Considerations to Extractables and Leachables Testing

CONSIDERATIONS TOCONSIDERATIONS TO EXTRACTABLES & LEACHABLES TESTINGLEACHABLES TESTINGHow to organize Extractables Assessments? Considerations from Pharmace tical Prod ction p to finished Dr gConsiderations from Pharmaceutical Production up to finished Drug Container

Dr. Andreas Nixdorf

October 2014 ; CPHI/ICSE Speaker’s Corner ParisSGS Life Science Services

WHY STUDY EXTRACTABLES?WHY STUDY EXTRACTABLES?

Safety assessment / Qualification Evaluation of safety profiles at each phase of development of a

pharmaceutical product For qualification of Container Closure Systems (container selection) For qualification of Container Closure Systems (container selection) Safety aspects in drug production process (leachables from

consumables/single used systems) Profile presence of toxic substancesProfile presence of toxic substances

By correlating extractables to leachables, then determining extractable limits that can provide safety aspects on leachables

Change management Change of packaging material or component of package Changes of production consumables / equipment / in production conditions Change of formulation Change of composition of packaging material Change of manufacturing process of packaging material Before start do your risk assessment, demonstrate that everything is under

t l

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control

MILESTONES OF AN EXTRACTABLE / LEACHABLE ASSESSMENT

PROJECT PREPARATION EXPERIMENTAL PHASEPROJECT PREPARATION EXPERIMENTAL PHASE

MILESTONES

PRELIMINARYWORK

RISK ASSESSMENT

EXTRACTABLE STUDY

METHOD VALIDATIONLEACHABLE

Collect Information e.g. suppliers, chemical compatibility of

Evaluate overall process

E al ate risk (ICH

Execute protocols for extractables testing

Method development and validationp y

materials, food compliance etc.

Rank, prioritize and

Evaluate risk (ICH Q8/Q9/Q10/Q11 tools)

Select materials

Identify extractables

Evaluate results

Product specific validation

Leachable studybracket different materials

Execute CDA and contract

Select materials

Study overall project protocol

Generate report

Define specification limits for Leachable

Leachable study

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contract Define project milestones

study: Toxicological Assessment

MEASUREMENTS FOR EXTRACTABLES AND LEACHABLES

EXTRACTABLES

Qualitative analysis of analyte above an Analytical Evaluation Threshold

LEACHABLES

Qualitative analysis looking for the Leachables from product preparedan Analytical Evaluation Threshold

(AET).

Controlled extraction studies using different solvents, worst case

diti th t i i /b k t

Leachables from product prepared fresh and taken from real-time or accelerated storage programs.

Quantitation of Leachables above a f t th h ldconditions that maximize/brackets

studies outcome.

Semi-Quantitation of analyte.

Profiling applying multiple methods

safety threshold.

Tabulation of method used, limits of quantification and typical chromatograms validation of

th d Profiling applying multiple methods demonstrated fit for that purposes.

Focus on identification, calculation of the amount of extractable/component in the closure device

methods.

Identification of unforeseen leached substance above safety limit and route cause (CAPA).in the closure device.

List of extractables with quantitation, sensitivity of methods, and results for submission.

Tabulation of levels of Leachablesseen from several batches (3) of product/device.

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PRODUCT DEVELOPMENT PROGRESSION (OINDP)PRODUCT DEVELOPMENT PROGRESSION (OINDP)

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THE RISK ICH Q9: SCHEME OF A DOWNSTREAM PROCESSICH Q9: SCHEME OF A DOWNSTREAM PROCESS

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RISK RANKING AND FILTERING (ICH Q9)RISK RANKING AND FILTERING (ICH Q9)

COMPARE AND PRIORITIZE RISKS

How to perform?How to perform?

Requires evaluation of multiple diverse quantitative and qualitative factors for each risk

Involves breaking down a basic risk question into as many components as neededto capture factors involved in the riskto capture factors involved in the risk

These factors are combined into a single relative risk score that can then be compared, prioritized and ranked

7ICH Q9

RISK RANKING AND FILTERING (ICH Q9) EXAMPLERISK RANKING AND FILTERING (ICH Q9)

Evaluation of products and processes with recurring quality relevant problems

Risk assessment: Risk identification, rationale Process step: the more the process advances towards the end,

the less the purification process could operate and the less the p p pdilution factor applies. It is the opposite as the concentration increases.

Product contact : with operations that change the product quality (microbiology filtration virus removal etc ) the contactquality (microbiology, filtration, virus removal, etc.), the contact surface has more impact on product than simple transfer.

Intermediate storage: during storage, interaction between product and consumable has a high significance (longer contact p g g ( gtime).

