Analysis of Extractables & Leachables in Pharmaceutical ... · Analysis of Extractables & Leachables in Pharmaceutical Products Dr. Andreas Tei Global Pharma Segment Manager Agilent

Analysis of Extractables & Leachables

in Pharmaceutical Products

Dr. Andreas Tei

Global Pharma Segment Manager

Agilent Technologies

Regulatory & Analytical Aspects

Topics

• Introduction

• Defining extractables and leachables

• Why worry about ?

• PQRI Guidelines

• Effects on biologic drug products

• The four essential steps of a study

• Application Example: analysis of volatile E&Ls by GC-MS

• Application Example: analysis of non volatile E&Ls by LC-MS

• Appendix

• References

Compliance Road Show E/L 2015

2

IntroductionDrug Containers And Modern Drug Delivery Systems

Drug containers and modern drug delivery systems meant to protect a

drug from environmental contamination but they are actually themselves a

source of contamination


3

U.S. FDA 21 CFR 211.94(a) statement (current as of April 2015)


4

U.S. FDA 21 CFR 211.94(a) statement (current as of April 2015)

“(a) Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter

the safety, identity, strength, quality, or purity of the drug beyond the official or established

requirements.

�(d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning,

sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug

product containers and closures.”

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.94

Plastic Materials: Source of Contamination


5

Sources of extractables are plastic and elastomeric components

(monomers, polymeric initiators, plasticizers, etc.) ink and adhesives

(label) and degradation products (processing, storage, sterilization)

Cindy Zweiben, Pfizer, Inc., Characterization of Extractables and Leachable in Parenteral Drug Products


6

Vulcanizing Agents

Antioxidants

Azo Dyes

Phthalates

Lubricants, Slip

Agents, Fatty Acids and EstersNitrosamines

Silicone

Oils

Toxic

Elements (Hg,

Cd, Pb, As, Cr,

W, Tl, Os, Ba)

PAHs

Monomers,

Dimers,

Oligomers

Wide variety of Chemical Classes, Polarity, Molecular Weights Impacts which separation method to use,

Column and Ionization Method, GC, LC or ?

Harmful Compounds Identified as Extractable/Leachable

Analytical Challenges


Objective: To detect a wide class of known and unknown organic/inorganic compounds that

maybe present in container closure systems at levels links to risk assessment threshold levels

Mass H

unte

r Data

Analy

sis

Mass H

unte

r Data

Analy

sis

Sam

ple

Separa

tion

Toxic elements/ Heavy metals

Non-volatile residues

Volatile Residues

7

Agilent delivers the most comprehensive analytical solutions portfolio

Defining Extractables, Leachables, Migrants

ExtractableChemical compounds that can be extracted out of

packaging component

• Analyze packaging component at

• High-temperatures: to obtain the worst case

leachable profile

• Solvent extraction: polar and non-polar

solvent to mimic similar properties as drug

product

Leachable• Chemical compounds from packaging component

that leach into the drug product

• Analyze drug product at

• Normal conditions

• Simulate extended storage conditions

Migrants• Crossed the primary packaging material barrier

from secondary and tertiary packaging,

accumulating in the drug product

Potential

Compound

Migration

Actual

Compound

Migration

Leachables

(Drug)

Extractables

(Packaging)


8

Extractables

Leachables are

often a subset of

extractables

Leachables/

Migrants Leachables

Extractables

New Leachables may be

identified

which have been not

observed as extractables

2014: FDA Drug Recalls Surges over 836 in 2014!

2014: FDA data shows the last two years have seen almost as many recalls

(2,061) as the previous nine years combined (2,217)—and that's only counting the

first seven months of 2014. Ref: raps.org August 2014

August 2015: FDA warns against use of Becton-Dickinson (BD) 3 ml and 5 ml

Syringes: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm458955.htm

Why Worry about Extractables/Leachables ?

https://assets.digital.cabinet-office.gov.uk/media/55191d6fe5274a142e000069/EL__15_A_02.pdf


USP Chapters dealing with E&L

Ref: Denise R. Jenke, Daniel L. Norwood, and Desmond G Hunt

10

Guidelines Delivered By Pharma Industry Expert Working Groups

PQRI (Product Quality Research

Institute) is a working group

established to developed regulatory

guidance for Extractable/Leachable

analysis, which is also recognized by

the FDA


11


PQRI issued guidance for OINDP:“Safety thresholds and best practices for extractables and leachables in orally inhaled and nasal drug products

(OINDP) also Applicable to parenteral and injectable products (PODP)

PQRI established safety thresholds for leachables:

• Safety Concern Threshold (SCT) ≤ 0.15 µg/day patient exposure which species represent no risk

• Qualification Threshold (QT) ≤ 5 µg/day patient exposure which a leachable is not considered for safety

qualification. Lower threshold applies to PAH’s, nitrosamines, and 2-mercaptobenzothiazole

• Estimated Analytical Evaluation Threshold (AET) (µg/g) = (SCT x total labeled doses) / (Doses per day x

mass of component)

“Best practices” include controlled extraction studies and leachables studies.

12

PQRI guidance for OINDP(Orally inhaled and nasal drug products)

Inorganic Impurities


13

New USP general chapters <232> and <233> for elemental impurities

USP<232> defines the analyte limits, while USP<233> defines sample preparation

options including closed vessel microwave digestion, and recommends the use of

modern instrumentation, such as multi-element ICP-MS and ICP-OES techniques.

Analytical equipment qualification under USP<233> is based on performance testing,

and includes requirements to demonstrate accuracy, repeatability, and the unequivocal

identification of analytes.

