thresholds and best practices for extractable and...

Thresholds and Best Practices for Extractable and Leachables

PQRI-PODP Working Group Recommendations: Parental Drug Products (PDP)

Ophthalmic Drug Products (ODP)

3rd PQRI/FDA Conference on Advancing Product Quality Washington DC, 22 March 2017

Overview of Thresholds and Best Practices for Extractable and Leachables(L&E)


Diane Paskiet Chair of PQRI PODP L&E Working Group

Director of Scientific Affairs, West Pharmaceutical Services

Objectives

• PQRI L&E Mission and Scope • Threshold Concept and Extraction Studies • Safety and Quality Points to Consider

3rd PQRI/FDA Conference on Advancing Product Quality 3

Mission Statement

The Product Quality Research Institute (PQRI) is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances

drug product quality and development.

By virtue of its diverse membership, PQRI provides a unique forum to focus critical thinking, conduct research, exchange information, and propose methodology or guidance to

pharmaceutical companies, regulators, and standard setting organizations.


OINDP Safety Thresholds and Best Practices


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

• <0.15 μg/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 pharmaceutical development • Not meant to be proscriptive

Finding Leachables


Before Thresholds

After Safety Thresholds

The Forest Through the Trees

Analytical Evaluation Threshold


“The AET is defined as the threshold at or above which an OINDP pharmaceutical development team should identify and quantify a particular extractable and/or leachable and report it for potential

toxicological assessment.”

“How low to go to Identify Potential Leachables”

Linking Chemistry (AET) to Toxicology (SCT)

×= /canisteractuations120

/dayactuations 8g/day 0.15 labeledAET Estimated µ

g/canister25.2 µ≈AET Estimated


Leachables and Extractables PODP Working Group PROPOSED WORK PLAN , March 2008 Development of Scientifically Justifiable Thresholds and Best Demonstrated Characterization Practices for Leachables and Extractables in Parenterals and Ophthalmic Drug Products (PODP) Approved 2009

8

Threshold concepts and best demonstrated practices developed for leachables in OINDP can be extrapolated to PODP with considerations of factors i.e. dose, duration, patient population, materials and product characteristics of PODP.

Considered for: Prefilled Syringe (PFS), Small and Large Volume Parenterals (SVP)/(LVP), and Ophthalmic/Blow Fill Seal (BFS)

Disposable systems should also be considered in the absence of defined and specific regulatory guidance

Consistent with the principles of QbD and good science

Safety Depends on Intended Use

• Dosage Form • Route of Administration • Material(s) of Construction • Patient Population • Dosing • Duration • Product Specific Attributes


Extractables Identification Process

Illustration of Extractable Testing


Test Articles (Material Type)

Format Composition (Supplier Information)

Application Category

Polycarbonate (PC)

Injection moulded plaques

• 0.05 PHR Irganox 1076 • 0.1 PHR Irgafos 168

Ports, Tubes

LVP

Rubber Elastomer (Bromobutyl)

Sheet • Brominated isobutylene isoprene copolymer (57.3%)

• calcined aluminum silicate, 38.2% • titanium dioxide, 1.2%; • paraffinic oil, 1.2%; • zinc oxide, 0.6% • polyethylene0.6% • SRF Carbon block mixture, 0.4% • calcined magnesium oxide, 0.3% • 4,4’-dithiodi-

morpholine/polyisobutylene, 0.3%

Closures, Plungers, Gaskets

SVP

Cyclic Olefin Copolymer (COC)

Plaques

• Irganox 1010 • Ultramarine Blue

Syringes, Vials

PFS, SVP

Polyvinylchloride (PVC)

Pellets • PVC resin • DEHP 30% • Epoxidized oil 7% • Zn stearate 0.5% • Ca stearate 0.5% • Stearamide 1%

Bags, Tubing

LVP

Low density polyethylene (LDPE)

Blown Film • Irganox B 215 (2:1 blend of Irgafos 168 and Irganox 1010) 1000 ppm

• BHT 200 ppm • Calcium Stearate 500 ppm • Erucamide 500 ppm • Chimassorb 944 2000 ppm

Overpouch, BFS, Containers

BFS, SVP, LVP

Recommendations Document


Thresholds

Best Practices

AET LVP, SVP, PFS Applications

Considerations Given Ophthalmics

Biologics

Development of Parenteral Drug Product (PDP) Thresholds • Database of 606 Extractable and Leachable compounds • Use of in-silico methods

– Modified Cramer approach (ToxTree) – Genotoxicants (DEREK & SARAH – Irritants and sensitizers (DEREK plus literature confirmation).

