Extractable & Leachable Study GBA GROUP PHARMA 04/10/19 5. Extractable Study • Execute protocol •

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  • Extractable & Leachable Study with Integrity Testing & Toxicological

    Assessment

    Dr. Heike Schmidt-Eisenlohr

  • 04/10/19GBA GROUP PHARMA 2

    Agenda

    • Collection of Supplier Information • Risk Assessment

    Project Planning

    • Integrity Testing • Extractable Study

    Experimental Phase I

    • Data evaluation & Search for available toxicity data

    • Classification in appropriate Cramer Class

    Evaluation & Tox Assessment

    • Method development and Matrix specific validation

    • Leachable Study

    Experimental Phase II

  • 04/10/19GBA GROUP PHARMA 3

    Extractables

    Leachables Volatiles

    General Introduction

  • Is the material uncritical for the intended use?

    04/10/19GBA GROUP PHARMA 4

    Mode of application: ophtalmic, parenteral,

    inhalor or oral

    Daily dose: one or several, time of

    application

    Material: glass or plastic, labels &

    printing ink

    Shelf life: time of possible interaction

    Patient: adults or infants

    Country: high or low regulated

    It depends! Risk based approach

  • 04/10/19GBA GROUP PHARMA 5

    Extractable Study

    • Execute protocol • Identify

    exctactables • Evaluate results • Deduce range for

    possible leaching

    Leachable Study

    • Develop methods • Validate the

    developed methods

    • Perform a leachable study

    Supplier Info

    • Material • Additives • Ranking

    Risk Assessm.

    • Evaluation of the process

    • Risk (ICH Q9) • Select

    material • Define AET

    Project Preparation Experimental Phase I

    Tox Assessm.

    Experimental Phase II (if needed)Evaluation

    • CAS identifier • Search for avai-

    lable toxicity data • Classification in

    appropriate Cramer Class

    • Define specifi- cations for leachable study if needed

  • 04/10/19GBA GROUP PHARMA 6

    Agenda

    • Collection of Supplier Information • Risk Assessment

    Project Planning

    • Integrity Testing • Extractable Study

    Experimental Phase I

    • Data evaluation & Search for available toxicity data

    • Classification in appropriate Cramer Class

    Evaluation & Tox Assessment

    • Method development and Matrix specific validation

    • Leachable Study

    Experimental Phase II

  • Supplier Information – Declaration of Conformance

    04/10/19GBA GROUP PHARMA 7

  • Risk Assessment – Product Contact?

    04/10/19GBA GROUP PHARMA 8

    Which plastic parts need to be extracted? • Reduction of workload • Reduction of costs • Avoid generation of data which are not required

  • Risk-based approach: AET definition – TTC concept

    04/10/19GBA GROUP PHARMA 9

    For each extractable from a device component, an Analytical Evaluation Threshold (AET) which is determined by consideration of the Safety Concern Threshold (SCT) and the specific drug product configuration needs to be determined as follows, e.g.

    Dt = total labelled doses (8 per container) Dd = doses per day (4) m = mass of component in g SCT =Safety Concern Threshold may be replaced by a TTC of 1.5 TTC = use of a numerical cancer risk value (1 in 100,000) and its translation into risk- based doses (TTC) according to ICH M7(R1) as a hypothetical concept which provides an estimate of safe long-term exposures for any mutagenic compound

    𝐴𝐴𝐴𝐴𝐴𝐴 = 𝑆𝑆𝑆𝑆𝐴𝐴 × 𝐷𝐷𝑡𝑡 𝐷𝐷𝑑𝑑 × 𝑚𝑚

    = 0.15 �µ𝑔𝑔 𝑑𝑑𝑑𝑑𝑑𝑑 × 8 �

    𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑐𝑐𝑑𝑑𝑚𝑚𝑐𝑐𝑑𝑑𝑐𝑐𝑑𝑑𝑐𝑐𝑐𝑐

    4 �𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑 × � 𝑚𝑚𝑑𝑑𝑑𝑑𝑑𝑑 𝑐𝑐𝑑𝑑𝑚𝑚𝑐𝑐𝑑𝑑𝑐𝑐𝑑𝑑𝑐𝑐𝑐𝑐

    = 0.3 𝑐𝑐𝑐𝑐𝑚𝑚

  • 04/10/19GBA GROUP PHARMA 10

    Agenda

    • Collection of Supplier Information • Risk Assessment

    Project Planning

    • Integrity Testing • Extractable Study

    Experimental Phase I

    • Data evaluation & Search for available toxicity data

    • Classification in appropriate Cramer Class

    Evaluation & Tox Assessment

    • Method development and Matrix specific validation

    • Leachable Study

    Experimental Phase II

  • Extractable study - Integrity Testing

    04/10/19GBA GROUP PHARMA 11

    Time point Differences in visible and

    tactile examination against a fresh sample

    7 Days slightly softer

    14 Days slightly softer and more flexible

    30 Days slightly softer and more flexible

    60 Days

    softer and more flexible; yellow coloring comes off

    when drying the tube with a paper towel

    90 Days

    softer and more flexible; yellow coloring comes off

    when drying the tube with a paper towel; pink color is paler

    Material not compatible with the product ⇒ Extractable study not required, ⇒ Choice of other material!

