Good Laboratory Practice

PRESENTED BY JEAN COBB SENIOR PROJECT ASSOCIATE PESTICIDE RESIDUE LAB For Field and Laboratory Research BIOCHEMISTRY

ALS 5204

What are GLPs?

Good Laboratory Practice standards (GLPs) are federal regulations mandated in the United States by:
Food and Drug Administration (FDA) in 21 CFR Part 58 Environmental Protection Agency (EPA) both for FIFRA in 40 CFR Part 160 and for TSCA in 40 CFR Part 792

Key Dates
1970 1980
1976 FDA GLP proposed

1978 FDA GLP regulations published

1982 OECD GLP published (30 countries incl. U.S.), UK GLP published, Japanese GLP published

1983 EPA GLP regulations published

1986 FDA GLP revised, European Union GLP Directives 1989 EPA GLP revised 1998 OECD GLPs revised, Canadian PMRA adopted GLPs 2002 OECD consensus document 2007 EPA may consolidate two parts of EPA GLPs

1990 2000

Where are the EPA GLP Regulations Published?

National Archives and Record Administration

Code of Federal Regulations (CFR)
Title 40 Protection of Environment (laws and regulations of U.S. EPA)
 Part 160: Good Laboratory Practice Standards, 160: Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), Subparts A-J A Part 792: Good Laboratory Practice Standards, 792: Toxic Substances Control Act (TSCA), Subparts A-J ANote: FIFRA regulates pesticides and TSCA regulates toxic substances

Why Were the GLPs Mandated?

In the 1970s, numerous cases of laboratory malpractice surfaced in toxicity testing of food and drugs in the U.S. FDA inspectors found inaccurate, sloppy, and fraudulent research studies Became a public safety issue

One of the first names to attract regulatory and media attention was IBT

Illustration by Dan Sherbo

IBT: Industrial Bio-Test Laboratories

Problems at Test Facilities

Many of IBTs (Industrial Bio-Test Laboratories) Biotest animals were housed in a water-logged waterroom known as the Swamp. Swamp. During the course of a two-year feeding study, twoinvolving more than 200 animals, the mortality rate in the Swamp reached 80 percent. Dead rats and micedecomposed so rapidly in the Swamp that their bodies oozed through wire cage bottoms and lay in purple puddles on the dropping trays.
- The Amicus Journal, Spring 1983, p.14

Problems with Sponsors

G. D. Searle Co. (Pharmaceutical Manufacturer) Because of the perfunctory nature of the observations, tissue masses come and go and animals die more than once. In fact some once. rats listed as dead later were recorded as alive, then dead, then resurrected once or even twice more.
The Impact of Publicity on Corporate Offenders, Ch. 12, 12, p. 138

The Regulatory Process

Before GLPs Few checks and balances
Test Facility

Industrial Bio-Test Laboratories (IBT), Craven BioLabs, Intertek Testing Services, & others
Submits Regulatory Data Yes! Permission to Market Regulated Product

Sponsor

Agency (EPA, FDA)

Approve?

Searle Co. ChemAgro Monsanto & others

No! Permission to Market Regulated Product Denied

Test Facility: Field and laboratory (contract) research facilities Sponsor: Pharmaceutical and pesticide manufacturers

The Regulatory Process

Before GLPs Few checks and balances
Test Facility

Inaccurate, sloppy, and fraudulent science???

Sponsor

Submits Regulatory Data

Agency (EPA, FDA)

Approve?

Yes! Permission to Market Regulated Product

Poor Management Practices ????

No! Permission to Market Regulated Product Denied

Would you want the FDA to issue a permit to manufacture of a drug based on sloppy research? Or for the EPA to register a pesticide based on fraudulent data? Probably not!

What Role Do GLPs Play?

Good Laboratory Practice standards help to assure the quality and integrity of studies submitted in support of FDA and EPA regulated products

The Regulatory Process

After GLPs
Test Facility

Internal audits and inspections (conducted by Quality Assurance Unit)

Yes! Permission to Market Regulated Product

Submits Regulatory Data Sponsor

Agency (EPA, FDA)

Approve?

External audits and inspections of sponsor and test facility (conducted by regulatory agency)

No! Permission to Market Regulated Product Denied

GLP Regulations

Greater scrutiny of field and laboratory studies of regulated products

Auditor/ Inspector

Who must comply with GLPs?

