04. GLP, CSA/DEA

Which Act gives rise to GLPs and is the law that gives authority to the FDA to enforce them.

Federal Food, Drug, and Cosmetic ACT of 1938 - 21 CFR Part 58

WHAT ARE GLP?

Establish standards for conducting and reporting nonclinical safety testing

Allows for a quality product and accurate repetition of the study

Apply to nonclinical laboratory studies intended to support applications for research or marketing permits for products regulated by the FDA

it is a management system

Good Laboratory Practices

Regulates nonclinical laboratory studies

-Human and animal drugs

-Medical devices for humans

-Biological products (exclude hormones like insulin)

-Human food and color additives

-Animal food additives

-Electronic products (e.g. MRI)

What is a nonclinical laboratory study?

in vivo or in vitro experiments in which test articles are studies prospectively in test systems under laboratory conditions to determine their safety

What is not included in a nonclinical lab study?

-no studies using human subjects

-no clinical studies

-no field trials in animals

-no basic exploratory studies (utility, physical or chemical characteristics of test article

What does GCP stand for?

GCP = Good clinical practices

What does GLP stand for?

GLP = Good Laboratory Practices

What does GMP stand for?

GMP = Good manufacturing practices

What does IND stand for?

IND = Investigational new drug

What does NDA stand for?

NDA = new drug application

Definition of Testing Facility

person who actually conducts the study (i.e. uses the test article in the test system)

A "testing facility" can be a "person"

Definition of Person

individual, partnership, corporation, association, scientific or academic establishment, government agency, or any other legal entity

Definition of Nonclinical Laboratory Study

in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety

Does not include: basic exploratory studies, studies utilizing human subjects or clinical studies, or field studies in animals

Definition of Sponsor**

Sponsor:

(1) A person who initiates and supports a nonclinical lab study; or

(2) A person who submits a nonclinical study to the FDA in support of an application for a research or marketing permit; or

(3) a testing facility, if it both initiates and conducts the study

Definition of Test system

animal, plant, microorganism, or subparts thereof to which a test or control article is administered or added for study. Includes appropriate groups or components of the system not treated with the test or control articles

Definition of Test article

any food or color additive, drug, biological product, electronic product, medical device for human use or any other article subject to regulations

Definition of study Director (SD)

individual with overall responsibility of the study

includes: technical conduct of the study; interpretation, analysis, documentation, and reporting of results;

represents the single point of study control

The study director shall assure what 6 things?

-  The protocol, including any change, is approved and is followed.

-  All experimental data are accurately recorded and verified.

-  Unforeseen circumstances that may affect the quality and integrity of the study are noted when they occur, and corrective action is taken and documented.

-  Test systems are as specified in the protocol.

- All applicable good laboratory practice regulations are followed.

- All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.

Definition of Study Initiation date

the date the protocol is signed by the SD

Definition of Study Completion date

the date the final report is signed by the SD

Application for research or marketing permit includes what 8 things?

(1) An investigational new drug application (IND).

(2) A new drug application (NDA).

(3) A Notice of Claimed Investigational Exemption for a New Animal Drug.

(4) A new animal drug application.

(5) An application for a biologics license.

(6) An application for an investigational device.

(7) An Application for Premarket Approval of a Medical Device.

(8) A Product Development Protocol for a Medical Device.

Each individual engaged in the conduct of or responsible for the supervision of a study shall have ____, to enable that individual to perform the assigned functions.

education, training, and experience, or combination thereof

Each testing facility shall maintain _____ for each individual engaged in or supervising the conduct of a study.

a current summary of training and experience and job description

How many people need to be available for the study to be conducted?

a sufficient number to conduct the procedure according to protocol

____ personnel should not work with animals (or test or control articles) if it will affect study.

Ill

For each nonclinical laboratory study, testing facility management shall:

• Designate a ____

• Replace the ___ promptly if it becomes necessary

• Assure there is a ____

• Assure test and control articles are tested for ID, strength, purity, stability and uniformity

• Assure personnel, resources, facilities, equiment, materials and methodologies are available as scheduled

• Assure that personnel ____ functions they are to perform

• Assure than any deviation from these regulations are reported by the ____ to the ____ and corrective actions are taken and documented

Study director

study director

Quality assurance unit (QAU)

e

e

understand

QAU to the Study Director

Definition of Quality Assurance Unit (QAU)

Responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part

If someone is apart of the Quality Assurance Unit (QAU) can they also be involved in the study?