• Reagents, Ligands, Catalysts

• Manufacturing Aids

• Inks and Dyes

Analytical Requirements for Inorganic Impurities

Page 14Compliance Road Show E/L 2015

All elements can be determined at sub-ppt DLs using 7900 ICP-MS (mostly 3 or 4

orders lower than ICP-OES).

Element

Conc Limits (µg/g)

for Oral Drug with

Max Daily Dose of

≤10g/day

Conc Limits (µg/g)

for Parenteral with

Max Daily Dose of

≤10g/day

Conc Limits (µg/g)

for Inhalation with

Max Daily Dose of

≤10g/day

ICP-MS ICP - OES

Cd 2.5 0.25 0.15 0.0001 0.1

Pb 0.5 0.5 0.5 0.0002 2

As 0.15 0.15 0.15 0.0005 1

Hg 1.5 0.15 0.15 0.0005 1.5

Ir 10 1 0.15 0.0001 2

Os 10 1 0.15 0.0005 5

Pd 10 1 0.15 0.0001 4

Pt 10 1 0.15 0.0001 2.5

Rh 10 1 0.15 0.0001 1

Ru 10 1 0.15 0.0001 2

Cr NA NA 2.5 0.001 0.2

Mo 10 1 1 0.0002 0.2

Ni 50 5 0.15 0.002 1

V 10 1 3 0.00002 0.2

Cu 100 10 10 0.0005 0.1

14

Special Concerns About E&L Effects on Biologics

E&L compound

as Impurity

Even contaminations at trace levels with reactive E&L impurities can be deleterious

for protein based drugs and will cause severe harm for the patient‘s health

(immunogenic reaction)

Contact materials are: plastics/elastomers, glass and stainless steel surfaces

Sources of E&Ls as contaminants in biological drugs

� Plastics / Elastomers� Crosslinking agents, volatile organic E&Ls

� Glass surfaces� Al 3+; Fe 3+/2+; Ca 2+; Ba 2+; Mn 2+; Zn 2+

� Stainless steel surfaces

� W 6+/4+; Fe 3+/2+; Cr 3+/2+; Ni 2+

� Sterile filtration processes are often a source of contamination

� Sterilization processes (steam autoclaving / gamma radiation) of drugcontainers will affect the concentration of leachables within the drugproduct

� Complexing agents (EDTA) facilitate migration of metal ions


16

E&Ls may affect protein drug products by:

• Aggregation

• Increase in particulates*

• Oxidation

• Unfolding

• Formation of clipped variants

• Formation of Protein Adducts

• Post translational events during fermentation (glycosylation)

• Altered protein translation

* See also new USP monograph <787> PARTICULATE MATTER IN

THERAPEUTIC INJECTIONS


17

Ref: Ingrid Markovic, CBER Presentation USP/PQRI E/L Workshop April 2014https://www.usp.org/sites/default/files/usp_pdf/EN/meetings/09_markovich_presentation.pdf

Critical Quality Attributes & Testing Methods for mAbs

Pyro-

Glutamate

Deamidation

/Oxidation

Fragmentation

(Hinge)

Glycosylation

(G0, G1, G2)

Truncation

(Lys 0, 1, 2)

Disulfide

Shuffling

Aggregation

HILIC

IEC

IEC

IEC

RP

SEC

RP

Aggregate Analysis of

Monoclonal Antibody

Key Principles of an E&L Study

Evaluating The Interactions Between Packaging Material AndThe Pharmaceutical Formulation And The Resulting Risks

Extractable Study: Applying Different Extraction ProceduresAnd Different Analytical Technologies

Toxicological Assessment: Defining Threshold Levels For The Extracted Compounds


19

Leachable Study: Detection, Identification and Quantitation Of

Leachables Within The Formulation

1

2

3

4

Step 1: Evaluating Interactions And Risks


20

Likelihood of interaction between packaging component and dosage form

Degree of concern

associated with

Route of Administration

High Medium Low

HighestInhalation aerosols and solution

Injections and injectable suspensions

Sterile powders

Injection powders

Inhalation powders

High

Ophthalmic solutions and suspensions

Transdermal ointments and patches

Nasal aerosols and sprays

Low

Topical solutions and suspensions

Topical and lingual aerosols

Oral solutions and suspensions

Topical powders

Oral powders

Oral tablets

Oral hard capsules

Oral soft gelatin capsules

Adapted from Guidance for Industry; Container Closure Systems for Packaging Human Drug and Biologics, US Department of Health and

Human Services, Food and Drug Administration, Rockville, MD, May 1999

• What contributes to the high-risk in pharmaceutical packaging?

• Prefilled syringe containing an injectable drug suspension

• Interacts with multiple components in the packaging material

(plastic barrel, rubber plunger, metal needle) with direct delivery

to the bloodstream

Step 2: Extractable Study & Extraction Procedures Parenteral and Ophthalmic Drug Products (PODP)


21

Thermal N-Hexane Isopropanol Isopropanol/

Water

Aqueous

pH 2.5

Aqueous

pH 9.5

Headspace X --- --- --- --- ---

Reflux --- X X PC/PVC only --- ---

Soxhlet --- X X --- --- ---

Sealed Vessel --- --- --- 55°C for 3d 121°C for 1hr 121°C for 1hr

Sonication --- --- --- --- X X

Autoclave conditions: (121°C for 1hr)

Temp

Solvent Polarity/Drug Product Similarity

Solvents should cover a wide range of polarity

Solvents should mimic drug product formulation

Vigorous conditions

No sample dissolving solvents

No material deformation

Hot extraction techniques

PQRI: Threshold and Best Practices for Parenteral and Ophthalmic Drug Product (PODP)

