Good Laboratory Practice Regulations

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Introduction and Objectives and Key Requirements

Good Laboratory Practice (GLP) deals with the organization, process and conditions under which laboratory studies are planned, performed, monitored, recorded and reported. GLP practices are intended to promote the quality and validity of test data.

Published GLP regulations and guidelines have a significant impact on the daily operation of an analytical laboratory.

GLP is a regulation. It is not only good analytical practice. Good analytical practice is important, but it is not enough. For example, the laboratory must have a specific organizational structure and procedures to perform and document laboratory work. The objective is not only quality of data but also traceability and integrity of data. But the biggest difference between GLP and Non-GLP work is the type and amount of documentation.

For a GLP inspector it should be possible to look at the documentation and to easily find out

who has done a study,
how the experiment was carried out,-
which procedures have been used, and
whether there has been any problem and if so
how it has been solved.

And this should not only be possible during and right after the study has been finished but also 5 to 10 or more years later.

Frequently the question comes: how much does this cost? It has been estimated that these additional organizational and documentation requirements increase operational costs of up to 30% compared to non-GLP operation.

The key requirements of a GLP type works are

Responsibilities should be defined for the sponsor management, for study management and for the quality assurance unit.
All routine work should follow written standard operating procedures.
Facilities such as laboratories should be large enough and have the right construction to ensure the integrity of a study, for example, to avoid cross contamination.
Test and control articles should have the right quality and instruments should be calibrated and well maintained
People should be trained or otherwise qualified for the job
Raw data and other data should be acquired, processed and archived to ensure integrity of data.

Unfortunately most laboratories are in situations where they have had to interpret the regulations. Procedures have been developed on an ad hoc basis, in isolation, in response to inspections by both their company’s Quality Assurance Unit and regulatory bodies.

Under such duress, many scientists in industry have developed procedures to validate their instrumentation even though the same approach will already have been applied at the instrument manufacturer’s site. Standard operating procedures written to accompany such validation efforts often duplicate extracts from operation manuals —why don’t the manufacturers provide the SOPs directly? When it comes to validating the instrument’s application software, the person responsible has to take the manufacturer’s word for it that the software has been validated and hope that supporting documents, such as test results and source code are available to regulatory agencies upon request.

This tutorial should help to understand requirements and with the help of SOPs and examples offered by Labcompliance, to implement requirement in a most cost effective way.

History of GLP and Relation to other Regulations

National Legislation

Various national legislation, e.g., the Federal Food, Drug, and Cosmetic Act in the United States places the responsibility for establishing the safety and efficacy of human and veterinary drugs (and devices) and the safety of food and color additives on the sponsor (manufacturer) of the regulated product. Public agencies (the United States government’s Food and Drug Administration, FDA, for example) are responsible for reviewing the sponsor’s test results and whether or not they can demonstrate the product’s safety and efficacy. Only when the agencies are satisfied that safety and efficacy have been established adequately is the marketing of the product permitted.

Fraud and misinterpreted data

Until the mid-1970s, the underlying assumption at the FDA was that the reports submitted by the sponsors to the agency accurately described study conduct and precisely reported the study data. A suspicion that this assumption was mistaken was raised during review of studies submitted by a major pharmaceutical manufacturer in support of new drug applications for two important therapeutic products. Data inconsistencies and evidence of unacceptable laboratory practices came to light. The FDA requested a "for cause" inspection of the manufacturer’s laboratories to determine the cause and the extent of the discrepancies (a "for cause" inspection is one initiated at the request of an agency when there are grounds for doubt surrounding an FDA regulated product), and revealed defects in design, conduct, and reporting of the studies. Further inspections at several other sites found similar problems.

FDA's Reaction

The conclusion that many of the studies on which proof of safety of regulated products had been based could indeed be invalid alarmed the FDA, the United States Congress, the public, and industry. Task forces were soon formed to develop ways and means of ensuring the validity and reliability of all non-clinical safety studies submitted for FDA decision making. They would eventually publish standards for measuring the performance of research laboratories and define an enforcement policy.

