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Pharmaceutical Development. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007. Pharmaceutical Development. Analytical Method Development

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Pharmaceutical Development

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

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Pharmaceutical Development

Analytical Method Development

Presenter: János Pogány, pharmacist, PhD

[email protected]

WHO expert

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Analytical Method Development

Outline and Objectives of presentation

  • Introduction, guidelines

  • Dossier requirements

    • Assay

    • Related substances

    • Other issues

  • Main points again

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Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Introduction, guidelines

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Interchangeability (IC) on Paediatric




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Pharmaceutical equivalence on Paediatric

  • FPPs meet same or comparable standards (e.g., marketing authorization, analytical methods)

    • Same API(chemical and physical equivalence)

    • Same dosage form and route of administration

    • Samestrength

    • Comparable labeling

  • Pharmaceutical development equivalence

  • Stability equivalence

  • WHO-GMP(manufacturing equivalence)

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Prequalification requirements on Paediatric

  • Analytical method validation is required by WHO for the prequalification of product dossiers. Non-compendial ARV APIs and FPPs were/are tested with methods developed by the manufacturer.

  • Analytical methods should be used within GMP and GLP environments, and must be developed using the protocols and acceptance criteria set out in the ICH guidelines Q2(R1)

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Guidelines used in PQP on Paediatric

  • „WHO-GMP 4.11 „It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures.”

  • Appendix 4. Analytical method validation(in WHO Expert Committee on Specifications for Pharmaceutical Preparations. 40th Report. Geneva, WHO, 2006 (WHO Technical Report Series, No. 937).

  • Validation of analytical procedures:text and methodology Q2(R1)ICH Harmonized Tripartite Guidelines, (2005)

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General requirements on Paediatric

  • Qualifiedandcalibrated instruments

  • Documented methods

  • Reliable reference standards

  • Qualified analysts

  • Sample selection and integrity

  • Change control

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Measure of variation (spread of data) on Paediatric



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Mean (average) chart on Paediatric

Abnormal variation of process – special causes

USL Upperspecification limit

Normal variation due to common causes

average = mean

LSL Lower specification limit

Abnormal variation of process – special causes

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A on Paediatric lmost all the measurements of a stable process fall inside the specification limits

USL – LSL681012

Cp1.00 1.331.662.00

OoS results: .27%.6 ppm

64 ppm2 ppb

Capable process

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NEVIRAPINE – Reference Standard on Paediatric

System suitability requirement:

RSD is NMT 0.85%

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Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Dossier requirements

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Use of analytical methods - on Paediatric Formulationsgenerics

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A on Paediatric Formulationsnalytical procedure characteristics

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Accuracy - ISO 5725 1-6 on Paediatric Formulations

Source: ISO. 1994. ISO 5725 1-6: Accuracy (Trueness and Precision) of Measurement Methods and Results. ISO, Geneva, Switzerland.

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Accuracy and precision on Paediatric Formulations

Inaccurate and imprecise



Accurate and precise

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Percent accuracy on Paediatric Formulations(hypothetical figures)

The data show that the recovery of analyte in spiked samplesmet theevaluation criterion for accuracy(100 ± 2.0% across 50–130% of target concentrations).

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Percent accuracy on Paediatric Formulations(hypothetical figures)

Red line: LA Green lines: USL and LSL

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The on Paediatric Formulationsprecision(VARIABILITY) of an analytical procedure is usually expressed as the standard deviation (S), variance (S2), or coefficient of variation (= relative standard deviation, RSD%.) of a series of measurements.

The confidence interval (CI) should be reported for each type of precision investigated.

Precision (of any process)

Measured meanReal mean


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Repeatability on Paediatric Formulationsexpresses the precision(spread of the data, variability) under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.

Repeatability (of any process)

Measured mean


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Repeatability on Paediatric Formulations(hypothetical figures)

The repeatability precision obtained by one analyst in one laboratory was 1.25% RSD for the analyte and, therefore, meets the evaluation criterionof RSD ≤2%.

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Intermediate precision on Paediatric Formulations expresses within-laboratories variations. #1, #2 and #3: different days, different analysts, different (manufacturing)equipment, etc.

Reproducibility expresses the precision between laboratories #1, #2 and #3 (collaborative studies, usually applied to standardization of methodology).(Transfer of technology)

Intermediate Precision and Reproducibility (of any process)

Measured means

Intermediate precision or Reproducibility

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Intermediate precision on Paediatric Formulations(ruggedness)

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Specificity (selectivity) on Paediatric Formulations

  • Specificity is the ability to assess unequivocally the analyte in the presence of components, which may be expected to be present. Typically these might include impurities, degradants and excipients.

  • An example of specificity criterion for an assay method is that the analyte peak will have baseline chromatographic resolution of at least 2.0 minutes from all other sample components

  • Stability indicating analytical methods should always be specific.