No, must be entirely separate from and independent of the personnel engaged in the direction and conduct of that study.

Who must QUALITY ASSURANCE UNIT(QAU) report deviations to?

Report deviations to the study director

The QAU is responsible for maintaining records of what?

1.Master schedule (indexed by test article)

2.Copy of protocols

3.Inspections (Dates, what was inspected, name of inspector, findings, actions recommended and actions taken)*.

*FDA inspections do not require access to these

The QAU is like the ____ and the study director is like the ____

IACUC

Insitutional Official

QAU is alot like the IACUC - so what shall they do?

1. Copy of master schedule sheet of all NCL studies at testing facility – include 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

2. Maintain copy of all protocols 

3. Inspect each nonclinical laboratory study at intervals – include: maintain written and properly signed records of each periodic inspection showing 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 reinspection.

   1. Any problems found that affect study integrity – report to study director immediately

4. management and the study director written status reports on each study – note problems & corrective actions 

5. no deviations from approved protocols or standard operating procedures were made without proper authorization and documentation

6. Review the final study report to assure that such report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the NCL study

7. Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to

Who inspects GLP facilities? Who do they report to?

FDA

The Animal Care Facility should be of sufficient size to assure what 4 things?

• separation of species

• isolation of individual projects

• quarantine of animals

• routine or specialized housing of animals

In the Animal Care Facility, there should be separate space for experiments with test and control articles known to be ____. There should also be a separate area for ____ of laboratory animal diseases. There should also be facilties to handle ____.

biohazardous (volatile substances, aerosols, radioactive materials, infectious agents)

diagnosis, treatment, and control

disposal of animal waste

Storage areas, for feed (certified diets), nutrients, soils, bedding, supplies, and equipment,_____ and protected against infestation or contamination. Perishable supplies shall be ____ by appropriate means.

separated from areas where the test systems are located

preserved

Again, separate areas for what three phases of test articles? Storage of all test articles should be separate from ___.

1. Receipt/storage of test/control articles

2. Mix of test/control articles w/ carrier

3. Storage of test/control article mixtures

test systems

Should the lab space for procedures (routine or specialized)?

Yes

There should also be a separate space for the ___ that is limited to authorized personnel only.

archives

Equipment should be cleaned and maintained. If this equipment generates measurements, it should be ___, ___, and ____. Equipment should have written ___ and ___.

tested, calibrated, and standardized

SOPs and records (inspection, testing, findings, nature of defect - how discovered and how fixed)

Any GLP study needs SOPs - if there is any deviation from the SOP it should be authorized and documented by the ___. Significant changed need authorization written by ____.

Study director

management

What are things that need an SOP?

(1) Animal room preparation.

(2) Animal care.

(3) Receipt, identification, storage, handling, mixing, & method of sampling of the test & control articles.

(4) Test system [ie animals] observations.

(5) Laboratory tests.

(6) Handling of animals found moribund or dead during study.

(7) Necropsy of animals or postmortem examination of animals.

(8) Collection & identification of specimens.

(9) Histopathology.

(10) Data handling, storage, & retrieval.

(11) Maintenance & calibration of equipment.

(12) Transfer, proper placement, & identification of animals.

What can be used to supplement and SOP and how long must SOPs be on file?

-published literature

-historical file of all SOPs and revisions made should be maintained

Reagents and solutions should be labeled with what?

 identity, titer, concentration, storage requirements, exp date

GLP - Newly received animals should be ____

isolated and health status evaluated

GLP - Study animals should be free of any disease. If they contract a disease they should be isolated and treated provided that ____. What should be documented and retained?

