Changing FDA Requirements for Extractables & Leachables ...cienciasfarmaceuticas.org.br/wp-content/uploads/2018/11/03_Sindusfar… · Nelson Labs –A Sotera Health Company 1 Founded:

Changing FDA Requirements for Extractables & Leachables Testing on Pharmaceutical Packaging Systems

CONFERÊNCIA INTERNATIONAL

“DESAFIOS E MODERNAS SOLUÇÕES NA FABRICAÇÃO DE MEDICAMENTOS INJETÁVEIS”

SAO PAULO, 21 NOVEMBER 2018

Nelson Labs – A Sotera Health Company

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Founded: 1985 by Dr. Jerry R. Nelson and Lynda S. NelsonGlobal Employees: 800+ with more than 450 scientists

75+ registered and specialist microbiologists (NRCM)Global Capacity: 13 global lab sites in the US, Mexico, Europe and ChinaHeadquarters: Salt Lake City, UTCapabilities: More than 700 microbiological and analytical testsCommittee Memberships: ASTM, ISO, AAMI, ANSI, IEST, PDA, AATB and moreCertifications: Nelson Labs facilities are FDA-registered as a GMP, GLP, and

GTP testing lab with ISO 17025 accreditation

Nelson Labs – A Sotera Health Company … IN EUROPE!

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Founded: 1991Headquarters: Leuven, BelgiumGlobal Employees: 300+ (more than 50% at PhD level)Certifications: FDA registered

ISO 17025 accreditedGLP and GMP certified

Pioneer and World Leader in Extractables and Leachables testing

More than 100 successful FDA submission contributions

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EXTRACTABLES & LEACHABLES

1. Introduction – Definitions - Regulatory aspects

2. Setting-Up Extractables Studies

3. Safety Thresholds - Bridging EXT data and LEA design

4. Setting-Up Leachables Studies

5. Conclusion

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INTRODUCTION

DEFINITIONS – REGULATORY REQUIREMENTS

Extractables & Leachables - Overview

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EXTRACTABLES STUDY• Characterization of Packaging• Laboratory “worst-case” conditions

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FDAEMA

Secondary Packaging!?

Primary Packaging

Solvent


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LEACHABLES STUDY• Characterization of Drug Product • Intended use conditions

Secondary Packaging!?

Primary Packaging

Drug product

TOXIC?

FDAEMA


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PHARMACEUTICAL CONTAINER

DRUG PRODUCT

FOCUS: Identification FOCUS: Quantification

Worst case condition Normal conditions

Screening

What CAN come out What DOES come out

Targeted&

Screening

EXTRACTABLES LEACHABLES

Analytics

Safety Threshold-driven

EXTRACTABLES

PHARMACEUTICAL CONTAINER

LEACHABLES

DRUG PRODUCT

FOCUS: Identification FOCUS: Quantification

Worst case condition Normal conditions

Screening

What CAN come out What DOES come out

Targeted&

Screening

Analytics Toxicology


What the FDA wants…

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Compliance:

USP: Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems

USP: Assessment of Leachables Associated with Pharmaceutical Packaging/Delivery Systems

1999 FDA Guidance for Industry: Container/Closure Systems for Packaging Human Drugs and Biologics

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SETTING UP EXTRACTABLES STUDIES

Extractables Studies

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!

MULTIPLE PURPOSES

Impurities profiling of materialso Identify as many compounds as possibleo Materials choice - Pinpoint “Bad Actors” in the materials

Identifying compounds that may need to be monitored as leachableo Toxicity o Concentrationo Risk of migration

Change controlo Batch variationo Same grade but change in supplier

THE PURPOSE OF AN EXT STUDY DETERMINES THE SET-UP!

WHAT IT’S NOT:

EXT STUDY ≠ FINAL STEP IN SAFETY ASSESSMENT = EARLY RISK EVALUATION


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STARTING POINTS

The Materialso Identify all critical components -> Primary

o Primary components are semipermeable -> Secondary!o Coated vs uncoated, Multi-layered films?

o Risk of compounds of concern?o Carbon black, rubber curing system, …

o Siliconized?o Expose to intended use conditions!

o Sterilization, washing, frozen, …

List of used additives ≠ EXT data: Screening techniqueso Impuritieso Degradation productso Trace levels vs known ingredients

Drug product composition o Worst-case approximationo Aqueous vs Organic vehicle?o Surfactants

ANALYTICS

DESIGN PARAMETERS (PER USP 1663)

Generating the extract

Extraction solventso Water, alcohol/water, alcohol, DCM, hexane, (DP itself), …o pH

Extraction techniqueso Static and dynamic incubation, reflux, sonication, one-sided, ...

