CRED CMC 2017 - Day 2 slides

CRED Chemistry Manufacturing and Controls (CMC) Day 2

Chemistry, Manufacturing & Controls: The Evolving Pharmaceutical Dossier 18-19 October 2017, DoubleTree by Hilton London, Victoria

Day 1 Programme: Drug Substance Chair: Vimal Patel, GlaxoSmithKline

Time 09:00 09:30

Activity

Speaker

Registration and Coffee

Vimal Patel GlaxoSmithKline Christopher Carr ERA Consulting

Welcome •

Overview of the day

Introduction to Preparing the Perfect Common Technical Document (CTD) Module 3 Part ‘S’ • Origin of the Common Technical Document • Overview of CTD structure - where drug substance data fits (Module 3.2.S) • Different routes to incorporate drug substance data into 3.2.S: originator data, DMF or CEP • Overview of variations in the EU • Due Diligence Tips • The elements of a specification o New drug substances o Multi-sourced substances (EP and other pharmacopoeial monographs) • Analytical Methods Data Requirements and Practical Guidance for Drug Substance Development • Issues for different phases of development • Specifications and analytical methods • Production (scale-up, validation, starting materials, application of principles of GMP) • Stability programmes and data requirements • ICH Q11 and QBD Regulatory Agency’s Perspective on the Drug Substance Section of Marketing Authorisation Applications (MAAs) • Potential pitfalls and practical issues experienced with the active drug substance section of an MAA o The importance of validated analytical methods • Falsified Medicines Legislation Lunch Tea, coffee break Control of Drug Substances • Sources of drug substances

09:40

10:15

Alan Watt AstraZeneca, UK

10:30

Kate Arnot AstraZeneca, UK

11:15

12:00 12:45

Sue Harris MHRA

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Time

Activity

Speaker

• An agency perspective on common findings arising during regulatory review • Current experience and advice on preparation of the drug substance section of the CTD • Quality Overall Summary –what reviewers want to see • Falsified Medicines Legislation • Inspection issues for drug substance manufacturers

13:25 13:45 14:00

Questions and Answers

Vimal Patel GlaxoSmithKline

Introduction and Preparation for the Case Study

Case Study Tea/coffee to be taken in case study groups

15:30 16:30

Feedback on Case Study Session

Data Requirements and Practical Guidance for Medicinal Product Development • Issues faced at different phases of development o The need to agree the specific product type required o Medicinal product production, scale up from development to production batches o Process validation requirements for different dosage forms o Stability programmes and data requirements • When/how to deal with changes during development to ensure this does not invalidate any of the clinical/other data already generated. • Specific data requirements for and issues associated with different dosage forms ICH Q8 and QBD

Graham Powell Mylan

Vimal Patel GlaxoSmithKline

17:15

Chairman’s Review of the Day

17:30

Close

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible.

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Chemistry, Manufacturing & Controls: The Evolving Pharmaceutical Dossier: Medicinal Product 18-19 October 2017, DoubleTree by Hilton London, Victoria

Day 2 Programme: Drug Product Chair: Francesca Buttigieg, Diamond BioPharm Limited

Time 09:30

Activity

Speaker

Chairperson’s Welcome • Overview of the day

Francesca Buttigieg Diamond BioPharm Limited Francesca Buttigieg Diamond BioPharm Limited

09:45

Introduction to Preparing the Perfect Common Technical Document (CTD) Module 3 Part ‘P’ • Legal framework • An outline of the different sections within Module 3.2.P and an overview as to content within each section. • Key Sources of reference information concerning the CTD and data requirements for the medicinal product • Due diligence tips • Variations How specifications for finished product are set and maintained • Review and development of specifications • Analytical Procedures/Validation of analytical procedures and justification of specifications • Application of ICH General Concepts in setting and reviewing of specification • Roles of competent authorities and pharmacopoeias in controlling the quality of medicinal product • Introduction to universal and specific tests/criteria for different dosage forms Regulatory Agency’s Perspective on the Medicinal Product Section of Marketing Authorisation Applications (MAAs) • Potential pitfalls and practical issues experienced with the medicinal product section of an MAA o An agency perspective on common findings arising during regulatory review for a range of product formulations o Current experience and advice on preparation and presentation of the medicinal product section of the CTD • Quality Overall Summary – what reviewers want to see Tea, coffee break Control of Medicinal Product •

10:15 10:30

Chris Abegunde GlaxoSmithKline

11:15

Diana van Riet- Nales Medicines Evaluation Board

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Time

Activity

Speaker

12:00 12:30 13.30

Questions and Answers

Lunch

Introduction and Preparation for the Case Study

Sargon Daniel Paraxel

13:45

Case Study Tea/coffee to be taken in case study groups

15:15

Feedback on Case Study Session

16:15

Chairperson’s Review of the Day and Close

Francesca Buttigieg Diamond BioPharm Limited

17:00

Close

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible.

