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Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager, CMC Analytical Services, LGC

Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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Page 1: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Science

for a safer world

Polymer extractable testing for the

pharmaceutical industry

Mike Ludlow, Technical Study Manager,

CMC Analytical Services, LGC

Page 2: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Introduction

• Background

• Typical analysis protocols

– Full E&L

– Simulated use

– Product packaging interaction

• Identification of unknowns

• Case studies

Page 3: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 4: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

LGC Pharmaceutical Services

• Extractables and leachables

• Particle characterisation

• Foreign particulates

• Impurities and contaminants

• Method development and validation

• Trace analysis

Page 5: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 6: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Key stages

• Initial assessment

• Extractables profile

• Toxicological review

• Development and validation of leachables methods

• Routine leachables analysis

• Product submission

Page 7: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Drug delivery devices

Page 8: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Initial assessment

Assessment of

Available Data

Extractable

ProfileSpecialised Tests

Supplier data

MSDS

PAHs

Nitrosamines

Mercaptobenzothiazole

etc

Page 9: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Specialised tests

• Material specific tests such as:

– Nitrosamines

– Polycyclic aromatic hydrocarbons (PAHs)

– Mercaptobenzothiazole

– Silicone oils

– Formaldehyde

Page 10: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 11: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 12: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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)

Page 13: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Routine extractables testing

• Quality control of devices

• Batch to batch variation

• Change of supplier

• Modification of component(s)

Page 14: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Toxicological review

Collate

Experimental

Results

Development of

Leachables

Method

Review

Quantitative

Extraction Profile

Toxicology

Assessment

Review

Safety Concern Threshold

(SCT)

Analytical Evaluation Threshold

(AET)

Page 15: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 16: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 17: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 18: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Potential source of unknowns

• Sample related

• Device related

• Process related

• Contamination

Page 19: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Drug Product

• Active ingredient

• Excipients

• By-products and degradants

• Solvents

• Catalysts

Page 20: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Process Related Impurities

• Foreign particulates

• Carry over

• Lubricants

• Pipework and fittings

Page 21: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

E & L relationship

Extractables

Leachables

Page 22: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

General approach

• LC-MSn

• HR-LC-MS

• Fraction collection

– NMR

– FTIR

– GC-MS

• Inorganics

– ICP-OES / ICP-MS

– SEM

Page 23: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 24: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 25: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Simulated use extraction

• Aqueous based formulations

• Use product as extraction solvent

– GC-MS

– LC-MS

– ICP-OES / ICP-MS

Page 26: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 27: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Product packaging interaction

• Key deliverables

– Potential extractables

– Leachables on storage

• Ambient

• Stressed

• Product specific

Page 28: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 29: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 30: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Case Studies

Page 31: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 32: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 33: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 34: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 35: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 36: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Case study – crystalline material

• Biopharmaceutical production process

• White crystalline material formed in silicone tubing

– Optical microscopy

– FTIR/ Raman spectroscopy

– EDX

– X-ray diffraction

Page 37: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Crystalline material – optical microscopy

Page 38: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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)

Page 39: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Crystalline material - EDX

Page 40: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 41: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 42: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

HPLC-MSn

• Complex analysis

– Multi component natural

product

• But……..

– Data characteristic of well

known (patented) product

– ??????????

Page 43: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 44: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Solution

• More commonly known as ViagraTM

Page 45: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 46: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

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

Page 47: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Drug development services – our locations

Lexington Teddington

Fordham Sandwich

Page 48: Polymer extractable testing for the pharmaceutical industry · Science for a safer world Polymer extractable testing for the pharmaceutical industry Mike Ludlow, Technical Study Manager,

Science

for a safer world

Thank you Mike Ludlow, Technical Study Manager,

CMC Analytical services, LGC