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Lab Inspections based on US FDA and China GMPs
Dr. Ludwig Huber
The Agilent Pharma Compliance and Validation Seminar and Workshop
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Overview
• Regulations along the drug life• Comparison US FDA and China CFDA GMPs• Overview on inspection items and key points• Quality management system requirements
applicable for the entire laboratory • GMP controls applicable for all workflow steps• Inspection items along the sample and data
workflow
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GxP Regulations Along the Drug Life
Clinical Trials
I, II, III, IV
Preclinical Development
DrugDiscovery
DiseaseDiscovery
Basic Research
Manufacturingincl. APIsQC Laboratories
GLP GMPNot Regulated GCP
Part 11 applies for computers that are used in all FDA regulated areas
GLP: Good Laboratory Practices GMP: Good Laboratory Practices GCP: Good Clinical PracticesGLP+GCP+GMP = GxP = Predicate Rules IND = Investigational New Drug NDA: New <drug Application
Submission & Review
IND NDAPost
MarketingSurveillance
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US-FDA CFR 211 GMP CFDA GMP
A. General provisionsB. Organization and personnelC. Buildings and facilitiesD. EquipmentE. Control of components,
/containers/F. Production and process controlsG. Packaging and labeling controlsH. Holding and distributionI. Laboratory controlsJ. Records and reportsK. Returned and Salvaged Drug
Products
1. General Provisions2. Quality management3. Organization and personnel4. Premises and facilities5. Equipment6. Materials and products7. Qualification and validation8. Documntation management9. Production management10. Quality control and QA11. Contract manufacture and (contract)
analysis12. Product distribution / recalls13. Self inspections14. Supplementary provisions
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Comparison of US FDA and China CFDA
• In general: requirements are similar• CFDA GMPs more modern
– Up-to-date elements of quality management systems
– Internal audits– Contract manufactoring and contract laboratories– Uses common up-to-date terminology,e.g.,
qualification and validation• CFDA GMPs more specific
CFDA GMPs based on WHO GMPs (EU GMP like)
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Level of Detail – Equipment Qualification
US FDA (211.68)•Equipment shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained
China CFDA (article 90)•Equipment should be regularly calibrated and checked according to procedures, in order to ensure their proper functioning. Calibration and checks should be recorded accordingly.
So far no difference
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Level of Detail – Equipment QualificationChina CFDA •Article 139: Equipment and testing instruments should be qualified1. Design qualification is to verify that the design of the equipment is suitable for the intended use2. Installation qualification is to verify that the premises, facilities and equipment have been built and installed in accordance with their design specifications;3. Operational qualification is to verify that the premises, facilities and equipment operate in accordance with their design specifications;4. Performance qualification is to verify that the premises, facilities and equipment, under normal operating procedures and process conditions, can consistently meet performance specifications;•Article 144: Qualification and validation should not be considered as a one time activity. After initial qualification and validation, requalification or revalidation should be carried out.
Similar to USP <1058>
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Laboratory Inspection Items and Key Points
SamplingSample handling
Testing Test reportsRecord
maintenance
Sampling plan & sampling documentingreserve samples
Sample identification &protection of sample integrity
Monitoring the quality of test results, generatecomplete records
Test conditions& test results, review and signatures
Ensure long term record integrity & security
GMP controls across all workflow steps
• Validation of analytical methods & procedures
• Equipment calibration testing & maintenance
• Qualification of material• Handling Out-of-
specification results
• Qualification of personnel• Controlled environmental
conditions• Written procedures
Quality management system controls across the laboratoryOrganization, documentation control, complaint handling, corrective & preventive actions, supplier & subcontractor management, internal audits, change management, management reviews, product reviews, continuous improvement,
Trace forwardTrace backward
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Inspecting the Laboratory Quality System • Quality manual and or policy?• Org. chart with responsibilities?• Supplier assessment program?
– Chemicals, reference standards, equipment?• Internal audit program? • Change control procedures?• Regular management review? • Risk management?• Complaint handling• Continuous improvement• Corrective and preventive action plans?
Is there a documented QS system and is it followed?
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Build the Right Organizational Structure - avoid conflict of interest -
Director
Finance & Admin.
Human Resources
Laboratory Mgmt.
Quality Assurance
IT/ISSafety Officer
Lab 1 Lab 2 Lab 3
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Develop GMP Compliant Documentation
High level, strategic documentation(regulations, business, quality)
Process related documentation, approaches(SOPs)
TrainingMaintenance
Validation, Audits
Product test records, validation results, training records,
chromatograms, log-book entries
Test proceduresOperating manuals,
QC procedures
PolicyMaster Plan
Product/event related documentation(work instructions, also called SOPsor test scripts, protocols)
Laboratory records(event related documentation)
Wri
tten
pro
cedu
res
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Use Consistent Documentation Across the Company• Validation master plan• Supplier qualification• Risk assessment• Validation procedures• Templates for records
→Improves efficiency→Improves consistency
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Reference and other Materials and Supplies
• Supplier assessment?– ISO 9000?
