Click here for event slides and audio Introduction to

Introduction to Extractables and LeachablesMichael Creese

Keith Scott

Smithers

March 2020

Click here for event slides and audio

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Introduction • Your moderator: Rea Kongwa

• Proceedings

• Questions & Answers

• Technical issues: use chat feature

• Post event survey


Michael Creese• Manager, Chemical Analysis

• Michael manages Smithers’ Extractables and Leachables (E&L) and Chemical Analysis consultancy team in the UK. He has been working with E&L for over 11 years both for Biopharmaceuticals and Pharmaceuticals, and joined Smithers in 2009.

• Expertise: Extractables and Leachables, Chemical Analysis, Method Validation and Development

• Previously Michael worked in the validation department for one of the largest Single Use System suppliers and previous to that a petrochemical organization. He has used his expertise to solve the challenges of the assessment of extractables and leachables for Single Use System suppliers and users (bags, tubing, filters, connectors etc.) and Final Container Closure Systems (pMDIs, stoppers, vials, pre-filled syringes, cartridges etc.).

• Michael’s team supports a diverse range of clients and industries require the support of analytical experts working within a cGMP and ISO17025:2005 environment.

• Michael has a BSc in Chemistry, and is a Member of the Royal society of Chemistry (MRSC).


Keith Scott• Senior Project Manager

• Keith is part of Smithers’ Extractables and Leachables (E&L) and Chemical Analysis consultancy team in the UK. He has been working at Smithers for 37 years and with E&L for over 15 years.

• Expertise: Extractables and Leachables, Method Validation and Development

• Keith began being involved in managing E&L studies in 2003. In 2007 I became a commercial manager responsible for the Medical and Pharmaceutical sector, developing profitable relationships with new and existing clients to retain business and expand sales.

• In January 2018 he took up a Senior Project Manager role in the Extractables and Leachables (E&L) and Chemical Analysis consultancy team providing technical leadership for analytical testing services to external and internal clients and acting as subject matter expert on the design and delivery of technical packages of work.

• Qualifications

• Keith has a BSc in Chemistry, and an MPhil (Lancaster).

Webinar Content



Outline• Definition of Extractables

• Definition of Leachables

• Why we undertake Extractable and Leachable testing

• Regulations and best practice guidelines

• Testing techniques

• An end of discussion Q&A.

Extractables and Leachables



Extractables

Organic or inorganic substances that can be released from components under laboratory conditions

• Accelerated / exaggerated temperatures, solvents or surface exposure

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Leachables• Organic and inorganic substances that can be released from components used in the manufacture and storage of drug

products under conditions of normal use.

• Leachables are typically a subset of extractables or are derived from extractables.

Sources:

• Manufacturing / in-process / single use systems:

• Bioreactors, containers, storage bags, filters, tubing, gaskets, valves etc.

• Primary packaging components (in direct contact with the drug product):

• Vials, syringes/prefilled syringes, ampoules, bottles.• Closures (screw caps, rubber stoppers).

• Container liners.

• Secondary / tertiary packaging components:

• Cardboard containers.

• Overwraps, over seals.• Container labels (e.g. ink, adhesives).

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Why do E&L Testing?



Leachables - Why a Concern• Patient Safety

• Leachables can increase the toxicity of the drug product,

• through addition of toxic impurities

• Leachables can change the function/properties of the drug product

• Can reduce the drugs availability to the patient

• Biological drug products particularly susceptible

• Unfolding / denature and aggregation of proteins


Post Market Failures• Leachables can lead to:

• Drug product appearance change

• Particulates

• Colour change

• Odour

• Failure of related drug substance test methods

• Product recall

Guidance and Regulations




Regulatory Authorities


Regulatory Requirement• Food, Drug and Cosmetic Act - Section 501(a)(3)

• “a drug is deemed to be adulterated if its container is composed, in whole or part, of any poisonous or deleterious substance which may render the contents injurious to health…”

• 21 CFR Part 211.94 (a)

• “Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality or purity beyond the official or established requirements.”


Guidances Available• Packaging components should be constructed of materials that will not leach harmful or undesirable

amounts of substances to which a patient will be exposed when being treated with the drug product.”1

• “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”2

1US FDA “Guidance for Industry: Container Closure Systems for Packaging Human Drugs, Biologics, Chemistry, Manufacturing and Controls Documentation”, May 19992US FDA, Code of Federal Regulations, 21CFR211.65


Standard Setting Bodies


Standard Setting Organizations• United States Pharmacopeia (USP)

• The USP is the official pharmacopeia of the United States

• Aim to improve global health through standards and programs that ensure the quality, safety and benefit of medicines and food.

