Empower MethodenValidierungsManager MVM · preservatives, flavoring agents Inactive Ingredients + Finished Drug Products ... Compare 6 test results acquired by different analysts,

©2018 Waters Corporation 1COMPANY CONFIDENTIAL

Empower Methoden Validierungs Manager MVM

Carsten Fischer


Outline

– Introduction: regulatory perspective on method validation

o Typical validation characteristics

o Guidelines for validation

o Challenges with method validation

– Overview of method validation with Empower MVM

– Validation protocol using Empower MVM

– Validation Study using Empower MVM


Empower Methoden Validierungs Manager MVM

Carsten Fischer


Pharmaceutical DevelopmentBackground

API or drug

substance

Binding materials, dyes,

preservatives, flavoring

agents

Inactive

Ingredients

+Finished Drug

Products

Each NDA and ANDA must include analytical procedures necessary to ensure the identity, strength,quality, purity and potency of the drug substance and drug product. Each BLA must include a fulldescription of the manufacturing process, including analytical procedures that demonstrate themanufactured product meets prescribed standards of identity, quality, safety, purity, and potency.

FDA CDER, Analytical Procedures and Method Validation for Drugs and Biologics, Guidance for Industry, July 2015

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCJj9i5vvl8kCFQlYJgodiR8GAw&url=http://www.horn-pharma.de/industries.html&bvm=bv.107467506,d.eWE&psig=AFQjCNHEbHmqYsi4YXc_BNkw5pPjZOdVDg&ust=1447863826504301

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLnh69SamMkCFYZuJgodZ5IISg&url=http://www.shreejipharma.co.in/excipients.html&psig=AFQjCNEp-jqWDihhX0R0LkjsG964zyGieQ&ust=1447872890225575

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCMngi_Ttl8kCFQzUJgodoxoOsg&url=http://www.ampakcompany.com/pharm.htm&bvm=bv.107467506,d.eWE&psig=AFQjCNECmwra-1uBAeLXuaEfijgqqGu64Q&ust=1447863453804528


Regulatory Perspective on Method ValidationGuidelines

ICH: ICH Q2, Validation of Analytical Procedures, International Conference on Harmonization, November 1996

USP: USP General Chapter, <1225>, Validation of Compendia Procedures, The United States Pharmacopeia Convention, official May 1, 2013

FDA: CDER, Validation of Chromatographic Methods, Center for Drug Evaluation and Research, November 1994and Analytical Procedures and Method Validation for Drugs and Biologics, Guidance for Industry, July 2015

ISO 5725-1/-2/-3/-4/-6 and ISO/IEC 17025: STSTP : Validation des procédures analytiques quantitatives : Harmonisation des démarches” Partie I -Generalites :

STP Pharma Prat., 7, 101-138, 2003, Partie II –Statistiques : STP Pharma Prat., 16, 31-60, 2006 and Partie III –Exemples : STP Pharma Prat., 16, 87-122, 2006

European Medicines Agency: EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2 (2012)

OMCL Network of the Council of Europe: PA/PH/OMCL (13) 82 2R (2014)


FDA Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics


FDA on Method Validation


Data Elements Required for ValidationUSP <1225> Requirements

Category 1: Assay for API contentCategory 2: Quantitative and limit tests for impuritiesCategory 3: Dissolution & drug release testsCategory 4: Identification tests

For each category different analytical information is neededAnalytical

Performance Characteristics

Category ICategory II

Category III Category IVQuantitative Limit Test

Accuracy Yes Yes * * NoPrecision Yes Yes No Yes NoSpecificity Yes Yes Yes * YesDetection Limit No No Yes * NoQuantitation Limit No Yes No * NoLinearity Yes Yes No * NoRange Yes Yes * * No* May be required, depending on the nature of the specific test.


