Best Practices for Leachables and Extractables Testing

Daniel L. Norwood, PhDIPAC-RS

Chair – PQRI Leachables and ExtractablesWorking Group

PQRI Leachables and Extractables WorkshopBethesda, MD

5 December 2005

Presentation Outline

• Why produce “Best Practice”recommendations?

• The Working Group’s hypothesis

• Laboratory work in support of recommendations

• Recommendation areas

• Introduction to recommendation specifics

Why Produce “Best Practice” Recommendations?

• To reduce uncertainty in the pharmaceutical development process for OINDP.

• To reduce or eliminate “Horror Stories” .

• To support Agency initiatives, such as Quality by Design and Risk Management.

Simulated Project Team Meeting

Can’t we all just get along?

Simulated Encounter with Senior Management

Simulated Project Team

Leader

Simulated VPBut it was a

Project Team decision!!!!

Simulated NDA

The Working Group’s Hypothesis

1. Scientifically justifiable thresholds based on the best available data and industry practices can be developed for:

a. the reporting and safety qualification of leachables in orally inhaled and nasal drug products, and

b. reporting of extractables from the critical components used in corresponding container/closure systems.

Reporting thresholds for leachables and extractables will include associated identification and quantitation thresholds.

2. Safety qualification of extractables, would be scientifically justified on a case-by-case basis.

Laboratory Work• Volunteer laboratories

• Custom made “Test Articles” (3 elastomers and one plastic, all with known formulations)

• Two Phases of extractables work (both protocol driven):

• Phase 1 – Qualitative Controlled Extraction Studies

• Phase 2 – Analytical Method Optimization/Validation

• Placebo leachables studies

Chemistry: Volunteer Laboratories

• Boehringer Ingelheim Pharmaceuticals, Inc.• Cardinal Health (Magellan Laboratories)• CIBA Expert Services• Merck and Company, Inc• West Monarch Analytical Laboratories• PPD• Valois, Inc• West Pharmaceutical Services• FDA• Owens Illinois• Chevron Phillips

Rubber Formulation A (Sulfur Cured)Ingredient %

CALCINED CLAY 8.96BLANC FIXE (barium sulfate) 25.80CREPE 38.22BROWN SUB MB 16.841722 MB 2.11

ZINC OXIDE 4.042, 2’ METHYLENE-BIS (6-TERTIARY BUTYL-4-ETHYL PHENOL) 0.56COUMARONE-INDENE RESIN 1.12PARAFFIN 1.12TETRAMETHYLTHIURAM MONOSULFIDE 0.11ZINC 2-MERCAPTOBENZOTHIAZOLE 0.29SULFUR 0.84

Polypropylene Formulation

Ingredient wt %

• Primary StabilizersTetrakis (methylene(3,5-di-t-butyl-4-hydroxyhydrocinnamate)) methane

Irganox 1010 (Ciba) 0.08 wt%Anox 20 (Great Lakes)

• Secondary StabilizersBis(2,4-di-t-butylphenyl)pentaerythritol diphosphite

Ultranox 626 (GE) 0.05 wt%

Polypropylene FormulationIngredient wt %

• Corrosion InhibitorsCalcium Stearate 114-50 (Ferro) 0.03 - 0.4 wt%

• AntistaticVegetable oil derived 90% alpha monoglycerides (soybean) Pationic 901 (Patco) 0.3 wt%Dimodan HS-KA (Danisco)

• Nucleating Agents3,4 -dimethyl dibenzylidene sorbitolMillad 3988 (Milliken) 0.2 wt%

State-of –the-Art InstrumentationState-of –the-Art Instrumentation

X

A “Modern” LC/MS SystemA “Modern” LC/MS System

Chemistry: Phase 1 Studies

• Controlled Extraction Studies

• Multiple solvents with differing polarities:

– Dichloromethane, 2-propanol, hexane

• Multiple extraction techniques

– Sonication, Soxhlet, reflux

• Multiple analytical techniques

– GC/MS, LC/UV (DAD), LC/MS

Representative Extraction Apparatus

GC/MS Extractables Profile of the Sulfur-Cured Elastomer

5.00 10.00 15.00 20.00 25.00 30.00 35.000

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

5000000

5500000

6000000

6500000

7000000

7500000

8000000

8500000

9000000

9500000

1e+07

1.05e+07

1.1e+07

1.15e+07

1.2e+07

1.25e+07

1.3e+07

1.35e+07

Time-->

Abundance

TIC: 02050302.D

24 hr Soxhlet extractionIn methylene chloride

GC/MS Extractables Profile of Valois Elastomer Methylene Chloride Soxhlet Extract

5.00 10.00 15.00 20.00 25.00 30.00 35.00

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

5000000

5500000

6000000

6500000

7000000

Time-->

Abundance

TIC: 08190302.D

BHTI.S.

C16

C182246

Irganox 1076

PeroxideFrags.?

LC/MS Extractables Profile of Polypropylene Methylene Chloride Reflux Extract

Reflux PP Disc/CH2Cl2

5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 Time 0

100

%

0

100

%

03270311 280 nm ANALOG

5.22e5 10.55

5.34

8.44

20.92

18.90 33.92

03270311 Scan AP- TIC

1.27e7 18.36

10.64

5.02 3.17 8.55

16.02

13.50

20.25

34.01

25.63 31.38 40.31 37.86 44.91

11

12

9

6

4

8

7

2

4

9

12

3

3 5 10

Chemistry: Phase 2 Studies

• Sulfur-cured elastomer (Ciba)– Completed optimization of extractions using Soxhlet

extraction with methylene chloride

– Completed validation on GC/FID method

– Details available in poster presentation

• Polypropylene (West Monarch)– Completed optimization of extractions using reflux in

isopropanol and THF

– Completed validation of LC/UV method

– Details available in poster presentation

SULFUR-CURED ELASTOMER EXTRACTABLES

PQRI Extractives Phase II Exp. 2

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8 10 12 14 16 18

Time, hours

Are

a ra

tio, a

naly

te to

IS

Phenolic

Docosane

Hexacosane

Coumarone indene

Placebo Leachables Study

• Samples contained in formulation development bottles (plastic coated)

• CFC-11• Sulfur-cured elastomer

Laboratory Scale Stability Chamber

• Note inner door• Note placebo

leachables study in storage

• 40°C/75%RH• 3 months storage

anticipated

Leachables Profile – 1 Week Timepoint

5.00 10.00 15.00 20.00 25.00 30.00 35.000

1000000

2000000

3000000

4000000

5000000

6000000

7000000

8000000

9000000

1e+07

1.1e+07

1.2e+07

1.3e+07

1.4e+07

Time-->

Abundance

TIC: 11100303.D

I.S. 40µg/canister

Leachables Profile – 1 Week TimepointExpanded

5.00 10.00 15.00 20.00 25.00 30.00 35.00

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

1100000

1200000

Time-->

Abundance

TIC: 11100303.D

Recommendation Areas

• Container/Closure System Components –Composition and Selection

• Controlled Extraction Studies

• Leachables Studies and Routine Extractables Testing

• The Analytical Evaluation Threshold (AET)

Specific Questions Addressed

1. What does it mean to “identify” a leachable or extractable?

2. How do you “correlate” extractables and leachables profiles? What does the term “correlate” mean?

3. How do you optimize extractables methods? What are “asymptotic” levels?

Introduction to Recommendation Specifics

1. Component Selection – Fran DeGrazio

2. Controlled Extraction Studies – Tom Feinberg

3. Leachables Studies and Routine Extractables Testing – Diane Paskiet

4. Analytical Evaluation Threshold – Dan Norwood

Final Points

• The “Best Practice” recommendations are designed to be comprehensive.

• We welcome your comments and suggestions.

• I did not personally create the issue of leachables/extractables in OINDP.