• Chapters numbered from <1000> to <1999> are considered to be interpretive, and are intended to provide information on, give definition to, or describe a particular subject

• USP chapters / monographs less than <1000> are enforceable.

• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

• Brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of pharmaceutical product registration.


USP E&L Related Chapters

USP <1663>Extractables

USP <1664>, <1664.1>Leachables

USP <381>Elastomeric Closures for Injection *

<382> Functional

<1381> & <1321> Informational *

USP <1031>Biocompatibility of Materials *

<87> Biological Reactivity In Vitro *

<88> Biological Reactivity In Vivo *

USP <661>Plastics Packaging Systems and their

Materials of Construction *

<661.1> Materials

<661.2> Packaging Systems

<665> Manufacturing Systems *

<1661> & <1665> Informational *

• Official (under revision)• New (not official)


<1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems

• Presents a framework for the design, justification, and execution of an extractables assessment for pharmaceutical packaging and delivery systems

• Establishes critical dimensions of an extractables assessment and discusses practical and technical aspects of each dimension

• Does not establish specific extraction conditions, analytical procedures, or mandatory extractablesspecifications and acceptance criteria for particular packaging and delivery systems or drug products

• Does not delineate every situation in which an extractables assessment is required


USP <1664> Assessment of Leachables Associated with Pharmaceutical Packaging Delivery Systems• Provides a framework for the design, justification and execution of a leachables assessment for pharmaceutical

packaging and delivery systems.

• Includes reference to USP <232> Elemental Impurities.

• USP <1664.1> Orally Inhaled Nasal Drug Products

• Considerations for leachables assessment in orally inhaled and nasal drug products (OINDP), including:

• Metered Dose Inhalers (MDIs);

• Nasal sprays;

• Inhalation solutions, suspensions, and sprays;

• Dry Powder Inhalers (DPIs).

• …to follow USP <1664.2> Parenteral and Ophthalmic Drug Products


Specific to medical devices• ISO 10993-12 - Sample preparation and reference materials

• ISO 10993-18 - Chemical characterisation of materials

• ISO 18562 - Contamination of breathing gas from gas pathways


Industry Consortia


Scientific and Academic Organizations


Guidances & Best Practices


Other Guidances of InterestBPOG (BioPhorum Operations Group)

• Collaboration of the major biopharmaceutical companies

• (taken from BPOG website)

Approach



Extractable and Leachable Stages• Risk assessment – identify components that require extractables data

• Extractable study

• Toxicological assessment of extractables

• Develop analytical methods for the determination of leachables

• Validate leachable methods

• Perform leachable time point analyses – 0, 3, 6, 12 months then yearly up to shelf life

• Extractable leachable-correlation shown

• Toxicological assessment of leachables

• Routine Extractables (leachables)

Component - routine batch release


Dosage Form - Leachable Risk / LikelihoodExamples of Packaging Concerns for Common Classes of Drug Products. (*)

Degree of Concern Associated with the Route of

Administration

Likelihood of Packaging Component-Dosage Form Interaction

High Medium Low

Highest Inhalation Aerosols and Solutions; Injections and Injectable Suspensions

Sterile Powders and Powders for Injection; Inhalation Powders

High Ophthalmic Solutions and Suspensions; Transdermal Ointments and Patches; Nasal Aerosols and Sprays

Low Topical Solutions and Suspensions; Topical and Lingual Aerosols; Oral Solutions and Suspensions

Topical Powders; Oral powders Oral Tablets and Oral (Hard and Soft Gelatin) Capsules

* U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CEDER) and Center for Biologics Evaluation and Research (CBER); Rockville, MD, Container Closure Systems for Packaging Human Drugs and Biologics; Guidance for Industry; May 1999; 1-41.


