Royal Decree 2043/1994 of 14 October 1994 incorporated into our legal order Directives 88 /320/EEC of 9 June 1989 and 90 /18/EEC of 18 December 1989 laying down the procedure for the inspection and verification of Good Laboratory Practice.

Commission Directive 1999 /12/EC of 8 March 1999 has amended Directive 88 /320/EEC, adapting to technical progress for the second time the Annex to that Directive in accordance with the Decision of the Council of the European Union. The Committee on Economic Cooperation and Development (OECD) dated 9 March 1995.

As a consequence of the previous adaptation, this Order replaces the annexes of Royal Decree 2043/1994 of October 14, by a single annex, incorporating into our legal order Directive 1999 /12/EC.

This Order is issued under the terms of the final provision of Royal Decree 2043/1994 of 14 October 1994.

In its virtue, on a proposal from the Ministers of Health and Consumer Affairs, Industry and Energy and Agriculture, Fisheries and Food, prior to the report of the Inter-Ministerial Commission for Food and Ear affected, I have:

Single item. Adaptation to technical progress of the procedure for inspection and verification of Good Laboratory Practice.

Annexes A and B to Royal Decree 2043/1994 of 14 October 1994 are replaced by the following Annex.

Single additional disposition. Regulatory enablement.

This Order is issued under the terms of the final provision of Royal Decree 2043/1994 of 14 October 1994.

Single end disposition. Entry into force.

This provision shall enter into force on the day following that of its publication in the Official Gazette of the State.

Madrid, 14 April 2000.

ALVEZ-HELMETS FERNANDEZ

Excms. Mr Ministers for Health and Consumer Affairs, Industry and Energy, Agriculture, Fisheries and Food.

ANNEX

Provisions for the Inspection and Verification of Good Laboratory Practices (GLP)

The provisions for the inspection and verification of the GLP contained in Parts A and B are those contained in Annexes I respectively (Guidelines on the procedures for the control of compliance with the Good Laboratory practices) and II (Guidelines for conduct in inspections of test facilities and study checks) of the Decision-Recommendation of the OECD Council on the implementation of the Principles of Good Practice Laboratory [C (89) 87 (Final)] of 2 October 1989, according to the OECD Council Decision "By amending the Annexes to the Decision-Recommendation of the Council on the implementation of the principles of good laboratory practice" [C (95) 8 (Final)] of 9 March 1995.

PART A

Guidelines for the procedures for monitoring compliance with Good Laboratory Practice (GLP)

The purpose of this part of the Annex is to provide detailed practical guidance on the structure, mechanisms and procedures to be adopted when establishing compliance monitoring programmes. Good Laboratory Practices, so that the respective programs are acceptable internationally.

The legal framework for GLP refers to chemical substances of different nature, which motivates the existence of more than one control organ, which can lead to more than one program of compliance. The guidance given in the following paragraphs refers to each of these authorities and to each compliance programme, as appropriate.

1. Definition of terms. This part of the Annex applies to the terms defined in the OECD's "Principles of Good Laboratory Practice", adopted pursuant to Royal Decree 822/1993 of 28 May 1993, for which the establish the principles of Good Laboratory Practice and its application in the conduct of non-clinical studies on chemicals and substances. The following definitions apply to you:

GLP Principles: The Principles of Good Laboratory Practice consistent with the OECD principles adopted under Royal Decree 822/1993 of 28 May.

Control of compliance with GLP: periodic inspection of laboratories and/or verification of studies in order to verify compliance with GLP principles.

GLP compliance program: Specific plan established to monitor, through inspections and study checks, the compliance of the GLP by the existing laboratories in the Spanish territory.

BPL control body: The management bodies of the State and the Autonomous Communities shall be understood as such with the task of supervising the compliance of the GLP by the laboratories existing in the the Spanish territory, and to carry out the other functions related to GLP to be determined at national level.

Laboratory Inspection: In situ examination of the procedures and practices of the laboratories, in order to assess their degree of compliance with the GLP principles.

