Current FDA Perspective on Excipients NJPhAST Meeting September 15, 2016

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1 Current FDA Perspective on Excipients NJPhAST Meeting September 15, 2016 Jeffrey B. Medwid, Ph.D., Office of New Drugs, API Branch II Senior CMC Reviewer OPQ/CDER/FDA

2 My presentation will touch on the following issues Overview of the new Office of Pharmaceutical Quality (OPQ) Why QbD for Excipients? Evaluating Variability in Excipients USP Excipient Monograph Modernization 2010 &

3 Specific Projects Methods for testing to detect absence of asbestos in Talc Elemental Impurities in Excipients Inactive Ingredients Database (IID) Gluten in Drugs 3

4 Objectives of OPQ Launched January 2015 ~ 1200 Staff Members A single unit in CDER dedicated to drug product quality Across all drug product areas new drugs, generic drugs, biotechnology products, and over-thecounter drugs Across all sites of manufacture domestic and foreign 4

5 Office of Pharmaceutical Quality Immediate Office New Director: Michael Kopcha Deputy Director: Lawrence Yu Office of Program and Regulatory Operations Acting Director: Giuseppe Randazzo Office of Policy for Pharmaceutical Quality Director: Ashley Boam Office of Biotech Products Director: Steven Kozlowski Office of New Drug Products Director: Sarah Pope Miksinski Office of Lifecycle Drug Products Director: Susan Rosencrance Office of Testing and Research Director: Lucinda Buhse Office of Surveillance Acting Director: Sarah Pope Miksinski Office of Process and Facilities Acting Director: Robert Iser 5

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7 Team-based IQA (OPQ) Team-based Integrated Quality Assessment Maximizes team expertise Provides aligned patient-focused and risk-based drug product quality recommendations An IQA team/original NDAs Application technical lead (ATL) Responsible for overseeing the scientific content of the assessment Regulatory business process manager (RBPM) Responsible for process and timeline Discipline reviewers Drug substance, drug product, process, facility, microbiology, biopharmaceutics, and Office of Regulatory Affairs (ORA) investigators. Other members (as needed) FDA laboratories (e.g., Office of Testing and Research), policy, surveillance, and other offices 7

8 ICH Q8(R2) Related to Excipients Key Principles to Q8(R2), Systematic approach to development Begins with predefined objectives Emphasizes product and process understanding and process control Based on sound science and quality risk management Applications should include the following minimal elements delineated in the ICH Q8(R2) Annex Quality target product profile (QTPP). Critical quality attributes (CQAs) of the drug product CQAs of the drug substance and excipients. Selection of an appropriate manufacturing process. Control strategy. 8

9 Why QbD for Excipients? Properties can affect CQAs of drug product Manufacturability Content uniformity Bioavailability Purity Stability Important to understand and control effects of variability 9

10 Traditional vs. QbD Approaches In traditional approaches, industry focused on: Similar excipient lots used in development and manufacturing (avoiding variation) Optimized formulation and frozen process Compendial specifications QbD approaches encourages: Understanding variation of excipients properties as they relate to product quality attributes Building robustness and flexibility into manufacturing process to mitigate variability Specifications appropriate to ensure product quality 10

11 Approaches to Excipient Evaluation Understanding Excipient Properties Physical Chemical Mechanical Drug-Excipient Compatibility Formulation Robustness Functionality Excipient Performance USP General Chapter <1059> Excipient Performance 11

12 Evaluating Variability in Excipients Meet regularly with your excipient Supplier What does your COA really say? Request samples from edges of your design space may not be available Discuss Prior Knowledge of the excipient with your supplier Consider performance tests such as those in the new USP General Chapter <1059> 12

13 Excipient Functionality Minimize formulation processing problems Flowability, compressibility, sticking, dust generation Hygroscopicity Palatability Dissolution, disintegration Facilitate safer/more efficient manufacturing processes Wet granulation to direct compression Facilitate the development of novel drug delivery systems Bioavailability enhancers Biotechnology products Orally disintegrating tablets (ODTs) for pediatric, geriatric and uncooperative patients 13

14 FDA Coordinates with USP on Excipient Monograph Modernization USP Compendial Modernization and Includes USP and NF excipient monographs in Pharmacopeial Discussion Group* (PDG) work program Over 100 Excipient Monographs identified for Modernization A Large group of FDA Liaisons to the USP I am on the Excipient Expert Panel Useful Chapters for suppliers and users USP <1059> EXCIPIENT PERFORMANCE USP <1080> Excipient COA 14

15 What is Talc? Talc is a powdered, selected, natural, hydrated magnesium silicate Pure talc has the formula Mg 3 Si 4 O 10 (OH) 2 May contain variable amounts of associated minerals Known to contain asbestos if mined from specific mines Talc is one of the most common excipients in drugs Estimated to be present in approximately 1 in every 4 tablets and to contribute on average 0.4% of the inactive ingredient content of all tablets 15

16 Detection of Asbestos in Talc The Current COA for Talc states the absence of asbestos. It also indicates which method specified under the test for Absence of Asbestos was used for analysis. Problem: Current Methods for Absence of Asbestos are not sensitive enough IR or XRD (as go/no-go for microscopy) (LOD is %) Light-Microscopy Alternative Asbestos methods are being evaluated and will be recommended: More sensitive microscopic techniques (PLM, SEM) 16

17 Modernization of Asbestos Testing in USP Talc a The current USP Talc monograph contains a test for Absence of Asbestos that includes three procedures. Analysts are given the option to perform either Procedure 1 or Procedure 2, which consist of infrared spectroscopy (Identification Tests General 191) and x-ray diffraction ( Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD) 941), respectively. If either test gives a positive result, then the third procedure, consisting of optical microscopy (Optical Microscopy 776) must be performed to confirm. 17