Risk Based -Extractable and Leachable Testing

2005 European Medicines Agency (EMEA) “Guideline on Plastic Immediate Packaging Materials”


Selection of Components for Assessment • Primary packaging -

• Direct contact with drug product:

• Secondary/tertiary packaging -

• Not in direct contact with drug product:

• Labels (inks, adhesives), external packaging –blister packs

• Manufacturing and and single use processing equipment -

• May contain vast number of components; filters, gaskets, tubing, bags…

http://images.google.co.uk/imgres?imgurl=http://img.directindustry.com/images_di/photo-g/adhesive-label-380444.jpg&imgrefurl=http://www.directindustry.com/prod/computype/adhesive-label-18924-380444.html&usg=__YjdUq4d5IctMur5PR7O8gKvwsOg=&h=750&w=1000&sz=139&hl=en&start=8&tbnid=dsZi9sVU_SQtQM:&tbnh=112&tbnw=149&prev=/images%3Fq%3Dadhesive%2Blabel%26gbv%3D2%26hl%3Den%26sa%3DG

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Extractables Assessments Support• Characterisation of packaging / delivery systems / manufacturing components, and their various

materials of construction

• Development of safe and effective packaging/delivery systems and processes by assisting in the selection of components and materials of construction

• Understanding of effects of various manufacturing processes on packaging components and their potential leachables(e.g. sterilization)

• Determining the worst-case potential leachables profile which facilitates the development of leachables studies and the safety evaluation of potential and actual leachables

• Establishment of qualitative and quantitative leachables-extractables correlations

• Development of extractables specifications and acceptance criteria

• Investigation into the origin(s) of identified leachables whose presence causes out-of-specification results for a marketed product


Scope - Based on Scientifically Justified Thresholds• Both extractables and leachables should be guided by safety thresholds.

• The Safety Concern Threshold (SCT) is a “threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects,” i.e., the default assumption was that leachables were all mutagenic in nature.

• 0.15 µg/day total daily intake for an individual organic leachable (inhalation drug products)

• 1.5 µg/day total daily intake for an individual organic leachable (parenteral/injectable drug products)

• In certain cases, a higher SCT could be justified based on such factors as duration of dosing. M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk Guidance for Industry, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), March 2018


Scope - Based on Scientifically Justified Thresholds• The Qualification Threshold (QT) is the threshold

below which a given noncarcinogenic leachable is not considered for safety qualification (toxicological assessments) unless the leachable presents structure-activity relationship (SAR) concerns.

• 5 µg/day total daily intake for an individual organic leachable (for inhalation drug products).

• Variable for parenteral products depending on the chemical classification of the individual leachable (under FDA review).

• 5 µg/day is also the SCT for the sensitization/irritation toxicology endpoint.

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Extraction Study Practical Considerations• Appropriate selection of extraction solvents, extraction conditions and preparation methods

• Use a wide range of analytical techniques – to cover the spectrum of extractables/leachables.

Generating the Extract Characterising the Extract


Design Aspects of an Extraction Study• The chemical nature of the extracting solvents

• The extraction time

• The extraction temperature

• The sample / solvent extraction ratios, final preparation stages


Extraction Intensity• Extraction conditions should allow completion in a reasonable time but should not be so aggressive as

to alter the nature of the resulting extractables profile.

• The most aggressive extraction conditions are reserved for the quantitative determination of chemical additive contents in components and materials.

Speed Integrity


Gentle versus Harsh ExtractionsThe Spectrum of Extraction “Intensity”

Exhaustive

HarshGentle

Actual Use Accelerated Vigorous

AggressiveDissolution/Digestion

Controlled Extraction

Studies

Simulation Studies


Extraction Solvent• The extracting power of polar aqueous

formulations consisting of soluble ingredients is driven primarily by drug product pH.

• Largely non-polar formulations can be readily simulated with organic solvents.

• “Aqueous” drug products containing stabilizers, solubilizing agents, and buffers, and products containing lipids, proteins, and peptides have a “polarity” that should be matched by the simulating solvent. Mixtures of miscible solvents (such as alcohol/water) can be used.

• Using multiple solvents with different “extracting powers” is appropriate for high risk dosage forms to best discover their potential leachables profiles.


Solvents• Solvents / oils can soften and swell the polymer

• Increased availability of migrating species within polymer

• Increased migration through the polymer

Polymer

Solvent


Further Considerations• Extraction / Solvent Ratios

• Extraction parameters consider the mass /surface area of the test article relative to the volume of the extracting solvent. Extraction ratios and preparation methods can be manipulated to facilitate the objective of the study meeting the required threshold limits for example the SCT.

• Final Extract Preparation

• Considers if any final filtration, concentration, dilution or liquid-liquid partition steps are required prior to analysis.