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CRED Chemistry, Manufacturing and Controls Drug Product

Introduction

October 2017

Francesca Buttigieg, Regulatory Affairs Manager, Diamond BioPharm Ltd.

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Domestic Arrangements

 We have a very busy day  Please return promptly from all breaks

 Emergency procedures

 Toilets

 Coffee/Lunch

 Questions

Learning Objectives

 How to prepare the best Common Technical Document – Module 3 Part P ● Legal framework ● Outline different section of Module 3 – Part P ● Due Diligence of the dossier  Quality control of the Finished Product ● How to set specification for the medicinal product, the related analytical procedures and their validation ● Justification of the specification set ● The use of guidelines and pharmacopoeias  Regulatory Agency’s Perspective ● Pitfalls and common issues encountered during dossier reviews

Agenda

 Introduction on how to prepare the perfect CTD Module 3- Part ‘P’ – Fran Coffee Break  Control of the Medicinal Product – Chris Abegunde (GSK)  Regulatory Agency’s Perspective on the Medicinal Product Section of the MAA – Diana van Riet-Nales  Q&A session Lunch  Case Study & Feedback  Day’s Review

Chemistry, Manufacturing & Controls (CMC)

Introduction to Preparing the Perfect Common Technical

Document (CTD) Module 3 - Part 'P'

October 2017

Francesca Buttigieg, Regulatory Affairs Manager

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

My Role at Diamond Pharma Services

• Worked in both Generics and R&D Pharma Industries • Opportunity to combine experience from both sectors in my new Role • New opportunities to gain experience in areas never encountered previously • Work entails working with a variety of clients: • companies with a completely virtual setup • large multi-national pharmaceutical companies

Further Info at: http://www.diamondpharmaservices.com

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Learning Objectives

 Brief history of the CTD and Legal framework  CTD dossier structure – where medicinal product fits within structure  Overview of content of module 3.2.P  Lifecycle management  Due Diligence

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Common Technical Dossier Pre – CTD • Different format and content for EU, US and Japan • Preparation of region specific dossiers CTD

• Harmonised format for 3 ICH * regions (US, EU and Japan) • Streamlined…. One dossier (CTD) • Regional specific documents contained in Module 1 and the ‘Regional Information’ section of Module 3

* ICH - The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

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CTD – History

CTD developed by ICH expert working group CTD is described in ICH M4(R3) ● Quality section is described in ICH M4Q(R1) Agreed in November 2000 & re-edited in 2002. Implementation date July 2003 in Europe & Japan. Strongly recommended by FDA (US). Legal situation in EU: ● Current requirements for the content of the application dossier are set out in Annex 1 of directive 2001/83 as amended by 2003/63 ● The CTD format is translated into the Notice to Applicants Vol 2B References: M4Q(R1) & The M4 Quality questions & Answers (R1)

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CTD Organisation

Will include GMP Certs, MLs, QP Declarations.

Module 1

Regional Administrative Information

CTD Table of contents CTD Introduction

Module 2

Non Clinical Overview Non Clinical Summary

Clinical Overview Clinical Summary

Quality Overall Summary

Module 3 Quality

Module 5 Clinical

Module 4 Non clinical

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Medicinal Product

The Quality section of the CTD is organised according to the following outline:

3.1 Table of Contents of Module 3 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

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Medicinal Product

Introduction

Module 2 QOS

Summary of Module 3 Follows same headings For sections P.1 to P.8

2.3.S Drug Substance

2.3.P Drug Product

Appendices

3.1 Introduction

Product information is divided into eight sections P.1 to P.8 Guidance on titles and content is given in M4Q(R1) Additional information in M4Q Q&As

Module 3

3.2.P Drug Product

3.2.S Drug Substance

3.2.AAppendices 3.2.R Regional Information 3.3 Literature References

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Overview of 3.2.P

P.1 Description and Composition of the Drug Product P.2 Pharmaceutical Development P.3 Manufacture P.4 Control of Excipients P.5 Control of Drug Product P.6 Reference Standard or Materials P.7 Container Closure System P.8 Stability

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3.2.P.1 Description and Composition of the Drug Product

• Description of the dosage form • Tabulated list of components, quantity on a per-unit basis, function, reference to quality standard (e.g. USP, Ph.Eur, national Pharmacopeias or in-house)  Include components of a capsule shell, inks, tablet coating  List processing aids that may not appear in final drug product (e.g. water, alcohol) • Description of accompanying reconstitution diluent  NB: if diluents are co-packaged with the drug product - details about the diluent need to go into a separate DP section • Type of container and closure used

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3.2.P.2 Pharmaceutical Development

P.2 contains the necessary information to establish that the development of the drug product, manufacturing process and container closure system and usage instructions are appropriate for intended purpose specified in the application

References: EU ‘Note for Guidance on Development Pharmaceutics’ ICH Q8 Pharmaceutical Development

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3.2.P.2 Pharmaceutical Development

P.2.1 Components of the Product Drug substance:

• Suitability and compatibility with components of the product • Physicochemical and biological properties that can influence drug product • For combination products compatibility of drug substances Excipients: • Discuss selection, concentration and characteristics and their relative influence on the drug product performance • E.g. A preservative efficacy test may be required and should be included here.

