Good Laboratory Practices - ACS Publications - American Chemical

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Chapter 13

Quality Assurance in Analytical Laboratories An

EPA Perspective

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Willa Y. Garner U.S.

Environmental Protection Agency, EN-342, Washington, DC 20460

The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Good Laboratory Practice (GLP) Standards regulations (1) are intended to ensure that regulatory studies are conducted with good planning and execution, complete documentation and validation, and integrity. Official GLP inspections include a review and evaluation of the testing facilities as well as an audit of the data generated by those f a c i l i t i e s . Chemistry auditors evaluate the entire study for environmental, residue, product chemistry and metabolism studies, but only the analytical phases of health effects and ecotoxicology studies. Sample collection, handling, transfer, and storage procedures are steps in an analytical study that may offer an opportunity for loss of sample integrity and must be documented in detail. Registrants are responsible for the retention of their raw data which must be maintained as long as the registration, which it supports, is active.

The conduct of a chemistry-related good laboratory practice (GLP) laboratory inspection and data audit will be discussed in this paper. This w i l l be accomplished by describing the basic audit procedure, then digressing into the objectives of an audit and the primary problem areas that have been experienced. Before addressing the fundamentals of an audit, let us review some of the regulatory background and history of the GLP regulations. These days, as you know, the regulatory testing laboratory has a new partner, the Federal auditor or inspector, who w i l l be c r i t i c a l l y reviewing a l l aspects of the selected study as well as those of the ongoing operations. This person is a verifier of accounts, as the dictionary phrases i t . He is sent to verify that the public's trust in science is well founded. The regulated community is fully aware that the Federal presence is the result of revelations that some laboratories were submitting false or faulty data as the basis for obtaining permits to s e l l

This chapter not subject to U.S. copyright Published 1988 American Chemical Society In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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GOOD LABORATORY PRACTICES

t h e i r products. There were inconsistencies between the raw data and the f i n a l reports. The t e s t protocols were poorly written and the t e s t data were not properly maintained. Consequently, i n granting permission to use toxic chemicals to control a g r i c u l t u r a l pests, Congress required i t s p u b l i c servants to assure themselves that no harm would occur to the users of these products or to the environment when used according to l a b e l d i r e c t i o n s . As a result, we f i n d ourselves i n a position, as Federal regulatory o f f i c i a l s , t o i n s i s t that there w i l l be q u a l i t y assurance and q u a l i t y control as an inherent accompaniment of a n a l y t i c a l work and that a n a l y t i c a l data accompanying a l l regulatory submissions s h a l l be c a r r i e d out i n compliance with good laboratory p r a c t i c e regulations. The GLP regulations are intended to ensure that studies are conducted with good planning and execution, complete documentation and v a l i d a t i o n , and i n t e g r i t y . Proposed Generic GLP

Regulations

An EPA committee worked f o r over a year on formulating a set of generic GLP regulations to cover a l l TSCA and FIFRA regulatory studies. The e f f o r t s of t h i s committee were published i n the Federal Register (2) on December 28, 1987, for a 90-day comment period. The proposed FIFRA GLP regulations appear as the l a s t chapter i n t h i s volume. VJhen the FIFRA GLP regulations become f i n a l they w i l l cover not only health e f f e c t s studies, but also environmental fate, r e s i due, metabolism, e c o l o g i c a l e f f e c t s , and e f f i c a c y studies. F i e l d studies w i l l be covered as well as laboratory work. For studies started before the GLP regulations beconE f i n a l rule, and completed a f t e r that date, the portion of the study conducted a f t e r the f i n a l rule date must have been conducted under the GLP regulations with proper documentation as to which part of the study was conducted under GLP and which part was not. It i s anticipated that the Revised FIFRA GLP regulations w i l l become f i n a l i n the summer of 1988. U.S.E.P.A. GLP

