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 µm. 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 at15-25°C. 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)

After this period. intermediate.Shelf life: The combination of physical. Re-test period: The period of time during which the drug substance is expected to remain within its specification and. 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). biological. Extraneous Contaminant: An impurity arising from any source extraneous to the manufacturing process. temperature.g. as long as it continues to comply with the specification. or by reaction with an excipient and/or the immediate container closure system. It can be a complex. and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its re-test period. can be used in the manufacture of a given drug product. or salt of a previously approved drug substance. 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. Reporting Threshold: A limit above (>) which an impurity should be reported. provided that the drug substance has been stored under the defined conditions. in the new drug substance specification. 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. 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. Degradation Profile: A description of the degradation products observed in the drug substance or drug product. 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. Identified Impurity: An impurity for which a structural characterization has been achieved. simple ester. 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. or that a drug product should meet throughout its shelf life. These can include solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms. It may or may not actually appear in the new drug substance. light. chemical. materials of inorganic or animal origin can also be present. Polymorphic Forms: Different crystalline forms of the same drug substance. 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. Impurity Profile: A description of the identified and unidentified impurities present in a new drug substance. A specified impurity can be either identified or unidentified. therefore. Reagent: A substance other than a starting material. Starting materials are normally commercially available and of defined chemical and physical properties and structure. 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. plant material and/or vegetable drug preparations as active ingredients. but not individually listed with its own specific acceptance criterion. Qualification Threshold: A limit above (>) which an impurity should be qualified. pH. Potential Impurity: An impurity that theoretically can arise during manufacture or storage. and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test.IMPURITIES Impurity: Any component of the new drug substance that is not the chemical entity defined as the new drug substance. Reporting threshold is the same as reporting level in Q2B. biological. chemical. or solvent that is used in the manufacture of a new drug substance.. Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. Unspecified impurity: An impurity that is limited by a general acceptance criterion. In some traditions. 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. chromatographic retention time). 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. Herbal Products: Medicinal products containing. Specification . . exclusively. Specification – Release: The combination of physical. water. Identification Threshold: A limit above (>) which an impurity should be identified.

05% 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 0.5% or 20 μg 10mg – 0.40% 0.05% Maximum Daily Dose 1.15% or 1.1 – <1 0.05%) 0.05% Identification Threshold 0.0% or 5 μg TDI.4 mg 5 mg 10-1000 mg 1250 mg 1500 mg ≥ 2000 mg Thresholds of Impurities in New Drug Product Report ing Thresh old 0.15% Very Soluble Freely Soluble Soluble Sparingly Soluble Slightly Soluble Very Slightly Soluble Practically insoluble (or) Insoluble .1% 0.5% or 200 μg TDI.1% >1 g 0.1% 0.05% 0. Whichever TDI.50% 0.05% 0.1% 0.03% Solubility as per EP/USP Solute Required for mg/ml ≥1000 100 – <1000 l 33 – 100 10 – 33 1 – 10l 0.1% 0.01 – 0.05% 0.1% 0.05% Qualification Identification Maximu Maximu Threshold Threshold m Daily m Daily Dose Dose < 10 mg 1.15% 0.07% 0.05% Identification Threshold 0.20% 0.0% 0. Whichever is lower is lower >2g 0.07% 0.16% 0.10% 0.1% 0. Whichever 2g TDI.40% 0.1% 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 Solute Required for g/ml ≥1 0.50% 0.1% >2g 0.033 0.Thresholds of Impurities in New Drug Substance Maximum Daily Dose ≤ 2g/day Reporting Threshold 0.08% 0.13% 0.05% 0.1 – 1 < 0.05% 0.10% or 1.30% 0.08% 0.05% Qualification Threshold 0. Whichever is lower is lower 1 – 10mg 0.1 0.14% 0. Whichever is lower is lower >10 mg 0.2% or 2 mg >100 mg0.05% 0. Whichever 100mg TDI.0001– 0.25% 0.033 – 0.01 0.10% 0.05% 0.10% 0.05% Qualification Threshold 0.10% Maximum Daily Dose 1 – 5 mg 10 – 40 mg 50 mg 75 mg 80 mg 100 – 1500 mg ≥ 2000 mg Reporting Threshold 0.2% or 3 mg -2g TDI.1% 0.10% 0.20% 0.05% Qualification Threshold 1.10% 0.0% or 50 μg < 1 mg 1.001 – 0.0mg per day intake (whichever is lower) 0.1% (0.001 < 0.15% 0.05% Identification Threshold 0.0 mg per day intake (whichever is lower) 0.

