AnalySys Sciences
1
Instrumental in your success
http://analysciences.com
http://analysciences.com
Validation
2
What is validation?
Validation is the process
used to confirm that the
analytical procedure
employed for a specific
test i...
4
Validation guidelines
Center for Drug
Evaluation and Research,
USFDA
http://www.fda.gov/cder/
Reference Standards
A reference standard is a highly purified
compound that is well characterized.
Chromatographic methods...
Accuracy
Accuracy is the measure of how close the
experimental value is to the true value.
Recommendations:
Recovery data,...
LOD / LOQ
Limit of Detection
The lowest concentration of analyte in a
sample that can be detected, but not
necessarily qua...
Linearity
That range of analyte concentrations over
which the detector yields a linear response.
The working sample concen...
Precision
Measure of how close the data
values are to each other for a
number of measurements under
the same analytical co...
Repeatability
Injection repeatability: Multiple
injections of the same sample in the
same conditions.
Analysis repeatabili...
Intermediate Precision
Evaluates the reliability of the method in a different environment other
than that used during deve...
Reproducibility
The precision between
laboratories as in
collaborative studies.
Recommendations:
It is not normally expect...
Range and Recovery
Range: The interval between the high and low levels of analyte studied.
Recommendation is usually +/- 2...
Robustness
Measure of the method's ability to
remain unaffected by small, but
deliberate variations in method
parameters.
...
Sample Solution Stability
Solution stability of the drug substance should be evaluated.
Most laboratories use autosamplers...
Specificity and Selectivity
The analyte should have no
interference from other
extraneous components and be
well resolved ...
System Suitability Tests.
The accuracy and precision of data begin
with a well-behaved chromatographic system.
The system ...
System Suitability Parameters - USP
Plate count > 2000 plates/meter
Tailing factor < 2
Resolution > 2
Partition ratio > 2
...
Typical
SST
report
19
General Points
The sample and standard should be dissolved in the mobile phase. If
that is not possible, then avoid using ...
Hardware validation – IQ/OQ/PQ
Installation Qualification
Was the instrument installed as per vendor’s guidelines?
Operati...
Software and data system validation
22
21 CFR Part 11
What is 21CFR-11?
CFR = Code of Federal Regulations
Codification of the general rules and
regulations of the US Federal
go...
21 CFR Part 11
Title 21 deals with the Food and Drug
Administration (FDA) rules and
regulations.
Title 21-Part 11 defines ...
21 CFR Part 11 Regulations
Three Subparts :
1) Subpart A : General Provision
2) Subpart B : Electronic Records
3) Subpart ...
Subpart A : General Provision
•Regulations establish the criteria the FDA considers for electronic records and electronic
...
Subpart B : Electronic Record
“Any combination of text, graphics, data, audio, pictorial, or other information
representat...
Contd….
•Allow for the performance of operational system checks, authority checks, and device
checks to ensure system, rec...
Contd..
•Signed electronic records must include the printed name of the signer, date and time of
signature, and the purpos...
Subpart C : Electronic Signature
“A computer data compilation of any symbol or series of symbols executed, adopted, or
aut...
Cont…
•Non-Biometric signatures must:
Contain at least two different identification components (e.g. User ID and Password)...
Cont…..
Persons using electronic signatures must use controls to ensure security and integrity and
should include:
Assurin...
Where does
21CFR-11 apply?
• Information management
related to manufacturing
processes.
GMP
• Clinical data managementGCP
...
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Validation basics

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Validation basics

  1. 1. AnalySys Sciences 1 Instrumental in your success http://analysciences.com http://analysciences.com
  2. 2. Validation 2
  3. 3. 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. 3
  4. 4. 4 Validation guidelines Center for Drug Evaluation and Research, USFDA http://www.fda.gov/cder/
  5. 5. 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. 5
  6. 6. 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. 6
  7. 7. LOD / LOQ Limit of Detection The 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 Quantitation The 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 7
  8. 8. 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. Recommendations The 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
  9. 9. 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 9
  10. 10. 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%. 10
  11. 11. 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. 11
  12. 12. Reproducibility The precision between laboratories as in collaborative studies. Recommendations: It is not normally expected if intermediate precision is accomplished. 12
  13. 13. 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. 13
  14. 14. 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. 14
  15. 15. 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. 15
  16. 16. Specificity and Selectivity The analyte should have no interference from other extraneous components and be well resolved from them. 16
  17. 17. 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. 17
  18. 18. 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 18
  19. 19. Typical SST report 19
  20. 20. 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. 20
  21. 21. Hardware validation – IQ/OQ/PQ Installation Qualification Was the instrument installed as per vendor’s guidelines? Operational Qualification Is the system performing as per claimed specifications? Performance Qualification Is the analysis compliant for each sample? (System suitability tests) 21
  22. 22. Software and data system validation 22
  23. 23. 21 CFR Part 11
  24. 24. What is 21CFR-11? CFR = Code of Federal Regulations Codification of the general rules and regulations of the US Federal government. Divided into 50 books (titles). Each title has several chapters.
  25. 25. 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.
  26. 26. 21 CFR Part 11 Regulations Three Subparts : 1) Subpart A : General Provision 2) Subpart B : Electronic Records 3) Subpart C : Electronic Signatures
  27. 27. 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.
  28. 28. 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 validated Maintain accurate and complete records Limit the system to authorized persons Protect records through retention period Contain 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
  29. 29. 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
  30. 30. 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.
  31. 31. 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
  32. 32. 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
  33. 33. 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 password Periodic check, recall, or revision of identification code and password Loss management and replacement procedures Testing 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 unit Management, as appropriate
  34. 34. Where does 21CFR-11 apply? • Information management related to manufacturing processes. GMP • Clinical data managementGCP • Data Acquisition • Laboratory InformationGLP
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