Parameter Uniformity of dosage units 2.9.

40/905
Uniformity of content

FINISHED PRODUCT SPECIFICATION/ ACCEPTANCE CRITERIA BP/ Ph.Eur/ USP 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]
2.9.6

Uniformity of mass 2.9.5/2.9.27

Tablets (Uncoated and film-coated) Capsules & granules (Uncoated, single-dose) and powders (singledose) granules, powders for oral use and liquids for oral use, which are supplied in multidose containers Specific for Product 0.5% is typical limit for LOD

80 mg or less 10% More than 80 mg and less than 250 mg 7.5% 250 mg or more 5% Less than 300 mg 10% 300 mg or more All 7.5% 10%

Not more than 2/20 of the individual masses deviate from the average mass by more than the percentage deviation and none deviates by more than twice that percentage.

Water 2.5.12/ 921 LOD 2.2.32/ 731 Friability 2.9.7/ For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding as near as possible to 6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets. NMT 1.0% 1216 Disintegration (2.9.1/ 701): For tablets and capsules <18 mm long use Apparatus A: If 1 or 2 dosage units fail to disintegrate, repeat the test on 12 additional dosage units. The requirements of the test are met if not less than 16 of the 18 dosage units tested have disintegrated. 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 screen with 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 60min
Oral 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 Conventional-release dosage forms At least 75% (Q = 75%) Active substance is released within 45 min In cases where a longer release time than that recommended above is justified, limits at 2 time intervals may be specified. Prolonged-release dosage forms Normally 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 forms at least 2 specification points

Immediate-Release Dosage Forms 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 or greater 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 the stated amount at the final test time. L2 6 The average value of the 12 units (L1 + L2) lies The first specification point is set after 1 h or 2 h in acidic medium within each of the stated ranges and is not less than The second specification point at buffer solution is Q = 75% the stated amount at the final test time; none is Acid Stage Delayed-Release Dosage Forms more than 10% of labeled content outside each of A1 6 No individual value exceeds 10% dissolved. the stated ranges; and none is more than 10% of A2 6 Average of the 12 units (A1 + A2) is not more than labeled content below the stated amount at the 10% dissolved, and no individual unit is greater than final test time. 25% dissolved. L3 12 The average value of the 24 units (L1 + L2 + L3) lies within each of the stated ranges, and is not less A3 12 Average of the 24 units (A1 + A2 + A3) is not more than the stated amount at the final test time; not than 10% dissolved, and no individual unit is greater more than 2 of the 24 units are more than 10% of than 25% dissolved. labeled content outside each of the stated ranges; Buffer Stage Delayed-Release Dosage Forms not more than 2 of the 24 units are more than 10% B1 6 Each unit is not less than Q + 5%. of labeled content below the stated amount at the B2 6 Average of 12 units (B1 + B2) is equal to or greater final test time; and none of the units is more than than Q, and no unit is less than Q 15%. 20% of labeled content outside each of the stated B3 12 Average of 24 units (B1 + B2 + B3) is equal to or ranges or more than 20% of labeled content below greater than Q, not more than 2 units are less than Q the stated amount at the final test time. 15%, and no unit is less than Q 25%. For compendial products as per Pharmacopoeia For New drug products as per ICH-Q3B DP Unless otherwise specified, The limit is NLT 95% and NMT 105% Assay Aqueous preparations for oral use Microbiological Non-aqueous preparations for oral use TAMC 102 CFU/g or CFU/ml 5.1.4/ 1111 TAMC 103 CFU/g or CFU/ml 2 TYMC 10 CFU/g or CFU/ml TYMC 101 CFU/g or CFU/ml Absence of Escherichia coli (1 g or 1 ml) Absence of Escherichia coli (1 g or 1 ml)

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 new drug substance. Solvent: An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis 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, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be re-tested for compliance with the specification and then used immediately. A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification. Specification Release: The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. Specification - Shelf life: The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its re-test period, or that a drug product should meet throughout its shelf life.