Known

Additives

Sonication

pH 2.5

Sonication

pH 9.5

Sealed Vessel

IPA/Water

Irganox 1010 --- --- X

BHT --- --- X

Erucamide X X X

Detection of additives in LDPE (Example)

Sonication successfully detects erucamide,

but no other anticipated additives

Solvents with different polarity provide better

understanding of the material

Step 2 Extractable Study: Threshold Levels and Actions


22

Ref: ITFG/IPAC-RS Collaboration Response to FDA MDI Guidance on 2001

Step 3: Toxicological Assessment & Thresholds(PQRI guidelines for OINDP)

� Based on Toxicological Thresholds of Concern (TTC) levels from to Kroes et al. (2004)

http://foodcontactmaterials.com/links/ttc.pdf

� Safety Concern Threshold: (SCT) 0.15 �g per day, which is defined as the threshold below which an

individual leachable would have a dose so low as to present negligible safety concerns from carcinogenic

and non-carcinogenic toxic effects.

� Qualification Threshold: (QT) 5 ug per day: Threshold below which a given leachable is not considered

for safety qualification (toxicological assessments) unless the leachable presents structure-activity

relationship (SAR) concerns.

� Analytical Evaluation Threshold: (AET) is determined by

consideration of the SCT and the specific drug product

delivery configuration (number of doses in a Drug Product vs

single dose)


23

D. Norwood, L.M. Nagao, C.L.M.Stults; J. Pharma Sci and Tech., (2013) 67(5), 413-429

AET: How much sensitivity is required ?


24

• Safety Concern Threshold (SCT) for a plasticizer = 0.15µg /d

• Weight ophtalmic solution container = 1 g

• Applied Dose = 3 containers/day

• Content = 3 mL/container

� 0.05 µg from a plasticizer have been extracted from each container

AET =�.��/��

�� /�� = 0.05 µg/g container material

� Analytical requirements to detect leachables within the formulation

Leachables: AET =�.��/��

�� /��1

��

��= 0.05μg/container

AET =�.��/��

��/�� = 0.017μ�/��

Calibration range for semi-quantitative compound determination


Page 25

Quantitation of DEHP C24H38O4

1 pg/µL to 50 ng/µL by Jet Stream ESI

UV Detection of BHT at 220 nm

Limit around 50 ppb

Step #4 Leachables Study:


26

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf

Threshold levels for leachables in drug products• Reported above 1 ppm (corresponding to 1µg /mL sample solution)

• Identified tentatively above 10 ppm

• Structure confirmation at 20 ppm

• Detection of leachables within the formulation

• Sample preparation for the formulation is required

Example: Results from semi-quantification process of leachables found in an ophthalmic solution

Compliance Road Show E/L May 2015

27

Leachables ppm ±30%

Sansocizer DINP 1.41 ±0.43

N-DOP 2.48 ± 0.74

Phthalic anhydride 0.14 ± 0.04

Methyl-2-benzoylbenzoate 0.11 ± 0.03

Irgacure 907 0.02 ± 0.005

Hexyl Amine 0.04 ± 0.01

Ionox 100 0.03 ± 0.01

Erucamide 1.68 ± 0.50

Glycerol dilaurate 0.08 ± 0.02

1,2-Benzenedicarboxylic acid, 1,2-bis(8-methylnonyl)ester 0.16 ± 0.05

Myristyl dimethylamine oxide 0.0009 ± 0.0003

Acetic acid, propyl ester 0.10 ± 0.03

Compounds found at concentration levels above 10 ppm should be re-quantified

after their identification by using a proper calibration standard

Reporting level >1 ppm

Summary

• Contamination of drug products by chemical compounds leaching from

the containment or by migrants (inks, labels or due an improper storage)

can cause product recalls

• Different regulatory agencies and workgroups providing guidance

documents

• The limits of detection and quantitation are often below 1 ppm and are

similar to environmetal or food safety threshold limits

• Due to the different physico-chemical properties of the compounds,

difficult matrices and often poor analytical responses multiple

hyphenated analytical techniques like Headspace GC-MS, GC-MS, LC-

MS and ICP-MS are required to obtain confident results

• Special concerns for biological drug products are required as the drug

might be affected from concentrations of E&Ls below the SCT. The drug

product might degradate and aggregate.


28


29

Summary: Analytical Technologies for the Analysis of E&Ls

CE: Capillary electrophoresis

GFC: Gel-filtration chromatography

SEC: Size-exclusion chromatography

IC: Ion chromatography (Metal Ions)

Polarity

Mole

cula

r W

eig

ht

HPLC

GC

SEC

CE

GFC

IC

Potential Analytical Techniques Depending

on Polarity and Molecular Weight

SFC

Analytical

Technology

Analytes

Headspace

GC/MS

Volatile compounds

(solvents, glues, adhesives)

GC/MS Semi-Volatiles

(plasticizers, PAHs, slip agents, lubricants)

LC-UV-MS Non-volatiles

(antioxidants, oligomers)

ICP-MS

ICP-OES

Metal Ions

Ion Mobility Mass

Spectrometry

Oligomers & Polymers

Orthogonal Chromatography

(SFC; 2DLC)

Non-Volatile or semi-volatile compounds in

difficult matrices, challenging to detect due

to polarity & resolution and ion suppression

issues,

Additional for biomolecules as

QC:

Size Exclusion

Chromatography (SEC) &

Light scattering detection

Ion Exchange

Chromatography (IEC)

