fp-spec-acc

7/22/2019 FP-Spec-Acc

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Parameter FINISHED PRODUCT SPECIFICATION/ ACCEPTANCE CRITERIA BP/ Ph.Eur/ USP

Uniformity of

dosage units

2.9.40/905

Stage 1: For 10 units L1

Stage 2: For 30 units L1

No individual content of the dosage unit is less than (1-L2x0.01)M or more than (1+L2x0.01)M [L1=15,

L2=25]Uniformity of content 2.9.6

Uniformity of mass

2.9.5/2.9.27 Tablets (Uncoated and film-coated)

80 mg or less 10%

More than 80 mg and less than 250 mg 7.5%

250 mg or more 5%Capsules & granules (Uncoated,

single-dose) and powders (single-

dose)

Less than 300 mg 10%

300 mg or more 7.5%

granules, powders for oral use andliquids for oral use, which are

supplied in multidose containers

All 10%

Not more than 2/20of the individual

masses deviate fromthe average massby

more than the

percentage deviation

andnone deviatesby

more than twicethatpercentage.

Water 2.5.12/ 921 Specific for Product

LOD 2.2.32/ 731 0.5% is typical limit for LOD

Friability 2.9.7/

1216

For tablets with a unit mass equal to or less than650 mg, take a sample of whole tablets corresponding as near as possible

to6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets. NMT 1.0%Disintegration (2.9.1/ 701):

For tablets and capsules 18 mm long use Apparatus B all 6 of the tablets or capsules must have disintegrated.Uncoated tablets: with in 15 min

Coated tablets: for coated tablets other than film coated 60 min. For film coated 30 min

Hard/ Soft Capsules: with in 30 min

Effervescent tablets:Place 1 tablet in a beaker containing 200 ml of water at 15-25 C disintegrate within 5 min(6 Tablets)Soluble/ Dispersible Tablets:Dispersible tablets disintegrate within 3 min, using water at 15-25 C. Fineness of dispersion:Place 2

tablets in 100 ml of water and stir until completely dispersed. A smooth dispersion is produced, which passes through a sieve screenwith a nominal mesh aperture of 710 m. Orodispersible tablets:Orodispersible tablets disintegrate within 3 min.Gastro-resistant coating:For tablets covered with a gastro-resistant coating, carry out the test with the following modifications.

Use0.1M hydrochloric acid as the liquid. Operate the apparatus for2h, Replace the acid by phosphate buffer solutionpH6.8and add a

disc to each tube. Operate the apparatus for 60minOral lyophilisate:Place1oral lyophilisate in a beaker containing200ml of water at15-25C. It disintegrates within3min. Repeat the test on 5 other

Dissolution 2.9.3/ 711 Immediate-Release Dosage Forms

Conventional-release dosage formsAt least 75% (Q = 75%) Active substance is released within 45

minIn cases where a longer release time than that recommended

above is justified, limits at 2 time intervals may be specified.

Prolonged-release dosage formsNormally 3 or more points.

The first specification point typically 20 to 30%

The second specification point is set around 50%The final specification point more than 80%

Delayed-release dosage formsat least 2 specification pointsThe first specification point is set after 1 h or 2 h in acidic medium

The second specification point at buffer solution is Q = 75%

Stage Units Acceptance Criteria

S1 6 Each unit is not less than Q + 5%.

S2 6 Average of 12 units (S1 + S2) is equal to orgreater than Q, and no unit is less than Q 15%

S3 12 Average of 24 units (S1 + S2 +S3) is equal to or

greater than Q, not more than 2 units are less than

Q - 15%, and no unit is less than Q - 25

Extended-Release Dosage Forms

L1 6 No individual value lies outside each of the stated

ranges and no individual value is less than thestated amount at the final test time.

L2 6 The average value of the 12 units (L1 + L2) lies

within each of the stated ranges and is not less thanthe stated amount at the final test time; none is

more than 10% of labeled content outside each ofthe stated ranges; and none is more than 10% of

labeled content below the stated amount at the

final test time.

Acid Stage Delayed-Release Dosage Forms

A1 6 No individual value exceeds 10% dissolved.

A2 6 Average of the 12 units (A1 + A2) is not more than10% dissolved, and no individual unit is greater than

25% dissolved. L3 12 The average value of the 24 units (L1 + L2 + L3)

lies within each of the stated ranges and is not lessA3 12 Average of the 24 units (A1 + A2 + A3) is not more


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IMPURITIES

Impurity: Any component of the new drug substance that is not the chemical entity defined as the new drug

substance.

