considerations to extractables and leachables testing
DESCRIPTION
How to organize Extractables Assessments? FDA continues to issue Warning Letters to companies that fail to properly complete Design Verification, Design Validation, and Process Validation, and recently to include failures of manufacturers in Risk Management. The evaluation of extractables and leachables has become an increasingly important aspect in the Quality by Design (QbD) initiative of the FDA in the area of drug product design, including materials used in the drug product production process and container and closure systems used for product packaging. This presentation provides general approaches and practical aspects in E&L testing.TRANSCRIPT
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
2
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
3
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
6
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
9
3. Critical quality events PROBABILITY
RISK RANKING AND FILTERING (ICH Q9) EXAMPLERISK RANKING AND FILTERING (ICH Q9)
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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RISK RANKING AND FILTERING (ICH Q9) EXAMPLERISK RANKING AND FILTERING (ICH Q9)
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
RISK RANKING AND FILTERING (ICH Q9) EXAMPLERISK RANKING AND FILTERING (ICH Q9)
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.
ANNEX – IMPORTANT REGULATORY REQUIREMENTS
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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ANNEX – IMPORTANT REGULATORY REQUIREMENTS
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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ANNEX – IMPORTANT REGULATORY REQUIREMENTS
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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