E&L for Drug Delivery Systems: Prefilled Syringe

E&L for Drug Delivery Systems: Prefilled Syringe

John Iannone

Program Manager/ Technical Specialist

1

» Material Qualification Testing

» ISO 10993 – Biocompatibility of a Device

» Basic Extractables Qualification

» What are the GAPs to your E&L needs?

» Reactive Leachables

» A useful tool for mitigating risk

Overview

Material Qualification

Typical USP Compendial Tests

<381> Elastomeric Closures for Injections

<661> Containers – Plastics

<87> Biological Reactivity Tests, In Vitro (Cytotox tests)

<88> Biological Reactivity Testing, In Vivo (Class Tests)

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European Pharmacopoeia:

3.1 Materials used in the manufacture of containers

3.1.1.1 PVC for human blood (components) containers

3.1.1.2 PVC for human blood (components) tubing sets

3.1.3 Polyolefines

3.1.4 PE without additives containers for parenteral/ophthalmic preps

3.1.5 PE with additives containers for parenteral/ophthalmic preps

3.1.6 PP containers for parenteral/ophthalmic preps

3.1.7 EVA for containers and tubing for parenteral/ophthalmic preps

3.1.9 Silicone elastomer for Closures and Tubing

3.1.10&11 non-plasticized PVC

3.1.14 Plasticized PVC

3.1.15 PET


European Pharmacopoeia:

3.2 Containers

3.2.1 GLASS containers for pharmaceutical Use

3.2.2 Plastic Containers/Closures for Pharmaceutical Use

3.2.2.1 Plastic Containers for aq. solutions for parenteral infusion

3.2.3 Sterile plastic containers for human blood (components)

3.2.4 Empty Sterile containers of plasticized PVC for human blood

3.2.5 Sterile containers of plasticized PVC for human blood,

containing anticoagulant

3.2.6 Sets for the transfusion of Blood and Blood components

3.2.8 Sterile single-use plastic syringe

3.2.9 Rubber Closures


Class Testing per USP <88>

» Extraction durations: 1 hr, 24 hrs, 72 hrs, 120 hrs

» Extraction Temperatures: 121⁰C, 70⁰C, 50⁰C, or 37⁰C

» Material Exposure: Cut & Cover

Ratio – 6 cm2/ml or 3 cm2/ml

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NaCl CSO EtOH PEG NaCl CSO EtOH PEG

I X X

II X X X X

III X X X X X X

IV X X X X X X X

V X X X X X X X X

VI X X X X X X X X X

Systemic Toxicity Intracutaneous ReactivityClass Implant

Material Qualification - Examine Class VI

ISO 10993 - Biocompatibility

Contact duration Cyto

toxic

ity

Sen

sit

ivit

y/S

en

sit

izati

on

Irri

tati

on

/In

tracu

tan

eo

us

Reacti

vit

y

Syste

mic

To

xic

ity

(Acu

te)

Pyro

gen

icit

y

Su

b a

cu

te a

nd

/or

Su

b

ch

ron

ic t

oxic

ity

Gen

eti

c

To

xic

ity/G

en

oto

xic

ity

Imp

lan

tati

on

Hem

oco

mp

ati

bil

ity

Ch

ron

ic T

oxic

ity

Carc

ino

gen

icit

y

Rep

rod

ucti

ve/

Develo

pm

en

tal

Bio

deg

rad

ati

on

/

Bio

deg

rad

ab

le

Category Contact

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

less than 24 hours

24 hours to 30 days

more than a 30 days

= Evaluation required by ISO, FDA and MHLW

= Evaluation required by ISO and FDA

=Evaluation required by FDA

=Evaluation required by ISO

Circulating Blood

Initial Evaluation Supplemental

Body Contact

Tissue/Bone/Dentin

Device Categories

Tissue/Bone

Blood

Skin

Mucous/Mucosal

Membrane

Breached/Compromised

Surface

Blood Vessels/Blood Path

Indirect

Body Surface

Contact

Device/Surface

Device

Devices

connecting the

internal to the

external/External

communicating

device

Internally

implanted

devices/Implant

device

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Biocompatibility of Material/Devices

