Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager, CMC Analytical Services, LGC
Science
for a safer world
Polymer extractable testing for the
pharmaceutical industry
Mike Ludlow, Technical Study Manager,
CMC Analytical Services, LGC
Introduction
• Background
• Typical analysis protocols
– Full E&L
– Simulated use
– Product packaging interaction
• Identification of unknowns
• Case studies
LGC overview
• Private company
– government agency privatisation
• Largest independent UK laboratory
• UK Government Chemist
• Host Medicines & Healthcare products Regulatory Agency
(MHRA) laboratory. Host British Pharmacopoeia laboratory
• UK Designated National Metrology Institute for Chemical &
Biochemical Measurements
• Our core business is measurement science with emphasis on
quality and complex chemical and biological characterisation
LGC Pharmaceutical Services
• Extractables and leachables
• Particle characterisation
• Foreign particulates
• Impurities and contaminants
• Method development and validation
• Trace analysis
E&L study protocol
Assessment of
Available Data
Extraction
Procedure
Characterisation
of Inorganics
Characterisation
of Organics
Collate
Experimental
Results
Extraction
Validation
Development of
Leachables
Method
Leachables
Validation
Review
Sonication
Microwave
Reflux
Soxlet/soxtect
ASE
GC-MS
HPLC-MS
ICP-OES
ICP-MS
AAS
GFAAS
Quantitative
Extraction Profile
Specialised Tests
Supplier data
MSDS
PAHs
Nitrosamines
Mercaptobenzothiazole
etc
Report/
Final Submission
Review
GC-FID
GC-Derivatisation
HPLC-UV
GC-MS
HS-GC-MS
AAS
GFAAS
Stability Testing
Toxicology
Assessment
Review
Safety Concern Threshold
(SCT)
Analytical Evaluation Threshold
(AET)
Routine
Extractables
Testing
Key stages
• Initial assessment
• Extractables profile
• Toxicological review
• Development and validation of leachables methods
• Routine leachables analysis
• Product submission
Drug delivery devices
Initial assessment
Assessment of
Available Data
Extractable
ProfileSpecialised Tests
Supplier data
MSDS
PAHs
Nitrosamines
Mercaptobenzothiazole
etc
Specialised tests
• Material specific tests such as:
– Nitrosamines
– Polycyclic aromatic hydrocarbons (PAHs)
– Mercaptobenzothiazole
– Silicone oils
– Formaldehyde
Extractable profile
Extraction
Procedure
Characterisation
of Inorganics
Characterisation
of Organics
Collate
Experimental
Results
Sonication
Microwave
Reflux
Soxlet/soxtect
ASE
GC-MS
HPLC-MS
ICP-OES
ICP-MS
AAS
GFAAS
Results
• Qualitative (semi-quantitative) assessment of extractable content
Benzophenone
Oleamide
Erucamide
Irganox 1076
Irgafos 168
Irganox 1010
5 .00 10.00 15.00 20.00 25.00 30.00 35.00 40.00
100000
200000
300000
400000
500000
600000
700000
800000
900000
T ime-->
Abundanc e
T IC: PP I_275138_040215_04.D \ da ta .ms
6 .910
10.659
13.188
14.10515.699
18.643
19.972
Figure 8 - TIC 10ppm mixed standard
RT (Min) Standard Name CAS no
10.6531 Benzophenone 119-61-9
13.1937 Octadecanoic acid 57-11-4
14.1100 Oleamide 301-02-0
15.6927 Erucamide 112-84-5
18.6359 Irgafos 168 31570-04-4
19.9687 Irganox 1076 2082-79-3
ug/g Al As Cd Cr Cu Fe Hg Mn Mo Ni Pb Se Zn
16408-1A <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-1B 1.2 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-2A <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-2B <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-3A <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-3B <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-4A <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-4B <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-5A <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
16408-5B <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1
Extractable profile – important factors
• Select suitable solvent / extraction technique
– screen a range of differing polarity solvents
– alternative extraction techniques
• Optimum extraction time
– determine experimentally
• Extract characterisation - semi-quantitative screen
– GC-MS and HPLC-MS – organics
– ICP-OES and ICP-MS – inorganics (Inc. heavy metals)
Routine extractables testing
• Quality control of devices
• Batch to batch variation
• Change of supplier