Soxhlet

Microwave

ASE

Reflux


Extraction Techniques

water condenser

soxhlet extractor

extraction flask

water condenser

air condenser

extraction flask

Shaking & sealed vessel

Sonication

Thermal Desorption / Headspace

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http://www.rampantapathy.co.uk/images/deprotect/12c505a/ultrasonic_bath.jpg


Characterisation of Extractables• Objective

• To discover, identify and quantify all extractables present at levels greater than an established threshold. • Qualitative –

• Identifies extractables

• Quantitative –

• Confirms presence with reference external standards,

• Gives levels / amount present, • Uses optimised extraction conditions

(asymptotic levels)

• Extractable assessments should employ multiple analytical techniques

• ICP-MS

• ICP-OES

• ESI & APCI

• LC-UV

• LC-MS/MS

• LC-HRMS

• Library

• GC-MS

• GC-HRMS

• EI & CI

• Library

• GC-MS

• GC-HRMS

• Headspace

• EI & CI

• LibraryVolatile

Impurities

Semi-Volatile Impurities

Elemental Impurities

Non-Volatile

Impurities


Analysis of Extractables & Leachables


Extractables Identification Techniques

Technique Extractables

GC-MS Solvents, Low molecular weight monomers, initiators, antioxidants, UV absorbers, lubricants, process aids, plasticisers, anti-static agents, flame retardants, modifiers and oligomers.

LC-MS Medium to high molecular weight polar species including antioxidants, UV absorbers, plasticisers, lubricants process aids, heat stabilisers.

ICP Trace elements, catalysts, fillers etc … USP 232 elemental impurity limits

Gravimetry (Non volatile Residue (NVR))

Total non volatile extractable species

FT-IR on NVR Higher molecular weight oligomers, mould release agents e.g. silicone oil etc.

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Gas Chromatography Mass Spectrometry (GC-MS)

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Total ion chromatogram of an HDPE nasal spray bottle

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#129888: 1-Docosene

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#186132: Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, octadecyl ester530

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Irganox 1076 a hindered phenolic polymer stabiliser


Liquid Chromatography Mass Spectrometry (LC-MS)

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Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES), Optical Emission Spectrometry (ICP-OES) or Mass Spectrometry (ICP-MS)

• Sample solutions are nebulised & introduced to plasma flame

• the emission rays which result (from the excited atoms returning to their natural state) are characteristic of a particular element

• MS detector – improves selectivity and

• sensitivity

• USP <232> specifies limits for the amounts of elemental impurities in drug products, serves a good base for scoping the extractables study. Thresholds are based on the specified permitted concentrations of the element which are dependant on root of administration.


Extractables Assessment Consensus• Volatile extractables by Headspace GC/MS; intact and dry materials or components.

• Multiple solvents with a range of polarities.

• Extracts should be characterised for:

• Volatiles and semi-volatile extractables by Direct Injection GC/MS.

• Non-volatile extractables by LC/UV/MS (positive and negative ion)

• Elemental extractables can be assessed in specially prepared acidic extracts by ICP/OES or ICP/MS

Extractables toxicological assessment



Objective• To rationalise the extractable list and provide a list of high priority extractables that should be targeted

during leachable studies.

• How?

• Based on a health risk assessment

• A toxicologist reviews and prioritises the identified extractables based on

• The chemical structure against potential toxic hazards / structural alerts

• Theoretical patient daily exposure against allowable daily patient exposures.

Output:• Some extractables will have negligible safety risk (safety assessment completed).• Some extractables may have unacceptable safety risk. Either packaging is rejected

or such extractables are established as targets for actual leachables studies

Leachable Studies



Leachable Overview and Study Goals• Leachables studies are accomplished as part of a drug stability program.

• To understand the trends in drug product leachable levels over the shelf-life of the product.• To determine maximum leachable levels up to the proposed shelf-life.• To characterise the leachables i.e. discovery, identification and quantification of leachables.

• Process Equipment Related Leachables (PERLs) can be determined in T=0 packaged product i.e. product set down, or taken from the first few product manufacturing batches.

• Analytical methods for leachables should be based on the analytical methods for extractables. • To help establish an extractable/leachable correlation.

• Qualitative correlation – Can be established if all of the leachables detected in a leachables study can be qualitatively linked either directly or indirectly to an identified extractable.

• Quantitative correlation – The leachables detected are demonstrated to be consistently less than the extractable which has been qualitatively correlated

• Test methods should be developed and validated.• To support a comprehensive safety evaluation of the drug product leachables.

