StatisticalStatistical Evaluation Using Design of Evaluation Using Design of Experiments of Total Organic Carbon Analysis Experiments of Total Organic Carbon Analysis Experiments of Total Organic Carbon Analysis Experiments of Total Organic Carbon Analysis (TOC) to Combine Cleaning Agent Method with (TOC) to Combine Cleaning Agent Method with

Drug Product MethodsDrug Product Methods

P t W l h Nik j V M i N it hP t W l h Nik j V M i N it h

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Peter Walsh, Nikunj Vasoya, Mariann Neverovitch, Peter Walsh, Nikunj Vasoya, Mariann Neverovitch, and Antonio Fernandezand Antonio Fernandez

Analytical and Analytical and BioanalyticalBioanalytical Development, Development, BristolBristol--Myers Squibb Co., New Brunswick NJ Myers Squibb Co., New Brunswick NJ

1919thth November, 2013November, 2013

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OutlineOutline

Cleaning BackgroundCleaning Background Current Practice & Project GoalCurrent Practice & Project Goaljj Design of Experiments (DoE)Design of Experiments (DoE) Data Analysis & ResultsData Analysis & Results Data Analysis & ResultsData Analysis & Results Risk AnalysisRisk Analysis ConclusionConclusion

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Why Do We Clean?Why Do We Clean?yy

Cleaning is importantCleaning is important EquipmentEquipmentCleaning is importantCleaning is importantEvery time we make a batch of Drug Every time we make a batch of Drug Product we have a chance of Product we have a chance of contamination from the previous batchcontamination from the previous batchcontamination from the previous batchcontamination from the previous batchWe avoid this by cleaning inWe avoid this by cleaning in--between between runs with detergent. Then in order to runs with detergent. Then in order to verify it’s clean we take a swab and test itverify it’s clean we take a swab and test itverify it s clean we take a swab and test it verify it s clean we take a swab and test it for API/detergent.for API/detergent.

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What Is Considered Clean?What Is Considered Clean?

Cleaned EquipmentCleaned EquipmentCleaned EquipmentCleaned EquipmentThe equipment is considered clean if the swab sample is below The equipment is considered clean if the swab sample is below its worst case Permitted Residue Limit (PRL). This is calculated its worst case Permitted Residue Limit (PRL). This is calculated from the contaminant’s Subject Exposure Limit (SEL) provided from the contaminant’s Subject Exposure Limit (SEL) provided by a toxicologist.by a toxicologist.

Cleaning Agent Limit:Cleaning Agent Limit:

PRL Limit: 13.5 parts per million Carbon (ppmC) PRL Limit: 13.5 parts per million Carbon (ppmC) Cleaning Limit: 1.00 ppmC (Alert Cleaning Limit)Cleaning Limit: 1.00 ppmC (Alert Cleaning Limit)

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Total Organic Carbon AnalysisTotal Organic Carbon Analysisg yg y

The TOC method is nonThe TOC method is non--specific in that it analyzes specific in that it analyzes how much organic carbon how much organic carbon i i l tii i l tiis in a solution.is in a solution.

This means ANY and ALLThis means ANY and ALLThis means ANY and ALL This means ANY and ALL contamination will be contamination will be accounted for in one accounted for in one analysis.analysis.

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Current Project And Project GoalCurrent Project And Project Goalj jj jBlender (Equipment to clean)Blender (Equipment to clean)

Current PracticeCurrent Practice Project GoalProject Goal

Drug Drug ProductProduct

Cleaning Cleaning AgentAgent Drug Product + Cleaning Drug Product + Cleaning

AgentAgentExample Settings:Example Settings:

•• 20 mL20 mL•• pHpH--22•• 2.0 µL/min2.0 µL/min

Example Settings:Example Settings:

•• 40 mL40 mL•• pHpH--77•• 0.0 µL/min0.0 µL/min

AgentAgent

Our Goal: To analyze only one sample for Our Goal: To analyze only one sample for both Drug Product and Cleaning Agent.both Drug Product and Cleaning Agent.

2.0 µL/min2.0 µL/min 0.0 µL/min0.0 µL/min

Drug Product and Cleaning Agents Drug Product and Cleaning Agents can be swabbed separately due to can be swabbed separately due to

different optimal solubility different optimal solubility parameters.parameters.