ISO 10993

» Cytotoxicity

» Sensitization

» Intracutaneous Reactivity

» Acute Systemic Toxicity

» Subacute & Subchronic Systemic Toxicity

» Genotoxicity

» Implantation Reactivity

» Hemocompatibility

» Chronic Systemic Toxicity

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Test Article Preparation for Biocompatibility Testing

» Most tests are performed with extractions created from

the finished device

» Extractions ratios are based on standards, regardless of

device type or clinical use - typically 3cm2/ml or 6cm2/ml

» Extractions occur at highest feasible temperature the

Standards provide as options - typically 70⁰C/24 hrs

» Extraction Solvents are Standard

• Polar & non-polar extraction vehicles are required

• Focus is to mimic environments within the body

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Extractability/Leachability

» Polymer type: Tg

» Polymer crystalinity: > amorphous, ↑ migration

» Additive size: ↑ MW, ↓ rate of diffusion

» Polarity: Like dissolves alike

» Processes: Aging, Sterilization, Solvating steps

» Temperature: ↑ temp, ↑ diffusion

» Contacting Product » components of DP formualtion: aqueous, organic, surfactants

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Diffusion

What does this all mean in terms of E&L?

1. Understand what Material qualification provides

2. Identify your specific E&L Needs

3. Determine the GAP & Design E&L program to

reduce risk

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The more we know…

The more we know we don’t know!

Anonymous,

Silver Springs 2014

Extractables/Leachable Testing Strategy

LEACHABLES Profile of a Pre-Filled Syringe

GC/MS Chromatogram of the analysis of the complex drug

solution in a PFS aged for 12 months at 30 ⁰C and 75% RH.

LEACHABLES Profile of a Pre-Filled Syringe

GC/MS Chromatogram of the analysis of the complex drug

solution in a PFS aged for 12 months at 30 °C and 75 % RH.

Same chromatogram as in

previous slide, but blown up.

36 Leachables

Sourcing: where do these

compounds come from?

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EXAMPLE of Potential set-up for an extraction study on the rubber

components of the Pre-Filled Syringe

TARGET COMPOUNDS ANALYTICAL METHOD Plunger Needle shield

WFI IPA Neat IPA Neat

Volatile Organic Compounds (VOC) Headspace- GC/MS - × × × ×

Semi-Volatile Organic Compounds

(SVOC) GC/MS × × - × -

Non-Volatile Organic Compounds

(NVOC) LC/MS (APCI+) × × - - -

Non-Volatile Organic Compounds

(NVOC) LC/MS (APCI-) × × - - -

Sulfur (S8) LC/UV × × - - -

Elements: Al, Ca, Fe, Mg, Si,

S (total), Ti, Zn ICP × - - - -

Anions: Br-, Cl- and F IC × - - - -

Extractable Studies Design

Extractable/Leachable Sources

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Potential

Inorganic

Compounds

of concerns

Metals

If you don’t look for it, you won’t find it!

Typical Extractables Study Design – GENERIC

» Extraction Ratios • Material to Solvent Exposure

• 1 syringe to x ml

» Extraction Solutions • Model Solvents

• Polar, apolar, alcohol, ↑ pH, ↓ pH, surfactants, etc.

» Extraction Temperature • 50⁰C, 70 ⁰C, reflux, etc.

» Extraction Duration • 1 day, 3 days, 1 wk, perhaps 1 mo, or 3 mo.

» Analytical Methods • Screening methods utilizing instruments like GC/MS, LC/MS, etc.

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What are the GAPS for my E&L testing Needs?

» Extraction Ratios • Sensitive enough to evaluate relevant exposure

• 6 cm2/ml as in ISO 10993-12 & USP <88>?

» Extraction Solutions • Consider the environment of concern

• Body Contact (ISO 10993-12: polar & apolar) • Drug product formulation

» Extraction Temperature • Simulated (Leachables) or Aggressive (Extractables) • Body Contact, Storage Conditions?