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3.2.P.2 Pharmaceutical Development

P.2.2 Drug Product • Include formulation development – rationale and history • Differences between clinical and final formulation should be discussed and justified • Provide and discuss comparative dissolution profiles • Discuss results from in vitro or in vivo comparative studies • Justify overages • Physicochemical and biological properties relevant to performance of the drug product e.g. pH, dissolution, polymorphism and particle size distribution

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3.2.P.2 Pharmaceutical Development

P.2.3 Manufacturing Process Development • Describe the selection and optimisation of the manufacturing process • Describe process qualification studies and scale up experience • Identify critical process parameters and related controls • If a Quality by Design approach is followed, discussion incorporated in this section along with overall design space

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3.2.P.2 Pharmaceutical Development

P.2.4 Container Closure System • Suitability of container closure system should be discussed • Consider materials, protection, compatibility, safety and performance e.g. closure integrity testing P.2.5 Microbiological Attributes • Discuss Microbiological attributes of the product, selection of preservative system – microbial limit testing – as appropriate. Relate decisions to ICH Q6A decision trees. P.2.6 Compatibility

• Discuss compatibility of the product with reconstitution diluents or dosage devices

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3.2.P.3 Manufacture

P 3.1 Name and Address of Manufacturers

P 3.2 Batch Formula (include overages) • Present the representative commercial batch size

P 3.3 Description of the Manufacturing Process • Flow diagram (including IPCs) and narrative description • Describe process parameters, identify critical process steps and controls (additional information is provided in P 3.4)

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3.2.P.3 Manufacture

P 3.4 Critical Steps and Intermediates • Provide tests and acceptance criteria for critical steps identified P.3.3 • Provide info on quality and control of intermediates isolated during the process (where applicable) P 3.5 Process Validation • Validation studies performed on critical steps - at full scale • In the E.U. 3 pilot scale batches are usually acceptable • Non-standard formulation e.g. Aseptic, low content or modified release; will have more stringent requirements. References: ICH Q8 (R2) – Pharmaceutical Development, EMA Scientific Guideline: Quality: Manufacturing

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3.2.P.4 Control of Excipients

• For compendial excipients reference the compendia and provide CofAs from both supplier and FPM • For non-compendial excipients provide:  Specification  Analytical procedures and validation  Specification justification (include batch data and/or CoAs) • For excipients of human or animal origin also provide adventitious agent information (3.2.A.2) • For novel excipients (first time in DP or route of admin.) full details (manufacture, characterisation and controls) should be presented in 3.2.A.3 – summarised in P.4.6 • For specialised excipients e.g. Components of a liposome, a full 3.2.S module will be required.

References: ICH Q8 (R2) – Pharmaceutical Development, EMA Scientific Guideline: Quality: Manufacturing

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3.2.P.5 Control of Drug Product

P.5.1 Specification • Release & End of Shelf Life specifications

• Specifications should confirm quality rather than full characterisation – ‘acceptable for its intended use’. • Include compendial tests for the respective dosage form • All information should be tabulated P.5.2 Analytical Procedures P.5.3 Validation of Analytical Procedures • Compendial tests do not require re-validating • Results should be summarised as required by ICH Q2

References: ICH Q6, Q4, Q2, Decision Trees, General Monographs from Pharmacopoeias.

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3.2.P.5 Control of Drug Product

P.5.4 Batch Analyses • Provide data on all relevant batches – clinical, non- clinical, stability – including all batches used to justify acceptance criteria P.5.5 Characterisation of Impurities • Provide information on the characterisation of impurities in the Product (not included in 3.2.S.3.2 ‘Impurities’) P.5.6 Justification of Specification • Rationale for the inclusion/omission of tests on the specification and associated acceptance criteria • In case of wider limits within a shelf-life specification a justification for these wider limits should be included References: ICH Q3B(R), Q4,Q3, Q2, Q6 EMA Scientific Guidelines 24

3.2.P.6 Reference Standard or Materials

• For primary packaging materials provide:  Detailed description (drawings and dimensions)  Specification  Testing methods for non-compendial components  Typical CofAs from Supplier and FPM 3.2.P.7 Container Closure System • Provide information on reference standard, if not already provided in 3.2.S.6  Declarations referring to compliance with EC Directive 2004/12/EC, CHMP guidance, USP & Ph.Eur requirements as required. • For non-functional secondary packaging components only a brief description is required. For functional secondary packaging components further detail is required • NB: suitability information should be located in P.2 25

