In 1976, the United States Food and Drug Administration (USFDA) received information from a whistleblower about some problems in data submitted by a company called Syntex. Erroneously, an FDA official picked up a file on a contract laboratory called IBT (Industrial Bio-Test Laboratories) which was under contract to Syntex.
On reviewing the data submitted by IBT, serious defects in the study were found, and the FDA performed an inspection of the IBT facility where even more shocking critical deficiencies in scientific procedures were unearthed. It was found that data was being fabricated, adverse health effect results were being removed from reports, dead study animals were being replaced with healthy ones, histopathology data were being fudged and report conclusions were being modified to make the drug appear favorable.
A little later, similar malpractices were found in the long-term toxicology studies being conducted in laboratories of the company called G.D. Searle and Company.
Suspecting that similar situations existed in most research facilities throughout the pharmaceutical sector, the FDA decided to institute a monitoring program to ensure sound and scientific laboratory practices were followed.
In August 1976, a draft proposal for Good Laboratory Practice (GLP) regulations was published in the Federal Register on 19th November 1976. These regulations laid down a uniform approach to ensuring the integrity of data produced during non-clinical laboratory studies. By creating a system of Quality Assurance (QA) unit in testing laboratories, it was sought to ensure that the facility complied with regulatory requirements. On 4th September 1987, the Good Laboratory Practice Regulations, The Final Rule, were published.
Definition of Good Laboratory Practice:
FDA defines GLP as, “A set of principles intended to assure the quality and integrity of nonclinical laboratory studies that are intended to support research or marketing permits for products regulated by government agencies.”
The term nonclinical laboratory study refers to the in-vitro or in-vivo experiments where the item being tested is studied in systems under laboratory conditions to evaluate how safe it will be.
Thus, GLP ensures that testing facilities comply with the minimum requirements the FDA expects for the planning, conducting, and reporting of safety studies related to non-clinical testing. By providing a framework for a well-controlled study, GLP assures overall accountability.
Scop of Good Laboratory Practice:
The term GLP applies to the non-clinical testing required for approval of new drug products for human and animal use. Its scope also extends to cover non-pharmaceutical compounds like food additives, color additives, food packaging, food contamination limits, biological products, electronic products, and medical devices.
If a firm hires the services of a contract laboratory or a consultant laboratory service for the testing, that laboratory must also abide by GLP.
The testing laboratory must permit an inspection of their facility and records of the studies being conducted by a duly authorized employee of the FDA.
GLP does not cover human clinical studies, discovery-related toxicology studies, nonclinical pharmacology studies to study efficacy and drug action, and bioanalysis of samples drawn from clinical trials.
Persons involved in conducting or supervising the study in the nonclinical laboratory must have the necessary education, training, and experience to ensure that they can perform their functions adequately. The details of these must be maintained in current condition.
Sufficient personnel must be employed for conducting the study as per the protocol. They must take all due precautions concerning personal health and sanitation to prevent contaminating the test systems and articles. Clothing of personnel must be apt for their duty; it must be changed as required to avoid chemical, microbiological or radiological contamination during testing.
Any person with an illness that could adversely affect the integrity and quality of the study must be excluded from it until full recovery.
Organization and Management of Test Facility:
Study Director: Before the start of a study, the management of the facility should appoint a study director. This person should be either a scientist or a professional who has the necessary education, training, and experience to manage the technical aspects of the study and also interpret, analyze, document, and report the study results.
Systems: Test protocol should be prepared and approved by an authorized person. All data collected during experiments must be recorded accurately and verified, including unanticipated responses. If any situation occurs that may affect the quality and integrity of the study, it must be noted, and corrective action must be taken and documented. All GLP regulations that apply to the study must be followed and testing must be carried out as laid out in the protocol. At the close of the study, all data, documents, samples, and final reports must be archived safely.
Management: The management of the test facility must make sure that all materials, facilities, resources, equipment, and personnel required for testing are available. It must also assure that tests for identity, purity, strength, stability, and uniformity, as applicable, have been performed adequately. Personnel must understand the functions they are to perform. Deviations if observed must be reported by the QA unit directly to the study director; corrective actions must be taken and documented.
QA Unit: A quality assurance unit must be set up in a manner as to be independent of the persons involved with the study. There must be written procedures, and details of responsibilities and records to be maintained by this unit.
This unit must monitor that equipment, facilities, personnel, practices, methods, records, and controls match the GLP regulations. It is this unit’s responsibility to have all information a master schedule sheet, protocols, etc of the studies performed by the lab. The QA unit must inspect the study regularly to verify the study integrity, and these inspections must be documented with signatures. Any problems that can compromise the integrity of the study must be reported to the study director and the management at once.