• Note: Ophthalmic qualification will emphasize concentration (ppm) not dose (µg/day) for leachables in an ophthalmic DP


PQRI Toxicology Team Approach 606 Compound Sort


Cramer (ToxTree) Sort

I (53%)

II (8%)

III (34%)

IV (11%)

I II

III (83%) Class IV

Cramer Classification Breakdown

PQRI Qualification Process


Routine Leachable Study Identify chemicals for safety assessment

1.50 µg

5 µg

50 µg

Genotoxic Concern? Yes – Qualify (ICH M7) No – Consider S/I Potential

S/I Concern? Yes – Qualify No – Consider Systemic Toxicity

Systemic Toxicity Concern? Yes – Qualify No – DP CCS is Qualified!

Application of AET


Experimental Key Characteristics Material Characterization (Tentative Leachables)

Screening of packaging candidates Establish composition of extractable materials Broad Based/Screening extraction and testing

protocols Semi-quantitative character

Toxicological Alerts

Simulation Study (Potential Leachables)

Establish worst case accumulation of leachables Conditions to mimic worst case exposure Justified simulating solvents Assessment of all extractables above the AET Identify Leachable Targets

Migration Study (Confirmed Leachables)

Establish the actual accumulation of target leachables Drug product under actual conditions of use Toxicological assessment of all targeted leachables

Outcome: Negligible or unacceptable safety risk Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products (PODP) Workshop February 22-23, 2011

System Compatibility &Safety

• Materials & Components Glass, Plastics, Rubbers, SS

• Processing Impact Washing/Coatings/ Sterilization System Assembly Storage Conditions Time/Temperature

• Packaging Secondary Fill/Finish Ancillary Tertiary


Material Understanding

Biologics Safety and Quality Considerations

• Minor or nontoxic leachables and incompatible materials may induce changes to product quality attributes,

stability, purity and/or efficacy

• Changes in product quality – Biologics are often unstable and quality characteristics may not

be completely defined – Characterization includes: physicochemical properties, biological

activity, immunochemical properties, purity

• Container Closure Systems Compatibility – Leachable interaction with biologic or formulation – Physical interaction with material surface or surface interfaces – Functional performance of manufacturing, storage and delivery

systems


Risk to Protein Aggregation

3rd PQRI/FDA Conference on Advancing Product Quality 18 Reference: Characterization of Protein Aggregation & Adsorption on Prefillable Syringe Surfaces; Esfandiary et al. University of Kansas; and Vinod Vilivalam, West Pharmaceutical Services, Inc.; 2008.

Siliconized No Silicone Oil

Silicone Oil

Compatibility Issue Safety Concern

Particulate formation of fusion protein 25 mg/mL; agitation conditions during simulated shipment

Risk to Protein Adsorption


Development of Analytical Techniques to Determine Protein Adsorption on Sterilized Parenteral Packaging Containers and Stoppers; Lloyd Waxman et. Al. AAPS Poster, 2015

Freeze Thaw Cycle Mechanical Stress


Adapted from G. Jiang et.al , Novel Mechanisms of Glass Delamination in Type1A Borosilicate Vials Containing Frozen Protein Formulations PDA J Pharm Sci and Tech 2013

Risk @ -70C for Particles/Lamella, Leachables, Cracks/Breakage

*Placebo samples and control showed 2-5 ppb leachable Al

Antibody Lamella ppb Si ppb B ppb Al*

Control 0 11,954 1,085 53

A (-30C) 0 11,589 1,140 43

B (-30C) 0 11,949 1,334 52

C (-70)C 13 11,686 1,123 35

D (-70C) 30 12,124 1,302 31

E (-70C) 17 11,082 939 29

F (-70C) 5 11,531 1,068 31

Process-relevant Stress Conditions/Actual Contact Surface Exposure

PODP Points to Consider

• A Safety Concern Threshold (SCT) of 1.5 µg/day for an AET

• A Classification Strategy was developed o qualify identified leachables and extractables in PDP

