Sample SQOS Chemical Drug

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 8 - Page 1 of 25

APPENDIX 8 SINGAPORE QUALITY OVERALL SUMMARY
New 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 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 note must immediately follow all NA
entries.

INTRODUCTION
Proprietary Name of Drug Product HSA Paracetamol
INN Common Name of Drug
Substance
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 the
relief of fever and headaches and minor aches and pains
and for the treatment of cancer.
Other introductory 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 for
pain and cancer therapy and all appropriate and relevant information has been submitted in
accordance with the current HSA guidelines. A shelf life of 2 years when stored at or below 30
0
C is
proposed.

The Singapore Reference Product is Initial Paracetamol, Singapore (SIN01234) which is approved in
1999.

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 submitted by 01/01/2009 (within one
month 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 is 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 and
appropriate analytical method validation data are included in the dossier.
Drug Substance meets in-house specifications. Analytical methods and appropriate
analytical 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
#
S7
If 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



Structural formula (including stereochemistry):

Molecular formula: C
8
H
9
NO
2

Molecular Mass: 151.169 g/mol

S 1.3 General Properties

Hard Copy Location/Pages: Module 3 Pg11-15

Physical description (e.g., appearance, colour, physical state): White to off-white powder
Physical form (e.g., polymorphic form, solvate, hydrate):
Two other known crystalline
anhydrous polymorphs denoted as
Form A and Form B. The XRPD
patterns for all crystalline forms are
different and XRPD has been used
to routinely differentiate the multiple
crystalline forms.
Solubilities (e.g., in common solvents, aqueous/non-aqueous
solubility 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 proposed
production site or facility involved in manufacture and testing:
Activity Name and Address *GMP Compliance (Please
indicate Approving Agency)
Site of Manufacture
Go Get Chemicals
22 Pine Valley
California
USA
Yes, US FDA
Site of Release testing
Good Testers
23 Grove Road
USA
No
Site of Batch Release
Go Get Chemicals
22 Pine Valley
California
USA
Yes, US FDA
* For information only.


S 2.2 Description 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):


S 2.3 Control of Materials


S 2.4 Controls of Critical Steps and Intermediates


S 2.5 Process Validation and/or Evaluation


S 2.6 Manufacturing Process Development


S 3 CHARACTERISATION

S 3.1 Elucidation of Structure and other Characteristics

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:
Chemical
Name/Laboratory Code
Origin/Type of Impurity Structure
4 aminophenol Degradation Product
Structure of impurity should be inserted
here, if available.
2 aminophenol Degradation Product
here
1 aminophenol Synthetic impurity
here


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 against
matt white background
Identity test by IR IR USP IR spectrum of the standard conforms
to the IR spectrum of the sample
Identity test by HPLC HPLC USP The HPLC chromatogram of the
standard peak corresponds to the
peak obtained in the chromatogram
for the sample solution
pH pH meter USP 3.5-5.5
Loss on drying USP USP Dry at 105
0
C, weight loss NMT 0.5%
of its weight
Residue on ignition USP USP NMT 0.1%
Impurities (%w/w)
4 Aminophenol
3 Aminophenol
2 Aminophenol
Any other unidentified
Total
HPLC In-house
NMT 0.2
NMT 0.1
NMT 0.2
NMT 0.1
NMT 0.5
Assay (%w/w) on a dried basis HPLC In-house 98.5-101.0


S 4.2 Analytical Procedures
S 4.3 Validation of Analytical Procedures

For each test, please indicate yes or no as appropriate
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Assay of Paracetamol Yes Yes Yes Yes Yes Yes Yes Yes Yes No
Impurities by HPLC Yes Yes Yes Yes Yes Yes Yes Yes Yes No


S 4.4 Batch Analyses

Batch Number Batch Size
Batch Type
(production/pilot)
Date of
Production
Site of Production
CA001 100kg Production 1 Jan 2001
Go Get Chemicals
22 Pine Valley
California
USA
CA002 100kg Production 15 Sept 2002
CA003 100kg Production 30 April 2003

S 4.5 Justification of Specification

E-Copy Location/File Name: CD 03/ S4.pdf

Test Justification of Specifications
Appearance Visual inspection allows for identification & detection of possible
defects
Impurities
The acceptance criteria applied is based on: 1) the maximum content
of impurities found in the batches used during the development for
toxicology studies and in the intentionally degraded and spiked batch
No. FE 349 used to qualify the impurities (Information located in
3.2.S.3.2.) 2) the qualification level of each impurity.
Assay The HPLC weight percent assay specification of 98.5-101.0% was
established from a review of the release data generated to date and
from consideration of the assay variability. The weight percent
release results ranged from 98.5% to 100.7% in the batch data. The
specification of 98.5-101.0% by weight describes the consistently
high quality of the drug substance and allows for typical analytical
variability.
Other tests Comply with USP requirements.