QA unit must provide written status reports of the study at regular intervals to the study director. Any problems and the corrective actions taken must be indicated. The unit must also ensure that no deviations from the standard operating procedures (SOPs) or protocol occur without duly documented authorization.
It is also the responsibility of the QA unit to review the study report at the end and check that it gives an accurate description of the methods and that the results being reported to match the findings as per the raw data generated in the study.
All QA documents must be made available for inspection by the authorized FDA representative.
The testing facility must be of a suitable size and constructed to allow proper conduct of the study, without any adverse effect on the study.
Animal Care Facilities: There must be enough animal areas or rooms to allow the separation of different species/test systems. Each project must be run in isolation. Housing and quarantine requirements of the animals must be sufficiently met. There must be entirely separate rooms and areas to carry out studies on materials that are biohazardous (such as aerosols, infectious agents, volatile substances, and radioactive materials). Separate areas must be kept for the isolation of animals who are carriers of disease or that have been diagnosed with any disease. Proper arrangements must be made to dispose of animal waste without causing odor, environmental contamination, vermin infestation, or disease hazards.
Animal Supply Facilities: Space must be provided for the storage of animal supplies such as bedding, feed, supplies, and equipment. These areas must be kept separate from the test system housing areas and kept free of contamination or infestation. Perishable supplies must be duly protected.
Test and Control Handling Facilities: Separate areas must exist for receiving and storing control and test articles, and test and control article mixtures, to prevent any contamination or mixup. These storage areas must be designed to prevent any change in the purity, strength, identity, and stability of the articles and mixtures.
Laboratory Operation Areas: There must be separate space for the laboratory where the study is to be performed including routine as well as specialized procedures.
Specimen and Data Storage Facilities: There must be enough space to archive specimens and data. Access to this area shall be restricted to only authorized personnel.
Design and Location: All equipment used to generate, measure, or assess data and to control the facility environment must be of a design and capacity sufficient to perform its expected function. The equipment must be located in a manner suitable for operation, cleaning, maintenance, and inspection.
Calibration and Maintenance: All equipment in the laboratory must be cleaned, inspected, and maintained as per written procedures. Any equipment that generates, measures, or assesses data must be regularly calibrated or standardized as required. There must be written SOPs for equipment operation, cleaning, inspection, maintenance, and testing/calibration/standardization. The SOPs must also specify the personnel to carry out each operation, and include information of remedial action to be performed if there is an equipment malfunction or failure.
All inspections, testing/calibration/standardization procedures, and maintenance actions must be recorded. Any non-routine repair work done after malfunction or failure of the equipment must also be documented with details of the nature of the defect and the remedial action taken.
Testing Facilities Operation:
Standard Operating Procedures (SOPs): Written SOPs and laboratory manuals must be present describing the study methods to be adopted to ensure data quality and integrity. The study director must authorize any deviations from the SOPs and the same must be documented. The manuals and SOPs must be immediately available in the area where the particular task is being performed. Data regarding all versions of SOPs must be maintained including details of revision dates.
Minimum required SOPs in a non-clinical laboratory:
- Preparation of animal room.
- Animal care.
- Test and control articles receiving, identification, handling, storage, mixing, and sampling methods.
- Laboratory tests.
- Test system observations.
- Handling of animals found dead in the course of the study.
- Necropsy/post-mortem examination of such animals.
- Collecting and identifying specimens.
- Histopathology study.
- Storage, handling, and retrieval of data.
- Calibration and maintenance of equipment.
- Placement and identification of animals and their transfer.
Solutions and Reagents: All solutions and reagents kept and used in the lab must be labeled to show the identity, concentration, expiry date, and storage requirements. Outdated substances must not be used.
Animal Care: Care, handling, feeding, and housing of animals must be done in keeping with written procedures. When animals are newly received at the laboratory, they must be isolated until their health status is evaluated as per standard veterinary medical practice. Only animals without any disease or condition that may interfere with the conduct or purpose of the study must be used when the study begins. If a disease is contracted by the animals during the study, such animals must be isolated if required. They may be treated for the disease but the treatment should not interfere with the study. Details of all such diagnoses, treatment authorization, its description, and the treatment dates must be documented and archived.
Warm-blooded animals being used in the study long-term, or those used in studies where they must be moved in and out of the cages, must be sufficiently identified. Each animal housing unit must bear details of all the animals housed in it. Separate housing must be provided for animals belonging to different species if necessary. Animals of the same species must not be kept together if they are being used in different studies as there could be a mix-up that affects the study outcomes. If common housing is unavoidable, care must be taken to allow separation by space and identification.