• Special Safety considerations apply for extractables and leachables

in Ophthalmic Drug Products (ODP)

• Special Quality considerations apply to biologics and system compatibility


PODP Points to Consider

• Extractable studies should be considered for materials of construction, finished components, complete packaging systems to inform on:

– Tentative Leachable (Characterization) • Extraction solvents with consideration of extraction pH,

organic solvent content, and other appropriate extraction conditions

– Potential Leachables (Simulation) • Situations of analytically challenging AETs for certain PODPs • Assessment of multiple components in final packing systems

• Simulation studies can establish an extractables profile representing the worst-case leachables profile.


PODP Chemistry Sub-Team


• Diane Paskiet, Director of Scientific Affairs, West Pharmaceutical Services – PODP Chair

• Dennis Jenke, Ph.D., Chief Executive Scientist, Triad Scientific Solutions, LLC – Chemistry Chair

• Jim Castner, Ph.D., Pharma Interface Analysis, LLC. • Thomas Egert, Boehringer Ingelheim Pharma GmbH & Co. KG • Thomas Feinberg, Ph.D., President, SCIO Analytical, LLC • Alan Hendricker, Ph.D., Principal Specialist, Becton Dickinson • Christopher Houston, Ph.D., Director, iuvo BioScience • Desmond G. Hunt, Ph.D., Senior Scientific Liason, USP • Michael Lynch, Ph.D., Executive Director, Keryx Biopharmaceuticals • Ingrid Markovic, Ph.D., Division of Therapeutic Proteins, FDA • Kumudini Nicholas, Team Leader, Pharmaceutical Quality Review, Bureau of

Pharmaceutical Sciences, Health Canada • Daniel Norwood, Ph.D., Executive Partner, SCIO Analytical, LLC • Mike Ruberto, Ph.D., Material Needs Consulting, LLC • Art Shaw, Ph.D., Associate Research Fellow, Pfizer (Retired) • Edward J. Smith, Ph.D., Packaging Science Resources, LLC

All research work supported under the direction of PQRI

PODP Toxicology Sub-Team

• Douglas J. Ball, MS, DABT, Research Fellow, Pfizer – Toxicology Chair

• Stephen A. Barat, Ph.D., Executive Director, Allergan • Steve Beck, CEMDD Liaison, GlaxoSmithKline • William P. Beierschmitt, Ph.D., Associate Research Fellow, Pfizer • David Jones, Principal Scientific Officer, New Chemical Entities Unit, MHRA • Abigail Jacobs, Ph.D., Associate Director for Pharmacology/Toxicology,

CDER, FDA • Jacqueline A. Kunzler, Ph.D., Vice President Quality Compliance, Baxter

Healthcare • Mary Richardson, Ph.D., DABT, Chief Scientific Officer, iuvo BioScience • Tim Robinson, Division of Pulmonary and Allergy Products, CDER, FDA • Alisa Vespa, Ph.D., Assessment Officer, Metabolism and Musculoskeletal

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


PODP Extended Team

• Laboratory Services – Baxter

• Roopang Shah, Research Associate II

• Marek Ciesla, Research Associate II

• Frank (Yousheng) Hua, Research Scientist

– Catalent Pharma Solutions • Paul Cvetich • Kimberly Davis • Michelle Cree • Tom Feinberg • Alan Hendricker

– Becton Dickenson • John Lennon

• Laboratory Services – Boehringer Ingelheim

• Daniel L. Norwood • Scott Pennino • James O. Mullis • Thomas Egert • Jurgen Mattes • David Strassburger

– Pfizer • Cindy Zweiben • Miguel Sandoval • Art Shaw

– Bausch & Lomb • Chris Houston • John Rider


PODP Extended Team

• Toxicology Services – Pfizer QSAR

[DEREK/Toxtree] • Russell Naven • Patricia Ellis

– TOX-RSA, LLC • Brenda Seidman, Ph.D., • Angela Howard, Ph.D

– ELSIE Consortium – Intertox

• Rick Pleus, PhD • Gretchen Bruce

– Toxikon • Piet.Christiaens • Christopher.Brynczka

• Ophthalmic Sub Team – Brenda Birkestrand Smith, Ph.D., DABT – Andrea Desantis Rodrigues, Ph.D. – Chris Houston, Ph.D. – Mary Richardson, Ph.D., DABT – Tao Wang, Ph.D.

