A Step-wise Approach for Leachables & Extractables ... · PDF fileA Step-wise Approach for Leachables & Extractables Evaluation in pMDI Product Development ... ICH guideline Q6A....

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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

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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


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

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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:


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

» …

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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» …


0

0.05

0.10

0.15

0.20

0.25

ethanol hexane dichloromethane

Conce

ntr

ation [

µg

/can]

ASE MASE Soxhlet


� Screening extraction

• Define extraction solvent and extraction system for each polymermaterial

Extractable 1

5



� 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



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



� 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


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

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� 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


� Response surface

• Minimisation of leachable concentration in formulation


-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

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� Minimisation of leachable concentration in formulation


Inte

nsity

[AU

]

100

200

300

400

500

600

700

800

18 19 20 21 22 23 24

Time [min]

formulation 2

formulation 1


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]

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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


� 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


� Qualitative correlation

• extractables and leachables profiles should comply qualitatively


10 11 12 13 14

250

500

750

time [min]

Inte

nsity

[mA

U]

15

1000

Extractables chromatogram

Leachable chromatogram

Matrix chromatogram



� 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

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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


Acknowledgement

� SDC Rudolstadt

� Cheryl Stults

� FSU Jena

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Discussion

Thank you for your attention…

A Step-wise Approach for Leachables & Extractables ... · PDF fileA Step-wise Approach for Leachables & Extractables Evaluation in pMDI Product Development ... ICH guideline Q6A....

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