Impurity Profile: A description of the identified and unidentified impurities present in a new drug substance.

Degradation Product:An impurity resulting from a chemical change in the drug substance brought about during

manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, pH, water, or by

reaction with an excipient and/or the immediate container closure system.

Degradation Profile: A description of the degradation products observed in the drug substance or drug product.

Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the new

drug substance specification. A specified impurity can be either identified or unidentified.

Identified Impurity: An impurity for which a structural characterization has been achieved

Unidentified Impurity:An impurity for which a structural characterisation has not been achieved and that is defined

solely by qualitative analytical properties (e.g., chromatographic retention time).

Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with

its own specific acceptance criterion, in the new drug substance specification.Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting threshold is the same as

reporting level in Q2B.

Identified Impurity: An impurity for which a structural characterization has been achieved.

Identification Threshold:A limit above (>) which an impurity should be identified.

Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual

impurity or a given impurity profile at the level(s) specified.

Qualification Threshold:A limit above (>) which an impurity should be qualified.

Potential Impurity: An impurity that theoretically can arise during manufacture or storage. It may or may not

actually appear in the new drug substance.

Starting Material: A material used in the synthesis of a new drug substance that is incorporated as an element into

the structure of an intermediate and/or of the new drug substance. Starting materials are normally commercially

available and of defined chemical and physical properties and structure.

Intermediate: A material produced during steps of the synthesis of a new drug substance that undergoes further

chemical transformation before it becomes a new drug substance.

Reagent:A substance other than a starting material, intermediate, or solvent that is used in the manufacture of a newdrug substance.

Solvent:An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in thesynthesis of a new drug substance.

Enantiomeric Impurity: A compound with the same molecular formula as the drug substance that differs in the

spatial arrangement of atoms within the molecule and is a non-superimposable mirror image.

Polymorphic Forms: Different crystalline forms of the same drug substance. These can include solvation or

hydration products (also known as pseudo-polymorphs) and amorphous forms.

Herbal Products: Medicinal products containing, exclusively, plant material and/or vegetable drug preparations as

active ingredients. In some traditions, materials of inorganic or animal origin can also be present.

Extraneous Contaminant: An impurity arising from any source extraneous to the manufacturing process.

New Drug Substance: The designated therapeutic moiety that has not been previously registered in a region or

member state (also referred to as a new molecular entity or new chemical entity). It can be a complex, simple ester, or

salt of a previously approved drug substance.

Re-test date: The date after which samples of the drug substance should be examined to ensure that the material is

still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.

Re-test period: The period of time during which the drug substance is expected to remain within its specification and,


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Thresholds of Impurities in New Drug Substance Thresholds of Impurities in New Drug ProductMaximum

Daily Dose

Reporting

Threshold

Identification

Threshold

Qualification

Threshold

Maximum

Daily Dose

Report

ing

Thresh

old

Identification

Threshold

Maximum

Daily Dose

Reporting

Threshold

Qualification

Threshold

2g/day 0.05% 0.10% or

1.0mgper day intake

(whichever is

lower)

0.15% or 1.0

mg per dayintake

(whichever is

lower)

