#1ICH Quality Guideline Q11 Development and Manufacture of APIs (An Update from the Trenches) Steven Mendivil (Amgen) Special thanks to Betsy Fritschel & Tim Watson March 2012 International Conference on Harmonisation of Technical TUTH Requirements for Registration of Pharmaceuticals for Human Use ICI+#2ICH Q11 Development and Manufacture of Drug Substance Disclaimer These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Use by permission only. Reference to ICH Q11 as draft Guidance. Q11 is a draft until it reaches Step 4 consensus. The views and opinions expressed in the following PowerPoint slides are those of the individual presenter. ICI+ March 2012 Slide 2#3ICH Q11 Development and Manufacture of Drug Substance ICH Q11 Today's Agenda ■ Late breaking news ■ Background and Process for Q11 ■ Step 2 document - highlights & controversies ■■ Q11 Nomenclature Quiz * Design Space * QbD development versus QbD submission ✶ Platform Manufacturing * Control Strategy March 2012 ICI+ Slide 3#4Value of Q11 Q10 3/23/12 Q9 Q8 ICI+ Q10 Q11 Q8 Q9#5ICH Q11 Development and Manufacture of Drug Substance Why Q11? ■ New ICH Guidelines ✶ Q8 Pharmaceutical Development ✶ Q9 Quality Risk Management ✶ Q10 Pharmaceutical Quality System Q10 Q11 Q8 Q9 ■ Concepts of these guidelines apply to Drug Substance as well as Drug Product ■ Process for manufacture of Drug Substance very different from Drug Product - purification ■Need Q11 to clarify principles of Q8, Q9, and Q10 as they relate to Drug Substance and provide examples March 2012 ICH 55 Slide 5#6ICH EARMONISATION OF TECHNI QUEMENTS FOR REGISTRATION OF PHARSFACES TICALS FORMAS F Q: D Type of Hero Act Are In Pipes (A Baskmand.est Sum Select of clay of d pagal ng bus bel CH pan Thigh Best Technical Gustamon Concept Paper April 2008 3/23/12 ICH Q11 EWG INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR WOMAN SE ICI+ Q11 EWG June 2008 Portland, Oregon#7ICH Q11 Development and Manufacture of Drug Substance Step 1 ■ 6 Face-to-face EWG meetings ■ Many teleconferences and net meetings ■ Many drafts (10 + depending on how you count) Draft 0 - 4 (June 2008 – November 2010) ■ Examples Remember: This is a negotiated consensus process . No party gets everything they want! March 2012 ICH 77 Slide 7#8ICH Q11 Development and Manufacture of Drug Substance Almost Step 2 We called it Pre-Step 2 March 2012 ICI+ Q11 EWG November 2010 Fukuoka Japan Slide 8#9raft Draft Draft Step e A few more revisions A lot more teleconferences And then finally reached consensus Step 2 May 2011 3/23/12 ICI+#10raft Draft Draft Step e ic ICH Harmonation or marim Topic Reference: 011 STEP 2 EXPERTS Q11: Development and Manufacture of Drug Substances Consensus on a document to be submitted to the ICH Steering Committee under Step 2 of the ICH Process Step 2 Experts Document signed off by the DESIGNATED EXPERTS FROM THE ICH EXPERT WORKING GROUP The official ICH procedure specifies that a Step 2 Document can be submitted to the SC for endorsement when the Designated Experts of the six ICH parties reach consensus and sigu the Step 2 Siguoff sheet. Document reference Document Date: ICH Parties ICH Q11, Step 2 28 April 2011 Kem MCMALD Pude Zuz EXC EFPIA Slate. Buy had MHLW ALTER BRENDAN HUGHES Dave 11 May 2011 *May 2011 May 10 all. Tergoddesh Anda 101ay 2011 Koji Takaki KOJI TAKAKI 10 May 2011 JOHN L SMITH 5/9/2011 Chantytes/a/n A A few more revisions A lot more teleconferences And then finally reached consensus Step 2 May 2011 JPMA FDA² 3/23/12 ICH PhRMA Autochel P.IV Bulay Fritschol My Ar wep 2, The Steering Commune agencias for wider, formal consultation in accordance with their normal ernal or external consultation procedure AS e document to the inte regional reginatory Due to its structured the representation of both CBER and CDER in ICH FDA May nammate wo Topic Leaders, one per Center (depending on the scope of the topic)#11CH Q11 Development and Manufacture of Drug Substance Public consultation June September - 1300 comments across 3 regions Regional review of comments More telecons and Net Meetings March 2012 Almost Step 4 We called it Pre-Step 4 Q11 EWG November 2011 Seville Spain