number of batches per strength and batchsizes
Three production batches, 200kg
Tests and acceptance criteria Same as registered in P5.1
Container closure system(s) Alu Alu Blisters
Testing frequency 0, 3, 6, 9, 12, 18 and 24 months
Storage conditions (and tolerances) of samples 30C/75%RH and 40C/75%RH
Other None
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(2) Stability protocol for continuing (i.e., ongoing) batches:
Protocol Parameter Descrip tion
Number of batches per strength per year andbatch sizes
One batch per year, 200kg
Tests and acceptance criteria Same as registered in P5.1
Container closure system(s) Alu Alu Blisters
Testing frequency 1, 12 and 24 months
Storage conditions (and tolerances) of samples 30C/75%RH
Other None
P 8.3 Stabili ty Data
Hard Copy Location/Pages: Module 3 Pg 225-230
E-Copy Location/File Name: CD 03/ P8.pdf
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P 9 PRODUCT INTERCHANGEABILITY
P 9.1 Bioavailability / Bioequivalence Study
Details of the batches usedfor BA/BE study
Generic Product Submitted toHSA for Registration
Current RegisteredSingapore Reference
Product
Product Name HSA Paracetamol Initial Paracetamol, Singapore
Strength of Dosage Form 100mg 100mg
Site of Manufacture HSA11 Biopolis Way
Singapore
First OneGrange Road
Singapore
Site of Batch Release N/A
Batch No. BE1001 RF1001
Batch size 200kg N/A
Product formula Same as section P.3.2
Yes
No, please provide justification
N/A
Study Report Number 12111
BA/BE Study Site (Name & Address) BE Site
Wheelock Road
Singapore
Date of Inspection of Study 1 Jan 2004
Name of Inspecting Agency/Author ity XX Authority of YYY
Availabi li ty of Inspection Report (Yes/No) Yes
Generic Product Usedin BA/BE Study
Reference Product Usedin BA/BE Study
Product Name HSA Paracetamol Initial Paracetamol, Hong Kong
Strength of Dosage Form 100mg 100mg
Site of Manufacture HSA11 Biopolis Way
Singapore
First OneGrange RoadHong Kong
Site of Batch Release HSA11 Biopolis Way
Singapore
First OneGrange RoadHong Kong
Country where the supply issourced for this study:
Singapore Hong Kong
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P 9.2 Comparative Dissolution Profil e
Product 1: = Initial Paracetamol, Hong Kong
Product 2: = Initial Paracetamol, Singapore
Study Report Number: 12111
Profile of Product 1 Profile of Product 2
Product Name Initial Paracetamol, Hong Kong Initial Paracetamol, Singapore
Strength of Dosage Form 100mg 100mg
Site of Manufacture First OneGrange RoadHong Kong
First OneGrange RoadSingapore
Site of Batch Release First One
Grange RoadHong Kong
First One
Grange RoadSingapore
Dissolution Method Used USP Paddle USP Paddle
Country where the supply issourced for this study:
Hong Kong Singapore
Dissolution Test Results Profile of Product 1 Profile of Product 2
Medium 1 pH 1
Range 99.0-102.2 98.0-105.3
Mean of 12 tablets 100.1 101,1
RSD 1.0 1.2
F2 Calculation 70
Medium 2 pH 4.6
Range 98.0-101.2 98.0-110.3
Mean of 12 tablets 100.4 101.7
RSD 1.0 1.2
F2 Calculation 68
Medium 3 pH 8.2
Range 99.0-102.2 98.0-102.3
Mean of 12 tablets 100. 101.1
RSD 1.0 1.2
F2 Calculation 71
Graphical Presentation Presented in Pages 12-24
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Statistical Analysis
Hard Copy Location/Pages: Module 3 Pg 231-250
E-Copy Location/File Name: CD 03/ P9.pdf
Other Relevant Information:
Bioequivalence study and dissolution comparison test results showed that the generic paracetamol isequivalent to Singapore Innovator Product.
A APPENDICES
A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)
Hard Copy Location/Pages: NA- not a requirement for Generic SubmissionE-Copy Location/File Name:
A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM, MANUFACTURER)
Hard Copy Location/Pages: NA- not a requirement for Generic Submission
E-Copy Location/File Name:
A 3 NOVEL EXCIPIENTS
Hard Copy Location/Pages: NA- No novel excipients are used
E-Copy Location/File Name:
Tan Ah Meng 01 Jan 2009
Applicants Name: Date:
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