Catalyzing Collaboration

January 13. 2011

WORKSHOP 2:

Optimizing Academic Labs to

Encourage Industry Relationships

Ann V. LeFever, Ph.D.

LeFever Consulting

alefever1@hotmail.com

262-853-3538

Good Laboratory Practice

for Nonclinical Laboratory Studies

Title 21 Code of Federal Regulations Part 58

The goal is to demonstrate SAFETY of test

article before use in humans

Do controlled, well-documented laboratory

studies

Use prospective and approved protocols

Document testing methods and findings

Provide Quality Assurance review

Organization of GLPs

Title 21 Code of Federal Regulations Part 58http://www.21cfrpart11.com/files/library/pred_rules/mcdowall_glp_annotate.pdf

GLP Subpart A ––GENERAL PROVISIONS

GLP Subpart B ––

ORGANIZATION AND PERSONNEL

GLP Subpart C ––

FACILITIES

GLP Subpart D ––

EQUIPMENT

GLP Subpart E ––

TESTING FACILITIESOPERATION

GLP Subpart F ––TEST AND CONTROL ARTICLES

GLP Subpart G ––PROTOCOL FOR AND CONDUCT OF STUDY

GLP Subparts H-I ––[RESERVED]

GLP Subpart J ––RECORDS AND REPORTS

GLP Subpart K ––DISQUALIFICATION OF TESTING FACILITIES

The 10 Commandments of GLP

1. Thou shalt appoint study directors and quality assurance

2. Thou shalt be competent, as a result of education, training and experience

3. Honor thy protocol and thy SOPs

4. Thou shalt conduct studies in adequate and clean facilities

5. Thou shalt identify test and control articles and document their use

The 10 Commandments of

6. Thou shalt maintain and calibrate equipmentaccording to a specified schedule

7. Thou shalt document and correct all deviations

8. Thou shalt not commit fraud; all thy work thou shaltnote, sign and date

9. Thou shalt have archives

10.Thou shalt not turn your back on the FDA

Fundamentals of GLP

Resources: organization, personnel, facilities &

equipment

Rules: protocols and written procedures

Characterization: test items & test systems

Documentation: raw data, final report &

archives

Quality assurance unit

Resources

Organization & Personnel

The structure of the research organization and

the responsibilities of the research personnel

must be clearly defined

Staffing levels must be sufficient to perform the

tasks required & the qualifications and training

of staff must be defined and documented

Resources

Facilities & Eequipment

Facilities and equipment must be sufficient to

perform the studies of the laboratory

All equipment must be in working word & a

strict program of qualification, calibration and

maintenance must be enforced

Rules

Protocols & Written Procedures

The main steps of research studies must be described in the study plan or protocol

The specific details on the activities required to achieve the data in the study plan is described in written standard operating procedures (SOPs).

Techniques used should be standardized & validated

Characterization

The materials used during the study should be

fully characterized

Material information including vendor, lot

number, specification, certificate of analysis,

expiration date, etc. must be documented in

each research experiment conducted

Documentation

If an activity is not documented ---

it never happened!

Documentation

Raw data: represents the basis for establishing results and drawing conclusions. Must reflect the procedures and conditions of the study

Final Report: The contents of the report describe the study accurately and includes the study director’s interpretation of the results

Archives: Storage of records must ensure safekeeping for many years together with ability for prompt retrieval

Quality Assurance

A team of staff members charged with assuring

management that GLP compliance has been

attained within the laboratory

QA staff operate independently of the

operational staff and function as witnesses to

the whole pre-clinical research process

GLP Principles

Main Goal – to help scientists obtain reliable, repeatable, auditable results that can be recognized by scientists worldwide

The purpose is not to assess the intrinsic value of a study

GLP principles are a set of organizational requirements

Goals of GLP

Ensure efficient use of resources

Ensure high quality results

Ensure comparability of results

Promote mutual recognition of results

Managerial Organizational

Concepts for GLP Studies

Performed

Recorded

Reported

Archived

Monitored

Planned

58.35

Quality Assurance Unit

Duties

QAU monitors each study to assure management

that all systems are in conformance with GLP

regulations

QAU shall be entirely independent of personnel

conducting a particular study

58.35

Quality Assurance Unit (cont.)