• Suppliers – Cameo Crafts: Stephanie Huibers – Ciba: Michael Ruberto – Schott: Horst Koller – Teknor Apex: Peter Gallard – West: Jeff Smythe

• Advisors – David Jones, Principle Scientific Officer,

MHRA – Lee Nagao, PhD Drinker/Biddle/Reath LLP


Overview of Thresholds and Best Practices for Extractable and Leachables (L&E)


Dennis Jenke Chair of PQRI PODP Chemistry Team

Triad Scientific Solutions, LLC

Objectives

• Best Practices for Controlled Extraction Studies: – Definition and Use of Controlled Extraction Studies – Extraction – Analysis of Extracts

• Case Studies: – Extractables from Secondary Sources – Large Volume Parenterals

PQRI-PODP, E&L Europe 2015, 11 Nov 2015 28


Best Practices for Controlled Extraction Studies

Controlled Extraction Study

Definition: A laboratory investigation into the qualitative and quantitative nature of extractables profiles of a container/closure system, its critical components and/or its materials of construction.

Purpose: To verify, complement or augment supplier information about material

composition To establish a basis for the development and validation of routine

quality control methods and acceptance criteria for critical components extractables profiles (consistency in composition)

To establish a basis for the development and validation of leachables methods

To allow for the correlation of extractables and leachables To produce an extractables profile that mimics the leachables profile

(simulation study)


Types of Controlled Extraction Studies

• Material characterization (i.e., identify and quantify the additives and ingredients in a material, as ingredients and additives may be used to forecast extractables),

• Packaging assessment (i.e., identify extractables as a means of forecasting leachables in a specific dosage form, simulation study),

• Quality Control (i.e., exercise control over the quality of incoming materials of construction for a packaging system).

• Change Control (i.e., respond to changes in the materials and/or processes associated with a packaging system.


Controlled Extraction Studies (CES) Should

• Use a combination of multiple extraction solvents of varying chemical nature and suitable extraction techniques, consistent with its intent and purpose,

• Use an analytical process with thoughtfully chosen multiple analytical techniques for the purpose of discovering, identifying and quantifying extractables,

• Include careful sample preparation based on a knowledge of the analytical techniques used, the chemical nature of the extracting media and the probable nature of the extracted substances,

• Include a defined and systematic process for the identification and quantitation of individual extractables,

• Include a re-examination of supplier information describing component formulation. 3rd PQRI/FDA Conference on Advancing Product Quality 32

Controlled Extractions; Range of Extractability


PODP Extraction Matrix


Extract Analysis Can Have Two Dimensions


USP/PQRI Workshop: Suitability and Compatibility for Packaging and Delivery Systems, Egert Dec 9-10, 2013

Analysis

Dimension #1; Screening Capture and identify unknowns showing up in standard protocols

Dimension #2; Targeting Consider dedicated protocols

‘analytically challenging‘ compounds

What did we miss ?

Informed by material composition: e. g. •dithiocarbamates •organotin compounds •nitrosamines, PNAs •formaldehyde …

RISK:

•confirmed •confident •tentative Select appropriate identification strategy!

Analytical Methods Elemental Extractables Trace elements and metals ICP-OES, ICP/MS

Organic Volatiles: Static Headspace-GC/MS Semivolatiles (GC-amenable) "Direct Injection" GC/FID/MS Semivolatiles (not GC-amenable) LC/UV; LC/MSn, HRMS Ions Ion Chromatography General Total Organic Carbon (TOC), UV absorbance, pH 3rd PQRI/FDA Conference on Advancing Product Quality 36

Identification Categories

Confirmed:

Confirmation obtained via match to an authentic standard

Confident:

Confidence obtained via sufficient supporting and collborating data which precludes all but the most closely related structures

Tentative:

Identification obtained via a single source or type of data (e.g., MS match with a database spectrum)


System Suitability Requirements to Monitor Result Integrity

Level 1 - Qualified instrumentation Level 2 – System suitability mixtures • Specific test mixtures to be analyzed by HS-GC, GC, LC and ICP • Test mixtures are suitable to demonstrate adequate and effective

analytical performance (separation efficiency, selectivity, sensitivity)

Level 3 - Internal standardization • Surrogate Internal Standard – added to the extract control of effectiveness of the sample preparation process

• Injection Internal Standard – added to the injection solution control of the sample introduction and chromatographic process for each sample run.