S 5 REFERENCE STANDARDS OR MATERIALS


Batch Number Source (e.g., USP, in-house)
Primary Reference Standard USP 1111 USP
Working Standard CA 0000 In-house


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 Conclusions

Stability study details:
Storage
Conditions
(C, % RH, light)
Batch
Number
Batch Size Site of
Manufacture
Completed Test Intervals
(months)
30C/75%RH CA011 100kg
Go Get Chemicals
22 Pine Valley
California
USA
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 Valley
California
USA
0, 3 and 6
CA012 100kg 0, 3 and 6
CA013 100kg 0, 3 and 6

Summary and discussion of all stability study results:


Proposed storage conditions and re-test period (or shelf life, as appropriate):
Container Closure
System
Storage Conditions Re-test Period (or Shelf Life, as
appropriate)
Polyethylene bags Store at or below 30C Retest period of 24 months

S 7.2 Post-approval Stability Protocol and Stability Commitment


Stability protocol for commitment batches (if applicable):
Protocol Parameter Description
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


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 into
Alu 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 Quality Standard Quantity per unit % 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

(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis
(including overages, if any):
Components Quality Standard Quantity per unit % 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

E-Copy Location/File Name: CD 03/ P2.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 (e.g., physicochemical tests, biological reactivity
tests, leaching, etc.):

P 2.5 Microbiological Attributes

Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies):

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.):

P 3 MANUFACTURE

P 3.1 Manufacturer(s)

production site or facility involved in manufacture and testing of product intended for Singapore:
Activity Name and Address
Site of Fabrication, Manufacturing
HSA
11 Biopolis Way
Singapore

production site or facility involved in manufacture and testing of product intended for Singapore:
Activity Name and Address
Site of Primary Packaging
Good Packagers
Johore Bahru
Malaysia
Site of Secondary Packaging
Excellent Packing
Bintan
Indonesia
Site of Release Testing
Trust Testers
Bangkok
Thailand
HSA
11 Biopolis Way
Singapore

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):
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 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



Please check appropriate boxes.

Development Pharmaceutics Report Starting page #:
Ending page#:
91
130

Validation Scheme Starting page #:
Ending page#:
151
155

3 (e.g. 2) Pilot batches were used in the validation
study
Starting page #:
Ending page#:
151
155

_____ (e.g. 3) full production batches were used in
the 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 Size
Batch Type
(production/pilot/experimental)
SQ1100 150kg Pilot
SQ2200 150kg Pilot
SQ3300 150kg Pilot

Post-Approval Commitment

(1) Validation protocol for commitment batches:
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 include
supplementary tests not required by the monograph(s) may be found in:


P 4.2 Analytical Procedures


P 4.3 Validation of Analytical Procedures


P 4.4 Justification 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.):

P 4.5 Excipients of Human or Animal Origin

Hard Copy Location/Pages: Module 3 Pg 176

P 4.6 Novel Excipients

Hard Copy Location/Pages: Module 3 Pg 176


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)
Release
Specification
Shelf Life
Specification
Appearance Visual In-house Round, white, flat plain tablets
Identification by IR IR In-house The IR spectrum of the sample
conforms to the reference IR
Identification by HPLC HPLC In-house The HPLC peak in the reference
standard conforms to the peak in the
HPLC chromatogram of the sample
Weight Variation BP Method BP Complies to BP -
Dissolution Time (Q at 30
min)
USP Method USP 80 70
Assay (% of label claim) HPLC In-house 95.0-105.0 90.0-110.0
Impurities (%w/w)
4 Aminophenol
3 Aminophenol
2 Aminophenol
Any other unspecified
Total
HPLC In-house

NMT 0.5
NMT 0.3
NMT 0.2
NMT 0.1
NMT 1.0

NMT 0.8
NMT 0.5
NMT 0.4
NMT 0.1
NMT 4.0
Microbial Limit Test USP USP - Complies

P 5.2 Analytical Procedures
P 5.3 Validation of Analytical Procedures

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Assay of Paracetamol Yes Yes Yes Yes Yes Yes Yes Yes Yes No
Impurities Method Yes Yes Yes Yes Yes Yes Yes Yes Yes No