Duties

The quality assurance unit shall:

Maintain a master schedule sheet of all studies,

indexed by test article and listing these elements:

test system, nature of study, study initiation date,

current status, sponsor identity, and name of the

study director

58.35

Quality Assurance Unit (cont.)

Duties

Maintain copies of all GLP protocols

Inspect each nonclinical laboratory study at adequate

intervals; maintain written signed records of periodic

inspections

Bring to the attention of the study director and

management immediately any problems found

during an inspection that may affect study integrity

58.35

Quality Assurance Unit (cont.)

Duties

Periodically submit to management and to the study

director written status reports on each study, noting

problems and corrective actions taken

Determine that no deviations from approved

protocols or standard operating procedures were

made without authorization and documentation

58.35

Quality Assurance Unit (cont.)

Duties

Review the final study report to assure accuracy in

description of methods and Standard Operating

Procedures, and that results accurately reflect the

raw data of the study

Prepare and sign a statement specifying dates of

inspections and when findings were reported to

management and study director

The QAU SOPs (and related)

Topics:

GLP Training

QA training within the GLP environment

Structure of the QAU, e.g.

Inspection group, archiving group, validation group

QA Reporting Systems, e.g.

To respond to QA findings

To report to management (including trend analysis)

The QAU SOPs (and related)

Topics (continued):

Good documentation practices

“Inspection” of computer systems

QA Master Schedule

Archiving procedures (including off site archiving)

Disaster recovery plan

Data Audit

Good Documentation Practice

Documentation should permit the complete

reconstruction of a study

Record data directly, promptly and legibly in indelible ink

(never pencil)

Initial and date all observations and any resulting changes, but do not obscure original data

Initial and date only work you’ve performed

Do not document selectively or in advance of performing the activity

Good Documentation Practice

Do not use white-out correction fluid or tape

Do not use ditto marks as raw data

Copy all heat sensitive paper and stamp “exact copy”

Explain why any raw data not used was not used

Verify critical calculations using a second person and document this

Notebook pages requiring a second signature shall be completed with that signature

Good Documentation Practice

Properly head all pages, tables, columns; identify units

Describe Statistical & Calculation Procedures used

Sign, Date, and File automated printouts (e.g., QC forms)

Retain all Raw Data (original records) in the Study File

Do not document by exception. Use positive documentation, even if only a check mark.

Good Documentation Practice

Documentation must allow another person to be able to accurately reconstruct what you have done

Keep all original observations including those observations recorded directly into a computer

Sign and date all computer printouts

Never back-date anything

Follow SOPs and Protocol

Good Documentation Practice

Document all deviations with accompanying explanations

Indicate in the record all applicable units and equipment used

Raw Data Correction

All changes to raw data must be made without

obscuring the original entry

All changes must be initialed and dated by the person

making the change, accompanied by an explanation for

the change

Abbreviations for Reasons

Notation Meaning Definition

EE Erroneous Entry Entry of a wrong number or

incorrect word

SP Spelling Error Entered word is misspelled

RD Repeated Data Data are already correctly

entered elsewhere

MC Miscalculation Number shown is the result

of a miscalculation

NL Not Legible Entry is illegible or has been

overwritten

OE-OK Original Entry OK Ignore single line cross-off

STET Original Entry OK Ignore single line cross-off

Reference:

Compliance Program Guidance

for FDA Staff

BIMO – Bioresearch Monitoring

7348.808 Good Laboratory Practice (Nonclinical

Laboratories) – FDA version

7348.808A Good Laboratory Practice Program

(Nonclinical Laboratories) – EPA Data Audit

Inspection

Bottom Line…

7348.808 Good Laboratory Practice (Nonclinical

Laboratories) is FDA’s instruction manual for its

inspectors’: http://www.fda.gov/downloads/ICECI/EnforcementActions/

BioresearchMonitoring/ucm133765.pdf

INSPECTIONAL

General Instructions

1. Determine the current state of GLP compliance by

evaluating the laboratory facilities, operations, and

study performance

2. Organization Chart - If the facility maintains an

organization chart, obtain a current version of the

chart for use during your inspection

INSPECTIONAL

General Instructions (cont.)