9. “Significant change” for a drug substance is defined as failure to meet its specification. 24. 18.. Specification: susceptible to change during storage and are likely to influence quality.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. and/or efficacy. & 6 (3 TP) 0.. Stability studies on fewer than three 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. 75% RH or greater Selection of Batches: Stability studies should be provided on at least three primary batches of the drug substance. 24. to a total of at least three 3. Re-test period: The period of time during which the drug substance is expected to remain within its specification and. **If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition. . one of the following commitments should be made. 12. safety. 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.. a commitment should be made to continue these studies 2. 0. 18. 3. 3. Otherwise. therefore. 1. Stability Commitment: the submission includes long term stability data on three production batches covering the proposed re-test period. 0.. 3. Not include stability data on production batches. 9. 50°C or 60°C temp. 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. 18. 40°C ± 2°C/ 75% ± 5% RH Intermediate** 30°C ± 2°C/ 65% ± 5% RH Long term* Refrigerator Freezer Below -20°C Accelerated Long term Long term Long term 25°C ± 2°C/ 60% ± 5% RH or 12 Months 30°C ± 2°C/ 65% ± 5% RH 25°C ± 2°C/ 60% ± 5% RH 5°C ± 3°C -20°C ± 5°C 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 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. 6. 9. 6. there is no intermediate condition. 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. 6. can be used in the manufacture of a given drug product. 6. & 12 (4 TP) 0.. a post approval commitment is considered unnecessary. Stability studies on at least three production batches. a commitment should be made to continue these studies and to place additional production batches. & 6 (3 TP) 0. 3. 12. 12. 24. 9. 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. 3..

In general. 6. 18. however. 6.. 12. phase separation. **If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition.g. Refrigerator Freezer Below -20°C Accelerated Long term Long term Long term *It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. caking. The testing should cover. biological. dose delivery per actuation). ## # If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition. 9. & 6 (3 TP) 0. 25°C ± 2°C/ 60% ± 5% RH or 12 Months 30°C ± 2°C/ 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. & 12 (4 TP) 0. 24. some changes in physical attributes (e. or failure to meet the acceptance criteria for potency when using biological or immunological procedures... 18. resuspendibility..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. A 5% change in assay from its initial value. 0. Any degradation product’s exceeding its acceptance criterion. hardness. 24. 6. if justified. color. and microbiological attributes. 18.. 12. Q1B Photostability Testing of New Drug Substances and Products . Failure to meet the acceptance criterion for pH. and/or efficacy. Accelerated Intermediate## Long term# 40°C ± 2°C/ NMT 25% RH 30°C ± 2°C/ 35% ± 5% RH 25°C ± 2°C/ 40% ± 5% RH or 30°C ± 2°C/ 35% ± 5% RH 25°C ± 2°C/ 60% ± 5% RH 5°C ± 3°C -20°C ± 5°C Case-by-case basis 6 months 6 months 12 months 6 Months 12 Months 12 Months 0. there is no intermediate condition. 3. 3.. 12. softening of suppositories. & 6 (3 TP) 0. “significant change” for a drug product is defined as: 1. 6. as appropriate for the dosage form: 4. & 12 (4 TP) 0. the physical. 3. 0. 12. chemical. 9. 3. 3. melting of creams) may be expected under accelerated conditions. & 6 (3 TP) 0. Failure to meet the acceptance criteria for appearance..g. 9.. safety. 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* 40°C ± 2°C/ 75% ± 5% RH 30°C ± 2°C/ 65% ± 5% RH 6Months 12 Months 0. 9. 5. It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH. 18. 9. 24. 24. 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. and. as appropriate. and functionality test (e. 9. 6. 2... 3. physical attributes. 6. or Failure to meet the acceptance criteria for dissolution for 12 dosage units. 3. there is no intermediate condition. 3.

