Zulassung und Common Technical Document CTD - … · Arzneimittel / Lektion 3 / Gally / 2010 Seite 1 Zulassung und Common Technical Document CTD Dr. Hans Ulrich Gally Partner GxP

Arzneimittel / Lektion 3 / Gally / 2010 Seite 1

Zulassung und Common Technical

DocumentCTD

Dr. Hans Ulrich GallyPartner

GxP GmbH


Inhalt• Zulassung in der Schweiz

• Zulassung in Europa

• Common Technical Document

• Präklinischer und klinischer Teil

• Qualität: Wirkstoff und Fertigprodukt


Zulassung in der Schweiz







http://www.swissmedic.ch/org/00006/00602/00604/00617/index.html?lang=de


Zulassung in Europa - EMA/EMEAIn 1993 the European Medicines Agency (EMEA) was founded with the primary task of providing scientific advice of the highest possible quality to the Community Institutions on all matters relating to medicinal products for human and veterinary use. EMEA's main task is to co-ordinate the scientific evaluation of the safety, efficacy and quality of medicinal products …

The European system offers several routes for the authorisation of medicinal products:

The centralised procedure, which is compulsory for products derived from biotechnology, for orphan medicinal products and for medicinal products for human use which contain an active substance authorised in the Community after 20 May 2004 (date of entry into force of Regulation (EC) No 726/2004) and which are intended for the treatment of AIDS, cancer, neurodegenerative disorders or diabetes.

Applications for the centralised procedure are made directly to the European Medicines Agency (EMEA) and lead to the granting of a European marketing authorisation by the Commission which is binding in all Member States.

The mutual recognition procedure, which is applicable to the majority of conventional medicinal products, is based on the principle of recognition of an already existing national marketing authorisation by one or more Member States.


Zulassung in Europa* The decentralised procedure, which was introduced with the legislative review of 2004, is also applicable to the majority of conventional medicinal products. Through this procedure an application for the marketing authorisation of a medicinal product is submitted simultaneously in several Member States, one of them being chosen as the "Reference Member State". At the end of the procedure national marketing authorisations are granted in the reference and in the concerned Member States.

Purely national authorisations are still available for medicinal products to be marketed in one Member State only.

Special rules exist for the authorisation of medicinal products for paediatric use, orphan drugs, traditional herbal medicinal products, vaccines and clinical trials.


Structure of the CTD -Module 3

Module 1

Module 2

Module 3 Module 4 Module 5

QualityNonclinical

Study Reports

ClinicalStudy

Reports

RegionalAdministrative

Information

NonclinicalSummary

ClinicalSummary

NonclinicalOverview

ClinicalOverview

QualityOverall

Summary

2.3

CH spezifisch

wie EU


3.2.S CTD General• The CTD is an international format for all types of drug

applications: NAS (new active substances), generics, new dosage forms and packages, drug master files, all kind of changes in the manufacture, packaging, …

• Identical structure “from Switzerland to China”,its easy to find the place to put in an informationor to find a specific information

• The content of the chapters is regulated by international regulations: mainly the ICH (International Conference on Harmonization) - Guidelines, but also EMEA (EU)-Guidelines, some national regulations (FDA, MHRA, Swissmedic, …) and the Pharmacopeias: Ph. Eur., Ph. Helv., USP, …


Structure of CTD3.1

3.2.S.1.13.2.S.1.23.2.S.1.33.2.S.2.13.2.S.2.23.2.S.2.33.2.S.2.43.2.S.2.53.2.S.2.63.2.S.3.13.2.S.3.23.2.S.4.13.2.S.4.23.2.S.4.33.2.S.4.43.2.S.4.5

3.2.S.53.2.S.6

3.2.S.7.13.2.S.7.23.2.S.7.3

3.2.P.1

3.2.P.2.33.2.P.2.43.2.P.2.53.2.P.2.63.2.P.3.13.2.P.3.23.2.P.3.33.2.P.3.43.2.P.3.53.2.P.4.13.2.P.4.23.2.P.4.33.2.P.4.43.2.P.4.53.2.P.4.63.2.P.5.13.2.P.5.23.2.P.5.33.2.P.5.43.2.P.5.53.2.P.5.6

3.2.P.63.2.P.7

3.2.P.8.13.2.P.8.23.2.P.8.3

3.2.A.13.2.A.23.2.A.3

3.2.R3.3 One f ile per

reference Note 5

Module 3 Note 1

The TOC is only needed in the paper version of theCTD; there is no entry needed for the eCTD

