Immediate Release uspension - IAGIM · Vol. 3-Semisolids Handbook of ... development process required for modern suspended oral dosage form. ... -In-process Quality Control Summary

HANDBOOK OF PHARMACEUTICAL GENERIC DEVELOPMENT

O R A L Suspension

VOLUME VII - Part One Drug Deve lopmen t - O ra l Suspens ion Dosage Fo rms

H a n d b o o k o f P h a r m a c e u t i c a l G e n e r i c D e v e l o p m e n t S e r i e s

I m m e d i a t e R e l e a s e

BLOCK J. D. & BELLE D.

ORAL SUSPENSION Generic Drug Development Series

24 VOLUME DRUG DEVELOPMENT SERIES PRODUCT DEVELOPMENT

SERIAL NUMBER - DO NO REMOVE! - REGISTERED WITH

34004945-08 LOCUM INTERNATIONAL PUBLISHERS REGISTRATION SERVICES

WARNING: THIS ISSUE A IS MULTIPLE PAGE UV ENCODED EDITION.

HPGD ORAL SUSPENSION - Part I First & Second Int. Edition - 01 & 02 (First & second print run) Published 1995/6/7/8. Third International Edition - 03 (1st, 2nd and 3rd printing) - Published 1999/2000/2001. Forth International Edition - 04 (First & second print) - Jan / July 2002 & 2003. Published and distributed in UK, US, EU, Israel, Asia, and Japan in by Locum International Publishing House (Houston, Israel, South Africa) in Hard Cover; Soft and Spiral Cover; Electronic CD ROM; and Online Editions. All print and electronic editions are identical in content and format. Fifth International Edition - 05 (1st International Printing) - Publishing Date - January 2004 Sixth International Edition - 06 (1st Edition Printing) - Publishing Date - January 2005 Seventh International Edition - 07 (1st International Printing) - Publishing Date-January 2006 Copyright © 1995 Handbook of Pharmaceutical Generic Development. Text Copyright © 1995 Handbook of Pharmaceutical Generic Development. Illustration copyright © 1995 Handbook of Pharmaceutical Generic Development. Locum International Group Publishing House 562 Monaco L Monaco Blvd. Delray Beach Florida 33446-1938 USA. - All right reserved ISSN 0793 8659 ISSN 0793 8667 - Electronic Version (Online, CD ROM and e-mail PDF™ versions)

Handbook Development 24 volume series General Generic Development ISSN Series number 0793 7407 General Generic Development ISSN Series number 0793 7792 - Electronic Issue (Online and CD ROM are identical in size and content to the printed hard or soft cover version.)

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The Complete Handbook Ser ies o f P h a r m a c e u t i c a l D r u g D e v e l o p m e n t

ISBN 0793 8632 - Electronic Version - Handbook Development 24 Volume Series ISSN Series Number 0793 761X - Electronic Version.

Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 1 - Tablets Oral Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 2 - Capsules Oral Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 3 - Semisolids

Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 4 - Liquids Oral Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 5 - SG Capsules

Handbook of Pharmaceutical Generic Development Vol. 6 - e-SOPs / SOPs Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 7 - Suspensions

Handbook of Pharmaceutical Generic Development Part I & II (Development x 2) & Part III & IV (Development ANDA (x 2) Vol. 8 - Eye & Nose

Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 9 - Aerosols MDI Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 10 -Tablets CR / MR

Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 11 -Capsules ER

Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 12 - Tablets Oral DR

Handbook of Pharmaceutical Generic Development Part I (Method Validation) & Part II (Analytical Methods 1994-2003)

Vol. 13 - Analytical (Top 50 Generic Assay Methods)

Handbook of Pharmaceutical Innovative Development Vol. 14 - Tablets Oral Handbook of Pharmaceutical Innovative Development Vol. 15 - Capsules Oral Handbook of Pharmaceutical Innovative Development Vol.16 - Suspensions Oral Handbook of Pharmaceutical Drug Development (Master Formula & Manufacturing Instructions Parts 1 - 5)