g. samples should be exposed to light providing an overall illumination of not less than 1. capsule to tablet. solution to suspension). 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. 6 months accelerated and 6 months long term data from ongoing studies) may be acceptable in certain justified cases. A reduced stability database at submission time (e. new specific functionality/delivery systems (e.g.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. another subset of samples for all factor combinations would be tested. At a subsequent time point.g. 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.. 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. 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”.Procedure: For confirmatory studies.. immediate release tablet to modified release tablet) and different dosage forms of the same administration route (e.g. 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 . strength. oral to parenteral)...

5 1.0 2.4 Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV (WHO/ Zone-III/ Zone-IVa) Stability condition: 30°C ±2°C/ 65% ±5%RH (ASEAN/ Zone-IVb) Stability condition: 30°C ±2°C/ 75% ±5%RH Storage condition: Testing conditions where stability has Required labelling statement been shown Accelerated 40°C / 75% RH Long term 25°C / 60% RH or 30°C / 65% RH 25°C / 60% RH(long term) Do not store above 30°C Do not refrigerate or freeze 30°C / 60 or 65% RH (intermediate) or or 30°C/65%RH (long term) Store below 30°C 25°C / 60% RH(long term) Do not store above 25°C or Store below 25°C 5°C±3°C (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 .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: 1.5 0.0 1.Shelf life Estimation with Upper Acceptance Criterion Based on a Degradation Product at 25C/60%RH 3.5 Degradation Product (%) 2.0 0.

2 Impurities 2.3.10 Information relating to Paediatrics Responses to Questions Additional Data Module 2: Common Technical Document Summaries 2.2.S.3.3.3.2 GMO 1.1 Elucidation of structure and other characteristics 2.6 Environmental Risk Assessment 1.4 Controls of critical steps and intermediates 2.7 Information relating to Orphan Market Exclusivity 1.S.S.3.3 Control of materials 2.2 Structure 2.S.1 Information for Bibliographical Applications 1.4 Information about the Experts 1.1.5 Product Information already approved in the Member States 1.8.3.3.S.3.3.3.S.S.5.S.3.9 Information relating to Clinical Trials 1.1.3.1 SPC.8 Information relating to Pharmacovigilance 1.2.2.4.S.5 Process validation and/or evaluation 2.5.1 Manufacturers 2.2 Analytical procedures 2.3.EUROPE Authority EMEA: European Medicines Evaluation Agency website EUDRALEX DOSSIER REQUIRMENTS Module 1: Administrative Information and Prescribing Information 1.2 Application Form 1.2 Information for Generic.4.3.S.4 Consultation with Target Patient Groups 1.1 Non-GMO 1.S DRUG SUBSTANCE (Drug substance manufacturer) 2.2 Manufacture 2.S.3 General properties 2.4.1 TABLE OF CONTENTS 2.2.4.8.S.3 Product Information 1.4.3 Validation of analytical procedures .3.1 Specification 2.2 Market Exclusivity 1.S.3.2 Risk-management System 1.1 General information 2. ‘Hybrid’ or Bio-similar Applications 1.1 Nomenclature 2.5.3.3 Characterisation 2.2 Description of manufacturing process and process controls 2.2.2 Mock-up 1.S.1.3.7.4.2 Non-Clinical 1.2.S.1 Similarity 1.6 Braille 1.3 Specimen 1.6. Labelling and Package Leaflet 1.3 (Extended) Data/Market Exclusivity 1.5 Conditional Marketing Authorisation 1.0 Cover Letter 1.4 Exceptional Circumstances 1.3.5 Specific Requirements for Different Types of Applications 1.S.S.3 Clinical 1.3.1 Quality 1.6 Manufacturing process development 2.5.3.3.3.1 Comprehensive Table of Contents 1.2 INTRODUCTION 2.1 Pharmacovigilance System 1.S.3.3.3.4 Control of drug substance 2.3.7.3 QUALITY OVERALL SUMMARY 2.5.6.