Aggregation and charge variants as

important quality attributes for

biopharmaceutical products


30

Analysis of Volatile & Semi-Volatile E&Ls by GC-MS

7697A Headspace Sampler

5977B with 7890B GC

7200 Q-TOF

Topics


31

� Routine Investigations of Pharmaceuticals by GC-MS

• DEHP a major concern

• Investigation of IV bags and other pharmaceutical products

• Results

• Summary

� Differential Analysis for E&L screening processes with HR-GC-MS

• Workflow Schematics

• Data Acquisition

• Differential Analysis

• Compound Identification

• Semi-Quantitation

Routine Investigations of pharmaceutical products by

� Headspace-GC-MS

� MMI – GC-MS (Multi Mode Injection)

The following products have been investigated

• Intravenous (IV) Bag Set & PVC Tubings

• Transdermal Patch

• Liquid Drug Product


32

Please read the full story……


5991-5616EN 5991-5605EN 5991-5632EN

33

5991-6142EN


34

Headspace – GC-MSSystem & Methods

� Headspace GC/MS

o System: 7697A Headspace Sampler and a 7890A GC & 5977A MSD

o MSD: EI mode, Scan 15-700 amu, atune.u

o Liner: 0.75-mm ultra-inert, straight tapered (p/n 5190-4048)

o Column: Agilent HP-5ms UI, 30m x 0.25mm, 0.5µm (p/n 190915-133UI)

� Experimental Method

o Packaging materials were cut into 1.0-cm2 pieces, placed into 10-mL

headspace vial and purged with N2 before analysis

o Equilibration temperatures investigated

o Plastics: 85, 100, 150, 200, 250 and 275 °C.

o Full evaporation: 85 and 100 °C

o Oven temp program: 35°C ( 3min) – 350°C (3min) / T Grad 5°C min-1

� Software

o MassHunter B.07.01

o NIST Library 14 Version 2.2g


35

MMI– GC-MSSystem & Methods� Multimode Inlet (MMI) GC/MS

o System: 7693A ALS and a 7890A GC coupled with a 5977A MSD.

Equipped with a Multimode Inlet (MMI) operated in solvent vent mode

o MSD: EI mode, Scan 29-700 amu, atune.u

o Liner: 4mm ID ultra inert (p/n 5190-3162)

o Column: Agilent HP-5ms UI, 30m x 0.25mm, 0.25µm (p/n 190915-433UI)

� Experimental Method

o Packaging material or liquid drug product were extracted with solvents by

sonication for 5-8 hours.

o Solvent utilized: dichloromethane (DCM), hexane, ethanol, acetone

Organic extracts were transferred to a glass vial with insert

o MMI Temp program: -5 (0.7min) – 325°C (5 min) / T grad 600°C min -1

o Oven temp program: 50°C (3min) – 340°C (5min) / T grad 6°C min -1

� Software

o MassHunter B.07.01

o NIST Library 14 Version 2.2g

A major concern: DEHP– Plasticizer in PVC plastics

What is DEHP?

• A chemical additive that provides flexibility to PVC

plastics

• PVC-based medical devices contain average of 20-

40% DEHP

High Risk population

• Critically ill male neonates

• Pregnant and lactating women

• Pediatric patients

• Adolescent boys

Patients/Animal Exposure to DEHP

• In NICU setting, neonates are exposed to DEHP from

IV bags

• Lab animals exhibit toxic response to DEHP in male

reproductive system, liver, kidney

• Patients receiving certain drugs that exacerbate

DEHP leaching

Major sources of DEHP leaching• IV solution bags

• IV tubing

Factors that affect the rate of leaching• Storage time

• Temperature

• Excipients

February 4, 2016

Confidentiality Label

36

DEHP Synonyms

di(2-ethylhexyl)phthalate (DEHP)

bis(2-ethylhexyl)phthalate (BEHP)

di-sec octyl phthalate (DOP)

octyl phthalate

Results: Headspace analysis IV tubing at 250 °C

tolu

ene

(sol

vent

)

Kod

afle

xT

XIB

(pl

astic

izer

)b

enzo

ph

eno

ne

(UV

sta

bili

zer)

palm

itic

acid

(pl

astic

izer

)

stea

ric a

cid

(pla

stic

izer

)

DE

HP

(p

lasi

tici

zer)

bis(

2-et

hylh

exyl

)is

opht

halic

acid

(pl

astic

izer

)

benz

ene

(sol

vent

)

5991-5616ENKodaflex TXIB: 2,2,4-Trimethylpentanediol-1,3-diisobutyrate

DEHP has been identified


38

Hexadecane (1)

Butylated Hydroxytoluene (BHT) (2) –antioxidant

Kodaflex TXIB (3) –plasticizer

Benzophenone (4) – UV stabilizer

Isobutyl nonyl phthalate (5)

7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione (6)

2-Mercaptobenzothiazole (7) - Rubber

Palmitic acid (8) – plasticizer

Isopropyl palmitate (9)

Palmitic acid, butyl ester (10)

2-Ethylhexyl trans-4-methoxycinnamate (11)

Benzyl butyl phthalate (12)

DEHA (13) –plasticizer

di(oct-3-yl) phthalate (14)

DEHP (15) –plasticizer

Irgafos 168 (16) –antioxidant

Tris(2,4-di-tert-butylphenyl) phosphate (17)

SIM analysis of DCM extracts from IV Bag and dextrose solution

to confirm the identification and possible DEHA and DEHP

migration

5991-5616EN

--IV Bag

--Dextrose Solution

1

2

3

4

5

17

6

78 9

10 11

12

1314

1516TIC of Dextrose IV bag

Results: MMI – GC-MS analysis

Compounds of interestwere palmitic acid and stearic acid

Top match was butyl ester palmitic acid and 2-methylpropyl ester stearic acid

SIM analysis for ions characteristics of palmitic acid and stearic acid

Require GC/QTOF for confirmation

SIM Analysis & Identification of Leachables

Summary: E&L s From Plastic Intravenous Bag SetsBackground

• PVC bags are a source of DEHP which can leach into liquid drug product

• DEHP extracts faster in non-polar solvents (fats and oils)

