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a Novartis company
A Step-wise Approach for Leachables & Extractables Evaluation in pMDI Product Development
Andrea MiethTechnical Development, Sandoz Development Center Rudolstadt, Germany
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Agenda
1. Regulatory requirements
2. Step-wise approach according to PQRI guideline
3. Critical assessment of the packaging system
4. Case Study I: Controlled Extraction Study
5. Case Study II: Formulation development with DoE
6. Case Study III: Correlation of L&E
7. Conclusions
2
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Regulatory Requirements
� Impurity guidelines
EMA guideline
Guideline on the limits of genotoxic impurities (TTC)
ICH guideline
Impurities in new drug substances (Q3A)
Impurities in new drug products (Q3B)
� EMA note for guidance
Note for guidance on specific limits for residues of metal catalysts or metal reagents
� ISO standard 10993
Biological evaluation of medical devices
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Regulatory Requirements
� FDA guidance
Container closure systems for packaging human drugs and biologics
� EMA guideline
Guideline on plastic immediate packaging
� ICH guideline Q8
Pharmaceutical development
� ICH guideline Q6A (Specifications)
Test procedures and acceptance criteria for new drug substances and
drug products
� PQRI leachables and extractables working group (recommendationsto the FDA)
Safety thresholds and best practices for extractables & leachables in orally
inhaled and nasal drugs
3
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Leachable and Extractable Testing
Step 1
Step 2
Step 5
Step 3
Step 4
CES (Controlled Extraction Study)
Correlation of L&E
Leachables study
Identification of L&E above AET
Critical assessment of the packaging system
� Step-wise approach according to PQRI recommendations:
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 1: Critical assessment of the packaging system
� Typical sources for L&E in pMDIs:
• Packaging
– Valve materials:
» Polypropylene (PP)
» Polybutylterephthalate (PBT)
» Polyoxymethylene (POM)
» Polychloroprene (PC)
» Ethylenepropylenediene monomer (EPDM)
» Polyamide (PA)
» Metals
» Lubricants
» …
– Can
» Coating material
» Metal
Gaskets
Stem
Spring
Body
Ring
• Typical leaching compounds
» Base material oligomers
» Antioxidants
» Processing aids
» Vulcanization agents
» Phthalates
» Fillers
» Metals
» …
4
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 2: Controlled Extraction Study
� Multiple solvents with differing polarities
» Methylene chloride
» Ethanol
» Hexane
� Multiple extraction techniques
» Soxhlet
» MASE® (Microwave Accelerated Solvent Extraction)
» ASE® (Accelerated Solvent Extraction)
� Multiple analytical techniques
» GC (semivolatile and volatile organic compounds (e.g. antioxidants)) • MS (identification and quantification)
• FID (quantification)
» LC (non volatile organic compounds (e.g. polymer oligomers))• MS (identification and quantification )
• HPLC-UV (quantification)
» ICP-MS or ICP-AAS» …
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
0
0.05
0.10
0.15
0.20
0.25
ethanol hexane dichloromethane
Conce
ntr
ation [
µg
/can]
ASE MASE Soxhlet
Step 2: Controlled Extraction Study
� Screening extraction
• Define extraction solvent and extraction system for each polymermaterial
Extractable 1
5
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 2: Controlled Extraction Study
� Extraction optimization
• Define optimum extraction conditions with DoE for each analyte
– Relevant parameters for ASE® extraction
» Extraction time
» Extraction temperature
» Extraction cycles
» Grinding
» Pressure
Optimization with DoEfractional factorial design
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 2: Controlled Extraction Study
full factorial design2³ experiments
fractional factorial design2³-1 experiments
Fractional factorial design for CES with 5 factors
Benefit: � 16 experiments (25-1) compared to 32 (25) experiments� numerical model for prediction of extractable concentration in extract
Cost: � effect can be confounded
t
T
c
t
T
c
6
