Transcript Operational qualification

Lab Inspections based on US FDA
and China GMPs
The Agilent Pharma Compliance and Validation
Seminar and Workshop
Dr. Ludwig Huber
[email protected]
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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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Slide 2
GxP Regulations Along the Drug Life
Basic
Research
Disease
Discovery
Drug
Preclinical
Discovery Development
Not Regulated
GLP
IND
Clinical
Trials
I, II, III, IV
GCP
NDA
Submission & Review
Manufacturing
incl. APIs
QC Laboratories
GMP
Post
Marketing
Surveillance
Part 11 applies for computers that are used in all FDA regulated areas
GLP: Good Laboratory Practices GMP: Good Laboratory Practices GCP: Good Clinical Practices
GLP+GCP+GMP = GxP = Predicate Rules IND = Investigational New Drug NDA: New <drug Application
Slide 3
Slide 3
US-FDA CFR 211 GMP CFDA GMP
A.
B.
C.
D.
E.
F.
G.
H.
I.
J.
K.
General provisions
Organization and personnel
Buildings and facilities
Equipment
Control of components,
/containers/
Production and process
controls
Packaging and labeling
controls
Holding and distribution
Laboratory controls
Records and reports
Returned and Salvaged Drug
Products
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1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
General Provisions
Quality management
Organization and personnel
Premises and facilities
Equipment
Materials and products
Qualification and validation
Documntation management
Production management
Quality control and QA
Contract manufacture and
(contract) analysis
12. Product distribution / recalls
13. Self inspections
14. Supplementary provisions
Slide 4
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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Slide 5
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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Slide 6
Level of Detail – Equipment Qualification
China CFDA
• Article 139: Equipment and testing instruments should be qualified
1. Design qualification is to verify that the design of the equipment is
suitable for the intended use
2. 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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Slide 7
Laboratory Inspection Items and Key Points
Trace forward
Trace backward
Sampling
Sampling plan &
sampling
documenting
reserve samples
Sample
handling
Sample
identification &
protection of
sample integrity
Testing
Monitoring the
quality of test
results, generate
complete records
Test reports
Test conditions
& test results,
review and
signatures
Record
maintenance
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-ofspecification results
• Qualification of personnel
• Controlled environmental
conditions
• Written procedures
Quality management system controls across the laboratory
Organization, documentation control, complaint handling, corrective & preventive actions,
supplier & subcontractor management, internal audits, change management,
management reviews, product reviews, continuous improvement,
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Slide 8
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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Slide 9
Build the Right Organizational Structure
- avoid conflict of interest Director
Finance
& Admin.
Human
Resources
Lab 1
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Laboratory
Mgmt.
Lab 2
Quality
Assurance
IT/IS
Safety
Officer
Lab 3
Slide 10
Develop GMP Compliant Documentation
Policy
Master
Plan
High level, strategic documentation
(regulations, business, quality)
Training
Maintenance
Validation, Audits
Process related
documentation, approaches
(SOPs)
Test procedures
Operating manuals,
QC procedures
Product/event related documentation
(work instructions, also called SOPs
or test scripts, protocols)
Laboratory records
Product test records, validation
(event related
results, training records,
documentation)
chromatograms, log-book entries
Slide 11
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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Slide 12
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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Slide 13
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
Efficient complaint handling
□ yes □ no
□ 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
Slide 14
Preparation of Working Standards
Primary Standard
Certified Reference
Material
Secondary
Standard
Company Internal
Reference Material
Working Standard
Method Validation
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Equipment
Calibration
System
Performance Check
Slide 15
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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Slide 16
Procedure for Qualification of Personnel
Job description
1. Define requirements
- what is the assigned task?
2. Identify knowledge
- education, experience, training
3. Determine gaps, identify training needs
4. Make a plan to fill the gaps
5. Train
6. Evaluate training
7. Document
1/2 year or yearly reviews
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Slide 17
Documenting Training and Effectiveness
Job description
Qualification
requirements
Name
Education
Experience
Gaps, Trainings plan

Trainings
Supervisor
(name,
signature)
Type,
content
Date
Duration
This documentation should be kept separated from other personnel
files, for example performance evaluations
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Slide 18
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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Slide 19
Equipment Qualification Phases
4Q Model (USP <1058>, CFDA 139)
Design Qualification
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Installation Qualification
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
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Operational Qualification


Performance Qualification
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

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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Slide 20
DQ – Selected Functional Specs
Verifies that the design of the equipment is suitable for the intended use (CFDA 139)
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Slide 21
OQ Test - Example
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
Date
Weight 1 Weight 2 Weight 3
2/3/06 9999.8 999.9
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100.0
o.k.
Test engineer
Name
Signature
yes Hughes
• Instrument ID
• Acceptance criteria
• Actual results
Slide 22
Equipment Maintenance Logs
Log
ID
Date
Person
Performing
Maintenance
Equipment
Owner
____________
Printed Name
___________
Signature
_________
Printed Name
___________
Signature
________
From
____________
Printed Name
__________
Printed Name
________
To
___________
Signature
___________
Signature
________
From
________
To
Type of
Maintenance
E.g., routine/non
routine
Comment
E.g.,
recalibrated
“Preventive maintenance plans and procedures should be established, and
the maintenance and repair activities should be recorded.” (CFDA 80)
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Slide 23
Computer System Validation – 4Q+
Design Qualification



Configuration
Installation Qualification




Operational Qualification



Performance Qualification


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User requirement specifications
Functional/config. specifications
Vendor qualification
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
Slide 24
Document Software Vendor Selection
Requirements
Results
Passed
□ yes □ no
1) Company
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
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•
•
•
•
•
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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Slide 26
Method Validation Parameters for
different Method Tasks
Identification
Impurity
Quantitative
Impurity
Qualitative
Assay
No
yes
No
Yes
No
No
No
Yes
Yes
Yes
No
No
No
Yes
Yes
Yes
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
Analytical Task
Accuracy
Precision
Repeatability
Intermediate
Reproducibility
Robustness
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Expected to be done during Method Development
Slide 27
Example: Report Summary Table
Validation
Parameter
Accuracy
Method
Precision
Intermediate
Precision
Specificity
Linearity
Range
Robustness
Ludwig Huber
Slide 28
Measure
Acceptance criteria
Results
Recovery – Conc1 (80%)
97 – 103 %
99%
Recovery – Conc2 (100%)
97 – 103 %
100%
Recovery – Conc3 (120%)
97 – 103 %
100%
RSD
≤ 1.5 %
0.4%
RSD
≤ 2.0 %
0.8%
Peak Resolution Factor R
R for all peaks >1.5
All peaks >2.0
Correlation Coefficient
≥ 0.9900
0.9900
Visual inspection of plot
Linear response plot
Shows linearity
Correlation Coefficient
≥ 0.9900
0.9900
Precision at 3 concentrations
≤ 1.5 %
<1%
Recovery at 3 Conc.
97 – 103%
99.6%
Column Temp. ±2 C
R for all peaks >1.5
R for all peaks >2.0
Mobile Phase ±2 %
R for all peaks >1.5
R for all l peaks >2.0
Sample extraction time -20 %
Recovery in spec.
Recovery in spec
Compound stability 6 days
<3% degradation
<2% degradation
Slide 28
Sampling and Sample Handling
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•
•
•
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
Sampling
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Sample
handling&
storage
Testing
Data review
and
approval
Slide 29
Sampling Plan Contents
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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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Slide 30
Reserve/Reference Samples • Samples used for retesting of the original
sample if the initial test results is nonconforming (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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Slide 31
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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Slide 32
System Suitability Testing
• SOP: When, how, acceptance criteria
• Is USP Chapter <621> followed for
chromatography?
• Are critical parameters defined for nonchromatographic 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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Slide 33
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
Sampling
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Sample
handling&
storage
Testing
Data review
and
approval
Slide 34
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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Slide 35
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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Slide 36
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?
CFDA GMP 4: The manufacturer should strictly implement
GMP with integrity. Any falsification and fraud is forbidden.
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Slide 37
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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Slide 38