Inspections

The laboratory to be inspected w i l l receive a l e t t e r approximately two weeks before the Agency inspection team arrives that s p e c i f i e s which studies w i l l be audited and i f a laboratory GLP inspection i s to be included. Upon a r r i v a l , the inspector w i l l present o f f i c i a l credentials and a Notice of Inspection form. The GLP portion of the audit i s now conducted as i f GLPs for a l l types of studies were i n e f f e c t . For those laboratories conducting non-GLP studies, t h i s i s done to give an idea of what to expect when, and i f , the GLP regulations become law. The laboratory inspection aspects w i l l be reviewed b r i e f l y and then the data audit portion w i l l be discussed. f4any of you have expressed an i n t e r e s t i n a format for your master schedule. Figure 1 depicts the format Mobay Chemical Corp. uses. I t i s s e l f explanatory and covers the items required i n the GLP regulations (test substance; test system; nature of study; study i n i t i a t i o n date; current status; sponsor i d e n t i t y , i f applicable; and name of study d i r e c t o r ) . For a contract laboratory, the sponsor's i d e n t i t y must appear on the master schedule sheet for each study l i s t e d . There are several terms that require d e f i n i t i o n . In

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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the proposed GLPs, experimental s t a r t date means the f i r s t date the test substance i s applied to the test system, and the experimental termination date i s the l a s t date on which data are c o l l e c t e d d i r e c t l y from the study. These dates must appear i n the protocol. The study i n i t i a t i o n date, which i s the date that i s entered on the master schedule, i s defined as the date the protocol i s signed by the study d i r e c t o r . The study completion date w i l l r e f e r to the date that the f i n a l report i s signed by the study director. The laboratory area i s inspected to ascertain i f space and equipment are adequate for the s i z e of the s t a f f and the scheduled workload. A l l equipment, such as gas and l i q u i d chromatographs, i n f r a red spectrometers, nuclear magnetic resonance spectrometers, etc., have service, preventative maintenance, or c a l i b r a t i o n logs. Laboratory requirements d i f f e r as to the amount of information documented i n t h e i r maintenance logs. Some laboratories provide l i t t l e information and others provide extensive amounts. Figure 2 depicts the information that A n a l y t i c a l Development Corporation (ADC) records for their gas chromatograph usage. Balance and pH meters must have c a l i b r a t i o n logs and must be c a l i b r a t e d and/or standardized e i t h e r once d a i l y or p r i o r to use, whichever i s appropriate. Dry chemicals, solvents and stock solutions must be properly labeled. The labels used at Tegeris Laboratories (Figure 3) give an example of the items to be addressed. Each storage container for a t e s t , c o n t r o l , or reference substance must be labeled by name, CAS or code number, batch number, and expiration date, i f appropriate. Where appropriate, storage conditions necessary to maintain the i d e n t i t y , strength, p u r i t y , and composition of these substances must be given. For studies of more than four weeks' duration, reserve samples from each batch of test, control, and reference substance must be retained as long as the q u a l i t y of the preparation a f f o r d s evaluation. A l l radioactive materials must be labeled as such. A l l equipment, including balances and hoods, must be r e g u l a r l y maintained and so documented. Minimally, hoods should be checked on a yearly schedule. Dow Chemical Company uses the l a b e l shown i n Figure 4 to document hood maintenance checks. Refrigerators and freezers must have a temperature recorder of some type or be manually checked and the temperatures recorded. This covers the major GLP related items i n the a n a l y t i c a l laboratory. Standard Operating Procedures (SOPs) are also an important concept of GLP regulations. If followed, they ensure that a laboratory's compliance with GLP regulations i s well defined and consistent, regardless of the personnel conducting the research. SOPs must be developed f o r such topics as: specifying the operation, c a l i b r a t i o n , and maintenance of pieces of equipment; defining how t o record raw data and what raw data to record; explaining what i n f o r mation i s to be logged when chemicals are received; i n d i c a t i n g how to design studies and take samples i n the laboratory or i n the f i e l d ; and explaining how to input and v e r i f y computerized data. Data Audits A data audit may be e i t h e r p r i o r i t y or routine. P r i o r i t y audits are conducted i f a discrepancy, data gap, or other p o t e n t i a l v i o l a t i o n i s suspected. Routine audits of studies submitted f o r p e s t i c i d e

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

86

GOOD LABORATORY PRACTICES MOBAY CHEMICAL CORPORATION CORPORATE TOXICOLOGY DEPARTMENT STANLEY RESEARCH CENTER, ST ILW ELL, KANSAS

*B = BATCH * F = FORMULA U L = LOT # R = REFERENCE ft

STUDIES IN PROGRESS SCHEDULE A S OF SEPTEMBER 1986

COMPOUND (B.F.L.&R)*

TYPE OF STUDY

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Figure 1.