Case Studies

Foreign Impurities: Secondary Sources

The individual components of the model container-closure system. The bottle used is shown with the label already applied. The major ingredients or extractables from the individual components of the test system are listed. The foil overpouch, used primarily as a barrier to reduce solvent loss from the test article, is not shown.


Bromombutyl Rubber Liner Palmitic acid (PA) Stearic acid (PA) C21-Oligomer

Label (Adhesive) NATIVE: 2,4,7,9-Tetramethyl-5-decyn-4,7-diol (TMDD) Dioctyl sulfosuccinate sodium salt (DOSS) SPIKED: 2-Butanone (MEK) Irgacure 1173 (Ic1173) Dipropylene glycol diacrylate (DPGDA) Benzophenone (BzPh)

PP Screw Cap Ethyl-4-ethoxybenzoate (Et-4-EthBzate) Irganox 1010 (Ix1010) Irgafos 168 (Is168) Irgafos 168 oxide (Is168ox) Monostearin

LDPE Bottle:

4-Nonylphenol (mix. of isomers) (4-NP) Irganox 1076 (Ix 1076) Trinonylphenolphosphite (TNPPite)

Foreign Impurities: Secondary Sources Leaching profile of a spiked label extractable, Irgacure 1173. The leaching of this non-ionic, highly water soluble and stable extractable is similar in all three leaching solutions.


Source: D. Jenke et al. Simulated Leaching (Migration) Study for a Model Container-closure System Applicable to Parenteral and Ophthalmic Drug Products (PODPs). PDA J Pharm Sci Technol.

Correlating Extractables and Leachables


• Extractable Elements: 2hr Sonication @ pH 2.5 • Capacity to Leach: 0.22g plunger; 5g stopper

Element µg/g Material

µg Plunger

µg Stopper

Ca 2.6 0.69 13 Mg 3.5 0.77 18 Al 0.66 0.15 3.3 Zn 2.9 0.64 15

Identify Extractables To Be Studied As Leachables

Simulated Leaching (Migration) Study for a Model Container-closure System Applicable to Parenteral and Ophthalmic Drug Products (PODP) www.pda.org/www.pqri.org

Controlled Extraction on Rubber Elastomer: PODP Workshop 2011; www.pqri.org

Rubber/LDPE Container Closure System (inverted)

http://www.pqri.org/

Large Volume Parenterals (LVPs) Among the numerous characteristics that differentiate LVPs from other dosage forms, their large dose volume is particularly noteworthy because of the practical implications of dose volume to the safety assessment of packaging system leachables.


The Situation-Relative Dose volume


Metered Dose Inhaler (small volume - large

number of doses)

Large Volume Parenteral (large volume - small number of

doses)

Daily Dose Volumes for General Classes of Pharmaceutical Products


0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

MDI Eye drops Syringe SVP LVP Dialysis

Daily Dose (mL)

Effect of Daily Dose Volume on the AET


13.50 14.00 14.50 15.00 15.50 16.00 16.50 17.000

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

Time-->

Abundance

TIC: 11100303.D

Practical Implication: More peaks to identify at lower concentrations

AET for MDI

AET for SVP

AET for LVP

Potential Analytical Approaches to Address LVP

• Controlled Extraction Study (material characterization and screening, impurity control).

• Simulation study (Extractables as actual case leachables, hazard assessment, targeting of potential hazards).

• Migration study (targeted leachables, safe risk assessment).


The Concept of Impurity Thresholds for Materials used in LVP Packaging • A pharmaceutical product consists of the drug-containing solution

and the packaging. • The packaging for a pharmaceutical product is thus a component of

that pharmaceutical product, in the same way that the active ingredient and exicpients are components of the drug-containing solution.

