Other Players

Personnel

• Required to have education, training and experience to enable them to perform assigned functions
• Facility must maintain records of training, experience and job descriptions
• Employ a sufficient # of personnel for timely and proper conduct of the study according to the protocol
• Take necessary personal sanitation and health precautions to avoid contamination of the test (investigational product) and control articles and the test system (what your test and control articles are being tested on e.g., typically, an organism…FDA defines this as “animals, plants, microorganisms, or subparts thereof…” treated with the test and control article. However, this also includes parts of the system not tested with the articles. )
• Wear appropriate clothing for the performed duties and change as necessary to prevent contamination of the test and control articles and the test system
• Prevent individuals from conducting the research who at any time have an illness that may adversely affect the quality and integrity of the research

Testing Facility Management

• Designate a Study Director
• Make sure there is a quality unit in place
• Make sure that the investigational product has been appropriately tested for identity, strength, purity, stability and uniformity, as applicable
• Make sure that personnel, resource, facilities, equipment, materials and methodologies are available as scheduled
• Assure proper training
• Assure reporting of deviations from the regulations are reported to the Study Director and corrective actions are taken and documented

Study Director

For each nonclinical laboratory study, a scientist or other professional of appropriate education, training and experience, or combination thereof, must be identified as a study director (who is like the nonclinical PI). The study director is responsible for the technical conduct of the study, and interpretation, analysis, documentation and reporting of results.

Responsibilities include ensuring

• the protocol is approved and followed
• all data are accurately recorded and verified
• deviations that may affect quality and integrity of the study are noted
• corrective actions for deviations are taken and documented
• test systems are specified in the protocol
• GLP is followed
• raw data, documentation, protocols, specimens and final reports are archived during or at the close of the study

Quality Assurance Unit

The preclinical testing facility is required to have a quality assurance unit which is responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, and controls are in conformance with the regulations. The quality assurance unit must be entirely separate from and independent of the personnel engaged in the direction and conduct of that study.

At LCCC, we are often able to use QA units in the GMP facility to serve as the quality assurance units for GLP studies. It is something to think about and discuss with GMP leadership when designing your GLP study.

Responsibilities include ensuring:

• Maintain a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director
• Maintain copies of all protocols
• Inspect nonclinical studies at intervals adequate to assure the integrity of the study
• Maintain written and properly signed records of inspections (including date of inspection, study inspected, phase or segment inspected, person performing inspection, finding and problems, action recommended and taken, scheduled date for reinspection)
• Bring any problem found during the inspection that are likely to affect study integrity 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 any problems and corrective actions taken
• Determine if deviations were properly documented and reviewed
• Review the final study report to assure that the report is accurate

The testing facility needs to be a suitable size and construction to facilitate the proper conduct of the preclinical research. It also has to be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study. All the following sub-facilities or areas are required.

Animal Care Facilities

The animal care facility must have:

• A sufficient number of animal rooms or areas to assure proper: (1) separation of species or test systems, (2) isolation of individual projects, (3) quarantine of animals, and (4) routine or specialized housing of animals
• A sufficient number of animal rooms or areas to ensure isolation of studies being done with test systems or test control articles known to be biohazardous, including volatile substances, aerosols, radioactive materials, and infectious agents
• Separate areas with effective isolation, as appropriate, for the diagnosis, treatment and control of laboratory animal diseases.
• Facilities for the collection and disposal of animal waste

Animal Supply Facilities

Animal supply facilities must have:

• Storage areas, as needed, for feed, bedding, supplies, and equipment
• Storage areas for feed and bedding separated from areas housing the test systems
• Protections against infestation or contamination
• Proper storage of perishable supplies

Facilities for handling the test product and control product

These facilities must have:

• Separate areas, to avoid contaminations or mix-ups, for: (1) receipt and storage of the test and control articles, (2) mixing the test and control articles with a carrier, e.g., feed, (3) storage of the test and control article mixtures
• Storage areas separate from areas housing the test systems
• Storage areas adequate to preserve the identity, strength, purity, and ability of the articles and mixtures

Laboratory Operation Area

You must have a separate laboratory space for the performance of routine and specialized procedures for the nonclinical studies.