3.2 3.2.S Note 2 3.2.S.1

3.2.S.2

3.2.S.3

3.2.S.4

3.2.S.7

3.2.P Note 3

3.2.P.2 3.2.P.2.1 Note 4

3.2.P.2.2 Note 4

3.2.P.3

3.2.P.4

3.2.P.5

3.2.P.8

3.2.A

Module 3

Ab 2010 kann die Dokumentation auch

elektronisch eingereicht werden:

eCTD


Module 3

3.1

3.2.S.1.13.2.S.1.23.2.S.1.33.2.S.2.13.2.S.2.23.2.S.2.33.2.S.2.43.2.S.2.53.2.S.2.63.2.S.3.13.2.S.3.23.2.S.4.13.2.S.4.23.2.S.4.33.2.S.4.43.2.S.4.5

3.2.S.53.2.S.6

3.2.S.7.13.2.S.7.23.2.S.7.3

3.2.P.1

3.2.P.2.33.2.P.2.43.2.P.2.53.2.P.2.63.2.P.3.13.2.P.3.23.2.P.3.33.2.P.3.43.2.P.3.53.2.P.4.13.2.P.4.23.2.P.4.33.2.P.4.43.2.P.4.53.2.P.4.63.2.P.5.13.2.P.5.23.2.P.5.33.2.P.5.43.2.P.5.53.2.P.5.6

3.2.P.63.2.P.7

3.2.P.8.13.2.P.8.23.2.P.8.3

3.2.A.13.2.A.23.2.A.3

3.2.R Note 53.3 One f ile per

reference Note 6

3.2.P.4

3.2.P.5

3.2.P.8

3.2.A

3.2.P.2 3.2.P.2.1 Note 4

3.2.P.2.2 Note 4

3.2.P.3

Module 3 Note 1

The TOC is only needed in the paper version of theCTD; there is no entry needed for the eCTD

3.2 3.2.S Note 2 3.2.S.1

3.2.S.2

3.2.S.3

3.2.S.4

3.2.S.7

3.2.P Note 3

One or multiple documents may be submitted at this level

Note 1 : In choosing the level of granularity for this Module the applicant should consider that it will be expected that replacements of completedocuments /files are provided in the CTD and eCTD when the information is changed at any point in the product's lifecycle.

Note 2 : For a drug product containing more than one drug substance, the information requested for part “S” should be provided in its entirety for each drug substance

Note 3 : For a drug product supplied with reconstitution diluent(s), the information on the diluent(s) should be provided in a separate part “P”, as appropriate

Note 6 : Literature References should be listed in the tables of contents. Note 5 : Refer to

regional guidance


MOD 4: NONCLINICAL SAFETY STUDIESIntroduction2.6.2 Pharmacology Written Summary

2.6.2.1 Brief Summary2.6.2.2 Primary Pharmacodynamics2.6.2.3 Secondary Pharmacodynamics2.6.2.4 Safety Pharmacology2.6.2.5 Pharmacodynamic Drug Interactions2.6.2.6 Discussion and Conclusions2.6.2.7 Tables and Figures

2.6.3 Pharmacology Tabulated Summary (see Appendix B)

Pharmakodynamik

Teilgebiet der Pharmakologie, die sich speziell mit der Wirkung von Arzneimitteln und Wirkstoffen im lebenden Organismus beschäftigt. Im Einzelnen werden u.a. die Dosis-Wirkbeziehungen und die Wirkmechanismen wie Nebenwirkungen und Toxikologie untersucht.


MOD 4: NONCLINICAL SAFETY STUDIES2.6.4 Pharmacokinetics Written Summary

2.6.4.1 Brief Summary2.6.4.2 Methods of Analysis2.6.4.3 Absorption2.6.4.4 Distribution2.6.4.5 Metabolism (interspecies comparison)2.6.4.6 Excretion2.6.4.7 Pharmacokinetic Drug Interactions2.6.4.8 Other Pharmacokinetic Studies2.6.4.9 Discussion and Conclusions2.6.4.10 Tables and Figures

Pharmakokinetik

Beschäftigt sich mit den Prozessen der Resorption, Verteilung, Transport, Speicherung, Biotransformation und Ausscheidung von Pharmakasowie deren Beschreibung und Modellierung.


