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.

1. CONSIDERATIONS TO
EXTRACTABLES &
LEACHABLES TESTING
How to organize Extractables Assessments?
Considerations from Pharmaceutical Production up to finished Drug
Container
Dr. Andreas Nixdorf
October 2014 ; CPHI/ICSE Speaker’s Corner Paris
SGS Life Science Services

2. 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)
 Safety aspects in drug production process (leachables from
consumables/single used systems)
 Profile 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

3. MILESTONES OF AN EXTRACTABLE /
LEACHABLE ASSESSMENT
PROJECT PREPARATION EXPERIMENTAL PHASE
MILESTONES
PRELIMINARY
WORK
RISK
ASSESSMENT
EXTRACTABLE
STUDY
METHOD
VALIDATION
LEACHABLE
 Collect Information
e.g. suppliers,
chemical
compatibility of
 Evaluate overall
process
 E al ate  Execute protocols
for extractables
testing
 Method
development and
p y validation
materials, food
compliance etc.
 Rank, prioritize and
Evaluate risk (ICH
Q8/Q9/Q10/Q11
tools)
 Select materials
 Identify extractables
 Evaluate results
 Product specific
validation
bracket different  Leachable  Generate report
materials
 Study overall project
protocol
 Define specification
 Execute CDA and
limits for Leachable
contract
study
3
 Define project
milestones
study: Toxicological
Assessment

4. MEASUREMENTS FOR EXTRACTABLES AND
LEACHABLES
EXTRACTABLES
 Qualitative analysis of analyte above
Evaluation Threshold
LEACHABLES
 Qualitative analysis looking for the
an Analytical Leachables (AET).
 Controlled extraction studies using
different solvents, worst case
diti th t i i /b k t
from product prepared
fresh and taken from real-time or
accelerated storage programs.
 Quantitation of Leachables above a
conditions that maximize/brackets f t th h ld
studies outcome.
 Semi-Quantitation of analyte.
 Profiling multiple safety threshold.
 Tabulation of method used, limits of
quantification and typical
chromatograms validation of
applying methods
th d
demonstrated fit for that purposes.
 Focus on identification, calculation of
the amount of extractable/component
in the device
methods.
 Identification of unforeseen leached
substance above safety limit and
closure device. route cause (CAPA).
 List of extractables with quantitation,
sensitivity of methods, and results for
submission.
 Tabulation of levels of Leachables
seen from several batches (3) of
product/device.
4

5. PRODUCT DEVELOPMENT PROGRESSION (OINDP)
5

6. THE RISK
ICH Q9: SCHEME OF A DOWNSTREAM PROCESS
6

7. RISK RANKING AND FILTERING (ICH Q9)
COMPARE AND PRIORITIZE RISKS
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 needed
to capture factors involved in the risk
 These factors are combined into a single relative risk score
that can then be compared, prioritized and ranked
7
ICH Q9

8. RISK RANKING AND FILTERING (ICH Q9) EXAMPLE
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
dilution 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 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
time).
 Process impact / conditions of use : sanitization process (for
example: steam or treatment with harsh solvents) is aggressive
the extractables release
8
for consumable and could increase

9. (EXAMPLE
Evaluation of RISK RANKING AND FILTERING ICH Q9)
products and processes with recurring quality relevant
problems
Risk assessment: Risk evaluation
Three columns
based on a
NG
20 125 > 500
L RATIN Probability
200
25 1
classical approach
by multiplying factors
10 100 400
5 50 250
TOTAL 1: No quality events expected
2: Could lead to quality events
3 1 2 3
PROBABILITY
T
9
3. Critical quality events

10. RISK RANKING AND FILTERING (ICH Q9) EXAMPLE
PROCESS STEP
Rating 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 particles
20 Final step ---
PRODUCT CONTACT
Rating Criteria
1 Short term contact, no change of the product quality Small contact surface of filter
5 Long term contact, change of the product quality Large contact surface of filter
20 Intermediate Storage ---
PROCESS IMPACT / CONDITION OF USE
Rating Criteria
1 Solvent with low extraction power for additives Low Temperature
5 Solvent with high extraction power for additives High Temperature
10