DATE

NAME

SPECIES

SIGNAL OVEN INLET DET

Figure 2 .

LOCATION EXPER/PROC/PATH

INITIATION DATE

EXPECTED COMPLETION

Master schedule format (Reproduced with permission from Mobay Chemical Co.).

PROJ.

TEMPERATURES

REQUEST

COLUMN

COLUMN

SIZE COATING

HEAD (ml/min) PSI FLOW

RECORDER RAMP SPEED PER MIN. INFO.

PURGE SYSTEM TOTAL SPLIT PURGE FLOW VENT VENT ON OFF

MAKE-UP

SAMPLE INFORMATION TYPE U VOL AUTO SOLVENT

GENERAL MAINTENANCE SEPTUM, GLASSWOOL, PROBLEMS

Information c o l l e c t e d on gas chromatograph maintenance l o g (Reproduced with permission from A n a l y t i c a l Development Corp.).

DATE RECEIVED:, EXPIRATION DATE:. INITIALS:

COMPOUND: SOLVENT:

CONC:

STORAGE:

EXP. DATE:

PREPARER'S INITIALS: PREPARATION DATE: Figure 3.

Information labels for d r y chemicals and solvents (top) and stock solutions (bottom) (Reproduced with permission from Tegeris Laboratories).

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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r e g i s t r a t i o n are c a r r i e d cut at a f a c i l i t y approximately at 15-month i n t e r v a l s . The i n t e r v a l may be shorter for audits of c e r t a i n p i v o t a l data submitted f o r r e r e g i s t r a t i o n or for the development of a r e g i s t r a t i o n standard. The chemistry auditor usually audits only the a n a l y t i c a l chemi s t r y portions for health e f f e c t s or ecotoxicology studies and the e n t i r e data f i l e f o r environmental, residue, product chemistry, and metabolism studies.

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Health E f f e c t s and Ecotoxicology Studies For the health e f f e c t s studies, the dosage preparations, including t e s t substance and reference standard characterization and s t a b i l i t y , and the diet preparations are reviewed by the auditor. Diet preparation aspects include homogeneity of the t e s t chemical i n the diet and the s t a b i l i t y of t h i s material i n the diet covering the period from the time i t i s mixed through the feeding period. The auditor w i l l also a s c e r t a i n i f the protocol was followed. If a change i n the study design occurs p r i o r to the event, the protocol should be formally amended to cover i t . Any protocol deviations noted during the study should be adequately documented. It i s important that the protocol approval date precede the experimental s t a r t i n g date. The same issues are addressed f o r the chemistry portions of the ecotoxicology studies. Feed and water data, i n cluding analyses for nutrients, contaminants, and other pertinent parameters w i l l also be reviewed by the chemistry auditor. C l i n i c a l chemistry i s another area subject to review during the chemistry audit. There are many sources of v a r i a b i l i t y r e l a t e d to the sampling, handling, transfer, and preservation of samples. The preparation, sampling, and analysis of animal feeds deserve s p e c i a l attention. It i s an established fact that the d i f f i c u l t i e s of d i s t r i b u t i n g parts per thousand, parts per m i l l i o n , and even parts per b i l l i o n of a test substance homogeneously i n t o a feed mixture are monumental. In looking at the dosage form of the t e s t a r t i c l e , the dosage preparation method i s evaluated and the c a l c u l a t i o n s for the concent r a t i o n levels are checked. Proof of s t a b i l i t y of the test a r t i c l e during the period of the stud/ and the a n a l y t i c a l procedures used to t e s t for s t a b i l i t y are evaluated. Proof of homogeneity, s t a b i l i t y , and proper concentration of the t e s t material i n the diet and the a n a l y t i c a l procedures used to a s c e r t a i n homogeneity and s t a b i l i t y are also evaluated. These properties must be addressed p r i o r to the i n i t i a t i o n of the study. In most cases, the concentration of the test substance i n the c a r r i e r i s expected to be within + 10% of nominal f o r concentrations greater than 10 ppm i n the diet, i f experienced analysts are u t i l i z i n g validated s p e c i f i c methods. I f t h i s l i m i t cannot be met, the protocol should be amended to show why t h i s was not possible, and why t h i s would not impact upon the v a l i d i t y of the study. Included i s a graph (Figure 5) from an a r t i c l e by William Horwitz which r e l a t e s a n a l y t i c a l p r e c i s i o n to concentration. I t shows that the a n a l y t i c a l v a r i a b i l i t y increases as the concentration decreases. The Horwitz data were generated from c o l l a b o r a t i v e studies where methodology was exactly defined. The data should be