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 2: Controlled Extraction Study
� Extraction optimization
• Define optimum extraction conditions with DoE-approach for each analyte (R² = 0.99)
-10
0
10
20
30
40
50
Effects
for
extr
acta
ble
[%
]
Time** Pressure Temperature* Grinding** Cycles*
* : p<0.05, ** : p<0.01, *** : p<0.001
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 3: Leachables study
� Leachable profile is extremely dependant on the formulation
• Propellant
• Typical excipients
» Fatty acid
» Ethanol
» PEG
» PVP
� fractional factorial experimental design (DoE)
» Cost: 16 experiments» Benefit: numerical model
for prediction of leachable
concentration in formulation
� Formulation development with regard to low leachable levels
7
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 3: Leachables study
� Optimize formulation with regard to leachable levels
• Approach: fractional factorial experimental design (DoE; R² = 0.98)
-20
-10
0
10
20
30
40
Effects
for
leacha
ble
Propellant* Ethanol*** PEG** Fatty acid*PVP*
* : p<0.05, ** : p<0.01, *** : p<0.001
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
� Response surface
• Minimisation of leachable concentration in formulation
Step 3: Leachables study
-5.00
-2.50
0.00
2.50
5.00
-1.00
-0.50
0.00
0.50
1.00
-20
0
20
40
60
80
100
B: HFA
C: ethanol ethanol
propallent
ethanol
propallent
ethanol
8
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
� Minimisation of leachable concentration in formulation
Step 3: Leachables study
Inte
nsity
[AU
]
100
200
300
400
500
600
700
800
18 19 20 21 22 23 24
Time [min]
formulation 2
formulation 1
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
0
100
200
300
400
500
600
700
800
18 19 20 21 22 23 24 25 26[min]
Inte
nsit
ät
Step 4: Identification of E&L above AET
Inte
nsity
[mA
U]
AET
� Identification of leachables
[ ]
[ ]µg/gm
valve) / (1can×AET =AET
µg/cann ×n
day / µg0.15=AET
valve / material valveE
can / actuations labeledday / actuations
time [min]
9
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 4: Identification of E&L above AET
� Identification of leachables
� GC-MS, LC-MS, NMR, UV, IR, X-ray, elemental analysis…
• Mass spectrum:
– Library search
– Compare molecular weight and fragmentation behavior
– Mass spectrum and chromatographic retention time match to
authentic reference substance
» Availability of reference substance
» Preparative HPLC and identification
» Contract synthesis labs
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
� Qualitative correlation
• extractables and leachables profiles should comply qualitatively
Step 5: Correlation of E&L
5 6 7 8 9
250
500
750
Extractables chromatogram
Leachable chromatogram
Matrix chromatogram
time [min]
Inte
nsity
[mA
U]
10
1000
10
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
� Qualitative correlation
• extractables and leachables profiles should comply qualitatively
Step 5: Correlation of E&L
10 11 12 13 14
250
500
750
time [min]
Inte
nsity
[mA
U]
15
1000
Extractables chromatogram
Leachable chromatogram
Matrix chromatogram
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Step 5: Correlation of E&L
� Quantitative correlation
• levels of leachables are generally less than the levels of extractables
0
500
1000
1500
2000
2500
3000
0 3000
co
nce
ntr
atio
n [
µg
/ca
n]
Leachables
Extractables
Lot 1 Lot 2 Lot 3
11
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Conclusions
� Step-wise approach for E&L is necessary for a successful product development
� Design of extraction studies has a high impact on extractable profile
� Extraction conditions need to be optimized considering the materials used in the pMDI
� CES of utmost importance for following leachable studies
� Accelerated formulation development by thorough understanding ofLeachable formulation interactions
� Establish E&L correlation to replace routine Leachable testing by control of raw material
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Acknowledgement
� SDC Rudolstadt
� Cheryl Stults
� FSU Jena
12
IPAC RS 2011 | A. Mieth | Sandoz SDC Rudolstadt | 31st of March 2011
Discussion
Thank you for your attention…