3.2.P.8 Stability (ICH Q1)

P.8.1 Stability Summary and Conclusions • Provide details of the type of stability studies conducted (including in-use & photostability studies), the protocols used and a summary of the results • Conclusions as to the shelf life, storage conditions and, if applicable, in-use storage conditions should also be given P 8.2 Post-Approval Stability Protocol and Commitments P 8.3 Stability Data • Provide tabulated results of stability studies • Include information on analytical procedures used to generate the data • OOS values should be highlighted. References: ICH Q1, EMA Scientific Guidelines; Quality 26

Appendices

3.2.A.1 Facilities and Equipment – Biotech products • Diagram illustrating the manufacturing flow • Details re manufacturing site, rooms used, their preparation and cleaning • Info required wrt preventing contamination & cross- contamination 3.2.A.2 Adventitious Agents Safety Evaluation • Information considering the risk with particular attention to potential contamination with adventitious agents should be provided 3.2.A.3 Excipients

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3.2.R Regional Information

Additional information relating to both the Drug Substance of Drug Product and specific to a region e.g.: • Process Validation Scheme for Drug Product (EU) • Certificate of Suitability (EU) • BSE/TSE (EU & Japan)

• Executed Batch Records (US) • Method Validation Package (US) • Comparability Protocols (US)

Regional guidelines should be consulted as required. 28

Examples of Rest of World Requirements

• Request for Samples, from each manufacturing site

• Declaration for source of Gelatin

• Declaration for no alcohol content

• Detail of Stability data requirements

• Power of Attorney’s from manufacturing sties

• Certificate of Pharmaceutical Product

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Lifecycle Management

For each variation or post-approval change – the applicant will need to update the relevant section of the dossier that is effected by the change Reference: EU: Variation Regulation (EC) No 1234/2008 – effective 01 January 2010 as amended by Commission Regulation 712/2012 • Type IA / IA IN (Minor - Tell & do, immediate implementation) − Change in imprints, bossing or other markings, addition of a 1° packaging site (Type IA IN – immediate notification) − Tightening of specification limits (Type IA – notification within 12 months) • Type IB (Minor - Tell, wait & do, 30 days before implementation) − Addition or replacement of a specification parameter as a result of a safety or quality issue • Type II (Major Change requiring HA approval: typically 60 days) − Deletion of a specification parameter which may have a significant effect on the overall quality of the finished product − Introduction of a new design space or extension of an approved design space for the finished product 30

Lifecycle Management

Reference: USA (Guidance for Industry – changes to an Approved NDA or ANDA) • Minor Change - The applicant must describe minor changes in its next Annual Report • Moderate Change - There are two types of moderate change: − FDA may identify certain moderate changes for which distribution can occur when FDA receives the supplement. This type of supplement is called a Change Being Effected (CBE) − One type requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product made using the change. This type of supplement is called a Change Being Effected in 30 days (CBE 30) • Major Change : Prior Approval Supplement (PAS ) − Requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change

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Due Diligence Tips – what should you check??? • Does the data which can be found in multiple sections of the dossier match? E.g.  Does the information in section P.1 (composition) correspond to the batch formula presented in section P.3.2? [And you application form and product information]  Does the flow diagram provided in section P.3.3 correspond to the manufacturing process description? • Are all CoAs that are required included?  Remember to check the details: Batch numbers, Batch size, date of manufacture, the manufacturing site, the API batch number and supplier used.  Has the correct specification been used? 32

Due Diligence Tips – what should you check???

• Has analytical method validation been carried out in line with ICH Q2 guidelines?

• Scrutinise stability data  Has been conducted in line with ICH GLs?  Has an OOS been missed?  Were there any ‘significant’ changes?

 Have the correct details been included (batch numbers, batch sizes, storage conditions, pack type, API batch number/ suppliers)

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Due Diligence Tips – what should you check???

• Have new Guidelines been issued? What are the authorities currently focussing on? • E.g. Current – EMA – [Draft] Reflection paper on the dissolution specification for generic oral immediate release products – Issued May 2016

• Check EMA guidance for dossier validation

• Check validation queries/review queries received for other procedures/products

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Due Diligence Tips – what should you check???

• Does the information in the application form match that in your module 3 and other module 1 documentation? • Have the correct documents been included in the correct section? • Are all documents which have been scanned clear and readable? • Once the eCTD or NeeS is published, check it. • If you were the assessor would the presentation of the dossier help your review?