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

GOOD LABORATORY PRACTICES INDUSTRIAL HYGIENE HOOD SURVEY HOOD IDENTIFICATION DATE OF SURVEY SURVEYOR STATIC PRESSURES*: S A S H CLOSED: S A S H FULLY OPEN:

INCHES WATER INCHES WATER

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FACE VELOCITIES, FPM (5) S A S H OPENINGS, INCHES:

@ @ @ CHEMICAL USED IN EVALUATING HOOD RESTRICTIONS:

'NOTE

IF STATIC PRESSURE READINGS VARY 25".. FROM THOSE MEASURED, EXHAUST SYSTEM SHOULD BE CHECKED

Figure 4.

Information c o l l e c t e d to document hood maintenance (Reproduced with permission from Dow Chemical Co.) •

F i g u r e 5.

Graph r e l a t i n g a n a l y t i c a l p r e c i s i o n t o c o n centration. (Reproduced from R e f . 3. Copyr i g h t I98I American C h e m i c a l S o c i e t y . )

Concentration

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

THE

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repeatable by a single analyst consistantly using the same exact method. An e a s i l y remembered reference point i s that a t 1 ppm i n the diet, the c o e f f i c i e n t of v a r i a t i o n i s + 16%. Records for documentation of the mixing procedure used t o achieve homogeneity of the test substance i n the c a r r i e r must be available for audit. Prior to the analysis of the study samples, a l l a n a l y t i c a l procedures must be validated i n terms of recovery, r e p r o d u c i b i l i t y , s e n s i t i v i t y , freedom from interference, and accuracy. If the t e s t substance mixture i s shown to be unstable i n the d i e t , i t i s important to either prepare the test substance-carrier mixture more frequently to achieve s t a b i l i t y or show unequivocally that the decrease i n concentration i s due to the chemical binding t o the c a r r i e r and that i t would s t i l l be b i o l o g i c a l l y available t o the test animal, i . e . , that i t would not be v o l a t i l i z i n g or decomposing into other compounds. Environmental Fate, Residue, and Metabolism Studies For the p r i s t i n e chemistry studies which include studies such as hydrolysis, s o i l and water photolysis, s o i l d i s s i p a t i o n , and rotat i o n a l crop under environmental fate, metabolism studies, residue studies, and product chenistry studies, such as vapor pressure, octanol-water p a r t i t i o n c o e f f i c i e n t , and water s o l u b i l i t y , the t o t a l study i s audited. This includes the GLP issues, such as adherence t o protocols, SOPs, and record accountability; completeness of raw data; the v a l i d a t i o n of data points; and the o v e r a l l s c i e n t i f i c issues. The chemical aspects of these studies focus p r i m a r i l y on the chemical characterization of the test substance and/or mixture. The i d e n t i t y of the test chemical should be proven, and the a n a l y t i c a l procedures used, such as gas or l i q u i d chromatography, nuclear magnetic resonance spectrometry, or mass spectroscopy, should be available for audit. This would include the chromatograms or spectra from these analyses. I t i s imperative that raw data be l e f t i n t a c t as they emerge from an instrument to maintain data i n t e g r i t y . Chromatographic printouts are t o remain attached and i n sequence. I f some data points are not used i n the f i n a l report, the reason i s t o be documented and those not used are t o remain with the study f i l e . No raw data are to be discarded. To comply with the portion of EPA Pesticide Registration Notice 86-5, which states that oversize computer printouts or fold-out pages not be included i n the r e g i s t r a t i o n package, i t i s suggested that photocopies be made of the chromatograms, and that the photocopies be cut t o f i t on an 8 1/2 x 11 inch page. Column conditions and other chromatographic parameters must appear i n the raw data. Types of information t o be documented are given i n Figures 6 and 7 for gas and l i q u i d chromatography, respectively. Quality c o n t r o l during sample analyses i s an important aspect i n the conduct of a s c i e n t i f i c a l l y sound study. Chemistry auditors w i l l ascertain i f replicates, recoveries, and reagent blanks were assayed with the samples, i f an independent audit mixture was employed to check out proper machine functioning p r i o r t o use, and i f the slope s e n s i t i v i t y was set c o r r e c t l y to assure proper integration for GC and HPIC analyses.

