PQRI PODP Extractables & Leachables Workshoppqri.org/wp-content/uploads/2018/04/2-PQRI-Paskiet-Final.pdf · process can be extrapolated to container closure systems for PODP. 3. Threshold

PQRI PODP Extractables & LeachablesWorkshop

Diane Paskiet, MS, West Pharmaceutical ServicesPODP Chair

April 2018

Introduction to PODP Recommendations: Risk Based Concepts

PQRI PODP E&L WorkshopApril 18-19, 2018

Mission

• PQRI is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality, manufacturing and regulation.

• A unique forum with diverse membership to:Focus critical thinkingConduct researchExchange informationPropose methodology/ guidance to pharmaceutical

companies, regulators, and standard setting organizations.

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Industry

Regulators Academics


PQRI Member Companies All research work supported under the direction of PQRI

• CHPA: Consumer Healthcare Products Association • FDA / CDER: U.S. Food and Drug Administration, Center for

Drug Evaluation and Research • HC Health Canada • IPEC-Americas International Pharmaceutical Excipients Council

of the Americas • PDA Parenteral Drug Association • USP United States Pharmacopeia

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Objectives

• PQRI L&E Working Group History –Orally Inhaled Nasal and Drug Products (OINDP) –Parenteral and Ophthalmic Drug Products

(PODP)

• Risked Based Concepts–Safety–Leachables–Drug Product Quality

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Leachables and Extractables Working Group 2000…....2006

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2008 PODP Hypothesis

1. Threshold concepts that have been developed for safety qualification of leachables in OINDP can be extrapolated to the evaluation and safety qualification of leachables in PODP.• consideration of factors and parameters such as dose, duration, patient

population and additional product-dependent characteristics unique to various PODP types.

2. The “good science” best demonstrated practices that were established for the OINDP pharmaceutical development process can be extrapolated to container closure systems for PODP.

3. Threshold and best practices concepts can be integrated into a comprehensive process for characterizing container closure systems with respect to leachable substances and their impact on PODP safety.

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• Safety Concern Threshold (SCT)− Low Risk Leachables Not Identified

• <0.15 ug/day

• Qualification Threshold (QT)− Assessment of Identified Leachable

• non-carcinogenic >5 µg/day

• Best Practices for E&L studies– Controlled Extraction Studies (CES)− Analytical Evaluation Threshold (AET)

• Identification threshold Note:• Designed to reduce level of uncertainty within the pharmaceutical development • Not meant to be proscriptive

OINDP Threshold and Best Practices


2009 PQRI PODP Work Plan

Chemistry Team• Dennis Jenke, PhD, Chief Executive Scientist, Triad Scientific

Solutions; Chemistry Team Chair• James Castner, Pharma Interface Analysis• Thomas Egert, Research Scientist, Boehringer Ingelheim• Thomas Feinberg, PhD, President, SCIO Analytical• Alan Hendricker, PhD, Principle Scientist, Becton Dickenson• Christopher Houston, PhD, Director, Bausch & Lomb• Desmond G. Hunt, M.S., PhD, Senior Scientific Liaison, USP• Michael Lynch, PhD, Executive Director, Keryx Biopharmaceuticals • Ingrid Markovic, PhD, US Food and Drug Administration Division of

Therapeutic Proteins • Kumudini Nicholas, MS, Advisor/Team Leader, Bureau of

Pharmaceutical Sciences, Pharmaceutical Quality Review, Therapeutic Products Directorate, Health Canada

• Daniel Norwood, M.S.P.H., PhD, Executive Partner, SCIO Analytical, LLC

• Mike Ruberto, PhD, President, Material Needs Consulting, LLC• Edward Smith, PhD, Principal Consultant, Packaging Science

Resources

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Toxicology Team • Douglas J. Ball, D.A.B.T, F.A.T.S, Research Fellow, Worldwide Drug

Safety Research and Development, Pfizer; Toxicology Team Chair• Stephen A. Barat, PhD, Head of Preclinical Research and Early

Development, SCYNEXIS, Inc.• Steve Beck, Non-clinical Development Manager, Xellia Ltd• William P. Beierschmitt, PhD, D.A.B.T, F.A.T.S., Research Fellow,

Worldwide Drug Safety Research and Development, Pfizer• David Jones, Principal Scientific Officer, New Chemical Entities

Unit, MHRA• Abigail Jacobs, PhD, Associate Director for

Pharmacology/Toxicology, CDER, FDA• Jacqueline A. Kunzler, PhD, Vice President Quality Compliance,