2 Post approval stability protocol and stability commitment 2.1 Manufacturers 2.3.P.4.3.3.P.1 Facilities and equipment 2.5 Clinical Overview 2.7 Clinical Summary Biopharmaceutics and Associated Analytical Methods Clinical Pharmacology Studies 2.3.R REGIONAL INFORMATION 2.P.3.3.3.3.4.2.3.3 Validation of analytical procedures 2.3.4.P.5.3.2 Batch formula 2.2 Overages 2.3.2 Excipients .3.4.1 Stability summary and conclusions 2.8 Stability 2.3.7.P.3.3 Stability data 2.3.P.3.3.1 Formulation Development 2.P.5.3.P.3.4 Batch analyses 2.3 Validation of analytical procedures 2.5.A.3.3.3.1 Stability summary and conclusions 2.4 Container closure system 2.6 Nonclinical Written and Tabulated Summary Pharmacology Pharmacokinetics Toxicology 2.3 Description of manufacturing process and process contro 2.P.3.P.1 Specifications 2.6 Compatibility 2.2 Pharmaceutical development 2.3.3.P.P.3.2.2.2.5 Microbiological attributes 2.3.5 Process validation and/or evaluation 2.3.3.3.P.3 Physicochemical and biological properties 2.7.4.P.3.S.8.4 Nonclinical Overview 2.3.2.1 Components of the drug product 2.S.P.S.1.3 Manufacturing process development 2.2.2.P.3.A.5.P.3.P.3 Stability data 2.P.2.A APPENDICES 2.2 Drug product 2.P.6 Novel excipients 2.4.2.4.5.P.2.3.3.7 Stability 2.2 Adventitious agents safety evaluation 2.3.3.S.P.3 Manufacture 2.6 Reference standards or materials 2.2.3.P.5 Characterisation of impurities 2.7 Container closure system 2.P.3.6 Container closure system 2.P.3.4 Controls of critical steps and intermediates 2.3.3.P.4 Batch analyses 2.S.3.3.1.P.P.3.5 Excipients of human and animal origin 2.P.2.P.2 Analytical procedures 2.3.2.S.3.8.3 Excipients 2.5 Control of drug products 2.2.3.4.5 Justification of specification 2.3.5.7.2.P.3.P.3.P.6 Justification of specification(s) 2.8.P.3.P.3.S.A.2 Analytical procedures 2.P.3.3.1 Description and composition of the drug product 2.P Drug product 2.5 Reference standards or materials 2.3.P.1 Drug Substance 2.P.2 Post approval stability protocol and stability commitment 2.4 Control of excipients 2.4 Justification of specifications 2.1 Specification(s) 2.S.P.