1- 4 mg 0.1% 0.50% 1 5 mg 0.1% 1.0%

5 mg 0.1% 0.40% 10 40 mg 0.1% 0.50%10-1000 mg 0.1% 0.20% 50 mg 0.1% 0.40%

1250 mg 0.05% 0.16% 75 mg 0.1% 0.30%

1500 mg 0.05% 0.15% 80 mg 0.1% 0.25%

> 2g/day 0.03% 0.05% 0.05% 2000 mg 0.05% 0.10% 100 1500 mg 0.1% (0.05%) 0.20%

2000 mg 0.05% 0.15%

Maximum

Daily Dose

Reporting

Threshold

Identification

Threshold

Qualification

Threshold

Solubility as per EP/USP

1 650 mg 0.05% 0.10% 0.15% Solute Required

for mg/mlSolute Required

for g/mlSolvent Parts

Required for

1 Part of Solute

Solubility Descriptive Term

700 mg 0.05% 0.10% 0.14%

750 mg 0.05% 0.10% 0.13%

1000 mg 0.05% 0.10% 0.10% 1000 1 < 1 Very Soluble

1250 mg 0.05% 0.08% 0.08% 100 10000 Practically insoluble (or) Insoluble

Maximu

m Daily

Dose

Identification

Threshold

Maximu

m Daily

Dose

Qualification

Threshold

< 1 mg 1.0% or 5 g

TDI, Whichever

is lower

< 10 mg 1.0% or 50 g

TDI, Whichever

is lower

1 10mg 0.5% or 20 g

TDI, Whichever

is lower

10mg

100mg

0.5% or 200 g

TDI, Whichever

is lower

>10 mg

- 2 g

0.2% or 2 mg

TDI, Whichever

is lower

>100 mg-

2 g

0.2% or 3 mg

TDI, Whichever

is lower

> 2 g 0.1% > 2 g 0.15%


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Q A Stability Testing of New Drug Substances and ProductsDrug SubstancesStress testing:Stress testing of the drug substance can help identify the likely degradation products, which

can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the

stability indicating power of the analytical procedures used. 50C or 60C temp; 75% RH or greater

Selection of Batches: Stability studies should be provided on at least three primary batches of the drugsubstance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route

Container Closure System: The stability studies should be conducted on the drug substance packaged in a

container closure system that is the same as or simulates the packaging proposed for storage and distribution.

Specification:susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.

Testing frequency/ Storage condition:

Intended for

storage

Study Storage condition Minimum time

period covered by

data at submission

Test time points

General case Accelerated40C 2C/ 75% 5% RH

6Months 0, 3, & 6 (3 TP)

Intermediate** 30C 2C/ 65% 5% RH 12 Months 0, 6, 9, & 12 (4 TP)

Long term* 25C 2C/ 60% 5% RH or

30C 2C/ 65% 5% RH

12 Months 0, 3, 6, 9, 12, 18, 24...

Refrigerator Accelerated 25C 2C/ 60% 5% RH 6 Months 0, 3, & 6 (3 TP)

Long term 5C 3C 12 Months 0, 3, 6, 9, 12, 18, 24...

Freezer Long term -20C 5C 12 Months 0, 3, 6, 9, 12, 18, 24...

Below -20C Long term Case-by-case basis

*It is up to the applicant to decide whether long term stability studies are performed at 25 2C/60% RH

5% RH or 30C 2C/65% RH 5% RH.

**If 30C 2C/65% RH 5% RH is the long-term condition, there is no intermediate condition.

Significant change for a drug substance is defined as failure to meet its specification.

Stability Commitment: the submission includes long term stability data on three production batches covering

the proposed re-test period, a post approval commitment is considered unnecessary. Otherwise, one of the

following commitments should be made.

1. Stability studies on at least three production batches, a commitment should be made to continue

these studies

2. Stability studies on fewer than three production batches, a commitment should be made to continuethese studies and to place additional production batches, to a total of at least three

3. Not include stability data on production batches, a commitment should be made to place the first threeproduction batches


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Drug ProductsPhoto-stability Testing:at least one primary batch of the drug product

Selection of Batches:Two of the three batches should be at least pilot scale batches and the third one can be smaller, if

justified.

Container Closure System: Thecontainer closure system proposed for marketing (including 1 and 2)Specification: susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. Thetesting should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservativecontent

Testing frequency/ Storage condition:

Intended for

storage

Study Storage condition Minimum time period

covered by data at

submission

Test time points

General case Accelerated40C 2C/ 75% 5% RH

6Months 0, 3, & 6 (3 TP)

Intermediate** 30C 2C/ 65% 5% RH 12 Months 0, 6, 9, & 12 (4 TP)

Long term* 25C 2C/ 60% 5% RH or

30C 2C/ 65% 5% RH

12 Months 0, 3, 6, 9, 12, 18, 24...

Impermeable

containers

Stability studies for products stored in impermeable containers can be conducted under any

controlled or ambient humidity condition.

Semi-permeable

containers

Accelerated 40C 2C/ NMT 25% RH 6 months 0, 3, & 6 (3 TP)

Intermediate##

30C 2C/ 35% 5% RH 6 months0, 6, 9, & 12 (4 TP)

Long term# 25C 2C/ 40% 5% RH or

30C 2C/ 35% 5% RH

12 months0, 3, 6, 9, 12, 18, 24...