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Useful References

ICH Guidance : www.ich.org M4(R3) “ Organisation Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use ” M4Q(R1) and M4Q Q&A – specific to Quality

ICH Quality topics FDA Guidance: www.fda.gov – new drug application EU Guidance: www.ema.europa.eu European Pharmacopeia United States Pharmacopeia

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Learning Objectives

• Brief history of the CTD and Legal framework • CTD dossier structure – where medicinal product fits within structure • Overview of content of module 3.2.P • Lifecycle management • Due Diligence

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Thank You

Questions???

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Tea and coffee break

Chemistry, Manufacturing & Controls (CMC)

Control of Medicinal Product

18 – 19 October 2017

Chris Abegunde - GlaxoSmithKline

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 How specifications for finished product are set and maintained  Review and development of specifications  Analytical Procedures/Validation of Analytical procedures and Justification of Specifications  Application of ICH General Concepts in setting and reviewing of Specification  Role of competent authorities and Pharmacopoeias in controlling the quality of medicinal product  Introduction to universal and specific tests/criteria for different dosage forms

How specifications for finished product are set and maintained

How specifications for finished product are set and maintained

How specifications for finished product are set and maintained

● Drug product specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. ● The final specifications need to ensure the safety, identity, strength, performance, and quality of the drug product at release and during its shelf-life. ● The specification limits are typically based on regulatory guidance, data from the manufacturing process, from development of the product, non- clinical, clinical, and stability studies.

How specifications for finished product are set and maintained

Specifications can be divided into two categories, product-specific specifications and compendial or regulatory specifications: ● Product-specific specifications are those for which specifications, methods, and limits are unique to the product (e.g. potency, impurities, pH, colour). ● Compendial or regulatory specifications are those for which specifications and limits are well defined by regulatory agencies (e.g., endotoxins, particulates etc.). Also includes finished product monographs.

Directive 2001/83/EC as amended ANNEX 1: Part 1, Module 3, CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL TESTING OF MEDICINAL PRODUCTS ……, Control of the finished medicinal product

For the control of the finished medicinal product , a batch of a medicinal product is an entity which comprises all the units of a pharmaceutical form which are made from the same initial quantity of material and have undergone the same series of manufacturing and/or sterilisation operations or, in the case of a continuous production process, all the units manufactured in a given period of time. Unless there is appropriate justification, the maximum acceptable deviation in the active substance content of the finished product shall not exceed ± 5 % at the time of manufacture Detailed information on the specifications , (release and shelf life) justification for their choice, methods of analysis and their validation shall be provided

How specifications for finished product are set and maintained

● The setting of specifications for drug product is part of an overall control strategy which includes control of raw materials and excipients, in- process testing, process evaluation or validation, adherence to cGMP, stability testing, and testing for consistency of lots. ● It is usual to set specifications in broader limits at the beginning of the life cycle of a finished product (justification of limits are necessary) ● More experience means to tighten specifications according to batch results (Variation procedure)

How specifications for finished product are set and maintained

● Information from development of the product ● Manufacturing process capabilities ● Batch analysis data from manufacture of product batches ● Stability of drug substance and drug product ● Any degradation of drug substance and drug product during storage ● Analytical Method Capabilities ● Data from Forced Degradation Studies ● Data from Photostability studies ● Regulatory/compendial requirements (e.g. impurities limits)

Review and development of specifications

● Review active specification ● Review Impurity Profile

● Review manufacturing experience ● Review analytical methodologies ● Review stability data ● Review storage conditions ● Update Specifications in Annual Review/ report ● It should be noted that changes in the specification after approval of the application may need prior approval by the regulatory authority.

Review and development of specifications Specification Development is a Continuous Improvement Process Knowledge

Refinement of Analytical Methodology

Refinement of Manufacturing Process and Raw material

Refinement of Acceptance Criteria Note: Refinement doesn’t always mean “tighter”

Analytical Procedures/Validation of analytical procedures and Justification of Specifications Analytical Procedure

● The analytical procedure refers to the way of performing the analysis. It described in details the steps necessary to perform each analytical test . ● This may include but not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.

Analytical Procedures/Validation of analytical procedures and Justification of Specifications validation of Analytical Procedure

● The objective is to demonstrate that the analytical procedure is suitable for its intended purpose . ● Required to be included as part of medicinal product registration application. ● The objectives of the analytical procedure should be clearly understood since this will govern the validation characteristics which need to be evaluated. ● Revalidation may be necessary if there are changes in: synthesis of the drug substance, composition of the finished product, and/or changes in the analytical procedure.

Analytical Procedures/Validation of analytical procedures and Justification of Specifications Typical Validation Characteristics

● Accuracy ● Precision

– Repeatability – Intermediate Precision – Reproducibility

● Specificity ● Detection Limit ● Quantitation Limit ● Linearity ● Range

Analytical Procedures/Validation of analytical procedures and Justification of Specifications Release and shelf life specifications

● It establishes more restrictive criteria for the release of a drug product than are applied to the shelf-life e.g. assay and impurity (degradation product) levels. ● an applicant may choose to have tighter in-house limits at the time of release to provide increased assurance that the product will remain within specification throughout its shelf-life. ● In the European Union there is a regulatory requirement for distinct specifications for release and for shelf-life where different limits may apply.