3 Control of materials 3.2.P.2.3 Validation of analytical procedures 3.2.4.P.5 Microbiological attributes 3.P.2.4 Controls of critical steps and intermediates 3.2.P.3.2 Structure 3.1 Formulation Development 3.1 TABLE OF CONTENTS 3.2.2.4.P.2.1 Drug Substance 3.2.S.2.3 Stability data 3.S.S.P.S.2.P.P.2.S. 3.P.1.1 General information 3.2.6 Novel excipients.P.2.2 Description of manufacturing process and process controls 3.3 Manufacture 3.2.1 Specifications 3.1 Description and composition of the drug product 3.P DRUG PRODUCT 3.2.1 Components of the drug product 3.1.2.3 Validation of analytical procedures 3.S. 3.3.5 Process validation and/or evaluation.2.S.4.2.4 Control of drug substance 3.S.2.S.2.2 Pharmaceutical development 3.2.2.5 Excipients of human and animal origin 3.2.2.S.2.2.P.6 Manufacturing process development 3.2.2 Drug product 3.P.4.1 Stability summary and conclusions 3.S.2.3.2.P.2.2.P.4.2.P.3 Manufacturing process development 3.2.S.4.2 Post approval stability protocol and stability commitment 3.2.S.4 Controls of critical steps and intermediates 3.2.4 Container closure system 3.2.4 Justification of specifications 3. 2.2.2.7.S.2.S.2.2.2 Analytical procedures 3.2.2.P.2.2.2.2 Batch formula 3.2.4 Control of excipients 3.2 Excipients .P.S.2.S.2.7.1.2.3.4 Batch analyses 3.7 Stability 3.5 Justification of specification 3.2.2 Overages 3.2.3.2 Manufacture 3.S.2.S.2.P.1.4.1 Elucidation of structure and other characteristics 3.1 Manufacturers 3.S.1 Specification 3.4.2.2.5 Process validation and/or evaluation 3.6 Container closure system 3.P.3 Description of manufacturing process and process control 3.4.2.2.2.2.4.3 Physicochemical and biological properties 3.2.2.2 Impurities 3.S.2.3.P.S.3.P.7.2.P.1.2.6 Compatibility 3.2.S DRUG SUBSTANCE (Drug substance manufacturer) 3.2.S.S.P.2 Analytical procedures 3.P.2.Clinical Efficacy Clinical Safety Synopses of Individual Studies Module 3: Quality 3.P.5 Reference standards or materials 3.3 General properties 3.2.P.1 Nomenclature 3.3 Characterisation 3.2 BODY OF DATA 3.2.S.S.2.4.1 Manufacturer(s) 3.2.

2.A.8.2.2.A.2.4 Medicinal products containing or using in the manufacturing process materials of animal and/ or human origin 3.5.1 Process validation scheme for the drug product 3. 3.2.P.1 Facilities and equipment 3.A APPENDICES 3.2.P.2.P.3 Certificate of suitability 3.R REGIONAL INFORMATION 3.P.P.2.2.8. 2. 3.3 Excipients 3.3 LITERATURE REFERENCES . 3.2 Post approval stability protocol and stability commitment.1 Stability summary and conclusions.8.7 Container closure system 3.P.5 Control of drug products 3. 3.2.5.2 Analytical procedures 3.P.2.P.P.P.2.2.R.2.3.2 Adventitious agents safety evaluation 3.A.8 Stability 3.2.P.2.P.R.5 Characterisation of impurities 3.6 Reference standards or materials 3.5.4 Batch analyses.2.5.3 Stability data.2.R.2. 2.1 Specification(s) 3.2.R.2 Medical device 3.P.6 Justification of specification(s).5.5.3 Validation of analytical procedures 3. 3.

