lect. 5+6. 2009-10 eli solomon m.sc 1 validation principles principles of qualification and...

Lect. 5+6. 2009-10Lect. 5+6. 2009-10 Eli Solomon M.ScEli Solomon M.Sc 11

VALIDATION PRINCIPLESPrinciples of qualification and validation which are applicable to the manufacture of medicinal products.

Analytical Method אנליזה מעבדתית

Medical Devices אביזרים ומכשור רפואי )אמ"ר(

Cleaning and Sterilization ניקוי ועיקור

Process: Development, Analysis, and Control. ובקרת תהליך פיתוח ניתוח


Laboratory Method FlowLaboratory Method Flow

APPROVEDAPPROVED

MethodDevelopment

פיתוח

MethodValidation Method

Transfer

וולידציה העברה


Why ValidateWhy Validate• Method validation is completed to ensure that an Method validation is completed to ensure that an

analytical methodology is accurate, reproducible analytical methodology is accurate, reproducible and rugged over specific range that an analyte will and rugged over specific range that an analyte will be analyzed. be analyzed.

• Provides assurance of reliabilityProvides assurance of reliability אמינותאמינות

• FDA ComplianceFDA Compliance התאמה מתועדת לשיטת הבדיקההתאמה מתועדת לשיטת הבדיקה The process of providing documented evidence The process of providing documented evidence that something does what it is indented to that something does what it is indented to do”do”


הגדרת המושג תיקוףValidation

) ) - נספח מתורגם4335מתוך ת”י

לצורך השגה, רישום הליך מתועד3.24וניתוח של התוצאות, הנדרשות כדי לקבוע

מוצר המתאים שתהליך יניב בעקביותלמפרטים שנקבעו מראש.


Validation ProcessValidation Process

Validation

Instruments

MethodValidation

SystemSuitability

Software


USP – Analytical Method Validation

Method Validation

PRECISION - דיק

ACCURACY - דיוק

LIMIT OF DETECTION (LOD)

LIMIT OF QUANTIFICATION (LOQ(

SPECIFICITY ייחודי -

LINEARITY AND RANGE

RUGGEDNESS"קשיחות" -

ROBUSTNESS "חוסן" -


The closeness of agreement between the values obtained in an assay. When the method is

applied repeatedly to multiple sampling of a homogenous sample

Expressed as % SD for a statistically significant number of samples

Should be performed at 3 levels.Repeatability (הדירות) Intermediate Precision ( ביניים) Reproducibility (שעתוק)

Precision Definition דיק -


Precisionדיק - Explanation and Enlargement

Repeatability: )USP analytical Procedure : )USP analytical Procedure Criterion(Criterion(

Same operating condition, short time interval.Same operating condition, short time interval.

Inter-assay PrecisionWithin-lab variations: Different days, analysts, Within-lab variations: Different days, analysts, equipment. Multiple determinations of a single equipment. Multiple determinations of a single sample, controls and reagents analyzed in sample, controls and reagents analyzed in

several several runs, same lab. runs, same lab.


Minimum of 9 determinations covering Minimum of 9 determinations covering specified range of procedure )3 levels 3 specified range of procedure )3 levels 3 replica. replica. each(, or Minimum of 6 determination each(, or Minimum of 6 determination

at 100% test conc.at 100% test conc. )expressed as % )expressed as % CV(CV(

ReproducibilityPrecision between labsPrecision between labsCollaborative studies, not relevant in Collaborative studies, not relevant in

manufacturing facilitymanufacturing facility

Precisionדיק - Explanation and Enlargement


Accuracy Definitionדיוק -

The closeness of agreement between the actual values of the drug and the

measured value

Spiked )known added amount( and Recovery studies are performed to measure accuracy


Expressed as % error between the observed value and the true value

)assay value / actual value x100%(

Accuracy Definitionדיוק – (Cont’)


Accuracy Determination(Cont’)

Drug Substance

Analysis of Reference material Compare results to a second, well characterized

methodImpurities (Quantification)

Analysis of Samples (Drug substances) spiked, with known amounts of impurities


ACCURACY vs PRECISION

Good Accuracy Poor Precision

Good Precision

Poor Accuracy

Good Precision Good Accuracy

The closeness of test results to the true value obtained by the method


Limit of Detection (LOD) Definitionגבול זיהוי -

Lowest Concentration of Analyte in a

Sample that can be detected )not necessarily quantitated(

Limit Test: Above or Below a Certain Level – P / F results

Expressed as Concentration )%, ppb(


Almost never necessary to be determined

May be based on standard deviation )STD( of the response and slope

DL=(3.3)STD / SSTD = Standard Deviation of the response S = Slope of calibration curve