• DEHP can be extracted when liquid is warmed or agitated

• Cyclosporin contains a large amount of non-ionic surfactant, Kolliphor EL

(polyoxyethylated castor oil) that can strip DEHP from PVC bags

Summary

Extractables identified using HS GC/MS

DEHP, benzophenone, acetophenone, palmitic acid, stearic acid, residual

solvents, and other plasticizers were identified in expired IV tubing. DEHP,

BHT (antioxidant), benzothiazole (rubber), acetophenone (ink, coating,

adhesives), residual solvents, and other plasticizers were characterized in

expired IV bag. Phthalates (diethyl phthalate, dibutyl phthalate, etc), BHT,

acetophenone, and Metilox (plasticizer) were identified in heated IV bag.

Extractables identified using MMI (Multi-Mode-Inlet) GC/MS

DEHP, BHT, benzophenone, phthalates, 2-mercaptobenzothiazole (special

case compound), fatty acids, fatty acid esters, DEHA (Diethylhexyladipat),

Irgafos 168 were identified in expired IV bag. BHT, Metilox, phthalates, and

residual solvents were identified in heated IV bag.

Compound migration identified using MMI GC/MS

DEHA and DEHP migration was observed in expired IV bags using Scan and

SIM analysis. Phthalates and DEHA migration were observed in heated and

surfactant containing IV bags


40

IV tubing

IV bag

IV solution

Samples Investigated

Expired IV tubing (3 years)

Expired 150-mL dextrose IV bag (8 years)

Heated 1-L NaCl IV bag (58d at 100°F)

Kolliphor + heated NaCl IV bag

Method

Headspace temperatures: 85-275°C

DCM and hexane solvent extraction

Application Note 5991-5632EN

Overall Summary

• IV bag system

- Phthalates migrated (DEHP, phthalates) due to extended storage, extended heating, and

infusion solution modeled in hospitals using MMI and SIM analysis

- Plasticizers were identified using headspace sampling and MMI in IV tubing and IV bags

• Lidocaine patch

- Pharmaceutical ingredients produce distorted or broad peaks due to concentration

- Different extractables (phthalate plasticizers) were identified in different solvent

extractions. MMI allows for large volume liquid injection, which aids in the identification of

extractables/leachables present in low levels.

• Liquid drug formulation

- Identified leachable compounds of interest by the generic pharmaceutical company using

MMI GC/MS (palmitic acid, stearic acid, and hexadecane)

- Require GC/QTOF for identification of leachables with similar fragmentation pattern (such

as DEHP and DPPP)

- Method can be applicable for investigating liquid drug formulation stored in plastic

containers at different risk categories


41

Agilent Application NoteComing soon…..


42

The Use of Differential Analysis for Screening E&Ls in

Pharmaceuticals Using an Agilent 7200A GC/Q-TOF System

1

10

100

1000

0.1 0.05 0.01 0.005 0.001 0.0005 0.0001

Mass Accuracy (amu)

176

386

882

1347

1672

5687

Po

ss

ible

formulas

Why TOF Technology? The Relationship of Mass Accuracy to theNumber of Possible Molecular Formulas by Mass


43

TOF – Mass accuracy

Acquisition

Library search

Compare data

Confirmation/ Expansion

Semi-quantification

Analytical Workflow

Agilent 7200A GC/QTOF System

Agilent Unknowns Analysis Software

44

Agilent Mass Profiler Professional

Software

MassHunter

Quantitative

Analysis software

• Accurate Mass Chemical

Ionization Acquisition

• PCDL


Acquisition Time (min)5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00

Control

Counts 8x10

0

0.25

0.5

0.75

1

1.25

1.5


Leachable

Counts 8x10

0

0.25

0.5

0.75

1

1.25


Extractable

Counts 8x10

0

0.25

0.5

0.75

1

1.25

TIC chromatograms in EI mode

Unheated Formulation

Leachable Sample

Heated Formulation

Leachable Sample

Container Extract

Extractable Sample


45

Library search using Unknown Analysis SoftwareExtractable, Benzene, 1,3-bis(1,1-dimethylethyl)- confirmed by EI NIST 14.0

Acquisition Time (min)13.00 14.00 15.00 16.00 17.00 18.00

Counts 6x10

0

1

2

3

4

5

6

15.1579

18.3937

16.5296

16.8674

13.8428

12.8268

14.9095

14.1962

19.0002

17.9956

Component RT: 15.1579

Mass-to-Charge (m/z)

0 25 50 75 100 125 150 175 200 225 250

Counts 1x10

-3

-2

-1

0

1

2

3

4

175.0

175.1485

57.0

57.0703

91.0

91.0542

147.0

147.0659

A: TIC

B: Ion Peaks

C(A): Experimental

spectra

C(B):

Library

spectra


Acquisition Time (min)

15.15 15.2 15.25

Counts 6x10

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

TIC

Component

175.1485

57.0703

190.1718

175.9785

91.0542

Di-Isobutylbenzene is potentially used for polymeric packaging

46


Comparing Data to Find Common CompoundsMass Profiler Professional Software

• Traditional blank subtraction could delete an extractable compound by

mistake as it might be also present in the solvent, but in lower concentration

• A fold change analysis between the extractable and a blank sample helps to

increase the confidence in results

47


Results: Common Compounds Found in E & L Samples

48

Retention Time Extractable and leachable compounds Fold Change in extractable

8.75 Octane, 3,5-dimethyl UP

15.16 Benzene, 1,3-bis(1,1-dimethylethyl)- UP

15.75 Dodecane, 4,6-dimethyl UP

16.19 Tridecane UP

16.20 Nonadecane UP

16.87 Cyclohexasiloxane, dodecamethyl- UP

19.92 Sulfurous acid, pentyl undecyl ester UP

20.53 Cycloheptasiloxane, tetradecamethyl- UP

• Benzene, 1,3-bis(1,1-dimethylethyl),

and other compounds were also

found in the non-heated leachable

sample. The origin of these

compounds are most likely from the

container closure system.