Thresholds of Impurities in New Drug Substance

Maximum Daily Dose 2g/day Reporting Threshold 0.05% Identification Threshold 0.10% or 1.0mg per day intake (whichever is lower) 0.05% Identification Threshold 0.10% 0.10% 0.10% 0.10% 0.08% 0.07% 0.05% Qualification Threshold 0.15% or 1.0 mg per day intake (whichever is lower) 0.05% Qualification Threshold 0.15% 0.14% 0.13% 0.10% 0.08% 0.07% 0.05% Maximum Daily Dose 1- 4 mg 5 mg 10-1000 mg 1250 mg 1500 mg 2000 mg

Thresholds of Impurities in New Drug Product

Report ing Thresh old 0.1% 0.1% 0.1% 0.05% 0.05% 0.05% Identification Threshold 0.50% 0.40% 0.20% 0.16% 0.15% 0.10% Maximum Daily Dose 1 5 mg 10 40 mg 50 mg 75 mg 80 mg 100 1500 mg 2000 mg Reporting Threshold 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% (0.05%) 0.05% Qualification Threshold 1.0% 0.50% 0.40% 0.30% 0.25% 0.20% 0.15%

> 2g/day Maximum Daily Dose 1 650 mg 700 mg 750 mg 1000 mg 1250 mg 1500 mg 2000 mg

0.03% Reporting Threshold 0.05% 0.05% 0.05% 0.05% 0.05% 0.05% 0.03%

Solubility as per EP/USP

Solute Required for mg/ml 1000 100 <1000 l 33 100 10 33 1 10l 0.1 1 < 0.1 Solute Required for g/ml 1 0.1 <1 0.033 0.1 0.01 0.033 0.001 0.01 0.0001 0.001 < 0.0001 Solvent Parts Required for 1 Part of Solute <1 1 10 10 30 30 100 100 1000 1000-10000 > 10000 Solubility Descriptive Term

Thresholds of Impurities in New Drug Product

Reporting Thresholds Maximum Daily Dose Threshold 1g 0.1% >1 g 0.05% Qualification Identification Maximu Maximu Threshold Threshold m Daily m Daily Dose Dose < 10 mg 1.0% or 50 g < 1 mg 1.0% or 5 g TDI, Whichever TDI, Whichever is lower is lower 1 10mg 0.5% or 20 g 10mg 0.5% or 200 g TDI, Whichever 100mg TDI, Whichever is lower is lower >10 mg 0.2% or 2 mg >100 mg0.2% or 3 mg -2g TDI, Whichever 2g TDI, Whichever is lower is lower >2g 0.1% >2g 0.15%

Very Soluble Freely Soluble Soluble Sparingly Soluble Slightly Soluble Very Slightly Soluble Practically insoluble (or) Insoluble

Q1A Stability Testing of New Drug Substances and Products Drug Substances

Stress 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 drug substance. 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 Study storage General case Accelerated Storage condition Minimum time Test time points period covered by data at submission 6Months 12 Months 0, 3, & 6 (3 TP) 0, 6, 9, & 12 (4 TP) 0, 3, 6, 9, 12, 18, 24... 0, 3, & 6 (3 TP) 0, 3, 6, 9, 12, 18, 24... 0, 3, 6, 9, 12, 18, 24...

40C 2C/ 75% 5% RH

Intermediate** 30C 2C/ 65% 5% RH Long term* Refrigerator Freezer Below -20C Accelerated Long term Long term Long term

25C 2C/ 60% 5% RH or 12 Months 30C 2C/ 65% 5% RH 25C 2C/ 60% 5% RH 5C 3C -20C 5C Case-by-case basis 6 Months 12 Months 12 Months

*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 continue these 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 three production batches 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, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions It is more appropriate to establish a shelf life than a re-test period.

Drug Products Photo-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: The container 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. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content Testing frequency/ Storage condition:
Intended storage for Study Storage condition Minimum time period covered by data at submission Test time points

General case

Accelerated Intermediate** Long term*

40C 2C/ 75% 5% RH 30C 2C/ 65% 5% RH

6Months 12 Months

0, 3, & 6 (3 TP) 0, 6, 9, & 12 (4 TP) 0, 3, 6, 9, 12, 18, 24...

