FDA GMP/GLP

GLPs (good laboratory practices) and cGMPs (current good manufacturing practices) are regulations published in the Code of Federal Regulations (CFR).

SGS is capable of performing both cGMP and GLP compliant analyses.

Good Laboratory Practices

(21 CFR part 58)

A quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. GLPs apply to non-clinical laboratory studies that support or are intended to support application for research or marketing permits for food and color additives, human and animal drugs, medical devices for human use, biological products and electronic products. GLPs have nothing to do with the manufacturing of the product.

The definition of “Non-clinical laboratory studies” is as follows (21 CFR 58.3)

“In vitro or in vivo experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The terms does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine the physical or  chemical characteristics of a test article.”

Main Responsibilities

Ownership – Facility Management

Main responsibility for the activity – Study Director

Responsibility for Analyses – Principal Investigator

Quality – Quality Assurance Unit

Facility Management (21 CFR 58.31)

One responsibility of management is to be sure a Study Director is to be designated before a study is initiated. Replacement of the Study Director is to be done promptly, if it becomes necessary. Management is to assure that there is a Quality Assurance Unit (QAU) and that the test and control article have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable. Management can authorize significant changes in SOPs and assures that any deviation from GLP regulations reported by the QAU are communicated to the Study Director and corrective actions are taken and documented.

Study Director (21 CFR 58.33)

“For each non-clinical laboratory study, a scientist or other professional of appropriate education, training and experience, or combination thereof, shall be identified as Study Director”

There can only be one person designated as Study Director; there cannot be a co-Study Director. However, there can be an alternate Study Director.

Quality Assurance Unit (21 CFR 58.35)

“A testing facility shall have a Quality Assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations. For any given study, the Quality Assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and conduct of the study.”

The responsibilities of the QAU included maintaining a copy of a master schedule sheet of all non-clinical studies conducted at the testing facility. The QAU is to maintain copies of all protocols and inspect each non-clinical study at adequate intervals. Also to be maintained are signed records of each inspection.

The three main things the QAU is responsible for verifying:

1. Is the Study being conducted in accordance with the protocol?
2. Is the Study being conducted in accordance with relevant SOPs?
3. Is the Study being conducted in accordance with the GLP regulations?

QA reviews SOPS for the compliance with GLPs but does not approves SOPs in a GLP environment. GLPs do not require that QA sign SOPs, but QA is responsible for assuring Management that working procedures comply with the SOPs and QA is responsible for reporting deviations to Study Directors and Management.

Protocols (21 CFR Part 58.120)

“Each study shall have an approved written protocol that clearly indicates the objectives and all the methods for the conduct of the study.”

“All changes in or revisions of an approved protocol and the reasons therefor shall be documented, signed by the Study Director and maintained with the protocol. ”

Protocols do not contain “fill in the blanks ”; they are stand alone documents. Protocol amendments are intended to document permanent changes. If a deviation from protocol is an error, it should not result in a protocol amendment.

Final Reports (21 CFR Part 58.185)

A final report shall be prepared for each non-clinical laboratory study and shall include, but not be limited to: the name and address of the facility performing the study, dates on which the study was initiated and completed with the date the study director signed the protocol and teh date the Study Director signed teh final report. A description of all circumstances that may have affected the quality or integrity of the data  shall be listed on the final report. This includes reporting all protocol and GLP deviations, which is done in the form of a Compliance Statement. Compliance Statements are signed by the Study Director, not by QA.

Facilities (21 CFR Part 58.81)

“A testing facility shall have standard operating procedures in writing setting forth non-clinical laboratory study methods that Management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study.”

“Each laboratory area shall have immediately available laboratory manuals and standard operating procedures relative to the laboratory procedures being performed. Published literature may be used as a supplement to standard operating procedures.” “A historical file of standard operating procedures, and all revisions thereof, including the dates of such revisions, shall be maintained.”

Retention of Records (21 CFR part 58.195)

Documentation records, raw data and specimens pertaining to a non-clinical laboratory study shall be retained in the archive(s) for which ever period is the shortest:

1. A period of 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 non-clinical laboratory study were submitted, is approved by the FDA
2.  A period of at least 5 years following the date on which the results of the non-clinical laboratory study are submitted to the FDA in support of an application for a research or marketing permit.

