APPENDIX C: HEI SPECIAL QUALITY ASSURANCE PROCEDURES

I. Policy Statement
II. Quality Assurance Components
III. Roles of Institutions and Individuals in Achieving Quality Assurance

I. POLICY STATEMENT

It is the policy of the Health Effects Institute to utilize special quality assurance (QA) procedures for research projects that may produce data of regulatory significance. These procedures augment the QA/QC procedures applied to all HEI studies and provide assurance that data are collected under defined conditions and are reliable and traceable. This will aid in assuring that conclusions drawn from the data are scientifically valid. If there is a QA program in place at the institute at which the research is being conducted, then HEI will assess its adequacy and modify its QA procedures as necessary.

Quality assurance is achieved through six basic components:

A. Use of a written protocol
B. Use of written standard operating procedures
C. Involvement of qualified personnel
D. Maintenance of written records
E. Use of appropriate data processing techniques
F. Use of quality control procedures for all data collected

In addition to QA components addressed in this document, it is essential that the appropriate institutional review boards approve the research plans for human studies.

II. QUALITY ASSURANCE COMPONENTS

A. A written research protocol, to be reviewed and approved by HEI, will define the experimental objectives, research strategy, and methodologies to be used. The protocol will be sufficiently complete and detailed as to ensure that the data collected are of known and documented quality. It will include, as applicable:

1. Name of Principal Investigator
2. Background of problem being addressed
3. A statement of the problem being addressed
4. Expected results and their significance
5. Description of all experiments to be conducted with reference to a particular standard operating procedure when appropriate (see Section B)
6. Subject selection procedures to be used, including inclusion and exclusion criteria (when applicable)
7. Details of the acceptance and testing of chemicals and reagents if they are to be used
8. Personnel needed to accomplish the research (see Section C)
9. Description of data to be collected
10. Methods of data processing (see Section E)
11. Quality control procedures to be used (see Section F)
12. Safety precautions needed

Any changes to the original protocol shall be made in writing by preparing an amendment to the protocol. All amendments must be approved by HEI.

B. Written standard operating procedures (SOPs) will be used to document all routine, critical experimental procedures and measurement techniques for which variability must be minimized. Critical experimental procedures are those procedures that result in the acquisition of experimental samples or data used to draw scientific conclusions.

Standard operating procedures will be developed by individuals knowledgeable of the specific procedures. They will describe what, when, where, how, and why in a stepwise manner. They will be sufficiently complete and detailed to ensure that the data collected are of known and documented quality and integrity and are generated to meet measurement objectives such that there is a minimum loss of data due to out-of-control conditions.

Standard operating procedures will be prepared in document control format. Each SOP will be uniquely identified. SOPs will be updated as needed, and revised SOPs will also be uniquely identified and dated. There will be copies of all SOPs readily available for reference by individuals as needed. They will generally be found in the immediate area where work is in progress. An up-to-date record of all approved SOPs will be maintained.

Deviations from SOPs will be justified and documented. The degree of adherence to the SOPs may be determined during periodic audits.

Standard operating procedures will be:

1. Adequate to establish traceability of standards, instrumentation, samples and data;
2. Simple, so that a user with a basic education, and experience or training can properly use them;
3. Complete enough so that individuals can follow the directions in a stepwise manner through the sampling, analysis, and data handling;
4. Consistent with sound scientific principles;
5. Consistent with current regulations and in general conformity with the intent of Good Laboratory Practice guidelines;
6. Consistent with the instrument manufacturer's specific instruction manuals.

To accomplish these objectives, standard operating procedures will be developed for procedures and equipment including the following as may be appropriate:

1. Laboratory instruments
2. Subject care, handling, treatment, and transportation
3. Sampling procedures
4. Analytical procedures
5. Special precautions for samples and specimens of all types that are collected, such as holding times and protection from heat, light, reactivity, and combustibility
6. Federal reference, equivalent, and alternate test procedures
7. Instrumentation selection and use
8. Collaboration and standardization procedures
9. Preventive and remedial maintenance
10. Replicate sampling and analysis
11. Blind and spiked samples
12. Quality control procedures
13. Precision, accuracy, completeness, representativeness, and comparability
14. Sample and specimen custody, handling and storage procedures
15. Sample transportation
16. Data handling and evaluation procedures
17. Automatic data processing procedures
18. Documentation and document control

C. Qualified personnel will conduct the proposed research. The qualifications of all participating individuals will be documented in resumes that will be maintained as a part of the permanent record of the project.

