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Pharmaceutical Development with Focus on Paediatric formulations. WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008. Analytical Method Development. Presented by: Birgit Schmauser, PhD Federal Institute for Drugs

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pharmaceutical development with focus on paediatric formulations
Pharmaceutical Development with Focus on Paediatric formulations

WHO/FIP Training Workshop

Hyatt Regency Hotel

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008

analytical method development
Analytical Method Development

Presented by:

Birgit Schmauser, PhD

Federal Institute for Drugs

and Medical Devices (BfArM)

b.schmauser@bfarm.de

analytical method development3
Analytical Method Development

In this presentation:

  • Standards in developing analytical methods for
    • Originator and multisource generic FPPs
      • Specifications
      • Stability
  • Parallel development of analytical methods for cleaning validation
analytical method development4
Analytical Method Development

Originator, First-timeGeneric and Multisource Generic

analytical method development5
Analytical Method Development
  • HPLC-method to assay potency and purity – risk assessment
analytical method development6
Analytical Method Development

Interchangeability (IC) of multisource generic FPPs

(Essential similarity with Innovator FPP)

Pharmaceutical + BioequivalenceEquivalence

IC = PE + BE

analytical method development7
Analytical Method Development
  • Pharmaceutical equivalence
    • FPPs meet the same or comparable standards by use of equivalent analytical methods
      • Same API (chemical and physical equivalence)
      • Same dosage form and route of administration
      • Same strength
      • Comparable labeling
    • Equivalence in pharmaceutical development
    • Equivalence in stability
    • Equivalence in manufacture (WHO-GMP)
analytical method development8
Analytical Method Development
  • Prequalification requirements
    • Validation of analytical methods is a prerequisite for prequalification of product dossiers
      • Non-compendial APIs and FPPs are tested with methods developed by the manufacturer
      • For compendial APIs and FPPs the „applicability“ of pharmacopoeial methodsto particular products must be demonstrated (verification)
    • Analytical methods must be developed and validated according to TRS 823, Annex 5, Validation of analytical procedures used in the examination of pharmaceutical materials; ICH Q2 (R1)
      • To be used within GLP and GMP environments
analytical method development9
Analytical Method Development

Use of analytical methods - generics

analytical method development10
Analytical Method Development

Machine

Man

Methods

calibrated

qualified

characterised

documented

robust

suitable

skilled

qualified

Quality of theanalytical method

Referencestandards

Vibrations

Time

Analysts´support

Irradi-ations

Tempe-rature

Supplies

Humidity

Quality

Material

Milieu

Management

  • Prerequisites for analytical method validation
    • Six “M”s
analytical method development11
Analytical Method Development

Method development

Initital Method Development

Development Plan –Project

Pre-Validation Evaluation

Method Optimization

Robustness

System Suitability

Customer EvaluationTesting

Validation Experiments

PeriodicallyMonitoring/Reviewof Methodsin Control Labs

Method TransferExperiments

Filed Method in Use

  • Method development life cycle

Planning

Development and Validation Policy

Objectives/Requirements of Method

Information Gathering

Resource Gathering

From: Analytical Chemistry in a GMP Environment. Edited by J.M. Miller and J.B. Crowther, ISBN 0-471-31431-5, Wiley & Sons Inc.

analytical method development12
Analytical Method Development
  • Validation should verify the suitability of an analytical method for its intended purpose
  • Validation should be founded on method development performed beforehand that suggest thesuitability and robustness of the method
  • Validation may be performed in different ways (individual purpose) according to common standards
slide13
Validation protocol
    • Method principle / objective
    • Listing of responsibilities
      • Laboratories involved and their role in the validation
    • Method categorization
    • List of reagents (including test lots) and standards
    • Test procedures to evaluate each validation parameter and proposed acceptance criteria
    • Plan or procedure when acceptance criteria are not met
    • Requirements for the final report
  • The validation process cannot proceed until the protocol and all parties involved approve the acceptance criteria
analytical method development14
Analytical Method Development
  • Innovator versus Generics
analytical method development15
Analytical Method Development
  • Validation Characteristics
analytical method development16
Analytical Method Development
  • Accuracy and precision