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

GOOD LABORATORY PRACTICES

90

Operator

_ —

Stationary Phase

—

Column No

Type _

Length

OD

ID .

Carrier Gas Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: May 11, 1988 | doi: 10.1021/bk-1988-0369.ch013

Detector.

Instrument.

Attenuation.

Range

Film Thickness

Flow Rates, cc/min. Make-up

. Type.

Hydrogen

_ Air _

On Column •

. Flow.

U

Date

Split •

Ratio

Chart Speed.

Splitless Injection •

Hole Time

Temperature-Det

Sample . Solvent.

Size

F i g u r e 6.

Column Initial Rate

Concentrations.

Inj Time Final

Gas c h r o m a t o g r a p h i c parameters d o c u m e n t a t i o n . (Reproduced w i t h p e r m i s s i o n from S u p e l c o , I n c . )

CHROMAT. NO. .

OPERATOR.

DATE.

_ LENGTH _

COL. NO.

Time

packed with

ID .

PCT

on (SUPPORT) .

(PHASE) . MOBILE PHASE AND GRADIENT .

TEMPS. (Reservoir)

(Col.)

PRESSURE DET.

(Det.)

FLOW RATE SENS.

mi./min. CHART SPEED

min. sec/in.

SAMPLE . SAMPLE CONC F i g u r e 7.

INJ. AMT. L i q u i d c h r o m a t o g r a p h i c parameters d o c u m e n t a t i o n . (Reproduced w i t h p e r m i s s i o n from Anspec Co.)

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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Test Substance/Mixture Characterization The method of t e s t substance synthesis or i t s source should be made a part of the documentation. I b i s would apply to any t e s t chemical, whether i t i s a technical material, a formulation, a metabolite, a by-product, or a radiolabeled compound. Any impurities greater than 0.1 % i n the t e s t material should be i d e n t i f i e d and quantified. I f a commercial or technical l o t i s s p e c i f i e d f o r the study, comparison should be made between the test chemical and i t s commercial counterpart. The test substance, or mixture, should meet routine s p e c i f i cations for chemical composition and p h y s i c a l properties. The source and l o t or batch number of the t e s t a r t i c l e and any diluants, such as acetone or corn o i l , should be given i n the raw data. Since, i n almost a l l cases, the test substance, or mixture, w i l l be shipped to the laboratory performing the study, a b i l l of lading describing the t e s t material as to name, p u r i t y , l o t number, quantity shipped, handling procedures, etc., i s needed along with chemical receipt records to provide a complete paper t r a i l to prove the transfer, handling, and receipt of the t e s t material. Storage and custodial procedures at the t e s t f a c i l i t y are necessary documentation f o r each test substance. Auditors w i l l ask to see the archived sample of the t e s t substance for studies whose term exceeds four weeks. At t h i s point, i t should be stressed that when characterization of the i d e n t i t y of parent chemical and/or metabolites i s required i n a study, that i d e n t i t y must be confirmed by an alternate technique. Data reported without a p p l i c a t i o n of suitable confirmatory techniques may not only be worthless, but what i s worse, incorrect information may be seriously misleading and may be unrectif iable. A l l data points should be used; one should not be s e l e c t i v e , i . e . , one from column A and another from column Bl Use s t a t i s t i c a l tests to determine i f data points i n the set are t r u e l y o u t l i e r s . One expects b i o l o g i c a l data to be f u l l of perturbations r e s u l t i n g from the many outside influences on the p a r t i c u l a r property we are measuring. Consequently, we get zig-zag patterns of these properties with time, complete with standard errors extending from each point which often do not overlap one another. An auditor should r e a l l y begin t o worry about the q u a l i t y of the observations when there i s no reasonable v a r i a b i l i t y component. Less than usual v a r i a b i l i t y suggests that some averaging has been going on. One can average out quite a few wild results, i f they are i n opposite d i rections, and get a f a i r l y decent mean. If one takes enough widely variable data points one can hide poor data by t h i s method. A bulk test chemical inventory must be maintained for labeled and unlabeled t e s t materials (Figure 8) which describes the chemical as to name, appearance, quantity, l o t number, storage conditions, etc. The rest of the form would have columns for date, person r e moving the material from stock, the quantity taken, the quantity remaining, and a column f o r the person receiving the material t o sign for i t . The p u r i t y of the test chemical must be shown p r i o r t o the i n i t i a t i o n of the study, as well as i t s s t a b i l i t y throughout the study. The a n a l y t i c a l procedures used to assure s t a b i l i t y must a l s o be available f o r audit. Reference standards must be characterized as to purity, batch or l o t number, source, storage requirements, and t r a c e a b i l i t y , and