Extractable

129 compounds

Leachables

in Heated

Formulation

Total 31

compounds


Eliminating Ambiguity


Mass-to-Charge (m/z)

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280

Counts 2x10

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

149.0

149.1314

177.0

177.1640

105.076.0

105.070465.0389

50.0 222.0194.015.0

Experimental

spectra

Library

spectra

NIST Library match of diethyl phthalate

Many other compounds also can give

the same spectra with matching factor

>80


49

Extractables Mass Formula PPM

.alpha.-Cubebene 204.188 C15 H24 3.52

1,2-Benzenedicarboxylic acid, bis(2-methylpropyl) ester 278.152 C16 H22 O4 4.18

1-Decanol, 2-hexyl- 242.261 C16 H34 O 3.67

2-Methyltetracosane 352.407 C25 H52 -0.6

9H-Fluorene, 9-methylene- 178.078 C14 H10 4.8

Benzene, (1-butylheptyl)- 232.219 C17 H28 3.59

Benzene, (1-butylhexyl)- 218.203 C16 H26 0.07

Benzene, (1-butyloctyl)- 246.235 C18 H30 4.56

Benzene, 1,2,4-trimethyl- 120.094 C9 H12 3.53

Benzene, 1,3-bis(1,1-dimethylethyl)- 190.172 C14 H22 1.44

Benzene, 1,3-dimethyl- 106.078 C8 H10 0.09

Benzene, 1-ethyl-3,5-dimethyl- 134.11 C10 H14 3.55

Benzophenone 182.073 C13 H10 O 3.71

Cyclopentasiloxane, decamethyl- 370.094 C10 H30 O5 Si5 2.85

Diethyl Phthalate 222.089 C12 H14 O4 0.82

Dodecane, 4,6-dimethyl-A 198.235 C14 H30 4.14

Hexadecanal, 2-methyl- 254.261 C17 H34 O 6.11

Naphthalene, 1,6,7-trimethyl- 170.11 C13 H14 5.91

Naphthalene, 2-methyl- 142.078 C11 H10 2.03

(E)-Hex-3-enyl (E)-2-methylbut-2-enoate 182.131 C11 H18 O2 4.99

Compound Confirmation by Chemical Ionization (CI)

3x10

0

0.5

1

1.5

2

2.5

3

3.5

Counts vs. Mass-to-Charge (m/z)140 160 180 200 220 240 260 280 300

Diethyl Phthalate (RT 22.4 min)


50

O

O

O

O

CH3

CH3

3x10

0

0.5

1

1.5

2

2.5

3

3.5

Counts vs. Mass-to-Charge (m/z)140 160 180 200 220 240 260 280 300

Compound confirmation by Collision Induced Dissociation Fragments & accurate mass for unambiguous compound confirmation


51

(C12H14O4)+H)+

Diethyl phthalate CI MS

CI MS/MS spectra can be stored in PCDL software to

built a custom library.

CI MS/MS

O

O+

O

H

(C8H4O3)+H)+

m/z 223.0937

m/z 149.0239

O

OH

OH

O

m/z 167.0278

(C8H6O4)+H)+

Creation of libraries from CI-MS/MS data

Database creation

Library creation

Adding the spectra

Creation of targeted libraries from EI data

2

34

1

EI results (extractable)

Library Editor

53

Semi-quantitative Determination of Impurities

Diethyl phthalate calibration curve from

10 ppb to 1000 ppb

54

Relative Concentration

-50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 10001050

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

y = 0.002667 * x + 0.001951R^2 = 0.99692334

Type:Linear, Origin:Ignore, Weight:None

Re

lative

Re

sp

on

se

s

• Quantification threshold: 5 ug/day

• Structure confirmed tentatively : 1ppm

• Structure elucidation: 20 ppm

• Semi quantitation: 0.1 ppm to 100 ppm

Retention

Time Leachables heated sample

Semi-quantitation

estimation (ppb)

±30%

6.03 Cyclotrisiloxane, hexamethyl- 88

9.06 Nonane, 2,6-dimethyl- 96

9.12

Sulfurous acid, 2-ethyl hexyl undecyl

ester 200

11.42 Octane 5 ethyl 2 methyl 83

13.85 Dodecane 123

15.17 Benzene, 1,3-bis(1,1-dimethylethyl)- 383

16.54 3-Eicosene, (E)- 128

16.79 Tetradecane 58

16.87 Cyclohexasiloxane, dodecamethyl- 127

18.40 Heptadecane, 2,6,10,15-tetramethyl 177

19.31 Dodecane, 2,6,10-trimethyl 44

19.92 Sulfurous acid, pentyl undecyl ester 80

20.75 Phenol, 2,5-bis(1,1-dimethylethyl)- 177

20.98 1-Decanol, 2-hexyl 87

23.89 Heptadecane, 2,6,10,15-tetramethyl 66

• The concentration of Benzene, 1,3-bis(1,1-dimethylethyl)- is ~ 0.4 ppm.

Based on the daily dosage the consumption (of 9 mL solution/d) is below the

quantitation threshold of 5 µg/day.