Analytical Procedures/Validation of analytical procedures and Justification of Specifications Acceptance Limits for Excipients

● Excipients which affect the bioavailability of an active substance must be quantitatively determined in each batch, (established on a case by case basis).

● For preservatives, content limits of 90-110% at release should be acceptable without further justification.

Analytical Procedures/Validation of analytical procedures and Justification of Specifications Control of Impurities

● Degradation products should be reported above specific thresholds ( usually <0.1% of drug substance ) ● Degradation products should be identified above certain thresholds (i.e. 1% for <10 mg dose of drug substance to 0.10% for >2g dose of drug substance ) ● Degradation products should be clinically qualified above certain thresholds (i.e. 1% for <10 mg dose of drug substance to 0.15% for >2g dose of drug substance )

Analytical Procedures/Validation of analytical procedures and Justification of Specifications Limited Data Available at Filing

● Limited amount of data may be available at the time of filing, which can influence setting of acceptance criteria. ● Acceptance criteria can be revised as additional experience is gained with the manufacture (limits for a specific impurity). ● The basis for the acceptance criteria at the time of filing should necessarily focus on safety and efficacy . ● Initially approved specifications should be reviewed as more information is collected for a possible modification. This could be loosening, as well as tightening the limits as appropriate.

Analytical Procedures/Validation of analytical procedures and Justification of Specifications

● When a specification is first proposed, justification should be provided for each parameter and acceptance criterion included. ● The justification should refer to the following as appropriate: – development data (from stability & validation batches) – pharmacopoeial standards (monographs) – test data for drug substances and drug products used in toxicology and clinical studies – results from accelerated and long term stability studies ● Alternative approaches may be acceptable, however should be justified by the applicant.

Analytical Procedures/Validation of analytical procedures and Justification of Specifications

● Presentation of test results in graphic format may be helpful in justifying individual acceptance criteria, particularly for assay and impurity. ● Data from development work and stability data should be included in such a presentation. ● Justification for proposing exclusion of a test from the specification should be based on development data and on process validation data (where appropriate). ● Application of any general concepts should be justified.

Application of ICH General Concepts in setting and Reviewing of Specification

● The following concepts are important in the development and setting of harmonised specifications. ● They are not universally applicable, but each should be considered in particular circumstances. ● Generally, proposals to implement these concepts should be justified by the applicant and approved by the appropriate regulatory authority before implementation .

Application of ICH General Concepts in setting and Reviewing of Specification Periodic or Skip Testing

● To perform specific tests at release on pre-selected batches or at predetermined intervals, rather than on a batch-to-batch basis ● batches not being tested still must meet all acceptance criteria, if tested. ● should be justified by applicant and approved by the regulatory authority before implementation. ● This concept may be applicable to residual solvents and microbiological testing for solid oral dosage forms.

Application of ICH General Concepts in setting and Reviewing of Specification Periodic or Skip Testing

● limited data may be available at the time of submission. Therefore this concept should be implemented post-approval . ● When tested, any failure to meet acceptance criteria for periodic testing should be notified to appropriate regulatory authority . ● Batch to batch testing should be reinstated if required.

Application of ICH General Concepts in setting and Reviewing of Specification Real Time Release (RTR) Testing

● New guideline on real time release testing (formerly Parametric Release) was implemented in October 2012 . ● It is a system of release that gives assurance that the product meets specification, based on the information collected during the manufacturing process (e.g. sterility testing). ● When approved, Real Time Release Testing can be used as an alternative to routine release testing in certain cases.

Application of ICH General Concepts in setting and Reviewing of Specification Real Time Release (RTR) Testing

● The Real Time Release Testing principle has been approved as an alternative to routine sterility testing of products terminally sterilised in their final container. ● Real Time Release testing may be applied to biological/biotechnological products provided that it can be demonstrated that acceptable level would be maintained in the final product level, if tested. ● When parametric release is performed, the parameter which is indirectly controlled (e.g., sterility), should be included in the specifications together with a reference to the associated test procedure.

Application of ICH General Concepts in setting and Reviewing of Specification Design and Development Considerations

● It may be possible to propose excluding or replacing certain tests on the basis of drug development data. ● microbiological testing for solid dosage forms which have been shown not to support microbial viability or growth. ● extractables from product containers where no extractables are found in the drug product or the levels meet accepted standards for safety. ● particle size may be performed as an in-process or release test, depending on product performance. ● dissolution testing for immediate release solid oral drug products made from highly water soluble drug substances may be replaced by disintegration testing

Application of ICH General Concepts in setting and Reviewing of Specification Alternative Procedures

● Alternative procedures may be used to measure an attribute if they are comparable or superior to the official procedure. ● Example: for tablets that do not degrade during manufacture, it may be permissible to use a spectrometric procedure for release instead of the official chromatographic procedure. ● However, the chromatographic procedure should still be used to demonstrate compliance with the specifications during shelf-life of the product.