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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GOOD LABORATORY PRACTICES

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ABC FORM NO.: 307 COMPOUND

STRUCTURE/ FORMULA

SPECIFIC ACTIVITY . TOTAL ACTIVITY

_

RADIOISOTOPE.

SOURCE

PURITY

DATE RECEIVED

LOT NO

RADIATION SAFETY OFFICER DATE

uCi USED

Figure 8.

uCi REMAINING

INVESTIGATOR LOCATION OF WORKING SOLUTION

NAME & INITIALS INVESTIGATOR

Information captured for the bulk test chemi c a l usage inventory (Reproduced with permission from A n a l y t i c a l Bio-Chemistry Laboratories, Inc.).

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

STUDY

U

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have p e r i o d i c p u r i t y assays i f the same l o t i s used over an extended period of time.

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Sample C o l l e c t i o n and Handling - F i e l d Studies Sample c o l l e c t i o n , handling, and storage are steps i n an a n a l y t i c a l study that o f f e r many opportunities f o r loss of i n t e g r i t y of the sample and must be described i n f u l l d e t a i l . Good judgement cannot be assumed; d e t a i l s must be provided. Complete sample control must be maintained from the time the samples are taken i n the f i e l d , i f t h i s i s the case, through t h e i r analysis i n the laboratory to f i n a l storage. Figure 9 depicts the type of information required for Dow Chemical Company residue f i e l d t r i a l s . Tools used to acquire the samples must be described, as well as the sample containers. I t i s a known fact that b o t t l e cap l i n e r s and aluminum f o i l which may be coated with drawing o i l may also be sources of contamination. These aspects must be considered when planning sample c o l l e c t i o n s . One needs to describe how the sample containers are cleaned and how the samples w i l l be shipped and then stored when they a r r i v e at the laboratory p r i o r to analysis, as well as the temperature and length of time f o r storage. Exposure to l i g h t and a i r are important considerations. Storage s t a b i l i t y data must be provided for the same matrix and cover the time period that samples are stored p r i o r to analysis. A l l samples must be logged i n and assigned unique numbers which are f u l l y traceable. F r a g i l e samples w i l l not need to be retained beyond q u a l i t y assurance review. To ascertain sample storage and handling procedures, the chemistry auditor often sets up the s i t u a t i o n of "I am a sample a r r i v i n g at the laboratory. Vtoat are your procedures for handling me from my point of a r r i v a l through extraction and analysis to f i n a l storage?" For a l l of the studies we audit, we ask for a curriculum v i t a e on each of the s t a f f members who are conducting and/or are involved with the study. We want to know about t h e i r education, experience, and t r a i n i n g i n the area they are working. Data V a l i d a t i o n A f t e r having looked through the laboratory's f i l e s for a l l of the information we have discussed, the auditor now begins the anal y t i c a l data v a l i d a t i o n phase of the audit. Usually, approximately 10% of the data points appearing i n the report submitted to EPA are randomly selected and validated. This means tracing a l l the raw data involved i n obtaining the selected data point i n the report back to t h e i r i n i t i a t i o n . Sometimes, the audit of a study w i l l be from photocopies rather than from the o r i g i n a l records. To document that the photocopy i s a "true" copy, i t must be c e r t i f i e d . Rohm and Haas Company uses the stamps depicted i n Figure 10 on t h e i r photocopies to assure v a l i d i t y . In looking through the raw data, the auditor also checks for overwrites and i n c o r r e c t l y executed cross-throuyhs, as depicted i n Figure 11. Overwrites and use of white-out are prohibited, according to the GLP regulations, and crcss-throughs should be executed as shown, with the person's i n i t i a l s , the date executed, and the reason for the change. Frequently, i n s u f f i c i e n t space i s available for