Accurate & precise

Accurate & imprecise

Inaccurate &

precise

Inaccurate & imprecise

analytical method development17
Analytical Method Development
  • Precision
    • Expresses the closeness of agreement between a series of measurements obtained from multiple sampling of the same homogenous sample
    • Is usually expressed as the standard deviation (S),variance(S2) or coefficient of variation(RSD) of a series of measurements
    • Precision may be considered at three levels
      • Repeatability(intra-assay precision)
      • Intermediate Precision(variability within a laboratory)
      • Reproducibility(precision between laboratories)
analytical method development18
Analytical Method Development
  • Normal distribution, probability function [P(x)]and confidence interval [CI]
    • Probability (P), that measurements from a normal distribution fall within [µ-xn, µ+xn] for xn = ns is described by the “erf-function” (µ= mean):
  • An interval of ± 3 scovers 99.73% of values

Number of times each value occurs

s

s

Values

2s

2s

3s

3s

analytical method development19
Analytical Method Development
  • Normal distribution, probability function [P(x)] and confidence interval [CI]
    • Probability-P Confidence interval [CI]centered around the mean [µ]in units of sigma [s] described by“inverse erf-function”:
    • A CI of 95% includes values± 1.95 s around the mean
analytical method development20
Analytical Method Development
  • Relationship of variability, probability and reliability of data
    • High variability of data (large s) generate large confidence intervals and thus lower the reliability of the mean
    • Low variability of data (small s) generate small confidence intervals and thus increase the reliability of the mean
analytical method development21
Analytical Method Development
  • Repeatability
    • Six replicate sample preparation steps from a homogenously prepared tablet mixture (nominal value of API 150 mg)

Mean ± 3 SD =Confidence interval of 99.73%

98.96 ± 3x1.32% = 95% - 102.92%

analytical method development22
Analytical Method Development
  • Intermediate precision
    • Expresses within-laboratories variations (different days, different analysts, different equipment etc.)

Mean ± 3 SD: (177252  100%)

Analyst 1: 98.96% ± 3 x 1.32%

Analyst 2: 99.12% ± 3 x 0.28

Analyst 3: 100.70% ± 3 x 0.51

Average of 3 analysts ± 3SD:95% - 102.23%

analytical method development23
Analytical Method Development
  • Reproducibility
    • Expresses the precision between laboratories
      • Collaborative studies, usually applied to standardisation of methodology
        • Transfer of technology
        • Compendial methods
analytical method development24
Analytical Method Development

mean

true

  • Accuracy
    • Expresses the closeness of agreementbetween the value which is accepted either as a conventional true valueor an accepted reference value and the value found
      • Sometimes referred to as „TRUENESS“
analytical method development25
Analytical Method Development

To find out whether a method is accurate:

  • Drug substance (assay)
    • Application of the method to an analyte of known purity (e.g. reference substance)
    • Comparison of the results of one method with those of a second well-characterised method (accuracy known)
  • Drug product (assay)
    • Application of the method to synthetic mixtures of the drug product component to which known quantities of the analyte have been added
      • Drug product may exceptionally be used as matrix
  • Drug substance/Drug product (Impurities)
    • Application of the method to samples spiked with known amounts of impurities
analytical method development26
Analytical Method Development
  • Accuracy: Application of the method to synthetic mixtures of the drug product componentsto which known quantitiesof the analytehave been added
  • Recovery reducedby ~10 – 15%

From: Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow Chan,Herman Lam, Y.C. Lee and Xue-Ming Zhang, ISBN 0-471-25953-5, Wiley & Sons

analytical method development27
Analytical Method Development
  • When to expect Accuracy problems
    • Insufficient selectivity of the method
      • Impurity peaks are not resolved and account for assay value
    • Recovery is < 100%
      • Irreversible adsorption of analyte to surfaces of the system
    • Incorrect assay value of a reference standard
      • Due to decomposition of reference standard
    • Incorrect assay value due to change in matrix
      • Analytical laboratory still uses the preceding matrix as standard
analytical method development28
Analytical Method Development
  • Specificity
    • Is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present (impurities, degradants, matrix…)
  • Identity testing
    • To ensure the identity of an analyte
  • Purity testing
    • To ensure accurate statement on the content of impurities of an analyte
  • Assay
    • To allow an accurate statement on the content of an analyte in a sample
analytical method development29
Analytical Method Development
  • Specificity:Overlay chromatogram of an impurity solution with a sample solution