FDA GLP Compliance

Required: PrePre-clinical safety studies for the development of food additives and drugs (before a marketing permit is issued) Regulated products: Pharmaceuticals, products: cosmetics, food & color additives, human medical devices
Note: pre-clinical refers to safety testing in animals, preplants, or microorganisms (not humans)

EPA GLP Compliance

Required: Field and laboratory studies of pesticides (before a marketing permit or application for research is issued) Regulated products: Pesticides and other products: substances that could spread during agricultural practice

GLP Regulations: Rules and Tools

GLP Regulations (Rules)
ORGANIZATION AND PERSONNEL FACILITIES EQUIPMENT FACILITY OPERATION TEST, CONTROL, AND REFERENCE SUBSTANCES RECORDS AND REPORTS

Documentation (Tools)
Training records, CVs, GLP training Maintain adequate space/separation of chemicals from office areas Calibration, logbooks of use, repair, and maintenance; check freezers Standard operating procedures Chemical and sample inventory, track expiration dates, labeling Timely reporting, storage of raw data and reports

Documentation

If you didnt write it down, it NEVER happened. (As far as an auditor is concerned)
Auditor/ Inspector

Equipment
40 CFR Part 160 (EPA GLP regulations)
Section 160.63 Maintenance and Calibration 160. of Equipment. (a) Equipment used in the generation, measurement, or assessment of data shall be adequately tested, calibrated, and/or standardized. (c) Written records shall be maintained of all inspection, maintenance, testing, calibrating, and/or standardizing operations. Do you know the difference between standardized, calibrated, and verified?

Equipment
Verification (Testing): external check of equipment accuracy (check balance accuracy against weights at laboratory- no adjustment) laboratory Calibration: equipment is adjusted based on comparison to certified or known reference materials (balance adjusted after comparison to certified weights by trained professional) Standardization: comparison with similar equipment (use two thermometers of similar design to compare readings)

Equipment
What about validation?
Electronic data management systems (computers, instrumentation) must be validated to confirm that they will perform their intended functions For example, a computer spreadsheet used for calculations during a GLP study could be validated as follows: enter identical raw data as previously and compare the calculations using the same software/options- they should software/optionsbe identical!

Use Logbooks
AGILENT GAS CHROMATOGRAPH SERIES: 6890n VT#0000322580
DATE 9/13/07 NAME John Smith (lab tech)
PROJECT SAMPLE MATRIX DETECTO R TYPE COLUMN TYPE/ SIZE OVEN TEMP c INLET TEMP c DET TEMP c GAS mL/min ROUTINE SERVICE (#) PROBLEM (#)

VCE07020

Water

ECD #8128/ ECD #5663

(dual column)

RTX-5 (30 m x 0.25 mm x 0.25 m)

60-275C

250C

350C

He-carrier, 2.3 mL/min, N2 makeup

Replaced He gas - VAC052 9/13/07 J.E.S.

N/A

9/14/07

Sally Jones (lab tech)

VCE07021

Plant Tissue

ECD #8128/ ECD #5663

(dual column)

RTX-5 (30 m x 0.25 mm x 0.25 m)

90-275C

250C

350C

He-carrier, 2.3 mL/min, N2 makeup

N/A

Power outage caused GC shutdown

9/17/07

Sally Jones (lab tech)

Standards only

N/A

NPD

RTX-OPP (30 m x 0.25 mm x 0.25 m)

60-275C

225C

300C

He-carrier, 1.0 mL/min, H2/Air det. gases

New glass insert & gold seal 9/17/07 S.J.

N/A

Record all pertinent operating parameters Take the time to record routine service and how problems were resolved (it may help if/when the same problem arises!)

Equipment
Was the equipment functioning properly? Who performed the work, what was the date, and what specific parameters did they use? What was there a problem? How was the problem fixed?

Reagents and Solutions

40 CFR Part 160 (EPA GLP regulations)
Section 160.83 Reagents and Solutions. All 160. reagents and solutions in the laboratory areas shall be labeled to indicate identity, titer or concentration, storage requirements, and expiration date. Deteriorated or outdated reagents and solutions shall not be used.

How do you know what expiration date to use?

Reagents and Solutions

General expiration guidelines:
Dry reagents: 5 years (unless reevaluated) Solvents: 1 year from date opened or 2 years from date received Solutions: Use the earliest date of components in the solution or no longer than 6 months

Question: Which takes precedence: the manufacturers expiration date or expiration date as stated in the facility SOPs? Answer: Whichever is earliest!