18 Implementation of ICH Q3D Elemental Impurities Requirements Analytical and Risk Assessment Challenges David R. Schoneker Director of Global Regulatory Affairs, Colorcon Vice Chair, Scientific and Regulatory Affairs IPEC-Americas Pb As Hg Cd Co V Ni Elemental Elements in Excipients 18

19 Q3D Overview ICH Q3D applies to: Finished human drug products Emphasizes the use of risk assessment as opposed to testing wherever possible Does not apply to: Components, i.e. Drug Substance/ Excipients However the Guideline discusses excipients extensively and may play a huge role in location Elemental Impurities Application of Q3D to existing products is not expected prior to 36 months after publication of the guideline by ICH. (January 2018) 19

20 ICH Q3D Appendix 2: Established PDEs for Elemental Impurities 1 ICH Q3D 20

21 Pharmacopeias USP General Chapters <232> and <233> are being harmonized with ICH Q3D to be implemented in January 2018 PhEur will harmonize their EI requirements with ICH Q3D to be implemented in December 2017 Both USP and PhEur will remove all Heavy Metals requirements from Monographs when they implement the harmonized Q3D requirements there is discussion of keeping some specific metal requirements (USP Stimuli Article in July 2016 and PhEur Meeting in Tallinn, Estonia in September 2016) JP will ultimately harmonize with ICH Q3D but the timing is unknown and it is uncertain if they will remove the heavy metal requirements from monographs China?? (2020?) Other Countries?? 21

22 March 27, 2015: Revision to General Notices section : Revision to General Notices section : Elemental Impurities in USP Drug Products and Dietary Supplements, establishing January 1, 2018 as the new date of applicability of General Chapters <232> Elemental Impurities Limits and <2232> Elemental Contaminants in Dietary Supplements. USP also announces a revision to General Chapter <231> Heavy Metals and its references to delay their omission until January 1, Through these revisions, USP specifies that users could either continue to utilize the current <231> approach or implement the new <232>/<2232> approaches until January 1, 2018, at which time General Chapters <232> and <2232> will be made applicable to drug product and dietary supplement monographs as described in General Notices and will be required unless specified otherwise in a monograph. 22

23 Mar-Apr 2016 PF 232 Elemental Impurities Limits, USP 39 page 268. This chapter is being revised to address comments received and to further align this chapter with ICH Q3D. USP s Elemental Impurities Expert Panel approved a recommendation to the General Chapters Chemical Analysis Expert Committee that this chapter be revised to align with the ICH Q3D Step 4 document to the greatest extent possible. Therefore, this revision is being proposed to include additional elements and their specific limits in this chapter. Additional changes are made to provide clarity on the topic of risk assessment. 23

24 FDA Inactive Ingredient Database Update ExcipientFest April 27, 2016 Susan Zuk Office of Policy for Pharmaceutical Quality OPQ, CDER, FDA 24

25 IID, Inactive Ingredient Database Also available on The old IID system was DPRF. The new database is Integrity. Shortly after transfer of the database from DPRF to Integrity, the IT staff reported an additional 2000 entries that did not show up in the last DPRF version of the IID. That is a good thing because it means that more ingredients were showing up in the new system. This may be because new products were entered into the system since the last publication or because the ingredients were previously filtered from the report before publication (left out for some reason). There have been a large number of approvals in the last few years, so new entries are showing up in the IID in each publication. Half of the current entries come from products that were approved since

26 Example - Talc Inactive Ingredient Route Dosage Form CAS Number UNII Maximum Potency MISTRON SPRAY TALC ORAL TABLET Pending NA TALC BUCCAL GUM, CHEWING SEV7J4R1U NA TALC BUCCAL TABLET SEV7J4R1U 1.5MG TALC BUCCAL/SUBLINGUAL TABLET SEV7J4R1U 15MG TALC ORAL CAPSULE SEV7J4R1U 220.4MG TALC ORAL CAPSULE (IMMED./COMP. RELEASE) SEV7J4R1U 0.44MG TALC ORAL CAPSULE, COATED PELLETS SEV7J4R1U 0.66MG TALC ORAL CAPSULE, COATED, HARD GELATIN SEV7J4R1U 10MG TALC ORAL CAPSULE, COATED, SOFT GELATIN SEV7J4R1U NA TALC ORAL CAPSULE, DELAYED ACTION SEV7J4R1U MG 26

27 Soliciting Input from Stakeholders How can we improve nomenclature? How should we identify excipient amounts? 27

28 2015 Backlog Formulas Inactive Ingredients 13,347 14,000 11,788 12,000 10,000 8,000 Product formulas to be entered 6,000 New entries , ,000 0 IID 2013 Integrity 2015 Integrity only 2015 Backlog of Products 28

29 April

30 Gluten In Pharmaceutical Huge effort to determine if Gluten is a problem in Pharmaceutical Dosage forms A guidance is being prepared Bottom line, it should be of very minor concern to the patient 30

31 Summary Excipients are important in assuring drug product manufacturability, SW16 quality and stability Understanding and controlling the functionality of excipients can lead to more robust, flexible processes Excipient specifications should be appropriate to assure product performance! Think Excipient Functionality / Performance! Applicants should talk regularly with their excipient suppliers and go visit them! FDA, USP & IPEC are working closely together to enhance the Quality of US Pharmaceuticals 31

32 Acknowledgement OPQ Slides prepared by Sarah Pope Miksinski, Ph.D., Director ONDP Steve Wolfgang Ashley Boam, Susan Zuk and Michael Boyne at FDA Catherine Sheehan and Hong Wang at USP Dave Schoneker at Colorcon Brian Carlin at FMC 32

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