Current Good Manufacturing Practices

(21 CFR Part 210 & 211)

cGMPs – Current Good Manufacturing Practices – are regulations established to promote the quality and validity of a laboratory’s data. They deal with the organization, process, and conditions under which laboratory analyses are planned, performed, monitored, recorded, and reported. 21 CFR Part 210 addresses current Good Manufacturing Practices in manufacturing, processing, packing, or holding drugs and 21 CFR Part 211 addresses current Good Manufacturing Practices for finished pharmaceuticals.

“If a person engages in only some operations subject to the regulations in this part… and not in others, that person need only comply with those regulations applicable to the operations in which he or she is engaged.” (21 CFR 210.2)

Below is how CSL complies with applicable cGMPs.

Facilities/Environment

1. Each employee needs adequate space to perform duties
   1. Keep area neat and tidy to ensure enough work space
   2. Separate areas for different types of duties
2. Separate space for different types of samples to avoid contamination and mix-ups
   1. Low level versus higher level samples
   2. Special or microwave digestions
   3. Lead versus non-lead samples

SOPs/Forms

1. Laboratories must have SOPs in writing with procedures or methods that ensure the quality, integrity, and consistency of the data generated
2. Deviations from SOPs or Forms must be authorized and documented in the raw data
3. SOPs and Forms can be modified if need be, but only by the Technical Director or Quality Assurance Unit
4. SOPs are available for all employees to read

Equipment

1. Equipment is of appropriate design and adequate capacity to function according to protocol
2. Equipment is suitably located to be adequately tested or calibrated
3. Equipment is inspected, cleaned, and maintained
4. Equipment is adequately tested and/or calibrated
5. Maintain written records of maintenance, testing, and calibrating of equipment to include, but not limited to:
   1. Thermometer calibration
   2. Instrument calibration
   3. Record instrument maintenance in the maintenance binder

Reagents/Solutions

1. Record lot numbers of reagents for traceability
2. Other traceability requirements include NIST references for standards and the reagent provider
3. Solutions must be labeled to indicate what it is, concentration, and expiration date
4. If several expiration dates, use the date that expires first
5. Second source calibration standards made from separate lot of material
6. Check reagents before each auto block use

Sample Information

1. The correct CSL number is used when labeling
2. Dilution amounts are entered correctly when keying into the instruments to include, but not limited to:
   1. 25mL versus 50mL final volumes
   2. Dilution factors
3. Correct tablet mass used when calculating results
4. Store and distribute samples in a way to avoid contamination, deterioration, or damage to sample or sample containers
   1. Properly seal containers
   2. CSL number must remain legible
5. When grinding or sampling, mixture is homogenous
   1. Grind tablets as well as possible
   2. Shake waters before sampling
6. Retain digested samples for two weeks after the final report is complete

Raw Data

1. Do not leave blank pages or blank spaces on pages in notebooks
   1. Draw a line through empty pages or spaces
   2. Initial and date empty pages
2. Record all data promptly and in blue or black permanent ink
   1. Date data entry with the current date
   2. Person who enters data signs or initials
3. Changes are crossed out once, dated, and initialed
   1. Original must still be legible
   2. Never write over top of errors to hide errors
4. Instrument data is raw data/official record
   1. Instrument data requires initials and date to any markings
5. Any deviations to normal procedures must be documented, to include:
   1. Description as to why a digestion failed
   2. Change in final volume from the norm
6. All entries must be reviewed by a second person for accuracy

Reports

1.  Final Reports include, but are not limited to:
   1.  Name of facility performing the testing
   2.  Date testing initiated (date received)
   3.  Date testing completed
   4.  Method used
   5.  Description of dosage, if given (2 caps/serving)
   6.  Description of any circumstances that may have affected the quality or integrity of data (ex. dry weight, composite, quality control failure)
   7.  Analyst initials
   8.  Signature
2.  Amended reports must be clearly marked
   1.  Supplemental Report
   2.  Revised Report

Contamination

1.  Wear and change gloves on a regular basis
2.  Cover all open items, such as test tubes, beakers, reagents
3.  Wipe counters/work surfaces daily
4.  Personal hygiene is avoided in laboratory areas, to include:
   1.  Applying make up
   2.  Combing hair
5. Change HEPA filters on a regular basis