Good Laboratory Practice is not less important than Good manufacturing practice. In the manufacturing of drugs, overall Control is essential to ensure that the customer receives drugs of high quality. As a result, there should be a comprehensive system that is well-designed, documented, implemented, and controlled, as well as well-equipped to provide assurance that the product will be consistent of quality, appropriate to their use. Three types of laboratory facilities are necessary for assuring the quality of pharmaceutical products like parenteral preparations, liquid orals, capsules, tablets, ointments, creams, gels, dry syrups, etc.
Guideline for Good Laboratory Practice:
Good Laboratory Practices is concerned with the Organizational processes and conditions under which laboratory tests are planned, performed, monitored, recorded, archived, and reported. Adherence by test facilities to the principles of GLP ensures proper planning of tests and the provision of adequate means to carry them out. It facilitates the proper conduct of tests, promotes their full and accurate reporting, and provides means whereby the validity and integrity of the tests and analytical data can be verified 1. Objective 2. Scope 3. Personnel 4. Facilities 5. Documentation 6. Calibration 7. Out of Specification 8. Validation to Analytical. Methods 9. Change Control 10. Laboratory Reagents and Reference Standards 11. Safety 12. Training 13, Quality Audit 14. Management Review
Compliance with GLP is a regulatory/ legal requirement for the acceptance of certain types of studies undertaken by facilities to be submitted to Regulatory/Health Authorities for risk assessment in Health and Environmental Safety. For example, in the UK, the Good Laboratory Practice Monitoring Authority (GLPMA) enforces compliance. The GLP regulations require that any test facility that conducts intends to conduct a “regulatory study” must be a member, or prospective member, of the UK Good Laboratory Practice Compliance program.
There are, however, test facilities that undertake studies, usually as part of a manufacturing company. (Tests) which are not “regulatory studies” This document is intended for such facilities. Besides this, in the arena of Life Sciences, whether in Research or Development or Manufacture, good testing is a must for building confidence that the basis of GMP and product Assessment is Logically and scientifically correct.
However, the various branches of Life Sciences need such specific testing facilities from recombinant DNA testing to Pharmacovigilance that it will not be possible to cover all such esoteric testing facilities. This document, therefore, provides the basic requirement in the running of a general testing Laboratory in terms of good practices. The objective is to facilitate the proper application and interpretation of GLP principles in a generic manner.
This document is intended to assist the Organization in applying and interpreting the GLP principles correctly. And for the Management of a Quality Control Laboratory and to provide guidance for the appropriate application of Good Laboratory Practice principles to testing. This guidance document is organized in such a way as to provide easy reference to the GLP principles.
The Test Facility must have adequate Personnel with the required qualification, experience, and training (and Approval from regulatory authorities wherever needed) to carry out the assigned functions in a timely manner According to the principles of GLP.
A Job Description of every category/level of Personnel in the Test Facility must be maintained. This should include everyone who is involved in testing, analyzing, or monitoring the analysis.
The training record for every individual is cross-referenced with the Job description and Departmental training. Material Safety Data Sheet must be available. The Test Facility Manager must have sufficient educational background, experience, and authority to ensure that the Principles of GLP have complied within the test facility.
The Manager will. Ensure that the Personnel clearly understand the functions they are to perform and, where necessary, provide training for these functions. The Indian Drugs and Cosmetics Act and Rules there under requires that each area of operations in the Laboratory has an “approved” person (competent technical Staff) to conduct the tests and/or sign off the documentation.
- FACILITIES ACCESS TO PRODUCTION
The Lab facility should ideally be situated with direct access to Personnel working in them. The manufacturing area shall be separated and should be separated from manufacturing areas.
This is particularly important for laboratories involved in the Control of biological and microbiological, which should also be separated from each other. Steps should be taken in order to prevent the entry of unauthorized Personnel. The area must not be used as a right of way by Personnel who do not work in them.
Laboratory personal, however, must have access to production areas for sampling and investigation as appropriate. Facilities should be designed to suit the operations to be carried out in them. Lighting, temperature, RH, and ventilation area should be appropriate and such that they do not directly affect the products being tested or their functioning instruments.
If sterility testing is conducted, then the area should mimic the aseptic production conditions and gowning and entry procedures, with the final stage of the changing room being, in the at-rest state, of some air quality/ air classification as that into which it finally opens, viz. the aseptic testing area. Sterility test must be performed under Grade A conditions, typically in a Laminar Air Flow Module, placed in class 100 conditions to avoid mix-ups and cross-contamination. There shall be Sufficient space should be available.