In the inspections, the administrative structures and the Standards of Work of each laboratory are examined, interviews with the technical staff are maintained and the quality and integrity of the data are evaluated. generated by the laboratory, presenting a report of all this.

Verification of studies: Comparison of primary data and corresponding records with interim and final reports, to determine whether the primary data has been accurately collected in the report and whether the tests have been carried out in accordance with the protocol and standard working procedures, in order to obtain additional information not provided in the report, and to determine whether or not the data have been used to undermine their validity.

Inspector: Person conducting laboratory inspections and verification of studies on behalf of BPL control bodies.

Degree of compliance with GLP: degree of fidelity of a laboratory to the GLP principles, evaluated by the control bodies of the GLP.

Regulatory Authority: Bodies of the General Administration of the State with legal powers in certain aspects of the control of chemical substances.

2. Elements of the procedures for monitoring compliance with GLP.

A) Administration: The implementation of a program of compliance with Good Laboratory Practice is a task for a properly constituted management body, with its own legal identity, with sufficient staff and to act within a well-defined administrative framework.

The competent authorities by reason of the matter shall be in charge of:

1. To ensure that the control bodies of the GLP are directly responsible for an adequate team of inspectors possessing the necessary technical and scientific competence, or that they are ultimately responsible for such equipment.

2. Publish documents relating to the adoption of GLP principles.

3. Release documents with detailed information about the GLP compliance program, including information on the legal or administrative framework within which the program operates, as well as references to published laws, regulatory documents (regulations, codes of practice, etc.), inspection manuals, guidelines, frequency of inspections, criteria for inspection programmes, etc.

4. To carry a file of the laboratories inspected (and their degree of compliance with the GLP) and of the verified studies, conceived to meet national and international needs.

(B) Confidentiality: The control bodies of the GLP will have access to very valuable information from the commercial point of view and it may occur that, on occasion, they should remove sensitive documents from a laboratory. commercial or make detailed mention of them in their reports.

The competent authorities by reason of the matter shall, where appropriate:

1. Adopt provisions for the preservation of the confidential nature, not only by the inspectors, but also by any person who has access to confidential information due to compliance control activities of the GLP.

2. The reason why, unless all sensitive and confidential information of a commercial nature has been removed, the reports on laboratory inspections and study checks are only made available to the public. (a) regulatory authorities and, where appropriate, laboratories inspected or interested in the conduct of studies and the promoters of studies.

C) Personnel and training: BPL control bodies should:

1. Vellar why the number of available inspectors is sufficient.

The required number of inspectors will depend on:

(a) The number of laboratories participating in the GLP compliance programme.

(b) The frequency with which the degree of compliance by the laboratories is to be judged, c) The number and complexity of the studies carried out by the laboratories.

(d) The number of inspections or special checks prescribed by the regulatory authorities.

2. Vellar why the inspectors have adequate qualifications and training.

The inspectors must be qualified and have practical experience in the range of scientific disciplines of interest for chemical testing. The control bodies of the GLP must:

(a) Make provision for the proper training of inspectors, taking into account the particular qualifications and experience of the inspectors.

b) Foster consultations with staff of the BPL control bodies of the other EU Member States and, in particular, joint training activities, where necessary, to promote harmonisation (a) international activities for the interpretation and application of the GLP principles, as well as for monitoring compliance with these principles.

3. Ensure that inspection personnel, including contracted experts, have no economic or other interest in the laboratories inspected, verified studies or companies sponsoring such studies.

4. Depart the inspectors of an identification means (for example, an identity card).

The inspectors can be:

(a) Members of the permanent staff of the control bodies of the GLP.

b) Members of the permanent establishment of a body other than the control bodies of the GLP.

(c) Employees by contract, or other form, by the BPL control bodies to carry out inspections of laboratories or verifications.