• Modification of component(s)
Toxicological review
Collate
Experimental
Results
Development of
Leachables
Method
Review
Quantitative
Extraction Profile
Toxicology
Assessment
Review
Safety Concern Threshold
(SCT)
Analytical Evaluation Threshold
(AET)
Toxicological review
• Assessment of toxicological data for extractable species to enable;
– Determination of SCT (safety concern threshold)
• Level below which species presents no toxicological risk
– Calculation of AET (analytical evaluation threshold)
• Relates SCT to final device
• Determines detection limit required for leachables analysis
SCT / AET
Example: For an MDI product specified to deliver 200 actuations with a
maximum daily recommended dose of 8 actuations. The estimated AET
for leachables can be calculated from the SCT as follows;
– AET = (0.15 µg/day / 8 actuations/day) x 200 actuations/canister
– AET = 3.75 µg/canister
Identification of unknowns
• Risk assessment approach must be adopted
• Specialised techniques can be utilised ‘if required’:
– Q-TOF-MS, 3Q-MS, HR-GC-MS, NMR
• Custom synthesis / use of surrogate standards
• Polymer expertise and regulatory experience essential
Potential source of unknowns
• Sample related
• Device related
• Process related
• Contamination
Drug Product
• Active ingredient
• Excipients
• By-products and degradants
• Solvents
• Catalysts
Process Related Impurities
• Foreign particulates
• Carry over
• Lubricants
• Pipework and fittings
E & L relationship
Extractables
Leachables
General approach
• LC-MSn
• HR-LC-MS
• Fraction collection
– NMR
– FTIR
– GC-MS
• Inorganics
– ICP-OES / ICP-MS
– SEM
Leachables testing
Development of
Leachables
Method
Leachables
Validation
Report/
Final Submission
Review
GC-FID
GC-Derivatisation
HPLC-UV
GC-MS
HS-GC-MS
AAS
GFAAS
Stability Testing
Leachables testing
• Specific to analytes determined in extractable study
– Possibly multi-technique
• Presence of formulated product
• Require full validation in accordance with ICH Q2
– Linearity
– LOD/ LOQ
– Accuracy / precision
– Robustness / repeatability etc
• Assay vs limit test
Simulated use extraction
• Aqueous based formulations
• Use product as extraction solvent
– GC-MS
– LC-MS
– ICP-OES / ICP-MS
Product packaging interaction study
(PPI)
• Forced extraction
– Positive control
• Accelerated stability
– Negative control
– Product in device
• Analysis
– LC-MS
– GC-MS
– ICP-OES / ICP-MS
Product packaging interaction
• Key deliverables
– Potential extractables
– Leachables on storage
• Ambient
• Stressed
• Product specific
E&L critical factors
• Knowledge of polymer materials and analysis
• Design of extraction protocols that are compatible with materials and
extractable components
• Selection of the correct analytical technologies to fully characterise
the extract
– Detection and identification down to ppb levels
– Use of multiple methods to cover full range of potential
extractables
– Tailored approach
E&L summary
• Impurities can be introduced throughout pharmaceutical production process
• Impurities not always derived from drug product and / or immediate packaging
• Multi-technique characterisation required
• High degree of analytical expertise
Case Studies
AU
-0.004
-0.002
0.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
Minutes
0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50 10.00
3.1
28
min2.5 5 7.5 10 12.5 15 17.5 20
mAU
0
20
40
60
80
100
120
140
160
VWD1 A, Wavelength=210 nm (SNAPSHOT.D)
5.1
64
5.9
16
6.6
02
10.5
28
10.8
02
12.3
82
13.4
48
14.3
24
15.8
88
17.7
57
18.2
15
21.4
54
m/z100 200 300 400 500
0
20
40
60
80
100
*MSD1 SPC, time=6.094:6.411 of SNAPSHOT.D API-ES, Pos, Scan
Max: 75352
184.2
185.1
Case study – quality control
Case study - odour
• Tryptic Soy Broth
• Metal Test Coupon
• HS-GC-MS
4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00
2000000
4000000
6000000
8000000
1e+07
1.2e+07
1.4e+07
1.6e+07
1.8e+07
2e+07
2.2e+07
2.4e+07
2.6e+07
2.8e+07
3e+07
3.2e+07
3.4e+07
Time-->
Abundance
TIC: 08070006.D\data.ms
8.18710.605
11.099
11.341
11.470
11.644
11.729
11.879
13.22413.27713.759
13.825
14.190 16.113
4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00
1000000
2000000
3000000
4000000
5000000
