Overview of GLP requirements on everyday laboratory operations

Published on: Dec 24, 2023

Pharmaceutical laboratories conduct sampling, testing, and reporting of medicinal batch results. As such, they perform a vital role in the overall quality assurance of medicinal products and, therefore, must conform to Good Laboratory Practice – GLP requirements.

There are several sections of the GLP requirements that specifically relate to laboratories. It is standard practice for government inspectors to audit laboratory activities and records against the GLP requirements.

Several different laboratory regulations cover the lifecycle of pharmaceutical products.

For example, the term GLP describes the regulations concerning pre-clinical safety and toxicity studies. The term Good (Control) Laboratory Practice G(C)LP describes the regulations and practices relating to pharmaceutical laboratory testing as part of Good Manufacturing Practice (GMP).

This article will focus on G(C)LP due to its significance in everyday laboratory operations.

Understanding GLP, G(C)LP and GCP

GLP: Good Laboratory Practices refer to the rules concerning testing new drugs before conducting clinical trials. GLP rules are applied explicitly to toxicity testing of chemicals, drugs and devices as a pre-condition for conducting clinical trials in humans.

G(C)LP: Good (Control) Laboratory Practices refer to the rules concerning the specific laboratory testing of drug manufacturers under GMP.

In a sense, G(C)LP is a subset of GMP that specifically relates to the sampling, inspection, testing and reporting of test results. There is no separate set of rules. They are contained in the GMP rules themselves.

GCP: Good Clinical Practices refers to the rules concerning the conduct of clinical trials in humans. Obviously, this is a potentially dangerous phase of new product development, and the rights of the patients and volunteers must be protected. The GCP rules provide strict guidelines concerning Phase I, II, and III trials.

These rules are globally agreed to, but local differences remain.

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Why GLP requirements are important?

Good Laboratory Practices is a set of regulations and guidelines that ensure the quality and integrity of non-clinical laboratory studies.

It sets the standards for performing tests and generating data in a reliable, reproducible, and valid way.

Compliance with GLP requirements is essential for pharmaceutical product research, development, and testing laboratories.

GLP is important because it helps minimise errors, enhance data integrity, and improve laboratory research quality. GLP compliance also helps maintain laboratory personnel’s safety and the environment.

The history and development of GLP requirements

GLP requirements have a rich history that dates back to the 1970s. The need for standardised practices and quality control in laboratory studies became evident due to several incidents of fraudulent data and unsafe practices.

As a response, regulatory authorities in various countries developed guidelines and regulations to ensure the integrity and reliability of laboratory studies.

The Organization for Economic Cooperation and Development (OECD) was crucial in developing GLP regulations. In 1981, the OECD published the first version of the Principles of Good Laboratory Practice, which provided a framework for implementing GLP.

Since then, many countries have adopted their own GLP requirements while aligning with the OECD principles.

Regulatory references of GLP requirements

The Food and Drug Administration (FDA) and Pharmaceutical Inspection Co-operation Scheme (PIC/S) codes of GMP contain few specific references to Good (Control) Laboratory Practices G(C)LP.

However, they contain many indirect references within the body of the codes and regulations that are directly applicable to the laboratory.

The points below outline some areas in the codes where G(C)LP regulations are embedded in the GMP regulations and guidance documents.

1. ISO/ IEC 17025: General requirements for the competence of calibration and testing laboratories. While not a mandatory laboratory standard, ISO 17025 provides excellent guidance for laboratory quality management systems.

2. FDA: 21 CFR regulations:

– Part 211, Section 160 (Laboratory Controls)

– Part 58 (GLP for Non-Clinical Studies)

– Guidance documents:

– Inspection of Pharmaceutical Quality Control Laboratories [1993]

– Analytical Method Validation & Chromatographic Methods

– Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

3. EU and PIC/S: Guide to Good Manufacturing Practice for Medicinal Products:

– Section 2.6-27: Key Personnel

– Sections 6.5-6.6: Good Quality Control Laboratory Practice

– Annex 8: Sampling of starting and packaging materials

– Annex 11: Computerised systems

– Pharmaceutical Quality Control Laboratories

GMP, GLP and Quality Assurance in the laboratory

According to PIC/S, quality assurance (QA) is a wide-ranging concept that covers all matters that influence the quality of a project.