Vol. 17 - MF and MMI

Handbook of Pharmaceutical Drug Development (Master Formula & Manufacturing Instructions Parts 6 -10)

Vol. 18 - MF and MMI

Handbook of Pharmaceutical Innovative Development Part I, II & III (Development, Manufacturing & Engineering)

Vol. 19-SOPs/PAI-Checklist

Handbook of Pharmaceutical Drug Development Part I (Development) & Part II (Formulation ; Development & ANDA)

Vol. 20 - Sterile Injections

Handbook of Pharmaceutical Generic Development Part I (Development) & Part II (Formulation ; Development & ANDA) Vol. 21 - Chew Tablets

Available as Print, Online, CD ROM or electronic mail attachment. Additional Drug Specific Volumes in Preparation.

An on-going electronic and print series. Available either as Hard Bound, Soft Bound or Soft Spiral Cover (for Updating).

For Drug Specific Handbooks refer to the 120+ Drug Development Series titled READY-TO-GO™ DRUG DEVELOPMENT SERIES

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L o c u m I n t e r n a t i o n a l P u b l i s h e r s

H a n d b o o k o f

Pharmaceutical G e n e r i c Development

Copyright © Locum Int. Publishing House Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming and recording, or by any information storage and retrieval system, without the permission of the publishers. A L o c u m H o u s e P u b l i c a t i o n

P a r t O n e

Suspensions Oral



INTRODUCTION Handbook of Generic Drug Development - Oral Suspension Dosage Forms

his handbook is the newest updated and expanded international edition of the ongoing 24 volume series under the cumulative title of Handbook of Generic Drug Development. It is a hands-on, technical presentation that portrays the

current drug requirement steps necessary at the time of going to print, of the Abbreviated New Drug Application for oral suspensions dosage forms. It is written in conjunction with Part Two of the Handbook which covers commercial development formulations and a development ANDA presentation as an example of the drug development process required for modern suspended oral dosage form. The Handbook is available in print and electronic formats namely CD ROM and online e-format. The Handbook's know-how technology is written by industrial, agency and academic authorities and the full set of regulatory requirements are up-dated once annually in order to keep them current.

This handbook provides a proven pathway to suspended oral dosage form technology and development. Modern commercial formulations highlight the common development pathways to produce an appropriate granule for reconstitution. Examples are specially chosen to demonstrate the formulation steps and process stages as a prerequisite to developing stable, elegant, robust and rugged formulas.

This expanded current edition of the Handbook includes additional data on process and analytical method validation has been redesigned to meet the current Guidance for Industry - Organization of an Abbreviated New Drug Application as well as all FDA key draft and final guidelines and requirements of the Center of Drug Evaluation and Research (CDER) until current print date. Editor-in-Chief.

International Edition LOCUM PRESS

World wide distribution © COPYRIGHT

All Rights Reserved

ISSN 0793 8632 An on-going series

A d d i t i o n a l V o l u m e s i n P r e p a r a t i o n

General Drug Development Series ISSN 0973 7601 Electronic Drug Development Series ISSN 0973 761X

© COPYRIGHT LOCUM Int.

T



Acknowledgments

I.A.G.I.M. (R&D) Foundation. I.A.G.I.M. Research Council.

Contributions - Generic & Research Firms Associate Universities, Technicons and Consultants.

Handbook Series Coordinating Committee. International Journal of Drug Development. International Journal of Drug Formulation. Journal of Pharmaceutical Development. International Journal of Generic Drugs.

International Journal of Drug R&D I.A.G.I.M. Drug Development Archives

Locum International Archives. FDA/OGD/CDER Maryland

Guides and Guidelines Library of Congress.

AIC Conferences. Editorial Board.

Pharm. Eur. USP/NF. USPC.

BP.

To Doribelle for her years of support and help

to Sean for his expert knowledge on computerization to David and Ari for running the project's computers

and lastly to Pat for his inestimable contribution.

