Transcript Good Laboratory Practices

Good Laboratory Practices
Michael C. Olson
Director, Division of Field Science
Office of Regulatory Affairs
U.S. Food & Drug Administration
Phone – 301-827-1232
e-mail – [email protected]
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG ADMINISTRATION
OFFICE OF THE COMMISSIONER
COMMISSIONER OF FOOD AND DRUGS
ACTING PRINCIPAL DEPUTY COMMISSIONER
OFFICE OF THE
CHIEF COUNSEL
OFFICE OF
INTERNATIONAL AND
CONSTITUENT RELATIONS
CENTER FOR BIOLOGICS
EVALUATION AND
RESEARCH
Policy
Research
Pre Market
Approval
Post Market
Approval
CENTER FOR FOOD
SAFETY AND
APPLIED NUTRITION
OFFICE OF
EQUAL
OPPORTUNITY
OFFICE OF THE
ADMINISTRATIVE
LAW JUDGE
OFFICE OF THE
SENIOR ASSOCIATE
COMMISSIONER
OFFICE OF POLICY,
PLANING, AND
LEGISLATION
OFFICE OF
MANAGEMENT AND
SYSTEMS
OFFICE OF SCIENCE
COORDINATION AND
COMMUNICATION
CENTER FOR DRUG
EVALUATION AND
RESEARCH
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CENTER FOR
VETERINARY
MEDICINE
CENTER FOR
DEVICE AND
RADIOLOGICAL HEALTH
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devices)
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OFFICE OF REGULATORY AFFAIRS
ASSOCIATE COMMISSIONER
Dennis E. Baker
(DBR)
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NATIONAL CENTER FOR
TOXICOLOGICAL
RESEARCH
(DT)
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DFS
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Policy
National Check Sample Program
Training
Personnel and Facilities
Research
Publications
Equipment Purchases
Programs, Compliance Issues
Accreditation
FIELD STAFFING
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386 Chemists
208 Microbiologists
25 Biologists
16 Entomologists
15 Engineers/Physicists
23 Research Scientists
122 Technicians/Aides/Sample Custodians
24 QA/Safety/Haz Waste Personnel
Total 819 Analysts
(Also….89 Managers, 30 + Science Advisors)
Changing Roles
FDA ANALYST’S ROLE
• Sample Analysis
• Inspections
• Monitor Contracts
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FUTURE
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Activities
You add value by
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Analyzing samples
Reviewing worksheets
Participating in inspections
Providing Technical Assistance
Activities
You add value by
• Developing/Improving Methods
• Creative Problem-Solving
• Interacting with customers and co-workers
Outputs
Your Work Products
• Are Legal Document
• Serve as a basis for regulatory
action…they should be:
legible
concise
scientifically sound
well organized
complete
timely
Personal Characteristics
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Integrity
Integrity
Integrity
Positive work ethic
Dedicated to the mission
Continuous learning
Inquisitive
Team player
ORA Lab Types
• 13 ORA Laboratories:
• 5 Regional Labs (“Mega-Labs”)
• 4 District Labs
• 4 Specialty Labs
ORA Lab Types
Regional Labs (general servicing labs)
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Northeast Regional Lab (New York)
Southeast Regional Lab (Atlanta)
Arkansas Regional Lab (Jefferson, AR)
Pacific Regional Lab Southwest (Irvine, CA)
Pacific Regional Lab Northwest (Bothell, WA)
ORA Lab Types
District Labs (general servicing labs)
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Kansas City District (Lenexa, KS)
Denver District (Lakewood, CO)
Detroit District (Detroit, MI)
San Francisco District (Alameda, CA)
ORA Lab Types