It is the sum of organised arrangements to ensure that medicinal products are of the quality required for their intended use. QA “rules” incorporate GMP and G(C)LP regulations and other factors.

Good Manufacturing Practice (GMP) refers to a set of licensing requirements to which companies must adhere to obtain and retain a manufacturer’s license. GMP rules have been agreed upon by the government and industry, and the rules have been gradually refined during 40 years of experience in practice.

According to PIC/S, GMP is that part of QA that ensures that products are consistently produced and controlled to an appropriate quality. GMP is concerned with both production and quality control.

Everyday activities in pharmaceutical laboratory operation

Quality control compliance encompasses many activities that are documented in the GMP and GLP rules. Four key aspects of QC compliance are listed below.

1. Laboratory sampling

The sampling of starting materials and finished products is entirely governed by GLP regulations. All sampling procedures and plans must be documented.

If wrong or insufficient samples are taken or a poor sampling technique is used, any subsequent testing may give misleading results.

As a result, a good product may be rejected, or, much worse, a defective product may be released.

2. Laboratory testing

Testing of samples in the laboratory is a mandatory requirement under GLP regulations. Its effectiveness, though, is limited because the entire batch cannot be tested, nor can the batch be tested for all types of potential contamination.

In fact, QC testing is limited to looking for defects after they have occurred. So, it is not a QA prevention system but rather a defect detection system.

3. Reporting results

Laboratory documentation and records must follow the same rules as manufacturing GMP documents. The QC lab is required to have SOPs, test methods, specifications, registers, logs and testing records in place.

These documents must be current, approved, accurate, traceable, and archivable for later review. Government auditors are particularly interested in the QC testing records when they conduct GMP audits.

4. Laboratory documentation

Each product has a specific set of specifications registered with the government authorities. Starting materials and finished products must be tested to these specifications, and the results must be reported to QA management if there is a problem.

Batches may not be released to the market if results do not conform to the approved specifications.

Some essential GLP requirements for laboratory operations

1. General GLP requirements

Laboratory activities and procedures must conform to many GLP requirements. Laboratory personnel should be familiar with these requirements. These are also rules that are commonly checked during regulatory audits.

– Conduct tests using approved, written test methods.

– Calibrate and quality instruments.

– All samples and standards are traceable and accounted for.

– Complete test records accurately and in real-time.

– All tests are supported by validated methods.

– Record or capture all generated raw data directly, promptly and legibly.

– Use traceable data sheets or sequentially numbered notebooks.

– Date and sign or initial data entries on the day of entry.

– Archive records so that they are protected, secure, and easily retrievable.

2. GLP requirements of laboratory equipment and instruments

Under GLP rules, equipment and laboratory instruments must be reliable and clean to ensure proper performance and must be qualified for use.

To ensure this, take the following steps:

– Install all equipment and instruments according to the manufacturer’s instructions.

– Operate all equipment according to written procedures and relevant safety instructions.

– Keep all measuring devices within calibration.

– Regularly verify performance by checking controls.

– Implement a maintenance program and retain all maintenance documentation.

3. GLP requirements of laboratory documentation

GLP rules place a heavy emphasis on maintaining documentation. From a regulatory standpoint, if something wasn’t recorded, it may as well not have happened.

Laboratory documentation and records that should be available include:

– Test methods and test reports

– Laboratory notebooks/sheets, instrument records, and calculations

– Conditions of tests and instrument settings.

– Test method validation protocols, data and reports

– Other records and data

i. Testing and standardisation of reference standards, reagents and standard solutions

ii. Calibration of laboratory instruments

iii. Records of all stability testing performed.

iv. Investigations of Out of Specification (OOS) conditions

v. Certificates of analysis from suppliers

Other examples of supporting records under GLP requirements include:

– Sample receipt registers

– Instrument and equipment maintenance logs

– Standards inventory lists

– Analyst training records

– Retention sample storage lists

– Chromatograms and instrument print-offs

– Incubator temperature records (for a microbiology laboratory)

4. GLP requirements of laboratory personnel

The manufacture and testing of quality products rely on people. Therefore, it is crucial that laboratory personnel have the right skills, knowledge and attitudes to perform their work correctly and diligently.

Types of training required include induction training, on-the-job skills training, training on SOPs and test methods for understanding of laboratory procedures, and knowledge of GMP rules. Training must be ongoing.

