Evolution & Changes in Monograph/Guidelines: Issues in Analytical Development

Dr. Bhaswat S. ChakrabortySenior Vice President, R&D, Cadila Pharmaceuticals

Waters Technology Seminar, Hyderabad, Dec. 10, 2008

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Hood et al. Nature Biotechnology  22, 1215 - 1217 (2004)

Main Changes in Guidelines and Monographs From an analytical perspective, the main changes have been

More and more drugs are now covered by pharmacopeial monographs Assay and RSs better defined

Compendial methods exist Better understanding the sources of impurities FDA guidances on method validation, impurity profiling are in place and

harmonized Q1, Q2, Q3, Q6A, FDA Analytical guidelines USP 31 Ch <1225>, <1226> Genotoxic impurities guidelines Association (Mfg., Medical, Scientific) guidelines Erudite papers

Although, most of the changes have been an improvement, the volume and complexity have also increased tremendously

Guidelines and Pharmacopeial Monographs Documents of excellence BUT…. Scientific (public or private standards) but treated as public

“must do” regulations Regulatory guidelines USP, NF, IP, BP

Often taken very seriously (rather rigidly) by reviewers and expert audit inspectors

Open to interpretations Often encourage inclusion of “nice to know” in the same

breadth as the “must know” information as long as it makes scientific sense

Can be idealistic rather than pragmatic

Today For a moment, understand the development of guidelines and

monographs and why they can be sometimes complex and over-demanding

Current validation The thrust on keeping the target error in control Special stress on impurrities

Unknown, toxic When do we

Method transfer Method verification Full (de novo) method validation Examples

Write to FDA and consult Experts?Discussion

Guidelines DevelopmentRegulatory agencies appoint Internal Guideline Committees or Working Groups or Expert Advisory Committees They deliberate

and come up with draft guidelines

Draft guidelines are commented upon by (may be 1-4 rounds)

ExpertsIndustryProvincial Formularies, FDAs or governmentsOther stakeholders like professional associations

Regulatory Impact

Analysis

Acceptance by the Ministry/Agency

& the Stakeholders

Monographing Process

Source: R. Williams & Expert Project Team 4, J Pharm Biomed Anal (2006), 40, 3-15

ICH Method Validation Parameters LOD LOQ Precision Accuracy Specificity Linearity Assay range Robustness System suitability

Data Elements Required for Validation

AnalyticalPerformance

CharacteristicsCategory I

Category II

Category III Category IVQuantitative Limit Tests

Accuracy Yes Yes * * No

Precision Yes Yes No Yes No

Specificity Yes Yes Yes * Yes

Detection Limit No No Yes * No

QuantitationLimit No Yes No * No

Linearity Yes Yes No * No

Range Yes Yes * * No

*May be required, depending on the nature of the specific test.

Data Elements Required for Validation Category I – Analytical procedures for quantitation of major components

of bulk drug substances or active ingredients(including preservatives) in finished pharmaceuticals products.

Category II – Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceuticals products. These procedures include quantitative as says and limit tests.

Category III – Analytical procedures for determination of performance characteristics (e.g., dissolution, drug release).

Category IV – Identification tests.

For each category, different analytical information is needed. Listed in Table 2 are data elements that are normally required for each of these categories.

More & More Reflection of ICH in USP During the 2000–2005 cycle, USP created a Guideline for

Submitting Requests for Revision to USP–NF The Guideline provides instructions to Sponsors intending to

submit Requests for Revision and harmonizes many elements of the USP monograph with the ICH Quality approaches

USP expects to revise this document continuously For selected candidate reference materials, USP will add a

section that provides a protocol with study design and analysis approaches

This protocol will focus initially on small molecule ingredient and impurity candidate materials and can be expanded subsequently for other candidate materials as needed

Source: R. Williams & Expert Project Team 4, J Pharm Biomed Anal (2006), 40, 3-15

Analytical Procedures & Validations Regulatory or Compendial

Analytical procedures in Pharmacopeia/Formulary recognized legally Alternative

Equal to or better than the regulatory analytical procedure. Provide a rationale for its inclusion and identify its use

e.g., release, stability testing validation data, and comparative data to the regulatory analytical procedure

Stability-indicating assay A validated procedure that can analyse changes with time in the pertinent

properties of the drug substance and drug product Validations

Full validation Revalidation

Verification or Partial validation System suitability Method transfer

Full Validation and Revalidation ICH Method Validation Parameters

LOD LOQ Precision Accuracy Specificity Linearity Assay range Robustness System suitability and

Stability of samples over period of analysis Information from stress studies Impurities labeled with their names and location identifiers

….next slide

Full Validation(Prednisolone)

Source: Gorog et al, J Pharm Biomed Anal (1998), 18, 511-525

System Suitability Tailing factor _ Relative retention _ Resolution _ Relative standard deviation (RSD) _ Capacity factor _ Number of theoretical plates

Impurities APIs

[mfg. & storage] Process & drug related organic impurities Inorganic impurities Residual solvents

Formulations Those forming during formulation

Method related Environment related Dosage form factor related

Those forming on aging Ingredient interactions Functional group related degradations

Hydrolysis, Oxidative Photolytic Decarboxylation

Impurities Profiling Pharmacopeial impurities are controlled through the

specifications of Related substances Chromatographic purity tests

System suitability Response factors

Does not consider differences in route of synthesis ICH overcomes this

Stability (Q1) Analytical validation (Q2) Impurities (Q3) Test Procedures and Acceptance Criteria for New Drug Substances and

New Drug Products (Q6A)

Ideal Control of Impurities Identifies all impurities >0.1%

Even <0.1% (sometimes in low ppm) if unusually potent or toxic

In any case, Qualification threshold must well defined

Official reference standards for all impurities are available

Route of synthesis is public or known to regulatory agencies

Both process-related and degradation impurities are identified and quantitated when required

When changes in monograph impurities are published, clear instructions are given whether full, partial or system suitability validations are required

Commitment by manufacturers, regulators, Pharmacopeias to stop counterfeits

ICH Thresholds for Impurity Identification & Quantification (Finished Products)

Dose Identification (%) Quantification (%)

<1 mg 1.0 1.01-10 mg 0.5 1.010-100 mg 0.2 0.5100 mg – 2 g 0.1 0.2>2 g 0.1 0.1

Yet there are Many issues And the common ones are: If the method is compendial, do I get a method transfer only with

a DMF sourcing? or Validate partially? Validate fully?

Should my method cover all known and unknown impurities? What should be range and LOQ? Should LOQ be a part of impurity specifications?

Process Impurities(Trimethoprim)

Source: Rao & Nagaraju, J Pharm Biomed Anal (2003), 33, 335-377

Degradation Products(Ramipril)

Source: Belal et al, J Pharm Biomed Anal (2003), 24, 335-342

Photodegradation(Trifluperazine)

Source: Abdel-Moety, J Pharm Biomed Anal (1996), 14, 1639-1644

Source: J. Ermer, J Pharm Biomed Anal (1998), 18, 707-714

When do You do a Full Validation?

System Suitability Tests (Fenofibrate)

Source: Lacroix et al, J Pharm Biomed Anal (1998), 18, 383-402

System Suitability. Six 5 ml aliquots of the system suitability solution were injected into thesystem. The system was deemed to be suitable if the efficiency of the column, calculated using the fenofibrate peak, was not less than 7000 plates, the resolution between compound V and fenofibrate was not less than 20, the retention time of fenofibrate was about 7.3 min, the relative retention time of compound V about 0.26, and the R.S.D. of the peak response from fenofibrate was not more than 5.0%.

Source: Lacroix et al, J Pharm Biomed Anal (1998), 18, 383-402

Validation vs. Qualification vs. Method Transfer Method Validation (Full Validation)

Assess all appropriate validation characteristics Pre-defined acceptance criteria Follows formal validation protocol/sign off by the QU ICH Guideline:

Q2 (R1): Validation of Analytical Procedures: Text and Methodology Method Qualification (Partial validation, suitable for

it’s intended purpose) Assesses a critical subset of validation characteristics No pre-defined acceptance criteria No official guidelines Suitable for early IND studies, characterization assays

Validation vs. Qualification vs. Method Transfer Method Validation (Full Validation)

Assess all appropriate validation characteristics Pre-defined acceptance criteria Follows formal validation protocol/sign off by the QU ICH Guideline:

Q2 (R1): Validation of Analytical Procedures: Text and Methodology Method Qualification (Partial validation, suitable for

it’s intended purpose) Assesses a critical subset of validation characteristics No pre-defined acceptance criteria No official guidelines Suitable for early IND studies, characterization assays

Validation vs. Qualification vs. Method Transfer Method Transfer

Transfer of validated analytical procedures to a new laboratory Assesses a subset of validation characteristics Pre-defined acceptance criteria No official guidelines

Method Transfer Transfer of validated analytical methods from originating

laboratory to secondary laboratory To ensure comparability in the validation characteristics between laboratories To prevent and/or detect changes in data trend

Assess a subset of validation parameters Using Equivalence Testing

Precision and Accuracy Using Key attributes

Precision LOD/LOQ Accuracy Identity Linearity

It may be useful to analyze historical data from the originating site to identify the greatest causes of variance in an assay to improve transfer success

Method Transfer

A recommended approach is to use equivalence testing as the statistical approach Assumes not equivalent as the default hypothesis

Concludes equivalent with enough evidence Does not penalize large sample size Need a predefined meaningful allowable difference

Traditional hypothesis testing assumes equivalence as default

Rewards assays with high variability Penalize large sample sizes, tiny differences will be significant if

sample size is large enough Not a reasonable approach

Prior to Formal Method Transfer

Receiving laboratory should perform the method Helps to determine where there are

differences and gaps in documentation Lack of detailed test method instructions

Assay Conditions Calculations System Suitability

Differences with instrumentation or reagents

Prior to Formal Method Transfer

Training of Personnel Review of relevant SOPs Observation of test procedure Performing test procedure

Helpful to include development, qualification and validation reports to recipient laboratory

Method Transfer

Typical Transfer should include: More than one lot of material

Reference Standards Samples at extremes of the established acceptable

limits Stress samples

One laboratory, typically the originating laboratory, will prepare initial samples to be tested at both laboratories.

One analyst at the originating laboratory and multiple analysts in the receiving laboratory

Method Transfer Protocol Test Method

Parameters being assessed Precision, specificity, etc.

Sample Preparation/Reagent Performance Parameters

Different analyst on different days Pre-defined Acceptance Criteria Statistical Analysis Sign-off by Quality Assurance Unit

Successful Method Transfers Pre-defined acceptance criteria using an

appropriate statistical approach. Prior to transfer, perform assay, train

personnel and determine if differences in equipment and reagents effect the assay results.

Test more than one lot of material.

Successful Method Transfers Include in the Regulatory Submission:

Transfer Protocol Final Transfer Study Report

Include representative and/or full data sets Deviations Statistical analysis Conclusions

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