24 Volume Series Handbook of Pharmaceutical Generic Development

International Edition

L O C U M P U B L I S H I N G H O U S E

Table of Contents.

Handbook of Pharmaceutical A 9 Generic Development

ContentsP H A R M A C E U T I C A L D E V E L O P M E N T

Table of Contents VIIIAcronyms - Abbreviations XIIIIntroduction XIVPreface XVForward XVI

Chapter 1Regulatory 1.1 - Pre-formulation checklist 1.3Getting the Right Documentation from A-Z 1.4- SOP Control checklist 1.7Development Notebooks 1.8- Development Notebooks checklist 10- SOP Control and Development Notebooks SOPs 11

Chapter 2Developing the Formula -an Overview 2.1- Formulation Check List 2.2- Development formulations 2.3Drug Development Checklist 2.4Development Formula SOPs 2.5Developing the Formula 2.7Design Considerations for Reconstituted Suspensions 2.12Product Development Flow Chart 2.29Product Development Guide 2.31

Chapter 3Active Ingredients 3.1-Do’s and Don’ts 3.2-Active checklist 3.3-Approved Suppliers Checklist 3.5-Standard Operating Procedures, Actives 3.6-Alternative Active Sources 3.7

Table of Contents.


Contents

Chapter 4Semi active ingredients 4.1-Validating the Semi-active ingredients, Checklist 4.2Qualifying the Antioxidant 4.3Antioxidant Tabulations 4.5Non active materials (excipients) 4.12-Checklist non active ingredient 4.14-Standard Operating Procedures, Non actives 4.15Purified Water - An ingredient for development 4.16

Chapter 5Container closure systems 5.1-Container-liner-closure systems, Checklist 5.3-Container-liner-closure systems, SOPs 5.4-Packaging Components 5.5-Packaging Components Documentation Requirements SOP 5.12

Chapter 6Manufacturing Instructions 6.1- Manufacturing Instructions; Checklist 6.3- The manufacturing Instructions and Controls 6.5- Batch Manufacturing instructions 6.31- In-process and Release Specifications 6.44- Manufacturing Flow Charts 6.51- Large scale manufacturing Instructions 6.52- Large scale Master Formula 6.53- Large scale Packaging Instructions 6.56

Chapter 7In-process Quality Controls 7.1-Manufacturing in-process controls; Checklist 7.3-In-process Quality Control Summary 7.7-In-process Quality Controls; SOPs 7.10

Chapter 8Finished Product Specifications 8.1- Finished Product Specifications example and Checklist 8.3- Release and Check Specifications for Suspensions 8.6- Release and Check Specifications - Special Considerations 8.8- Glossary of Terms 8.10- Finished Product Specifications; Required SOPs 8.12

Table of Contents.


Contents

Chapter 9Process Optimization and Procedures 9.1Evaluation product specifications 9.3Qualification of Antioxidant and Chelating Agents 9.6Qualification of Antioxidant Limits 9.7

Chapter 10Scale-up Procedures 10.1- Scale-up procedures; checklist 10.4- Scale-up procedures; SOPs 10.5

Chapter 11Cleaning Limits 11.1Cleaning Limits Procedures; Checklist 11.6Cleaning Validation Requirements; SOPs 11.8Cleaning procedures as the FDA see it 11.9

Chapter 12Analytical Validation Requirements 12.1-Analytical Testing Out of Specification 12.21-Analytical Testing Do's and Don'ts 12.23-Out of Specification Checklists 12.24-Out of Specification test Results 12.27- The Ins and Outs of Outliers 12.36-Impurities in Drug Substances 12.38-Impurities Do's and Don'ts 12.50-Impurities Glossary of terms 12.41-Impurities Decision Trees 12.42-Analytical Post approval Changes -PAC-ALTS 12.51-PAC-ALTS Checklist 12.54-Analytical Testing TLC ID & Impurity Methods 12.61Analytical Testing Assay Method 12.69-Ruggedness and Robustness 12.79

Chapter 13Process Qualification Batch 13.1-Process Qualification Batch; Checklist 13.2-Process Qualification Batch; SOPs 13.3-Process Qualification Blend Analysis 13.5-Process Qualification Blend Analysis - Do's and Don'ts 13.7- BUA blend Uniformity Analysis - Guidance 13.8Content Uniformity Protocol 13.13

Table of Contents.