In the latter two cases, the control bodies of the GLP shall be responsible for determining the degree of compliance of GLP by the laboratory and the quality and/or acceptability of the verification of a study, as well as to take any necessary measures concerning the results of the inspection or verification.

D) GLP compliance programs: The purpose of the GLP compliance control is to check that the laboratories have applied the GLP principles when performing the studies and that they can provide the assurance that the data The results are of adequate quality. Detailed information on the Good Laboratory Practice compliance program will be published. Such information should:

1.o Define the scope and breadth of the program:

A GLP compliance programme may be subject to only a limited range of chemicals such as industrial chemicals, pesticides, pharmaceuticals, etc., or to cover all of these chemicals. chemical substances. The scope of compliance monitoring should be defined, both with regard to the classes of chemical substances and the types of tests subject to such surveillance, e.g. physical, chemical, toxicological and/or ecotoxicological tests.

2. To indicate the mechanism by which laboratories are registered in the program: The application of the GLP principles to data on health protection and the environment obtained for regulatory purposes can be mandatory. There should be a mechanism whereby the control bodies of the GLP can verify compliance with the GLP principles by the laboratories.

3. Provide Information on the categories of inspections and verifications: GLP compliance programs should include:

(a) Provisions on laboratory inspections. These inspections should include both the general inspection of installations and the verification of one or more studies which have been carried out or have already been completed.

(b) Provisions on special inspections and verifications requested by a regulatory authority such as those motivated by doubts resulting from the submission of data to a regulatory authority.

4. Define the authority of the inspectors to access the laboratories and the data they possess (including samples, Standards of Work, and other documents): Although the inspectors will abstain In order to ensure that access to the laboratory and data is essential for the protection of public health and the environment, it is normally necessary to access laboratories against the will of the management. Therefore, the power conferred in such cases on the control bodies of the GLP should be established.

5. Describe the procedures for inspection of laboratories and verification of studies on compliance with GLP compliance: This documentation should indicate the procedures to be followed to examine the Organisational procedures and the conditions under which the laboratories are planned, performed, controlled and recorded. Part B of this Annex provides guidance on these procedures.

6. Describe the measures that may be taken as a result of inspections and studies.

E) Monitoring of laboratory inspections and study verifications: Once the inspection of a laboratory and the verification of studies has been completed, the inspector shall draw up a report with its conclusions.

Measures shall be taken when, in the course of laboratory inspection or the verification of studies, or after examination, deviations from the GLP principles are observed. The appropriate measures shall be described in the documents of the control bodies of the Good Laboratory Practice.

If the inspection of a laboratory or the verification of a study reveals only slight deviations from the GLP principles, the laboratory should be asked to correct them. It may be necessary for the inspector to visit the laboratory again at the time to verify that the corrections have been made.

When no deviation is observed, or only slight deviations, the control organs of the GLP shall:

1. Make a statement saying that the lab has been inspected, and it has been proven to work in accordance with the GLP principles. The declaration must include the date of the inspection and, where appropriate, the categories of the studies inspected.

These statements may serve to convey information to the authorities responsible for the control of GLP in other Member States; and in addition (or alternatively), 2.o Make it to the regulatory authority that there is requested the verification of the study a detailed report of the conclusions.

When serious deviations are observed, the measures taken by the control bodies of the GLP will depend on the particular circumstances of each case, as well as the legal or administrative provisions under the the monitoring of the GLP has been established. The measures to be taken, inter alia, are listed below:

1. The formulation of a statement that sets out in detail the inadequacies or defects observed that may affect the validity of the studies performed in the laboratory.

2. The formulation of a recommendation to reject a study addressed to the regulatory authority.

3. Suspension of inspections and/or laboratory studies in the laboratory and, for example, and where administratively possible, to discharge the laboratory in the GLP compliance programme or from any list or registration of laboratories subject to GLP inspections.

