GLP-GOOD LABORATORY PRACTICES AND REQUIREMENTS OF PREMISES AND EQUIPMENTS

GLP-GOOD LABORATORY PRACTICES AND REQUIREMENTS OF PREMISES AND EQUIPMENTS

General Requirements OF GLP :-

1. The laboratory or the organization it belongs to must have legal authorization to operate and be held accountable under the law.
2. The management is responsible for ensuring that the laboratory conducts its testing, calibration, validation, and other technical activities in compliance with Good Laboratory Practices (GLP) requirements.
3. The laboratory management should appoint a qualified individual, known as the quality manager or technical manager, to oversee all technical activities and implement a documented quality system. This individual should report directly to the top management.
4. The quality manager should create a schedule for technical audits of the laboratory to ensure GLP compliance. These audits should be conducted by experts appointed by the top management, who are independent of the laboratory’s in-charge. The quality manager should also ensure the maintenance of a documented quality system as outlined in the quality manual.

Premises for GLP:-

1. The laboratories should be designed, constructed, and maintained in a way that prevents the entry of insects, rodents, and cross-contamination.
2. The interior surfaces, including walls, floors, and ceilings, should be smooth, crack-free, and easy to clean and disinfect.
3. Adequate space and equipment should be provided for conducting necessary tests, as well as utilities such as water, power, and gas.
4. The air ventilation system should ensure a dust-free environment.
5. The laboratories should have sufficient lighting and ventilation. If needed, air-conditioning should be installed to maintain appropriate temperature and relative humidity, which should not negatively impact the testing and storage of drugs or the accuracy of laboratory equipment.
6. The drainage system should be designed to facilitate proper maintenance and prevent water logging in the laboratory.
7. Tabletops should be constructed using acid, alkali, and solvent resistant materials. They should also be smooth and free from crevices.

Personnel:

1. Staff members working in the laboratory must possess the necessary qualifications, undergo proper training, and have sufficient experience for their assigned duties.
2. It is mandatory to maintain a training record for all personnel in the laboratory.
3. The head of the laboratory should have a high level of professional expertise in drug analysis and laboratory management. They are responsible for:

(i) Ensuring the control and maintenance of documents, including the quality system, as per the requirements of regulatory authorities. This includes raw data, SOPs, documentation exhibits, protocols, training charts, etc.

(ii) Planning and organizing audits of the quality system, as well as initiating and following up on corrective actions, if necessary.

(iii) Investigating technical complaints.

(iv) Taking final responsibility for recommending any regulatory action in case of noncompliance with tested samples.

Equipment’s:

4. The laboratory should be equipped with all necessary types of equipment for carrying out various activities.
5. Analytical instruments must be housed in a dust-free environment, and conditions of temperature and humidity should be maintained as required. Regular checks on temperature and humidity should be conducted and recorded.
6. The instruments, instrument bench, and surrounding areas should be kept clean and tidy at all times.
7. Instruments that require calibration should be calibrated at regular intervals, and records of such calibration or maintenance should be maintained. Standard Operating Procedures should be in place for the operation, maintenance, and calibration of these instruments.

Equipment records must be maintained and should include the following information:

1. Name of the equipment, machine, or apparatus.
2. Manufacturer’s name, model number, and type of identification.
3. Serial number.
4. Date when the equipment was received in the laboratory.
5. Current location of the equipment.
6. Condition of the equipment when received (e.g., new, used, re-conditioned).
7. Copy of the manufacturer’s operating instructions.
8. Frequency of calibration.
9. Frequency of maintenance.
10. Log Book with day-to-day entries, including the equipment’s status.
11. Staff responsible for monitoring the calibration and maintenance status of the equipment.
12. Calibrating records.
13. List of authorized users or operators, if applicable.
14. History of any damage, malfunction, modification, upgrade, repair, and calibration.
15. List of spares and accessories, if any.

(f) It is necessary to maintain a progress register for non-functional equipment and take appropriate action for the procurement of spares and accessories. Additionally, the monitoring of this process should also be documented.

(g) The laboratory should develop a Standard Operating Procedure for the preventive maintenance of machines, equipment, or apparatus. This procedure will ensure that regular maintenance activities are carried out effectively.

(h) Before accepting and using equipment such as burettes, pipettes, volumetric flasks, weight boxes, thermometers, etc., it is essential to conduct a thorough check to ensure the accuracy of calibration. This step is crucial for maintaining the quality and reliability of measurements.