• Impurities in the drug-containing solution can be derived from the active ingredient and excipients. The levels of such contaminants in the drug containing solution can be controlled by controlling the limits of these contaminants in the active ingredient and/or the excipients.

• Impurities in the drug-containing solution can also be derived from the packaging. The levels of such foreign impurities in the drug-containing solution can be controlled by controlling the levels of these impurities in the packaging.


The Mathematics of Impurity Limits for Materials used in LVP Packaging

Scenario: LVP bag weighing 20 grams that holds 1 L of drug-containing solution Extractable Impurity Level in the packaging = 1 μg/g (1 ppm by weight, note that 1 ppm = 0.0001% impurity level) Question: What is the level of the packaging related impurity in the drug-containing solution? Answer: 1 μg/g x 20 grams/1L = 20 μg/L (20 ppb by volume) AET (one bag per day scenario): 1.5 μg/day ÷1L/day = 1.5 μg/L (ppb by volume)


PQRI Recommendations for Ophthalmic Drug Products

Christopher T. Houston, Ph.D. PQRI-PODP Working Group and

Director of Analytical Chemistry, iuvo BioScience

3rd PQRI/FDA Conference on Advancing Product Quality 22 March 2017

Objectives

• Landscape and context – Brief review of prior PQRI concepts – PODP hypotheses

• Scope of ophthalmic drug products (ODP) for PODP working group

• History of E&L in ophthalmic drug products • Challenges posed by E&L in ODP • Outcomes


Landscape and Context


Review of Existing PQRI Concepts

• Output from PQRI-OINDP E&L Working Group – “Safety Thresholds and Best Practices

for Extractables and Leachables in Orally Inhaled and Nasal Drug Products”, published in 2006

• Introduced concept of the Safety Concern Threshold (SCT) – “…threshold below which a leachable would have a dose

so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects.”

– SCT = 0.15 µg/day – Allows calculation of an Analytical Evaluation Threshold

(AET) with concentration units for use as a reporting limit

53 3rd PQRI/FDA Conference on Advancing Product Quality

54

Review: Application of AET to Chromatography

13.50 14.00 14.50 15.00 15.50 16.00 16.50 17.000

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

Time-->

AET

Substances below the AET do not have to be identified

Substances above the AET: Identify and report to a toxicologist for a risk assessment

Application of SCT-derived AET exchanges “look as low as you can”…

…for a scientifically-justified, consistent standard for how low to look

3rd PQRI/FDA Conference on Advancing Product Quality

Dosage Forms Are Not Created Equally

55

Degree of Concern Associated with the Route of Administration

Likelihood of Packaging Component – Dosage Form Interaction

High Medium Low

Highest Inhalation aerosols and sprays

• Injections and injectable suspensions

• Inhalation solutions

• Sterile powders and powders for injection

• Inhalation powders

High Transdermal ointments and patches

• Ophthalmic solutions and suspensions

• Nasal aerosols and sprays

--

Low • Topical solutions and suspensions

• Topical and lingual aerosols

• Oral solutions and suspensions

-- • Oral tables and oral capsules (hard and soft gelatin)

• Topical powders • Oral powders

Adapted from USP <1664>, items in red denote revisions from FDA 1999 packaging guideline


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SCT by Therapeutic Area

Drug Product

OINDP (PQRI-OINDP)

Injectables / PDP (PQRI-PODP)

SCT 0.15 µg/day 1.5 µg/day

Origin / Published

• PQRI-OINDP Guideline 2006

• E&L Handbook 2012 • USP <1664.1>

• PQRI-PODP WG • Paskiet et al., PDA J.

Pharm. Sci. Technol., 2013, 67 (5) 430-447

Comments Used metered dose inhaler as a model; highest risk profile, most conservative SCT

PQRI-PODP guideline in draft, anticipated in 2017

With PODP recommendations, we are evolving toward SCTs specific to therapeutic area


PQRI-PODP, E&L Europe 2015, 11 Nov 2015 57

Three Part PQRI-PODP Hypothesis

• “Threshold concepts that have been developed for safety qualification of leachables in OINDP and the existing FDA/EMEA guidance documents can be extrapolated to the evaluation and safety qualification of packaging systems (such as container closure systems, CCS) for PODP.” – Goal was to extrapolate OINDP concepts (SCT, AET) to PODP, not

necessarily the thresholds themselves • “The ‘good science’ best demonstrated practices that were

developed for the OINDP pharmaceutical development process can be extrapolated to packaging systems for PODP.” – PODP recommendations will be nuanced, however, by a strong

emphasis on aqueous formulations (both chemistry and safety) • “Threshold and best practices concepts can be integrated into a

comprehensive process for characterizing packaging systems with respect to leachable substances and their associated impact on PODP safety.”