4. The requirement to attach to the reports on specific studies a statement detailing the deviations.

5. Action through the courts, where circumstances warrant and permit legal or administrative procedures.

F) Resolution of discrepancies:

The problems or differences of opinion among the inspectors and the direction of the laboratories will normally be resolved in the course of the laboratory inspection or the verification of studies. The authorities responsible for the matter must establish a procedure which allows the laboratories to submit claims, when the same and the management of the laboratories persist in the differences of opinion on the matter. the result of an inspection or verification of studies for the control of compliance with good laboratory practice, and/or on the measures to be taken by the competent authorities.

PART B

Guidelines for conduct in laboratory inspections and study checks

1. Introduction. The purpose of this part of the Annex is to provide guidance for the conduct of laboratory inspections and study checks which are mutually acceptable to the Member States. This part of the annex deals mainly with the laboratory inspections, which the BPL inspectors devote much of their time to.

An inspection of a laboratory usually includes a verification of studies or "review", but there will be occasions when studies must be carried out at the request of a regulatory authority, for example.

At the end of this annex, a general orientation for the conduct of study verifications is provided.

Laboratory inspections are carried out to determine the extent to which laboratories and studies comply with the GLP principles and to determine the integrity of the data, so as to ensure that the data are the resulting data are of sufficient quality for the deliberation and decision-making by the regulatory authorities. The inspections are translated into reports describing the degree of compliance of the GLP by a laboratory. Laboratory inspections should be carried out regularly and as a regular way of creating and maintaining a register showing the degree of compliance of the GLP by the laboratories.

If more information is desired on the points discussed in this part of the annex, the OECD's BPL consensus documents can be consulted (e.g. the role and responsibilities of the OECD). director of the study) and the documents published in this respect by the various ministries involved.

2. Definition of terms. This part of the Annex applies to the terms defined in the OECD's "Principles of Good Laboratory Practice", adopted pursuant to Royal Decree 822/1993 of 28 May.

3. Laboratory inspections. -Inspections to verify compliance with GLP principles can take place in any type of laboratory that generates data concerning the protection of health or the environment for normative purposes. Inspectors may need to verify data relating to the physical, chemical, toxicological or ecotoxicological properties of a product or a preparation. In some cases, inspectors may need expert assistance in certain disciplines.

The great diversity of laboratories, both in terms of the material provision and the administrative structure, coupled with the variety of types of studies that the inspectors face, makes them use their own criteria for judging the extent and extent of compliance with GLP principles.

However, inspectors should strive to adopt a uniform approach when assessing whether, in the case of a particular laboratory or study, a satisfactory degree of compliance with each principle has been achieved.

The following section provides guidance on the various aspects of the laboratories, including their staff, and the procedures that the inspectors usually have to examine. Each section specifies the purpose and gives an illustrative list of the specific points which can be examined in the course of an inspection. The lists are in no way exhaustive.

The inspectors should not be concerned about the need or objectives of the study, nor the interpretation of the conclusions of the studies as regards the risks to human health or the environment.

These aspects concern the regulatory authorities to which data are presented for regulatory purposes.

It is inevitable that laboratory inspections and study checks will alter the normal operation of laboratories. Therefore, the inspectors should carry out their work in carefully prepared plans and, as far as possible, respect the wishes of the management of the laboratory as regards the time of visits to certain parts of the laboratory. facilities.

By conducting laboratory inspections and study checks, inspectors will have access to confidential, commercially valuable information. It is essential to ensure that only authorised personnel can access such information.

Your duties in this regard should be set within the GLP compliance control program.

4. Inspection procedures.

A) Pre-inspection:

Purpose: To familiarize the inspector with the laboratory that will inspect, as regards the administrative structure, the physical layout of the buildings and the range of studies.

Before carrying out an inspection of a laboratory or a verification of studies, the inspectors should familiarize themselves with the facilities to be visited. To this end, they will have to study all available information on these, in consultation with documentation such as previous inspection reports, data on the disposal of facilities, organisation charts, reports on studies, protocols and curriculum vitae of the staff. These documents will contain information regarding:

1. The type, dimensions and layout of the facilities.

2. The range of studies that are likely to be found in the course of the inspection.

3. The administrative structure of the facilities.

Inspectors should review with particular attention any deficiencies identified in previous inspections.