25C 2C/ 60% 5% RH or 12 Months 30C 2C/ 65% 5% RH

Impermeable containers Semipermeable containers

Stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition. Accelerated Intermediate## Long term# 40C 2C/ NMT 25% RH 30C 2C/ 35% 5% RH 25C 2C/ 40% 5% RH or 30C 2C/ 35% 5% RH 25C 2C/ 60% 5% RH 5C 3C -20C 5C Case-by-case basis 6 months 6 months 12 months 6 Months 12 Months 12 Months 0, 3, & 6 (3 TP) 0, 6, 9, & 12 (4 TP) 0, 3, 6, 9, 12, 18, 24... 0, 3, & 6 (3 TP) 0, 3, 6, 9, 12, 18, 24... 0, 3, 6, 9, 12, 18, 24...

Refrigerator Freezer Below -20C

Accelerated Long term Long term Long term

*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 or 30C 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 using biological or immunological procedures; 2. Any degradation products exceeding its acceptance criterion; 3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form: 4. 5. Failure to meet the acceptance criterion for pH; or Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Q1B Photostability Testing of New Drug Substances and Products

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) and different 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 term data 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 design Matrixing: 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. Q1E Evaluation 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 the application, 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
120 115 Assay (% of Label Claim) 110 105 Raw Data 100 95 90 85 80 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time Point (Months) Upper confidence limit Lower confidence limit Regression line Upper acceptance criterion: 105 Lower acceptance criterion: 95

Shelf life Estimation with Upper Acceptance Criterion Based on a Degradation Product at 25C/60%RH
3.0 2.5 Degradation Product (%) 2.0 1.5 1.0 0.5 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time Point (Months)

Raw Data Upper confidence limit Regression line Upper acceptance criterion: 1.4

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 Required labelling statement been shown Accelerated 40C / 75% RH Long term 25C / 60% RH or 30C / 65% RH 25C / 60% RH(long term) Do not store above 30C Do not refrigerate or freeze 30C / 60 or 65% RH (intermediate) or or 30C/65%RH (long term) Store below 30C 25C / 60% RH(long term) Do not store above 25C or Store below 25C 5C3C (long term) Store in a refrigerator or Store and transport refrigerated Below zero Store in a freezer or Store and transport frozen Do not freeze Do not refrigerate or freeze None Additional labelling statement*, where relevant Do not refrigerate or freeze

EUROPE Authority EMEA: European Medicines Evaluation Agency website EUDRALEX DOSSIER REQUIRMENTS
Module 1: Administrative Information and Prescribing Information 1.0 Cover Letter 1.1 Comprehensive Table of Contents 1.2 Application Form 1.3 Product Information 1.3.1 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 States 1.3.6 Braille 1.4 Information about the Experts 1.4.1 Quality 1.4.2 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 Applications 1.5.3 (Extended) Data/Market Exclusivity 1.5.4 Exceptional Circumstances 1.5.5 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 Similarity 1.7.2 Market Exclusivity 1.8 Information relating to Pharmacovigilance 1.8.1 Pharmacovigilance System 1.8.2 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 Summaries 2.1 TABLE OF CONTENTS 2.2 INTRODUCTION 2.3 QUALITY OVERALL SUMMARY 2.3.S DRUG SUBSTANCE (Drug substance manufacturer) 2.3.S.1 General information 2.3.S.1.1 Nomenclature 2.3.S.1.2 Structure 2.3.S.1.3 General properties 2.3.S.2 Manufacture 2.3.S.2.1 Manufacturers 2.3.S.2.2 Description of manufacturing process and process controls 2.3.S.2.3 Control of materials 2.3.S.2.4 Controls of critical steps and intermediates 2.3.S.2.5 Process validation and/or evaluation 2.3.S.2.6 Manufacturing process development 2.3.S.3 Characterisation 2.3.S.3.1 Elucidation of structure and other characteristics 2.3.S.3.2 Impurities 2.3.S.4 Control of drug substance 2.3.S.4.1 Specification 2.3.S.4.2 Analytical procedures 2.3.S.4.3 Validation of analytical procedures