P 5.4 Batch Analyses

Batch Number Batch Size
Batch Type
(production/pilot)
Date of
Production
Site of
Production
Site of Batch
Release
SQ55 200kg Production 1 Mar 2000 HSA 11
Biopolis Way
Singapore
HSA 11 Biopolis
Way 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 of
actual and potential degradation products, basis for setting the acceptance criteria, etc):
Chemical Name/Laboratory
Code
Origin/Type of Impurity
4 Aminophenol Degradation product

P 5.6 Justification of Specification(s)


Appearance Visual inspection allows for identification & detection of possible
defects
Identification
Two identification tests carried out routinely: HPLC and infrared
spectrum. Although the retention times obtained from HPLC may not
be regarded as being specific, the combination of infrared spectrum
with it is sufficient and acceptable to identify the drug substance
without ambiguity.
Impurities
The acceptance criteria applied is based on: 1) the maximum content
of impurities found in the batches used during the development for
toxicology studies and in the intentionally degraded and spiked batch
No. FE 250 used to qualify the impurities 2) the qualification level of
each impurity.
Assay The HPLC weight percent assay specification was established from
a review of the release and stability data generated to date and from
consideration of the assay variability. The specification describes
the consistently high quality of the drug product and allows for
typical analytical variability.

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

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:
Description 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


Proposed Commercial Batch Size (kg): 200kg
Batch
Number
Batch Size Date of
Manufacture
Site of
Manufacture
Source of Active
Ingredient and
Batch Number
Container
Closure
System
BA001 100kg 1 June 2003
HSA
11 Biopolis Way
Singapore
Go Get Chemicals
22 Pine Valley
California
USA
Alu Alu blisters
BA002 100kg 2 June 2003 Alu Alu bisters
BA003 100kg 3 June 2003 Alu Alu bisters

Storage Conditions (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 Start
of In-use Stability Testing
Completed In-use Test Intervals
(e.g. minutes/ hours/ days)

Proposed storage conditions and shelf life:
Container Closure
System
Storage Conditions (and In-use
Storage Conditions, if
applicable)
Shelf Life (and In-use Period, if
applicable)
Alu Alu Blisters Store at or below 30
0
C 24 months

P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1) Stability protocol for commitment batches:
Number of batches per strength and batch
sizes
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


(2) Stability protocol for continuing (i.e., ongoing) batches:
Number of batches per strength per year and
batch 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 Stability Data


P 9 PRODUCT INTERCHANGEABILITY

P 9.1 Bioavailability / Bioequivalence Study

Details of the batches used
for BA/BE study
Generic Product Submitted to
HSA for Registration
Current Registered
Singapore Reference
Product
Product Name HSA Paracetamol Initial Paracetamol, Singapore
Strength of Dosage Form 100mg 100mg
Site of Manufacture
HSA
11 Biopolis Way
Singapore
First One
Grange 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/Authority XX Authority of YYY
Availability of Inspection Report (Yes/No) Yes
Generic Product Used
in BA/BE Study
Reference Product Used
in BA/BE Study
Product Name HSA Paracetamol Initial Paracetamol, Hong Kong
Site of Manufacture
HSA
11 Biopolis Way
Singapore
First One
Grange Road
Hong Kong
HSA
11 Biopolis Way
Singapore
First One
Grange Road
Hong Kong
Country where the supply is
sourced for this study:
Singapore Hong Kong


P 9.2 Comparative Dissolution Profile

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
Site of Manufacture
First One
Grange Road
Hong Kong
First One
Grange Road
Singapore
First One
Grange Road
Hong Kong
First One
Grange Road
Singapore
Dissolution Method Used USP Paddle USP Paddle
Country where the supply is
sourced 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

Statistical Analysis

Other Relevant Information:

Bioequivalence study and dissolution comparison test results showed that the generic paracetamol is
equivalent to Singapore Innovator Product.

A APPENDICES

A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)

Hard Copy Location/Pages: NA- not a requirement for Generic Submission
E-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

A 3 NOVEL EXCIPIENTS

Hard Copy Location/Pages: NA- No novel excipients are used

Tan Ah Meng 01 Jan 2009
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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009

SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

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