Refrigerator Accelerated 25C 2C/ 60% 5% RH 6 Months 0, 3, & 6 (3 TP)

Long term 5C 3C 12 Months 0, 3, 6, 9, 12, 18, 24...Freezer Long term -20C 5C 12 Months 0, 3, 6, 9, 12, 18, 24...

Below -20C Long term Case-by-case basis

*It is up to the applicant to decide whether long term stability studies are performed at 25 2C/60% RH 5% RH or

30C 2C/65% RH 5% RH.

**If 30C 2C/65% RH 5% RH is the long-term condition, there is no intermediate condition.

#

It is up to the applicant to decide whether long term stability studies are performed at 25

2C/40% RH

5% RH or30C 2C/35% RH 5% RH.

##If 30C 2C/35% RH 5% RH is the long-term condition, there is no intermediate condition.

In general, significant change for a drug product is defined as:

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when usingbiological or immunological procedures;


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Procedure: For confirmatory studies, samples should be exposed to light providing an overall illumination of

not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt

hours/square meter to allow direct comparisons to be made between the drug substance and drug product.

Q1C Stability Testing for New Dosage Forms

Such pharmaceutical product types include products of different administration route (e.g., oral to parenteral),

new specific functionality/delivery systems (e.g., immediate release tablet to modified release tablet) anddifferent dosage forms of the same administration route (e.g., capsule to tablet, solution to suspension).

A reduced stability database at submission time (e.g., 6 months accelerated and 6 months long termdata

from ongoing studies) may be acceptable in certain justified cases.

Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Bracketing:Bracketing is the design of a stability schedule such that only samples on the extremes of certain

design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full designMatrixing:Matrixing is the design of a stability schedule such that a selected subset of the total number of

possible samples for all factor combinations would be tested at a specified time point. At a subsequent time

point, another subset of samples for all factor combinations would be tested.

Q1EEvaluation for Stability Data

The guideline provides recommendations on establishing retest periods and shelf lives for drug substances and

drug products intended for storage at or below room temperature.

Extrapolation is the practice of using a known data set to infer information about future data. Extrapolation to

extend the retest period or shelf life beyond the period covered by long-term data can be proposed in theapplication, particularly if no significant change is observed at the accelerated condition.

Shelf life Estimation with Upper and Lower Acceptance Criteria Based on Assay at

25C/60%RH

80

85

90

95

100

105

110

115

120

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Time Point (Months)

Assay(%o

fLabelClaim)

Raw DataUpper confidence limit

Lower confidence limit

Regression line

Upper acceptancecriterion: 105

Lower acceptancecriterion: 95


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Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV

(WHO/ Zone-III/ Zone-IVa) Stability condition: 30C 2C/ 65% 5%RH

(ASEAN/ Zone-IVb) Stability condition: 30C 2C/ 75% 5%RH

Storage condition:

Testing conditions where stability has

been shown

Required labelling statement Additional labelling statement*,

where relevantAccelerated 40C / 75% RH

Long term 25C / 60% RH or

30C / 65% RH

None Do not refrigerate or freeze

25C / 60% RH(long term)

30C / 60 or 65% RH (intermediate) or

30C/65%RH (long term)

Do not store above 30C

or

Store below 30C

Do not refrigerate or freeze

25C / 60% RH(long term) Do not store above 25C

or

Store below 25C

Do not refrigerate or freeze

Shelf life Estimation with Upper Acceptance Criterion Based on a Degradation

Product at 25C/60%RH

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Time Point (Months)

Degra

dationProduct(%)