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 conclusions 2.3.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.2.2 Drug product 2.3.P.2.2.1 Formulation Development 2.3.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 system 2.3.P.2.5 Microbiological attributes 2.3.P.2.6 Compatibility 2.3.P.3 Manufacture 2.3.P.3.1 Manufacturers 2.3.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 excipients 2.3.P.4.1 Specifications 2.3.P.4.2 Analytical procedures 2.3.P.4.3 Validation of analytical procedures 2.3.P.4.4 Justification of specifications 2.3.P.4.5 Excipients of human and animal origin 2.3.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 analyses 2.3.P.5.5 Characterisation of impurities 2.3.P.5.6 Justification of specification(s) 2.3.P.6 Reference standards or materials 2.3.P.7 Container closure system 2.3.P.8 Stability 2.3.P.8.1 Stability summary and conclusions 2.3.P.8.2 Post approval stability protocol and stability commitment 2.3.P.8.3 Stability data 2.3.A APPENDICES 2.3.A.1 Facilities and equipment 2.3.A.2 Adventitious agents safety evaluation 2.3.A.3 Excipients 2.3.R REGIONAL INFORMATION 2.4 Nonclinical Overview 2.5 Clinical Overview 2.6 Nonclinical Written and Tabulated Summary Pharmacology Pharmacokinetics Toxicology 2.7 Clinical Summary Biopharmaceutics and Associated Analytical Methods Clinical Pharmacology Studies

2.3.P.2.1.1 Drug Substance 2.3.P.2.1.2 Excipients

Clinical Efficacy Clinical Safety Synopses of Individual Studies Module 3: Quality 3.1 TABLE OF CONTENTS 3.2 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 Manufacturers 3.2.S.2.2 Description of manufacturing process and process controls 3.2.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 Characterisation 3.2.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 Specification 3.2.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 commitment 3.2.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.2.2 Drug product 3.2.P.2.2.1 Formulation Development 3.2.P.2.2.2 Overages 3.2.P.2.2.3 Physicochemical and biological properties 3.2.P.2.3 Manufacturing process development 3.2.P.2.4 Container closure system 3.2.P.2.5 Microbiological attributes 3.2.P.2.6 Compatibility 3.2.P.3 Manufacture 3.2.P.3.1 Manufacturer(s) 3.2.P.3.2 Batch formula 3.2.P.3.3 Description of manufacturing process and process control 3.2.P.3.4 Controls of critical steps and intermediates 3.2.P.3.5 Process validation and/or evaluation. 3.2.P.4 Control of excipients 3.2.P.4.1 Specifications 3.2.P.4.2 Analytical procedures 3.2.P.4.3 Validation of analytical procedures 3.2.P.4.4 Justification of specifications 3.2.P.4.5 Excipients of human and animal origin 3.2.P.4.6 Novel excipients.

3.2.P.2.1.1 Drug Substance 3.2.P.2.1.2 Excipients

3.2.P.5 Control of drug products 3.2.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 impurities 3.2.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 evaluation 3.2.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

Module 4: Nonclinical Study Reports 4.1 Module 5 Table of Contents 4.2.1 Pharmacology 4.2.1.1 Primary Pharmacodynamics 4.2.1.2 Secondary Pharmacodynamics 4.2.1.3 Safety Pharmacology 4.2.1.4 Pharmacodynamic Drug Interactions 4.2.2 Pharmacokinetics 4.2.2.1 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 Toxicology 4.2.3.1 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 vitro 4.2.3.3.2 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 repeatdose 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 5 5.2 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 Reports 5.3.1.3 In 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 Reports 5.3.2.2 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 Reports 5.3.3.3 Intrinsic Factor PK Study Reports 5.3.3.4 Extrinsic Factor PK Study Reports 5.3.3.5 Population PK Study Reports 5.3.4 Reports of Human Pharmacodynamic (PD) Studies 5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5.3.4.2 Patient PD and PK/PD Study Reports 5.3.5 Reports of Efficacy and Safety Studies 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication 5.3.5.2 Study Reports of Uncontrolled Clinical Studies 5.3.5.3 Reports of Analyses of Data from More Than One Study 5.3.5.4 Other Clinical Study Reports 5.3.6 Reports of Post-Marketing Experience 5.3.7 Case Report Forms and Individual Patient Listings 5.4 Literature References