MOD 4: NONCLINICAL SAFETY STUDIES2.6.6 Toxicology Written Summary

2.6.6.1 Brief Summary2.6.6.2 Single-Dose Toxicity2.6.6.3 Repeat-Dose Toxicity (including supportive toxicokinetics

evaluation)2.6.6.4 Genotoxicity2.6.6.5 Carcinogenicity (including supportive toxicokinetics

evaluations)2.6.6.6 Reproductive and Developmental Toxicity (including range-

finding studies and supportive toxicokinetics evaluations)2.6.6.7 Local Tolerance2.6.6.8 Other Toxicity Studies (if )2.6.6.9 Discussion and Conclusions2.6.6.10 Tables and Figures


MODULE 5: CLINICAL STUDY REPORTS5.1 Table of Contents of Module 55.2 Tabular Listing of All Clinical Studies5.3 Clinical Study Reports5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports5.3.1.2 Comparative BA and Bioequivalence (BE) Study

Reports5.3.1.3 In Vitro – In Vivo Correlation Study Reports5.3.1.4 Reports of Bioanalytical and Analytical Methods

for Human Studies


MODULE 5: CLINICAL STUDY REPORTS5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using

Human Biomaterials5.3.2.1 Plasma Protein Binding Study Reports5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction

Studies5.3.2.3 Reports of Studies Using Other Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports5.3.3.2 Patient PK and Initial Tolerability Study Reports5.3.3.3 Intrinsic Factor PK Study Reports5.3.3.4 Extrinsic Factor PK Study Reports5.3.3.5 Population PK Study Reports


MODULE 5: CLINICAL STUDY REPORTS5.3.4 Reports of Human Pharmacodynamic (PD) Studies

5.3.4.1 Healthy Subject PD and PK/PD Study Reports5.3.4.2 Patient PD and PK/PD Study Reports

5.3.5 Reports of Efficacy and Safety Studies5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to

the Claimed Indication5.3.5.2 Study Reports of Uncontrolled Clinical Studies5.3.5.3 Reports of Analyses of Data from More than One Study5.3.5.4 Other Study Reports

5.3.6 Reports of Post-Marketing Experience5.3.7 Case Report Forms and Individual Patient Listings5.4 Literature References


Common Technical Documentfür Wirkstoffe:

CTD Module 3.2.S


GxP GmbH


3 CTD “Quality” Structure3.1 Table of Contents

3.2 Body of Data

3.2.S Drug Substance

3.2.P Drug Product

3.2.A Appendices

3.2.R Regional Information

3.3 Literature References


CTD 3.2.S (Substance): Contents

2.3.S DRUG SUBSTANCE 2.3.S.1 General Information 2.3.S.2 Manufacture 2.3.S.3 Characterisation 2.3.S.4 Control of Drug Substance 2.3.S.5 Reference Standards or Materials2.3.S.6 Container Closure System 2.3.S.7 Stability


3.2.S Drug Substance• There can be several Parts S (S1, S2, S3) depending on number of

active pharmaceutical ingredients (APIs) and on the number of producers of the API

• For each API-producer there must be a separate Part 3.2.S

• Because the way of syntheses, the impurity profile, the particlesize, the polymorphic form etc. is often different for API’s from different manufacturers

• There are three ways to supplement the information on the API needed for the application:- Full part 3.2.S from the applicant or,- Drug Master File from a external manufacturer or,- CEP or CoS: Certificate of suitability for monograph of the EPissued by the EDQM in Strasbourg.


3.2.S Drug Substance: DMF

Applicants PartUSA: Open Part

Restricted PartUSA: Closed Part

Public information: All the applicant must know

Confidential information: details of production

In part 3.2.S of the CTD Goes directly to the authorities

The drug master file discloses only the necessary infor-mation to the applicant (applicants part), confidential information is disclosed to the authorities only (restricted part).A “Letter of Access” allows the authority to assess the DrugMaster File for a specific application for marketing authorization


3.2.S Drug Master Files


3.2.S Drug Substance: CEP


3.2.S Drug Substance: CEP

Confirmation that the current version of the EP is suitable to control the quality of the substance. Additional tests are included if the monograph isn’t sufficient – mostly additional impurities and residual solvents.


S 1 General InformationS 1.1 NomenclatureInformation on the nomenclature of the drug substanceshould be provided. For example:• Recommended International Non-proprietary Name

(INN);• Compendial name if relevant;• Chemical name(s);• Company or laboratory code;• Other non-proprietary name(s), e.g., national name, • United States Adopted Name• (USAN), Japanese Accepted Name (JAN); British

Approved Name (BAN), and• Chemical Abstracts Service (CAS) registry number.


S 1 General InformationNAS=New Active Substance/NCE=New Chemical EntityS 1.2 Structure

The structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided.