Baxter Healthcare • Mary Richardson, PhD, Chief Scientific Officer, iuvo BioScience• Tim Robinson, Division of Pulmonary and Allergy Products, CDER,

FDA• Alisa Vespa, PhD, Assessment Officer, Metabolism and

Musculoskeletal Drugs Division, Bureau of Metabolism, Oncology and Reproductive Sciences, Therapeutic Products Directorate, Health Canada

Diane Paskiet, MS, Sr. Director of Scientific Affairs, West Pharmaceutical Services, PQRI PODP L&E Working Group ChairFrank Holcombe, Jr., PhD, US Food and Drug Administration; PQRI Development Technical Committee Liaison


PODP Scope

• Prefilled syringes (PFS)• Small Volume Parenterals (SVP)• Large Volume Parenterals (LVP)• Topical Ophthalmic Routes of Administration.

Considerations for drug product/packaging system design space– nature of the dosage form– compatibility between a formulation and a packaging system– context of the formulation/packaging system contact

• Parenteral products limited to intravenous, subcutaneous, and intramuscular routes of administration

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2009-2011 Extractable Protocols

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MEHP

Bisphenol A

Diphenylamine

IS:Bisphenol M

IS: 2-Fluoro-biphenyl

IS: Irganox415

BHT

DEHP

(www.PQRI.org)


2010…....2017 Extended Teams

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Laboratory ServicesBaxter

Roopang Shah, Marek Ciesla,Frank (Yousheng) HuaCatalent Pharma SolutionsPaul CvetichKimberly DavisMichelle CreeTom FeinbergAlan Hendricker

Becton DickensonJohn Lennon

Boehringer IngelheimDaniel L. NorwoodScott PenninoJames O. MullisThomas EgertJurgen MattesDavid Strassburger

PfizerCindy ZweibenMiguel SandovalArt Shaw

Bausch & LombChristopher HoustonJohn Rider

Toxicology ServicesPfizer QSAR [DEREK/Toxtree

Russell Naven Patricia Ellis

TOX-RSA, LLCBrenda Seidman, Ph.D.,Angela Howard, Ph.D

ELSIE ConsortiumIntertox

Rick Pleus, PhDGretchen Bruce

ToxikonPiet.ChristiaensChristopher.Brynczka

AdvisorsMHRA: David Jones, Principle Scientific OfficerFDA: Dan Mellon, David Joseph, Tim McGovernNIHS: Akihiko HiroseDrinker/Biddle/Reath LLP: Lee Nagao, PhD

Ophthalmic Sub Team Allergan

Tao Wang, Director, Analytical Sciences Brenda Birkestrand Smith, PhD, DABT,Andrea Desantis Rodrigues, PhD,

Suppliers:Cameo Crafts: Stephanie HuibersCiba: Michael RubertoSchott: Horst KollerTeknor Apex: Peter GallardWest: Jeff Smythe

Biologics SubteamAmgen

Kim Li, PhD, DABT, MPH, Senior Manager, Product Stewardship Toxicology

Momenta PharmaceuticalsJamie Tsung, PhD, Principal Scientist,

Momenta Pharmaceuticals


Risk Management Approach

• FDA Guidance on Container Closure Systems • ICH Q3A-D guidelines• ICH Q9 Quality Risk Management• FDA Guidance for Industry: Quality Systems

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Risk Based Approaches

• Assess risks and manage the potential issues posed by leachables Identity levels that leachables will accumulate in the finished drug

product over its shelf-life. Establish the magnitude of patient exposure (dose) and the safety risk

posed by an individual leachableLikelihood of any compatibility issues involving the drug product.

• Leachables assessments considers: Primary packaging/delivery systemCertain critical secondary packaging components that are non-contacting

but potentially interactingPackaging and delivery system materials of construction

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L&E Risk Based Assessment of Dosage Forms

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OINDP PODPParenteral Ophthalmic

RepresentativeDosageForms

Metered dose inhaler (focus of PQRI recommendations)

• Prefilled syringes• Small and large volume

parenterals (vials, IV bags)

Topical solutions and suspensions (eyedrops)

Formulation • Strong solvents (MDI propellants)

• “All extractables are leachables”

• Primarily aqueous• Less aggressive than MDI formulations• pH effects matter

Examples ofCritical PackagingMaterials

Elastomers (MDI valve) • Polyolefins• Elastomers• Cyclic olefin copolymers• Polyvinylchloride• Polycarbonate

• Polyolefins (1°)• 2° packaging

components

Typical Dosing

Pulmonary Direct to bloodstream or tissue

Topical, ocular (local)