Treatment does not interfere with study

diagnosis, authorizations of treatment, description of treatment, and each date of treatment shall be documented and shall be retained.

What animals are required to receive appropriate identification? All information needed to specifically identify each animal within an housing unit shall appear where?

warm blooded animals excluding suckling rodents

on outside of housing unit

Can animals of different species be housed in the same room? Can animals of the same species, but different studies be housed in the same room??

No

Usually no especially if inadvertent mix up could affect outcome of either study

Does GLP list specifics on when animal cages, racks, and accessory equipment should be cleaned and sanitized?

No, just says regularly

What two things given to animals should be analyzed periodically? Documentation of the analysis should be maintained as raw data.

Feed and water

If any pest control materials are used their use shall be ____. It it could potentially interfere with the study it can’t be used.

documented

The identity, strength, purity and composition or other characteristics which will appropriately define the test or control article shall be determined for ____ and shall be documented.

each batch

The stability of each article shall be determined ___ or ___, according to SOP.

before the study initiation OR periodically for each batch

Each storage container for a test or control article shall be labeled by ____

name, chemical abstract number or code number, batch number, expiration date, if any and where appropriate, storage conditions necessary.

Studies more than ______ weeks duration will retain reserve samples from each batch of test/control articles. ___ of articles shall also be tested for uniformity and concentration.

4

mixtures

In GLP, how to handle SOP revisions? old versions?

A historical file of standard operating procedures, and all revisions thereof, including the dates of such revisions, shall be maintained.

What is the order of importance? GLP Regs, Protocol, SOPs

GLP Regs > Protocol > SOPs

Who signs amendment in GLP? who signs final report in GLP?

-Amendments must be signed and dated by SD

-Final report must be signed by SD and individual scientists or other professionals involved

Test and control article handling - Procedure for proper storage, contamination free distribution, proper ID throughout distribution, receipt of each batch (include ____)

date and quantity of batch distributed/returned

Mixed articles w/ carriers - If it’s mixed with carrier, what testing should be done? When does it expire?

1. determine uniformity & periodically concentration 

2. determine stability either (A) BEFORE study initiation OR (B) according to SOPs providing periodic analysis of articles 

Expiration date must be CLEAR, if multiple components have expiration date – EARLIEST date shown.

What should be included in the protocol?

(1) A descriptive title and statement of the purpose of the study.

(2) Identification of the test and control articles by name, chemical abstract number, or code number.

(3) The name of the sponsor and the name and address of the testing facility at which the study is being conducted.

(4) The number, body weight range, sex, source of supply, species, strain, substrain, and age of the test system.

(5) The procedure for identification of the test system.

(6) A description of the experimental design, including the methods for the control of bias.

(7) A description and/or identification of the diet used in the study. 

(8) Each dosage level, expressed in milligrams per kilogram of body weight or other appropriate units.

(9) The type and frequency of tests, analyses, and measurements to be made.

(10) The records to be maintained.

(11) The date of approval of the protocol by the sponsor and the dated signature of the study director.

(12) A statement of the proposed statistical methods to be used.

Any changes to the protocol should be documented, signed by ___, ___, and maintained with ____.

study director, dated, maintained with the protocol

Recording of data generated during the conduct of study should be ____ and ____ by person entering data. Any change in entries shall be made so as ______, ____, and _____.

dated on the date of entry and signed or initialed by the person entering the data. Any change in entries shall be made so as not to obscure the original entry, shall indicate the reason for such change, and shall be dated and signed or identified at the time of the change.  (same)

-dated and signed/initialed

-not to obscure original entry, indicate reason for change, dated and signed or identified at time of change

The final report shall include what 14 things?

(1) Name and address of the facility and the dates on which the study was initiated and completed.

(2) Objectives and procedures stated in the approved protocol, including changes. 

(3) Statistical methods used.

(4) The test and control articles identification.

(5) Stability of the test and control articles.

(6) A description of the methods used.

(7) A description of the test system used. Where applicable, the final report shall include the number of animals used, sex, body weight range, source of supply, species, strain and substrain, age, and procedure used for identification.