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Identification – a special case on Paediatric Formulations

  • Diethylene glycol (DEG) in paediatric dosage forms has been implicated as the causative agent in numerous deaths since 1937. The victims were mainly children.

  • Illustrative analytical issues of investigation

    • IR identity test was able to detect DEG at about 20 %w/w

    • Testing of DEG in Glycerol (and in Propylene Glycol) was recommended with a LOD (sensitivity) of NLT 0.1 %. For detecting DEG at low levels, GC seemed preferable.

    • The assay was the most relevant test (accurate within ± 0.2%)

  • Illustrative regulatory issues

    • Legislation

    • GMP

  • Specificity is an essential but not sufficient characteristic of identification

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Specificity on Paediatric Formulations(hypothetical figures and data)

HPLC chromatograms of (a) API reference standard, (b) FPP and (c) placebo

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SPECIFICITY – degradants on Paediatric Formulations

There were no peaks in the placebo chromatogram at the retention times of nevirapine (N), methylparaben (MP) and propylparaben (PP) peaks.

*Sum of N, MP and PP peak areas. The three ingredients can be assessed in the presence of (non-expected) degradants. The peaks are homogeneous and pure. The method is selective, specific and stability-indicating.

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LOD, LOQ and SNR on Paediatric Formulations

  • Limit of Quantitation (LOQ)

  • Limit of Detection (LOD)

  • Signal to Noise Ratio (SNR)





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LOD and LOQ on Paediatric Formulations(hypothetical figures)

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LOD and LOQ on Paediatric Formulations

  • The limit of detection (LOD) is defined as the lowest concentration of an analyte in a sample that can be detected, not quantified. It is expressed as a concentration at a specified signal:noise ratio (SNR), usuallybetween 3 and 2 :1.

  • In this study, the LOD was determined to be 0.086 μg/ml(Impurity 1) with a signal:noise ratio of 3.6 : 1

  • The limit of quantitation (LOQ) is defined as the lowest concentration of an analyte in a sample that can be determined with acceptable precision and accuracy under the stated operational conditions of the method. The ICH has recommended a signal:noise ratio (SNR) of 10:1.

  • The LOQ was 0.171 μg/ml(Impurity 1) with a signal:noise ratio of 11.3. The RSD for six injections of the LOQ solution was ≤2%.

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Linearity on Paediatric Formulations expresses differences in precision at different points of a given range.

„The linearity of an analytical procedure is its ability (within a given range) to obtain test results, which are directly proportional to the concentration (amount) of analyte in the sample.”




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Linearity and range on Paediatric Formulations

Acceptance criterion: correlation coefficient should not be less than 0.9990

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Linearity and range on Paediatric Formulations

  • Concentration range1.0–1.3 mg/ml (10–130% of the theoretical concentration in the test preparation, n=3)

  • Regression equation was found by plotting the means ofpeak area (y) against the analyte concentration (x) expressed in %:

    y = 36.124x -7.2984 (R2 = 0.9998).

  • The regression coefficient demonstrates an excellent relationship between peak area and concentration of analyte.

  • The analyte response is linear across 10-130% of the target nevirapine concentration.

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Range (minimum requirements) on Paediatric Formulations

  • Assay of an API or a FPP: ±20% of the test concentration.

  • Content uniformity: ± 30% of the test concentration (unless a wider more appropriate range, based on the nature of the dosage form (e.g., metered dose inhalers), is justified).

  • Dissolution testing: ±20 % over the specified range.

  • Impurity: from the reporting level of an impurityto 120% of the specification. (Unusually potent or toxic impurities, LOD and LOQ should be commensurate with ICH requirement.)

  • If assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities to 120% of the assay specification

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Stability on Paediatric Formulations (of the analytical solution) expressesvariationof the measured mean as a function of time.

#1 … First measurements

#2, #3, #4, …n Series of measurements of the same sample within a relatively short period of time.

Stability of analytical solution

Stability Measured means

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Stability of test analytical solution on Paediatric Formulations

An analytical solution prepared from Nevirapine 50mg/5ml Oral Suspension was spiked with Impurity-1 at specification level and stored in a capped volumetric flask on a laboratory bench at uncontrolled room temperature under normal lighting conditions for 25 hours.

Conclusion: the stability of the analytical solution of Impurity-1 is not a source of variation.

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Sensitivity and robustness on Paediatric Formulations

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Robustness on Paediatric Formulations

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Methods for cleaning validation on Paediatric Formulations

  • 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)], and

      • 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)

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Main Points Again on Paediatric Formulations

  • Analytical procedures play a critical role in pharmaceutical equivalence and risk assessment/ management:

    • establishment of product-specific acceptance criteria, and

    • stability of APIs and FPPs.

  • Validation should demonstrate that the analytical procedure is suitable for its intented purpose.

  • HPLC systems and method validation deserves special attentionduring the assessment of dossiers for prequalification.

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THANK YOU on Paediatric Formulations