Good Laboratory Practice (GLP) regulations were finally proposed on November 19, 1976 for assuring a study’s validity. The proposed regulations were designated as a new part, 3.e., of Chapter 21 of the Code of Federal Regulations. The final regulations were codified as Part 58 (21CFR).

EPA's Reaction

The United States Environmental Protection Agency (EPA) issued almost identical regulations in 1983 to cover the required health and safety testing of agricultural and industrial chemicals under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)4 and the Toxic Substances Control Act (TSCA),5 respectively. The GLPs were promulgated in response to problems encountered with the reliability of submitted studies. Some of the studies were so poorly conducted that "the resulting data could not be relied upon for the EPA’s regulatory decision making process." 6 The EPA regulations were extensively amended in 1989 and now cover essentially all testing required to be submitted to EPA under either Act.7, 8 Both GLP regulations are of a similar format and have, with few exceptions, the same wording.

Even though GLPs were only issued for these two specific official programs, the possession of sound data is an equally important consideration for Agency decision makers in all EPA programs to protect public health and the environment. We can thus expect the GLP regulations to be more widely adopted — the Office of Solid Waste has included GLP terms in its contracts for reproductive toxicology studies.

For example, GLP regulations have been transferred under the umbrella of the OECD as principles of Good Laboratory practices to other countries like Europe and Asia .

Applicability and Relation to other Regulations

GLP vs. GCP, GMP and Part 11

Figure 1 illustrates how so called Good Practices regulations correlate to the life of a drug, starting from basic research and drug discovery on the left side through preclinical development in the middle and clinical trials and manufacturing at the right

GLP vs. GCP and GMP

Figure 1. GLP vs. GCP, GMP and 21 CFFR Part 11

Typically research and drug discovery are not regulated at all. GLP starts with preclinical development, for example toxicology studies. Clinical trials are regulated by good clinical practice regulations and manufacturing through GMPs. There is a frequent misunderstanding that all laboratory operations are regulated by GLP. This is not true. For example, Quality Control laboratories in manufacturing are regulated by GMPs and not by GLPs. Also Good laboratory Practice regulations are frequently mixed up with good analytical practice. Applying good analytical practices is important but not sufficient, as we will see in this presentation. When small quantities of active ingredients are prepared in a research or development laboratory for use in samples for clinical trials or finished drugs, that activity has be covered by GMP and not by GLP.

Part 11 is FDA’s regulation on electronic records and signatures and applies for electronic records or to computer systems in all FDA regulated areas. For example, it applies for computers that are used in GLP studies.

Characteristic for GLPs is that they are study based where as GMPs are processed based.

Independent from Location and Duration of a Study

GLPs regulate all non-clinical safety studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA, or by similar other national agencies. This includes drugs for human and animal use but also aroma and color additives in food, biological products and medical devices. The duration and location of the study is of no importance. For example GLP applies to short term experiments as well as to long term studies. And if a pharmaceutical company subcontracts part of a study to a university, that university still must comply with the same requirements as the sponsor company. Some laboratories tried to get away from GLP through outsourcing, but I can tell you this does not work.

Glp is needed for

Facility Management and Other Personnel

Qualification of Personnel

Like all regulations also GLPs have chapters on personnel.

The assumption is that in order to conduct GLP studies with the right quality a couple of things are important:* Number one there should be sufficient people and second, the personnel should be qualified.

The FDA is not specific at all what type of qualification or education people should have. Qualification can come from education, experience or additional trainings, but it should be documented. This also requires a good documentation of the job descriptions, the tasks and responsibilities.

Facility management

Responsibilities of facility management are well defined. They include to designate a study director and also to monitor the progress of the study and if it is not going well to replace the study director.

The management is responsible for many things, basically they should assure that a quality assurance unit is available, test and control articles are characterized, and that sufficient qualified personnel is available for the study.

Because it is obvious that management can not take care personally about all this they have to rely on other functions, for example GLPs require that the QA should give a regular report on the compliance status of the study.

