Cleaning Validation for Pharmaceutical Manufacturing Using Online SFE/SFC

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    A Novel Approach to Cleaning Validation for Pharmaceutical Manufacturing: Using Online Supercritical Fluid Extraction/Supercritical Fluid Chromatography

    Kenichiro Tanaka1, William Hedgepeth1, Daisuke Nakayama2, Hidetoshi Terada2, Minori Nakashima2, Tadayuki Yamaguchi2 1: Shimadzu Scientific Instruments, Inc., MD, USA, 2: Shimadzu Corporation, Kyoto, Japan

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    Introduction

    Cleaning validation is necessary to establish the quality and safety of pharmaceutical drug products. In cleaning validation protocols, direct sampling is performed with swabs, which are sticks with textiles at one end. The sample on the swab after swabbing the surface of equipment is analyzed with a TOC analyzer and HPLC. Recently, HPLC has been more preferable because of the growing need for the individual analysis of products. Before the HPLC analysis, manual processes such as a sample extraction and a sample condensation are required. Such manual processes may affect to the quality of results. Thus, we evaluated the application of a novel on-line supercritical fluid extraction/chromatography system for the cleaning validation.

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    Experimental

    Materials and Reagents A commercially available detergent containing alkylbenzene sulfonates was diluted with methanol and used as a standard sample. For the test of sample extraction, the sample was dropped onto a swab (ITW Texwipe, USA). System Nexera UC system (Shimadzu corporation, Japan) was used for both the screening of the method using supercritical fluid chromatography (SFC) (Figure 1A) and the supercritical fluid sample extraction (SFE) followed by SFC directly (SFE/SFC) (Figure 1B). The schematic diagram for static and dynamic extraction of supercritical fluid extraction unit is shown in Figure 1C.

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    Figure 1: Flow diagrams of Nexera UC system

    System

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    Analytical Conditions

    Column : Shim-pack UCX series columns (250 mm L. x 4.6 mm I.D., 5 m) (I) UCX-RP (ODS with polar group), (II) UCX-GIS (ODS), (III) UCX-SIL, (IV) UCX-DIOL

    Mobile Phase : A: CO2; B: Methanol Time program : Shown in the figure Flow Rate : 3.0 mL/min Column Temp. : 40C Back pressure : 15 MPa Wavelength : 220 nm Injection Vol. : Shown in figure

    Table 1: SFC Analytical conditions

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    [Sample Preparation] A total of 10 to 500 g standard samples in methanol were dropped onto a total of three swabs. The swabs were enclosed into an extraction vessel and set to the SFE/SFC unit. [Static extraction] Extraction time : 3 min Mobile phase : A: CO2; B: 0.1% (w/v) ammonium formate in methanol B conc. : 10% Flow rate : 3.0 mL/min Back pressure : 15 MPa [Dynamic extraction] Extraction time : 3 min Mobile phase : A: CO2; B: Methanol B Conc. : 10% Flow rate : 3.0 mL/min Back pressure : 15 MPa [SFC] Column : Shim-pack UCX-SIL (250 mm L. x 4.6 mm I.D., 5 m) Mobile Phase : A: CO2; B: Methanol Time program : 10%B (0-2 min), 10-60%B (2-7 min), 60%B (7-9 min), 10%B (9-13 min) Flow Rate : 3.0 mL/min Column Temp. : 40C Back pressure : 15 MPa Wavelength : 220 nm

    Table 2: On-line SFE/SFC Analytical conditions

    Analytical Conditions

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    Results Analytical method developmentThe analytical method for SFC was developed by screening four columns and gradient conditions. The UCX-SIL column showed excellent peak shape (Figure 2) and was used for further analysis.

    Figure 2: Comparison of columns for SFC analysis of standard detergent sample

    0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 min

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    (l) UCX-RP

    0 10 20 30 40 50

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    B C

    onc.

    [%]

    Time [min]

    (lll) UCX-SIL

    (ll) UCX-GIS (lV) UCX-DIOL

    5-50%B (0-7 min)

    Time program:

    5-40%B (0-7 min)

    5-30%B (0-7 min)

    RT : 7.87 min N : 16454 Tf : 1.767

    RT : ND N : ND Tf : ND

    RT : 8.56 min N : 59056 Tf : 0.693

    RT : 7.96 min N : 48053 Tf : 0.692

    Abbreviations: RT : Retention time N : Theoretical plate Tf : Tailing factor (5%)

    Injected sample: 1 L of 1% Standard sample

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    Results The time program was developed in consideration of on-line SFE/SFC (data not shown). The optimized time program and the result of performance evaluations were shown in Figure 3.

    Figure 3: Performance evaluations of SFC analytical method

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    (l) Linearity test

    (ll) Reproducibility test

    1% Sample concentration:

    0.50% 0.10% 0.05% 0.01% 0.005% 0%

    0.00 0.25 0.50 0.75 1.000

    2.0

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    Peak Area (x100,000)

    Conc. (%)

    R2 = 0.998

    Sample

    Reproducibilities (n=6, %RSD)

    Retention time Area

    0.10% standard sample

    0.17 2.46

    Time program: 10%B (0-2 min), 10-60%B (2-7 min), 10%B (9-13 min)

    Injected sample: 2 L of 0 to 1% Standard samples

    0 20 40 60

    0 2 4 6 8 10 12 14

    B C

    onc.

    [%]

    Time [min]

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    Results

    On-line SFE/SFC analysis of detergent in swabBased on the optimized SFC analytical condition, an on-line SFE/SFC analytical condition was developed and its performance was evaluated (Figure 4).

    Figure 4: On-line SFE/SFC analysis of standard detergent sample-spiked swabs

    (l) Sequential diagram of on-line SFE/SFC

    0 10 20 30 40 50 60

    -6 -3 0 3 6 9 12

    B C

    onc.

    [%]

    Time [min]

    SFC Analysis (13 min)

    Dynamic Extraction

    (3 min)

    Static Extraction

    (3 min)

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    Results

    Figure 4: On-line SFE/SFC analysis of standard detergent sample-spiked swabs

    50 g

    100 g

    200 g

    500 g

    Spiked sample amount:

    (ll) Linearity test

    0 100 200 300 400 g/Swab0.00

    0.25

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    0.75

    1.00

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    Peak Area(x10,000,000)

    500

    R2 = 0.996

    SFC Analysis

    Dynamic Extraction

    Static Extraction

    0

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    1.0

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    3.0

    mAU

    -5.0 -2.5 0.0 2.5 5.0 7.5 min

    Alkylbenzenesulfonate

    10 g

    20 g

    (lll) Reproducibility test

    SFC Analysis

    Dynamic Extraction

    Static Extraction

    0

    0.5

    1.0

    1.5

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    mAU

    -5.5 -2.5 0.0 2.5 5.0 7.5 min

    Sample

    Reproducibilities (n=5, %RSD)

    Retention time Area

    100 g standard sample

    0.19 5.76

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    Conclusion

    The evaluation results showed that the on-line SFE/SFC can provide reliable data for the cleaning validation for pharmaceutical manufacturing. The benefit of on-line SFE/SFC analysis is not only data reliability but also the convenience and safety gained by eliminating the manual extraction process. It may streamline laboratory processes and improve productivity and safety of pharmaceutical manufacturing facilities.

    The sample was provided by DAIICHI SANKYO COMPANY, LIMITED. Acknowledgement

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