Cages, equipment, racks must be cleaned and sanitized regularly. The water and feed supplied to the animals must be tested at regular intervals to rule out their contamination. Details of such testing must be documented as raw data. Bedding used in the cages must not interfere with the study; it should be changed often enough to ensure animals are clean and dry. Pest control materials used must be such as to not interfere with the study. The use of such materials must be documented.
Characterization of Test and Control Articles: For every batch of control and test articles, their purity, strength, identity, and composition must be determined and documented. Their synthesis method must be documented by either the study sponsor or the testing laboratory. The stability of these articles must be evaluated either before the study begins or along with the study, as per written SOPs.
The containers in which test and control articles are stored must be labeled with appropriate information such as name, code number, batch number, storage conditions, and expiry date. Containers must not be changed until the end of the study. When the study duration is longer than 4 weeks, reserve samples must be drawn and retained from each batch of the control and test articles.
Handling of Control and Test Articles: Test and control articles must be handled in a way that they are stored, identified, and distributed in a way that avoids contamination or deterioration, and their receiving and distribution (with quantities) are to be documented.
Article-carrier Mixtures: When a control or test article is mixed with a carrier, there must be tests performed to ensure mixture uniformity, concentration, and stability of the articles in the mixture. Stability may be assessed either before the study commences, or during the study according to written SOPs. The expiry date of the mixture must be indicated.
Protocol for Conduct of Nonclinical laboratory Study:
Protocol: Written and approved protocols must exist for each study, and they must indicate the purpose of the study and methods to be adopted in conducting the study. The following information must form a part of the protocol:
- Title and purpose statement for the study.
- Test and control articles identified by name, code number, or chemical abstract number.
- Study sponsor name, and testing facility name, and address.
- Test system being used number, sex, age, body weight range, species, strain, substrain, and supplier details.
- Procedure to identify test system.
- Experimental design description, methods used for bias control.
- Description of items to be used in the study diet of animals, solvents, or emulsifiers, and limit values for contaminants likely to be found in these that may interfere with the study.
- Dosage levels (in mg/kg body weight) of control and test articles; the frequency and method of administration.
- Tests, measurements, analyses to be performed and their frequency.
- Information regarding the statistical methods that will be used in the study.
- Date when study protocol was approved by sponsor, and signature with a date by the study director.
- Any changes/revisions in an approved protocol must be documented along with the reason; it must be signed and dated by the study director and this document must be kept along with the protocol.
Conduct of the Study: The non-clinical laboratory study must be conducted according to the protocol. All specimens must be labeled with details of the study, test system, nature, and date of collection. If a specimen is to be examined histopathologically by a pathologist, the gross findings from post-mortem examination must be also available.
Data generated during a study (except automatically collected data) must be recorded at once, directly, and in legible ink. The dates and initials of the person making the entry should be affixed. If any change is to be made, it shall be done in a manner to not deface the original entry. The reason for the change must be documented, and dated, and signed. In the case of automated data collection systems, the person responsible for data input must be identified. Any changes in data must follow the same procedure as for other means of data collection.
Records and Reports:
Reporting Study Results: The final report must be prepared for each study, containing the following information:
- Name of the facility, address, and dates of study commencement and completion.
- Details of purpose and procedure as per approved protocol, and any changes in protocol.
- Statistical data analysis methods.
- Test and control article’s names, code numbers, purity, strength, composition, etc.
- Stability parameters of control and test articles under study conditions.
- Methods used in the study.
- Test system description – details of animal numbers, sex, species, strain, and substrain, body weight range, age, identification procedure.
- Details of dose, dosage regimen, duration, route of administration.
- All circumstances that may have affected the data quality or integrity.
- Names of study director, other scientists or professionals, and supervisory personnel who participated in the study.
- Details of calculations and other procedures performed with the data, data analysis, and summary, and conclusions inferred from the analysis.
- Dated and signed reports of each scientist/professional who was part of the study.
- Locations of storage of raw data, specimens, and final report.
- A prepared statement signed by the QA unit.
The study’s final report must have the date and signature of the study director. Any corrections in the final report must be reported separately as an amendment, and the reasons for correction must be specified, along with the date and signature by the person responsible for the correction.
Data and Records Storage and Retrieval: All documents, protocols, raw data, specimens, and final reports generated during the study must be retained except wet specimens of urine, blood, feces, and biological fluids and the ones from mutagenicity tests. These reports must be stored in an orderly manner to allow easy retrieval when required, with adequate precautions against deterioration of the documents or specimens. Such storage may be done off-premises and details of where it has been stored must be retained in the laboratory.