Specimen and Data Storage Facilities

You must have a space for archives with limited access only by authorized personnel and for storage and retrieval of all raw data and specimens from the completed studies.

There are rules that you must follow for both equipment design and maintenance and calibration of equipment.

Equipment Design

Equipment used in the generation, measurement or assessment of your data and equipment used for the facility environmental control must be of appropriate design and adequate capacity to function according to the protocol. It also has to be suitably located for operation, inspection, cleaning and maintenance.

Equipment Maintenance and Calibration

Equipment maintenance and calibration must follow the following rules:

• Equipment must be adequately inspected, cleaned and maintained
• Equipment used for generation, measurement and assessment of data must be adequately tested, calibrated and/or standardized
• SOPs must be written to detail:
  • Methods, material and schedules to be used in routine inspection, cleaning, maintenance, testing, calibration and/or standardization of equipment
  • Remedial action to be taken in the event of equipment failure or malfunction
  • The person responsible for the performance of each operation
• Written records must be maintained of all inspections, maintenance, calibrating and/or standardizing operations and include date of the operation, whether the maintenance operations were routine and followed SOPs
• Written records must be kept of all nonroutine repairs as the result of failure and malfunction including the nature of the defect, how and when the defect was discovered, and any remedial action taken in response to the defect.

Standard Operating Procedures (SOPs)

The requirements for SOPs include:

• The testing facility must have SOPs in writing to ensure the quality and integrity of the data
• All deviations to the SOPs must be authorized by the study director and must be documented in the raw data
• Significant changes in established SOPs must be properly authorized in writing by management
• Each lab must have immediately available lab manuals and SOPs relative to the lab procedures being performed
• Historical files of SOPs and revisions (including dates of revision) must be maintained.

SOPs must be established for, but not limited to, the following:

• Animal room preparation
• Animal care
• Receipt, identification, storage, handling, mixing, and method of sampling the test and control articles
• Test system observations
• Lab tests
• Handling of animals found moribund or dead during the study
• Necropsy of animals or postmortem examination of animals
• Collection and identification of specimens
• Histopathology
• Data handling, storage and retrieval
• Maintenance and calibration of equipment
• Transfer, proper placement and identification of animals

Reagents and Solutions

All reagents and solutions must be labeled to indicate:

• Identity
• Titer or concentration
• Storage requirements
• Expiration date

Deteriorated or outdated reagents and solutions may not be used.

Animal Care

Animal care operations must include:

• SOPs for housing, feeding, handling and care of animals
• Isolation and health status evaluation of newly received animals from outside sources in accordance with acceptable veterinary medical practice
• Use of disease or condition free at the initiation of a nonclinical study
• Isolation of animals, if necessary, that contract a disease or condition during the course of the study. Animals may be treated for disease or signs of disease provided treatment doesn’t interfere with the study.
• Retained documentation of the diagnosis, authorizations of treatment, description of treatment, and date of each treatment
• Appropriate identification of warm-blooded animals, excluding suckling rodents, used in lab procedures that require manipulations and observations over an extended period of time or in studies that require the animals be removed from and returned to their home cage for any reason (e.g., cage cleaning, treatment, etc.).
• Separate rooms for animals of different species when necessary
• Separate rooms for animals of the same species, used in different studies, when inadvertent exposure to control or test articles or animal mix-up could affect the outcome of either study. If such mixed housing is necessary, adequate differentiation by space and identification must be made.
• Cleaning and sanitizing of animal cages, racks and accessory equipment at appropriate intervals
• Periodic analyzing of feed and water used for the animals to ensure contaminants known to be capable of interfering with the study and reasonably expected to be present in such feed or water are not present at levels above those specified in the protocol. Documentation of such analyses must be maintained as raw data.
• Use of bedding in animal cages or pens that will not interfere with the study
• Changing of animal bedding as often as necessary to keep the animals dry and clean
• Preventing use of cleaning and pest control materials that interfere with the study
• Documentation of any pest control materials used

IACUC SOPs are adequate in some cases for certain aspects of the study.