Contents

Chapter 14Pivotal batch-The Pivotal Batch 14.1-Pivotal batch Checklist 14.2-Pivotal batch SOPs 14.3-Sampling and Testing the Pivotal Batch 14.5-Auditing the Pivotal batch 14.9-Auditing the Pivotal batch Checklist 14.10

Chapter 15Bioequivalence vs. RLD 15.1Test Designs - Overview 15.3Statistical Bioequivalence 15.13IBE Equation explained 15.14IBE Big Picture (Pros and Cons) 15.15Comparing IBE and ABE 15.16Generic Drug Dissolution and the RLD 15.19Typical IVIVC Models 15.22Dissolution Testing of IR Dosage Forms 15.24Similarity Factor in dissolution testing 15.30Biowaivers 15.32Overall Dissolution Picture 15.36Biopharmaceutics Classification System 15.37Class One to Class four Drugs 15.38Performance Verification in Dissolution testing 15.42BA & BE - general Considerations 15.56Food-Effects in BA-BE Studies 15.82Bioanalytical Methods Validation 15.90Bioanalytical Methods Validation Checklist 15.101Dissolution tresting of IR Solid Oral Dosage Forms & BCS 15.102BioPharmaceutical Classification System 15.106FDA Narrow therapeutic List 15.115Similarity Testing - Chow, Pitt and Others 15.116

Chapter 16Technical Transfer Documentation 16.1-Technical Transfer Documentation; checklist 16.5-Technical Transfer Documentation; Pharmaceutical Part 16.7-Technical Transfer Documentation; Analytical Part 16.10-Laboratory Equipment Installation & Operation Qualification 16.13

Table of Contents.


Contents

Chapter 17Process Validation batches 17.1-The Process Validation Batches; checklist 17.3-Process Validation Requirements; SOPs 17.4-Reserved page 17.5-Process Validation Master Plan 17.6-Bulk Suspension Single Fill 17.8-Bulk Suspension Two Stage Fill 17.9-Process Validation Master Protocol 17.10-Process Validation Stability & Statistics 17.11

Chapter 18Pre--Approval Inspections 18.1PAI Summary 18.8Pre--Approval Inspection Audit - Team Set Up 18.9Pre--Approval Inspection Audit - Team Activities 18.11

Chapter 19Stability Testing of Drug Substance and Drug Product I 19.1Stability Commitment 19.8Stability Protocol 19.9Stability Summary - Results 19.10Stability Reports 19.12Stability Testing of Drug Substance and Drug Product II 19.17Stability Testing of Drug Substance and Drug Product II 19.23Stability Testing Significant Change SOP 19.27Storage Conditions 19.31Photostability 19.33

Chapter 20Standard Operational Procedures Setting up a functional Stability Unit 20.1Stability SOPs Development 20.9Development SOPs - Training Tool 20.15

APPENDIXDevelopment Guidances 20.21Master Formula & Processes - Title 17 Series

Table of Contents.


NOTES

ISSN 0793 8632A n o n - g o i n g s e r i e s

A d d i t i o n a l V o l u m e s i n P r e p a r a t i o nISBN 0793 8640 - Electronic Version

Handbook Development 24 Volume SeriesISSN Series Number 0793 7792 - Electronic Version

Handbook of PharmaceuticalGeneric Development Series

Immediate Release uspension - IAGIM · Vol. 3-Semisolids Handbook of ... development process required for modern suspended oral dosage form. ... -In-process Quality Control Summary

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