S 1.3 General PropertiesA list should be provided of physicochemical and other relevant properties of the drug substance, including biological activity for Biotech.Reference ICH Guidelines: Q6A and Q6B


S 1 Particle Size

0

10

20

30

40

50

60

70

80

90

100

110

0 15 30 45 60 75 90min

% d

isso

lved

PT9547 D 01 PT9547 D 02PT9547 D 03 PT9547 D 04PT9547 D 05 PT9547 D 06PT9547 D 07 PT9547 D 08PT9547 D 09 C206132 (300mg in 900ml)

Different dissolution profiles due to different particle sizes of the API


S 2 ManufactureS 2.1 Manufacturer(s)

The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

API-manufacturer must comply with the GMP-rules:ICH Q7A = EU-GMP-Rules, part IIThe applicant must audit the API-manufacturerOfficial GMP-certificates for API-producers are uncommon, except in Switzerland


S 2 ManufactureS 2.2 Description of Manufacturing Process and Process

ControlsThe description of the drug substance manufacturing process represents the applicant’s commitment for the manufacture of the drug substance. Information should be provided to adequately describe the manufacturing process and process controls. For example:NAS (NCE):A flow diagram of the synthetic process should be provided that includes molecular formulae, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and drug substance reflecting stereochemistry, and identifies operating conditions and solvents.


S 2 ManufactureCritical Question:• What is the pivotal, key raw materiel?• Does it contains the essential structure?• Are the starting materials commercially

available?• From which step of the process must GMP be

observed and process validation be done?

Reference ICH Guidelines: Q5A, Q5B, and Q6B


S 2 ManufactureS 2.3 Control of MaterialsMaterials used in the manufacture of the drug substance (e.g., raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. Information demonstrating that materials (including biologically-sourced materials, e.g., media components, monoclonal antibodies, enzymes) meet standards appropriate for their intended use (including the clearance or control of adventitious agents) should be provided, as appropriate. For biologically-sourced materials, this can include information regarding the source, manufacture, and characterisation. Reference ICH Guidelines: Q6A and Q6B


S 2 ManufactureS 2.4 Controls of Critical Steps and IntermediatesCritical Steps: Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in S2.2 of the manufacturing process to ensure that the process is controlled should be provided.Intermediates: Information on the quality and control of intermediates isolated during the process should be provided. Reference ICH Guidelines: Q6A and Q6B

S 2.5 Process Validation and/or EvaluationProcess validation and/or evaluation studies for aseptic processing and sterilisation should be included.


S 2 Manufacture

S 2.6 Manufacturing Process DevelopmentNAS (NCE):A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the drug substance used in producing nonclinical, clinical, scale-up, pilot, and, if available, production scale batches.Reference should be made to the drug substance data provided in section S4.4.Reference ICH Guideline: Q3A


S 3 CharacterisationS 3.1 Elucidation of Structure and other CharacteristicsNAS (NCE):Confirmation of structure based on e.g., synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.Reference ICH Guideline: Q6A

S 3.2 ImpuritiesInformation on impurities should be provided.Reference ICH Guidelines: Q3A, Q3C, Q5C, Q6A, and Q6B


S 4 Control of Drug Substance S 4.1 SpecificationThe specification for the drug substance should be provided.Reference ICH Guidelines: Q6A and Q6BS 4.2 Analytical ProceduresThe analytical procedures used for testing the drug substance should be provided.Reference ICH Guidelines: Q2A and Q6BS 4.3 Validation of Analytical ProceduresAnalytical validation information, including experimental data for the analytical procedures used for testing the drug substance, should be provided.Reference ICH Guidelines: Q2A, Q2B, and Q6B


S 4 Control of Drug Substance

Quality of copies must be adequate



S 4.4 Batch AnalysesDescription of batches and results of batch analyses should be provided.Reference ICH Guidelines: Q3A, Q3C, Q6A, and Q6BS 4.5 Justification of SpecificationJustification for the drug substance specification should be provided.Reference ICH Guidelines: Q3A, Q3C, Q6A and Q6B



Maximumdaily dose

Reportingthreshold

Identificationthreshold

Qualificationthreshold

≤ 2 g/day > 0.05 per cent > 0.10 per cent or a daily intake of > 1.0 mg (whichever is the lower

> 0.15 per cent or a daily intake of > 1.0 mg (whichever is the lower)

> 2 g/day > 0.03 per cent > 0.05 per cent > 0.05 per cent

Ph. Eur.: Substances for pharmaceutical use (2034)/Related substances.