(i) To ensure proper maintenance of equipment, it is imperative to prepare Maintenance Procedures in the form of Standard Operating Procedures. These procedures should be followed by the maintenance engineer or specialist, and regular servicing must be performed accordingly.

(j) Any equipment or instrument that produces anomalous results or is defective should be clearly labeled as “out-of-order” until it is repaired. After the instrument is repaired, it must undergo calibration before being used again to ensure accurate and reliable results.

(k) Competent individuals should be responsible for handling the maintenance of equipment related to services such as electricity, gas, water, steam, and compressed gas. This ensures that these essential services are properly maintained and function efficiently.

(l) Autoclaves used in the laboratory must meet specific requirements for operations, safety, and validation procedures. The laboratory should record the validation process carried out to ensure that the autoclaves meet the necessary standards.

Chemicals and Reagents:

1. Chemicals and reagents should be stored and handled in a manner that takes into account their physicochemical properties and the potential hazards associated with their use.
2. Proper labeling is required for all reagents and solutions in the laboratory.
3. The laboratory should maintain a standardization register, along with raw data and Standard Operating Procedures, for the preparation and standardization of stock solutions, standard solutions, and volumetric solutions. This is to provide guidance for the staff.
4. Containers of stock solutions and standard solutions must include the name of the analytical chemist who prepared the solution, the date of preparation, a “use before date” for each volumetric solution based on its stability, and standardization records.
5. When transferring hazardous chemicals and reagents from one container to another, it is important to use appropriate equipment and prioritize safety. Make-shift or hazardous methods should not be used.

Good housekeeping and safety.-

(a) Each staff member shall receive both general and specific written instructions for safety, which will be periodically revised as necessary. These instructions may be circulated through various means such as poster displays, audio-visual materials, seminars, or conferences.

(b) A Standard Operating Procedure for safety, housekeeping, and loss prevention shall be developed in accordance with the rules and regulations of the Government of India. This procedure shall include the following requirements:

(i) Prior to conducting any testing, safety data sheets must be made available to staff members.

(ii) Eating, drinking, and smoking are strictly prohibited in the laboratories. Additionally, no food intended for human consumption should be stored or kept in the working or storage areas.

(iii) Staff members must wear appropriate protective clothing, including laboratory coats, gloves, face masks, and eye protection, whenever necessary.

(iv) The laboratories should be equipped with sufficient first aid kits and firefighting equipment, strategically located in the appropriate areas. Staff members should be familiar with the use of firefighting equipment, including fire extinguishers, fire blankets, and gas masks.

(v) Operators conducting sterility tests must wear sterilized garments, including headgear, face masks, and shoes.

(vi) Staff members should receive education and training in first aid techniques, emergency care, and the use of antidotes.

(vii) Safety rules regarding the handling of compressed gas cylinders, including the observation of relevant color identification codes, must be strictly followed by the staff.

Protective Precautions to be taken in Laboratories:

3. In order to ensure safety in laboratories, it is essential to implement protective precautions. Firstly, water showers should be installed at appropriate locations within the laboratory. This will enable quick and effective response in case of any accidents or chemical spills.
4. Another important precaution is the use of rubber suction bulbs on manual pipettes and siphons. This helps to prevent any potential contamination or exposure to hazardous substances during laboratory procedures.
5. It is crucial to provide clear warnings, precautions, and written instructions for tasks involving violent, uncontrollable, or dangerous reactions. This includes activities such as mixing water and acids, as well as handling infectious agents. By doing so, the risk of accidents or mishaps can be minimized.
6. Adequate facilities for the collection, storage, and disposal of laboratory wastes must be made available. This ensures proper management of potentially harmful substances and prevents any environmental or health hazards.
7. Staff members should be well-informed about safe disposal methods for corrosive or dangerous products. This includes neutralization or deactivation techniques, as well as the complete disposal of mercury and its salts. By following these guidelines, the risk of harm can be significantly reduced.
8. Additionally, it is crucial for staff to be aware of the safety precautions when handling potassium cyanide and cyanogen bromide. These substances are highly toxic and require special care to prevent any accidents or exposure.
9. Lastly, it is recommended to develop a Standard Operating Procedure (SOP) for the handling, collection, and disposal of chemical and biological wastes. This SOP will serve as a comprehensive guide for laboratory personnel, ensuring consistent and safe practices are followed.