Raw DataUpper confidence limit

Regression line

Upper acceptancecriterion: 1.4


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EUROPE

Authority EMEA: European Medicines Evaluation Agency

website EUDRALEX

DOSSIER REQUIRMENTS

Module 1: Administrative Information and Prescribing Information1.0 Cover Letter

1.1 Comprehensive Table of Contents

1.2 Application Form

1.3 Product Information1.3.1 SPC, Labelling and Package Leaflet

1.3.2 Mock-up

1.3.3 Specimen

1.3.4 Consultation with Target Patient Groups

1.3.5 Product Information already approved in the Member States1.3.6 Braille

1.4 Information about the Experts

1.4.1 Quality1.4.2 Non-Clinical

1.4.3 Clinical

1.5 Specific Requirements for Different Types of Applications

1.5.1 Information for Bibliographical Applications

1.5.2 Information for Generic, Hybrid or Bio-similar Applications1.5.3 (Extended) Data/Market Exclusivity

1.5.4 Exceptional Circumstances1.5.5 Conditional Marketing Authorisation

1.6 Environmental Risk Assessment

1.6.1 Non-GMO

1.6.2 GMO

1.7 Information relating to Orphan Market Exclusivity

1.7.1 Similarity1.7.2 Market Exclusivity

1.8 Information relating to Pharmacovigilance

1.8.1 Pharmacovigilance System1.8.2 Risk-management System

1.9 Information relating to Clinical Trials

1.10 Information relating to Paediatrics

Responses to Questions

Additional Data

Module 2: Common Technical Document Summaries2.1 TABLE OF CONTENTS

2.2 INTRODUCTION

2.3 QUALITY OVERALL SUMMARY2.3.S DRUG SUBSTANCE (Drug substance manufacturer)

2.3.S.1 General information2.3.S.1.1 Nomenclature

2.3.S.1.2 Structure

2.3.S.1.3 General properties

2.3.S.2 Manufacture2 3 S 2 1 M f t


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2.3.S.4.4 Batch analyses

2.3.S.4.5 Justification of specification

2.3.S.5 Reference standards or materials

2.3.S.6 Container closure system

2.3.S.7 Stability

2.3.S.7.1 Stability summary and conclusions2.3.S.7.2 Post approval stability protocol and stability commitment

2.3.S.7.3 Stability data

2.3.P Drug product

2.3.P.1 Description and composition of the drug product

2.3.P.2 Pharmaceutical development

2.3.P.2.1 Components of the drug product

2.3.P.2.1.1 Drug Substance

2.3.P.2.1.2 Excipients

2.3.P.2.2 Drug product2.3.P.2.2.1 Formulation Development2.3.P.2.2.2 Overages

2.3.P.2.2.3 Physicochemical and biological properties

2.3.P.2.3 Manufacturing process development

2.3.P.2.4 Container closure system2.3.P.2.5 Microbiological attributes

2.3.P.2.6 Compatibility

2.3.P.3 Manufacture

2.3.P.3.1 Manufacturers2.3.P.3.2 Batch formula

2.3.P.3.3 Description of manufacturing process and process contro

2.3.P.3.4 Controls of critical steps and intermediates

2.3.P.3.5 Process validation and/or evaluation

2.3.P.4 Control of excipients2.3.P.4.1 Specifications

2.3.P.4.2 Analytical procedures

2.3.P.4.3 Validation of analytical procedures2.3.P.4.4 Justification of specifications

2.3.P.4.5 Excipients of human and animal origin2.3.P.4.6 Novel excipients

2.3.P.5 Control of drug products

2.3.P.5.1 Specification(s)2.3.P.5.2 Analytical procedures

2.3.P.5.3 Validation of analytical procedures

2.3.P.5.4 Batch analyses2.3.P.5.5 Characterisation of impurities

2.3.P.5.6 Justification of specification(s)

2.3.P.6 Reference standards or materials2.3.P.7 Container closure system

2.3.P.8 Stability

2.3.P.8.1 Stability summary and conclusions2.3.P.8.2 Post approval stability protocol and stability commitment

2.3.P.8.3 Stability data

2.3.A APPENDICES


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Clinical Efficacy

Clinical Safety

Synopses of Individual Studies

Module 3: Quality

3.1 TABLE OF CONTENTS3.2 BODY OF DATA

3.2.S DRUG SUBSTANCE

(Drug substance manufacturer)

3.2.S.1 General information

3.2.S.1.1 Nomenclature

3.2.S.1.2 Structure

3.2.S.1.3 General properties

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturers3.2.S.2.2 Description of manufacturing process and process controls3.2.S.2.3 Control of materials

3.2.S.2.4 Controls of critical steps and intermediates

3.2.S.2.5 Process validation and/or evaluation

3.2.S.2.6 Manufacturing process development

3.2.S.3 Characterisation3.2.S.3.1 Elucidation of structure and other characteristics

3.2.S.3.2 Impurities

3.2.S.4 Control of drug substance

3.2.S.4.1 Specification3.2.S.4.2 Analytical procedures

3.2.S.4.3 Validation of analytical procedures

3.2.S.4.4 Batch analyses

3.2.S.4.5 Justification of specification

3.2.S.5 Reference standards or materials

3.2.S.6 Container closure system

3.2.S.7 Stability

3.2.S.7.1 Stability summary and conclusions

3.2.S.7.2 Post approval stability protocol and stability commitment3.2.S.7.3 Stability data