ICI+ Slide 11#12ICH Q11 Development and Manufacture of Drug Substance Current Status of Q11 ■ Step 1 EWG Consensus April 2008 - April 2011 ■ Step 2 - Signatures May 2011 ■ Step 3 - Stage 1 Public comment Target June - Sept 2011 Stage 2 Resolve comments Target 1st Quarter 2012 ■ Step 4 publication of final version ■ Step 5 Implementation March 6 telecon consensus March 2012 ICI+ Slide 12#13ICH Q11 Development and Manufacture of Drug Substance What took so long? ■ Many different expectations * Traditional vs Enhanced Small vs Large * Alignment with regional guidelines and expectations ■ Many different agendas Team dynamics 25+ people ■ Only two face to face meetings per year ■ Virtual meetings ok for simple editing but not a good venue for true discussion March 2012 ICI+ Slide 13#14ICH Q11 Development and Manufacture of Drug Substance Outline of Q11 Step 2 document 1. Introduction 2. Scope 3. Manufacturing Process Development 4. Description of Manufacturing Process 5. Selection of Starting Material 6. Control Strategy 7. Process Validation/Evaluation 8. Submission in CTD Format 9. Lifecycle Management 10. Illustrative Examples 11. Glossary ICH March 2012 Slide 14#15ICH Q11 Development and Manufacture of Drug Substance Outline of Q11 Step 2 document Introduction 1. 2. Scope 3. Manufacturing Process Development 4. Description of Manufacturing Process 5. Selection of Starting Material Format: General Principles What to Submit 6. Control Strategy 7. Process Validation/Evaluation 8. Submission in CTD Format 9. Lifecycle Management 10. Illustrative Examples 11. Glossary ICH March 2012 Slide 15#16ICH Q11 Development and Manufacture of Drug Substance Outline of Q11 1. Introduction 2. Scope 3. Manufacturing Process Development Important to read Q11 as a "whole" NOT individual sections out of context Process Validation/Evaluation Submission in CTD Format 7. 8. 9. Lifecycle Management 10. Illustrative Examples 11. Glossary March 2012 ICH Slide 16#17ICH Q11 Development and Manufacture of Drug Substance Q11 Introduction ■ Traditional Approach * Defined set points and operating ranges for process parameters ✶ Drug Substance control strategy typically based on ■ Demonstration of process reproducibility ■ Testing to meet established acceptance criteria ■ Enhanced Approach * Risk management and more extensive scientific knowledge to select process parameters and unit operations * Evaluation in studies to establish design space and control strategies applicable over the lifecycle of the drug substance ICI+ March 2012 Slide 17#18ICH Q11 Development and Manufacture of Drug Substance Q11 Introduction ■ Traditional Approach * Defined set points and operating ranges for process parameters ✶ Drug Substance control strategy typically based on ■ Demonstration of process reproducibility ■ Testing to meet established acceptance criteria ■ Enhanced Approach * Risk management and more extensive scientific knowledge to select process parameters and unit operations Evaluation in studies to establish design space and control strategies applicable over the lifecycle of the drug substance ■ Not mutually exclusive. Company can choose: * Traditional * Enhanced * Combination of both March 2012 ICI+ Slide 18#193 Manufacturing Process Development Enhanced Traditional Identify Potential CQA's Define Manufacturing Process Define Control Strategy Systematic evaluation and understanding Functional relationships that link material attributes and process parameters to CQAS QRM to establish an appropriate control strategy which can include proposals for Design Space and/or RTRT 3/23/12 ICH#20ICH Q11 Development and Manufacture of Drug Substance 4 Manufacturing Description ■ Description of DS manufacturing process represents applicant's commitment Information to adequately describe mfg process and process controls ✶ Flow diagram * Sequential process narrative ✶ In-process controls * Scale-factors (when process is scale dependent) * Any design spaces in the mfg process should be included as part of the mfg process description ICI+ March 2012 Slide 20#21ICH Q11 Development and Manufacture of Drug Substance Important Definition & Distinction Design Space (Q8) The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (emphasis added) Important distinction between QbD development and QbD submission March 2012 ICH Slide 21#22ICH Q11 Development and Manufacture of Drug Substance Example 1 ◉ This example illustrates development of a design space using prior knowledge and chemistry first principles. It depicts both a traditional and enhanced approach to determination of the ranges for parameters controlling the formation of a hydrolysis impurity Value: high priority for PhRMA LDKIT Multivariate design is NOT DoE, Drug substance has many tools to develop and design space. * Demonstrate "fixed parameters" in MVD (eg. reflux temperature) Example proposed, developed, and supported by both regulators and industry ■ Not a complex example, and very "basic"; BUT the intent is very valuable to the disciple of drug substance. March 2012 ICH 2222 Slide 22#23ICH Q11 Development and Manufacture of Drug Substance Design Space Discussion for Biotech ■ The development and approval of a design space for some biotechnology/biological drug substances can be challenging due to factors including process variability and drug substance complexity (e.g., post- translational modifications). These factors can affect residual risk (e.g., potential for unexpected changes to CQAs based on uncertainties related to scale sensitivity) which remains after approval of the Design Space. Depending on the level of residual risk, it may be appropriate for an applicant to provide proposals on how movements within a Design Space will be managed post approval. These proposals should indicate how process knowledge, control strategy and characterisation methods can be deployed to assess product quality following movement within the approved design space. ICI+ March 2012 Slide 23#24CH Q11 Development and Manufacture of Drug Substance Example 2 This example illustrates how results from an iterative quality risk assessment can be used to communicate the rationale for classification and proposed future management of changes to process parameters. Risk Ranking of Ion Chromatography Process Parameters Feedstock Conductivity (A) Feedstock pH (B) Load Density (C) Buffer Conductivity (D) Feedstock Impurity Level (E) Parameter X (F) Resin Age (G) Flow Rate (H) Parameter Y (1) Feedstock Salt Composition (J) Buffer Salt Composition (K) Butter Titrant Concentration (L) Resin Lot (M) Temperature (N) Feedstock Titrant (0) Biotechnology Product Concentration (P) Cleaning Buffer (Q) Start of Pooling (R) End of Pooling (S) Parameter (1) Lower Risk TT ПОДДО Higher Risk Extension of ranges would normally initiate a regulatory post-approval change process The applicant can include in the original submission a proposal for extension of ranges for these parameters Extension of ranges is addressed primarily via the PQS (Q10) -#25ICH Q11 Development and Manufacture of Drug Substance 5 Selection of Starting Materials and Source Materials ■ 6 general principles for consideration ■ All general principles should be considered rather than strictly applying each general principle General principles paraphrased 1. Changes within early steps of a given synthesis lower potential impact on API Describe enough so that reviewer can understand where and how impurities in the API are formed and why proposed Control Strategy is suitable 2. 4. 5. Steps impacting impurity profile should normally be included Each branch of a convergent synthesis begins with one or more starting material Substance with defined chemical properties and structure - usually isolated 6. Significant structural fragment Example 4 clarifies how to use these principles March 2012 ICH Slide 25#26ICH Q11 Development and Manufacture of Drug Substance 6 Control Strategy General Principles ■ Control Strategy is a planned set of controls, derived from current product and process. understanding, that assures process performance and product quality ■ Every drug substance manufacturing process whether developed through traditional or enhanced (or combination of both) has an associated control strategy ICI+ March 2012 Slide 