validation basics

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Page 1: Validation basics

AnalySys Sciences

1

Instrumental in your success

http://analysciences.com

http://analysciences.com

Page 2: Validation basics

Validation

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Page 3: Validation basics

What is validation?

Validation is the process used to confirm that the analytical procedure employed for a specific test is suitable for its intended use.

Analytical methods need to be

validated or revalidated:

-before their introduction into

routine use,

-whenever the analytical

conditions change,

-whenever the method is changed.

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Page 4: Validation basics

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Validation guidelines

Center for Drug

Evaluation and Research,

USFDA

http://www.fda.gov/cder/

Page 5: Validation basics

Reference Standards

A reference standard is a highly purified

compound that is well characterized.

Chromatographic methods rely heavily

on a reference standard to provide

accurate data. Therefore the quality of

the reference standard is critical.

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Page 6: Validation basics

Accuracy

Accuracy is the measure of how close the experimental value is to the true value.

Recommendations:Recovery data, at least in triplicate, at each level (80, 100 and 120% of label claim). The mean is an estimate of accuracy and the RSD is an estimate of sample analysis precision.

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Page 7: Validation basics

LOD / LOQ

Limit of DetectionThe lowest concentration of analyte in a sample that can be detected, but not necessarily quantitated. Usually s/n 2:1 or 3:1

Limit of QuantitationThe lowest concentration of analyte in a sample that can be determined with acceptable precision and accuracy under the stated conditions. Usually s/n 10:1

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Page 8: Validation basics

Linearity

That range of analyte concentrations over

which the detector yields a linear response.

The working sample concentration and samples

tested for accuracy should be in the linear

range.

RecommendationsThe linearity range depends on the purpose of the test

method. For example, the range for drug content

uniformity would be NLT ± 20%.

Regression coefficient (R2) NLT 0.999. Intercept and slope

should be indicated.8

Page 9: Validation basics

Precision

Measure of how close the data

values are to each other for a

number of measurements under

the same analytical conditions.

Precision is defined by three

components:Repeatability

Intermediate precision

Reproducibility

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Page 10: Validation basics

Repeatability

Injection repeatability: Multiple injections of the same sample in the same conditions.

Analysis repeatability: Multiple measurements of a sample by the same analyst under the same analytical conditions.

Recommendation: A minimum of 10 injections with an RSD of 1%.

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Page 11: Validation basics

Intermediate Precision

Evaluates the reliability of the method in a different environment other than that used during development of the method.

The objective is to ensure that the method will provide the same results when similar samples are analyzed once the method development phase is over.

Depending on time and resources, the method can be tested on multiple days, analysts, instruments, etc.

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Page 12: Validation basics

Reproducibility

The precision between

laboratories as in

collaborative studies.

Recommendations:

It is not normally expected if

intermediate precision is

accomplished.

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Page 13: Validation basics

Range and Recovery

Range: The interval between the high and low levels of analyte studied.

Recommendation is usually +/- 20%.

Recovery: The amount/weight of the compound of interest analyzed as a

percentage to the theoretical amount present in the medium.

Full recovery should be obtained for the compound(s) of interest.

Simpler sample preparation procedure will result in a lower variation of recovery.

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Page 14: Validation basics

Robustness

Measure of the method's ability to

remain unaffected by small, but

deliberate variations in method

parameters. e.g., column type, column temperature, pH of

mobile phase, reagents, flow rate, etc.

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Page 15: Validation basics

Sample Solution Stability

Solution stability of the drug substance should be evaluated.

Most laboratories use autosamplers with overnight runs and the sample will be in

solution for hours before the test procedure is completed. This is of concern

especially for drugs that can undergo degradation by hydrolysis, photolysis or

adhesion to glassware.

Recommendations: Data to support the sample solution stability under normal

laboratory conditions for the duration of the test procedure should be generated.

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Page 16: Validation basics

Specificity and Selectivity

The analyte should have no

interference from other

extraneous components and be

well resolved from them.

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Page 17: Validation basics

System Suitability Tests.

The accuracy and precision of data begin

with a well-behaved chromatographic system.

The system suitability specifications and tests

are parameters that help achieve this

purpose.

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Page 18: Validation basics

System Suitability Parameters - USP

Plate count > 2000 plates/meter

Tailing factor < 2

Resolution > 2

Partition ratio > 2

Relative retention > 1.5

Precision / repeatability RSD </= 1% for n >/= 5

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Page 19: Validation basics

Typical

SST

report

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Page 20: Validation basics

General Points

The sample and standard should be dissolved in the mobile phase. If that is not possible, then avoid using too much organic solvent as compared to the mobile phase.