The role of Competent Authorities in controlling the quality of medicinal product

The role of Competent Authorities in controlling the quality of medicinal product

● Evaluate and approve initial drug product specifications ● Deal with OOS results – batch specific variations?

● Assessment and approval of variations to change specifications ● Inspections of manufacturing facilities (including Quality Control Laboratories) to ensure compliance ● Confirm compliance of specification with applicable monographs and latest guidance ● Official batch release

The role of Competent Authorities in controlling the quality of medicinal product

Official Control Authority Batch Release (OCABR) ● Article 4.3 of Council Directive 89/342/EEC and Article 4.3 of Council Directive 89/381/EEC allow (but do not require) a member state laboratory to test a batch of a vaccine or blood product before it can be marketed. ● Issue a batch release certificate when the results are satisfactory; Known as "official batch release" and is additional to the batch release carried out by the manufacturer. ● In UK, the batch release authority is NIBSC ( National Institute for Biological Standards and Control )

The role of Pharmacopoeias in controlling the quality of medicinal product

The role of Pharmacopoeias in controlling the quality of medicinal product

● Provide public standards, specifications, and test methods that are likely to be used for quality control ● The control of APIs, excipients, and drug products that are used by industrial manufacturers, official medicines' control laboratories, and regulatory authorities ● Play an important role in the fight against counterfeit medicines ● Provide Reference Standards or Materials for use as standards in assay, identification or purity tests

The role of Pharmacopoeias in controlling the quality of medicinal product

Pharmaceutical products can usually be tested and qualified by various Pharmacopoeia. Current existing pronounced standards include:

● British Pharmacopoeia ● European Pharmacopoeia ● Japanese Pharmacopoeia ● The International Pharmacopoeia ● United States Pharmacopoeia

The role of Pharmacopoeias in controlling the quality of medicinal product

● Wherever appropriate, pharmacopoeial procedures should be utilised. ● Whereas difference exist amongst the regions, a harmonised specification is possible only if the procedures and acceptance criteria defined as acceptable to regulatory authorities in all regions. ● Pharmacopoeial Discussion Group (PDG) was formed in 1989 with representatives from Ph. Eur., JP and USP. ● PDG expressed commitment is to achieve harmonisation of the procedures and/or acceptance criteria in a timely manner across all three regions. ● More than 40 excipient monographs and 27 general methods have been harmonised.

Introduction to universal and specific tests/criteria for different dosage forms New Drug Product (non-Biological)

● The following tests and acceptance criteria are considered generally applicable to all new drug products: – Description: A qualitative description of the dosage form should be provided (e.g., size, shape, and colour). – Identification: Identification testing should establish the identity of the new drug substance(s) in the new drug product and should be able to discriminate between compounds of closely related structure which are likely to be present. – Assay: A specific, stability-indicating assay to determine strength (content) should be included for all new drug products. In many cases it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of impurities. – Impurities: Organic and inorganic impurities (degradation products) and residual solvents are included in this category.

Introduction to universal and specific tests/criteria for different dosage forms New Drug Product (non-Biological)

● In addition to the universal tests, the following tests may be considered on a case by case basis for drug products ● Individual tests/criteria should be included in the specification when the tests have an impact on the quality of the drug product ● Tests other than discussed may be needed in particular situations or as new information becomes available ● Additional tests and acceptance criteria generally should be included for particular new drug products.

Introduction to universal and specific tests/criteria for different dosage forms Tablets, Capsules and Granules

● Dissolution: The specification for solid oral dosage forms normally includes a test to measure release of drug substance from the drug product. Single- point measurements are suitable for immediate-release dosage forms, multiple time point testing for extended-release dosage forms and two- stage testing for delayed-release dosage forms. ● Disintegration: For rapidly dissolving products containing drugs which are highly soluble throughout the physiological range, disintegration may be substituted for dissolution. ● Hardness/friability: usually just an in-process control unless they have a critical impact on drug product quality (e.g., chewable tablets), their acceptance criteria should be included in the specification.

Introduction to universal and specific tests/criteria for different dosage forms Tablets, Capsules and Granules

● Uniformity of dosage units: This term includes both the mass of the dosage form and the content of the active substance in the dosage form; a pharmacopoeial procedure should be used. ● Water content: A test for water content should be included when appropriate. ● Microbial limits: It is advisable to test the drug product unless its components are tested before manufacture and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination or proliferation.