D. Written records will be maintained to document all aspects of the research effort. This shall include the use of bound notebooks, standard forms, and computer input and output. All entries shall be made in indelible ink. The entries should be dated and signed or initialed by the individual making the entry. Notebook entries shall be made in chronological order. If a blank space is left between entries, it shall be crossed-hatched to render it unusable. Entries shall not be erased or otherwise obscured. If any entry is to be changed because it is in error or for any other reason, a single line will be drawn through the entry and a correction made in the margin. The altered entry shall carry an explanation of the reason for the change, the date of the change, and the initials or the signature of the individual making the change.

The Principal Investigator for the project shall periodically, at not less than biweekly intervals, review the records to verify their completeness and accuracy. This review shall be documented by the Principal Investigator signing and dating the reviewed record.

E. Documented procedures will be used to assure the integrity and appropriateness of data processing procedures. Data processing includes all manipulations performed on raw, (i.e. "as collected") information to change its form of expression, its location, or its quality. This includes data collection, validation, storage, transfer, reduction, and analysis.

1. Collection
The protocol and SOPs will address both manually and electronically collected data. The internal checks that must be used to ensure suitable quality in the data collection process will be identified.

2. Validation
Validation of raw data will also be addressed in the protocol and SOPs. The validation in process may include many forms of manual or computerized checks, but it clearly involves specified criteria.

3. Storage
Data storage involves keeping the data in such a way that they are not degraded or compromised. and that all values will be uniquely identified. At every stage of data processing at which a "permanent" collection of data is stored, there will be a physically separate copy for purposes of integrity and security.

4. Transfer
The protocol will address quality assurance procedures that will be used to characterize data transfer, error rates, and how information loss is minimized in the transfer.

5. Reduction
Data reduction includes all processes that change either the value or number of data items, i.e., the original data set from which it is generated cannot be recovered from it. This process is distinct from data transfer in that it entails a reduction in the size of the data set and an associated loss of information.

Validation of the reduction process will be appropriate to the level of effort involved. When a computer is used to process large quantities of data, reference to the specific program documentation and data base documentation will be provided. Each type of processing should provide sufficient information to allow a reviewer to check the validity of the conversion process against a current methodology.

6. Data analysis
Data analysis frequently includes computation of summary statistics and their standard errors, confidence intervals, tests of hypotheses relative to the parameters, and model validation (goodness of fit tests). The protocol will address the specific statistical procedures to be used, the reliability of computations, appropriateness of the models as a framework for investigating the study questions and robustness of statistical procedure to model inaccuracies.

F. Quality control procedures will be included, to the extent possible, in the protocol and SOPs to address the quality of all data generated and processed and to assess the data for precision, accuracy, representativeness, comparability, and completeness. The aspects of data quality are:

1. Precision
Each SOP concerned with measurement will contain a mechanism for displaying the reproducibility of the measurement process.
Examples of activities to assess precision are:

a. Replicate samples
Replicate sample data shall be within predetermined acceptance limits.

b. Instrumental checks
Each measurement device shall have routine checks done to demonstrate that variables are within predetermined acceptance limits.
Examples of checks include:
   (1) Zero and span
   (2) Noise levels
   (3) Drift
   (4) Flow rate
   (5) Linearity

2. Accuracy
Each SOP concerned with measurements will contain a mechanism for showing the limits of accuracy for reported data. This will be accomplished with the following procedures:

a. Traceability of instrumentation
Each instrument used to produce data critical to the quality of project output will be assigned a unique identification number or be identified uniquely in another way. The specific instrument used, where and when used, maintenance performed, and the equipment and standards used for calibrations will be identified.

b. Traceability of standards
Each standard and each measurement device will be calibrated against a standard of known and higher accuracy. The standards used will be defined in the Protocol.

c. Traceability of samples
When samples are extracted from the test system, each sample will be assigned a unique identification number or be identified uniquely in another way. Documentation shall identify sampling time, place, and action taken on each sample.

d. Traceability of data
Data will be documented to allow complete reconstruction, from initial records through data storage system retrieval and final reporting of data in various progress reports and publications.

e. Methodology
Methodology if available, Federal reference, equivalent, or approved alternate test methods will be used.

f. Reference or spiked samples
Recoveries will be within predetermined acceptance limits, as defined in the SOPs and Protocol.