11. RISK RANKING AND FILTERING EXAMPLE
For each element, a weighing of critical points will b
attributed. The total rating can then be calculated:
Risk evaluation added to production problems:
Total rating = Process Step x Product Contact x Process Impact
11

12. RISK RANKING AND FILTERING (ICH Q9) EXAMPLE
Weighing grid for other plastic consumables risk analysis
TOTAL RATING CRITICALITY OF THE ELEMENT
1
5
Non critical element
10
20
RISK MATRIX (1)
25
50
100
125 Overlapping area
200
250
Critical element : extractables and leachables studies must
be performed / available
400
500
1000
12
2000

13. RISK RANKING AND FILTERING (ICH Q9) EXAMPLE
MEASURE
RISK MATRIX (2)
RISK
A B C HIGH extensive
FILTERING
ONE
ATION
MEDIUM
TWO
RISK
SSIFICA
LOW
THREE
CLAS
13

14. SOURCES – POLYMER CHEMISTRY –
IS SUPPLY CHAIN UNDER CONTROL?
14

15. HOW TO KEEP THE SUPPLY CHAIN UNDER
CONTROL?
THE CHALLENGES
Oft difi ti f l
THE SOLUTIONS
 Often modifications of polymers Sti l t th bli ti tti
by vendors.
P th i l
 Stipulate the obligation getting
informed in timely manner by
quality agreements.
 Permanent changing polymer Q lif lt ti d thi
market.
 Qualify alternative vendors; this
secures the user the required
delivery.
 Routinely control incoming
vendors material by chemical
profiling of critical polymeric
components.
 Make certain that your supplier
keep the quality of his product
under  Frequently perform quality
audits.
15
control.

16. CONSIDER STRESSFUL PROCESS
CONDITIONS
 Carbonic acids:
Gamma 20 C1, C2, C3 etc.
 C2 – C5 -Aldehydes
20-
25/45 kGy
 Ketones
 BHT derived from Irganox

1010, 1076
 2,5-di-tert-butyl benzene and
2 5-di-tert- phenol 2,5 di tert butyl from
Irgafos 168
16
BHT: 3,5-di-tert-butyl-4-hydroxytoluol

17. 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
boiling point
 Drug vehicle if feasible  Extraction below boiling point
 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
 Isopropyl alcohol
17

18. CHOOSE REALISTIC EXTRACTION
CONDITIONS
A complete extractables
assessment will involve:
 Multiple extraction
conditions (Soxhlet, Reflux)
 Duration and temperature of
extraction
 Material weight to extraction
matrix volume
 Extraction process
 More aggressive conditions
than which system will
normally be used
 Avoid decomposition of
polymer
18

19. QUANTITATIVE EVALUATION: THE USE OF
SAFETY THRESHOLDS
Correlating Threshold Values for Different levels of Cancer Risk
ent/day)
1 5 *
ke (μg/patie
* FDA
1.5 0.15
*
daily intak
EMA-TTC
PQRI
0.00015 *
-6 -5 -4 -3 -2
Totally
Log (lifetime cancer risk = LCR)
Decreasing risk Increasing risk
19
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.