There should be adequate storage space for samples and records. All laboratory instruments and equipment should be qualified and calibrated in accordance with the manufacturer’s recommendations and pharmacopoeial requirements.
All the test instruments and equipment must have unique identification numbers (for their use, cleaning, calibration, service, and maintenance) that can be linked to raw analytical data, calibration reports, and logbooks.
Separate rooms which are climate controlled may be necessary to protect sensitive instruments from that electrical interference, humidity, vibrations, etc. Control samples or reference samples also will need a separate room that is equipped with temperature and humidity control capable of achieving the same storage conditions as stated on the labels of the materials being tested.
Proper consideration should be given to ventilation requirements of the areas depending on the activities carried out therein, e.g. extraction, handling of fuming chemicals, solvents, distillation involving heating, etc. PPE should be worn by Personnel in the lab. Ideally, a Lab coat is advised for Personnel.
If part or all of the testing is contracted out and a contract testing laboratory is used, this should be audited and approved based on compliance with Good Laboratory Practice. A technical agreement must be in place between the contract giver and the contract acceptor with a system inside updated authorized analytical methods and specifications for the analysis in pace to pro evolved. A change control system must also be in place with the contract testing laboratory.
The availability of a complete set of standard operating procedures necessary to govern all the activities and procedures in the test facility is an absolute requirement.
They define how to carry out protocol specificities. They should in chronological order listing different steps in the accomplishment of an activity. There must be a Clear mention of responsibilities. SOPs must remain user-friendly. Major consideration should be given to the degree of details incorporated in them. Some of the key SOPs which need to be addressed include
- Samples handling and accountability,
- Receipt of materials, identification of materials, storage condition, method of sampling of test and control articles.
- Recordkeeping, reporting, storage, and retrieval of data.
- Operating of technical audit personnel in conducting and reporting audits, inspections reports, reviews.
- Routine inspection of cleaning, maintenance, testing, calibration of equipment.
- Handling of Out of Specification (the 00S) results.
- Calibration management.
- Validation of analytical methods.
- Change control procedure.
- Health and safety protection.
- Animal room preparation and animal care.
- Storage, maintenance, and traceability of microbial cultures.
- Storage, use of reference standards, and Reagents.
- Laboratory waste handling.
There must be an SOP in the Laboratory for glassware cleaning, and it should be based on glassware washing efficiency both related to chemical labs and micro labs. Sensitive items like cells for photometry readings. Must-have cleaning procedures that demonstrate adequate cleaning.
All documents used should be reviewed, authored prior to use. In case of software and processes used should be validated and suitable measures put in place to ensure controls over passwords. Documents should be reviewed periodically and revised whenever needed to ensure continuing suitability.
Invalid or supersedes documents must be promptly removed or otherwise assured against unintended use. Changes to documents should be reviewed and approved by the same function that performed the original review. Procedures should be established to describe how changes in documents in computerized Systems can be made and controlled.
Additionally, clear-cut procedures must be evolved for ill storage, distribution, retrieval, and destruction of documents. Provision must be made to retain raw data, SOPs, documents, final reports for a predetermined period. There should be archives for orderly storage and expeditious retrieval. Conditions of storage should minimize deterioration. Persons responsible for archiving must be identified, and only authorized persons must enter the archives.
Raw data should be recorded on duly controlled raw data sheets or repaginated authorized logbooks. It should be verified independently by another competent person. The raw data, including the automated instrument printouts, should be immediately signed and dated by the QC officer who Performing the test. The data stored on temporary storage media (e.g., thermal paper) should be transferred to robust storage media ( e.g. Photocopy or scan of the printout) and duly authorized, establishing traceability to the original raw data. Data should be recorded wherever Possible so as to facilitate trending.
Tests performed must be recorded, and the records should include at least the following data:
- Name of the material and Batch no. where applicable dosage from.
- Reference to the relevant specifications and test procedures
- Test results, including any observations and fair calculations, and reference to any Certificates Analysis
- Date of testing.
- Must have Initials of the person that performed the test.
- Initials of the person who verified the testing and the calculations where appropriate.
- A clear statement of the status decision (release or reject etc.) and the dated signature of the designated Facility Manager or Responsible Person.