Maintenance, calibration, and validation of equipment:

(a) All equipment, instruments, and other devices utilized in the laboratory must adhere to appropriate methods and procedures for all tests or calibrations, and they must undergo regular calibration and validation. The calibration frequency may vary depending on the specific instrument.

(b) In determining the calibration frequency, it is important to consider the recommendations provided by the original equipment manufacturer, as well as the expertise of the laboratory staff and the frequency of equipment usage.

(c) The laboratory should develop Standard Operating Procedures and a calibration schedule for most equipment and instruments. Additionally, each laboratory should maintain a logbook to ensure proper documentation of calibration results.

Reference materials:-

Reference materials are essential for the testing, calibration, validation, or verification of samples and equipment. These materials must be traceable to an agency authorized by the Government of India or any other international body.

The laboratory is responsible for preparing working standards by comparing them with the reference standards. These working standards should be regularly checked for their purity, considering parameters such as identity, loss on drying or water, impurity, and assay.

When a new reference material is received, the laboratory must assign a code number to it. This code number should be mentioned in the laboratory notebook and analytical work sheet. The working standard should also have an identification code.

To keep track of reference and working materials, the laboratory must maintain a register. This register should include details such as the source of supply, code number of the reference material, date of receipt, batch number or identification number of the supplying agency, assay value, water content, storage condition, date of expiry (if applicable), and date of manufacturing (if available).

All working standards should be checked at appropriate intervals or before use to ensure that they have not deteriorated or decomposed during storage. These observations should be recorded in the register. Additionally, all reference and working standards should be stored under appropriate storage conditions. If storage between 2-8°C is recommended, a refrigerator should be used. Freezing may not be allowed for certain materials, as indicated by the recommendations.

Microbiological Cultures:-

1. Laboratories must prepare a Standard Operating Procedure for the maintenance and sub-culturing of microbial cultures.
2. In the event that the cultures have become non-viable or mutant, a proper procedure should be followed to destroy them through autoclaving, under the supervision of authorized personnel for biological testing. It is recommended to limit the number of passages to five.
3. All activities related to microbiological cultures should be conducted in an aseptic area by authorized individuals.
4. The laboratories are required to conduct standard biochemical tests on the sub-cultures, as described in the literature, in order to ensure their viability.

The quality system is intended to achieve the following goals:

1. The measurements and calibrations must fully adhere to the compendial requirements, and the methods used must be based on validation protocols that have been proven effective.
2. It should be efficient in ensuring that the activities, processes, techniques, or practices align with the planned arrangements.
3. It aids in the early identification and rectification of non-conformities.
4. Appropriate remedial actions are taken based on the findings from internal and external audits.
5. The organization must have a documented quality policy in place.

Internal quality system audits.-

(a) Internal quality system audits are conducted periodically with a predetermined schedule and procedure, using an appropriate checklist. These audits are essential to ensure the integrity of the analysis and to verify that operations continue to comply with the requirements of the quality system and regulatory authorities. Trained and qualified personnel, who are independent of the activity being audited, carry out these internal quality audits.

(b) The Head of the laboratory determines the frequency of the quality audits, ensuring that each activity is audited at least once a year.

(c) It is the responsibility of the Head of the laboratory to initiate corrective actions based on the findings of the audits and to verify the implementation of these corrective actions.

(d) In case of any non-compliance or deviation from the quality policy or quality system protocols, the Quality Manager will address the issue. The problem will be thoroughly analyzed, and appropriate actions will be taken, with proper documentation.

(e) The Quality Manager is responsible for maintaining records of all conducted analyses, including details such as the test system, type of analysis, and date of analysis. Additionally, the Quality Manager keeps copies of all protocols related to the activities checked by the audit team.

Management review –

Management shall conduct quality system reviews on a yearly basis, with the agenda typically including the following items:

1. Internal audit reports or input
2. Matters arising from previous reviews
3. Reports from external audits, if applicable
4. Surveillance reports, if applicable
5. Results of proficiency testing
6. Complaints or feedback received from laboratory service users
7. Details of in-house quality control checks
8. Identification of any necessary amendments to the quality system and documentation
9. Induction training for new staff
10. Any other requirements specific to the laboratory.

