Implementing New USP Chapters for Analytical Method Validation

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Implementing New USP Chapters for Analytical Method Validation

March 2010

Ludwig Huber

Fax.: +49 7243 602 501 E-mail:

[email protected]

Today’s Agenda

• Handling Method Changes vs. Adjustments – EU, ICH; FDA, Enforcement Practices

– (Recent) Recommendations from USP and EP – Changing HPLC column particle size and ID

• Verification of Compendial methods according to USP <1226>

• Transferring methods: New USP proposal

• Interactive Exercises

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Reference Material

• Master Plan: Transfer of Analytical Methods

• SOP

– Validation of Analytical Methods – Transfer of Analytical Methods – Method Changes vs. Adjustments

• USP Stimuli Paper: Transfer of Analytical Procedures:

A Proposal for a New General Chapter (Link)

References

www.labcompliance.com/misc/conferences/dublin-aiq.aspx (available until April 10, 2010)

FDA CGMP Regulation -

21 CFR Part 211.194 (a) (2)

• Laboratory records shall include a statement of each method used in the testing of the sample

used in the testing of the sample.

• The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper

standards of accuracy and reliability as applied to the product tested

• If the method employed is in the current revision of the United States Pharmacopoeia, or in other recognized standard

references or is detailed in an approved new drug application and

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references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice.

• The suitability of all testing methods used shall be verified under actual condition of use.

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FDA Guidelines For Method Validation

• Analytical Procedures and Methods Validation (Draft)

• FDA - Industry Guidance

Bioanalytical Method Validation

• Methods Validation for Abbreviated New Drug Applications

pp

• Guideline for Submitting Samples and Analytical Data for Methods Validation

• Validation of Chromatographic Methods

Other Guidelines For Method Validation

• ICH - Guidance for Industry - Q2(R1) Validation of Analytical Proceduresy - Terminology and Methodology-

• United States Pharmacopeia 32, <1225> : Validation of Compendial Methods,

• United States Pharmacopeia 32, <1226> : Verification of Compendial Methods

• United States Pharmacopeia 32 <621>

• United States Pharmacopeia 32, <621>

Recommendations for Accepted Adjustments to Validated Methods :

ICH = International Conference for Harmonization

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Change vs. Adjustment of Methods

• Receiving Laboratory can not get performance as specified by transferring Laboratory

• Transferring to New Technology

1. Check USP <621> and EP 5, Section 2.2.4 for allowed variables, e.g., flow rate, col. Temperature 2. If modifications are in the allowed range, perform

system suitability testing.

3 If SST pass continue with analyses Transferring to New Technology

3. If SST pass, continue with analyses.

If not make further modifications. If total modifications are in allowed ranges, go back to 2. Otherwise revalidate

USP 30 - Supplement 2

<621>: Method Variations

• Adjustments of operating conditions to

t t it bilit i t

meet system suitability requirements may be necessary

• The user should verify the suitability of the method under the new conditions by assessing the relevant analytical

performance characteristics potentially ff t d b th h

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affected by the change

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Allowed Variations USP/EP

HPLC Column

USP EP

Length ±70% ±70%

Internal diameter ±25% ±25%

Particle size Reduction of 50%, no increase

Reduction of 50%, no increase

Allowed Variations USP/EPs

HPLC

USP EP

Flow rate ±50% ±50%

Column Temperature

±10 Deg C ±10%

Max 60 C Injection volume Change allowed as

long as SST criteria are met

May be decreased (if LOD and repeatability ok..)

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Allowed Variations USP/EP

HPLC

USP EP

pH ±0.2 ±0.2 (+-1% for

neutral substances) UV wavelength No change outside

manufacturer specs

No adjustment permitted

manufacturer specs permitted Conc. of salts in

buffer

±10% ±10%

Allowed Variations USP/EP

HPLC M bil Ph C iti

USP EP

Composition of mobile phase

Minor components (<50%)

±30% or ±10%

absolute whichever is

Minor components

±30% or ±2%

absolute whichever is larger

HPLC Mobile Phase Composition

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absolute whichever is smaller

larger

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Allowed Variations USP/EP

Gas Chromatography - Column

USP EP

Length ±70% ±70%

Internal diameter ±50% ±25%

Particle size Changes allowed

SST t

-50%, no increase

SST must pass

Film Thickness -10 to +100% -10 to +100%

Allowed Variations USP/EP

Gas Chromatography

USP EP

Flow rate ±50% ±50%

Oven. Temperature ±10% ±10%

Injection volume Change allowed as May be decreased Injection volume Change allowed as

long as SST criteria are met

May be decreased (if LOD and repeatability ok..)

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Handling Instrumental Changes (USP only, HPLC only)

• Going from 4.6 to 2.1 or 1.0 mm columns to save bil h

1. Colum diameter; As of Dec 1, 2009 (USP 32-2), column diameter can be reduced as long as flow rate is also reduced (performance based approach) 2 P ti l i

mobile phase

• Reducing particle size to reduce analysis time

2. Particle size

A USP discussion paper also suggests a

performance based approach, but not yet official

USP Stimuli Paper: Transfer of HPLC Procedures to suitable Columns of Reduced Dimensions and Particle Sizes

Flow Diagram: Change vs. Adjustment

System Suitability

Test

yes Continue with Pass?

Adjust method parameters

yes

sample analysis no

Pass?

no yes

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Partial or full Revalidation Changes in permitted

range?

Document Run System Suitability Test yes

no

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Validation of Compendial Methods?

• FDA GMPs refer to USP or other standards

• Typically no need for validation, if the method has not been modified

• Suitability must be verified under conditions of actual use

• No further guideline from FDA and equivalent international agencies

g

• USP has developed drafts on ‘Verification’ of Compendial Procedures

USP <1226>: Verification of Compendial Procedures)

USP <1226> - Goal and Scope

• Clarify on how to verify the suitability of compendial methods

• Provide consistency between laboratories and regulatory agencies

• Present a high level view of the verification process

• Provide guidelines on how to apply performance characteristics while allowing free flexibility to characteristics while allowing free flexibility to determine which performance characteristics are most appropriate

• For new methods, not retroactive application to already existing methods

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USP <1226> Statements

f

• Users of compendial analytical procedures are not required to validate these

procedures when first used in their laboratories,

• But documented evidence of suitability should be established under actual

diti f

conditions of use.

USP <1226> Verification Process

• Laboratory personal should be qualified to understand and perform the compendial p p methods as written

• Acceptance criteria for verification should be established

• If the verification of the compendial procedure is no successful, it may be concluded that the procedure may not be suitable for use with the

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procedure may not be suitable for use with the article being tested

• It may be necessary to develop and validate an alternate procedure

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USP <1226> Verification Requirements (I)

• Verification requirements should be based on an assessment of the complexity of both the procedure and the material to which the procedure is applied

• Only those characteristics that are considered to be appropriate for the verification of the particular method need to be evaluated

• Some of the analytical performance characteristics as listed in USP <1225> may be used

USP <1226> Verification Requirements (II)

• The degree and extent of the verification process will depend on the verification process will depend on

– The level of training and experience of the user – Associated equipment or instrumentation

– The specific procedural stepsThe specific procedural steps – The material to be tested

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Performance Characteristics to be Considered for Testing

C f

• Chromatographic method: specificity to evaluate impurity profiles of drugs from different suppliers, that are not addressed in the compendial procedure

• Assessment of the limit of detection for an impurities procedure

• Precision of an assay procedure

To demonstrate suitability of the compendial method under actual use

Examples where Verification is NOT Required

• For common compendial test procedures that are routinely performed in a laboratory

– Loss on drying – Residue on ignition

– Various wet chemical procedures, e.g., acid value Simple instrumental methods e g pH measurements

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– Simple instrumental methods, e.g., pH measurements Unless there is an indication that the compendial

procedure is not appropriate for the article under test

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Recommendations for Planning and Execution

1 Develop a verification plan 1. Develop a verification plan

2. Describe test procedure, performance characteristics and acceptance criteria 3. Define and perform critical tests using USP

procedure

4. Compare tests results with acceptance criteria

5. Perform and document assessment

6. Write a statement that the compendial procedure can be used

Recommendations for HPLC Performance Testing

• Application 1: Quantitation of major compounds of drug substances in finished drugs or APIs

T t i i ifi it li it

– Tests: precision, specificity, linearity

• Application 2: Quantitative determination of impurities in drug substances or degradation products in finished drugs

– Tests: Precision, specificity, quantitation limit

• Application 3: Limit tests of impurities in drug pp p g substances or degradation products in finished drugs

– Tests: Specificity, limit of detection

Tests are application and instrument specific

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Recommendations for Deviations

• If the tests don’t pass acceptance criteria, identify

th f th bl

the source of the problem

• Develop corrective action plan – Provide additional training – Use other equipment

• Update verification document

• Repeat the tests

• If successful, document initial results, corrective actions and final results

• If not successful, develop alternative procedure

Verification of Compendial Methods - Steps

Match Define Scope

no Change or

Develop and Validate

Compendial method?

Test for suitability

yes Validate

(full/partial) Document

Corrective Action?

yes

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Document Acceptable?

Root Cause?

no no yes

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Occurrence of Method Transfer

• Sponsor company to contract lab

• Analytical development to QC labs

• Across different sites – The same lab conditions – Different lab conditions

• Existing to new instrumentation – With different specifications

With diff t t h l

– With different technology

• Supplier of material to client

• Transfer to new instruments with different instrument characteristics

FDA 483

• There is no assurance that analytical methods transferred from other laboratories are adequate for transferred from other laboratories are adequate for use in that the current SOP

– Does not requirepredetermined acceptance criteria for the transfer from the technical services laboratory to the Quality control laboratory

– Does not provide provisions for technical

transferfrom an external Quality Control laboratory – Solely requires a ruggedness testif a validation

protocol has been established for the test procedure

Ref: GMP trends

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Warning Letter

Failure to establish and document the

• Failure to establish and document the accuracy and reproducibility of test methods employed. (W-186)

• For example, methods that were

validated at one facility and transferred to xxx site are being used without a methods transfer or revalidation

methods transfer or revalidation protocol. (W-186)

Ref: www.fdawarningletter.com

FDA Warning Letter

• The firm does not have sufficient data to support analytical method transfer

analytical method transfer

• Method transfer protocol, which was prepared to transfer the analytical testing method, did not require testing of the XX (100 mg and 400 mg), and only require testing of one lot of the 200 mgtablets

• The method transfer protocol and the method transfer report were not signed nor dated

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• There was no formal analytical methods transfer facilities

Ref: APV Education Course, Dr. Scheidegger

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FDA Warning Letter

• The firm failed to perform finished product test method transfers for 34 products (W-187)

• The firm has failed to perform method validations, method verifications, or method transfers for any of the laboratory test methods used to test active pharmaceutical ingredients (W-187)

Ref: www.fdawarningletter.com

Definition of Method Transfer

Process that qualifies a laboratory to use an

• Process that qualifies a laboratory to use an analytical test procedure

• Process of establishing documented evidence that the analytical test procedure works in the receiving laboratory as well as it does in the transferring laboratory

Ref: Margareth Marques, Ph.D., US Pharmacopeia

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Why Controlled Method Transfer

Expected by agencies

• Expected by agencies

– The suitability of all testing methods used shall be verified under actual condition of use

• Reduces failure rate

• Improves the quality of the testing at the new place

Problems can come up due to different

equipment, different analysts and lab environment

FDA Guidance on Method Transfer

• We recommend that you hold a training session at which personnel from your reference laboratory demonstrate the method for representatives from p the participating laboratories, to highlight or clarify practical details of the assay method.

• During the training session, you should also discuss all aspects of the protocol(s) to ensure everyone understands the procedures and objectives

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j

• This can help you identify key points that may cause difficulties in the transfer study

Ref: FDA Industry Guidance: Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods

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USP Stimuli Paper: Transfer of Analytical Procedures:

A Proposal for a New General Information Chapter

• Published in Pharmacopeial Forum , Nov 2009

• Provides the basis for a new USP chapter:

Analytical Method Transfer

• Content

– Discussion of 4 types of analytical transfer Elements recommended for transfer of

– Elements recommended for transfer of analytical procedures

– The importance transfer protocol – The analytical procedure and report

Options for Method Transfer

Comparative Testing

• Comparative Testing

• Co-validation

• Complete or partial validation or revalidation

• Omission of formal transfer

Criteria: type of method (simple, complex), experience and capabilities of receiving lab

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Comparative Testing

• Most frequently used

• The same tests are carried out by both labs

• Should only be performed with validated methods

• Used with complex methods

• Requires pre-approved protocol – 2-5 lots analyzed by both labs

• Well defined test procedures and acceptance

Well defined test procedures and acceptance criteria

• Results are compared with a set of pre-determined acceptance criteria

Co-validation

• Received lab is part of original method validation

• Transferring and receiving lab conduct the same g g validation experiments

• Useful for methods not (fully) validated

• Should challenge all USP or ICH validation parameters

• Include receiving lab in validation inter-laboratory tests.

• Ensures harmonization of method at both sites

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A site that performs validation studies is qualified to run the method

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Method Validation on/or Revalidation

Received lab repeats some or all of the validation

• Received lab repeats some or all of the validation experiment

• Done after initial method validation

• Validation parameters depend on the method e.g., – Limit selectivity and limit quantitation for

impurities

– Precision for content uniformity assays

Similar process as verification of compendial methods

Transfer Waivers

• Method is used without special revalidation or testingg

• Reasons should be well justified and documented – Receiving lab already testing the product and is

familiar with the method

– Receiving lab already testing a similar method – Method developer moves from transferring to

i i l b receiving lab

Waiver should be well justified and documented

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Prerequisites

for Successful Method Transfer

Analytical methods validated

• Analytical methods validated – Includes ruggedness testing – Includes robustness testing

• Scope well defined – Sample, matrix

– Performance characteristics acceptance

Performance characteristics, acceptance criteria

– Equipment,

Required Documents

• Transfer Master Plan (TMP) used as frame work

• Transfer project plan or method transfer protocol (MTP)

– Approach for controlled transfer and justification

• SOPS for step-by-step implementation

T l t d f f ffi i d

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• Templates and forms for efficiency and consistency

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Transfer Plan or MT Protocol

• Reason and purpose of the transfer

• Scope of the plan and method transfer

• The approach

• Description of transfer process

• Responsibilities

– Transferring, receiving labs, project owners, QA

• Assumptions

E A l t i th i i l b t f ili ith

– E.g., Analysts in the receiving lab not familiar with the method

• Training details

• Test Plan

MTP = Method Transfer Protocol

Test Plan

• Tests to be performed and test parameters

• Rational behind tests

• Description of materials and samples

• Description of equipment

• Number of lots, batches replicates, injections

• Pitfalls that may be encountered

• Test schedule

• Acceptance criteria

• Documentation, approvals

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Two Step Process

• Step 1: Analysts in receiving familiar with the method

– Ensures that the receiving lab understand the method and have the equipment and expertise to perform the analysis

– Receiving lab performs complete analysis according to the protocol

• Step 2

Step 2

– Comparative tests with the complete transfer study set

Steps for Comparative Testing

• Develop and approve a test plan

• Order missing equipment and materials

• Training

• Concurrent execution of the protocol

• Evaluation of test results

– Compare with acceptance criteria R l ti f d i ti if th

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• Resolution of deviations, if there are any

• Gather all required documents

• Write method transfer report (MTR)

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Experiments - Example

Five replicates of the study samples

• Five replicates of the study samples

• Five replicates of the study samples fortified at 0.5x the lowest expected concentration

• Five replicates of the study samples fortified at 1.5x the highest expected concentration

• Analyze the study sample set over several days

Considerations for Testing

• Number of samples, lots, batches (2-5)

• One or more concentrations (1-3)

• Number of repetitive analysis / sample (4-6)

• One or more analysts? (1-2)

• One or more days? (2-5)

• Equipment from one or more f t ? (1 ll) manufacturers? (1 - all)

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Possible Pitfalls

• Scope of the method not defined – equipment

• Method not fully validated

• Methods are not robust

• Resources not well planned – Equipment, people, time

• Analysts not trained

• Acceptance criteria not well defined

Recommendations for Deviations

• If the tests don’t pass acceptance criteria, identify

th f th bl

the source of the problem

• Develop corrective action plan – Provide additional training – Use other equipment

• Update the procedure

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• If successful, document initial results, corrective actions and final results

• If not successful, develop alternative procedure

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Method Transfer Report

Report items and format to be specified in the study transfer planp

• Summary of method familiarization results

• Detailed results of transfer study

• Description of any deviations and from expected results and how they have been resolved

• Signatures of individuals responsible for transfer t di

studies

• Copies of supporting material, e.g., chromatograms and spectra

• Assessment of the transfer study results

Thank You

I ld lik t th k I would like to thank

• All attendees for your attention

• IVT for organization and invitation to the conference

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