Study Director

The position of a study director is unique for GLP. He/she has overall responsibility for the technical conduct of the safety studies, as well as for the interpretation, analysis, documentation and reporting of the results. He or she is designated by and receives support from management. The study director serves as the single point of study control. It is important that this is a single individual person and not a department or any other grouping of people. An assistant study director is not permitted but there may be an alternate study director who serves as study director only in that person’s absence.

The study director may be the laboratory manager and may be responsible for more than one study. However, he or she should not be over-burdened—an auditor could otherwise get the impression that the study director cannot monitor all studies carefully.

xxx See Table from old version!!!

Quality Assurance Unit

The quality assurance unit (QAU) serves an internal control function. It is responsible for monitoring each study to assure management that facilities, equipment, personnel, methods, practices, records, controls, SOPs, final reports (for data integrity), and archives are in conformance with the GLP/GALP regulations. For any given study, the QAU is entirely separate from and independent of the personnel engaged in the direction and conduct of that study.

As well as immediately reporting of any problems, GLP/GALP regulations require the QAU to maintain and periodically submit to laboratory management comprehensive written records listing findings and problems, actions recommended and taken, and scheduled dates for inspection. A designated representative from the FDA or EPA may ask to see the written procedures established for the QAU’s inspection and may request the laboratory’s management to certify that inspections are being implemented, and followed-up in accordance with the regulations governing the QAU.

Part-time or full-time personnel may be used depending on whether the volume of work is sufficient to justify employing one or more full-time quality assurance professionals. Full-time professionals are the preferred arrangement, because such an arrangement provides a degree of independence and removes the possibility that the demands of the person’s second job will interfere with his or her performance of the QA function. For small organizations it might not be possible to designate a full-time person.

The FDA mandates that responsibilities and procedures applicable to the QAU, the records maintained by the QAU, and the method of indexing such records be in writing and be maintained. The agency further requires that these items, including inspection dates, the description of the study inspected, the phase or segment of the study, and the name of the individual performing the inspection, be made available for review by an authorized FDA agent. The FDA agent cannot request the findings of the QAU audit .

Main Responsibilities of the Quality Assurance Unit

Maintain copy of master schedule sheet of all studies conducted. These are to be indexed by test article and must contain the test system, nature of study, date the study was initiated, current status of each study, identity of the sponsor, and name of the study director.

Maintain copies of all protocols pertaining to the studies for which QAU is responsible.
Inspect studies at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection. These records must show the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for re-inspection. Any problems discovered which are likely to affect study integrity are to be brought to the attention of the study director and management immediately.

Periodically submit to management and the study director written status reports on each study, noting problems and corrective actions taken.
Determine whether deviations from protocols and SOPs were made with proper authorization and documentation.

Review the final study report to assure that it accurately describes the methods and SOPs and that the reported results accurately reflect the raw data of the study.
Prepare and sign a statement to be included with the final study report that specifies the dates of audits and dates of reports to management and to the study director.
Audit the correctness of the statement, made by the study director, on the GLP compliance of the study.

Facilities

All GLP regulations also have requirements for facilities, for example, animal care facilities are listed as well as animal supply facilities, facilities for handling test and control articles, and laboratories and storage facilities. The main purpose of this is to ensure integrity of the study and of study data. Three main requirements for facilities are

Limited access to buildings and rooms
Adequate size and
Adequate construction.

For example, if a testing facility is to small to handle the specified volume of work there may be a risk to mix incompatible functions. Or if the air conditioning system is wrongly designed, there may be cross contamination between different areas.

Equipment and Computer Systems

All GLP regulations also have requirements for equipment. They are related to design, calibration, maintenance and validation. This includes analytical equipment such as chromatographs, spectrophotometers, and computerized equipment for instrument control and direct data capture, data evaluation, printing, archiving and retrieval. .

Design

Equipment used in generation, measurement, or assessment of data and equipment used for facility environmental control shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance. The equipment should undergo a validation process to ensure that it will consistently function as intended. Examples are analytical equipment such as chromatographs, spectrophotometers, computerized equipment for direct data capture, and computers for statistical analysis of data.

