Sciencefor 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

ExtractionProcedure

Characterisation of Inorganics

Characterisation of Organics

Collate Experimental

Results

ExtractionValidation

Development of Leachables

Method

Leachables Validation

Review

SonicationMicrowave

RefluxSoxlet/soxtect

ASE

GC-MSHPLC-MS

ICP-OESICP-MS

AASGFAAS

Quantitative Extraction Profile

Specialised Tests

Supplier dataMSDS

PAHsNitrosamines

Mercaptobenzothiazole etc

Report/Final Submission

Review

GC-FIDGC-Derivatisation

HPLC-UVGC-MS

HS-GC-MSAAS

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

Specialised tests

• Material specific tests such as:

– Nitrosamines

– Polycyclic aromatic hydrocarbons (PAHs)

– Mercaptobenzothiazole

– Silicone oils

– Formaldehyde

Extractable profile

Results

• Qualitative 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

Time-->

Abundance

TIC: PPI_275138_040215_04.D\data.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

Toxicological review

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, MALDI-MS, FTICR-MS

• 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

Leachables testing

• Specific to analytes determined in extractable study

– Possibly multi-technique

• Presence of formulated product

• Require full validation

– Linearity

– LOD/ LOQ

– Accuracy / precision

– Robustness / repeatability etc.

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

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

Minutes0.50 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

3.12

8

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.

528

10.

802

12.

382

13.

448

14.

324

15.

888

17.

757

18.

215

21.

454

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, ScanMax: 75352

184

.2 1

85.1

Case study – quality control

Case study - odour

• Tryptic Soy Broth

• Metal Test Coupon

• HS-GC-MS4.00 5.00 6.00 7.00 8.00 9.00 10.0011.0012.0013.0014.0015.0016.0017.00

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

11.64411.729

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

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700000

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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, dimethyl60 80 100 120 140

0

50

100

50

61

79

94

SS

Case study - discolouration

• Nasal spray

• PE device

• GC-MS4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00

200000

250000

300000

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500000

550000

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Time-->

Abundance

TIC: 08021002.D

3.30

8.58 11.27

14508-1 CONTROL EXTRACT

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

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m/z-->

Abundance

Scan 259 (6.664 min): 08021003.D\data.ms149.0

120.985.0

57.0

105.0 207.0165.0 190.9 257.3236.9

(mainlib) 5-Chloro-2-methyl-3(2H)-isothiazolone20 30 40 50 60 70 80 90 100 110 120 130 140 150 160

0

50

100

27

30

36

42

45

53

57

61

68 71 74

76

79

85

87

8992

9499 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 crystals

35

40

45

50

55

60

65

70

75

80

85

90

95

100

105

%Tr

ansm

ittan

ce

500 1000 1500 2000 2000 3000 4000 Wavenumbers (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 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, MALDI-MS, FTICR-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

LexingtonTeddington

FordhamSandwich

Sciencefor a safer world

Thank you

Mike Ludlow, Technical Study Manager, CMC Analytical services, LGC