3. 2.P DRUG PRODUCT

3.2.P.1 Description and composition of the drug product

3.2.P.2 Pharmaceutical development

3.2.P.2.1 Components of the drug product

3.2.P.2.1.1 Drug Substance

3.2.P.2.1.2 Excipients3.2.P.2.2 Drug product

3.2.P.2.2.1 Formulation Development3.2.P.2.2.2 Overages

3.2.P.2.2.3 Physicochemical and biological properties

3.2.P.2.3 Manufacturing process development3.2.P.2.4 Container closure system

3.2.P.2.5 Microbiological attributes

3.2.P.2.6 Compatibility


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3.2.P.5 Control of drug products3.2.P.5.1 Specification(s)

3.2.P.5.2 Analytical procedures

3.2.P.5.3 Validation of analytical procedures

3.2.P.5.4 Batch analyses.

3.2.P.5.5 Characterisation of impurities3.2.P.5.6 Justification of specification(s).

3.2.P.6 Reference standards or materials

3.2.P.7 Container closure system

3.2.P.8 Stability

3.2.P.8.1 Stability summary and conclusions.

3.2.P.8.2 Post approval stability protocol and stability commitment.

3.2.P.8.3 Stability data.

3. 2.A APPENDICES

3.2.A.1 Facilities and equipment

3.2.A.2 Adventitious agents safety evaluation3.2.A.3 Excipients

3. 2.R REGIONAL INFORMATION

3.2.R.1 Process validation scheme for the drug product

3.2.R.2 Medical device

3.2.R.3 Certificate of suitability

3.2.R.4 Medicinal products containing or using in the manufacturing process materials of animal and/ or human origin

3.3 LITERATURE REFERENCES


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Module 4: Nonclinical Study Reports

4.1 Module 5 Table of Contents4.2.1 Pharmacology

4.2.1.1 Primary Pharmacodynamics

4.2.1.2 Secondary Pharmacodynamics

4.2.1.3 Safety Pharmacology4.2.1.4 Pharmacodynamic Drug Interactions

4.2.2 Pharmacokinetics4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available)

4.2.2.2 Absorption 4.2.2.3 Distribution 4.2.2.4 Metabolism 4.2.2.5 Excretion

4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)

4.2.2.7 Other Pharmacokinetic Studies

4.2.3 Toxicology4.2.3.1 Single-Dose Toxicity (in order by species, by route)

4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including supportive toxicokinetics evaluations)

4.2.3.3 Genotoxicity 4.2.3.3.1 In vitro4.2.3.3.2 In vivo (including supportive toxicokinetics evaluations)

4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations)

4.2.3.4.1 Long-term studies (in order by species; including rangefinding studies that cannot appropriately be included under repeat-

dose toxicity or pharmacokinetics)

4.2.3.4.2 Short- or medium-term studies (including range-finding studies that cannot appropriately be included under repeat dose

toxicity or pharmacokinetics)4.2.3.4.3 Other studies

4.2.3.5 Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If

modified study designs are used, the following sub-headings should be modified accordingly.)4.2.3.5.1 Fertility and early embryonic development

4.2.3.5.2 Embryo-fetal development 4.2.3.5.3 Prenatal and postnatal development, including maternal function

4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated.

4.2.3.6 Local Tolerance 4.2.3.7 Other Toxicity Studies (if available)

4.2.3.7.1 Antigenicity 4.2.3.7.2 Immunotoxicity 4.2.3.7.3 Mechanistic studies (if not included elsewhere)4.2.3.7.4 Dependence 4.2.3.7.5 Metabolites 4.2.3.7.6 Impurities 4.2.3.7.7 Other

4.3 LITERATURE REFERENCES

Module 5: Clinical Study Reports

5.1 Table of Contents of Module 55.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports5.3.1.3In vitro-In vivo Correlation Study Reports

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

5.3.2.1 Plasma Protein Binding Study Reports5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

5.3.2.3 Reports of Studies Using Other Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports

5.3.3.2 Patient PK and Initial Tolerability Study Reports5.3.3.3 Intrinsic Factor PK Study Reports

5 3 3 4 E t i i F t PK St d R t


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