Extraction conditionso Temperature and Timeo Extraction ratio

Testing the extract

Analytical Techniques – minimum 5o Screening for organicso Targeted for inorganicso Targeted for compounds of concern (PAHs, nitrosamines, ...)


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Reflux

HS-GC/MS

Screening

GC/MS

Screening

UPLC/MS

ScreeningICP/OES IC

VOCVolatile Organic Compounds

o Monomer Residueso Solvent Residues from Production stepso Residues from polymer treatments (e.g. Washing)o Small Polymer Breakdown products


Reflux

HS-GC/MS

Screening

GC/MS

Screening

UPLC/MS

ScreeningICP/OES IC

SVOCSemi-Volatile Organic Compounds

o Lubricantso Plasticizerso Antioxidantso Polymer degradation productso Solvents with an elevated boiling point

VOC


Reflux

HS-GC/MS

Screening

GC/MS

Screening

UPLC/MS

ScreeningICP/OES IC

NVOCNon-Volatile Organic Compounds

o Fillerso Plasticizerso Antioxidantso Anti-slip agents

SVOCVOC


Reflux

HS-GC/MS

Screening

GC/MS

Screening

UPLC/MS

Screening

ICP/OES

ICP/MS

IC

NVOCSVOCVOC

HS-GC/MS

Screening

GC/MS

Screening

UPLC/MS

Screening

ICP/OES

ICP/MS

Targeted

IC

Targeted


NVOCSVOCVOC

HS-GC/MS

Screening

GC/MS

Screening

UPLC/MS

Screening

ICP/OES

ICP/MS

Targeted

IC

Targeted


NVOCSVOCVOC

Reflux

Suited for clean solvents

Very selective quantification

Preselected targets

Quantitative/Validated

Screening Targeted

Reporting limit

IS


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Provide Justification for the methods (solvents, time, temperature, etc…):

This requirement is in line with USP : it is necessary to justify your selection of solvents, techniques, and extraction conditions as being an exaggerated condition compared to the leachables. What FDA wants to avoid is that there are surprises during a leachable study, because of an ill-designed Extraction study


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EXT data set

?

AnalysisExtraction Interpretation?

Packaging

INTERPRETATION

LONG LISTS OF EXTRACTABLES

What to do with this bunch of data?

o Threshold approach filters out “Extractables of Concern”


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A Toxicological risk assessment should, in general, not be based on extraction study results alone

The current thinking of the FDA is that it are leachables that represent the true risk to the patient, and leachable results should be the basis of an adequate toxicological risk assessment

Extractable - Leachable correlations

FDA considers the ability to make a good correlation between the extractable results and the leachable results as a requirement

Justify your selection of “to be monitored” leachablesbased upon the outcome of a well-designed and justified extraction study

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Safety Thresholds

Bridging EXT data and LEA design

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SAFETY CONCERN THRESHOLD (SCT)“Threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and non-carcinogenic toxic effects”

PQRI for PDP

– SCT in function of toxicological endpoint

– Excess cancer risk of 1 in 1.00.000 over life-time exposure

THRESHOLD OF TOXICOLOGICAL CONCERN (TTC)

“Threshold of Toxicological Concern (TTC) concept was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects”

ICH M7 guideline

– TTC in function of therapy duration

– Evaluation of genotoxic impurities

– Excess cancer risk of 1 in 100.000 over life-time exposure

Threshold approach – Organics

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SAFETY CONCERN THRESHOLD (SCT)“Threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and non-carcinogenic toxic effects”

PQRI for PDP

THRESHOLD OF TOXICOLOGICAL CONCERN (TTC)“Threshold of Toxicological Concern (TTC) concept was developed to define an acceptable intake for any unstudied

chemical that poses a negligible risk of carcinogenicity or other toxic effects”

