Current FDA Perspective on Excipients

NJPhAST Meeting – September 15, 2016

Jeffrey B. Medwid, Ph.D., Office of New Drugs, API Branch II

Senior CMC ReviewerOPQ/CDER/FDA

Jeffrey.Medwid@FDA.HHS.ov

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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 & 2015

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Specific Projects

• Methods for testing to detect absence of asbestos in Talc

• Elemental Impurities in Excipients• Inactive Ingredients Database (IID)• Gluten in Drugs

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Objectives of OPQ

• Launched January 2015~ 1200 Staff Members

• A single unit in CDER dedicated todrug product quality

– Across all drug product areas• new drugs, generic drugs, biotechnology products, and over-the-

counter drugs– Across all sites of manufacture

• domestic and foreign

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Office of Pharmaceutical Quality

Office of Process and FacilitiesActing Director:Robert Iser

Office of SurveillanceActing Director:Sarah Pope Miksinski

Office of Testing and Research Director:Lucinda Buhse

Office of Program and Regulatory OperationsActing Director: Giuseppe Randazzo

Office of Lifecycle Drug ProductsDirector:Susan Rosencrance

Immediate OfficeNew Director: Michael KopchaDeputy Director: Lawrence Yu

Office of Policy for Pharmaceutical QualityDirector:Ashley Boam

Office of New Drug ProductsDirector:Sarah Pope Miksinski

Office of Biotech ProductsDirector:Steven Kozlowski

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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

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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.

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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

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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

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Approaches to Excipient Evaluation• Understanding Excipient Properties

– Physical – Chemical – Mechanical

• Drug-Excipient Compatibility • Formulation Robustness • Functionality – Excipient Performance• USP General Chapter <1059>

Excipient Performance

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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>

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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

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FDA Coordinates with USP on Excipient Monograph Modernization

• USP Compendial Modernization 2010-2015 and 2015-2020– 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

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What is Talc?• Talc is a powdered, selected, natural, hydrated

magnesium silicate – Pure talc has the formula Mg3Si4O10(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

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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 0.1-0.5%)– Light-Microscopy

• Alternative Asbestos methods are being evaluated and will be recommended:– More sensitive microscopic techniques (PLM, SEM)

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Modernization of Asbestos Testing in USP Talca

• 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.

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Elemental Elements in Excipients

• David R. Schoneker• Director of Global Regulatory Affairs, Colorcon• Vice Chair, Scientific and Regulatory Affairs –• IPEC-Americas• dschoneker@colorcon.com

Implementation of ICH Q3D Elemental Impurities RequirementsAnalytical and Risk Assessment Challenges

Pb As Hg Cd Co V Ni

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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)

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ICH Q3D Appendix 2: Established PDEs for Elemental

Impurities

1 ICH Q3D

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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??

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March 27, 2015: Revision to General Notices section 5.60.30 :

– Revision to General Notices section 5.60.30 :– 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, 2018.

– 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 5.60.30 and will be required unless specified otherwise in a monograph.

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• 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.

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FDA Inactive Ingredient Database Update

ExcipientFest April 27, 2016Susan Zuk

Office of Policy for Pharmaceutical QualityOPQ, CDER, FDA

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IID, Inactive Ingredient Database

• http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm

• Also available on www.fda.org

• 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 2000.

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Example - TalcInactive Ingredient Route Dosage Form CAS Number UNII Maximum Potency

MISTRON SPRAY TALC ORAL TABLET Pending NA

TALC BUCCAL GUM, CHEWING 14807966 7SEV7J4R1U NA

TALC BUCCAL TABLET 14807966 7SEV7J4R1U 1.5MG

TALC BUCCAL/SUBLINGUAL TABLET 14807966 7SEV7J4R1U 15MG

TALC ORAL CAPSULE 14807966 7SEV7J4R1U 220.4MG

TALC ORAL CAPSULE (IMMED./COMP. RELEASE)

14807966 7SEV7J4R1U 0.44MG

TALC ORAL CAPSULE, COATED PELLETS

14807966 7SEV7J4R1U 0.66MG

TALC ORAL CAPSULE, COATED, HARD GELATIN

14807966 7SEV7J4R1U 10MG

TALC ORAL CAPSULE, COATED, SOFT GELATIN

14807966 7SEV7J4R1U NA

TALC ORAL CAPSULE, DELAYED ACTION

14807966 7SEV7J4R1U 130.13MG

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Soliciting Input from Stakeholders•• How can we improve

nomenclature?

• How should we identify excipient

amounts?

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2015 Backlog - 4000 Formulas

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

IID 2013 Integrity 2015 Integrity only 2015 Backlog of Products

11,788

13,347

2152

3815

Inactive Ingredients

New entries

Product formulas to be entered

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April 2016

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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

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Summary

• Excipients are important in assuring drug product manufacturability, 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

SW16

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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