Specialty Labs
• Philadelphia District (Pharmaceuticals)
• San Juan District (Pharmaceuticals)
• Winchester Engineering and Analytical Center
(WEAC: Winchester, MA) (Engineering, Radio
nuclides)
• Forensic Chemistry Center (FCC, Cincinnati)
(criminal analysis support)
ORA Lab Types
• Specialized Analyses Within General Servicing
Labs
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Seafood Products Research: Seattle Lab
Metals Analysis: San Francisco Lab
Animal Drug Research and Analysis: Denver Lab
Nutritional Analysis: Atlanta Lab
Total Diet Program: Kansas City Lab
Dioxin Analysis: Arkansas Lab
ORA Lab Activities
Food Analysis
• Chemistry:
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Pesticide Residues
Metals
Mycotoxins
Seafood Toxins
Nutrients
Radio nuclides
Antibiotics
Food Additives
Color Additives
ORA Lab Activities
Food Analysis, cont…
• Microbiology
– Bacterial Pathogens
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Salmonella
Listeria
Coliforms
Shigella
E. Coli 0157:H7
C. Botulinum
C. Perfringens
Campulobacter
B. Cereus
S. Aureus
ORA Lab Activities
Food Analysis, cont…
• Can Seam Analysis
• Sensory (organoleptic)
• Sanitation (Filth)
ORA Lab Activities
Pharmaceutical Analysis
• Chemistry:
– Potency
– Identity
– Impurities/Degradants
– Release Rate
ORA Lab Activities
Pharmaceutical Analysis Cont…
• Microbiology
– Sterility
– Particulates
– Endotoxins
ORA Lab Activities
Veterinary Product Testing
• Medicated Feeds
• Feeds / BSE
ORA Lab Activities
Medical Device Testing
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Condoms/Gloves
X-Ray devices
Microwave Ovens
In-Vitro Diagnostics
ORA Lab Activities
Other Activities
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Research
Collaborative Studies
Petition Validations
Inspections
Private Lab Audits
Outreach
Numbers of Samples
FY 03 Workplan
• Import 29K
• Domestic 20K
• Total 49 K
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Foods 40K
Pharmaceuticals 2K
Vet foods and Drugs 5K
Medical Devices 2K
Quality Initiatives in ORA
• Three interrelated issues concerning the
quality of laboratory data.
– ORA Wide Quality Management System
initiative
– Revision of ORA Laboratory Quality
Assurance Program
– Agency wide Laboratory Accreditation
ORA Wide Quality Management
System [ QMS]
• 1997 – Move to National Quality System
with focus on building in quality
• Based on International Organization for
standardization, ISO 9000 quality
standards
• Recognize internationally
ORA Wide Quality Management
System [ QMS]
• ORA Wide Systems Approach
– Includes Headquarters and Field Operations
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Investigations
Laboratory
Compliance
Administrative
ORA Wide Quality Management
System [ QMS]
• ORA Quality principles
– Implementation of a system of control
where you plan, manage, and monitor
all critical activities which significantly
affect the quality of a product or service.
ORA Wide Quality Management
System [ QMS]
• Senior Management Quality Goals
– Increase management’s assurance of work
quality
– Provide consistent and uniform application of
ORA requirements
– Protect ORA’s knowledge base
– Improve work products and processes
Quality Assurance (what is it)?
• Assuring what is there is really there
• Assuring the level is what you report
• Assuring you did not add it through
contamination.
• Assuring if you report negative findings
it really isn’t there.
