pqri podp extractables & leachables...
TRANSCRIPT
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.
2
Industry
Regulators Academics
PQRI PODP E&L WorkshopApril 18-19, 2018
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
3
PQRI PODP E&L WorkshopApril 18-19, 2018
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
4
PQRI PODP E&L WorkshopApril 18-19, 2018
Leachables and Extractables Working Group 2000…....2006
5
PQRI PODP E&L WorkshopApril 18-19, 2018
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.
6
PQRI PODP E&L WorkshopApril 18-19, 2018
• 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
PQRI PODP E&L WorkshopApril 18-19, 2018
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
8
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
PQRI PODP E&L WorkshopApril 18-19, 2018
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
9
PQRI PODP E&L WorkshopApril 18-19, 2018
2009-2011 Extractable Protocols
10
MEHP
Bisphenol A
Diphenylamine
IS:Bisphenol M
IS: 2-Fluoro-biphenyl
IS: Irganox415
BHT
DEHP
(www.PQRI.org)
PQRI PODP E&L WorkshopApril 18-19, 2018
2010…....2017 Extended Teams
11
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
PQRI PODP E&L WorkshopApril 18-19, 2018
Risk Management Approach
• FDA Guidance on Container Closure Systems • ICH Q3A-D guidelines• ICH Q9 Quality Risk Management• FDA Guidance for Industry: Quality Systems
12
PQRI PODP E&L WorkshopApril 18-19, 2018
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
13
PQRI PODP E&L WorkshopApril 18-19, 2018
L&E Risk Based Assessment of Dosage Forms
14
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
PQRI PODP E&L WorkshopApril 18-19, 2018
Unique Risk Factors
Safety QualityCompatibility
Ophthalmic Drug Products (ODP)Parenteral Drug Products (PDP)
Biologic Products
15
PQRI PODP E&L WorkshopApril 18-19, 2018
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
16
PQRI PODP E&L WorkshopApril 18-19, 2018
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
17
PQRI PODP E&L WorkshopApril 18-19, 2018
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).
18
PQRI PODP E&L WorkshopApril 18-19, 2018
Leachable Discovery and Qualification
Potential Extractables/LeachablesMaterial Charaterization
Probable LeachablesSimulation/ AET
Confirmed LeachablesAccelerated/Real Time/ AET
Qualification Safety Concern Threshold (SCT)
Safety Qualification Categories
19
PQRI PODP E&L WorkshopApril 18-19, 2018
Material Characterization – Potential Leachables
20
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
21
ISTD2
x RE-IW-2
RE-pH9.5-2
RE-pH2.5-1
38 ISTD1
36 32
29
28 26
28 26
25
24
21 20
20
18
16
18 17 16
15
14
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
52000
54000
56000
58000
60000
62000
64000
66000
68000
70000
72000
74000
76000
78000
80000
82000
84000
86000
Time-->
Abundance
Signal: 26JAN2010014RE.D\FID1A.CHSignal: 26JAN2010010blk.D\FID1A.CH
33.0034.0035.0036.0037.0038.0039.0040.0041.0042.0043.00
50000
55000
60000
65000
70000
75000
80000
85000
90000
95000
100000
105000
110000
115000
120000
125000
130000
135000
140000
145000
150000
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
200
300
400
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
300000
400000
500000
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
PQRI PODP E&L WorkshopApril 18-19, 2018
Simulation Studies – Probable Leachables
21
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
PQRI PODP E&L WorkshopApril 18-19, 2018
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.
22
PQRI PODP E&L WorkshopApril 18-19, 2018
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.
23
PQRI PODP E&L WorkshopApril 18-19, 2018
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
24
PQRI PODP E&L WorkshopApril 18-19, 2018
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
25
PQRI PODP E&L WorkshopApril 18-19, 2018
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)
26
PQRI PODP E&L WorkshopApril 18-19, 2018
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
27
PQRI PODP E&L WorkshopApril 18-19, 2018
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
28