To do this we needed to prove that no To do this we needed to prove that no variation occurs when changing the variation occurs when changing the parameters for the Cleaning Agent.parameters for the Cleaning Agent.

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Design of Experiment (DoE)Design of Experiment (DoE)g p ( )g p ( )Full Factorial DoE was conducted with 3 factors, 2 levels, Full Factorial DoE was conducted with 3 factors, 2 levels,

and 5 replicates in the statistical program Minitaband 5 replicates in the statistical program Minitab

Run Run OrderOrder

Water Water pHpH

Diluent Diluent Volume (mL)Volume (mL)

Oxidizer Flow Oxidizer Flow Rate (µL/min)Rate (µL/min)

Cleaning Agent Cleaning Agent Results (ppmC)Results (ppmC)

and 5 replicates in the statistical program Minitab and 5 replicates in the statistical program Minitab

OrderOrder pHpH Volume (mL)Volume (mL) Rate (µL/min)Rate (µL/min) Results (ppmC)Results (ppmC)

11 22 1515 4.84.8 0.920.9222 77 3535 0 00 0 1 001 0022 77 3535 0.00.0 1.001.0033 77 3535 4.84.8 0.940.9444 77 1515 4.84.8 0.930.9355 2 2 3535 4.84.8 0.920.9266 22 1515 0.00.0 1.011.0177 22 3535 0.00.0 1.021.02

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88 77 1515 0.00.0 1.011.01

Main Effects PlotsMain Effects PlotsDoE results for Cleaning AgentDoE results for Cleaning Agent

Little to NO Little to NO slope!slope!

Very slight Very slight Variation forVariation forVariation for Variation for

OxidizerOxidizer

Lowest Lowest Reading Reading

Observed was Observed was 0.15 ppmC 0.15 ppmC less than less than

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theoreticaltheoretical

Interaction Plots Interaction Plots DoE results for Cleaning AgentDoE results for Cleaning Agent

-- No angles!No angles!

-- Lines are Lines are almost almost

completely completely p yp yoverlapping!overlapping!

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Quantifying Oxidizer Variation Quantifying Oxidizer Variation Q y gQ y gOxidizer was individually varied for Cleaning AgentOxidizer was individually varied for Cleaning Agent

1 50

1.75

2.00

Oxidizer Oxidizer VariationVariation

0.50

0.75

1.00

1.25

1.50

TOC

(ppm

C)

0.00

0.25

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5Oxidizer Flow Rate (µL/min)

Average Deviation at 4.8 Oxidizer: 0.08 ppmC less than Average Deviation at 4.8 Oxidizer: 0.08 ppmC less than theoreticaltheoretical

Worst case error was observed during DoE with 0.15 Worst case error was observed during DoE with 0.15 C l th th ti lC l th th ti l

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ppmC less than theoreticalppmC less than theoretical

Risk AnalysisRisk AnalysisyyUsingUsing alertalert limit,limit, ii..ee.. 11..0000 ppmCppmC whichwhich meansmeans rere--cleanclean thethe equipmentequipment ififTOCTOC isis 11 ppmCppmC oror higherhigher.. Therefore,Therefore, thethe worstworst casecase scenarioscenario wouldwould bebepppp gg ,,acceptingaccepting aa samplesample atat 11 ppmppm whenwhen itsits contaminationcontamination isis actuallyactually 11..1515ppmCppmC.. However,However, thethe actualactual PRLPRL LimitLimit isis 1313..55 ppmCppmC..

Therefore the Therefore the detergent detergent gg

contamination will contamination will ALWAYS be well ALWAYS be well

within the PRL limit.within the PRL limit.

NO RISK!NO RISK!

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ConclusionConclusion

Based on the data gathered we conclude Based on the data gathered we conclude there is NO significant variation when there is NO significant variation when changing parameters for both detergentschanging parameters for both detergentschanging parameters for both detergents.changing parameters for both detergents.

Th f bi l i fTh f bi l i fTherefore, we can combine analysis of Therefore, we can combine analysis of Detergent with API.Detergent with API.

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