(8) A description of the dosage, dosage regimen, route of administration, and duration.

(9) A description of all circumstances that may have affected the quality or integrity of the data.

(10) The name of the study director, the names of other personnel, involved in the study.

(11) A description of the transformations, calculations, or operations performed on the data, a summary and analysis of the data, and a statement of the conclusions drawn from the analysis.

(12) The signed and dated reports of each of the individual scientists or other professionals involved in the study.

(13) The locations where all specimens, raw data, and the final report is stored.

(14) The statement prepared and signed by the QAU.

(b) The final report shall be signed and dated by the study director.

Any corrections or additions to the final report should be amended by whom?

study director

All raw data, documentation, protocols, final reports, and specimens (Except ____) generated as result of a nonclincical laboratory study shall be retained.

-obtained from mutagenicity tests, wet specimens of blood, urine, feces, biological fluids

Since the results from GLP studies need to be kept indefinitely in the archives, what can a facility do?

contract with commercial archive holder to provide repository for data. Raw data/specimen can be retained elsewhere if specific reference to location included

Who is responsible for archives? What is a key feature of the archives?

an individual

able to retrieve information quickly

FDA-RETENTION OF RECORDS- how long are documentation, raw data and specimens retained in the archives?

Whichever of the following is shortest:

If study is not submitted... 2 years from the date the study is completed/discontinued/terminated

5 years following results submission to FDA

2 years following application approval by FDA

Doesn't apply to investigational new drug (IND) studies or investigational drug exemptions (IDEs)... keep these for 5 years following results submission

How long should slide records be held for? What about wet specimens?q

-same amount of time as data records

-as long as quality of preparation affords evaluation but not longer than data records

What happens to the records if the testing facility goes out of business? Who needs to be notified?

all data/documentation transferred to archives of SPONSOR

notify FDA in writing of transfer

What should happen to the data collected by a disqualified testing facility?

should still be submitted to FDA even if NCL study will not be considered in support of the application

When can a testing facility be disqualified?

-failed to comply with GLP regs

-noncompliance adversely affects validity of NCL study

-lesser regulatory action have not/will not be adequate to achieve compliance with GLP

How is a facility notified that they may be disqualified? What happens next?

Commissioner issues written notice

hearing for disqualification conducted

When does the commissioner evaluate records of disqualification? What are the 2 results of this evaluation?

-after hearing or time for requesting hearing expires w/o request made

-either does or does not make findings required for disqualification

-Notified testing facility with copy of order

What happens if a facility is disqualified?

-each application for research/marketing permit weather approved or not relying on NCL study from disqualified testing facility is examined

-FDA determines if study is acceptable regardless of facility disqualification

What happens to an NCL study apart of an application that was approved and found to be conducted at a disqualified facility BEFORE it was disqualified?

Decide if study was acceptable or unacceptable

-If acceptable regardless of facility disqualification - may require establish that study was not affected by circumstances that led to disqualification

-if study is unacceptable - data is eliminated from application - may justify termination/withdrawal of approval of application

What happens to an NCL study that began after date of facility disqualification?

study will not be considered in application, but does NOT mean you can’t submit the data gathered from the study

The Commissioner of the FDA can let other interested persons know of facility disqualification. What happens if the notice is sent to another federal government agency vs another person? Can the public see these records?

-Government agency - FDA will recommend agency consider whether or not NCL study should be accepted

-another person - FDA is not advising any action be taken by person notified
-yep

What are alternatives to disqualification?