Traditional QA Operations
• ORA Quality Assurance Program, 1988
– General Guidance
– Specific Procedures left to each office
– Covered all branches (IB, compliance, lab,
admin)
Traditional QA Operations
• Quality of Equipment
– Periodic performance check schedule
– Periodic performance check procedure
– Performance check log
– Instrument repair log
– (Instrument Monitor)
Traditional QA Operations
• Laboratory Portion:
– Quality of equipment
– Quality of Standards
– Quality of Analytical Work
– Quality of Documentation
– Sample Accountability
– National Check Sample Program
Traditional QA Operations
• Quality of Standards
– Identification of Primary vs. Secondary
– Testing of secondary standards
– Handling, storage, and security criteria
Traditional QA Operations
• Quality of Analytical Work
– Critical review of original / check analyses
– On-Site reviews
Traditional QA Operations
• Sample Accountability
– Sample Accountability Records
– Sample storage and security
– Sample disposition
Traditional QA Operations
• National Check Sample Program
– Sample Selection: by Ad-Hoc Committee
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Full range of field programs
Methods recognized as suitable
Standard equipment
Homogeneous sample available and not too costly
Traditional QA Operations
• Quality of Documentation
– Supervisory Review of Worksheets
– Internal Lab Audit of Worksheets
– Oral Reviews
Traditional QA Operations
• National Check Sample Program
http://web.ora.fda.gov/dfs/check_sample.htm
PURPOSE:
– To evaluate field lab capability in full range of programs
– To demonstrate that results from various field labs are
analytically equivalent
– To Identify and resolve problems that’s may be uncovered
Traditional QA Operations
• National Check Sample Program
– Originating Laboratory
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Obtain sample
Assess suitability of message
Assess suitability of sample
Upon DFS concurrence, distribute sample
Analyze sample as participating laboratory
Traditional QA Operations
• National Check Sample Program
– Participating Laboratory
• Analyze sample as normal regulatory procedure,
using specified instructions
• Document as a normal regulatory sample
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• Submit worksheet package to DFS
Traditional QA Operations
• National Check Sample Program
– Division of Field Science
• Evaluate lab submissions
• Generate final report
ORA Laboratory Accreditation
• Driving force –
– ACRA, charge at 1997 Lab Directors Conference.
– Facilitate Harmonization:
• MRA’s and equivalency of health protection systems with
other countries.
– Seafood’s Program with Canada
• Exchange of laboratory data with USDA Labs
• Exchange of laboratory data with State Labs
– Food Safety initiative Pilot
• FSIS/State Labs/CDC/FDA
ORA Laboratory Accreditation
• Driving Force –
– 1997 Justice Department Inspector General
Report on the FBI Crime Laboratory
• The findings:
– scientifically flawed testimony and reports in four cases
including the World Trade Center, and Oklahoma City
federal building bombings
1997 Justice Department Inspector General
Report on the FBI Crime Laboratory
• The findings continued:
• Inaccurate testimony
• Examiners without scientific qualifications
• Incomplete or missing documentation
1997 Justice Department Inspector General
Report on the FBI Crime Laboratory
• The findings continued:
– Insufficient documentation of test results
– Failure by FBI management to resolve issues
of incompetence
– Failure of management to resolve scientific
disagreements
– Failure to pursue lab accreditation
Benefits of Lab Accreditation
• Opportunity to formalize and improve lab
quality systems
• Complies with ISO internationally
recognized standards
• Improve:
Uniformity/consistency/credibility
Benefits of Lab Accreditation
• Assessment of quality system and
technical competency by outside ISO
recognized accreditation body
• The increased focus on quality, and
resulting training will improve the science
base
Disadvantages of Lab Accreditation
• Accreditation does not provide guarantees
about all test results
• Costs:
– FTE’s for drafting policy and procedures
documentation, and maintenance of program
– Accreditation Fees
ISO/IEC International Standard 17025 General
Requirements for the Competence of Testing
and Calibration Labs
• Includes all requirements that testing labs
have to meet to demonstrate that they
operate a quality system, are technically
competent, and can generate technically
valid results
• Compliance with 17025 also assures
compliance with ISO 9001
ISO 17025
• “Say what you do, and do what you say”
• Incorporates many of our existing
procedures
• Improves document control
• Improves operational control
• Improves uniformity among labs
• Allows for international recognition
ISO 17025
• “Say what you do, and do what you say”
• Standards are very general
• Laboratories write policies, procedures,
and work instructions to comply with
17025 standards
• Flexibility in interpretation
ISO 17025
• “…contains all of the requirements that
testing and calibration laboratories have to
meet if they wish to demonstrate that they
operate a quality system, are technically
competent, and are able to generate
technically valid results.”
