Changing FDA Requirements for Extractables & Leachables Testing on Pharmaceutical Packaging Systems
CONFERÊNCIA INTERNATIONAL
“DESAFIOS E MODERNAS SOLUÇÕES NA FABRICAÇÃO DE MEDICAMENTOS INJETÁVEIS”
GOIÂNIA, 19 NOVEMBER 2018
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CONTENTS
1. Introduction – Definitions - Regulatory aspects
2. Setting-Up Extractables Studies
3. Safety Thresholds - Bridging EXT data and LEA design
4. Setting-Up Leachables Studies
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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
Extractables & Leachables - Overview
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LEACHABLES STUDY• Characterization of Drug Product • Intended use conditions
Secondary Packaging!?
Primary Packaging
Drug product
TOXIC?
FDAEMA
Extractables & Leachables - Overview
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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
Extractables & Leachables - Overview
What the FDA wants…
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Compliance:
USP<1663>: Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems
USP<1664>: 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!
EXT STUDY ≠ FINAL STEP IN SAFETY ASSESSMENT = EARLY RISK EVALUATION
Extractables Studies
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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
Worst-case approximation of the Drug Product o 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, ...)
Extractables Studies
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Extractables Studies
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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
Extractables Studies
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
Extractables Studies
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
Extractables Studies
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
Extractables Studies
NVOCSVOCVOC
HS-GC/MS
Screening
GC/MS
Screening
UPLC/MS
Screening
ICP/OES
ICP/MS
Targeted
IC
Targeted
Extractables Studies
NVOCSVOCVOC
Reflux
Suited for clean solvents
Very selective quantification
Preselected targets
Quantitative/Validated
Screening Targeted
Reporting limit
IS
What the FDA wants…
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Provide Justification for the methods (solvents, time, temperature, etc…):
This requirement is in line with USP<1663> : 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
Extractables Studies
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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”
What the FDA wants…
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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
Threshold approach – Organics
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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
Threshold approach – Organics
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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
AET =50 µ𝑔/𝑑𝑎𝑦
10𝑚𝐿/𝑑𝑎𝑦= 5 mg/L
Threshold approach – Organics
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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
AET =5 µ𝑔/𝑑𝑎𝑦
10𝑚𝐿/𝑑𝑎𝑦= 0,5 mg/L
AET =50 µ𝑔/𝑑𝑎𝑦
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 – Organics
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
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
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)
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
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?
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
Threshold-driven analytics
Complex drug matrices
Comparative studyo Contact vs. Blank o Leachables are differential
Contact solution
Blank solution
AET
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
Threshold-driven analytics
Complex drug matrices
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!
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
Threshold-driven analytics
Complex drug matrices
Comparative study
Trend analysiso Testing over shelf-life at intended storage conditions
➢ Including the blank solution
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
Threshold-driven analytics
Complex drug matrices
Comparative study
Trend analysiso Testing over shelf-life at intended storage conditionso Highest concentrations not always at end of shelf-life
Leachables studies – Challenges
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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
Leachables studies – Challenges
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KEY CHARACTERISTICS/CHALLENGES
Threshold-driven analytics
Complex drug matrices
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!
What the FDA wants…
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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.
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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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