Test and Control Article Characterization

The following are required for test and control article characterization:

• The identity, strength, purity, and composition or other characteristics must be determined for each batch and documented
• Methods of synthesis, fabrication, or derivation must be documented
• Marketed products will be characterized by their labeling
• Stability must be determined for the test and control articles by the testing facility or the sponsor (the entity providing financial or other support to the study; Note: a Sponsor may also be the test facility) either: 1. Before study initiation OR 2. Concomitantly according to SOPs, which provide for the periodic analysis of each batch
• Each storage container for the test and control articles needs to be labeled by:
  • Name
  • Chemical abstract # or code #
  • Batch #
  • Expiration date, if any
  • Storage conditions (when necessary to maintain identity, strength, purity and composition)
• For studies with a >4-week duration, samples of test and control articles should be kept for the timeframes described below in “Retention of Records”

Test and Control Article Handling

Procedures need to be put in place establishing a system for handling of the test and control article to ensure:

• Proper storage
• Distribution in a way that prevents contamination, deterioration or damage
• Distribution in a way that makes sure that the proper identification is maintained throughout the process
• Receipt and distribution of each batch is documented (including date and quantity that has been distributed or returned)

Mixtures of Articles with Carriers

When you mix a test or control article with a carrier, tests by appropriate analytical method must be conducted to determine:

• Uniformity of the mixture
• Concentration of the test or control article in the mixture (performed periodically)
• Stability in the mixture either: 1. Before study initiation OR 2. Concomitantly according to SOPs, which provide for the periodic analysis of each batch

The expiration date of the mixture should be clearly displayed on the container, and if more than one component has an expiration date, the earliest date should be the one shown.

Writing a Clinical Protocol

There needs to be an approved written protocol that includes:

• Objectives
• Title
• Statement of purpose
• Identification of the test and control articles by name, chemical abstract # or code #
• Name of the sponsor
• Name and address of the testing facility where the study is being conducted
• #, body weight range, sex, source of supply, species, strain, substrain and age of the animals (test system) used
• Procedure for identifying what animals (test system) will be used
• Experimental design, including methods to control bias
• Description/Identification of the diet used including a description of solvents, emulsifiers, and/or other materials used to solubilize or suspend the test or control articles before mixing with the carrier
• Specification for acceptable levels of contaminants that are reasonable expected to be present in the dietary materials and are known to be capable of interfering with the purpose or conduct of the study if they are present at levels greater than established by the specifications
• Each dosage level, expressed in mg/kg of body weight or other appropriate units of the test or control article
• Method and frequency of test or control article administration
• Type and frequency of test, analysis and measurement to be made
• Records to be maintained
• Date of approval by the sponsor
• Dated signature of the study director
• Statistical methods

Any and all revisions to the protocol and the reason for those changes must be documented. The revisions must be maintained with the protocol and must be signed and dated by the study director.

Conduct of a Nonclinical Laboratory Study

The nonclinical study must be conducted in accordance with the protocol.

Additionally:

• Test systems must be monitored in conformity with the protocol
• Specimens must be identified by test system, study, nature and date of collection on the specimen container or in a manner that precludes error in recording the specimen data
• Records of gross findings for a specimen from postmortem observations should be available to a pathologist when examining that specimen histopathologically
• All data generated, except those that are generated by automatic data collection system, must be recorded:
  • Directly
  • Promptly
  • Legibly
  • In ink
• All data entries must be:
  • Dated on the date of entry
  • Signed or initialed by the person entering the data
• Any changes to data entries must be done such that it:
  • Does not obscure the original entry
  • Indicates the reason for the change
  • Is dated and signed or identified at the time of the change
• In automated data collection system, the individual responsible for direct data input must be identified at the time of data input. Any changes in entries must be done such that it:
  • Dose not obscure the original entry
  • Indicates the reason for the change
  • Is dated
  • Identifies the responsible individual