» Extraction Duration • Exhaustive, Simulated, Accelerated, Asymptotic Behavior

» Selectivity • Some compounds are not detected (must use multiple methods)

» Sensitivity • Some compound conc. too low to cause reaction

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19 CONFIDENTIAL

Cumulative levels of Target compounds X, Y, & Z

20 CONFIDENTIAL

Elution Data for Target Compound X, Y, Z

Threshold

21 CONFIDENTIAL

Biocompatibility for a Drug Delivery System

CONFIDENTIAL

Reactive Leachables

EXTRACTABLES & LEACHABLES TESTING

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Extractables/Leachables

» LEACHABLES are typically a SUBSET of EXTRACTABLES

» NOT ALL LEACHABLES are EXTRACTABLES

Prefilled Glass Syringe

Contents were Aqueous

Stored for 3y at 25°C/60% R.H.

Passed all Biocompatibility and Compendial Tests

» Initial Extractables Study on Plunger (WFI, IPA)

» Leachables (Screening) Analyses after 3 years

» Headspace GC/MS: Volatiles

» DCM extraction + GC/MS: Semi-Volatiles

» DCM extraction + LC/MS (APCI+/-): Non-Volatiles

» 6 different Combinations (Syringe/Plunger/Needle Shield)

were tested.

Unpredicted Leachables – Case Study

CONFIDENTIAL

Chromatogram of Extractable Study in WFI

Conditions:

Reflux 8h, ratio 1g /10 mL

DCM extraction of WFI, concentration step of

DCM, followed by GC/MS analysis for Semi-

Volatiles Analysis

12 COMPOUNDS AT RELATIVELY LOW CONC.

RESULT OF WFI EXTRACTABLE STUDY OF THE PLUNGER

Unpredicted Leachables

CONFIDENTIAL

Chromatogram of Extractable Study in IPA

Conditions:

Reflux 8h, ratio 1g /10 mL

3 COMPOUNDS AT RELATIVELY LOW [CONC]

RESULT OF IPA EXTRACTABLE STUDY OF THE PLUNGER


CONFIDENTIAL

RESULT of the LEACHABLE Screening Study of the PREFILLED SYRINGE

Contents maintained for 3 YEARS AT 25°C – 60% R.H.


CONFIDENTIAL

Observations when comparing the results of the Extractable

Studies on the Rubber Plunger with the Leachable

Screening study on the PFS system

» Concentrations of Leachables were Higher than the

Extractables found with WFI as an Extraction Solvent

» Also for more Aggressive solvents (e.g. IPA), not a

good match between Extractables & Leachables

» Observations were independent of rubber type


CONFIDENTIAL

LEACHABLES: compounds originating from:

1. Rubber Plunger

2. Hydrolyzed Compounds from Rubber Plunger

3. Compounds from Needle Shield

4. Hydrolyzed/Oxidized Compounds from Needle Shield

Concentration range: from 10 µg/L to > 10 mg/L!


CONFIDENTIAL

What is not investigated (sufficiently) in an extractable study?

1 MATERIAL DEGRADATION (ageing)

2 The REACTION (WFI: hydrolysis / O2: oxidation) of the leachables with the

Drug Product (solution)


CONFIDENTIAL

CONFIDENTIAL

Putting the pieces together

“FIRST PASS” Testing for Extractable Studies

Try to Fully Characterize the Extraction Profile of material, using:

Standard Analytical Equipment, e.g. 1. Headspace GC/MS

2. GC/MS

3. LC/MS Orbitrap

4. ICP

5. Ion Chromatography

Optimized Procedures & Procotols

» Leverage Compound Database (TOX-RAY) for First Pass Analytical Techniques

built on expertise & high volume of studies allows high level ID in First Pass

Dedicated Equipment to Standardized Methods

Efficiency/Cost effectiveness is Key in FIRST PASS Experiments

Analytical Methods for E&L Determination

EXTRACTABLES & LEACHABLES TESTING

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Extractables/Leachables

» LEACHABLES are typically a SUBSET of EXTRACTABLES

» NOT ALL LEACHABLES are EXTRACTABLES

Additional Study

Design

ACCELERATED LEACHABLES testing

In some cases: a SIMULATION study

» As a step in between an Extraction Study and a “Formal Leachable” Study

» Understanding the real risk of which extractabe compounds may become a

leachable

» Account for unexpected leachables and for secondary leachables

» Using screening methodologies, not optimized for the specific matrix.