The company must be able to demonstrate that training has been conducted satisfactorily in the above areas by monitoring training records for each person.

Additional GLP requirements for personnel include:

– There must be sufficient laboratory staff.

– Personnel must undergo periodic health checks.

– Personnel must wear appropriate gowning.

– Personnel must always follow written procedures.

5. GLP requirements of human errors and behaviour

Many incidents leading to defective drug products result not from technological failures but from human error or simple mistakes.

Therefore, the behaviour, attitude, care and knowledge of employees are critical elements in manufacturing safe drug products.

The laboratory must document procedures and quality control rules, but they have no value unless employees know and follow them in all their work practices.

6. GLP requirements of test methods

Laboratory test methods have a well-defined lifecycle from origin to publication, through to update and retirement. GMP and GLP rules determine these pathways.

a. Source of methods: Test methods generally originate from one of the three resources. These include official pharmacopoeias, new methods from a development laboratory, and/or methods adapted from literature.

b. Method development: During development, methods are tested for suitability according to the product they are being used for and the analytical validation performance parameters.

c. Published methods: Once a method has been suitably developed, it is published in a formal that should be unambiguous and easy to follow for an analyst. The published method should also reference any instrumentation and corresponding settings.

d. Method validation: Once a method is published, it must be validated according to ICH Q2(R1) or equivalent criteria. This method validation package should confirm the suitability of the method. The validation report is generally submitted to a regulatory agency as proof that the method is fit for use and validated.

e. Method transfer to laboratory: When a test method is suitably validated, it is transferred to the QC laboratory for commercial use. At this point, QC analysts become responsible for the test method.

f. Verify suitability: As part of the transfer, validated test methods must be verified as to their suitability in the QC laboratory. This generally involves partial validation to confirm that the transferred method remains in a validated state and is still lit for use, using the QC laboratory using the instruments and analysts.

g. Use method in testing: Once correctly validated, the test method is used for the routine testing of target products and should be reliable and robust.

h. Update methods: Test methods require updating occasionally through change management. Some reasons for the update include alignment with pharmacopoeias or improvements to the method itself. Updated methods generally require partial revalidation. The older version of the test method should be archived in case it needs to be referred to later.

7. GLP requirements of test method reliability

The following are the factors that support the reliability of test methods:

– All test methods are validated so that the methods are “fit for purpose”. Where required, they are revalidated.

– Methods are precisely written to minimise ambiguity and misinterpretation.

– Test methods are maintained in line with the current pharmacopoeia.

– Laboratory analysts are trained and “qualified to the method.

– Laboratory equipment is calibrated and maintained.

– There are in-built performance checks per run (e.g. system suitability, controls, blanks)

– The laboratory undertakes trend reviews of assay performances.

8. GLP requirements of sampling plans and procedures

There should be a written sampling protocol for each starting material, in-process bulk and finished product. Sampling plans should be based on sound statistical or rational principles and carried out in such a manner as to preclude bias.

The laboratory should publish written sampling procedures that describe:

– The method of sampling and environmental conditions

– The number, location and amount of sample

– The sampling equipment

– Instructions as to the subdivision or proofing of the sample

– The identification procedure for sample containers

– The sample storage conditions

– Any safety precautions required

9. GLP requirements for internal auditing in laboratory

Good internal auditing practices mean establishing a cooperative focus on “improvement” to the levels of compliance rather than issuing a list of non-conformances.

To do this, the audited department should be open and helpful to the audit group, and the audit group should be constructive in any criticisms. After all, the purpose is to ensure that the laboratory meets acceptance compliance standards. It’s in everyone’s interests.

An essential part of any laboratory operating with a laboratory quality management system is conducting audits as part of a quality assurance program. This is required by ISO-17025 and regulatory agencies.

Audits are conducted to verify good procedures and practices and identify problems and improvement opportunities.

When conducting internal auditing, the laboratories should consider:

– Quality or compliance audits

– Regular monitoring of test performances

– Quality system reviews

The credibility of the laboratory hinges on good quality management.

Documentation and records maintained in the laboratory should be able to withstand auditing. Specifically, internal audits aim to verify that:

– Results are reliable and accurate

– The information flow to customers is timely

– Test results are unambiguous

– The laboratory is economically efficient

– Historical records and data are retrievable

– The laboratory operates independently in quality assessment.

