How we set specifications for impurities (including Genotoxic impurities) 24 May 2017 Elisabeth Kovacs, Apotex CSO Chemistry and Analytical Sci.

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1 2017 AAM CMC Workshop How we set specifications for impurities (including Genotoxic impurities) 24 May 2017 Elisabeth Kovacs, Apotex CSO Chemistry and Analytical Sci.

2 The information within this presentation is based on the presenter's expertise and experience and represents the views of the presenter for the purposes of stimulating discussion at this workshop.

3 We all aim to do the right thing PAGE 3

4 We all aim to do the right thing Clinical Relevance Context, Connections and Collaboration FDA/PQRI Conference March 22, 2017 Sarah Pope Miksinski Director (acting), Office of Surveillance Director, Office of New Drug Products PAGE 4

5 Guidances available to industry 1. ICH Q 3 A&B: Impurities in Drug Substance and Drug Products-Identification and qualification threshold based on MDD or MDI 1. ICH Q3 C Residual Solvents- PDE 2. ICH3D- PDE 3. ICH M7- TTC, duration of treatment, structural similarity to API 4. FDA Guidance for ANDA ( API and Product) +RLD and USP 5. FDA Guidance on Refuse to Receive (RTR) (same as #5) PAGE 5

6 Clinically Relevant Specifications *Clinically Relevant Specifications ( CRS) Test Methods and acceptance criteria that identify and reject/accept drug product batches that are likely to perform inadequately / adequately in the indicated population (s) The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably.** Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points ( (c)). ** Predetermined Quality Requirement = Clinically Relevant Specifications *Richard (Rick) Lostritto, Ph.D CDER/FDA, PQRI, Conference on Evolving Product Quality, September 16-17, 2014, Bethesda, Maryland ** Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 PAGE 6

7 ICH Guidelines Clinically relevant Specifications RLD Qualification ( impurities exceeding qualification threshold) Establishing Limits for impurities USP Qualification of Identified impurities Limits unidentified impurities to levels below the ICH level No Reporting Threshold Batch Data ( process capability) 5/23/2017 Progressing through the process limits tend to become increasingly tighter 7

Not Negotiable Patient Risk I bit of reality check Fact At the time Of filing Risk to Quality #1 #2 #3 #4 #5 #6 #7 #8 Limited no of batches (pilot) Limited stability data ( 6 Mo) Limited no of API

8 Not Negotiable Patient Risk I bit of reality check Fact At the time Of filing Risk to Quality #1 #2 #3 #4 #5 #6 #7 #8 Limited no of batches (pilot) Limited stability data ( 6 Mo) Limited no of API batches No experience with scale up No experience with commercial process No information about RLD at expiry or the variability of the RLD API may be using a different synthetic route Product manufacturing process may be different than the RLD leading to different impurities ( degradation products) 5/23/2017 8

9 If the quality of a product confirmed by meeting the specification, than a lot depends on how we establish specifications Acceptance criteria based on process capability Acceptance criteria based on safety (Clinically Relevant Specifications) Potentially reject acceptable batches (failed batches, stability failures, recall, reduced shelf life) Specifications design based on product/ process understanding following scientific risk based principles linked to patient safety Impact on process capability (introduce variation at a level that has is not linked to quality) no value added Impact on process capability ( controls variability at levels relevant for product quality) Specifications can be too wide, to tight, or altogether irrelevant Cannot and do not improve the quality of a drug substance or product by tightening a specification This can only be done by changing the production process 5/23/2017 9

10 CRS vs Specifications established based on Process Capability Good Product, Good Process CRL UL: 0.5% Bad Process Bad Product? Batch data UL: 0.3% Batches 1->n PAGE 10

11 Considerations for RLD Limited number of batches available ( variability?) Typically at or around filing the RLD has years before expiring Do the levels observed in the RLD represent safety or process capability? Qualification? Metabolites Chiral Impurities PAGE 11

Lot# Other opportunities: Setting Specifications Solvent: methanol ICH Limit ( ICH Q3C): Option 1 (based on 10g/day intake) 3000 ppm Option 2: PDE (permitted daily exposure) 30mg/day Drug API:

12 Lot# Other opportunities: Setting Specifications Solvent: methanol ICH Limit ( ICH Q3C): Option 1 (based on 10g/day intake) 3000 ppm Option 2: PDE (permitted daily exposure) 30mg/day Drug API: example Maximum daily intake in the example is: 7g/day Results ppm (Method Precision:6 samples) RSD: 6.6% SD= 198 ppm Calibration (6 injections): RSD 3.5% (SD=105ppm) Mean: 2640ppm SD: 259 ppm RSD: 10.9% Considerations for specifications: ICH option 1 : 3000 ppm ICH Option 2 (based on PDE): 4285 ppm PDE 30mg methanol : the maximum methanol content to ensure NMT 30mg daily exposure is 4285 ppm, based on the MDD ( maximum daily dose of example) of 7g/day. In other words, methanol content of NMT 4285ppm will correspond to NMT 30mg of methanol daily intake. Options for acceptance criteria: a) 3000 ppm* b) 0.3% c) 0.30% d) 4285 ppm (PDE) e) 0.4% f) 0.40% Acceptance Criteria Probability of being within spec % > USL NMT 3000 ppm 91.76% 8.24% (>8/100) NMT 0.30% 94.33% 5.67% (6/100) NMT 0.3% 99.95% 0.05% (1/10000) NMT 4285 ppm >99.99% 0.00% NMT 0.40% >99.99% 0.00% NMT 0.4% >99.99% 0.00% NA; (>PDE) Points to consider: An acceptance criteria of 3000 ppm will render a result of 3001 OOS An acceptance criteria of 0.3% will be considered in spec up to % An acceptance criteria of 0.30 will be considered in spec up to % An acceptance criteria 4285 ppm (PDE) will render a result of 4286 ppm as OOS An acceptance criteria of 0.4% will be considered in spec up to 4499 (>PDE) An acceptance criteria of 0.40% will be considered in spec up to % Using this mean and SD for a sample of size 1,000,000 random draws from a normal distribution the following can be predicted for future batches: 5/23/

13 Generic Product Synthetic route for API is often different from the RLD (at times unique) Different impurities Different form Different solvents Manufacturing Process for the Drug Product Different composition Different manufacturing process PAGE 13

14 Control Strategy Control Strategy - A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) PAGE 14

15 Control Strategy for the Generic Product As a result the specifications for impurities can be quite different from the RLD It will require an analytical procedure designed and developed to control impurities that may not be present (or possible) in the RLD Some of the impurities in the RLD may not be present (or possible) in the generic product The USP method may not be suitable, will not detect, will overestimate or underestimated the new impurities ( equivalence?) The Drug Product while it meets ICH may not meet the USP limits using the USP analytical procedure PAGE 15

16 Generic Product and USP The USP specification for impurities ( analytical procedure and acceptance criteria) are representative of the monograph s sponsor s approved specifications. Are relevant to sponsor's Process ( API and Drug Product) Represent the sponsor s Process Capability The question that needs to be asked: 1. How USP specifications relate to Clinically Relevant Specifications? 2. How accurate are the following: A. USP limits always represent safety limits? B. USP specifications for impurities are always relevant for a generic product? C. The analytical procedure for impurities published in the USP is always appropriate for a generic product? PAGE 16

17 ICH Reporting Threshold- levels found below reporting threshold are not included in the calculation of total In Drug Product: Synthetic impurities not reported or included in the calculation of total impurities Impurities exceeding identification threshold can be identified and acceptance criteria established accordingly Matrix ( placebo Peaks) are excluded PAGE 17 Other Challenges in establishing specifications USP vs ICH USP No Reporting Threshold (occasional discard limit that only reflect method capability) All detected peaks are reported and included in total impurities No provision to identify impurities found to exceed identification threshold No provision to exclude matrix (placebo peaks)

18 Paths and processes developed by USP In cases where a product or an API may not meet the USP (current at that time) specifications (with the USP published procedure), USP developed procedures to allow compliance All paths however require FDA approval before it can be published and progress to official text Pending monographs Flexible monographs Interim Revision Procedure USP GC <476> and <1082> Organic Impurities in Drug Substances and Drug Products. 5/23/

19 Pending Monographs Three main stages for Pending Monographs: Draft (on USP website; 90-day comment) Authorized (by USP Expert Committee) Official in USP/NF Following publication in PF, the proposals remain in unofficial status until FDA s approval of the market application USP Guideline for Submitting Requests for Revision to USP NF General Information for All Submissions G Page 6 of 7 EFFECTIVE DATE 04/29/2016 by the sponsor. PAGE 19