Process impact / conditions of use : sanitization process (for example: steam or treatment with harsh solvents) is aggressive for the consumable and could increase extractables release

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for the consumable and could increase extractables release

RISK RANKING AND FILTERING (ICH Q9) EXAMPLE

Evaluation of products and processes with recurring quality relevant

RISK RANKING AND FILTERING (ICH Q9)

Evaluation of products and processes with recurring quality relevant problems

Ri k t Ri k l tiRisk assessment: Risk evaluationThree columns

based on a NG

20 125 > 500

classical approach by multiplying factors

10 400100

L R

ATIN

Probability 200251

250505

TOTA

LProbability1: No quality events expected2: Could lead to quality events3 Critical quality events

1 2 3

200251

PROBABILITY

T

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3. Critical quality events PROBABILITY


PROCESS STEPRating Criteria

1 At beginning of process Size exclusion

5 In middle of process Filtering basic or acidic substances, ion-exchange

10 End of process Filtering of particles20 Final step ---

PRODUCT CONTACTRating Criteria

1 Short term contact, no change of the product quality Small contact surface of filter1 Short term contact, no change of the product quality Small contact surface of filter5 Long term contact, change of the product quality Large contact surface of filter

20 Intermediate Storage ---

PROCESS IMPACT / CONDITION OF USERating Criteria

1 Solvent with low extraction power for additives Low Temperature

5 Solvent with high extraction power for additives High Temperature

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RISK RANKING AND FILTERING EXAMPLERISK RANKING AND FILTERING

For each element, a weighing of critical points will b attributed. The total rating can then be calculated:

Risk evaluation added to production problems:

T t l ti P St P d t C t t P I tTotal rating = Process Step x Product Contact x Process Impact

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Weighing grid for other plastic consumables risk analysisTOTAL RATING CRITICALITY OF THE ELEMENT

1

5

Non critical element

10

20

25

RISK MATRIX (1)

25

50

100

125 Overlapping area125

200

250

Overlapping area

Critical element : extractables and leachables studies must be performed / available

400

500

1000

12

2000


MEASUREMEASURE

RISK

RISK MATRIX (2)

CA B HIGH extensiveRISK FILTERING

ONE

ATIO

N MEDIUM

TWO

RIS

K

SS

IFIC

A

LOW

THREECLA

S

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SOURCES – POLYMER CHEMISTRY –IS SUPPLY CHAIN UNDER CONTROL?

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HOW TO KEEP THE SUPPLY CHAIN UNDER CONTROL?

THE CHALLENGES

Oft difi ti f l

THE SOLUTIONS

Sti l t th bli ti tti Often modifications of polymers by vendors.

P t h i l

Stipulate the obligation getting informed in timely manner by quality agreements.

Q lif lt ti d thi Permanent changing polymer market.

Qualify alternative vendors; this secures the user the required delivery.

R ti l t l i i Routinely control incoming vendors material by chemical profiling of critical polymeric components.

Make certain that your supplier keep the quality of his product under control.

components.

Frequently perform quality audits.

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under control.

CONSIDER STRESSFUL PROCESS CONDITIONS

Carbonic acids:C1 C2 C3 tGamma 20 C1, C2, C3 etc.

C2 – C5 -Aldehydes

Gamma 20-25/45 kGy

Ketones

BHT derived from Irganox 1010 1076 1010, 1076

2,5-di-tert-butyl benzene and 2 5-di-tert- butyl phenol from

2,5 di tert butyl phenol from Irgafos 168

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BHT: 3,5-di-tert-butyl-4-hydroxytoluol

CHOOSE REALISTIC EXTRACTION CONDITIONS – SOLVENTS

Soft solvents: Water at neutral pH Extraction at boiling point (refluxing) Water at high pH (9 5) and low pH (2 5) Extraction below Water at high pH (9.5) and low pH (2.5) Extraction below

boiling point Drug vehicle if feasible Extraction below boiling point

Mi t d f (b ff ) d i difi Mixtures composed of aqueous (buffer) and organic modifier:isopropyl alcohol/water (1/4:3/4; 1:1 mixtures) Extraction below boiling point

Harsh solvents are Extraction at boiling point (refluxing): Dichloromethane n-Hexane Isopropyl alcohol Dichloromethane, n Hexane, Isopropyl alcohol Isopropyl alcohol

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CHOOSE REALISTIC EXTRACTION CONDITIONS

A complete extractablesassessment will involve:

Multiple extraction pconditions (Soxhlet, Reflux) Duration and temperature of

extraction Material weight to extraction Material weight to extraction

matrix volume Extraction process

More aggressive conditions More aggressive conditions than which system will normally be used