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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SHIP TO OOW CHEMICAL U S A • RESIDUE RESEARCH. AGRICULTURAL PRODUCTS f>€PT. 9001 BLDQ . MIDLAND. MICH. • INSTRUCT CARRIER TO NOTIFY ON ARRIVAL - Telephone No 5l7-«3»

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Quality Assurance: An EPA Perspective

GARNER

This is au^exact copy of the j^igmai document.

This is an exact copy reduced in size of the oriainaPdo€ument.

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Figure 10.

Rhetoric f o r documentation of a photocopy as a "true" copy (Reproduced with permission from Rohm and Haas Co.).

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Figure 11.

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Sample laboratory notebook page depicting overwrites and i n c o r r e c t l y and c o r r e c t l y executed crcxss-throughs (reproduced with permission from Uniroyal Chemical Co., Inc.).

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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GOOD LABORATORY PRACTICES

describing the reason f o r the change. To conserve space, speed up the correction process, and provide consistency throughout the laboratory, ADC developed the following numerical l i s t i n g :

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EXPLANATION OF NOTEBOOK ENTRY ERRORS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Misspelled Mathematical Error Wrong Entry (date, sample no., word, etc.) Transposition or Sequencing Error Transcription Error Procedural Change Wrong Conclusion I l l e g i b l e Entry Unnecessary Entry Footnoted Explanation Additional Comment

Each time an error i s made, i t i s i n i t i a l e d , dated, and one of the code mmbers i n the l i s t i s placed next to the i n i t i a l s and c i r c l e d . A copy of the l i s t i s placed i n the front of each notebook for reference. Pencil or white out are not to be used under any circumstances. Note at the bottom of Figure 11 the place for the witness or supervisor to sign. During audits, we have had many discussions about t h i s . The consensus i n the O f f i c e of Compliance Monitoring i s , i f there i s a place f o r a signature, sign i t . If t h i s p r a c t i c e i s not acceptable to the laboratory, an SOP should be developed t o explain t h i s deviation i n the use of the form. Raw data used to be a very simple concept: they were the numbers a c t u a l l y indicated by a measuring device, whether i t was the sum of weights on a balance, a determination on an instrument d i a l , or a measurement on a recorder chart. The analyst had f u l l control and r e s p o n s i b i l i t y over the production of the data at every step. With mechanization and automation, where the r e s p o n s i b i l i t y for instrument c a l i b r a t i o n i s assigned to the manufacturer of the equipment or the proper functioning of the instruments i s assumed to be b u i l t - i n by the instrument designers and computer operators, the production of data has s h i f t e d from a straight l i n e function, ent i r e l y under the d i r e c t supervision of the professional s c i e n t i s t , to a more complicated operation managed by a laboratory d i r e c t o r . Automated instruments measure the samples, execute the iianipulations, determine the response, perform the calculations, and present the f i n a l answer i n whatever form or units desired. The f i n a l value may be copied from a d i a l , recorded on tape, drawn on a chart, or not presented at a l l , to be stored i n a computer for coordination with past and future values, presenting the e n t i r e sequence as the result of the experiment. These f i n a l results are raw data just as much as the d i r e c t measurements are. Whether the results come d i r e c t l y from manual observations or from automated instruments i s not important. What we should be asking i s "Are these data correct?", "Are they o r i g i n a l data?", and "How do we know?" I t i s sometimes d i f f i c u l t to reconstruct computer generated data points because of d i l u t i o n factors, rounding of numbers, e t c . Check to see i f you can recalculate the numbers before you have to do i t for an auditor.