ICH M7 guideline


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PERMITTED DAILY EXPOSURE (PDE)

ICH Q3D

– Lists PDEs in function of administration route

– PDEs can be converted

– No PDEs for typical rubber- or glass related elements

Threshold approach – Elements

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ANALYTICAL EVALUATION THRESHOLD (AET)

Converting the SCT into an analytically relevant concentration

Screening methods are semi-quantitative: a correction factor of 50% is introduced

Cornerstone of all E&L testing:

Compounds detected below the (Final) AET should not be considered for toxicological assessment

AET =1.5 µg/day

maximum administered volume/day

Final AET=𝐴𝐸𝑇

2


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NARROWING DOWN THE LIST

VOC extractables

Result (mg/L)

COMPOUND #1 0,1

COMPOUND #2 0,2

COMPOUND #3 1,25

COMPOUND #4 2

COMPOUND #5 0,4

COMPOUND #6 0,25

COMPOUND #7 13

COMPOUND #8 0,1

COMPOUND #9 27

COMPOUND #10 0,4

COMPOUND #11 0,1

COMPOUND #12 5,5

COMPOUND #13 32,5

COMPOUND #14 1,2

COMPOUND #15 0,35

Max daily dose of 10 mL / day

Class I Compounds

Class II Compounds

Class III Compounds

AET =1.5 µ𝑔/𝑑𝑎𝑦

10𝑚𝐿/𝑑𝑎𝑦= 0.15 mg/L

AET =5 µ𝑔/𝑑𝑎𝑦

10𝑚𝐿/𝑑𝑎𝑦= 0,5 mg/L


10𝑚𝐿/𝑑𝑎𝑦= 5 mg/L


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NARROWING DOWN THE LIST

VOC extractablesMax daily dose of 10 mL / day

Class I Compounds

Class II Compounds

Class III Compounds

AET =1.5 µ𝑔/𝑑𝑎𝑦

10𝑚𝐿/𝑑𝑎𝑦= 0.15 mg/L


10𝑚𝐿/𝑑𝑎𝑦= 0,5 mg/L


10𝑚𝐿/𝑑𝑎𝑦= 5 mg/L

result (mg/L) ClassThreshold (µg/day)

AET for Class (mg/L)

COMPOUND #1 0,10 I 50 5

COMPOUND #2 0,20 I 50 5

COMPOUND #3 1,25 III 1.5 0,15

COMPOUND #4 2,00 I 50 5

COMPOUND #5 0,40 II 5 0,5

COMPOUND #6 0,25 I 50 5

COMPOUND #7 13,00 II 5 0,5

COMPOUND #8 0,10 III 1.5 0,15

COMPOUND #9 27,00 I 50 5

COMPOUND #10 0,40 II 5 0,5

COMPOUND #11 0,10 III 1.5 0,15

COMPOUND #12 5,50 I 50 5

COMPOUND #13 32,50 III 1.5 0,15

COMPOUND #14 1,20 I 50 5

COMPOUND #15 0,35 II 5 0,5


Threshold approach

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Extractables of Concern

- Compound #3- Compound #7- Compound #9

- Compound #12- Compound #13

EXT data set

AnalysisExtraction Interpretation?

Packaging

EXTRACTABLES DATA

Applying threshold limit approach filters out “EXT of Concern”o Critical information for LEA study

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SETTING UP LEACHABLES STUDIES

Leachables studies

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PURPOSEGenerating a data set which will allow the assessment of the impact of the container/closure system on- DP safety

o Concentrations of leachables

- DP qualityo Interaction with API (secondary leachables)

FOCUS ON QUANTIFICATION- Targeted

o Extractables of concern

- Screeningo Unexpected leachables, secondary leachables

EXTRACTABLES-LEACHABLES CORRELATIONS- Direct correlation

o EXT levels ≥ LEA levels

- Indirect correlationo Secondary leachables

TOXIC?

Drug potency?

Leachables studies – Challenges

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KEY CHARACTERISTICS/CHALLENGES

Threshold-driven analyticso AET is calculated based on worst-case class III SCT

o Analytical methods suitable at AET level?e.g. Large Volume Parenteral

SCT for parenterals = 1,5 µg/day


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Threshold-driven analyticso AET is calculated based on worst-case class III SCTo Analytical methods should be suitable at AET level o Quantitative -> Method Development & Validation?