Use Labels
Clearly label chemicals and solution containers Make sure that the expiration date and storage requirements are included on the label If a solution, what date was it prepared?
CHEMICAL LABEL CHEMICAL___ ____________ ________ CHEM ID#______________________________ _ DATE RECEIVED:___________________________ DATE OPENED: ____________________________ EXPIRATION DATE__ _ _______STORAGE______

SOLUTION LABEL CONCENTRATION_____________________ SOLUTION____________________________ FROM CHEM ID#_____________________ DATE PREPARED_____________________ EXPIRATION DATE______ STORAGE______

Use Forms
PESTICIDE RESIDUE LABORATORY 2007 CHEMICAL INVENTORY FORM LAB CHEMICAL ID (s): __C070014______________

Assign a unique number to each chemical received by the facility Record the purity, date received, storage conditions, and source Use the form to jog your memory about the information you need to collect

CHEMICAL NAME: ethyl acetate CAS NO.: 141-78-6 SOURCE: Fisher Scientific LOT NO.: 067720 PURITY/GRADE: Pesticide Grade QUANTITY RECEIVED: 4 L EXPIRATION DATE: 9/7/12 STORAGE CONDITIONS: ambient, in solvent cabinet DATE RECEIVED: 9/7/07 SIGNATURE:

Jean M. Cobb

COMMENTS: N/A

DATE INSPECTED/METHOD: N/A NEW EXP DATE: N/A

Test, Control, & Reference Substances

Are the test, control, and reference substances of known quality and purity? Are these substances used within expiration dates? Are they adequately stored?

Raw Data
Question: What happens if you make a mistake?

Answer: Do not obscure original data!! Instead, draw a single strikeout, then add reason code, initials, and date of change. (Preserve the original data).

Documentation
Record data using permanent ink (never pencil) Date and sign every entry (who is responsible?) Keep records in real time (no catching up later) No rewrites, need original entries (reduces rewrites, transcription errors)

Documentation is important in all sorts of situations!!

Raw Data
40 CFR Part 160 (EPA GLP regulations) Section 160.3 Definitions. Raw data 160. Raw means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a study and are necessary for the reconstruction and evaluation of the report of that study.
If you scribble some notes on a scrap of paper, are those notes considered raw data? Answer: Yes!

Raw Data
Can you list examples of raw data?
Logbooks (to record temperatures or equipment use, repair, and maintenance) Field or laboratory notebooks Forms (for field or laboratory observations, chain-ofchain-ofcustody, sample or chemical receipt) Training reports Computer printouts Recorded data from automated instruments

How can anyone remember all these details?

Answer: You dont have to thats one of the functions of the Standard Operating Procedures (SOPs).

Write Standard Operating Procedures (SOPs)

SOPs are written, approved procedures that describe routine activities that are specific for daily operations at each facility. SOPs should allow appropriately qualified personnel to perform a procedure once trained.

Standard Operating Procedures

40 CFR Part 160 (EPA GLP regulations) Section 160.81 Standard operating 160. procedures. (a) A testing facility shall have standard operating procedures in writing setting forth study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study.
Personnel perform the same tasks using the same procedures.

SOP Writing Guidelines

SOPs should accurately reflect how routine tasks are performed (written by each facility based on their specific field and/or laboratory operations) Make sure they are useful in daily operations They should be scientifically sound Remember to update as necessary, rewrites are part of the process

Writing Guidelines
Cautions:
Avoid restrictive language such as vortex for exactly 1 minute but include clear instructions such as vortex until homogenized if that satisfies the purpose Dont add unnecessary steps such as consult the manual unless personnel are required to follow this step

Writing Guidelines
The primary goal is to avoid confusion

Did your supervisor say to make a 1 in 4 dilution or was it a 1 to 4 dilution? If it is written in an SOP, the instructions can be verified.

What if you dont have to comply with GLP regulations?

GLP Compliance
Not Required: Basic research (most of the research conducted at universities like Virginia Tech) Studies to develop new analytical methods Chemical tests used to derive the specifications of a marketed food product Instead, emphasize GLP principles during research

GLP Principles
GLP principles are a good idea even if you are not required to comply with the regulations.
Say What You Do (with written standard operating procedures) Do What You Say (follow the procedures) Be Able to Prove It (with good record keeping)

Is GLP Experience Important to Employers?

Yes! In some cases

GLP Experience
An employer may find it useful if you have: Practical experience with working on a study conducted in compliance with GLP regulations Experience working at a facility that emphasizes GLP principles Familiarity writing and using standard operating procedures at a GLP facility

Why Do We Need GLPs?

Everyone makes mistakes Mistakes cost $$$ Increasing the quality of an operation is good for business and science

What GLPs SOPs Cant Do

Guarantee good science Guarantee good documentation Replace common sense Prevent all mistakes

What GLPs Can Do

Fulfil the legal requirements of some FDA and EPA research studies

GLP principles can be followed to increase the quality of basic research

Websites
Code of Federal Regulations (CFR)- all (CFR) EPA GLP Regulations FDA GLP Regulations USDA- Pesticide Data Program (PDP) USDAStandard Operating Procedures