20 Flexible Monographs (cont.) General Notices : Applicability of Test Procedures multiple procedures may be included in particular monographs specifically for the purpose of assuring the availability of an appropriate procedure for a particular product. In such cases, a labeling statement to indicate the appropriate application of the procedure(s) will be included in the monograph. A labeling statement is not required if Test 1 is used. PAGE 20

21 Interim Revision Announcements (IRAs) Interim Revision Announcements (IRAs) are published in Pharmacopeial Forum (PF) as proposed IRAs. After a 90-day notice and comment period and approval by the relevant USP Expert Committee, IRAs are posted as official text on the USP website, and are incorporated into the next available official publication (USP NF or Supplement). PAGE 21

22 USP GC<476> & <1086) Follows ICH Concepts Identification threshold Qualification threshold Limits based on MDD PAGE 22

23 RTR Guidance Pursuant to the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA),7 the Office of Generic Drugs (OGD) is tasked with a number of activities, including the development of enhanced refusal to receive standards for ANDAs and other related submissions by the end of year 1 of the program. Enhanced RTR standards are important because the practice of submitting an ANDA that is not sufficiently complete to permit a substantive review, which then is repaired via several cycles of applicant resubmission and FDA response, is inherently inefficient and a drain on FDA resources. 5/23/

24 Closing Remarks The agency is moving toward Clinically Relevant Specifications and guiding industry to consider risk in the context of clinical performance Encourage industry to use science and risk considerations when establishing specifications that should lead to tests and acceptance criteria based on clinical relevance and not on process capability and/or batch data Give industry opportunities to work in the framework of the USP processes that rely on FDA review and approval before changing and/or progressing to official text. PAGE 24

25 Closing Remarks (cont.) Understand the challenges industry faces when expected to commit to compendia limits when these do not represent safety therefore are not clinically relevant but rather represent the monograph s sponsor process capability Industry would appreciate a more in-depth evaluation during the technical review stage and more flexibility over the enhanced assessment which occurs at filing. Collaborate with industry to move from what appears to be a one measure fits all approach to a more science and risk based process for establishing limits for impurities in products that reflects the innovation in FDA s regulatory approaches. PAGE 25

26 A Generic Industry Perspective on Establishing Impurity Limits And a Corresponding Control Strategy An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDE ( ICH Q3D) An applicant is not expected to tighten limits for impurities based on process capability provided that the impurities in drug products do not exceed the qualified levels Is this enlightened philosophy consistently followed by FDA re: organic impurity limits in ANDAs? Nicholas Cappuccino, PhD Vice-President, Head of Quality and Scientific Affairs, Dr. Reddy s Laboratories, Inc GPhA CMC Workshop October 2016, Bethesda Marriott 5/23/

A Generic Industry Perspective on Establishing Impurity Limits And a Corresponding Control Strategy An applicant is not expected to tighten the limits based on process capability, provided that the

27 A Generic Industry Perspective on Establishing Impurity Limits And a Corresponding Control Strategy An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDE ( ICH Q3D) An applicant is not expected to tighten limits for impurities based on process capability provided that the impurities in drug products do not exceed the qualified levels* ICH Q9: PRINCIPLES OF QUALITY RISK MANAGEMENT Two primary principles of quality risk management are: The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk. *Nicholas Cappuccino, PhD Vice-President, Head of Quality and Scientific Affairs, Dr. Reddy s Laboratories, Inc GPhA CMC Workshop October 2016, Bethesda Marriott 5/23/

28 CRS vs Specifications established based on Process Capability Good Product, Good Process CRL UL: 0.5% Bad Process Bad Product? Batch data UL: 0.3% Batches 1->n PAGE 28

29 CRS vs Specifications established based on Process Capability Good Product, Good Process CRL UL: 0.5% Batches 1->n PAGE 29

30 We all aim to do the right thing PAGE 30

31 Thank you for your attention Any Questions? Elisabeth Kovacs, Apotex, 150 Signet Drive Toronto Ontario, Canada, M9L 1T9 PAGE 31

Regulatory expectations on impurities in drug substances - Pavia, October 2, Luisa Torchio Euticals SpA

Regulatory expectations on impurities in drug substances - Pavia, October 2, 2015 Luisa Torchio Euticals SpA An Impurity is defined as any substance or element present in a drug substance (DS) that is