» Either as qual./semi-quant Screening (not for submission!!) or with more

quantitative methods


Kinetics of Extraction Extraction Accelerated Leachable St.

Real time/temp Leachable St.

H2O e.g. 8h reflux

DCM or IPA e.g. 8h reflux

e.g. 6 Mo, 40°C e.g. 3 y at 25°C

EXTRACTION SLOW – Incomplete no swelling/enhanced diffusion

FAST – complete Enhanced Diffusion Almost Asymptotic

Enhanced Diffusion controlled leaching is T-dependent D = D0 exp(-E/RT)

SLOW, but long term contact!

MATERIAL DEGRADATION

Slightly enhanced ASTM 1980: reflux at 100°C/8h: 60d at RT Even if they will be formed, will they come out?

Very Slightly enhanced ASTM 1980: (IPA) reflux at 80°C/8h: 15d at RT

Slightly enhanced ASTM 1980: 6 Mo ageing at 40°C ≡ 17 Mo at 25°C

SLOW, but evaluated over LONG period! (e.g. 3y)

REACTION KINETICS • Dissolved O2 in H2O • Hydrolysis (H2O) • Reaction with DP and leachates/materials • ...

Slightly enhanced Low [extr]init will limit the formation of reaction comp. (i.e. for slow reactions)

Not relevant! Enhanced, k = k0 exp(-Ea/RT) Ea: Activation Energy, reaction dependent (Pseudo) first order kinetics

SLOW, but evaluated over LONG period! (e.g. 3y)

Consider – if possible – an additional accelerated Leachable study (e.g. with

screening methods) to verify the presence of “unexpected leachables”

CONFIDENTIAL

LEACHABLES testing

Select Targets, based upon

» Extraction Studies

» Accelerated Leachable Studies

» Toxicological Assessment information


Additional Screening is advised!

•Qualify

• Source

•Control

• Screening Leachables

• Synthesis

• Quantify

• Identify • Potential

Leachables

• Early Risk Assessment

TOX-RITETM

TOX-RAYTM

TOXICOLOGY

ASSESSMENT TOX-

SYNTHTM

Extractables

Leachables

Bringing it all together!

THANK YOU

John Iannone Program Manager

Technical Specialist

[email protected]

15 Wiggins Ave, Bedford, MA 01730

800-458-4141 x142

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mailto:[email protected]

mailto:[email protected]

EXAMPLE N°1 (Oxidation):

Dissolved Oxygen in WFI /DP(V) will Oxidize Irganox 1076 over time!

Occurrence of “oxaspiro” as a leachable is much more frequent than as an

extractable!

OXIDATION

REACTIVITY OF LEACHABLES - DRUG PRODUCTS

CONFIDENTIAL

EXAMPLE N°2 (Hydrolysis):

BHT-OH is seldom seen as an extractable, but it is regularly seen as a leachable!

H2O

BHT BHT-OH

HYDROLYSIS

CONFIDENTIAL


EXAMPLE N°3: Halogenated Rubber Oligomers – PART 1

C13H24 and C21H40 Oligomers


CONFIDENTIAL

H3C

CH2

CH3H3C

H3C CH3

CH3

H3C CH3CH3

H3C

CH2

H3C

H3C CH3

CH3

** *

C13 oligomer C21 oligomer

Cresol containing drug products, Bromocresol may be formed in the

presence of Bromobutyl Stoppers (Mechanism is unknown)

OHH3C

H3C

Br

OH

EXAMPLE N°4: Halogenated Rubber Oligomers – PART 2


CONFIDENTIAL

Documents

E&L for Drug Delivery Systems: Prefilled Syringe