➢ Method suitability Test ( = spiking experiment at AET level in screening mode)

➢ Limit test

➢ Limited validation

➢ Full validation

Incre

asing

com

plexity per ICH Q2 (R1)


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Threshold-driven analytics

Complex drug matriceso Compatibility with sample preparation procedures

o Liquid/liquid extraction to organic solvento Concentration of L/L extract

o Analytical interference -> Method Development & Validation?o Simulation study?


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Complex drug matrices

Comparative studyo Contact vs. Blank o Leachables are differential

Contact solution

Blank solution

AET


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Comparative studyo Contact solution (DP in CCS) vs. Blank solution (DP in inert packaging) o Leachables are identified as differential compoundso The scope of the study is determined by the blank solution

➢ Ideally: Collection after filling line➢ Biologics!➢ LYO!


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Comparative study

Trend analysiso Testing over shelf-life at intended storage conditions

➢ Including the blank solution


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Comparative study

Trend analysiso Testing over shelf-life at intended storage conditionso Highest concentrations not always at end of shelf-life


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Trend analysiso Testing over shelf-life at intended storage conditions

o Highest concentrations not always at end of shelf-life

Case study: LEACHABLES STUDY

100 mL flexible multi-layer bag incl. Drug solution, ageing at 25°C for 24 months;Volatile Organic Compounds and monitoring Ethylacetate and Cyclohexane

Conclusion: WORST CONCENTRATION IS NOT ALWAYS AT THE END OF SHELF LIFE!!

0

20

40

60

80

100

120

140

160

180

200

0 5 10 15 20 25 30

am

ou

nt

(pp

b)

time (weeks)

leaching behaviour of two volatile compounds

ethylacetate

cyclohexane


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Comparative study

Trend analysiso Testing over shelf-life at intended storage conditionso Highest concentrations not always at end of shelf-lifeo Plan ahead and in parallel with stability study!


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Evaluate at least three batches of your to-be-marketed drug product for leachables

Preferably, this leachables assessment should be done on three different batches where different lots of the container/closure system are used

Include assessments of multiple time points over the course of your stability studies in order to identify trends over time

Preferably, this leachables assessment should be done on three different batches where different lots of the container/closure system are used

Ensure your AET is appropriate: from a general toxicology perspective

CONCLUSIONS

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➢ STEP 1: COLLECT INFORMATION ON MATERIALS USED

➢ STEP 2: CAREFULLY PLAN, PERFORM AND EVALUATE EXTRACTABLE STUDY

➢ STEP 3: SELECT TARGET COMPOUNDS AMENABLE TO LEACHABLE STUDY

➢ STEP 4: CARRY OUT LEACHABLES STUDY UNDER “SIMULATED USE CONDITIONS”

➢ STEP 5: CARRY OUT TOXICOLOGICAL ASSESSMENT ON LEACHABLES RESULTS

“What the FDA wants”

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With the presentation that was given by Dr. Dan Mellon of the FDA (CDER), at the joint PDA-PQRI meeting in Washington of October 2017, the requirements from the FDA wrtthe type of E/L data to be provided to the Agency became much more clear.

If you are in need of more information please contact [email protected]@nelsonlabs.com.

mailto:[email protected]:[email protected]

Leachables studies

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Focus on quantification of target compounds

Can’t we just feed the drug product to the EXT flow?

NO!• No clean solvents• Pharmaceutical matrix may not be compatible with generic methods• Design of LEA study is based on threshold-driven analytics• Quantification of “EXT of concern”

Good LEA study design! (per USP 1664)

Content

1. Introduction – Definitions - Regulatory aspects

2. Setting-Up Extractables Studies

3. Safety Thresholds - Bridging EXT data and LEA design

4. Setting-Up Leachables Studies

5. Conclusion

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Documents

Changing FDA Requirements for Extractables & Leachables ...cienciasfarmaceuticas.org.br/wp-content/uploads/2018/11/03_Sindusfar… · Nelson Labs –A Sotera Health Company 1 Founded: