monograph changes
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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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