Reporting of Nonclinical Laboratory Study Reports

A final study report must be prepared for each nonclinical laboratory study and must include the following:

• Name and address of the testing facility where the study was conducted
• Date of when the study was initiated and completed
• Objectives and procedures in the protocol including any changes to the original protocol
• Statistical methods
• Test and control articles identified by name, chemical abstracts # or code number, strength, purity, and composition or other appropriate characteristics
• Stability of the test and control articles under the conditions of administration
• Description of the methods used
• Description of the animal model (test system) used including (where applicable)
  • # of animals used
  • Sex
  • Body weight range
  • Source of supply
  • Species
  • Strain
  • Substrain
  • Age
  • Procedure used for identification
• Description of the dosage, dosage regimen, route of administration and duration
• Description of all circumstances that may be affected the quality or integrity of the data
• Name of the study director
• Names of other scientists or professionals, and the names of all supervisory personnel involved in the study
• Description of the transformations, calculations, or operations performed on the data
• Summary and analysis of the data
• Statement of the conclusions drawn from the analysis
• Signed and dated reports of each of the individual scientists or other professionals involved in the study including any third party analysis (e.g., 3^rd party histology reports that must also be run in a GLP compliant manner)
• Locations where all specimens, raw data, and the final report are to be stored
• A statement prepared by and signed by the QA unit

The final report must be signed and dated by the study director.

Corrections or additions to the final report must be in the form of an amendment by the study director. The amendment must clearly identify the part of the final report that is being added to or corrected and the reasons for the correction or addition. The amendment must be signed and dated by the person responsible.

Storage and Retrieval of Records and Data

What needs to be stored?

All of the following resulting from the nonclinical laboratory study:

• Raw data
• Documentation
• Protocols
• Final reports
• Specimens (except those obtained from mutagenicity tests and wet specimens of blood, urine, feces, and biological fluids)

How should they be stored?

They should be stored in the following way:

• Orderly and indexed in a way that allows expedient retrieval of all items
• Under conditions that minimize deterioration of the items
• May contract with commercial archives to provide a repository for all material to be maintained
• Raw data and specimens may be retained elsewhere provided the archives have specific reference to those locations
• An individual must be identified as responsible for the archives
• Only authorized personnel have access to enter the archives

Retention of Records

Documentation records, raw data and specimens pertaining to a nonclinical laboratory study must be retained in the archive(s) for whichever of the following periods is the shortest:*

• At least 2 years following the date on which an application for a research or marketing permit, in support of which the results of the nonclinical laboratory study were submitted, is approved by the FDA (this does not apply to studies supporting INDs and/or IDEs)
• At least 5 years following the date on which the results of the nonclinical laboratory study are submitted to FDA in support of an application for a research or marketing permit (aka your full FDA approval) (this applies to studies supporting INDs and/or IDEs)
• If the nonclinical study does not result in submission of the study in support of an FDA approval, at least 2 years following the date on which the study is completed, terminated or discontinued

*Wet specimens (except those specimens obtained from mutagenicity tests and wet specimens of blood, urine, feces, and biological fluids), samples of test or control articles, and specifically prepared material, which are relatively fragile and differ markedly in stability and quality during storage, shall be retained only as long as the quality of the preparation afford evaluation. In no case shall retention be required longer then below.

What else must be maintained?

The following must also be maintained for the above time periods in easily accessible systems:

• Master schedule sheet
• Copies of the protocol
• Records of quality assurance inspections
• Summaries of training
• Experience and job descriptions
• Records and reports of the maintenance and calibration and inspection of equipment

How many the records be retained?

The records may be retained either as original records or true copies such as photocopies, microfilm, microfiche, or other accurate reproductions. If the facility conducting the nonclinical testing goes out of business, all records should be transferred to the archives of the sponsor of the study and the FDA must be notified in writing of the transfer of the records.