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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
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
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
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
PRODUCT DEVELOPMENT PROGRESSION (OINDP) 
5
THE RISK 
ICH Q9: SCHEME OF A DOWNSTREAM PROCESS 
6
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
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
(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
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
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
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
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
SOURCES – POLYMER CHEMISTRY – 
IS SUPPLY CHAIN UNDER CONTROL? 
14
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.
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
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
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
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.
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
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
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
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
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
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
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 
26
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.
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
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
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 
30
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.” 
31

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Considerations to Extractables and Leachables 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
  • 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 26
  • 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 30
  • 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.” 31