When no previous inspection has been performed, a pre-inspection visit may be made to obtain the relevant information.

The laboratories must be informed of the date and time of arrival of the inspectors, the purpose of the visit and the time the inspectors are planning to remain in the premises. This will enable the laboratory to ensure the presence of the staff and to have adequate documentation. Where certain documents or records are to be examined, it may be useful to indicate them to the laboratory before the visit, so that they are available when the inspection is carried out.

B) Preliminary meeting:

Purpose: To inform the management and staff of the laboratory of the reasons for the laboratory inspection or the verification of studies to be carried out and to specify the areas of the laboratory and the study or studies to be carried out. verification object, as well as the documents and personnel to which it may affect.

The administrative and practical details of a laboratory inspection or study verification should be discussed with the management at the beginning of the visit.

At the preliminary meeting, inspectors should:

1. º Expose the purpose and scope of the visit.

2. To indicate the documentation that they will need for laboratory inspection, for example: Lists of studies in execution and completed, planned studies, standard procedures of work, reports on studies, etc. Access to documents of interest and, where appropriate, measures to make copies of them should be agreed at this meeting.

3. Acquire a clear notion of the administrative structure (organization) and laboratory personnel or request information on the particular.

4. Request information on the conduct of studies not subject to the GLP principles in the laboratory areas where GLP studies are conducted.

5. Indicate the parts of the laboratory which, in principle, will be inspected.

6. To indicate the documents and specimens that will be needed for the verification of the study or the studies, in execution or completed, that have been selected.

7. Indicate that at the end of the inspection a final meeting will be held.

Before continuing the inspection, it is appropriate for the inspector to establish contact with the Quality Assurance Unit (UGC) of the laboratory.

As a general rule, inspectors will verify that, when inspecting laboratories, it is useful to be accompanied by a member of the Quality Assurance Unit. In addition, the inspectors should request that they be given an appropriate place for the examination of documents and other activities.

C) Organization and staff:

Purpose: To determine whether the facilities have qualified personnel, human resources and sufficient support services for the range and the number of studies performed on them, if the organisational structure is adequate and if the management has established a policy of training and monitoring the health of the staff, appropriate to the studies carried out in the facilities.

You must be prompted to provide documents such as:

1. º Planes of the different floors of the building.

2. Arrange of the management of the installation, of its organization at the scientific level.

3. º Curriculum vitae of the technical staff involved in the type or types of studies to be checked.

4. Lists of studies in execution and completed with information on the type of study, the start and end dates, experimental systems, method of application of the test products and name of the study director.

5. Health surveillance policy.

6. Description of personnel tasks and personnel training programs and records.

7. The Index of Normalized Labor Procedures (NPT).

8. Special NPCs related to the studies or procedures subject to inspection or verification.

9. List of study directors and promoters related to verified studies.

The inspector should check in particular:

1. The lists of the studies in execution and completed, to make sure the volume of work done by the laboratory.

2. The identity and qualification of the directors of the studies, and the head of the Quality Assurance Unit and the remaining management staff.

3. º The existence of PNTs applicable to all relevant testing activities.

D) Quality Assurance Program:

Purpose: To determine the adequacy of the mechanisms applied for the Management to ensure that the laboratory studies are carried out in accordance with the GLP principles.

To this end, the Head of the Quality Assurance Unit must be asked to demonstrate the systems and methods of inspection and control of studies for Quality Assurance purposes, as well as the system of registration of the observations made during that control. Inspectors should check:

1. The title of the responsible and the staff of the Quality Assurance Unit.

2. The Quality Assurance Unit performs its functions independently of the personnel involved in the studies.

3. The way in which the Quality Assurance Unit plans and conducts inspections, as it monitors the critical phases detected in a study and which resources it has for inspection and control activities for the purpose of Quality Assurance.