7 Other 4.3.1 Plasma Protein Binding Study Reports 5.3.2.2.4.1.3.3.2.1 Table of Contents of Module 5 5.3.3 Intrinsic Factor PK Study Reports 5.4 Extrinsic Factor PK Study Reports 5.3.5.2.6 Reports of Post-Marketing Experience 5.7.2.3 Genotoxicity 4.2 Reports of Hepatic Metabolism and Drug Interaction Studies 5.3.2 Patient PD and PK/PD Study Reports 5.2.2.3.3 Safety Pharmacology 4.3 Reports of Human Pharmacokinetic (PK) Studies 5.1 Reports of Biopharmaceutic Studies 5.2.4 Dependence 4.7 Case Report Forms and Individual Patient Listings 5.3.2.2.2 Repeat-Dose Toxicity (in order by species.4.3 Reports of Analyses of Data from More Than One Study 5.7.2.2.5.3.2. including rangefinding studies that cannot appropriately be included under repeatdose toxicity or pharmacokinetics) 4.2 Immunotoxicity 4.2.2. including supportive toxicokinetics evaluations) 4. 4.5 Population PK Study Reports 5.2.3.4 Reports of Human Pharmacodynamic (PD) Studies 5.2.7.5 Reports of Efficacy and Safety Studies 5.3 In vitro-In vivo Correlation Study Reports 5.4 Metabolism 4.3.4 Pharmacodynamic Drug Interactions 4.6 Impurities 4.6 Local Tolerance 4.2.5.2.3.3.7 Other Toxicity Studies (if available) 4.1 Module 5 Table of Contents 4.2.2.7.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated.3 Reports of Studies Using Other Human Biomaterials 5.2 In vivo (including supportive toxicokinetics evaluations) 4.3.3.3.3.2.2.2.3.1.3.1 In vitro 4.1 Primary Pharmacodynamics 4.7.) 4.2 Comparative BA and Bioequivalence (BE) Study Reports 5.3.7. by route) 4.1.1 Long-term studies (in order by species.2.2 Secondary Pharmacodynamics 4.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication 5.3.3.3.2.1 Fertility and early embryonic development 4.3 LITERATURE REFERENCES Module 5: Clinical Study Reports 5.4 Carcinogenicity (including supportive toxicokinetics evaluations) 4.2.7.2.3.2.3.or medium-term studies (including range-finding studies that cannot appropriately be included under repeat dose toxicity or pharmacokinetics) 4.1.2 Tabular Listing of All Clinical Studies 5.5 Metabolites 4.1 Healthy Subject PK and Initial Tolerability Study Reports 5.2 Study Reports of Uncontrolled Clinical Studies 5.3.2 Patient PK and Initial Tolerability Study Reports 5.1 Antigenicity 4. including maternal function 4.1 Bioavailability (BA) Study Reports 5.3.1 Analytical Methods and Validation Reports (if separate reports are available) 4.3.5.3.Module 4: Nonclinical Study Reports 4.3 Clinical Study Reports 5.3.1.1 Single-Dose Toxicity (in order by species.3.1 Pharmacology 4.1.2.3.3.4 Other Clinical Study Reports 5.2.2.2.3.4.3.2. the following sub-headings should be modified accordingly.2.3.5.3.3.2.2.3.3.1.3. by duration.3.3.3 Mechanistic studies (if not included elsewhere) 4.2.6 Pharmacokinetic Drug Interactions (nonclinical) 4.3 Distribution 4.2.2.5.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials 5.7 Other Pharmacokinetic Studies 4.4 Literature References .3.3.2.4.2.3.4 Reports of Bioanalytical and Analytical Methods for Human Studies 5.2 Embryo-fetal development 4.3.2.2 Short.3.2.1.2 Pharmacokinetics 4.2.3.5 Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study designs are used.2.5.2 Absorption 4.4.3.3.3.5.3 Other studies 4.3.5 Excretion 4.3.3 Prenatal and postnatal development. by route.1 Healthy Subject PD and PK/PD Study Reports 5.2.3 Toxicology 4.