ISO/IEC International Standard 17025 General
Requirements for the Competence of Testing
and Calibration Labs
• Fourteen “Management Requirements”
elements:
– 4.1 Organization
– 4.2 Quality System
– 4.3 Document Control
– 4.4 Review of requests, tenders, contracts
– 4.5 Subcontracting of tests and calibrations
– 4.6 Purchasing services and supplies
ISO/IEC International Standard 17025 General
Requirements for the Competence of Testing
and Calibration Labs
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4.7 Service to the client [Centers, Headquarters]
4.8 Complaints
4.9 Control of Nonconforming [OOS] testing
4.10 Corrective Action
4.11 Preventive Action
4.12 Control of Records
4.13 Internal Audits
4.14 Management
ISO/IEC International Standard 17025 General
Requirements for the Competence of Testing
and Calibration Labs
• Ten “technical requirements” elements.
– 5.1 General
– 5.2 Personnel
– 5.3 Accommodation and environmental
conditions
– 5.4 Test and calibration methods, and method
validation
ISO/IEC International Standard 17025 General
Requirements for the Competence of Testing and
Calibration Labs
– 5.5 Equipment
– 5.6 Measurement traceability
– 5.7 Sampling
– 5.8 Handling of test and calibration items
[samples]
– 5.9 Assuring the quality of test and calibration
results
– 5.10 Reporting the results
Methods: Selection
17025 Requirement:
– Appropriate for the Intended Use
– Meet the needs of the clients*
• *lab makes determination when client does not
specify
– Standard Methods Preferable*
• *published in international, regional, or national
standards, in technical journals, or by
manufactures of equipment
– Non-Standard Methods Require Validation
Methods: Selection
Traditional FDA Policy:
“Official Methods:” specified in FD&C Act or Code
of Federal Regulations
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USP Methods
AOAC methods, sometimes
PAM methods
NDA/ANDA approved methods
Methods: Selection
Traditional FDA Policy:
Non-Official but Mandated Methods:
–compliance programs
–assignments
–require “verification”
Methods: Selection
Traditional FDA Policy:
Non-Official Methods
–Journal Articles
–LIBs
–In-house methods
–Require validation
Methods: Validation
21CFR 211.165 (e) (Drug GMPs:
Product Testing)
The accuracy, sensitivity, specificity, and
reproducibility of test methods…shall
be established and documented…in
accordance with 211.194 (a) (2)
Methods: Validation
21CFR 211.194 (a) (2) (Laboratory
Records)
The statement shall indicate the location of
data that establish that the methods
used in the testing of the sample meet
proper standards of accuracy and
reliability as applied to the product
tested..
Methods: Validation
21CFR 211.194 (a) (2) (cont.)
(If the method employed is in the current
revision of the United State Pharmacopeia,
National Formulary, Association of Official
Analytical Chemists Book of Methods, or in
other recognized standard references, or is
detailed in an approved new drug
application… a statement indicating the
method and reference will suffice.)
Methods: Validation
21CFR 211.194 (a) (2) (cont.)
The suitability of all testing materials used
shall be verified under the actual
conditions of use.
Methods: Validation
USP. Section <1225>
VALIDATION of an analytical method is the
process by which it is established, by scientific
studies, that the performance characteristics
of the method meet the requirements for the
intended analytical applications.
Methods: Validation
ISO/IEC 17025,5.4.5.1
VALIDATION is the confirmation by
examination and the provision of
objective evidence that the particular
requirements for a specific intended
use are fulfilled.
Methods: Validation
ISO/IEC 17025,5.45.1
Minimum validation criteria:
All critical characteristics should be
defined and agreed upon by the end
user of the method.
Methods: Validation
Analytical Characteristics
(Validation Parameters)
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Accuracy
Precision
Specificity
Limit of Detection
Limit of Quantitation
Linearity
Range
Robustness
Ruggedness
Methods: Validation
Accuracy
The measure of agreement between the
experimentally determined value and
the true value of the analyte.
(Recovery, spike)
Methods: Validation
Precision
The repeatability or degree of scatter in
results obtained from multiple analyses
of a homogeneous sample.