Unless otherwise prescribed, organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table 2034 (human use only).

Specific thresholds may be applied for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects.

If the individual monograph does not provide suitable control for a new impurity, a suitable test for control must be developed and included in the specification for the substance.


S 5 Reference Standards / MaterialsS 5 Reference Standards or MaterialsInformation on the reference standards or reference materials used for testing of the drug substance should be provided.Reference ICH Guidelines: Q6A and Q6B


S 6 Container Closure System A description of the container closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). For non-functional secondary packaging components (e.g., those that do not provide additional protection), only a brief description should be provided.The suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the drug substance ,including sorption to container and leaching, and/or safety of materials of construction.


S 7 Stability S 7.1 Stability Summary and ConclusionsThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.Reference ICH Guidelines: Q1A, Q1B, and Q5C

S 7.2 Postapproval Stability Protocol and Stability CommitmentThe post-approval stability protocol and stability commitment should be provided.Reference ICH Guidelines: Q1A and Q5C


S 7 Stability S 7.3 Stability DataResults of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.Reference ICH Guidelines: Q1A, Q1B, Q2A, Q2B, and Q5C


Common Technical Documentfür Fertigprodukte: CTD Module 3.2.P


GxP GmbH


3.2.P Finished Product: Contents2.3.P DRUG PRODUCT2.3.P.1 Description and Composition of the Drug Product2.3.P.2 Pharmaceutical Development 2.3.P.3 Manufacture2.3.P.4 Control of Excipients 2.3.P.5 Control of Drug Product 2.3.P.6 Reference Standards or Materials 2.3.P.7 Container Closure System 2.3.P.8 Stability


A description of the drug product and its composition should be provided. The information provided should include, for example:

- Description of the dosage form;

- Composition, i.e., list of all components of the dosage form, and their amount on a per-unit basis(including overages, if any) the function of the components, and a reference to their quality standards - Description of accompanying reconstitution diluent(s); and

- Type of container and closure used for the dosage form and accompanying reconstitution diluents, if applicable.

Reference ICH Guidelines: Q6A and Q6B

P.1 Description and Compositionof the Drug Product


P 2 Pharmaceutical Development The Pharmaceutical Development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and drug product quality. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the application.Reference ICH Guidelines: Q6A and Q6B


P 2 Pharmaceutical Development P 2.1 Components of the Drug ProductP 2.1.1 Drug SubstanceThe compatibility of the drug substance with excipients listed in P1 should be discussed. Additionally, key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the drug substance that can influence the performance of the drug product should be discussed.For combination products, the compatibility of drug substances with each other should be discussed.P 2.1.2 ExcipientsThe choice of excipients listed in P1, their concentration, their characteristics that can influence the drug product performance should be discussed relative to their respective functions.


P 2 Pharmaceutical Development P 2.2 Drug ProductP 2.2.1 Formulation DevelopmentA brief summary describing the development of the drug product should be provided, taking into consideration the proposed route of administration and usage. The differences between clinical formulations and the formulation (i.e. composition) described in P1 should be discussed. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate. Link to module 5 Clinical Study reports!P 2.2.2 OveragesAny overages in the formulation(s) described in P1 should be justified.


P 2 Pharmaceutical Development P 2.2.3 Physicochemical and Biological PropertiesParameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.P 2.3 Manufacturing Process DevelopmentThe selection and optimisation of the manufacturing process described in P3.3, in particular its critical aspects, should beexplained. Where relevant, the method of sterilisation should beexplained and justified.Differences between the manufacturing process(es) used to produce pivotal clinical batches and the process described in P3.3 that can influence the performance of the product should be discussed.


P 2 Pharmaceutical Development

Polymorphism of Q-35:Balofloxacin


P 2 Pharmaceutical Development P 2.4 Container Closure SystemThe suitability of the container closure system (described in P7) used for the storage, transportation (shipping) and use of the drug product should be discussed.This discussion should consider, e.g., choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).


P 2 Pharmaceutical Development P 2.5 Microbiological AttributesWhere appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.

P 2.6 CompatibilityThe compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed toprovide appropriate and supportive information for the labelling.


P 3 ManufactureP 3.1 Manufacturer(s)The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

P 3.2 Batch FormulaA batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.


