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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)
3
Material Qualification
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
Material Qualification
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
Material Qualification
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
6
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
7
Biocompatibility of Material/Devices
ISO 10993
» Cytotoxicity
» Sensitization
» Intracutaneous Reactivity
» Acute Systemic Toxicity
» Subacute & Subchronic Systemic Toxicity
» Genotoxicity
» Implantation Reactivity
» Hemocompatibility
» Chronic Systemic Toxicity
8
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
9
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
10
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
11
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?
15
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
16
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.
17
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
18
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
23
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
Unpredicted Leachables
CONFIDENTIAL
RESULT of the LEACHABLE Screening Study of the PREFILLED SYRINGE
Contents maintained for 3 YEARS AT 25°C – 60% R.H.
Unpredicted Leachables
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
Unpredicted Leachables
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!
Unpredicted Leachables
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)
Unpredicted Leachables
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
34
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
Analytical Methods for E&L Determination
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
Analytical Methods for E&L Determination
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
15 Wiggins Ave, Bedford, MA 01730
800-458-4141 x142
39
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
REACTIVITY OF LEACHABLES - DRUG PRODUCTS
EXAMPLE N°3: Halogenated Rubber Oligomers – PART 1
C13H24 and C21H40 Oligomers
REACTIVITY OF LEACHABLES - DRUG PRODUCTS
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
REACTIVITY OF LEACHABLES - DRUG PRODUCTS
CONFIDENTIAL