Limit of Detection (LOD) Limit of Detection (LOD) DefinitionDefinitionגבול זיהויגבול זיהוי -- (Cont’)


Limit of Quantification (LOQ) Definition

Lowest concentration of analyte in a sample that can be determined with acceptable precision and accuracy under stated operational conditions

Expressed in Concentration of Analyte

Signal To Noise Ratio )10:1 is typical(


Limit of Quantification (LOQ) Explanation and Enlargement

QL = (10) STD / SSTD = Standard Deviation of the response S = Slope of Calibration curve

DL and QL are validated by analyzing a suitable number of samples

Method should be documented


The ability to measure accurately and specifically The ability to measure accurately and specifically the analyte in the presence of components that may the analyte in the presence of components that may be expected to be present in the productbe expected to be present in the product

The Degree of InterferenceThe Degree of InterferenceActive IngredientsActive IngredientsExcipientsExcipientsImpuritiesImpuritiesDegradation ProductsDegradation ProductsPlacebo IngredientsPlacebo Ingredients

Specificity (Selectivity) DefinitionSpecificity (Selectivity) Definition


Specificity DeterminationSpecificity Determination Qualitative Identification Test

Demonstrate ability to select between compounds of closely related structure

Confirm Positive and Negative results

AssayDemonstrate that the results are unaffected by spiked impurities or excipients


Linearity and Rangeליניאריות ותחום

Linearity The ability of the method to elicit test results

that are directly proportional to concentration within a given range

- Expressed as the Variance of the Slope of the Regression Line

Range• Interval between upper and lower levels of

analyte demonstrated by the method


Prepare Minimum 5 Concentrations )Preferable 6-8 sample dilutions

across the range(

Test each dilution in triplicates for 3 runs. )5x3x3=45(

Linearity EvaluationLinearity Evaluation


Linearity Evaluation

Record expected values, actual values, and % recovery for each one.

Analyze each set of dilutions for statistical methods: Regression, Correlation Coefficient, y-intercept,

Slop, Plot.


Range Determinationקביעת התחום

Minimum Specified Ranged Assay: 80 - 120 %

Impurities Test: From QL – 120% of Spec. Toxic or Potent impurities: Fit with the controlled level.

Content Uniformity: 70 – 130% of Test Concentration.

Dissolution Testing + 20% over Specified Range.


RuggednessRuggedness""קשיחותקשיחות""

Degree of Reproducibility of Test Results under a Variety of Conditions

Different: Laboratories, Analysts, Instruments, Reagents, Days

Expressed as % RSD


Measure The Capacity to Remain Unaffected by Small Variation in Method Parameters.

Indication or Reliability During Normal Use.

Robustness"חוסן"


Why is Method Validation Considered a Bottleneck צוואר בקבוק -

- Every Method validation Process Consists About 80 -100 Analyses

- Each of Them Produce About 4 specific Results; These results

in a total of about 400 Numbers


- All of These Numbers Need to be mathematically Processed:

Manual )Calculator, Excel Macro(

Dedicated Method Validation Program

Why is Method Validation Considered a Bottleneck (Cont’)


• To Take Advantage of a New Technology

- Cost/Benefit Economic Exercise- Instrumentation, Methods

• Formulation Changes

Why Revalidate


Why Revalidate (cont’)

• Manufacturing Batch Changes

• Changes in Incoming Raw Material

• Changes in Method


CONCLUSIONסיכום

Defined Validation and its ImportanceDefined Validation and its Importance

Examined The steps of Method ValidationExamined The steps of Method Validation

Learned How each Step is Documented andLearned How each Step is Documented and Measured:Measured: ))System Suitability, USP/ICH(System Suitability, USP/ICH(

Protocol and Pitfalls: Protocol and Pitfalls: RevalidationRevalidation


ANALYTICAL METHOD VALIDATION REFERENCE

Initial Method Validation Guidance -1987Guidance for submitting samples and analytical data for methods validation. FDA, February 1987. US Government Printing office: 1990-281-794:20818.Update in August 2000 )Draft Guidance(Analytical Procedures and Method Validation. Fed.Reg.659169(, 52,776-52,777, 30 August 2000

All Guidance are on FDA Web site: www.fda.gof/cder/guidance

lect. 5+6. 2009-10 eli solomon m.sc 1 validation principles principles of qualification and...

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