• Check of incoming material?– Procedure?
• Procedure for preparation of working standards from primary standards?
• Procedure validated?• Reagents/chemicals labeled?
– Date of preparation, concentration, expiration date?
Is the material in in the box same as the label
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Documenting Material Supplier Selection Items Requirem Results Passed
Recognition in the market place □ yes □ no
Experience with the vendor □ yes □ no
Quality assurance
ISO Certification □ yes □ no
Efficient complaint handling □ yes □ no
Support
Provide Certificates of Analysis □ yes □ no
Provide expiration dates □ yes □ no
Provides test methods □ yes □ no
Phone and onsite support □ yes □ no
Product offering
Certified Reference Material □ yes □ no
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Preparation of Working Standards
Company Internal Reference Material
Primary Standard
Working Standard
Method Validation
Certified Reference Material
Equipment Calibration
System Performance Check
Secondary Standard
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Personnel
• Adequate number in line with assigned tasks?• Descriptions of tasks and requirements for each
job?• Qualification records?• Training plans?• Training plans followed?• Trainings documented?• Verification and documentation of effectiveness?• Ongoing evaluation?• GMP training?
Are there enough qualified people for the assigned task?
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Procedure for Qualification of Personnel
1. Define requirements - what is the assigned task?
2. Identify knowledge - education, experience, training
3. Determine gaps, identify training needs4. Make a plan to fill the gaps5. Train6. Evaluate training7. Document
1/2 year or yearly reviews
Job description
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Documenting Training and Effectiveness
Job description
Qualification requirements
Name
Education
Experience
Gaps, Trainings plan
Trainings
Type, content
Supervisor(name, signature)
DateDuration
This documentation should be kept separated from other personnel files, for example performance evaluations
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Equipment• List of all equipment?• Calibration?
– Timely?• Qualification?
– Timely?• Maintenance?• Labeling with status
– calibrated, out-of-service?• Log-books?• Records: qualification/calibration/maintenance?
Is the instrument suitable for the intended use
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Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
Equipment Qualification Phases 4Q Model (USP <1058>, CFDA 139)
User requirement specifications Functional specifications Operational specifications Vendor qualification
Check arrival as purchased Check proper installation of
hardware and software Test of operational functions Performance testing Test of security functions
Test for specified application Preventive maintenance On-going performance tests
HP/Agilent way since 1990, USP since 2007, CFDA 2010
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DQ – Selected Functional Specs
Verifies that the design of the equipment is suitable for the intended use (CFDA 139)
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OQ Test - Example
Date Weight 1Weight 2 Test engineerName Signature
Weight 3 o.k.
yes9999.8 999.9 100.0 Hughes2/3/06
Instrument BestBalance
Serial number 55236A
Maximal weight 11 g
Control weight 1 10,000 mg Limit +-10 mg
Control weight 2 1,000 mg Limit: +-1 mg
Control weight 3 100 mg Limit: +- 0.1 mg
• Instrument ID• Acceptance criteria• Actual results
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Equipment Maintenance Logs
Log ID
Date Type of Maintenance
Person Performing
Maintenance
EquipmentOwner
Comment
________From________To
E.g., routine/non routine
____________Printed Name___________Signature
_________Printed Name___________Signature
E.g., recalibrated
________From
________To
____________Printed Name
___________Signature
__________Printed Name
___________Signature
“Preventive maintenance plans and procedures should be established, and the maintenance and repair activities should be recorded.” (CFDA 80)
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Configuration
Installation Qualification
Operational Qualification
Performance Qualification
Computer System Validation – 4Q+
Configuration design Configuration implementation
E.g., User acess rights
Check arrival as purchased Check proper installation of
hardware and software Test of configuration specifications Test of functional specifications Test of security functions
Test for user requirement specifications
Preventive maintenance
Design Qualification User requirement specifications Functional/config. specifications Vendor qualification
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Document Software Vendor SelectionRequirements Results Passed
1) Company □ yes □ no
Experience with the vendor □ yes □ no
Recognition in the market place
2) Quality Assurance
ISO Certification □ yes □ no
Documented software development □ yes □ no
3) Product functions (provide detailed list) □ yes □ no
4) Services and Support
Provide specifications list □ yes □ no
Installation service □ yes □ no
IQ/OQ services □ yes □ no
Phone and onsite support □ yes □ no
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Analytical Methods and Procedures
• SOP for validation?• Validation parameters, tests, acceptance criteria defined?• Verification of standard methods?• SOP for method transfer?• Scope defined?• Change control?
– When is revalidation required (USP chapter <621>)?• All methods and method changes approved?
Testing methods should be validated or verified (CFDA 12).