Different risk factors require different approaches


Unique Risk Factors

Safety QualityCompatibility

Ophthalmic Drug Products (ODP)Parenteral Drug Products (PDP)

Biologic Products

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ODP Unique Issues

• Insufficient safety database on all toxicity endpoints relevant to ocular delivery, the Working Group cannot recommend a specific safety-based SCT / AET for ophthalmic drug products.Safety assessment of leachables in ODP requires a greater focus on

local effects than assessments of leachables from PDP or OINDP. Semipermeable container closure systems that do not make direct

drug product contact are critical risks. Simulation studies on these components are recommended to bring

focus to the most relevant extractables (i.e., probable leachables).

Principles for Management of Extractables and Leachables in ODP

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PDP Toxicology Outcome

1. An SCT approach can be applied to leachables and extractables qualification in parenteral drug products.

2. Based on most Parenteral Drug Product (PDP): of 1.5 µg/day for an individual organic leachable can be used to calculate an AET.

3. The QT developed for OINDP was further evaluated adapted from the Cramer Classification to identify and qualify leachables .

» Class 1 (systemic toxicity) 50 µg/day» Class 2 (sensitizer/irritant) 5 µg/day» Class 3 (mutagens/carcinogens) 1.5 µg/day

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PDP Chemistry Outcome4. Extraction studies for parenteral drug products should be considered for

appropriate materials of construction, finished components, and complete packaging systems.

5. Extractables studies for PDP packaging systems should include aqueous-based extraction solvents with appropriate consideration of pH, organic solvent content, and other appropriate conditions (e.g., extraction time, extraction temperature, technique, and sample-to-solvent ratio).

6. Where appropriate, extractables assessments, extraction studies, and leachables assessments for PDP should consider the possibility of migration across packaging barriers.

7. In situations of analytically challenging AETs for certain PDP (e.g., large volume parenterals), a special type of extraction study, termed a “Simulation Study,” could supplement and guide drug product leachables studies. (probable leachables).

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Leachable Discovery and Qualification

Potential Extractables/LeachablesMaterial Charaterization

Probable LeachablesSimulation/ AET

Confirmed LeachablesAccelerated/Real Time/ AET

Qualification Safety Concern Threshold (SCT)

Safety Qualification Categories

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Material Characterization – Potential Leachables

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6 8 10 12 14 16 18 20 22 24 26 100000 200000 300000 400000 500000 600000 700000 800000 900000

1000000 1100000 1200000 1300000

Time

Response_ Signal: RS006.D\FID1A.CH

x - Peaks with this symbol are similar in size, Extract vs Extraction blank

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ISTD2

x RE-IW-2

RE-pH9.5-2

RE-pH2.5-1

38 ISTD1

36 32

29

28 26

28 26

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20

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18 17 16

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11 11 10

11 10

9 8 5 4 3 2

x

x

x

1

1

x

x

Signal: RS017.D\FID1A.CH (*) Signal: RS027.D\FID1A.CH (*)

UNDERIVATIZED RUBBER ELASTOMER SAMPLES OVERLAY

4.006.008.0010.0012.0014.0016.0018.0020.0022.0024.0026.0028.0030.00

48000

50000

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58000

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68000

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Time-->

Abundance

Signal: 26JAN2010014RE.D\FID1A.CHSignal: 26JAN2010010blk.D\FID1A.CH

33.0034.0035.0036.0037.0038.0039.0040.0041.0042.0043.00

50000

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100000

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Time-->

Abundance

Signal: 26JAN2010014RE.D\FID1A.CHSignal: 26JAN2010010blk.D\FID1A.CH

min2.5 5 7.5 10 12.5 15 17.5 20 22.5

mAU

-100

0

100

200

300

400

500

DAD1 A, Sig=220,4 Ref=550,50 (F:\3\500_B...ASETS\50_RESULTS_MATERIALS\03_RE\LC-UV\009-0901_REF3_IPA_RE.D)

min5 10 15 20

mAU

-100

0

100

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DAD1 A, Sig=220,4 Ref=550,50 (F:\3\500_B...SETS\50_RESULTS_MATERIALS\03_RE\LC-UV\013-1101_REF3_NHEX_RE.D)