All test and measuring equipment are likely to influence the test results directly or indirectly and be subject to calibration.
The frequency of calibration depends on the instrument, the recommendation from the manufacturer, laboratory experience, and extent of use Procedures employed for calibration must be clearly written down, and the test report must conclude with a statement of “status”.
In case of noncompliance, the report must indicate corrective and preventive action. All the test instruments and equipment must have a unique identification number that should be linked to raw analytical data, calibration reports, and logbooks for their use.
Calibration certificate/ calibration record/ calibration report should carry a unique identification number, the name, and address of the agency, if the outside expert is involved, in addition to the identification and description of a test procedure, including traceability to primary standards if used.
The certificate should also indicate the calibration results and the due date for the next calibration. There shall be calibration tags on instruments. Wren, an instrument for calibration, has been adjusted or replaced. The calibration results before and after repair, if available, should be reported.
Reference materials used must be characterized, certified, purchased From prominent sources, and attributable to national and international measures. When an instrument is found “Out of Calibration”, it should be conspicuously labelled as such so that its use for testing is prevented.
The test results between non-compliant calibration results and List successful calibration should be reviewed to confirm the correctness of the test result reported, and appropriate action should be taken used on the outcome of the investigation. in case of frequent failures, the frequency of calibration and preventive maintenance should be reviewed, and if necessary
7. OUT OF SPECIFICATION (OOS)
Out of Specification (the OOS), results are those results generated during testing that do not comply with the relevant specification or standards or with the defined acceptance criteria, if at any time during the process of study or testing, the result is obtained that is out of specification is considered “atypical” (for example during stability testing) a defined procedure should be followed to identify and investigate the result and find the course of action.
The objective of the procedure is to ascertain if the OOS result or atypical result is valid and if the result is valid to determine its probable cause and impact. The OOS or atypical results can arise from causes that can be categorized.
- Laboratory Error
- Operator error-Non process-related
- Process Related – Manufacturing Process Error
The first stage of the procedure is a laboratory investigation to determine if the OOS is clearly assignable to laboratory error. If so, then the result may be discarded and the test repeated. If the OOS is not clearly due to Laboratory, error them the investigation is expanded outside the laboratory testing and can include re-sampling.
The aims of expanded investigation are to identify the probable cause of the OOS or atypical result and to determine the significance of the result when making decisions about the material or product under test. Under certain circumstances, there may be Justification for not following the above procedure when OOS or Atypical result is obtained. Examples of such situations include, but are not to limited to:
- Pharmacopeia specifications that give specific guidance in test-like content Uniformity, Dissolution, Sterility Testing, etc.
- The Stability Testing, where prediction from trend analysis indicates that the result is valid.
- OOS is supported by results for other tests like low assay with the high result for impurify content.
- Investigation of OOS for a starting material, raw material, or intermediate rimy, where justified, be restricted to a consideration of the suitability of the material for processing.
In circumstances where the SOP is not followed, Justification must be documented and approved by the Head of the department.
8. VALIDATION OF ANALYTICAL METHODS
All analytical methods, particularly non-standard and in-house lest methods, must be validated by a laid down procedure. All analytical equipment must be appropriately qualified before method validation.
To ensure Good Laboratory Practice, The degree of validation should reflect the purpose of the analysis and the type of product being tested. For example, there should be an increasing degree between packaging materials, raw materials, intermediates, and finished product, clinical trial materials. The validation methodology must clearly be documented and should include:
- Selectivity and specificity
- Linearity and range
- Limit of detection
- Limit of quantification
A record must be maintained of any modification of the validated method and should include the reason for modification and appropriate data to verify that results are as accurate and reliable as the established method.
The suitability of all methods should be verified under actual conditions of use documented. In addition, it would also be ‘useful to perform an inter-laboratory comparison of results periodically.
9. CHANGE CONTROL
All changes in equipment, test environment, test method, services, systems, or location that may affect reproducibility, accuracy, or standards must be formally requested, documented, and accepted. The impact of the change should be classified, and the change control procedure should be there to ensure that sufficient supporting data are generated to determine that change does not affect the and result or the in-house or registered specifications.
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10. LABORATORY REAGENTS and REFERENCE STANDARDS
There must be written procedures in place for the handling of reagents and preparation o standard solutions. A primary standard is one that has been shown by an extensive set of analytical tests to be authentic material of established quality.