The sample and standard concentrations should be close if not the same.

The samples should be bracketed by standards during the analytical procedure.

If the sample is filtered, adhesion of the analyte to the filter can happen. This will be of importance especially for low level impurities. Data to validate this aspect should be submitted.

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Page 21: Validation basics

Hardware validation – IQ/OQ/PQ

Installation QualificationWas the instrument installed as per vendor’s guidelines?

Operational QualificationIs the system performing as per claimed specifications?

Performance QualificationIs the analysis compliant for each sample? (System suitability tests)

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Software and data system validation

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Page 23: Validation basics

21 CFR Part 11

Page 24: Validation basics

What is 21CFR-11?

CFR = Code of Federal RegulationsCodification of the general rules and

regulations of the US Federal

government.

Divided into 50 books (titles).

Each title has several chapters.

Page 25: Validation basics

21 CFR Part 11

Title 21 deals with the Food and Drug

Administration (FDA) rules and

regulations.

Title 21-Part 11 defines the criteria

under which electronic records and

electronic signatures are considered to be

trustworthy, reliable and equivalent to

paper records.

Page 26: Validation basics

21 CFR Part 11 Regulations

Three Subparts :

1) Subpart A : General Provision

2) Subpart B : Electronic Records

3) Subpart C : Electronic Signatures

Page 27: Validation basics

Subpart A : General Provision

•Regulations establish the criteria the FDA considers for electronic records and electronic signature to be trustworthy, reliable, and generally equivalent to paper.•Applies to all records in electronic form under any records requirement within any FDA regulation.•Electronic records are considered equivalent to full handwritten signatures, initials, and other general signings.•Electronic records may be used in accordance with Part 11 unless paper records are specifically required.•Computer system (hardware and software), controls, and relevant documentation must be available for review during FDA inspections.

Page 28: Validation basics

Subpart B : Electronic Record

“Any combination of text, graphics, data, audio, pictorial, or other information

representation in digital form that is created, modified, maintained, archived, retrieved,

or distributed by a computer system.”

Must develop procedures and controls to ensure authenticity, integrity and

confidentiality, and that signer cannot repudiate the signed record.

The controls must:Be validatedMaintain accurate and complete recordsLimit the system to authorized personsProtect records through retention periodContain audit trails that are secure, operator independent, computer-generated, time-stamped, cover the creation , modification and deletion of records and do not obscure previous information

Page 29: Validation basics

Contd….•Allow for the performance of operational system checks, authority checks, and device

checks to ensure system, record, and data integrity

•Ensure appropriate personnel qualifications

•Policies written and followed to hold personnel accountable for actions and to deter

records falsification.

•Control over system documentation including distribution, access, use, revision and change

control.

•Must develop procedures and controls that ensure authenticity, integrity, and

confidentiality of electronic records and comply with all other parts of Section 11.10

•Must use additional measures (e.g. document encryption, digital signature standards) to

ensure authenticity, integrity, and confidentiality

Page 30: Validation basics

Contd..

•Signed electronic records must include the printed name of the signer, date and time of

signature, and the purpose of the signature (e.g. review, approval etc.) Each of these must

be readable by display or printout.

•Electronic signature and handwritten signatures must be linked to ensure signatures

cannot be excised, copied, transferred or falsified.

Page 31: Validation basics

Subpart C : Electronic Signature“A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.”

•Must be unique to an individual and not reassigned•Identity of individual must be verified by organization•Must certify electronic signature system to the agency prior to or at the time of use of the system•Certification must be submitted in paper form and, upon agency request, provide certification that signature is legally binding

Page 32: Validation basics

Cont…

•Non-Biometric signatures must:

Contain at least two different identification components (e.g. User ID and Password)

Single sign-on with multiple tasks: Use all identification components at first, with partial

identification for each task thereafter

Multiple sign-on without continuous access requires all identification components to be used

each time

Be used only by the owner

Ensure use by other individuals is precluded and does not occur without collaboration by at

least two other individuals

•Biometric signatures must ensure use by the owner

Page 33: Validation basics

Cont…..Persons using electronic signatures must use controls to ensure security and integrity and should include:Assuring that no two individuals have the same combination of identification code and passwordPeriodic check, recall, or revision of identification code and passwordLoss management and replacement proceduresTesting of devices (i.e. tokens or cards) that produce or maintain identification codes or passwords to ensure proper function and unaltered state.•Unauthorized use safeguards•Report attempts in to:Security unitManagement, as appropriate

Page 34: Validation basics

Where does

21CFR-11 apply?

• Information management related to manufacturing processes.

GMP

• Clinical data managementGCP

• Data Acquisition

• Laboratory InformationGLP