Extracted Amount, µg/g pH2.5 Extracts pH9.5 Extracts

Sonicate Sealed Vessel

Sonicate Sealed Vessel

Br 17.5 0.29 9.40 20.5

K ME1 ME1 6.84 NP3

Ca 2.60 4.07 2.072 NP3

Mg 3.50 0.06 2.83 2.90Al 0.66 0.03 2.19 3.56Zn 2.89 0.04 0.49 NP3

min0 2 4 6 8 10 12 14 16

0

100000

200000

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600000

700000

800000

*MSD1 TIC, MS File (MCI1310\MC000048.D) API-ES, Neg, Scan, Frag: 100, "Negativ e"*MSD1 TIC, MS File (MCI1310\MC000056.D) API-ES, Neg, Scan, Frag: 100, "Negativ e"*MSD1 TIC, MS File (MCI1310\MC000064.D) API-ES, Neg, Scan, Frag: 100, "Negativ e"

min0 2 4 6 8 10 12 14 16

0

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

*MSD2 TIC, MS File (MCI1310\MC000012.D) API-ES, Pos, Scan, Frag: 100, "Positiv e"*MSD2 TIC, MS File (MCI1310\MC000020.D) API-ES, Pos, Scan, Frag: 100, "Positiv e"*MSD2 TIC, MS File (MCI1310\MC000028.D) API-ES, Pos, Scan, Frag: 100, "Positiv e"

www.pqri.org

http://www.pqri.org/


Simulation Studies – Probable Leachables

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pH 2.5pH 9.5I/W

I/W

Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products:PDA J Pharm Sci and Tech 2017, 71 68-87


Analytical Evaluation Threshold (AET)

• The SCT is used to develop (AET) that allows the SCT to be applied to leachables profiles of particular drug products.

• Leachables should be characterized at levels above a calculated AET.

• The AET is not a control threshold like the TTC, but rather a trigger point for identification and toxicological assessment.

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Biologic Considerations

• Biologics have unique considerations compared to chemically synthesized drug products.

• Comprehensive risk assessments should include biologic activity, efficacy and safety related to the following: Interactions affecting product quality attributes, i.e., degradation,

oxidation, chemical modification, immune adjuvant activity.• Aspects of material compatibility, surface characteristics,

organic/inorganic alert compounds Individual components and system interfaces, performance and functionality

• Leachables assessment performed on the product under stress conditions, and under real-time storage.

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Safety Thresholds and Best Demonstrated Practices

Part 1. Introduction and Summary of RecommendationsPart 2. Justification of Thresholds for Leachables in PDPPart 3. Best Practices for Extractables and Leachables Assessment in PDPPart 4. Special Topics: Considerations for BiologicsPart 5. Appendices

1: Method for Establishing the ADI2: Use of In Silico Tools to Classify Chemicals in the PQRI E &L Database3: Relationships Between PODP and OINDP Best Practices Recommendations4: Links to Publications by the PODP Working Group5: Glossary of Acronyms and Abbreviations

Reference: Principles for Management of Extractables and Leachables in ODP

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Risk to Safety and Quality

Every material will have some risks to understand

• Realize the propensity of the drug product formulation to extract chemicals from contact materials or interact with materials surfaces.

• Understand material suitability during development and through out the product lifecycle.

• Build knowledge on safety and compatibility of components and systems consistent with intended use.

• Characterize storage and delivery systems to inform leachable and compatibility studies to enable risk evaluations

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PODP Publications (www.PQRI.org)

The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Opthalmic Drug Product (PODP)

Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products

Simulated Leaching (Migration) Study for a Model Container Closure System Applicable to Parenteral and Ophthalmic Drug Products (PODPs)

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Workshop Overview

• Day 11. Derivation of Parenteral SCT

2. Derivation and Validation of Parenteral Classification Strategy

3. Best Practices Generating Extractable Profiles

4. Analytical Technologies and Compound Identification

5. Component Characterization: Sources of Potential Leachables

6. The Analytical Evaluation Threshold: Derivation and Use

7. Purpose of Simulation Studies: A Case Example

8. Biologic Quality and Compatibility Considerations

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Workshop Overview

• Day 21. Experimental Design Considerations for Ophthalmic Drug Products (ODP): Chemistry & Toxicology

2. Application of Thresholds and Expectations: Regulatory Perspectives FDA & NIHS

3. Application of Thresholds Concept Applied to Container Closure System for PDP 4. Problem Solving Breakouts: SVP - Vaccine LVP - Oncology PFS - Cardiovascular ODP – Topical Solution

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Documents

PQRI PODP Extractables & Leachables Workshoppqri.org/wp-content/uploads/2018/04/2-PQRI-Paskiet-Final.pdf · process can be extrapolated to container closure systems for PODP. 3. Threshold