26#27ICH Q11 Development and Manufacture of Drug Substance 6 Control Strategy General Principles (cont'd) A control strategy can include, but is not limited to: Controls on material attributes (including raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc) ■ Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps (biotech) or order of addition of reagents (chem)) In-process controls (including in-process tests and process parameters) ■ Controls on drug substance (e.g., release testing) March 2012 ICI+ Slide 27#286 Control Strategy Enhanced Traditional Set points and operating ranges set tightly to ensure consistency More emphasis on assessment of CQAs at DS More systematic identification of sources of variability More meaningful and efficient controls Iterative process as process understanding increases Can provide for flexibility in operating ranges for process parameters 3/23/12 ICH#293/23/12 April 2011 Control Is the "lar Strategyains specifications and critical quality attributes in addition to other types of controls Every specification is part of the control strategy There are things in the control strategy that do not have a corresponding test in the drug substance Control Strategy can also include In-process Controls Material Attributes Process Parameters ICH Slide 29#303/23/12 April 2011 Control Strategy In-process Controls Process Parameters Filed Control Strategy Material Attributes ICH Slide 30#313/23/12 April 2011 Control Strategy In-process Controls Critical Spec Quality Attribute Process Parameters Filed Control Strategy Material Attributes ICH Slide 31#32ICH Q11 Development and Manufacture of Drug Substance 10 Illustrative Examples ■ Provide examples of implementation of concepts ■ Not intended to create any new expectations beyond current regulatory requirements 11 Glossary ICI+ Slide 32 March 2012#33ICH Q11 Development and Manufacture of Drug Substance Section 11 Glossary New term defined: Platform Manufacturing: The approach of developing a production strategy for a new drug starting from the manufacturing processes similar to those used by the same applicant to manufacture other drug of the same type (e.g. Mab). March 2012 ICI+ Slide 33#34ICH Q11 Development and Manufacture of Drug Substance What Q11 does not do: 1. Define or clarify regulatory flexibility 2. Define criticality (i.e. CPP) 3. Define starting material based strictly on number of steps 4. Clarify what goes into the manufacturing description section of CTD 5. Clarify what CPV? March 2012 ICI+ Slide 34#35ICH Q11 Development and Manufacture of Drug Substance Value of Q11 1. Recognizes that traditional and enhanced are not mutually exclusive 2. Gives context for scientifically justifying control strategy (provides an example of risk management for process. parameters) 3. Provides general principles for defining Starting Material 4. Introduces the concept of "Platform Manufacturing" 5. Drug Substance CQA can reference a control strategy for "material attributes" upstream March 2012 Disclaimer: This is MY opinion ICH Slide 35#36MREU H011 Development and Manufacture of Drug Substance ICH March 2012 Slide 36#37ICH Q11 Development and Manufacture of Drug Substance Is ICH worth the effort? Top Four Reasons. 4. Allows discussion / debate of draft and proposed expectations face-to-face with regulators 3. Allows all parties to hear each other's concerns including probable unintended consequences. 2. Allows debating specific wording with regulators and hearing underlying meaning of specific words 1. Reduces regional specific guidance March 2012 Disclaimer: Also MY opinion ICH Slide 37#38ICH Q11 Development and Manufacture of Drug Substance Special Thanks to John Donaubauer Abbott Vance Novack GSK Steve Mendivil Amgen Betsy Fritschel J&J Bryan Mobbs Astra Zeneca Wendy Mavroudakis J&J Rodney Parsons BMS Sally Anliker Lilly Jonathan Walker BMS Mark Butchko Lilly Andrew Gee Boehringer Ingleheim John Lepore Merck Linda Hendricks Centocor John Curran Merck Vincent Djuhadi Cephalon Tim Watson Pfizer Carly Evans Genzyme Zareen Ahmed Sanofi Clive Meerholz GSK March 2012 ICH Slide 38#39Thank you 3/23/12 ICI+