Good Laboratory Practices (GLP) and Current Good

Manufacturing Processes (cGMP)

Before any drug or device can be marketed in the United States, it must meet a series
of regulations set by the Food and Drug Administration (FDA) that ensure its safety and
efficacy. These regulations, part of the Federal Food, Drug and Cosmetic Act, apply to
all stages of the development, testing and manufacture of drugs and devices.

In order to make judgements on product safety, the FDA requires pharmaceutical
companies to submit sound, traceable analytical data. Good Laboratory Practices
(GLP) and current Good Manufacturing Practices (cGMP), part of Chapter 21 of the
Code of Federal Regulations (21 CFR), are the result of this requirement. The FDA
ensures that GLP and GMP are followed, continually keeping companies current on
what are considered to be compliant practices. Companies, in turn, interpret these
regulations and develop their own procedures for qualification and validation of
equipment, computers and analytical methods.

This backgrounder reviews the essential features of GLP, GMP and 21 CFR Part 11,
the FDA regulation that hinges on securing the authenticity and integrity of data.

Good Laboratory Practices
A drug or device must be proven safe in nonclinical, or toxicity, studies before it can be
tested for safety and efficacy in humans. Good Laboratory Practice (GLP), defined in 21
CFR 58, ensures that a nonclinical study has been conducted properly and that the
collected data is valid and of high quality. GLP deals with the organization, process and
conditions under which studies are planned, performed, monitored, recorded and
reported. Once a nonclinical study has been fully documented, reviewed and approved,
testing in humans can begin.

Shortly after the FDA introduced GLP, the Organization for Economic Cooperation and
Development (OECD) published a compilation of GLP regulations. OECD member
countries have since incorporated GLP into their own legislations. Guidelines on quality
assurance for measuring equipment and for calibration have also been published by the
International Organization for Standardization (ISO).

Good Manufacturing Practices
Once a drug or device successfully completes clinical studies, it can be manufactured
and made available to the consumer. Good Manufacturing Practices (GMP), often
called current Good Manufacturing Practices (cGMP) to reflect their dynamic nature,
regulate the manufacture and distribution of a product. The purpose of GMP is to
ensure that safe and effective products are consistently produced and controlled to the
quality standards appropriate for their intended use. Compliance with GMP, defined in
21 CFR 210 and 211, requires validation of all critical steps in the manufacturing and
distribution processincluding cleaning and testing.

Any drug marketed in the United States must be manufactured in accordance with
GMP. Because of this, FDA regulations have set an international benchmark for
pharmaceutical manufacturing. In Europe, local GMP regulations exist in many
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Good Laboratory Practices (GLP) and Current Good
Manufacturing Processes (cGMP)
countries and are intended to establish a minimum manufacturing standard for all
member states.

GMP are general and represent the minimum requirements around which a company
should develop its own specific quality program. Some basic requirements of quality
control include:

Adequate facilities, trained personnel and approved procedures for sampling,
inspecting, testing and, where appropriate, monitoring environmental conditions of
all materials and products
Samples of all materials and products, taken using methods approved by quality
control
Validated test methods
Records, made manually and/or by recording instruments, demonstrating completion
of required sampling, inspection and testing procedures, thoroughly documenting
any deviations
Active ingredients that comply with the composition of marketing authorization, are
of the required purity and are enclosed within a proper container that is correctly
labeled
Records of inspection results and formal assessment against specification of all
materials and products, including a review and evaluation of relevant production
documentation and an assessment of deviations from specified procedures

What is Validation?
One of the key requirements of GLP and GMP for analytical laboratories is validation,
the evaluation of processes, products or analytical methods to assure that they will
consistently produce a product that meets its predetermined specifications and quality
attributes. Properly functioning and well-documented instruments, computer
hardware and software and validated analytical methods are needed to fulfill
regulatory requirements. Validation also includes checking functions related to
data integrity, security and traceability. Validation is not a one-time event but
ongoing, covering all phases of a product or process.

What must be validated?

Equipment. All computerized equipment used to create, modify, archive, retrieve or
distribute critical data for GLP/GMP purposes must be validated. Validation of
hardware includes testing the instrument according to documented specifications. If
instruments consist of several modules, the entire system should be validated.
Validation of computer systems must include the qualification of hardware and
software.
Analysis method. Validation covers testing significant method characteristics such
as sensitivity and reproducibility.
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Good Laboratory Practices (GLP) and Current Good
Manufacturing Processes (cGMP)
Analysis system. The system combines instrument, computer and analytical
method. This validation is usually referred to as system suitability testing and tests
for documented performance specifications for the specific analysis method.
Data. When analyzing samples the data must be validated. The validation process
includes documentation and checks for data plausibility, consistency, integrity and
traceability. A complete audit trail must be in place, which allows tracing back the
final result to the raw data for integrity.
Personnel. People should be qualified for their jobs. This includes education,
training and/or experience.
Reference standards. Reference standards should be checked for purity, identity,
concentrations and stability.

21 CFR 11
21 CFR 11 provides rules for the sole use of electronic records in lieu of manual
printouts and for the use of electronic rather than handwritten signatures and record
archives. With 21 CFR 11, electronic records and signatures can be equivalent to paper
records and handwritten signatures. The regulation applies to all industry segments
regulated by the FDA, including GLP and GMP.

The primary requirements of 21 CFR Part 11 are:
Limited system access to authorized individuals.
Use of validated computer systems.
Secure retention of electronic records to instantly reconstruct the analysis.
User-independent, computer-generated and time-stamped audit trails.
Use of secure electronic signatures for closed and open systems.
Use of digital signatures for open systems.

Agilent and Compliance
The Agilent 1100 Series high-performance liquid chromatography and Agilent
6890/6850 gas chromatography systems provide a reliable, cost-effective path to
regulatory compliance and are designed with built-in automated calibration and
validation features. In addition, Agilent offers software modules that provide 21 CFR
Part 11 support as part of or in conjunction with most of its major analytical software
products.


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