From: Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow Chan,Herman Lam, Y.C. Lee and Xue-Ming Zhang, ISBN 0-471-25953-5, Wiley & Sons

analytical method development30
Analytical Method Development

Specificity and stability

  • Stress stability testing to ensure the stability indicating potential of an analytical method
    • Apply diverse stress factors to the API
    • Apply diverse stress factors to the FPP
      • Stress conditions: e.g. Supplement 2 of Generic Guideline; TRS 929, Annex 5
  • Assure that the API can be assessed specifically in the presence of known and unknown (generated by stress) impurities
  • Assure that known impurities/degradants can be specifically assessed in the presence of further degradants
  • By peak purity assessment and (overlay of) chromatograms
analytical method development31
Analytical Method Development
  • Stress stability studies versus forced degradation studies
analytical method development32
Analytical Method Development
  • Limit of Detection (LOD, DL)
    • The LOD of an analytical procedure is the lowest amount of analyte in sample which can be detected but not necessarily quantitated as an exact value
  • Determination is usually based on
    • Signal to noise ratio (~3:1) (baseline noise)

or

    • Standard deviation of response (s) and Slope (S)
      • 3.3 s/S
analytical method development33
Analytical Method Development
  • Limit of Quantitation (LOQ, QL)
    • The LOQ is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy
      • The quantitation limit is used particularly for the determination of impurities and/or degradation products
  • Determination is usually based on
    • Signal to noise ratio (~10:1) (baseline noise)

or

    • Standard deviation of response (s) and Slope (S)
      • 10 s/S
analytical method development34
Analytical Method Development

LOD, LOQ and Signal to Noise Ratio (SNR)

LOQ

Signal to Noise = 10:1

LOD

Signal to Noise = 3:1

Noise

analytical method development35
Analytical Method Development
  • LOQ
    • Quantitation by SNR is accepted
    • Quantitation by Standard deviation of response (s) and Slope (S) (10 s/S) is more adequate as it involves the response of the actual analyte
    • Best to calculate in the region close to y-intercept
analytical method development36
Analytical Method Development
  • LOQ and impurities
    • In determination of impurities in APIs and FPPs the LOQ should be determined in the presence of API
      • LOQ should be NMT reporting level
      • LOQ should be given relative to the test concentration of API
    • Specificity of impurity determination should always be demonstrated in the presence of API at API specification levels
      • Spiking of test concentration (API/FPP) with impurities at levels of their specification range
analytical method development37
Analytical Method Development
  • Spiking
    • API test concentration (normalised)
      • 0.1 mg/ml (100%)
    • Impurity spiking concentrations
      • 0.001 mg/ml (1%) – specification limit
      • 0.0001 mg/ml (0.1%) – limit of quantitation (minimum requirement)

API at test concentrations

API below test concentrations

analytical method development38
Analytical Method Development
  • Linearityof an analytical procedure is its ability (within a givenrange) to obtain test resultswhich are directly proportional to the concentration (amount) of analyte in the sample
    • If there is a linear relationship test results should be evaluatedby appropriate statistical methods
      • Correlation coefficient (r)
      • Y-intercept
      • Slope of regression line
      • Residual sum of squares
      • PLOT OF THE DATA
analytical method development39
Analytical Method Development
  • Usual acceptance criteria for a linear calibration curve
    • r > 0.999; y-intercept a < 0 to 5% of target concentrationRSD (wrt calibration curve) < 1.5-2%