Standard Operating Procedures:-

Standard Operating Procedures are written protocols for various activities carried out in a laboratory. These procedures should possess the following characteristics:

They should be organized in a sequential manner, listing the different steps involved in drug analysis or instrument calibration.

Testing laboratories must have Standard Operating Procedure manuals and regularly review them.

The documents should be user-friendly and clearly designate the person responsible for each activity.

In addition to the recommended procedures for different activities, Standard Operating Procedures should also be prepared for the following minimum requirements:

Handling and accountability of samples.

Receipt identification, storage, mixing, and method sampling of test and control articles.

Record keeping, reporting, storage, and retrieval of data.

Coding of different studies and handling of data, including the use of computerized data systems.

Operation of technical audit personnel in conducting and reporting audits, inspections, and final report reviews.

Regular inspection of instrument cleaning, maintenance, testing, calibration, and standardization.

Actions to be taken in case of equipment failure.

Analytical data methods.

The raw data.

Data handling and storage retrieval.

Health and safety protection.

Preparations for animal rooms.

Storage and maintenance of microbial cultures.

Maintenance of sterility rooms, including constant monitoring and maintenance of aseptic conditions.

Use and storage of reference standards.

Procurement of supplies and equipment.

Monitoring of sample testing.

Method of retaining unexpended samples, their location, maintenance, and disposal.

Document control.

Resolution of technical complaints.

Housekeeping.

Corrective and preventive actions.

Working procedures for test methods.

Calibration manual.

Training manual.

Protocols and specifications.-

(a) Each laboratory must maintain an archive of protocols and specifications. The current versions of all necessary specifications should be stored in accordance with the requirements of the Act, the rules made under it, and the National Pharmacopoeia (Indian Pharmacopoeia).

(b) To prevent the use of outdated sections, all updates and corrections should be recorded in the master volumes of Pharmacopoeias. Additionally, supplements and addendums should be made accessible in the laboratory.

(c) The specification archive should include the following:

(i) A list of all the pharmacopoeias.

(ii) A file containing test methods for patent and proprietary medicines (non-Pharmacopoeia) that have been prepared and validated by the manufacturer or the laboratory itself. These test methods should be submitted to the relevant Drug Control Authority. The validated test methods developed by the manufacturer or the laboratory must meet the requirements of compendial parameters, such as precision, accuracy, reproducibility, specificity, linearity, and ruggedness, etc.

Raw data:-

(a) Raw data encompasses various forms of information collected during laboratory work, such as laboratory work sheets, note books, analysis sheets, records, and other related activities. This includes handwritten notes, photographs, software, drawings, computer printouts, spectral charts, dictated observations, or recorded data from automated equipment. Additionally, raw data comprises records of animal receipt, results of environmental monitoring, calibration, equipment records, integrator output from analytical equipment, and even the work-sheet used to read a note. It also encompasses information obtained from the Light Emitting Diode (LED) display of any equipment.

(b) When making changes to data, a single line should be drawn through the information being modified. The correct information should then be recorded alongside the old data, and the reason for the change should be documented. The analyst responsible for the change must sign and date the entry. In the case of automated data collection systems, the person accountable for the data output should be identified. It is crucial to preserve the original entry, and the system should have an audit trail to track all data modifications.

(c) It is imperative to uphold data integrity and security, ensuring that unauthorized individuals cannot access the data.

Storage and archival.-

(a) The residual sample must be stored appropriately for a duration of one year following the issuance of the final report.

(b) The laboratory is required to establish and maintain procedures for the identification, collection, indexing, retrieval, storage, maintenance, and disposal of all quality documents.

(c) All raw data, documentation, Standard Operating Procedures, protocols, and final reports must be retained, and there should be designated archives for organized storage and efficient retrieval of these materials. The archives must provide a suitable environment to prevent any modification, damage, deterioration, or loss.

(d) The storage conditions for original documents must ensure their security and confidentiality.

(e) Prolonged exposure to high humidity should be avoided for paper documents, while raw data in the form of tapes and discs must be carefully preserved.

(f) If only optical discs are being stored, their lifespan should exceed the storage duration.

(g) Raw data on thermal paper may fade over time; therefore, a photocopy of the thermal paper must also be retained in the archive.

(h) The duration for which records are retained should be specified in the relevant documents.

Good Manufacturing Practices (GMPs)