Records must be retained for whichever of the following is the shortest duration:
- At least 2 years after the date when an application for research or marketing permit (for which the study was conducted) is approved by FDA.
- At least 5 years after the date when results of the study were submitted to FDA to support an application for a research or marketing permit.
- At least 2 years after the date of study completion or discontinuation or termination, in cases where the study results are not used to support an application for research or marketing permit.
- Wet specimens (except mutagenicity tests) and wet specimens of urine, blood, biological fluids and feces, and other samples that are fragile and deteriorate on storage must be kept only until their quality allows evaluation.
- Protocol copies, master schedule sheets, and QA inspection reports must be stored by the QA unit to be easily accessible.
- Job descriptions, summaries of employee training, and experience must be retained with other employment records for a duration as mentioned in the first two points.
- Reports of equipment calibration, inspection, and maintenance must be retained.
- Records must be kept either in original form or true copies as photocopies, microfiche, microfilm, etc.
If the facility conducting the study goes out of business, all the documentation, raw data, and other records must be transferred to the study sponsor for storage, and the FDA must be given written notice of this.
Disqualification of Testing Facilities:
Purpose: Disqualification may serve the following purposes:
1. To exclude from being considered the completed studies that were performed by a facility that has failed to comply with GLP regulations until it can be proved that such non-compliances did not occur during a particular study or that the non-compliance did not affect the acceptability of data generated during that study.
2. To exclude from being considered, all the studies that have been completed following disqualification until the facility undertakes to conduct studies according to GLP regulations.
If a testing facility is disqualified, the sponsor of the study that was performed (and disqualified) cannot use that as an excuse to not submit the study in their application for research or marketing permit. They must get the study repeated and submit it with the application.
Reasons, why a testing facility may be disqualified, include:
- Failure to comply with one or more of the GLP regulations.
- The non-compliance has created an adverse effect on the validity of the study.
- Previous incidents of warnings or individual study rejections have not helped to achieve compliance with GLP guidelines.
When the FDA has relevant information to justify a test facility disqualification, the Commissioner issues a written notice to the concerned facility proposing the disqualification. A regulatory hearing will then be conducted as per legal guidelines.
Final Disqualification Order: After the regulatory hearing, or after the time permitted for a contest by the facility passes without such action, the Commissioner of FDA evaluates the records of the proceedings and issues the final order to disqualify the facility, with the reason for the disqualification. A copy of this order must be sent to the testing facility.
Actions Following Disqualification: After the disqualification of a testing facility, scrutiny is done of every application for research or marketing permit that contains data from a study conducted by the disqualified testing facility. It is determined if that study is acceptable or not. If the study is considered unacceptable, the onus lies on the study sponsor to prove that the study was unaffected by the non-compliances that led to the disqualification. This may include validating the data by a repeat study.
Any study done by a disqualified testing facility will be invalid for application for a research or marketing permit unless the facility has been reinstated after the due procedure.
Public Disclosure of Disqualification: After a testing facility has been disqualified by the final order, the FDA Commissioner notifies all interested persons at his discretion if he believes the disclosure is in the public interest, or that it will promote compliance with GLP. If public notice is given, it must include a copy of the final disqualification order along with the statement that the FDA will not consider any studies done by the said facility in support of any application for research or marketing permit.
Termination or Suspension of Testing Facility by Sponsor: If a sponsor suspends or terminates a laboratory from further participation in the study, it must notify the FDA in writing within 15 working days, along with the reasons for such action.
Reinstatement of a Disqualified Testing Facility: The disqualified testing facility may apply to the FDA Commissioner assuring that it will comply with GLP regulations in the future, along with details of the corrective actions that have been taken or are intended to be taken, and the reasons why it believes it must be reinstated. On examining this submission, and following an inspection, if the Commissioner determines that GLP regulations are being followed, he may reinstate the testing facility as a source for the study. The testing facility must be notified and any other involved persons, such as the sponsor, and information about the reinstatement is publicly disclosed.
Before a new drug is introduced into the market, it has to undergo certain in-vitro and in-vivo experiments in a non-clinical setting. This is usually achieved through a study that involves testing of the drug on animal specimens, or on microbiological or biological test systems. For the results of such studies to be valid and authentic, the study must have been conducted under conditions that ensure data validity and integrity. GLP guidelines provide information regarding these conditions to be maintained by testing facilities and complying with these is the key to a successful application for a new drug.
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