3. Facility Floor-plan –

• Obtain a diagram of the facility

• Identify any areas that are not used for GLP

activities

• Use the floor plan during the inspection to ensure

that it is really up-to-date

SOP Evaluation

1. Review the SOP index and representative samples of SOPs to ensure coverage of all of the areas identified in GLPs

2. Verify that only current SOPs are available at the personnel workstations

3. Review key SOPs in detail and check for proper authorization signatures and dates, and general adequacy with respect to the content (i.e., SOPs are clear, complete, and can be followed by a trained individual)

SOP Evaluation (cont.)

4. Verify that changes to SOPs are properly authorized

and dated and that a historical file of SOPs is

maintained

5. Ensure that there are procedures for familiarizing

employees with SOPs

6. Determine that there are SOPs to ensure the quality

and integrity of data, including input (data checking

and verification), output (data control), and an audit

trail covering all data changes

SOP Evaluation (cont.)

7. Verify that a historical file of outdated or modified computer programs is maintained. If the firm does not maintain old programs in digital form, ensure that a hard copy of all programs has been made and stored.

8. Verify that SOPs are periodically reviewed for current applicability and that they are representative of the actual procedures in use

9. Review selected SOPs and observe employees performing the operation to evaluate SOP adherence and familiarity

Storage and Retrieval of Records

Determine how and where computer data and backup

copies are stored, that records are indexed in a way to

allow access to data stored on electronic media, and

that environmental conditions minimize deterioration

Assess the procedures by which the

study director:

Is assigned and replaced

Assures the protocol and any amendments have been

properly approved and are followed

Assures that all data are accurately recorded and

verified

Assures that data are collected according to the

protocol and SOPs

Assess the procedures by which the

study director also:

Documents unforeseen circumstances that may affect the quality and integrity of the study and implements corrective action

Assures that study personnel are familiar with and adhere to the study protocol and SOPs

Assures that study data are transferred to the archives at the close of the study

QAU Operations

Ratio QA employees to all employees (5 to 8%)

Review and verify QAU SOPs to assure that they cover all methods and procedures for carrying out the required QAU functions, and confirm that they are being followed:

1. Maintenance of a master schedule sheet

2. Maintenance of copies of all protocols and amendments

3. Scheduling of its in-process inspections and audits

QAU Operations (cont.)

4. Inspection of each nonclinical laboratory study at

intervals adequate to assure the integrity of the study,

and maintenance of records of each inspection

5. Immediately notify the SD and management of

problems likely to affect the INTEGRITY of the

study

6. Submission of periodic status reports on each study to

the SD and management

QAU Operations (cont.)

7. Review of the final study report

8. Preparation of a statement to be included in the final

report that specifies the dates inspections were made

and findings reported to management and to the SD

9. Inspection of computer operations

10. Training

More scrutiny of QAU

Verify that, for any given study, the QAU is entirely separate from and independent of the personnel engaged in the conduct and direction of that study

Evaluate the time QAU personnel spend in performing in-process inspection and final report audits

Determine if the time spent is sufficient to detect problems in critical study phases and if there are adequate personnel to perform the required functions

Facilities

Document any conditions that would lead to contamination of test articles or to unusual stress of test systems

Determine that computerized operations and archived computer data are housed under appropriate environmental conditions (e.g., protected from heat, water, and electromagnetic forces)

Equipment

(other than computers) For representative pieces of equipment check the

availability of the following:

SOPs and/or operating manuals

Maintenance schedule and log

Standardization/calibration procedure, schedule, and

log

Standards used for calibration and standardization

Testing Facilities

Operations Determine if the testing facility has established and

follows written SOPs necessary to carry out study operations in a manner designed to ensure the quality

and integrity of the data (including method validation)

Determine if the testing facility has appropriate controlled storage for study samples

Determine if the testing facility maintains and calibrates instrumentation as per SOPs

Test and Control Articles

Characterization and Stability of Test Articles - The responsibility for carrying out appropriate characterization and stability testing may be assumed by the facility performing the study or by your company

If you intend to perform the test article characterization and stability testing, verify that the test facility has the procedure in place to document that this testing will have been conducted according to GLP (or GMP)

Archiving

Determine the number of archive locations –waterproof? Fireproof?

Determine who is the individual assigned as archivist

Verify method of indexing and the time period when documents/slides/computer data are archived after completion of the study

CONCLUSION!

The basic concepts underlying quality systems are

quite simple:

Say what you do,

do what you say,

prove it and

improve itJanet Woodcook, M.D.

Director, Center for Drug Evaluation and Research

FDA