-civil or criminal judicial proceedings or other regulatory action CAN HAPPEN AT SAME TIME

-FDA can refer another federal, state, or local government law enforcement or regulatory agency for action

-can refuse NCL study if study not conducted in accordance with GLP w/o disqualifying testing facility

If a sponsor terminates a testing facility from further participation in a nonclinical lab study as part of an application that has been submitted to the FDA, it shall notify the FDA in writing within ____ of the action

15 days

The Commissioner can approve reinstatement of a testing facility if they can prove compliance. To do this, the facility must present what and to whom? If the Commissioner reinstates the facility, how is this done? is this disclosable to the public

-in writing to Commissioner

-reasons it should be reinstated, detailed description of corrective actions taken or intends to take, assure acts or omissions which led to disqualification will not recur

-After inspection - Commissioner must notify in writing testing facility & all persons notified of disqualification

-yes

What does ENVIRONMENTAL PROTECTION AGENCY (EPA) do?

Regulates chemicals and monitors compliance with environmental laws

water and air compliance

Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) - 40 CFR part 160

Toxic Substances Control Act (TSCA) - 40 CFR part 792

What is the difference between Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) and Toxic Substances Control Act (TSCA)?

A major difference between EPA FIFRA and TSCA is the process used to review new Substances. While FIFRA calls for extensive test data as part of a complex registration process, TSCA requires only a 90-day advance notice to produce a new chemical.

EPA-RETENTION OF RECORDS- how long are documentation, raw data and specimens retained in the archives?

Whichever period is longest:

5 years following submission of results

2 years following termination, discontinuation, or completion

Cage cards, which contain animal identification numbers, are considered raw data and must be transferred to the archives during or at the close of study.

Answer: F, cage cards are NOT considered raw data.

Which Act passed by Congress is referenced as part of GLPs?

Federal Food, Drug and Cosmetics Act, as amended

A testing facility cannot be considered a Sponsor. T or F?

F- it can be if it initiates AND conducts the study

Testing facilities may be unexpectedly inspected by which governmental agency which will look specifically at records supporting an application for a research or marketing permit?

USDA

EPA

FDA

ISO

FDA

Deviations from SOPs are to be authorized by whom?

The Study Director

The Study Sponsor

The Testing Facility

The Quality Assurance Unit

The Study Director

Which animals do not need identification?

Adult mice

Guinea Pigs

Suckling Rodents

Farm animals

Suckling Rodents

Wet specimens such as blood, urine, feces, and biological fluids do not need to be maintained after the completion of a GLP study. T or F?

T

What types of studies are covered by Good Laboratory Practice regulations?

Clinical and Field Trials in animals

Non-Clinical Safety Testing

Basic Research Studies

Human Subject Trials

Non-Clinical Safety Testing

What is the law basis of DRUG ENFORCEMENT ADMINISTRATION (DEA)? Who administers it? Who enforces it?

Controlled Substances Act (CSA) - 1970 - Title 21 CFR 1300

Administered by the Secretary of Health and Human Services

Enforced by the DEA (est. 1973)

For which schedule drugs must supplier invoices be retained?

III-V

Schedule I-V drugs

- Schedule I: heroin, LSD, marijuana

- Schedule II: morphine, oxycodone, amphetamines, Oxymorphone, Pentobarbital(Nembutal), Fentanyl

- Schedule III: codeine mixtures (Tylenol #3), Telazol, Ketamine, Euthasol, Pentothal, Buprenorphine

- Schedule IV: diazepam, Darvon, Midazolam, tramadol, Phenobarbital

- Schedule V: codeine-containing cough syrup (pseudoephedrine)

Schedule 1 drugs?

high potential for abuse, have no currently accepted medical use in treatment

heroin, LSD, marijuana, peyote

Schedule II drugs?

high potential for abuse, severe psychological or physical dependence

Cocaine

Codeine

Fentanyl

Hydrocodone

Methadone

Hydromorphone

Morphine

Opium

Oxymorphone

Pentobarbital

Sufentanil

Schedule III drugs?

moderate or low physical dependence or high psychological dependence

Buprenorphine

Hydrocodone (< 15 mg)

Ketamine

Opium combination product (<25 mg/du)

Thiopental 

Tiletamine

Tiletamine + Zolazepam

Zolazepam

Schedule IV drugs?

limited physical dependence or psychological dependence

Butorphanol

Chloral Hydrate

Diazepam

Lorazepam

Midazolam

Phenobarbital

Alfaxalone

Tramadol