Analysis of Non-Volatile E&Ls by LC-MS

Detection and Identification of non volatile E&Ls in an ophthalmic solution by

LC-QTOF-MS and MassHunter MassProfiler data mining software


55

1290 Infinity II UHPLC+ 6500 Series

QTOF System

Topics


56

� General aspects how to anaylze E&Ls by LC-QTOF-MS

• The power of exact mass determination

• Why chromatography matters

• Why ionization and detection matters

• Why intelligent data mining software matters

• Developing a method for an ophthalmic drug product

• Differential analysis of samples

• Semi-quantitation of identified compounds

The non-targeted analysis approach of E&Ls


Objective: To detect a wide class of known and unknown organic/inorganic compounds that

maybe present in container closure systems at levels links to risk assessment threshold levels M

ass H

unte

r Data

Analy

sis

Mass H

unte

r Data

Analy

sis

Sam

ple

Separa

tion

Toxic elements/ Heavy metals

Non-volatile residues

Volatile Residues

57

Major Compound C24H24O10

0.19 ppm Error


58

The power of exact mass determination

Isotope Pattern MatchingConfirm the calculated formula by a second criteria


Red Boxes are Theoretical

Isotope Pattern

59

General Extractable/Leachable LC-QTOF Workflow

60

Mass H

unte

r Data

Analy

sis

Mass H

unte

r Data

Analy

sis

Sam

ple

Separa

tion

Semi-Volatile and

Non-volatile Residues

Extra

ctio

ns

Samples -Standards

-Extracts Drug Containers

-Extracts Drug Product

ChromatographyColumns: C18/C8/C3

Organic Mobile Phase:

ACN, MeOH, ACN/IPA,

MeOH/IPA

Varied Buffers: None,

0.1% Formic Acid, 2mM &

4mM NH4Acetate

Ionization SourcesJet Stream (ESI),

APCI, Multimode

MS-Instrument 6530 / 6545 / 6550


Good Chromatography Matters…Ways to improve separation and reproducibility

Ultra-Clean Mobile Phase Tubing Kit

Ultra-high purity LC mobile phase*

Finger Tight Quick Connects

• Eliminate Dead Volume and Leaks

Column Selection is Critical: C18, C8, C3

Agilent Poroshell 120 Columns (C18, C8)

• Maintain low backpressure, even at high flow rates

• Resists plugging with 2 um frit

• Column Guards extend life

• Better peak shapes at pH 6-8


61

Comparing C3, C8, C18 Separations Using Same BuffersBase Peak Chromatograms

C3

C8

C18


62

C3 Column Optimum for Higher Mass Extractables

Achieving Orthogonality by using multiple chemistries

Why ionization matters……Comparing Ionization: APCI, ESI and Jet Stream ESI

Jet Stream

MM: APCI

APCI

APCI

Jet Stream

MM: APCI

MM: MixedMM: Mixed

MM: Mixed

AJS

MM: APCI

APCI

Ionic species poorer

Ionization with APCI

Irgafos 168

Phosphate

Irgafos 168


63

Review Additive Analysis LCMS: W. Buchberger and Martin Stftinger; Adv Polym. Sci (2012) 248, 39-68

Agilent App Note from Johannes Kepler University: 5991-5169EN Compared ESI, APCI, APPI 22 additives

Irganox 1093

Irganox 1076

Irganox 1330

Irgacure 369

C38H78SO7

C26H29PO4

Irganox 1035


64

Comparing Ionization: APCI and Jet Stream ESIIrganox and Irgacure Mixture

Red = APCI

Blue = Jet Stream

Comparing ionizationReducing Fragmentation by Jet Stream ESI


Jet Stream

APCI

65

1290 Infinity II Evaporative Light Scattering DetectorIncreasing confidence in compound detection

• Complementary to LC/MS

• Universal detection of low volatile compounds

• No chromophors required

• Sensitivity low ng range

• Subambient evaporation 10oC for enhanced

detection of semi-volatile compounds


66

PEG 106

Parabens

Polysorbate 20

http://www.agilent.com/en-us/products/liquid-chromatography/lc-detectors/1290-infinity-ii-evaporative-light-scattering-detector

Why compound detection matters….


67

MassHunter Software Tools

Why intelligent data mining software matters�.

Data mining is an essential step of the analytical workflow and as important as

a successful chromatographic separation and detection of organic compounds

Developing a Method for an ophthalmic drug productSystem Suitability Test Mix For Method Development


68

A list of common plasticizers has been compiled after literature investigation.

The listed compounds have been selected according to their polarity.

Analytical Challenges: Can I Detect All My Compounds ?Applying Positive & Negative ES Ionization Mode and UV Absorption


69

Negative mode

TCC

Positive mode

TCC

System suitability mix (at 50 ppb level)

Ophthalmic bottle extract

Overlay of positive & negative TIC

Data acquisition in MS/MS mode

UV absorption ESI pos; TIC & EIC ESI neg; TIC & EIC

MassHunter Mass Profiler Software (Rev. 7.0) Differential analysis between the sample and the solvent blank


70

Mass Profiler Software supports the statistical comparison of data sets.After applying a cut off filter of >3,000 and a >4-fold change (abundance by height) andabundance, 66 compounds (positive and negative ionization modes) have been displayedfor the bottle extract

+4X

+1X

-4X

+2X

-2X

Mass Profiler SW: Database Search & Formula Generation

71

Mass Profiler Software has been used to identify compounds by PCDL comparison

Unknown compounds have been identified by Molecular Structure Correlator Software


Personal Compound Databases (PCDL)