P 3 ManufactureP 3.3 Description of Manufacturing Process and Process ControlsA flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity, where relevant.Steps in the process should have the appropriate process parametersidentified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section P3.4. In certain cases, environmental conditions (e.g., low humidity for an effervescent product) should be stated.Reference ICH Guideline: Q6B


P 3 ManufactureP 3.4 Controls of Critical Steps and IntermediatesCritical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in P3.3 of the manufacturing process, to ensure that the process is controlled.

Intermediates: Information on the quality and control of intermediates isolated during the process should be provided.Reference ICH Guidelines: Q2A, Q2B, Q6A, and Q6B

P 3.5 Process Validation and/or EvaluationDescription, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g., validation of the sterilisation process or aseptic processing or filling). Viral safety evaluation should be provided in A2, if necessary.Reference ICH Guideline: Q6B


EMEA: Note for Guidance on Process Validation


P 4 Control of Exipients

3.2.P.4.6 Novel excipients: Complete Part 3.2.S + 4 (Safety)

BSE/TSE -> 3.2.A.2

There are monographs for most Excipients in the Ph. Eur.


P 5 Control of Drug ProductP 5.1 Specification(s)The specification(s) for the drug product should be provided.Reference ICH Guidelines: Q3B, Q6A and Q6B

P 5.2 Analytical ProceduresThe analytical procedures used for testing the drug product should be provided.Reference ICH Guidelines: Q2A and Q6B

P 5.3 Validation of Analytical ProceduresAnalytical validation information, including experimental data, for the analytical procedures used for testing the drug product, should be provided.Reference ICH Guidelines: Q2A, Q2B and Q6B


P 5 Control of Drug Product: SpecificationsICH Guideline Q6A: solid forms <- pharm. develop.

Dissolution: single point for immediate release,multi-timepoint for modified release -> clinical studies, part 5, bioavailability or bioequivalence for generics

Uniformity of dosage units: Ph. Eur. 2.9.40

Hardness/breakability: minimum hardness for packaging/handling – but must be breakable, each subunit must fulfil the requirements for dosage unif.

Water content: hydroscopic forms – stability

Microbial limits: material of natural origin


P 5 Control of Drug ProductP 5.4 Batch AnalysesA description of batches and results of batch analyses should be provided.Reference ICH Guidelines: Q3B, Q3C, Q6A, and Q6B

P 5.5 Characterisation of ImpuritiesInformation on the characterisation of impurities should be provided, if not previously provided in "S 3.2 Impurities".Reference ICH Guidelines: Q3B, Q5C, Q6A, and Q6B

P 5.6 Justification of Specification(s)Justification for the proposed drug product specification(s) should be provided.Reference ICH Guidelines: Q3B, Q6A, and Q6B


ICH Q3B(R2): IMPURITIES IN NEW DRUG PRODUCTS


Impurities- Limits (Ph. Forum Vol 32(5))• For drug substances and drug products, limits are

appropriately set no higher than the level that can be justified and no lower than the level achievable by the manufacturing process and analytical capabilities

• Where there are no safety concerns, limits should be based on (a) data generated on actual batches of the drug substance or drug product, allowing sufficient latitude to deal with the normal process and analytical variations, and (b) stability characteristics.


P 5 Control of Drug ProductLimits for impurities/3-sigma-rule

Level ofImpurities

Validation/Production

Validation-/production-batches for setting the limits!

Development


P 6 Reference Standards / MaterialsInformation on the reference standards or reference materials used for testing of the drug product should be provided, if not previously provided in "S 5 Reference Standards or Materials".Reference ICH Guidelines: Q6A and Q6B


P 7 Container Closure SystemA description of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included where appropriate. For non-functional secondary packaging components (e.g., those that neither provideadditional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.Suitability information should be located in P 2.


P 8 Stability P 8.1 Stability Summary and ConclusionThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.Reference ICH Guidelines: Q1A, Q1B, Q3B, and Q5C, Q6A

P 8.2 Post-approval Stability Protocol and Stability CommitmentThe post-approval stability protocol and stability commitment should be provided.Reference ICH Guidelines: Q1A and Q5C


P 8 Stability

ICH-Guideline Q1A


P 8 Stability P 8.3 Stability DataResults of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.

Information on characterisation of impurities is located in P 5.5.

Reference ICH Guidelines: Q1A , Q1B, Q2A, Q2B and Q5C


http://www.zum.de/Faecher/G/BW/Landeskunde/rhein/staedte/basel/bs_gall1.nvm

Documents

Zulassung und Common Technical Document CTD - … · Arzneimittel / Lektion 3 / Gally / 2010 Seite 1 Zulassung und Common Technical Document CTD Dr. Hans Ulrich Gally Partner GxP