20. TO GO?
EXAMPLE
HOW LOW ANALYTICAL METHOD SENSITIVITY
• Correlate solvent volume, e.g. sample weight, Analytical
Evaluation Threshold (AET) with Limit of Quantitation of the
analytical method to surpass methods sensitivity (LOQ)
AET [ / ] S l W i ht [ ]
M SampleWeig g S 
μg/g factor
ExVol ml
[ ]


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 methods 20
to adjust sensitivity

21. 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:
 FID and MS detector
 Non-Volatiles organics by HPLC:
 DAD, LC-MS/(MS) with accurate mass assignments
 Metals / Elements:
 ICP-MS, ICP-OES
 Kations, Anions
 Ion chromatography
 Special Techniques for critical compounds:
 GC-TEA for Nitrosamines
 Perfluorinated Carboxylic acids, -Amides, -Sulfonamides by LC-MS/MS
 NMR 21
NMR- Technology and others

22. WHAT IS A TRUSTABLE IDENTIFICATION?
 Identification Categories
 Establish a classification scheme that characterizes the significance of peak
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
standard
Identificatio
n category
Identification Data
A Interpretation of Mass spectrometric
f tti bh i t ldb
Attribute Description
Confirmed A Confirmed identification means that identification
fragmentation behavior or component could be categories A, B (or C), and D (or E or F) have been
grouped to a series
B Confirmation of molecular weight
C Confirmation of elemental composition (not
conducted in this study)
D M t t h t t d lib
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
Mass spectrum matches automated library or l
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
22
X No characterization possible

23. LEACHABLES STRATEGY
 Toxicological assessment,
select substances of concern
 Validate the analytical
methods, methods should
have the capability to discover
unexpected leachables
 Methods for leachables
studies are specific to the
finished product
 Determine shelf-life
acceptance criteria for
leachables based on the
toxicological risk assessment
 Use three different production
batches
23

24. LEACHABLES STRATEGY
 Storage Conditions and Suggested Points for
Leachables Analysis
Condition
Temperature
[°C]
Relative Humidity
[%RH]
Time Points
[months]
Long Term1 25 ±2 60 ±5
0, 6, 12, 24, 36
30 ±2 65 ±5
Intermediate 30 ±2 65 ±5 0, 6, 12, 24, 36
Accelerated 40 ±2 75 ±5 0, 3, 6, (9, 12)
1 Either set of conditions can be used for Long Term Storage
 Demonstrate a complete 24
profile
 Endpoint analysis is not adequate

25. SUMMARY THE CHEMICAL – LINK
Identify
Extract
Packaging
FINISHED
PRODUCT
PACKAGING
MATERIAL
Extractant
Component
Leachables Extractables
Discovery
Id if
Identify
Investigate
Determine
toxicity of
Extractant
FINISHED
Identify
Determine
Relevance
Develop & Validate
Finished Product
Determine
Relevance
Develop & Validate
Finished Product
D l
Linking 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
25
stability in drug

26. THANK YOU FOR YOUR ATTENTION
LIFE INSPIRED
Dr. Andreas Nixdorf
Team Leader E&L/Senior Scientist QC
Life Science Services
SGS Germany
 phone: +49 6128 744-372
 fax +49 6128 744-700
 e-mail : andreas.nixdorf@sgs.com
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27. 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.
 EMEA: Guideline on the limits of genotoxic impurities.
 ICH Q8: Pharmaceutical development.
 ICH Q6A: Specifications: Test procedures and acceptance criteria for new drug
substances 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
27
)
intended to come into contact with food.

28. ANNEX – IMPORTANT REGULATORY
REQUIREMENTS
 Guidelines and others (2):
 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)
 US: “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products
– Chemistry, Manufacturing, and Controls Documentation” (FDA-Guidance for
Industry)
 US: “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products” –
Chemistry, Manufacturing, and Controls Documentation” (FDA-Guidance for
Industry)
 21 CFR 600.11 (b) “Equipment”, 21 CFR 600.11 (h) “Containers and closures”
28

29. 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
<87> Biological Reactivity Tests, In Vitro (Cytotoxicity tests)
<88> Biological Reactivity Testing, In Vivo (Class Tests)
<1031> Biocompatibility
29

30. 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
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31. ANNEX – 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
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: 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 of
Validation for Chromatographic Methods used to Quantitate
Leachables/Extractables in Pharmaceutical solutions.”
 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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