    Minor changes of the material may be acceptable

  • Extractable study - Extraction of the plastic parts

    04/10/19GBA GROUP PHARMA 12

    Harsh Solvents, e.g. • Water at neutral pH

    • Water at high pH (e.g. 9.5)

    • Water at low pH (e.g. 2.5)

    • Mixture of buffer and organic modifier

    • Placebo

    • Different durations

    • Different temperatures

    • Toluene • N-Hexane • Isopropanol

    Extraction & concentration

    Evaporation & concentration

    Soft Solvents, e.g. according USP

  • Extractable study - pictures

    04/10/19GBA GROUP PHARMA 13

  • Extractable study – Special Case

    04/10/19GBA GROUP PHARMA 14

    Application of a polymer in the gastrointestinal tract

    Do toxicologically relevant substances leach from this polymer into the gastrointestinal tract? Can elemental impurities of class 1+2A (As, Cd, Pb, Hg, Co, V, Ni) relevant for oral application be detected by ICP-MS?

    Extraction in media simulating human colonic fluid e.g. • fluid simulated small intestine, fasted, pH 6.5 • fluid simulated small intestine, fed, pH 5.0 • fluid simulated stomach, fasted, pH 1.6

  • Extractable study – Special Case

    FDA Guideline "Container Closure Systems for Packaging-Human Drugs and Biologics“  e.g. for terminal sterilized vials with PTFE coated stoppers

    04/10/19GBA GROUP PHARMA 15

    autoclaving for 121°C for 1 h

    Worst-case scenario which may be relevant to address intactness of PTFE coating after terminal sterilization

  • Extractable study - Analysis of the extracts

    04/10/19GBA GROUP PHARMA 16

    Analysis of non-volatile Extractables

    (NVOCs) Analysis of volatile

    Extractables (VOCs)

    • UPLC-DAD • HPLC-MS (single quad) • Q Orbitrap I. (Semi)-quantitative Analysis II. Screen (Fingerprint) III. Structure elucidation (E+L database)

    • GC-FID • GC-MS • HS-GC-FID • HS-GC-MS I. Fingerprint II. Screen for peaks above AET III. Structure elucidation (NIST data base)

  • Targeted analysis

    04/10/19GBA GROUP PHARMA 17

  • Targeted analysis of volatiles via HS-GC-FID

    04/10/19GBA GROUP PHARMA 18

    Reference 2 : 2-Methyl-1,3-Butadiene

    Reference 1: Isobutene

    Gasket sample

  • Screen

    04/10/19GBA GROUP PHARMA 19

  • Extractable study - LC-MS Screen – APCI (pos. and neg.)

    04/10/19GBA GROUP PHARMA 20

  • Orbitrap; APCI + full scan; zoomed isotopes

    04/10/19GBA GROUP PHARMA 21

    2018LAT008_BA_103 #7685-7899 RT: 24.81-25.37 AV: 50 NL: 1.51E10 T: FTMS + p APCI corona Full lock ms [100.0000-1500.0000]

    100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 m/z

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    Re lat

    ive A

    bu nd

    an ce

    547.4008

    435.2750305.1381 165.0187 933.7031417.2639 577.5178472.3067 663.4520 1349.9581223.0602 793.6410 992.7969 1093.7951 1467.33911282.9561

    2018LAT008_BA_103 #7685-7899 RT: 24.81-25.37 AV: 50 NL: 1.51E10 T: FTMS + p APCI corona Full lock ms [100.0000-1500.0000]

    544.0 544.5 545.0 545.5 546.0 546.5 547.0 547.5 548.0 548.5 549.0 549.5 550.0 550.5 551.0 551.5 552.0 m/z

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    Re lat

    ive A

    bu nd

    an ce

    547.4008

    548.4036

    549.4064

    550.4092 551.4107545.3874 546.3890 547.8169546.9867 548.8242

    547.5045547.2942

    545.7415 549.0691

    548.4840

    548.1320 544.4001

  • Structure Proposal: Tri-N-octyl trimellitate

    04/10/19GBA GROUP PHARMA 22

  • Extractable study FID – Fingerprint