6000000
7000000
8000000
9000000
1e+07
1.1e+07
1.2e+07
1.3e+07
1.4e+07
1.5e+07
1.6e+07
1.7e+07
1.8e+07
1.9e+07
Time-->
Abundance
TIC: 08070008.D\data.ms
3.701
8.226 10.603
11.100
11.359
11.472
11.645
11.748
11.873
13.22613.285
13.827
16.116
Odour
40 50 60 70 80 90 100 110 120 130 140 1500
100000
200000
300000
400000
500000
600000
700000
800000
900000
1000000
1100000
m/z-->
Abundance
Scan 45 (3.695 min): 08070008.D\data.ms94.0
78.9
61.0
50.9 69.9 137.9123.1108.6 148.9
(mainlib) Disulfide, dimethyl
60 80 100 120 1400
50
100
50
61
79
94
S
S
Case study - discolouration
• Nasal spray
• PE device
• GC-MS
4 .0 0 6 .0 0 8 .0 0 1 0 .0 01 2 .0 01 4 .0 01 6 .0 01 8 .0 02 0 .0 02 2 .0 0
2 0 0 0 0 0
2 5 0 0 0 0
3 0 0 0 0 0
3 5 0 0 0 0
4 0 0 0 0 0
4 5 0 0 0 0
5 0 0 0 0 0
5 5 0 0 0 0
6 0 0 0 0 0
T im e - ->
A b u n d a n c e
T IC : 0 8 0 2 1 0 0 2 .D
3 .3 0
8 .5 8 1 1 .2 7
1 4 5 0 8 -1 C O N T R O L E X T R A C T
4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00
200000
300000
400000
500000
600000
700000
800000
900000
1000000
1100000
1200000
1300000
1400000
1500000
Time-->
Abundance
TIC: 08021003.D\data.ms
3.310
3.487
5.063
6.670
7.684
8.581
8.673 8.805 9.835
10.730
11.204
11.263
Discolouration
40 60 80 100 120 140 160 180 200 220 2400
10000
20000
30000
40000
50000
60000
70000
80000
90000
100000
110000
120000
130000
140000
150000
160000
170000
180000
190000
200000
m/z-->
Abundance
Scan 259 (6.664 min): 08021003.D\data.ms149.0
120.9
85.0
57.0
105.0 207.0165.0 190.9 257.3236.9
(mainlib) 5-Chloro-2-methyl-3(2H)-isothiazolone
20 30 40 50 60 70 80 90 100 110 120 130 140 150 1600
50
100
27
30
36
42
45
53
57
61
68 71 74
76
79
85
87
8992
94
99 105
114
121
123
125
149
151
153
S N
ClO
Case study – crystalline material
• Biopharmaceutical production process
• White crystalline material formed in silicone tubing
– Optical microscopy
– FTIR/ Raman spectroscopy
– EDX
– X-ray diffraction
Crystalline material – optical microscopy
Crystalline material – FTIR / Raman
white crys ta ls
35
40
45
50
55
60
65
70
75
80
85
90
95
100
105
%T
ran
sm
itta
nc
e
500 1000 1500 2000 2000 3000 4000
Wav enumbers ( cm-1)
Crystalline material - EDX
Crystalline material - XRD
Position [°2Theta]
10 20 30 40 50 60
Counts
0
10000
20000
30000
40000
13992-1; 2009316.CAF
NaCl
Na2HPO4.2H2O
KH2PO4
Case study - herbal ‘pick-me-up’
• Rapid expansion in market for
natural remedies
– Herbals
– Supplements
– Chinese medicine
• LGC asked to identify potential
contaminant identified during
routine QC
HPLC-MSn
• Complex analysis
– Multi component natural
product
• But……..
– Data characteristic of well
known (patented) product
– ??????????
Solution
• Component identified as;
1-[[3-(4,7-dihydro-1-methyl-7-oxo-
3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-5-yl)-4-
ethoxyphenyl]sulphonyl]4-
methyl-piperazine
NNCH3 S
O
O
O
N
O NN
CH3
CH3
CH3
Solution
• More commonly known as ViagraTM
Summary
• Extraction and measurement approaches require a detailed knowledge
of polymer systems and associated measurement approaches.
• A range of technologies, including advanced and novel instrumentation
(ASE, Q-TOF-MS, HR-GC-MS), need to be applied intelligently in order
to efficiently deliver defensible extractable profiles.
• An informed and effective extractables programme will lead to faster,
more cost effective, more reliable data
Sources of information
• Extractables and Leachables Handbook – Norwood et al (Wiley)
• PQRI Safety Thresholds and Best Practices for Extractables and Leachables
in Orally Inhaled and Nasal Drug Products (Draft - 2006)
• BS EN ISO 10993-12:2009 Biological evaluation of medical devices Part 12:
Sample preparation and reference materials
• ISO 10993-18:2009 Biological evaluation of medical devices. Chemical
characterisation of materials
• BS EN ISO 17025:2005 General requirements for the competence of testing
and calibration
• USP <1663> Extractables and <1664> Leachables
• ICH.org
– Q1: Stability
– Q2: Validation
– Q3: Impurities
– M7: Genotoxic impurities
Drug development services – our locations
Lexington Teddington
Fordham Sandwich
Science
for a safer world
Thank you Mike Ludlow, Technical Study Manager,
CMC Analytical services, LGC