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

13. GARNER

Quality Assurance: An EPA Perspective

97

Data transformation steps should be documented i n laboratory notebooks. Inspection Closing

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At the end of the f a c i l i t i e s inspection and data audit, the inspector w i l l present the laboratory with a Receipt for Samples form. This form l i s t s a l l of the copies of documents, samples, etc., the i n spection team c o l l e c t e d for use i n documenting the findings of the audit i n t h e i r report. The laboratory w i l l be given a c l o s i n g session i n which the auditors and the Inspector w i l l discuss t h e i r findings. Frequently, t h i s conference also provides a time for a question and answer session or an exchange of ideas. I t i s 10:00 p.m. Do you know where your raw data are? It i s very important that you do. It could be c o s t l y i f you do not. Under Section 8 of FIFRA, the registrants are responsible for t h e i r raw data, for i t s i n t e g r i t y , and for i t s protection. The Code of Federal Regulations, 40 CFR 14, §169.2 (k), Maintenance of Records, states that "Records containing research data r e l a t i n g to registered p e s t i c i d e s , including a l l t e s t reports submitted to the Agency i n support of a tolerance p e t i t i o n , a l l underl y i n g raw data, and interpretations and evaluations thereof, whether i n the possession of the producer or i n the possession of the independent t e s t i n g f a c i l i t y or laboratory ( i f any) which performed such tests on behalf of the producer. These records s h a l l be retained as long as the r e g i s t r a t i o n i s v a l i d and the producer i s i n business." Under the paragraph e n t i t l e d C i v i l Penalties i n Section 14 of FIFRA, "Any r e g i s t r a n t , commercial applicator, wholesaler, dealer, r e t a i l e r , or other d i s t r i b u t o r who v i o l a t e s any p r o v i s i o n of t h i s Act may be assessed a c i v i l penalty by the Administrator of not more than $5,000 f o r each offense." In assessing the r e s u l t s from these audits, for the most part, the lack of raw data has been the most c r i t i c a l deficiency, along with occasional findings of careless science. If data are missing, a c i v i l f i n e may be l e v i e d , and the study may have to be repeated. An auditor or inspector's r e s p o n s i b i l i t y i s to present and document the facts: They do not i n v a l i d a t e studies, and they do not levy fines or penalties. The l e v e l of s o p h i s t i c a t i o n shown i n the implementation of the GLP regulations varies greatly between the d i f f e r e n t laboratories. Most contract laboratories are w e l l into compliance since they perform FDA r e l a t e d GLP studies and have been involved with QA for several years now. Second i n rank come the in-house company l a b oratories who a l s o perform studies for FDA. There has been some information exchange between the toxicology groups and the a n a l y t i c a l groups. The rest of the companies, e s p e c i a l l y those units who do only environmental or residue chemistry studies, are for the most part behind t h e i r counterparts, and many s t i l l have a long way to go to catch up. The GLP regulations are being accepted as the minimum standards of research q u a l i t y ; however, compliance with the p r i n c i p l e s outlined i n the GLPs does not i n i t s e l f ensure q u a l i t y research data. Any

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research q u a l i t y assurance program should include the GLP concepts as part of i t s basic structure. I t cannot be overemphasized that an e f f e c t i v e q u a l i t y assurance program must have the support and i n volvement of multiple l e v e l s of management and research personnel. Acknowledgments Appreciation i s extended t o Dean H i l l , USEPA, NEIC, Denver, 00, f o r h i s h e l p f u l comments and suggestions i n the review of t h i s paper.

Literature Cited

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1.

Pesticide Programs; Good Laboratory Practice Standards; Final Rule, Fed. Reg., 43:53946, November 29, 1983. 2. Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) and Toxic Substances Control Act (TSCA); Good Laboratory Practice Standards; Proposed Rules, Fed. Reg., 52:48920, December 28, 1987. 3. Horwitz, W. Analytical Measurements: How Do You Know Your Results Are Right? In "The Pesticide Chemist and Modern Toxicologist" (1981) S. Kris Bandal, Gino Marco, Leon Goldberg, Marguerite Leng, Eds.; ACS Symposium Series 160, American Chemical Society, Washington, DC. RECEIVED March 21, 1988

In Good Laboratory Practices; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.