FLOW CHART FOR THE MRP Applicant requests RMS to update Approx. 90 days Assessment Report (AR) and before sub to CMS allocate procedure number Applicant submits the dossier to Day -14 CMS. RMS circulates the AR including SPC, PL and labelling to CMSs. Validation of the application in the CMSs. RMS starts the procedure Day 0 CMSs send their comments to the Day 50 RMS and applicant Applicant sends the response Day 60 document to CMSs and RMS RMS circulates their assessment of Until Day 68 the response document to CMSs. CMSs send their remaining Day 75 comments to RMS and applicant. A break-out session can be organised between day 73 80). CMSs send any remaining comments Day 85 to RMS and applicant. CMSs notify RMS and applicant of Day 90 final position (and in case of negative position also the CMD secretariat of the EMEA). If consensus is reached, the RMS closes the procedure. If consensus is not reached, the points for disagreement submitted by CMS(s) are referred to CMD(h) by the RMS within 7 days after Day 90. Day 150 For procedures referred to CMD(h): If consensus is reached at the level of CMD(h), the RMS closes the procedure. If consensus is not reached at the level of CMD(h), the RMS refers the matter to CHMP for arbitration Applicant sends high quality national translations of SPC, PL and labeling to CMSs and RMS. Granting of national marketing authorisations in the CMSs subject to submission of acceptable translations.

Before Day -14 Day 14 Assessment step I Day 0 Day 70 Until Day 100 Until Day 105

Flow Chart of the Decentralised Procedure Applicant discussions with RMS RMS allocates procedure number. Creation in CTS. Submission of the dossier to the RMS and CMSs Validation of the application . RMS starts the procedure RMS forwards the Preliminary Assessment Report (PrAR),SPC , PL and labeling to the CMSs CMSs send their comments to the RMS Consultation between RMS and CMSs and applicant. If consensus not reached RMS stops the clock to allow applicant to supplement the dossier and respond to the questions. Applicant may send draft responses to the RMS and agrees the date with the RMS for submission of the final response. Applicant sends the final response document to the RMS and CMSs within a recommended period of 3 months, which could be extended if justified Valid submission of the response of the applicant received. RMS restarts the procedure. RMS updates PrAR to prepare Draft Assessment Report (DAR) draft SPC, draft labelling and draft PIL to CMSs. RMS may close procedure if consensus reached. Proceed to national 30 days step for granting MA If consensus not reached RMS sends the DAR, draft SPC, draft labelling and draft PIL to CMSs CMSs sends final comments to RMS RMS may close procedure if consensus reached. Proceed to national 30 days step for granting MA If consensus is not reached by day 150, RMS to communicate outstanding issues with applicant, receive any additional clarification and prepare a short report for discussion at Coordination Group Breakout Group of involved Member States reaches consensus on the matter Closure of the procedure including CMSs approval of assessment report, SPC, labelling and PIL, or referral to Co-ordination group. Proceed to national 30 days step for granting MA. If consensus was not reached at day 210, points of disagreement will be referred to the Coordination group for resolution Final position adopted by Co-ordination Group with referral to CHMP/CVMP for arbitration in case of unsolved disagreement Applicant sends high quality national translations of SPC, labelling and PIL to CMS and RMS Granting of national marketing authorisation in RMS and CMSs if no referral to the Co-ordination group. (National Agencies will adopt the decision and will issue the marketing authorisation subject to submission of acceptable translations). Granting of national marketing authorisation in RMS and CMSs if positive conclusion by the Coordination group and no referral to the CHMP/CVMP. (National Agencies will adopt the decision and will issue the marketing authorization subject to submission of acceptable translations).