Accurate Mass and MS/MS Library Searchable Databases


Polymer Additive Database contains

over 1850 Compounds Building MS/MS Searchable Library

72

MassHunter Mass Profiler Software (Rev. 7.0) Differential analysis between the E and the L sample


74

Extractable and leachable sample comparison to identify common compounds

and their distribution. A total of 61 compounds were common to both sample types

+4X

-4X

+2X

-2X

1X


75

Extractables identified by database

diethylene glycol dibenzoate

tridecyl alcohol

sodium ricinoleate

irganox 5057

ethyl(2,4,6-trimethylbenzoyl)-phenylphosphinate

isocyano cyclohexane

degradant of irganox

hexadecanoic palmitic acid

Dioctyl Adipate

Methyl-2-benzoylbenzoate

Irgacure 907

Erucamide

Diisononyl phthalate

Dioctyl phthalate

Phthalic anhydride

Hexyl Amine

Ionox 100

Glycerol dilaurate

Diisodecyl Phthalate

Results: List of identified compounds by PCDL

Leachables identified by database

Diisononyl phthalate

Dioctyl phthalate

Phthalic anhydride

Methyl-2-benzoylbenzoate

Irgacure 907

Hexyl Amine

Ionox 100

Erucamide

Glycerol dilaurate

Diisodecyl Phthalate

Myristyl dimethylamine oxide

Acetic acid, propyl ester

Semi-quantitative compound determination


Page 76

Quantitation of DEHP C24H38O4

1 pg/µL to 50 ng/µL by Jet Stream ESI

UV Detection of BHT at 220 nm

Limit around 50 ppb

Required sensitivity for compound quantification

Results : Semi-Quantification of identified E&Ls


77

Leachables ppm ±30%

Sansocizer DINP 1.41 ±0.43

N-DOP 2.48 ± 0.74

Phthalic anhydride 0.14 ± 0.04

Methyl-2-benzoylbenzoate 0.11 ± 0.03

Irgacure 907 0.02 ± 0.005

Hexyl Amine 0.04 ± 0.01

Ionox 100 0.03 ± 0.01

Erucamide 1.68 ± 0.50

Glycerol dilaurate 0.08 ± 0.02

1,2-Benzenedicarboxylic acid, 1,2-bis(8-methylnonyl)ester 0.16 ± 0.05

Myristyl dimethylamine oxide 0.0009 ± 0.0003

Acetic acid, propyl ester 0.10 ± 0.03

78


Acknowledgements

David Weil Senior Applications Scientist

Syed Salman Lateef Pharma Application Scientist

Diana Wong GC/MS Applications Scientist

Roger Firor Senior GC/MS Applications Scientist

Anthony Macherone Senior GC/MS Applications Scientist

Amir Liba US SPSD AE Manager


79

Appendix

• Posters published in 2015

• References


80

Posters for ASMS 2015 on E/L


81

Posters for ASMS 2015 on E/L


82


83

Poster for AAPS 2015 on E/L

Poster for E&L Conference London November 2014


84

Common Abbreviations

AET = Analytical Evaluation Threshold

SCT = Safety Concern Threshold

TDI = Total Daily Intake

TTC= Threshold of Toxicological Concern

DP = Drug Product

OINDP = Orally Inhaled and Nasal Drug Product

MDI = Metered Dose Inhaler

QT = Qualification Threshold

SAR = Structure-Activity-Relationship


85

References


86

• USP Plastic Packaging General Chapters: An Overview, D. Jenke, D. Norwood, Packaging, Storage, and Distribution Expert Committee, USP,

http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/stim_article_661_final.pdf

• USP <1663> ASSESSMENT OF EXTRACTABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS

http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/m7126.pdf

• USP <1664> ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS

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• Extractables and leachables in pharma – A serious issue, F. Moffat, White Paper,

http://pat.solvias.com/sites/default/files/whitepaper_extractables_and_leachables.pdf

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BioProcess International 5(11):pp36-49 (December 2007),

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BioProcess International 6(1):pp44-53 ( January 2008) ,

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D. Jenke, European Pharmaceutical Review, Volume 18, Issue 1, 2013,

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M.A.J. Rennen et al., Food and Chemical Toxicology 49.(2011) 933-940

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First Edition, D. Ball, D. Norwood, C Stults, L. Nagao, John Wiley& Sons, Inc, Published 2012

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Douglas Ball et al., Toxicological Sciences 97 (2), 226 – 236 (2007)

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https://www.usp.org/sites/default/files/usp_pdf/EN/meetings/09_markovich_presentation.pdf

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PRODUCTS, PQRI, 2006, http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf

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D. Lewis, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf

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http://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Focus_Groups/Protein_Aggregation_and_Biological_Consequences/PABCFG

Wrkshp20114_Singh.pdf

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Pharm Sci and Tech 2015, 69, 590-619, http://www.ncbi.nlm.nih.gov/pubmed/26429108


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88

• Perspectives on the PQRI Extractables and Leachables “ safety thresholds and best practices” recommendations for inhalation drug products,

D. Norwood, L. Nagao, C. Stults, PDA J Pharm Sci and Tech 2013, 67, 413 – 429

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PQRI, 2006, http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf

• Current FDA Perspective on Leachable Impurities in Parenteral and Opthalmic Drug Products, AAPS Workshop on Pharmaceutical Stability, 2011,

D. Lewis, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf

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• Validating the Agilent 7700x/7800 ICP-MS for the determination of elemental impurities in pharmaceutical ingredients according to draft

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References

Documents

Analysis of Extractables & Leachables in Pharmaceutical ... · Analysis of Extractables & Leachables in Pharmaceutical Products Dr. Andreas Tei Global Pharma Segment Manager Agilent