4. " If there are control provisions by means of samples of the cases in which the duration of the studies is so short that it is not feasible to monitor each one of them.

5. º The breadth and depth of control for Quality Assurance purposes of the practical phases of the study.

6. º The amplitude and depth of the control for the purpose of Quality Assurance of the usual laboratory operation.

7. The Quality Assurance procedures to verify the final report, in order to check their agreement with the primary data.

8. º If the Management receives from the Quality Assurance Unit reports on problems that may affect the quality or integrity of a study.

9. The measures taken by the Quality Assurance Unit when deviations are observed.

10. The function that the Quality Assurance Unit performs when the studies or parts of them are performed in subcontracted laboratories.

11. The role of the Quality Assurance Unit in the work of examining, reviewing and updating the NPCs.

E) Installations:

Purpose: To determine whether the facilities, both indoor and outdoor, meet suitable conditions in terms of dimensions, construction, design and location to meet the requirements of the studies.

The inspector should check that:

1. The design allows a sufficient degree of separation so that, for example, chemical substances, animals, food, pathological samples, etc., of a study cannot be confused with those of another.

2. There are environmental monitoring and control procedures that work properly in critical areas, such as animalums and other biological experimental systems, storage areas of substances or laboratory areas.

3. The general conditions of maintenance of the various installations are adequate and procedures for pest control are available in cases of need.

F) Care, accommodation and confinement of the elements used in biological experimental systems:

Purpose: To determine if the laboratory, in case of studies with animals or other elements used in biological experimental systems, has auxiliary means and suitable conditions for the care, housing and containment of the same, in order to avoid stress or other problems that could affect the experiment and, consequently, the quality of the data.

It is possible for a laboratory to perform studies that require different species of animals or plants, microbial systems, or other cellular or subcellular systems. The type of experimental system used shall determine the aspects to be monitored by the inspector in respect of care, accommodation and confinement.

Using your own criteria, the inspector must check, based on the tests performed, that:

1. Facilities suitable for the experimental systems used and their requirements are available.

2. There are measures for the quarantine of animals and plants that are introduced into the facility and that these measures work satisfactorily.

3. There are measures to isolate animals (or other elements of biological experimental systems, if necessary) to be known or suspected to be sick or carriers of a disease.

4. There are activities of supervision and control of the state of health, behavior and other aspects, appropriate to the experimental system.

5. The team to achieve the environmental conditions required by each test is well maintained and effective.

6. The cages of animals, feeders, tanks and other containers, as well as the fitting equipment, are kept sufficiently clean.

7. The analysis to check the environmental conditions and the auxiliary systems is carried out.

8. º There are means to extract and evacuate waste and residues of animal origin, and elimination is done by minimizing parasite infestation, bad odours, risks of disease and contamination of the environment. environment.

9. For all tests, storage areas of food intended for animals or similar materials are available; whereas these areas are not used to store other materials such as test products, pesticides chemicals or disinfectants, which are separated from areas where animals are housed or biological products are stored.

10. Food and animal waste material are protected against deterioration due to adverse environmental conditions, infestation or contamination.

G) Appliances, materials, reagents and specimens:

Purpose: To verify that the laboratory has instruments, operating and located correctly, in sufficient quantity and adequate capacity to meet the requirements of the tests performed at the facility, and check that the materials, reagents and specimens are correctly labelled, used and stored.

The inspector should check that:

1. The appliances are kept clean and in good working order.

2. Registration, maintenance, checking, calibration and validation of equipment and measuring instruments (including computer systems) are carried out.

3. Chemical materials and reagents are correctly labelled and stored at appropriate temperatures, taking into account the expiry dates. The labels of the reagents should indicate their origin, identity, concentration and other relevant information.

4. º Specimens are successfully identified by experimental system, study, nature and sample date.