Maintenance, calibration, testing and validation

Equipment shall be adequately inspected, cleaned, and maintained. Equipment used for generation, measurement, or assessment of data shall be adequately tested, calibrated and/or standardized. These activities are frequently called qualification for equipment hardware and single modules and validation for software and complete systems. A laboratory shall establish schedules for such operations based on manufacturer’s recommendations and laboratory experience.

Time interval for calibration, re-validation and testing

The frequency for calibration, re-validation and testing (performance verification) depends on the instrument itself, the recommendations from manufacturers of equipment, laboratory experience, and the extent of use. For instance, a pH meter should be calibrated before each use and the wavelength of an HPLC variable wavelength detector should be calibrated about every month or whenever the cell is removed and reinstalled. Typically proof of chromatographic instrument performance should be done every 6 to 12 months.

Equipment Records and Other Documents

Written records shall be maintained of all inspection, maintenance, testing, calibrating and/or qualification / validation operations. These records, containing the date of operation, shall describe whether the maintenance operations followed written SOPs. Written records shall be kept of non-routine repairs performed on equipment as a result of failure and malfunction. Such records shall document the nature of the defect, how and when the defect was discovered, and any remedial action taken in response to the defect. Written records may be in log books especially designed for that purpose. A log book should accompany the instrument when it is moved. Remedial action should include a review of effects on data generated before the defect was discovered. Such equipment records should be maintained as long as the data generated by the equipment.

Equipment records should include

name of the equipment
name of the manufacturer,
model or type for identification s
serial number
date equipment was received in the laboratory
condition when received (new, used)
details of checks made for compliance with relevant calibration or test standard specification
date equipment was placed in service by the laboratory
current location in the laboratory, if appropriate
copy of manufacturer's operating instruction(s)
details of maintenance carried out
history of any damage, malfunction, modification or repair
person responsible for the equipment

Important questions to be answered for any analytical instrument:

For an auditor there are several important questions to be answered for any analytical instrument:

What is the equipment being used for and are there specifications?
Is the instrument within specification and is the documentation to prove this available?
If the instrument is not within specifications, how much does it deviate by?
If the instrument is not within specifications, how long has this been the case?
If the instrument is not within specifications what action has been taken to overcome the defect?
Can the standards used to test and calibrate the instruments be traced back to national standards?

Standard Operating Procedures

Standard operating procedures (SOPs) are written procedures for a laboratories program. They define how to carry out protocol-specified activities. Most often they are written in a chronological listing of action steps.

Routine inspection, cleaning, maintenance, testing, calibration and standardization of instruments
Actions to be taken in response to equipment failure
Analytical methods
Definition of raw data
Data handling, storage, and retrieval
Health and safety precautions
Receipt, identification, storage, mixing, and method sampling of test and control articles
Record keeping, reporting, storage, and retrieval of data
Coding of studies, handling of data, including the use of computerized data systems
Operation of quality assurance personnel in performing and reporting study audits, inspections, and final study report reviews

SOPs should preferably be written in the laboratory close to the instrument, and not in an office. It should be either written or thoroughly reviewed by the instruments’ operators. SOPs should not be written to explain how procedures are supposed to work, but how they work. This ensures that the information is adequate and that the document invites rather than discourages routine use.

Sops are frequently mentioned as deviations in FDA warning letters where three major deviations come up:

SOPs are not available
They are not adequate or
They are not followed.

One of the first procedures should be an SOP on writing SOPs. This is important for consistency and efficiency. For example, it should be defined who is responsible for initiating, authoring, and approving SOPs and how procedures are distributed and how the use of SOPs is enforced.

GLPs allow to deviate from SOPs but deviations should be approved and documented.

Reagents and Solutions

To ensure ongoing quality of reagents and solutions used for GLP studies, purchasing and testing should be handled by a quality assurance program. That also should include qualification of suppliers.

All 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. If reagents and solutions used for non-GLP regulated work are stored in the same room as reagents for GLP-regulated studies, all reagents must be labeled. Reagents that are not adequately labeled, even if not intended for use in GLP-regulated studies, may have an adverse effect on GLP regulated laboratory work. It is also good practice to include the Date opened:. This can be critical for some chemicals such as ether.