3. Representativeness
Each sampling SOP will contain procedures to ensure and document that each sample collected represents the media sampled as far as is possible. This will involve detailed consideration of the total system being sampled and its manipulation in relationship to the validity of raw data finally recorded.

Parameters used for this aspect of data quality will be specified (e.g., storage temperature) and recorded as part of the raw data.

4. Comparability
Each measured SOP will contain procedures to assure the comparability of data.

Examples are:
   a. Consistency of reporting units
   b. Standardized setting, sampling, and analysis
   c. Standardized data format

III. ROLES OF INSTITUTIONS AND INDIVIDUALS IN ACHIEVING QUALITY ASSURANCE

A. Health Effects Institute

Dr. Jane Warren, Director of Science, has overall responsibility for implementation and oversight of the HEI Special Quality Assurance Procedures. Members of the HEI Research Committee, consultants to it, and HEI staff members shall serve as facilitators of the research. This shall include aid in the identification of the experimental objectives and the methodologies by which the objectives are to be achieved. These individuals may offer suggestions to facilitate the conduct of the research. They may periodically critique the research in progress.

For each study, Dr. Warren will approve, on behalf of HEI, the protocol and amendments to it and, if appropriate, the SOPs.

B. Project Personnel

1. Principal Investigator

The Principal Investigator has the primary responsibility for specifying the detailed experimental objectives and the research methodologies by which the objectives will be achieved. He or she has the primary responsibility for the preparation of the protocol and all standard operating procedures and shall review and approve them by signing them.

The Principal Investigator has the responsibility for the actual conduct of the research according to the protocol and SOPs. He or she has the primary responsibility of managing all aspects of data collection, validation, storage, transfer, reduction, and analysis. The Principal Investigator has the responsibility for assuring that the research is conducted with qualified personnel and in accordance with this quality assurance plan.

2. Professional personnel

The professional personnel associated with each center have the responsibility for carrying out their aspects of the research according to this quality assurance plan. They are expected to be knowledgeable of the protocol and the SOPs being used in their research. They have the responsibility for assuring that personnel working under their supervision carry out their activities according to approved SOPs.

3. Technical and supporting personnel

The technical and other supporting personnel at each research institution shall have the responsibility for carrying out their assigned activities in accordance with this quality assurance plan. They should have a detailed knowledge of the SOPs used in the conduct of their research activities.

C. Special QA Oversight

If not provided by the institute at which the research project is being carried out, HEI shall engage a qualified individual to serve as Quality Assurance Officer for the project. This individual shall report to HEI's Director of Science and be responsible for overseeing the implementation of this quality assurance plan. The QA Officer shall review the protocol and, when appropriate, the SOPs, and advise the HEI staff if modifications are necessary to assure their QA adequacy. The QA Officer shall maintain signed copies of the protocol and all SOPs.

The Special QA Officer may conduct periodic audits of the research while in progress and when it is completed to ascertain compliance with the HEI’s special QA procedures. These audits shall include such matters as review of research procedures, notebooks, data forms, and data management activities. At the conclusion of each audit, the QA Officer shall provide a verbal summary to the Principal Investigator of significant findings that need to be addressed. The QA Officer shall also prepare a "Business Confidential" report of the audit. The report shall detail the nature of the audit significant findings, and any requirements for corrective action(s). The audit report shall be provided to the HEI Director of Science, who will then transmit it to the HEI project manager for transmission to the Principal Investigator. If corrective action is required, the Principal Investigator shall see that such action is taken and return the summary to the HEI project manager with a copy to the QA Officer noting the action taken. All copies of the audit report are to be marked as "Business Confidential" and are to be destroyed after use or maintained in a file separate from other records of the project. These audit reports are only to be released to people directly involved in management of the projects. To give these reports to people who are not directly involved violates the confidential nature of the audits and potentially reduce the degree of candor required in communications within the project on matters requiring corrective action. The QA Officer shall maintain a log of all audits indicating for each audit: the date conducted, participating personnel, and the nature of the audit.

The Health Effects Institute "A Partnership of the U.S. Environmental Protection Agency and Industry"

APPENDIX C: HEI SPECIAL QUALITY ASSURANCE PROCEDURES

The Health Effects Institute
"A Partnership of the U.S. Environmental Protection Agency and Industry"