Clock-off period

Day 106 Day 106 - 120 Day 120 Assessment step II Day 120 (Day 0) Day 145 (Day 25) Day 150 (Day 30) Until 180 (Day 60) Until Day 205 (Day85) Day 210 (Day 90)

Day 210 (at the latest) Day 270 (at the latest) Day 110/125/155/215/275 National step Day 135/150/180/240

5 days after close of procedure 30 days after close of procedure

Day 300

SUPAC CMC, DISSOLUTION & IN-VIVO DOCUMENTATION FOR IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS
SUPAC COMPONENTS/ COMPOSITION
LEVEL

EXAMPLE - CHANGE

L1 L2

a) Deletion(partial-De) color or flavor or Ink b) Changes in excipients within % range a) excipient grade b) Changes in excipients over/ double the L1 range a) Any Q&Q excipient changes b) Changes in the excipient ranges Site changes within a single facility Site changes within a contiguous campus, or between facilities in adjacent city blocks, A different campus is defined as one that is not on the same original contiguous site or where the facilities are not in adjacent city blocks. Up to and including a factor of 10 times the size of the pilot/ bio-batch Batch size beyond a factor of 10 times the size of the pilot/bio-batch Non-automated to automated/ non-Mechanical to Mechanical same design and operating principles of the same or of a different capacity Change in equipment to a different design and different operating principles. Mixing times and operating speeds within application/validation ranges. Mixing times and operating speeds outside of application/validation ranges. Change from wet granulation to direct compression of dry powder.

L3

SITE CHANGES

L1 L2

L3

BATCH -SIZE

L1

L2

TEST DOCUMENTATION a) Stability 1 batch long-term b) Disso-Complies a) Stability 1 batch 3M-Acc b) Disso-Case A-HP/HS-Drugs Case B-LP/HS-Drugs Case C-LP/LS-Drugs a) Batch records. b) Stability 1 batch 3M-Acc c) Disso-Case B a) Stability- None b) Disso-Complies a) Updated batch records. b) Stability 1 batch long-term c) Disso-Complies a) Updated batch records. b) Stability 1 batch 3M-Acc c) Disso- Case B a) Updated batch records. b) Stability 1 batch long-term c) Disso- Complies a) Updated batch records. b) Stability 1 batch 3M-Acc c) Disso- Case B a) Updated batch records. b) Stability 1 batch long-term c) Disso- Complies a) Updated batch records. b) Stability 1 batch 3M-Acc c) Disso- Case C a) Disso- Complies a) Updated batch records. b) Stability 1 batch long-term c) Disso- Case B a) Updated batch records. b) Stability 1 batch 3M-Acc c) Disso- Case B; d) BE/IVIVC

FILING Annual report Prior approval supplement/ AR-(Lt-stab) Prior approval supplement/ AR-(Lt-stab) Annual report Changes being effected supplement/ AR-(Lt-stab) Changes being effected supplement/ AR-(Lt-stab) Annual report

% of Exp in Formulation Filler 5 Disintegrant Starch 3 Other 1 Binder 0.5 Lubricant (Ca) or (Mg) Sterate0.25 Other 1 Glidant Talc 1 Other 0.1 Film Coat 1

Changes being effected supplement/ AR-(Lt-stab) Annual report

Case A DissoQ = 85% in 15 minutes in 900 milliliters (mL) of 0.1N HCl Case B DissoMulti-point dissolution profile at 15, 30, 45, 60, and 120 minutes Case C DissoMulti-point dissolution profiles water, 0.1N HCl,& USP buffer pH 4.5, 6.5, and 7.5 (5 profiles)

Mfg. EQUIP

L1

L2

Prior approval supplement/ AR-(Lt-stab) Annual report Changes being effected supplement/ AR-(Lt-stab) Prior approval supplement/ AR-(Lt-stab)

Mfg. PROCESS

L1 L2

L3

Significant body of information not available: Up to 3 batches with 3M accelerated stability data reported in supplement; upto1&/or3 batch long-term stability data reported in AR.