5. The instruments and materials used do not significantly alter the experimental systems of the tests.

H) Experimental systems:

Purpose: To verify that there are adequate procedures for the management and control of the various experimental systems required for the studies performed at the facility, such as chemical systems and physical, cellular and microbial, plant or animal.

Physical and chemical systems: The inspector should check that:

1. When required by the protocols, the stability of the test and reference products has been determined, and the reference products specified in the protocols have been used.

2. º In automated systems, data generated in the form of charts, collected in records or computer listings are treated as primary data documents and archived.

Biological systems: Taking into account the aforementioned points relating to the care, accommodation and confinement of biological experimental systems, the inspector should check that:

1. The experimental systems are those specified in the study protocols.

2. º The experimental systems are properly identified, or especially when necessary, at all times during the study, and a file with detailed information on the reception of the systems and the number of these received, used, replaced or discarded.

3. The enclosure and confinement spaces of the systems are properly identified and with all the necessary information.

4. There is an adequate separation of the studies that are carried out with the same species of animals (or the same biological experimental systems), but with different products.

5. There is an adequate separation of animal species (and other biological experimental systems) in both space and time.

6. The environment of the experimental systems is the one specified in the protocol or the Normalized Labor Procedures (TNP) in terms of aspects such as temperature and light-dark cycles.

7. The records concerning the reception, handling, accommodation, confinement, care and health assessment are the appropriate ones for the experimental systems.

8. º Written records of the examinations, quarantine measures, morbidity, mortality, behaviour, diagnosis and treatment of animal and plant experimental systems, and similar aspects, as appropriate for each biological experimental system.

9. There are provisions for the proper disposal or disposal of waste and waste at the end of the tests.

I) Test and reference products:

Purpose: To determine whether the laboratory has standard procedures for: (i) To ensure that the identity, activity, quantity and composition of the test and reference products are in accordance with the respective requirements. specifications, and (ii) to receive and store appropriate test and reference products.

The inspector should check that:

1. There are written procedures for recording reception (including the identification of the responsible person), handling, sampling, use and storage of test and reference products.

2. The containers of test products and reference products are duly labelled.

3. The storage conditions are suitable for maintaining the concentration, purity and stability of the test and reference products.

4. The records are written on the identity, purity, composition and stability of the test and reference products, as well as, where appropriate, to prevent contamination of the products.

5. There are procedures to determine, where appropriate, the homogeneity and stability of mixtures containing test products and reference products.

6. ° The containers containing mixtures (or dilutions) of test and reference products are labeled, and records are kept on the homogeneity and stability of the respective contents, as appropriate.

7. When the study is longer than four weeks, samples have been taken from each batch of test products and reference products for analysis, and have been retained for an appropriate period.

8. The product mix procedures have been designed to prevent identification errors or reciprocal contamination.

J) Standardized Work Procedures (PNT):

Purpose: To establish whether the laboratory has Normalized Procedures of Work written for all important aspects of the activities it performs, taking into account that the written PNTs constitute one of the more important means of controlling the activities of the facilities. NPT has a direct relationship with the most current aspects of the tests performed in the laboratory.

The inspector should check that:

1. Each area of the laboratory has the relevant copies of the TNP, duly authorized and of immediate availability.

2. There are procedures for the revision and updating of the TNP.

3. All modification of the TNP has been authorized and dated.

4. The historical file of the Normalized Labor Procedures is maintained.

5. º PNT available for the following activities, not necessarily limited to them:

(a) Reception; identification of identity, purity, composition and stability; labelling; handling; sampling; use; and storage of test and reference products.

b) Use, maintenance, cleaning, calibration and validation of measuring instruments, computer systems and environmental control equipment.

c) Preparation of reagents and dosage formulations.

d) Log, notify, store, and retrieve files and reports.

e) Environmental preparedness and control of the areas in which the experimental systems are located.

f) Reception, transfer, situation, characterization, identification and care of the experimental systems.

g) Manipulation of experimental systems before, during and after the completion of the study.

h) Elimination of experimental systems.

i) Use of pest control and cleaning agents.

j) Activities within the Quality Assurance Program.