Validation Assay of API

Specificity ⚫ Demonstrate that the assay result is unaffected by the presence of impurities or excipientsby spiking drug substance or drug product with appropriate levels of these materials

Linearity

⚫ Minimum of 5 concentrations ranging from 80 to 120% of the test concentration⚫ Calculate

―Correlation coefficient―Y-intercept―Slope of the regression―Residual sum of squares

Accuracy

⚫ For a drug substance, compare test results to the reference standard & calculate recovery⚫ For a formulated product, spike drug product components or drug product with known

amounts of analyte & calculate recovery⚫ 3 levels: 80, 100 & 120%, in triplicates

Precision - Repeatability ⚫ Minimum of six determinations at 100% of the test concentration

Intermediate Precision (Ruggedness) ⚫ Compare 6 test results acquired by different analysts, on different days & different systems

General Guidelines for API Assay ProceduresUSP <1225>


Validation Impurities Method

Specificity ⚫ Demonstrate that impurities can be separated & determined with appropriate accuracy & precision by spiking drug substance or drug product with appropriate levels

Linearity

⚫ Minimum of 5 concentrations ranging from reporting threshold level to 120% of the acceptance criteria

⚫ Calculate―Correlation coefficient―Y-intercept―Slope of the regression―Residual sum of squares

Accuracy

Accuracy should be assessed using drug substance or drug product spiked with known amount of impurities⚫ 3 levels ranging from reporting level to 120% of the specification, in triplicates⚫ Calculate % Recovery

Precision - Repeatability ⚫Minimum of 6 determinations

Intermediate Precision (Ruggedness) ⚫ Compare 6 test results acquired by different analysts, on different days & different systems

General Guidelines for Validation of Impurities ProceduresUSP <1225>


SFSTP Commission: harmonized approach


Some Challenges with Validation of Chromatographic Methods

Lack of guidelines Incomplete validation procedure Missing validation criteria

Incomplete Validation SOP’s

Lack of adherence to the validation specifications

Results not consistently calculated

Lab deviations & procedure modifications not recorded

Lack of approval signatures

Incorrect Data Collection & Processing

No retention & traceability of data

Inadequate document control policies

Lack of usernames or passwords

Poor security control over lab electronic data

Poor Documentation Practices


FDA Warning LetterMissing Validation Tests


FDA Warning LetterDeleted and Fabricated Results


Increase Efficiency of Method Validation✓Create, store & approve validation protocols for different method

types & products

✓Execute the entire validation study in one Empower project

Instrument set up, data acquisition, reviewing, approval & reporting

Statistical calculations

✓Perform Design of Experiments (DoE) for Method Robustness & Intermediate Precision

✓Ensure compliance

Check status of each step against validation requirements

Flag out-of-specification (OOS) results

Secure data storage & traceability

Sign off via electronic signatures

Method Validation with Empower ® MVM


Method Validation Workflow with Empower MVM▪ Define validation requirements

‒ Validation tests & acceptance criteria‒ Sample set for each test‒ System precision‒ Approval requirements

▪ Manage study in one project‒ Data acquisition, review & processing‒ Statistical calculations‒ Results review & approval‒ Compliance of ongoing tests against requirements

▪ Validation report templates▪ Customize reports as needed▪ Electronic signatures

Protocol

Validation Study

Reporting


Empower MVM License

Activate license for Empower MVM


Validation Report 11

Workflow

Injection Channel 1 Result 11 Report 111

Report 112

Result 12

Report 121

Report 122

Channel 2

Method Set

Temp = 40ºCFlow = 1 ml/minLambda =273 nmVial = 1 Volume = 15 ul

Instrumentmethod

Threshold = 2Peak width = 25RT cafeine = 0.9 min

A4MarginsGraphics and tables

Processingmethod

ReportMethod

ID1010ID1003

ID1001ID1002

ID1004

ID1005

ID1006

ID1007

ID1009

ID1008

ID2010

ValidationProtocolMethod

Validation Tests: Specificity, Linearity (5 levels), IntermediatePrecision (Analyst, Column, etc.)

Acceptance criteria:RSD% ≤ 2,0 %,

R ≥ 0,996

Validation Result 11

ID2013

Result 21

ValidationStudy


Empower Validation Project Types

Validation Project Types

▪ Validation Template – create & store validation protocols

▪ Validation Working – validation study‒ Acquire data‒ Review & process ‒ Compare results against validation criteria

(process validation)‒ Create validation reports‒ Sign off electronically


Empower Validation ProjectExample of Empower MVM project

Sample Set Method (SSM)

Sample Set (SS)

Result Set (RS)

Run

Validate

Sign-off

Process

Signed-of Result Set

Validation Results (VR)

Validation Study


Workflow for Method Validation Study with Empower MVM Project Type: Validation Working

Yes

Complete all validation tests

Process validation data & attach validation result ID

Process chromatographic data & attach result set ID

Run sample set to collect data for each validation test & attach sample set ID

Create validation study using previously created validation protocol methodAdd or modify validation tests & attach sample set method to each test if needed

Validation Study Complete

No

Study approval required? Approve

Note: Approve each step of validation if Approvals/Sign Offs are required


Validation Protocol for Impurity MethodCase Study

Imp.

F

API

Imp.

A Imp.

G

Imp.

9

Imp.

HIm

p. C

Imp.

D

Imp.

BAU

0.00

0.02

0.04

Minutes1.10 1.65 2.20 2.75 3.30 3.85 4.40

Processing method: select component type for each peak

Goal: validate a UPLC method for Metoclopramide API & related compounds


Method Validation Protocol Empower MVM

▪ Define validation requirements‒ Validation tests & acceptance criteria‒ Sample set for each test‒ System precision‒ Approval requirements

Protocol


Creating Validation Protocol Project Type: Validation Template


Workflow for Creating Validation Protocol Method Project Type: Validation Template

Identify ▪ Compound Type▪ Analytical Method Type▪ Development Phase▪ Protocol Comments

Specify Validation Test

Create Validation Protocol

Method

Define▪ Acquisition Parameters (required)▪ Processing Parameters (required)▪ Acceptance Criteria (optional)▪ Sample Set Method (optional)

Add Validation Test?

YesNoSystem Precision Required?

Approval(s)/Signoff(s)required?

No

Skip System Precision tab

Yes

No

Skip Approval/ Signoff tab

YesSave Validation Protocol

Validation ProtocolMethod Complete


Protocol Setup


Method ClassificationValidation Protocol1. Select compound type

2. Select analytical method type

3. Select development phase


Validation TestsValidation Protocol

Typical validation characteristics


Validation Test Parameters for Linearity Validation Protocol

Example 1: Linearity Test


Validation Test Parameters for Linearity Validation Protocol (continued)

Example 1: Linearity Test

Enter• Criteria• Levels• # of preparations• # of injections per prep.

Need total of 21 injections!

7 levels


Validation Test Parameters for Linearity Validation Protocol (continued)

Complete data acquisition requirement for linearity


Linearity: Processing and Acceptance CriteriaValidation Protocol

Processing & Acceptance Criteria

for Linearity


Linearity: Processing and Acceptance CriteriaSelection of Validation Target Response Factor & RRF Formula


Linearity: Acceptance Criteria for Component TypeSet Acceptance Criteria for Components

Component Types same as in processing method

Select component type, channel, matrix, significance level


Linearity: Acceptance Criteria for Component Type (continued)

Target RF Source

FitWeighting

Average by


Select Criteria Table

Linearity: Relative Acceptance Criteria


Linearity: Acceptance Criteria Field Types


Linearity: advanced conditional programming

LT(ROUND(@Vr:Assessed Field Mean,-3),0.01)*(@Vr:Assessed Field % RSD) LTE 30,0 with precision of 1


Acceptance Criteriafor UPLC method

Acceptance Criteria Per Component

Linearity: Acceptance Criteria per ComponentUPLC Method


Acceptance Criteria Per Component Type per Level

Define criteria for specific level if needed

Linearity: Criteria per Component Type per Level


Create Sample Set Method for LinearityValidation Protocol

▪ Create a sample set method to meet the validation test acquisition requirement (total of 21 injections)

▪ Then, attach a Linearity sample set method

Attach Sample Set


▪ Display ‘linearity column’ ▪ Select injections specific for

linearity▪ Levels, # of injections &

preparation must match validation requirements

▪ Total of 21 injections are needed for linearity

Sample Set Method for Linearity


Linearity with Test Parameters and Sample Set Validation Protocol

‘SSM Status’ meets requirements ‘SSM Status’ X does not meet requirements

Attach sample set

method

Sample set method must match the acquisition requirement


Accuracy TestValidation Protocol

Example 2: Accuracy Test

Select ‘Accuracy’ from validation list &

enter test parameters


Accuracy: Acquisition Parameters Validation Protocol

Acquisition▪ 3 levels▪ 3 preps & 1 injection/prep▪ Total of 9 injections


Accuracy: Processing and Acceptance CriteriaAssessed Fields

Select parameter or field to be assessed for recovery


Accuracy: Processing and Acceptance Criteria

Acceptance Criteria▪ %Rec: 90 – 100%▪ %RSD: < 10%


Intermediate Precision: 2 AnalystsProtocol

Example 3: Intermediate Precision for 2 analysts

2 analysts using 2 different systems


Intermediate Precision for 2 Analysts: Acquisition

Acquisition▪ Experiment grouped by

analysts▪ 2 experiments

‒ Experiment 1: analyst 1‒ Experiment 2; analyst 2

▪ 6 preps per each analyst with 1 injection

▪ Total 12 injections


Intermediate Precision for 2 Analysts: Acceptance Criteria

▪ Assessed field: Recovery

▪ Acceptance Criteria‒ %Rec: 90 – 100%‒ %RSD: < 10%


Intermediate Precision for 2 AnalystsSample Sets

Need 2 sample set methods

Total of 12 injections: 6 preps by Analyst A & 6 by Analyst B

Analyst A Analyst B


Intermediate Precision for 2 AnalystsAttaching Sample Sets

Attach Sample Set MethodsMUST have 2 sample set methods ▪ Data acquired by Analyst 1▪ Data acquired by Analyst 2

Error for only one sample set


Robustness Validation Protocol

Robustness

Example 4: Robustness


Robustness: Acquisition Validation Protocol

Acquisition • Define # of factors

o column temp.o flow rateo wavelengths

• 2 levels/Factor• 5 center points preps

2 Experimental Designs• Full & ½ factorial

Method ConditionsColum temp. 45°CFlow rate 0.60 mL/minWavelength 270 nm


Robustness: Full Factorial Experiment DesignValidation Protocol

Full Factorial 8 experiments with combination of: • column temp.• flow rate• wavelengths



Create Sample Set Method with Empower® Sample Set Generator

Open MVM Robustness Test

View Factors in Sample Set Generator

“Map” factors to instrument or sequence parameters

Select blank & System Suit Strategy

Click “Generate”

Sample Sets & Method Sets Created


Robustness Sample Set for Full Factorial Created using a Sample Set Generator

Full Factorial 8 experiments with combination of:• column temp.• flow rate• wavelengths



Robustness Partial Factorial Experiment DesignValidation Protocol

1/2 Factorial4 experiments with combination of: • column temp.• flow rate• wavelengths



Robustness: Processing and Acceptance CriteriaValidation Protocol

Criteria to assess the USP Rs

USP Rs ≥ 2.0


Validation Protocol Example Project Type: Validation Template

Validation protocols are customizable

Typical Validation Characteristics


Efficient Sample Sets to Reduce Analysis TimeValidation Protocol

ONE sample set for multiple validation tests▪ Select injections for each

test


System Precision RequirementsValidation Protocol

System suitability criteria


Approval Requirements Validation Protocol

Approval requirements for different steps


Approvals/Sign OffsValidation Protocol

Enter username/password

Approve or Disapprove Protocol Method


Summary

Organized & completed validation protocol is critical to a successful validation

Validation protocol with Empower MVM– Validation test with data acquisition & acceptance criteria requirements– Create sample set methods – MVM checks sample set methods for adherence to the acquisition requirements

& flags any errors– Electronic approval– Improves compliance!!!


Validation Study Example Project Type: Validation Working

✓Each validation step checked for adherence to the requirements

✓OOS results flagged

✓Unique IDs assigned for data traceability

✓Electronic Sign Off(s)


Conclusions

Empower MVM Software

Improve compliance

Integrate protocols & specifications Monitor status of ongoing tests Review & approve data via electronic signatures Monitor audit trails & user privileges

Increase efficiency Manage the entire study in one place Automated & customizable reporting

Reduce errors Perform statistical calculations No more spreadsheets or additional software

Confidence Adherence to the validation requirements Eliminate transcription errors No more security concerns


References– ICH Q2B, Validation of Analytical Procedures, International Conference on Harmonization, November 1996. – USP General Chapter, <1225>, Validation of Compendial Procedures, The United States Pharmacopeia Convention,

official May 1, 2013. – US FDA, Analytical Procedures and Methods Validation for Drugs and Biologics: Guidance for Industry, July 2015– Maziarz M., McCarthy S.M., Wrona M., Increasing Efficiency of Method Validation for Metoclopramide HCl and Related

Substances with Method Validation Manager Software, Application Note [2014], Part Number 720005111EN

Consultation Services – Please contact Ilse Hoes ([email protected])

Resources

Documents

Empower MethodenValidierungsManager MVM · preservatives, flavoring agents Inactive Ingredients + Finished Drug Products ... Compare 6 test results acquired by different analysts,