Many reagents can be stored under ambient temperature: does this mean we have to put a label on all these? One practical recommendation to avoid too much paper work is to have a procedure that has a sentence like this: "You don’t need to label environmental conditions on each reagent if it is stored under ambient temperature.” So everybody in your lab should know: reagents and solutions without storage temperature do not require cooling for storage

Expiration Date

The expiration date depends on the nature of the chemical. Sodium chloride has practically no expiration date. In these cases it might be acceptable to indicate NONE or Not applicable (N/A) on the label for expiration date. The laboratory must be prepared to justify this designation. Formal studies are not always required to justify assigned expiration dates. It is sufficient to assign expiration dates based on literature references and/or laboratory experience.

Test and Control Articles

Control articles or reference substances as they re called in the OECD principles are of utmost importance because they are commonly used to calibrate the instrument. The accuracy of the reference substances also determines the accuracy of the analytical method. In other words, if the reference standard is wrong, also the test result.

Main requirements for control articles are: The identity, strength, purity, composition and other characteristics should be determined for each batch and documented. * Methods of synthesis, fabrication, or derivation of test and control articles should also be documented. Copies of this documentation must be stored with the study data and must be available for FDA inspection.

In addition, the stability of each test or control article should be determined. This can be done either before study initiation, or simultaneously according to written SOPs which provide for periodic reanalysis of each batch.

Each storage container for a test or control article should be labeled by name, chemical abstract number or code number, batch number, expiration date, and, where appropriate, storage conditions necessary to maintain the identity, strength, purity and composition.

Furthermore, storage containers should be assigned to a particular test article for the length of the study.

Certified reference standards can be purchased from appropriate suppliers. If standards are not available, the recommendation is to take a lot of your own material, and analyze, certify and use it as the standard. However, they should be made from high purity material and be compared against the primary standard to ensure the traceability chain. For the comparison, validated test methods should be used.

Conduct of a Study, Study Protocol and Study Report

Study Protocol

Each GLP study should be conducted according to a study protocol. The study director writes the study protocol to document what should be done and when, it also describes anticipated exceptions from SOPs. Most important is the description of the experimental design and the type and frequency of tests and analyses. The study protocol also documents which records should be archived and available for inspections.

As a minimum the study protocol should include:

Title and statement of the purpose of the study
Identification of test and control article *
Identification of test system
Name of the sponsor,
Description of experimental design,
Type and frequency of tests and analyses
Records to be maintained

Conduct of a Study

The study should follow strictly the protocol and any deviations should be documented, if there are any. This section also includes requirements on how hand-recorded data and data captured from automated equipment should be recorded. For example, hand written data must be recorded in ink and not with a pencil. Changes must not obscure the original entry but and must be dated and signed together with a reason for the change.
When data are acquired from an automated system, the person responsible for the system and the system itself should be identified and documented.

Records

GLP regulations specify what should be recorded. Examples include

Name and address of the laboratory
Objectives and procedures
Statistical methods
Test and control articles, incl. stability data
Description of methods
Description of test system
Description of dosage, route of administration, duration
Name of the study director
Location where raw specimens and data are stored
Descriptions of transformations and calculations

Most of requirements are quite obvious, but let’s look at the last bullet:. GLP inspectors want to see on how final results have been derived from raw data. This means to document it on paper when you use a calculator, it also can mean to store the formulas as part of an Excel spreadsheet, or for commercial systems formulas are included in the operation manual. Sometimes software companies don’t disclose calculations used in their software to protect intellectual proprietary. This usually did not appear to be a big problem as long as you document it.

Retention and Retrieval of Records

GLPs have several paragraphs with details on how to store and retrieve records and data, for example, what should be archived and retention time.

What should be archived

The list of documents that should be archived includes everything from raw data to final results, but also protocols from meetings, if decisions related to the integrity of a study have been made.

GLPs require the position of an archivist. This is either a part time or full time person who is responsible for the archive. Some companies have a procedure that requires documents from an archive to only be checked out by the archivist or his designate. Whenever documents are taken out of the archive this should be documented, and the person who requests it should sign a statement that nothing has been changed, added or deleted.