This standard may be obtained from a recognized source (like USP, BP, etc.) or may be prepared by independent synthesis or by further purification of existing production material.
An “in-house primary standard” is an appropriately characterized material prepared by the manufacturer from a representative lot for the purposes of physicochemical testing of subsequent lots and against which in-house reference material is calibrated. A “secondary standard” is a substance of established quality, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.
Dates should be mention on Reagents as soon as received and a “use by” date assigned based on experience or alternatively a short date (1 year) and first assigned, which can then be extended based on retesting. Laboratory reagents planned for prolonged use should be the date of preparation and the signature of the officer who prepared them. There shall be mention of expiry date label on the reagents, and culture media should be indicated on the label, together with specific storage conditions.
In addition, for volumetric solutions, the last date of standardization and the last current factor should be indicated. Reagents and chemicals should be stored by their hazard class and not in alphabetical order. For example, storage should be by segregating into groups of oxidizers, reactive, corrosives.
11 . SAFETY
Safety is most important for Good Laboratory Practice. People who work in scientific laboratories are exposed to many kinds of hazards. This can be said of most workplaces; in some, the hazards are well recognized (those of ordinary fire, for example), and the precautions to be taken are obvious.
The Laboratories must be equipped with adequate extinguishers, personnel protective equipment (PPE), Safety Shower, Eyewash, and First Aid Kits. The design should facilitate the change of street clothes and footwear to specific (PPE) needed by the laboratory personnel.
No employee should work alone in a laboratory or chemical storage area when performing a task that is considered usually hazardous by the laboratory supervisor or safety officer. Clothing worn in the Laboratory should offer protection from splashes and spills, should be easily removable in case of an accident, and ideally should be fire-resistant.
No food, beverage, or cosmetic products should be allowed in the laboratory or chemical storage area at any time. Laboratories using cylinders compressed gas should ensure that they are safe on the wall or placed in a holding cage to prevent tipping.
In summary, careful procedures are necessary for handling the various compressed gases, the cylinders containing the compressed gases, regulators or valves used to control glow, and the piping used to confine gases during flow. Ideally, Cylinders are placed outside of labs, with labelled piping identifying the gas.
Storage of flammable solvents should be kept to a minimum, and cabinets used to hold flammable liquids should be appropriately handled and maintained, with only suitable ingredients being stored together.
The record must be maintained of persons who are adjudged competent and authorized, including date of authorization to perform a specific task such as sampling, testing, calibration, operating, typical equipment, issuing of test reports, etc. in addition, the records of their educational and professional undergone, skills, and experience shall also be maintained for Good Laboratory Practice.
13. QUALITY AUDIT
To ensure that tests are performed correctly, the testing facility should have a documented Quality Assurance (QA) Program/studies performed are in compliance with these principles of good Laboratory Practice. The QA program or Self Audit should be carried out by an individual or by individuals who are designated by and directly responsible to the Facility Manager and who are thoroughly familiar with the test procedures. These individuals must not be involved in the conduct of the study/test being assured. The responsibilities of these QA/Audit personnel include, but are not limited to, the following functions;
- Maintain a copy of all approved test methods/study plans and SOPS in use in the test facility.
- Verify that the test methods/study plans contain the information required for compliance with these principles of Good Laboratory Practice.
- Conduct audits and inspections to ensure that tests are carried out in compliance with these GLP standards. Inspections can be of three types as specified by the QA SOP:
- Study/Test-based inspection
- Facility-based inspection
- Process-based inspection
- Document and retain records of all inspections.
- Inspect the final reports to confirm that the methods, procedures, and observations an accurately and completely described and that the reported results accurately and completely reflect the raw data of the studies/tests.
14. MANAGEMENT REVIEW
The management of the test facility has the responsibility to ensure Promptly report inspection results in writing to the corrective action is put in place if necessary. The ultimate obligation for ensuring that a test facility works in conformity lies with its management with the Good Laboratory Practice principles.
This will involve the implementation of a Quality Assurance or Quality Audit program, which is independent of the actual conduct of qualification, training facility Manager test/study and is designed to assure the test facility management of compliance principles of Good Laboratory Practice.
Normally an inspector from a Regulatory Agency will not request to see an actual report of audit as such requests could inhibit auditors when preparing inspection reports. It is sufficient to show that a program of self-audit exists through documented evidence and to Qhow that a procedure for corrective action is also in place.