Scope and History of ODPs


PODP & ODP: Scope

59

Ophthalmic dosage forms • In scope

o Topical solutions, suspensions, gels (“eye drops”) Most common

o Topical ointments • Out of scope

o Solid inserts o Implants o Injections


History of E&L in Ophthalmology

• US-FDA - Ophthalmology1

– Unpublished set of consistent practices in place for ~ 15 years – Specification limits on individual, unspecified impurities: NMT 0.1%

• Higher limits negotiable for potent APIs – Avoid penalizing companies for potent drugs

• Surrogate means of monitoring for unexpected leachables – For confirmed leachables:

• Report in ppm, ug/mL or ug/g; % vs API is not relevant • Above 1 ppm – report • 10 ppm – identification (in practice, most companies ID at 1 ppm) • 20 ppm – qualify (in practice, most companies assess at 1 ppm) • Thresholds are concentration-based, not dose-based (PQRI)

– Ophthalmic manufacturers continue to use this approach for US filings

• These US practices have been successfully used for EU filings, but there does not appear to be a consistent practice in place

60

1. Linda Ng, FDA Office of New Drug Quality Assessment. “Current Regulatory Recommendations for Leachables in Ophthalmic Products”. Presented at PQRI Workshop on Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products, Bethesda, MD, 22-23 Feb 2011.


Challenges Posed by E&L in ODP


E&L Challenges in ODP (1)

• Packaging systems for solutions, suspensions, and gels – Bottle is often molded from a barefoot, LDPE resin

• LDPE is semipermeable

– Closures are often harder plastic with more additives, but make minimal product contact

– Primary container closure rarely imparts leachables to aqueous ODPs

• Personal experience: in 15 years of studying E&L in topical ophthalmics at two different companies:

– Never observed a significant leachable from these primary packaging systems

– All migrants originated from secondary components



• Secondary packaging – Includes

• Labels, unit cartons, product information inserts • Inks / varnishes, adhesives, substrates (plastic, paper,

cardboard)

– Often commodity materials with poor change control or subject to frequent changes

• Short timeframe to assess E&L impact on product, ~ 6 months • Multiple products in the same plant may be affected • Insufficient time to perform full shelf-life leachable studies • Insufficient resources to execute leachable studies on all

impacted products

– Migration from 2° packaging can be more complex than 1° packaging (see next slide)


Migration from Primary Packaging

Ophthalmic ointment example in laminate tube

Diffusion from 1° package is often simple partitioning between two phases (package and product)

64

Irgafos 168

DTBB

Foil

barr

ier


Migration from 2° Packaging

• 2° packaging migrants will not necessarily diffuse directly into product

• Some vapor pressure is required

• Environment strongly influences partitioning

• Is there a driving force for a 2° packaging substance to partition into drug product?



• Developing a science-based SCT threshold – Hypotheses of the PQRI OINDP and PODP teams:

• “Scientifically justifiable thresholds based on the best available data and industry practices”

– Ocular toxicity data in the literature are scant compared to the systemic data mined by PQRI to recommend SCTs for OINDP and PDP

• Do adequate data exist at all? – Systemic safety data not very relevant to Ophthalmology

• What endpoints must be considered? • What data would need to be generated to develop such a

threshold? – Is generation of such a dataset tractable?