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Method Validation Parameters for different Method Tasks
Analytical TaskIdentifi-cation
ImpurityQuantitative
Impurity Qualitative
Assay
Accuracy No yes No Yes
Precision
RepeatabilityIntermediate
Reproducibility
NoNoNo
YesYesYes
NoNoNo
YesYesYes
Specificity Yes Yes Yes Yes
Limit of detection No No Yes No
Limit of quantitation No Yes No No
Linearity No Yes No Yes
Range No Yes No Yes
Robustness Expected to be done during Method Development
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Example: Report Summary TableValidation Parameter
Measure Acceptance criteria Results
Accuracy
Recovery – Conc1 (80%)
Recovery – Conc2 (100%)
Recovery – Conc3 (120%)
97 – 103 %
97 – 103 %
97 – 103 %
99%
100%
100%Method
PrecisionRSD ≤ 1.5 % 0.4%
Intermediate Precision
RSD ≤ 2.0 % 0.8%
Specificity Peak Resolution Factor R R for all peaks >1.5 All peaks >2.0
LinearityCorrelation Coefficient
Visual inspection of plot
≥ 0.9900
Linear response plot
0.9900
Shows linearity
Range
Correlation Coefficient
Precision at 3 concentrations
Recovery at 3 Conc.
≥ 0.9900
≤ 1.5 %
97 – 103%
0.9900
<1%
99.6%
Robustness
Column Temp. ±2 C
Mobile Phase ±2 %
Sample extraction time -20 %
Compound stability 6 days
R for all peaks >1.5
R for all peaks >1.5
Recovery in spec.
<3% degradation
R for all peaks >2.0
R for all l peaks >2.0
Recovery in spec
<2% degradation
Ludwig Huber Slide 28
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Sampling and Sample Handling
• Developing a sampling plan• Documentation of the sampling system• Ensure representative sampling: a major FDA concern• Prevent deterioration during sample transfer• Maintain and document sample integrity• Keeping and regularly inspect reserve/reference
samples
SamplingSample
handling&storage
TestingData review
and approval
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Sampling Plan Contents
Type of sampling equipment Sampling method Sampling frequency Sample amount Exact sampling location and places Documentation how representative
sampling is ensured Any safety or other precautions Amount of reserve/reference samples Instructions for cleaning and storage of sampling tools
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Reserve/Reference Samples - • Samples used for retesting of the original sample if the
initial test results is non-conforming (out of specifications) in the event of customer complaints
• Reserve/reference samples should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the original results.
CFDA: The reference samples should be visually examined at least once a year during storage period (article 225)
US FDA: Reserve samples should be visually inspected every year for possible deterioration (FDA)
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Sample Handling• SOP: transfer, registration, labeling• Ensure sample integrity?
– Storage conditions: temperature, humidity?• Avoid cross contamination?• Storage and inspection of reserve samples?• Sample stability during storage time before
analyzed?• Sample tracking?
How did you ensure sample integrity?
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System Suitability Testing
• SOP: When, how, acceptance criteria• Is USP Chapter <621> followed for
chromatography?• Are critical parameters defined for non-
chromatographic systems?• Is the frequency defined by procedures?• Are procedures followed?• Are results documented?• Are deviations handled by failure investigations?
Do system suitability tests check for critical parameters
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Sample Testing• Develop test program for APIs, finished drugs,
raw material
• Document clear specifications before testing
• Document acceptance criteria and actual results
• Ensure qualification of equipment
• Document test procedures and test equipment
• Formally review and approve test results
– Analysts
– Second person (technical & independent reviewer)
• Document test conditions with test results
SamplingSample
handling&storage
TestingData review
and approval
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Inspection Questions related to Out-of-Specification Test Results
Can you show me a list of OOS results from the last 6 months?
Is there a procedure for OOS situations? Are investigations completed in a timely manner? Are investigations documented properly? Are investigation findings subject to proper
review? Does the procedure include root cause analysis,
impact analysis, and corrective actions and preventive actions?
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Data Review and Approval • Procedure for review: who, what, when, checklist?• Review if technically correct?
– All peaks resolved?– Correct chromatographic baseline– Correct calculations?
• Unexpected peaks?• All supporting material available
– Chromatograms, spectra?• All raw and meta data available?• Review and approval by second person?
– Supervisor? QA?
Are test results reviewed, approved and documented
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Recording and Archiving of Data• Raw data defined? Are records complete?• Procedure on how to maintain and archive records
– Paper, electronic, original electronic format, standard files?
• Integrity of paper records– Permanent ink? – Original record readable after change?
• Integrity of electronic records?– Part 11 controls, e.g., electronic audit trail?
• Electronic archiving system– Validated, secure, availability of data?
Which controls are in place to ensure data integrity?
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CFDA GMP 4: The manufacturer should strictly implement
GMP with integrity. Any falsification and fraud is forbidden.
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FDA Statement about Deleting HPLC e-Raw Data after Printing
• The printed paper copy of the chromatogram would not be considered a “true copy” of the entire electronic raw data used to create that chromatogram, as required by 21 CFR 211.180(d).
• The chromatogram does not generally include, for example, the injection sequence, instrument method, integration method, or the audit trail, of which all were used to create the chromatogram or are associated with its validity
• Therefore, the printed chromatograms used in drug manufacturing and testing do not satisfy the predicate rule requirements in 21 CFR Part 211.
• The electronic records created by the computerized laboratory systems must be maintained under these requirements
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm
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