• End goal • The collated leachable data permits a toxicological assessment to be made.

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Leachables – the Analytical ChallengeLarge Volume Parenterals (LVPs)

• Consider an LVP with 1L of drug product packaged in a container/bag (20 g total weight of appropriate polymeric material), with a recommended dose of 1 container per day. For an individual organic leachable the estimated AET would be:

Estimated AET = 1.5 µ𝑔/𝑑𝑎𝑦

1 𝑏𝑎𝑔/𝑑𝑎𝑦× 1 𝑙𝑎𝑏𝑒𝑙𝑙𝑒𝑑 𝑑𝑜𝑠𝑒/𝑏𝑎𝑔

Estimated AET = 1.5 µg/bag = 1.5 ng/mL or 0.075 µg/g

• Low target concentrations in complex matrices can prove analytically challenging ...... and in some instances ‘simulated’ leachable studies are required.


Validation• Documented evidence to demonstrate that an analytical procedure, is suitable for its intended

purpose.

• Should follow industry accepted practices:

• ICH Q2 (R1) ‘Validation of Analytical Procedures: Text and Methodology’ guidelines.

• USP 1225 Validation of Compendial Procedures.

• A detailed validation protocol is prepared containing:

• Experimental details.

• Validation acceptance criteria

https://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjassrJzZbiAhWS1uAKHR9SDMcQjRx6BAgBEAU&url=https://www.ascopost.com/issues/october-25-2018/has-the-promise-of-precision-medicine-been-oversold/&psig=AOvVaw1IX7v1s6dESRarYTw5jg7f&ust=1557771590655140


Validation Parameters to be considered• For quantitative testing of impurities:

• Instrument precision

• Linearity

• Method accuracy and repeatability

• Intermediate precision

• Specificity / resolution

• LoD and LoQ

• Range

• System suitability tests

• Robustness

https://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiUm4CFzZbiAhWDxoUKHeHfCbcQjRx6BAgBEAU&url=https://www.reddit.com/r/coolguides/comments/9zfg06/the_difference_between_accuracy_and_precision/&psig=AOvVaw2O8-YCsOiAdShCWolGTsvD&ust=1557770672606819

Lot A’ Inverted

Lot A’ Upright

Lot A Inverted

Lot A Upright

• Metered Dose Inhaler drug product under accelerated storage. • Lot A’ - unwashed elastomeric components• Lot A - pre-washed elastomeric components


Example Leachables Trend Diagrams


Correlating Leachables and Extractables• Predicted Maximum Levels of Extractables and the Corresponding Leachables Following Storage for 18

months

Target Leachables Maximum Predicted Total Extractables

(µg/valve)

Drug Product Leachables (18 Month Inverted; 30 °C/70%RH)(µg/canister)

Lot A Lot B Lot C

Peroxide related leachables

3.2 2.4 0.9 0.7

Myristic acid 332 107 95.0 87.2Ethyl myristate <LOD 44.4 16.3 15.3

Palmitic acid 710 188 123 124Ethyl palmitate <LOD 111 67.9 54.5

Stearic acid 1230 289 184 165Ethyl stearate <LOD 113 60.9 70.2PBT dimer 5620 192 185 178PBT trimer 1810 20.6 20.1 19.2PBT tetramer 270 0.4 <0.4 0.6PBT pentamer 227 <LOD <LOD <LOD


Conclusions

• We all have the same goal… providing treatments to market: effectively, quickly, and assure patient safety.

EUROPEShawbury, ShrewsburyShropshireSY4 4NRUnited Kingdom +44 (0) 1939 250383

Cleeve RoadLeatherheadSurrey, KT22 7RUUnited Kingdom +44 (0) 1372 802000

NORTH AMERICA425 West Market StreetAkron, OH 44303+1 (330) 762-7441

6539 Westland Way, Suite 24Lansing, MI 48917+ (517) 322-2400

CHINABuilding #6A, 668 Fengting Road Suzhou Industrial Park (SIP) Jiangsu Province, China 215122+86 (0)512 6253 5581

Contact usContact our team with any questions or to request a quote


Michael CreeseManager of Project Management E: [email protected]: +44 (0) 1939 252 427

www.smithers.com/extractables-and-leachables

Keith ScottSenior Project ManagerE: [email protected]

T: +44 (0)1939 252422

mailto:[email protected]

http://www.smithers.com/extractables-and-leachables

mailto:[email protected]

Thank you


Documents

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