Avoid decomposition of Avoid decomposition of polymer

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QUANTITATIVE EVALUATION: THE USE OF SAFETY THRESHOLDS

Correlating Threshold Values for Different levels of Cancer Risk

ent/d

ay)

1 5 *ke(µ

g/pa

tie

*FDA

0.15

1.5 *

*

daily

inta

k *EMA-TTC

PQRI

-6 -5 -4 -3 -20.00015 *To

tally

Log (lifetime cancer risk = LCR)Decreasing risk Increasing risk

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Norwood, D.L. and Ball, D. Product Quality Research Institute: Safety thresholds and best practices for extractables and leachables in orally inhaled nasal drug products, PQRI submission 2006.

EXAMPLEHOW LOW TO GO?

ANALYTICAL METHOD SENSITIVITY

HOW LOW TO GO?

• Correlate solvent volume, e.g. sample weight, Analytical ( ) f Q fEvaluation Threshold (AET) with Limit of Quantitation of the

analytical method to surpass methods sensitivity (LOQ)

][]/[ htS l W iAET ][

][]μg/g[ factormlExVol

ghtSampleWeigAETM S

AET - the allowable amount/substance to be released representing the AET

MS - the posited methods analytical sensitivity with MS > LOQ

ExVol - the volume of extraction solvent

factor - the concentration factor to adjust methods sensitivity

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factor - the concentration factor to adjust methods sensitivity

CHOOSE APPROPRIATE TOOLS FOR SEPARATION & DETECTION

Volatiles organics by GC: Head-space technique, TDMS, FID and MS –detector

Semi-Volatiles organics by liquid injection GC:Semi Volatiles organics by liquid injection GC: FID and MS detector

Non-Volatiles organics by HPLC: DAD LC MS/(MS) with accurate mass assignments DAD, LC-MS/(MS) with accurate mass assignments

Metals / Elements: ICP-MS, ICP-OES

Kations, Anions Ion chromatography

Special Techniques for critical compounds: Special Techniques for critical compounds: GC-TEA for Nitrosamines Perfluorinated Carboxylic acids, -Amides, -Sulfonamides by LC-MS/MS

NMR Technology and others

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NMR- Technology and others

WHAT IS A TRUSTABLE IDENTIFICATION?WHAT IS A TRUSTABLE IDENTIFICATION?

Identification Categories Establish a classification scheme that characterizes the significance of peak

identification data (tentative confident confirmed and unknown)identification data (tentative, confident, confirmed and unknown). Best identification means the comparison of both the retention index and the

mass spectrum of an extracted component with its authentic reference standardstandard

Identification category

Identification Data

A Interpretation of Mass spectrometric f t ti b h i t ld b

Attribute Description

Confirmed A Confirmed identification means that identification categories A, B (or C), and D (or E or F) have beenfragmentation behavior or component could be

grouped to a seriesB Confirmation of molecular weight

C Confirmation of elemental composition (not conducted in this study)

D M t t h t t d lib

categories A, B (or C), and D (or E or F) have been fulfilled.

Confident A Confident identification means that sufficient data to preclude all but the most closely related structures have been obtained, Library match factor ≥ 90.

Tentative A Tentative identification means that data have been obtained that are consistent with a class of molecule

lD Mass spectrum matches automated library or literature spectrum

E chromatographic retention index match authentic specimen

F Mass spectrum and chromatographic retention index match authentic specimen

only.unknown No sufficient information’s could be obtained

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X No characterization possible

LEACHABLES STRATEGYLEACHABLES STRATEGY

Toxicological assessment, select substances of concern

Validate the analytical ymethods, methods should have the capability to discover unexpected leachables

Methods for leachablesstudies are specific to the finished product

Determine shelf-life acceptance criteria for leachables based on the t i l i l i k ttoxicological risk assessment

Use three different production batches

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LEACHABLES STRATEGYLEACHABLES STRATEGY

Storage Conditions and Suggested Points for Leachables Analysis

ConditionTemperature

[°C]Relative Humidity

[%RH]Time Points

[months]

Long Term1 25 ±2 60 ±50, 6, 12, 24, 36

30 ±2 65 ±5

1 Either set of conditions can be used for Long Term Storage

Intermediate 30 ±2 65 ±5 0, 6, 12, 24, 36Accelerated 40 ±2 75 ±5 0, 3, 6, (9, 12)

1 Either set of conditions can be used for Long Term Storage

Demonstrate a complete profile

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Demonstrate a complete profile Endpoint analysis is not adequate

SUMMARY THE CHEMICAL LINK

IdentifyExtract

Packaging

SUMMARY – THE CHEMICAL LINK

FINISHED PRODUCT

PACKAGINGMATERIAL

Identify Extractant

Packaging Component

DiscoveryId if

Investigate

ExtractablesLeachables

DiscoveryIdentify

InvestigateFinished Product

Determine toxicity of Extractant

FINISHED

IdentifyDetermine Relevance

Develop & Validate

Finished ProductIdentify

Determine Relevance

Develop & Validate

Finished Product

D lLinking of chemical

relationship

Develop method for assaying

extractant in drug product

Assay for presence of leachables.