Regular internal audits in the laboratory ensure the trust of laboratory results. Be aware that loss of credibility results in:

– Loss of confidence and scepticism by users

– Inappropriate resource utilization, leading to excessive costs

– A focus on ‘defending” results

– Rejection of good and acceptance of bad quality

– An isolation of the laboratory

– Undue regulatory or external pressure on the company

Preparation for internal audits

GLP requirements dictates internal audits to be conducted in following areas:

– Safety

– Compliance

– Regulatory

– Investigation

– Trend Analysis

Auditors will most likely want to see laboratory notebooks, test methods, and “objective evidence” on how you conducted a test or calculated a result.

Have all the documentation that might be needed readily available. You may be asked because you are either an expert in the area or have particular knowledge of an issue or event.

10. GLP requirements for external audits

External audits are generally conducted by purchasers, contractors, and accrediting bodies.

Generally, GLP rules require external audit to include at least the following areas:

– The laboratory quality management system.

– The written procedures.

– The validation of test methods.

– The control over instrumentation and equipment.

– The test methods and how they are applied.

– The laboratory record keeping practices.

– The procedures for evaluation and release of results.

Best practices for ensuring compliance to GLP requirements

Compliance with GLP requirements requires a proactive and systematic approach. Here are some best practices to ensure GLP compliance in your laboratory:

1. Establish a culture of compliance

GLP compliance should be ingrained in the culture of your laboratory. This starts with the commitment and support of top management. All personnel should understand the importance of GLP requirements and their individual responsibilities in achieving them.

2. Develop and implement procedures

Develop and implement robust procedures for all aspects of your laboratory operations. This includes SOPs for conducting experiments, performing tests, and documenting results. Procedures should be clear, concise, and consistent with GLP requirements.

3. Invest in training and education

Invest in training and education programs for your personnel. Ensure that all personnel have the necessary knowledge and skills to perform their tasks in compliance with GLP requirements. Provide regular training updates to keep personnel informed about changes and updates in GLP.

4. Implement quality control measures

Could you implement quality control measures to monitor the reliability and validity of your data? This includes regular checks of equipment, reagents, and test methods. Establish a system for identifying and addressing any deviations or errors that may affect the quality of your studies.

5. Maintain accurate and complete documentation

Accurate and complete documentation is a fundamental GLP requirement. Could you set up a documentation system that guarantees the traceability and integrity of all study-related data? Train personnel on proper record-keeping practices and implement electronic systems for documentation and record-keeping.

6. Conduct internal audits

Conduct regular internal audits to ensure ongoing compliance with GLP requirements. Internal audits help identify any non-compliance issues and provide an opportunity to correct them before external inspections. Please make sure that internal auditors are independent of the studies being audited and have the necessary expertise.

7. Prepare for external inspections

Prepare for external inspections by maintaining proper documentation and records. Be aware of the requirements and expectations of regulatory authorities in your country or region. Conduct mock inspections to assess your readiness and address any non-compliance issues.

8. Continuously improve and update

GLP requirements and best practices are constantly evolving. Continuously improve and update your laboratory practices to stay in line with the latest developments in GLP regulations.

Conclusion

Pharmaceutical laboratories are integral to ensuring the quality of medicinal products through activities like testing and reporting batch results. To maintain high standards, these laboratories must adhere to Good Laboratory Practice or GLP requirements.

Good control laboratory practice – G(C)LP, a subset of Good Manufacturing Practice (GMP), specifically addresses daily laboratory testing activities. Another subset of GLP, Good Clinical Practices (GCP), regulates clinical trials, prioritising patient safety.

Understanding the distinctions between GLP, G(C)LP, and GCP is important so you can focus on the set of requirements that will apply to your daily tasks.

Compliance to GLP requirements is crucial for laboratories involved in pharmaceutical research and testing. It ensures the reliability of non-clinical studies, minimising errors, enhancing data integrity, and improving research quality. GLP Compliance contributes to the safety of laboratory personnel and the environment.

Author: Kazi Hasan

Kazi is a seasoned pharmaceutical industry professional with over 20 years of experience specializing in production operations, quality management, and process validation.

Kazi has worked with several global pharmaceutical companies to streamline production processes, ensure product quality, and validate operations complying with international regulatory standards and best practices.

Kazi holds several pharmaceutical industry certifications including post-graduate degrees in Engineering Management and Business Administration.