r > 0.997

r < 0.997

From: Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow Chan,Herman Lam, Y.C. Lee andXue-Ming Zhang, ISBN 0-471-25953-5, Wiley & Sons

analytical method development40
Analytical Method Development
  • Range
    • The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity
analytical method development41
Analytical Method Development
  • Range
    • Assay
      • 80 to 120% of test concentration
    • Content uniformity
      • 70 to 130% of test concentration
    • Dissolution
      • Q-20% to 120%
    • Impurities
      • Reporting level – 120% of specification limit (with respect to test concentration of API)
    • Assay & Impurities
      • Reporting level to 120% of assay specification
analytical method development42
Analytical Method Development
  • Linearity is limited to 150%of shelf life specification of impurities
    • Test concentration can beused to determine impurities
    • To determine drug substance(assay) the test concentrationmust be diluted
    • The range is 0 – ~ 150% ofimpurity specification

From: Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow Chan,Herman Lam, Y.C. Lee and Xue-Ming Zhang, ISBN 0-471-25953-5, Wiley & Sons

analytical method development43
Analytical Method Development
  • Robustness
    • Robustness of an analytical procedure should show the reliabilityof an analysis with respect to deliberate variations in method parameters
    • The evaluation of robustness should be considered during the development phase
    • If measurements are susceptible to variations in analytical conditions the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure
analytical method development44
Analytical Method Development
  • Influence of buffer pH and buffer concentration in mobile phase on retention times of API and impurities
  • Conclusion: The buffer composition should be maintained in a range of 85 ± 0.5%
    • Missing: Acceptance criterion for maximal deviation of retention time should be defined unless justified
analytical method development45
Analytical Method Development
  • System suitability testing
    • Based on the concept that equipment, electronics, analytical operations and samples to be analysed constitute an integral system that can be evaluated as such
    • Suitability parameters are established for each analytical procedureindividually
      • Depend on the type of analytical procedure
analytical method development46
Analytical Method Development
  • Method stability
    • System suitability over time
      • Sample solution stability
        • A solution of stavudine is stable for ~ 2 h, then it starts to degrade to thymine
      • Impurity-spiked sample solution stability
        • A solution containing stavudine spiked with its impurity thyminedoes not allow to clearly distinguish between degradation and spike
        • A solution containing stavudine of a FPP-stability sample solution does not allow to clearly distinguish between FPP-stability degradation and sample solution degradation
        • Should be analysed immediately
analytical method development47
Analytical Method Development
  • When to be „surprised“ about validation data:
    • Precision ofimpurity determination
    • Precision ofAPI determination
    • Method precision ofreleased API (dissolution)
analytical method development48
Analytical Method Development
  • Specification range (USL-LSL)
    • Process variability (usually ± 2 SD)
    • Analytical variability (± 3s)
      • ~ NMT 30% of total specification range
  • Analytical variabilityProcess variability
    • Reliability of evaluation of major process variables by analytical procedures depends on analytical variability
    • Impurities
      • LOQ and specification limit (e.g. qualification limits NMT 0.15%)
        • Response factors (LOQ modified by response factor)
analytical method development49
Analytical Method Development
  • Methods for cleaning validation
    • Method for assay and related substances used in stability studies of API and FPP
      • Specificity (in samples taken from a cleaning assessment)
      • Linearity of response (from 50% of the cleaning limit to 10x this concentration; R2≥0.9900)
      • Precision
        • Repeatability (RSD ≤5%)
        • intermediate precision [ruggedness (USP)]
        • Reproducibility
      • Limits of detection and quantitation
      • Accuracy or recovery from rinsate (≥80%), swabs (≥90%), and process surface (≥ 70%)
      • Range (lowest level is at least 2x higher than LOQ)
analytical method development50
Analytical Method Development

Summary

  • Analytical procedures play a critical role in pharmaceutical equivalence and risk assessment/management
    • Establishment of product-specificacceptance criteria
    • Assessment of stability of APIs and FPPs
  • Validation of analytical procedures should demonstrate that they are suitable for their intended use
  • Validation of analytical procedures deserves special attention during assessmentof dossiers for prequalification