labelling and PIL. If consensus is not reached at the level of CMD(h).  FLOW CHART FOR THE MRP Applicant requests RMS to update Approx. RMS updates PrAR to prepare Draft Assessment Report (DAR) draft SPC. Granting of national marketing authorisations in the CMSs subject to submission of acceptable translations. Submission of the dossier to the RMS and CMSs Validation of the application –. Day 150 For procedures referred to CMD(h): If consensus is reached at the level of CMD(h). RMS may close procedure if consensus reached. If consensus was not reached at day 210. Proceed to national 30 days step for granting MA If consensus is not reached by day 150. (National Agencies will adopt the decision and will issue the marketing authorisation subject to submission of acceptable translations). Proceed to national 30 days step for granting MA. the RMS closes the procedure. Proceed to national 30 days step for granting MA If consensus not reached RMS sends the DAR. CMSs notify RMS and applicant of Day 90 final position (and in case of negative position also the CMD secretariat of the EMEA). Applicant sends the final response document to the RMS and CMSs within a recommended period of 3 months. or referral to Co-ordination group. Creation in CTS. draft labelling and draft PIL to CMSs. Clock-off period Day 106 Day 106 . 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. RMS starts the procedure RMS forwards the Preliminary Assessment Report (PrAR). the RMS refers the matter to CHMP for arbitration Applicant sends high quality national translations of SPC. 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. PL and labeling to CMSs and RMS. SPC. Granting of national marketing authorisation in RMS and CMSs if positive conclusion by the Coordination group and no referral to the CHMP/CVMP. Applicant may send draft responses to the RMS and agrees the date with the RMS for submission of the final response. Validation of the application in the CMSs. draft SPC. RMS circulates the AR including SPC.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 . the points for disagreement submitted by CMS(s) are referred to CMD(h) by the RMS within 7 days after Day 90. draft labelling and draft PIL to CMSs CMSs sends final comments to RMS RMS may close procedure if consensus reached. 90 days Assessment Report (AR) and before sub to CMS allocate procedure number Applicant submits the dossier to Day -14 CMS. 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. If consensus is reached. If consensus not reached RMS stops the clock to allow applicant to supplement the dossier and respond to the questions. PL and labelling to CMSs. RMS restarts the procedure. A break-out session can be organised between day 73 – 80). CMSs send their remaining Day 75 comments to RMS and applicant. labelling and PIL to CMS and RMS Granting of national marketing authorisation in RMS and CMSs if no referral to the Co-ordination group. which could be extended if justified Valid submission of the response of the applicant received. the RMS closes the procedure. CMSs send any remaining comments Day 85 to RMS and applicant. If consensus is not reached. RMS to communicate outstanding issues with applicant. 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. PL and labeling to the CMSs CMSs send their comments to the RMS Consultation between RMS and CMSs and applicant.SPC . (National Agencies will adopt the decision and will issue the marketing authorization subject to submission of acceptable translations).

1N HCl. b) Stability 1 batch 3M-Acc c) Disso. and 7. upto1&/or3 batch long-term stability data reported in AR. b) Stability 1 batch 3M-Acc c) Disso-Case B a) Stability. Mixing times and operating speeds within application/validation ranges. and 120 minutes Case C DissoMulti-point dissolution profiles water. b) Stability 1 batch 3M-Acc c) Disso.Complies a) Updated batch records.& USP buffer pH 4.SUPAC CMC. b) Stability 1 batch long-term c) Disso. b) Stability 1 batch 3M-Acc c) Disso. b) Stability 1 batch long-term c) Disso.1N HCl Case B DissoMulti-point dissolution profile at 15. or between facilities in adjacent city blocks.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. 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.25 Other ±1 Glidant Talc ±1 Other ±0. 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.Case B a) Updated batch records. b) Stability 1 batch long-term c) Disso-Complies a) Updated batch records.None b) Disso-Complies a) Updated batch records. b) Stability 1 batch 3M-Acc c) Disso.Complies a) Updated batch records.5.5. 30. b) Stability 1 batch long-term c) Disso. 60.5 (5 profiles) Mfg. 6.Case B a) Updated batch records. 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.  .Case B a) Updated batch records.5 Lubricant (Ca) or (Mg) Sterate±0. Change from wet granulation to direct compression of dry powder. 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. Mixing times and operating speeds outside of application/validation ranges.Case B.Case C a) Disso. DISSOLUTION & IN-VIVO DOCUMENTATION FOR IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS SUPAC COMPONENTS/ COMPOSITION LEVEL EXAMPLE . 45. 0. PROCESS L1 L2 L3 Significant body of information not available: Up to 3 batches with 3M accelerated stability data reported in supplement.Complies a) Updated batch records.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. 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.