Validate method

for leachable

Put product

on t bilit

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in drug stability

THANK YOU FOR YOUR ATTENTIONTHANK YOU FOR YOUR ATTENTION

LIFE INSPIRED

Dr. Andreas NixdorfTeam Leader E&L/Senior Scientist QCLife Science ServicesSGS GSGS Germany

phone: +49 6128 744-372 fax +49 6128 744-700 il andreas nixdorf@sgs com e-mail : [email protected]

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ANNEX – IMPORTANT REGULATORY REQUIREMENTS

Guidelines and others (1):

EMEA: Guideline on plastic immediate packaging materials. EMEA: Note for guidance on specific limits for residues of metal catalyst.g p y EMEA: Guideline on the limits of genotoxic impurities. ICH Q8: Pharmaceutical development.

ICH Q6A: Specifications: Test procedures and acceptance criteria for new drug ICH Q6A: Specifications: Test procedures and acceptance criteria for new drugsubstances and drug products: chemical substances.

ICH Q3C: Guideline for residual solvents ICH Q3B: Impurities in new drug substances:

Impurities arising from excipients present in a new drug product or extracted or leached from the container closure system are not covered by this guidance.

Directive 2003/63/EC amending Directive 2001/83/EC (Medicinal Products for Human Use)

COMMISSION REGULATION (EU) No 10/2011: on plastic materials and articles

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( )intended to come into contact with food.


Guidelines and others (2):

US: Container closure systems for packaging human drugs and biologics US: Container closure systems for packaging human drugs and biologics US: CFR 174 – 186 Indirect food additive Regulations Medical devices: ISO 10993: Biological evaluation of medical devices (Parts 1 –

20)20) US: “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products

– Chemistry, Manufacturing, and Controls Documentation” (FDA-Guidance for I d t )Industry)

US: “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products” –Chemistry, Manufacturing, and Controls Documentation” (FDA-Guidance for I d t )Industry)

21 CFR 600.11 (b) “Equipment”, 21 CFR 600.11 (h) “Containers and closures”

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Compendium Testing (3):

Ph. Eur. 3.1. Materials used for the manufacture of containers- Monographs for selected polymers

Ph. Eur. 3.2 Containers- Monographs for different types of containers

USP: Chemical / Physical Tests:<381> Elastomeric Closures for Injections<661> Containers (will be changed soon)

USP Biological Tests USP Biological Tests<87> Biological Reactivity Tests, In Vitro (Cytotoxicity tests)<88> Biological Reactivity Testing, In Vivo (Class Tests)<1031> Biocompatibility<1031> Biocompatibility

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Compendium Testing; revision of USP in progress (4):

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

USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems

USP <1664 1> Orally Inhaled and Nasal Drug Products USP <1664.1> Orally Inhaled and Nasal Drug Products

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ANNEX LITERATUREANNEX – LITERATURE

Recommended Literature (5): 2006: “PQRI Safety Thresholds and Best Practices for E/L in OINDPs” D J Ball D L Norwood C L M Stults L M Nagao; “ Leachables and D. J. Ball, D. L. Norwood, C. L. M. Stults, L. M. Nagao; Leachables and

Extractables Handbook”; Wiley 2012. Pharmaceutical Research, Vol. 25, No. 4, April 2008 (# 2007) “Best Practices for

Extractables and Leachables in Orally Inhaled and Nasal Drug; Products: AnExtractables and Leachables in Orally Inhaled and Nasal Drug; Products: An Overview of the PQRI Recommendations.”

J. of Liquid Chromatography & Related Technologies; Vol. 27, No. 20 (2004) 3141 3176 “Guideline for the Design Implementation and Interpretation of3141-3176. Guideline for the Design, Implementation, and Interpretation of Validation for Chromatographic Methods used to Quantitate Leachables/Extractables in Pharmaceutical solutions.”Regulatory Toxicology and Pharmacology 44 (2006) 198 211 “A rationale for Regulatory Toxicology and Pharmacology 44 (2006) 198–211 A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity.”

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Considerations to Extractables and Leachables Testing

Healthcare

Transcript of Considerations to Extractables and Leachables Testing