(RSD of multiple trials)
Methods: Validation
Specificity
The ability of a method to accurately
measure an analyte in the sample
matrix.
(compare to matrix blank; use method
generally accepted as specific, i.e. MS,
IR)
Methods: Validation
Limit of Detection
The Lowest level of an analyte that can be
detected above the background on a
particular test instrument.
(signal: noise ratio)
Methods: Validation
Limit of Quantitation
The lowest level of an analyte that can be
quantitatively determined with an
acceptable level of accuracy and
precision.
(signal: noise ratio)
Methods: Validation
Linearity
The determination of the sample
concentration range where the analyte
response is directly proportional to the
analyte concentration.
(standard curve, linear regression)
Methods: Validation
Range
The upper and lower concentration interval
over which the analytical procedure has
an acceptable accuracy, linearity, and
precision.
(standard curve, LOQ)
Methods: Validation
Robustness
The ability of a method to remain
unaffected by small, usually deliberate,
variations in method parameters.
(minor changes in instrumental
parameters, solvent composition, etc.)
Methods: Validation
Ruggedness
The ability of a method to perform
acceptably in the hands of a competent
analyst in a different laboratory, or with
different instruments of the same type.
(inter-lab or intra/lab collaborative study)
Methods: Validation
Occasionally misunderstood point:
Most validation parameters are done in a
single laboratory…usually the
originating laboratory.
Methods: Validation
Do you need to do each of these all the time?
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-Accuracy
-Precision
-Specificity
-Limit of Detection
-Limit of Quantitation
-Linearity
-Range
-Robustness
-Ruggedness
Methods: Validation
Answer: Do what makes sense scientifically!!
Remember the validation definitions:
..verified under the actual conditions of use
..for the intended analytical applications
..the particular requirements for a specific intended
use
Methods: Validation
Categorization of Methods
(ref. USP <1225> Data Elements Required
for Validation:
-Quantitation of Major Ingredients
-Quantiation of Trace Ingredients
-Qualitative Tests
-Performance Tests
Methods: Validation
Examples
Major Ingredients, Quantitative Determination:
LOD and LOQ not required, Accuracy and Precision are
critical
Trace Ingredients, Qualitative Determination:
LOD and Specificity are critical, Precision not required
Trace Ingredients, Quantitative Determination:
LOD, LOQ, Accuracy, and Precision probably all critical
Methods: Validation
References
– USP, Section <1225>
– ISO/IEC 17025 – Section 5.4.5
– CDER: Guideline for Submitting Samples and
Analytical Data for Methods Validation
– CVM: Guideline for Collecting and Submitting
Analytical Data for Validation of Methods
GMP Principles Involved
• 21 CFR 211.165 (f) Drug products failing
meet established standards or specifications and
any other relevant quality control criteria shall be
rejected. Reprocessing may be performed. Prior
to acceptance and use, reprocessed material
must meet appropriate standards, specifications,
and any other relevant criteria.
CDER
• Violations of Laboratory GMP’s
– Majority of enforcement actions
– Majority of objectionable observations for
Domestic and Foreign Inspections
Laboratory CGMP Problems Include
• Lack of Documentation
• Lack of proper instrument calibration and
maintenance
• Test methods not validated
• System suitability tests not performed
• Laboratory data not reviewed by second
person for accuracy
Laboratory CGMP Problems Include
[cont’d]
• Out of specification {OOS} test results
• Lack of/ inadequate stability program
• Stability test methods not shown to be stability
indicating
• Improper sample and/or standard storage
• Untrained Lab personnel
• Lack of /inadequate standard operating
procedures
Laboratory CGMP Problems Include
[cont’d]
• Improper use of secondary [ non-USP]
standards
• Lack of /inadequate drug component or finished
product testing
• Equipment cleaning test methods are not
appropriately validated
• Lack of laboratory data integrity
• Lack of impurity profile
Laboratory GMP’s of the Future
• “OSP-17025’
• & SPECIFIC Requirements
?