Introduction to universal and specific tests/criteria for different dosage forms Oral Liquids and Powders for reconstitution as oral liquids

● Uniformity of dosage units: This term includes both the mass of the dosage form and the content of the active substance in the dosage form; a pharmacopoeial procedure should be used. ● pH: Acceptance criteria for pH should be provided where applicable and the proposed range justified. ● Microbial limits: It is advisable to test the drug product unless its components are tested before manufacture and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination or proliferation. ● Antimicrobial preservative content: For oral liquids needing an antimicrobial preservative, acceptance criteria for preservative should be established.

Introduction to universal and specific tests/criteria for different dosage forms Oral Liquids and Powders for reconstitution as oral liquids

● Antioxidant preservative content: Release testing for antioxidant content should normally be performed and when it is performed should be justified. ● Extractables: Should normally be performed except where development and stability data shows evidence that extractables from the container/closure systems are consistently below safe levels. ● Alcohol content: Where it is declared quantitatively on the label in accordance with pertinent regulations, the alcohol content should be specified.

Introduction to universal and specific tests/criteria for different dosage forms Oral Liquids and Powders for reconstitution as oral liquids

● Dissolution: May be included for oral suspensions and dry powder products for resuspension. Single-point measurements are suitable for immediate- release dosage forms, multiple time point testing for extended-release dosage forms and two-stage testing for delayed-release dosage forms. ● Particle size distribution: May be appropriate for oral suspensions. Developmental data should be considered when determining the need for either a dissolution or particle size distribution procedure. ● Redispersibility: For oral suspensions which settle on storage (product sediment), acceptance criteria for redispersibility may be appropriate. Shaking (mechanical or manual) may be the procedure and should be indicated.

Introduction to universal and specific tests/criteria for different dosage forms Oral Liquids and Powders for reconstitution as oral liquids

● Rheological properties: For relatively viscous solutions or suspensions, it may be appropriate to include rheological properties (viscosity/specific gravity) in the specification. ● Reconstitution time: Acceptance criteria for reconstitution time should be provided for dry powder products which require reconstitution. ● Water content: For oral products requiring reconstitution, a test and acceptance criterion for water content should be proposed when appropriate. Loss on drying is generally considered sufficient if the effect of absorbed moisture vs. water of hydration has been adequately characterized during the development of the product. In certain cases a more specific procedure (e.g., Karl Fischer titration) may be preferable..

Introduction to universal and specific tests/criteria for different dosage forms Parenterals

● Uniformity of dosage units: This term includes both the mass of the dosage form and the content of the active substance in the dosage form; a pharmacopoeial procedure should be used. ● pH: Acceptance criteria for pH should be provided where applicable and the proposed range justified ● Sterility: All parenteral products should have a test procedure and acceptance criterion for evaluation of sterility even when RTRT ● Endotoxins/Pyrogens: A test procedure and acceptance criterion for endotoxins, using a procedure such as the limulus amoebocyte lysate (LAL) test, should be included in the specification. ● Pyrogenicity testing may be proposed as an alternative to endotoxin testing where justified. ● Particulate matter: Parenteral products should have appropriate acceptance criteria for particulate matter.

Introduction to universal and specific tests/criteria for different dosage forms Parenterals

● Water content: For non-aqueous parenterals, and for parenteral products for reconstitution, a test procedure and acceptance criterion for water content should be proposed when appropriate. ● Antimicrobial preservative content: For parenteral products needing an antimicrobial preservative, acceptance criteria for preservative content should be established. ● Antioxidant preservative content: Release testing for antioxidant content should normally be performed. ● Extractables: Where data demonstrate the need, acceptance criteria for extractables from the container/closure components are considered appropriate for parenteral products packaged in non-glass systems or in glass containers with elastomeric closures. This testing may be performed at release only

Introduction to universal and specific tests/criteria for different dosage forms Parenterals

● Functionality testing of delivery systems: Parenteral formulations packaged in pre-filled syringes, autoinjector cartridges, or the equivalent should have test procedures and acceptance criteria related to the functionality of the delivery system. ● Osmolarity: When the tonicity of a product is declared in its labelling, appropriate control of its osmolarity should be performed. ● Particle size distribution: Quantitative acceptance criteria and a procedure for determination of particle size distribution may be appropriate for injectable suspensions. ● Redispersibility: For injectable suspensions which settle on storage (produce sediment), acceptance criteria for redispersibility may be appropriate. ● Reconstitution time: Acceptance criteria for reconstitution time should be provided for all parenteral products which require reconstitution.

Learning Outcomes: Recap

 How specifications for finished product are set and maintained  Review and development of specifications  Analytical Procedures/Validation of Analytical procedures and Justification of Specifications  Application of ICH General Concepts in setting and reviewing of Specification  Role of competent authorities and Pharmacopoeias in controlling the quality of medicinal product  Introduction to universal and specific tests/criteria for different dosage forms

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