67

PODP Are Not a Uniform Class

• Similarities – Primarily aqueous formulations

• Do all PODP have the same safety concerns? – Parenterals / Injectables (PDP)

• Direct administration to bloodstream or tissue • Systemic effects • Cancer risk as a conservative endpoint (like OINDP)

– Ophthalmic solutions and suspensions (ODP) • Local, topical effects • Ocular irritation/toxicity is a key endpoint

• Differences in PODP may drive separate strategies – As a result, the PODP recommendations differ between

parenterals (PDP) and ophthalmics (ODP)


Further Challenges to PODP Team

• Reconciliation of different paradigms – Historic FDA reporting practices focus on a concentration based

threshold (1 ppm) • Concentration may be more relevant to ocular irritation/toxicity, a key

endpoint – PQRI recommendations for OINDP and PDP focus on a

reporting/ID threshold based on total daily intake (SCT) • Systemic exposure for topical ophthalmics is generally low

• Right people at the table – PQRI process requires dialogue between industry and regulators – Health Canada and MHRA are part of the team – No consensus was reached with US-FDA Ophthalmology;

currently, the US FDA prefers for leachable assessment to occur on a case-by-case basis for this product type


Outcomes


Simulation in E&L Studies for ODP


Extractables Leachables

Simulation studies are extractable studies skewed toward the realistic

Broadly applicable Narrowly applicable

Rapid Real time

Exaggerated Realistic

Ambiguous relevance Certain relevance

Simulation

Value of Simulation Studies in Ophthalmology

• To observe a migrant from secondary packaging, it must… – Migrate from the original component – Permeate the bottle – Dissolve in the formulation

• Secondary packaging profiled by simulation – Simulating solvent placed inside the bottle – Label affixed to bottle exterior and/or – Bottle placed inside unit carton

• Creates a realistic contact condition where the selectivity of the packaging system and properties of the extractables reveal probable leachables/migrants


Simulation Study Setup

• Enclosure of system in a sealed vessel drives equilibrium toward simulant in bottle – Allows for elevated temperature

(40°C) storage w/out false negatives; shortens study

• Without enclosure, high temperature storage often results in loss of target migrants

– Increases risk of false positives

• Parameters – Run to equilibrium – Account for worst case mass:volume ratio – Solvent choice

• Moderately better sink than formulation(s) • “Reasonable worst case” – balanced risk


Importance of Simulation to ODP

• In the ODP recommendations, simulation is identified as essential for efficiently generating knowledge in cases where 2° packaging is critical

• Simulation: – Characterizes important and/or relevant extractables from 2°

packaging components • Useful because 2° components are often chemically complex, but

not all extractables will become leachables/migrants • Manage complex partitioning behavior of migrants

– For change control situation, simulation allows • Rapid assessment of impact (often < 1 month) • May provide insight across multiple products in the same packaging

system if designed appropriately


Conclusion: PQRI ODP Recommendations

• Safety – Safety assessment of leachables in ophthalmics requires a greater

focus on local effects than leachables from PDP or OINDP – Lacking a sufficient safety database on all toxicity endpoints relevant to

ocular delivery, the working group cannot recommend a specific safety-based SCT (and, thus, AET) for ODP at this time

• Chemistry – E&L assessments of drug products in semipermeable container closure

systems (e.g., ODP in LDPE) must include packaging components that do not make direct drug product contact (e.g., labels, product information inserts, unit cartons)

– Simulation studies on these components are recommended to bring focus to the most relevant extractables (i.e., probable leachables) and expedite assessments for packaging changes

– Strategies for managing these issues are included in the recommendations


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Acknowledgements

• PQRI Parenteral and Ophthalmic (PODP) Leachables and Extractables Working Group

– Chair: Diane Paskiet, Director of Scientific Affairs, West Pharmaceutical Services

– Toxicology Sub Team Chair: Douglas J. Ball, Research Fellow, Pfizer

– Chemistry Sub Team Chair: Dennis Jenke, PhD, Chief Executive Scientist, Triad Scientific Solutions, LLC

– Development Technical Committee Liaison Frank Holcombe, Jr., PhD, US Food and Drug Administration

• PQRI-PODP Ophthalmology Subteam

– Brenda Birkestrand Smith, PhD, DABT, Allergan – Andrea Desantis Rodrigues, PhD, Allergan – Christopher Houston, PhD, Director of Analytical Chemistry, iuvo BioScience – Mary Richardson, PhD, DABT, Chief Scientific Officer, iuvo BioScience – Tao Wang, PhD, Director, Analytical Sciences, Allergan

All research work supported under the direction of PQRI 3rd PQRI/FDA Conference on Advancing Product Quality

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