Retention Periods

GLPs also specify for how long records and specimens should be retained.
For example, in the US material supporting FDA submissions should be retained until

2 years after FDA approval or
5 years after FDA submission

For wet specimens may be shorter: they should only be retained as long as the quality affords evaluation However, this is only for US FDA and retention times in other countries may be different.

The numbers such as 2 and 5 years don't look as a long time. However, two years are after FDA approval and 5 years are after an FDA submission can be a long time. Sometimes it may take ten or more years between the time GLP studies have been conducted and approved by the FDA.

GLP says you can keep either the original or an exact copy of a record. An exact copy can be a copy of an instable thermo paper to durable plain paper or when paper records are scanned into TIF or PDF files.

Responsibility for Archiving

The sponsor company is responsible for the records. When a sponsor company out-sources studies or also just the archiving part, the sponsor company must make sure that archiving of records complies with GLP regulations and in case the contractor goes out of business the sponsor company has access to all data. Long archiving time as require by GLP typically is no problem for normal paper records, but it may be one for electronic records, especially when records are archived as original records in the proprietary applications format. Examples are chromatographic or spectroscopic data. So the question is always whether electronic records can be printed and the original records can be deleted. For this discussion we take a closer look into the definition of raw data.

Raw Data

GLPs also have specific requirements for raw data. They are defined as any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the results of original observations and activities of a study. The term covers all data necessary for the reconstruction of the report of the study. Raw data may include hand-written notes, photographs, microfiche copies, computer print-outs, magnetic media, dictated observations, and recorded data from automated instruments.

Examples also include records of animal receipt, results of environmental monitoring, instrument calibration records, and integrator output from analytical equipment. Raw data may also be entries in a worksheet used to read and note information from an LED display of an analytical instrument.

Electronic Records

Raw data are well defined as long as information is recorded on paper. For example original observations are recoded on paper and exact copies can be made if necessary. A more frequently discussed question is what is an exact copy of a paper print-out that comes from an electronic record. Most important here is to look again at the definition of an exact copy: as long as the print-out includes everything that is necessary to reconstruct the study, there should not be a problem. Or as an FDA professional explained to a conference audience: as long as you can demonstrate compliance with the regulation.
For example, one requirement of GLP is to document in an audit trail when data have been changed. So look if the print-out includes the audit trail information, for example when data on the computer have been changed. An other question would be if all chromatographic peak in the print-out are on scale?

GLP Inspections and Enforcement

It is FDA’ responsibility to enforce the federal Food, drug and Cosmetic Act to ensure safety and effectiveness of drugs and medical devices. This is enforced through regulations, guidance documents and FDA inspections. The FDA has the responsibility to inspect GLP studies related to products that are marketed in the United States, it does not matter where the products are developed or manufactured.

Inspection Program

The FDA has developed an inspection program with two types of inspections: Routine inspections and ‘For cause’ inspections. Routine inspections should be conducted at least every second year. It is an on-going evaluation of a laboratory’s compliance with GLP regulation.

For cause inspections are less frequent, they constitute only about 20% of all GLP inspections. Reasons for such inspections could be a follow up of an inspection with serious deficiencies or when the FDA suspect non-compliance when investigating NDA applications. It also may happen that the FDA gets some hints from external sources about non-compliance in laboratories.

Typically the FDA does not announce GLP inspections. If a laboratory refuses to accept FDA inspections, either in full or also part of it, the FDA will not accept studies in support of new drug applications.

Enforcement

Deviations from GLP requirements are documented in different ways: if the inspection team finds deviations, they write them in a specific form which has the number 483. The deviations are discussed during the exit meeting and the laboratory can respond. Then the lead inspector writes a full inspection report which is called: establishment inspection report. This may be up to 20 or 30 pages. Depending on the deviations the inspector will or will not to write a warning letter. This letter is sent to the company’s management. Within 14 days the company should respond with a corrective action plan.

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Links to international GLP regulations and guidelines

Links to FDA regulations

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