K) Review of the study:

Purpose: To verify that written protocols exist and that the same and the execution of the study conform to the BPL principles.

The inspector should check that:

1. The study protocol has been signed by the study director.

2. The Director of the study has signed and dated all the modifications of the protocol.

3. º The date on which the promoter accepted the protocol (where applicable) has been recorded.

4. º The measurements, observations and examinations are in accordance with the protocol and the corresponding PNTs.

5. The results of these measurements, observations and examinations have been recorded directly and promptly, accurately and legibly, and were signed (or visas with the initials) and dated.

6. The changes to primary data, including computer stored, do not hide previous entries, including the reason for the change, the person responsible for the change, and the date it was made.

7. The identification of the data generated or stored on the computer and the adequacy of the procedures to protect them from unauthorized modifications and possible losses is assured.

8. The computer systems used in the study are reliable, accurate and have been validated.

9. All the unforeseen events recorded in the primary data have been investigated and evaluated.

10. The results presented in the (interim or final) reports of the study are congruent and complete, and correctly reflect the primary data.

L) Reports on the results of the study:

Purpose: Determine whether the final reports are prepared in accordance with the BPL principles.

When examining the final report, the inspector must check that:

1. The report is signed and dated by the Director of the study, indicating that it accepts responsibility for its validity and confirming that the study has been conducted in accordance with the GLP principles.

2. The report is signed and dated by other leading scientists in case of reports of cooperating disciplines.

3. The report includes a quality, signed and dated statement.

4. The amendments, if any, have been made by the competent staff.

5. The report indicates the location in the files of all samples, specimens, and primary data.

M) File and record preservation:

Purpose: To determine whether the laboratory has generated satisfactory records and reports and whether adequate arrangements have been made for the storage and preservation of records and information material.

The inspector should check:

1. º The person responsible for the file was specified.

2. The protocols file, primary data (including those of interrupted BPL studies), final reports, samples and specimens, as well as the personnel qualification and training files.

3. The procedure for retrieving archived documentation.

4. The procedures by which access to files is permitted only to authorized personnel and a record of the persons granted access to primary data, slides, etc.

5. º An inventory of the entries and documentation outputs of the files is taken.

6. º That records and documentation are preserved for the time necessary or appropriate, and that they are protected against loss or damage due to fire, adverse environmental conditions, etc.

5. Verification of studies. -In general, laboratory inspections shall include, inter alia, verifications of studies in which studies are to be reviewed in implementation or completed. These types of checks often requested by the regulatory authorities can be carried out independently of laboratory inspections. Given the wide variety of types of studies which may be subject to checks, it is preferable to provide guidance of a general nature, so that the inspectors and other participants in the study checks must carry out last instance according to its own criteria when deciding on the nature and extent of its examinations. The purpose will be to reconstruct a study, comparing the final report with the protocol, the relevant Standard Working Procedures, the primary data and other archived materials.

In certain cases, such as when you need to examine tissue cuts under a microscope, the inspectors may need assistance from other experts to perform an effective check.

When checking a study, the inspector must:

1. Getting names, job description and abstracts of the qualifications, training and experience of a selection of participants in the study or studies, such as the Director and the scientists principal.

2. Check that there is sufficient trained personnel in the subjects of interest for the study or studies concerned.

3. Identify each apparatus or component of the special equipment used in the study, and examine the calibration, maintenance, and service records of the equipment.

4. Examine the records concerning the stability of the test products, the analysis of these products and the compounds, the analysis of the food for the animals, etc.

5. Try to determine, by means of interviews, if possible, the functions assigned to the persons participating in the study during the period of the study, in order to ensure that these persons they had time to perform the tasks specified in the study protocol or report.

6. To obtain copies of all the documents concerning the control procedures, or to form an integral part of the study, among them:

a) The protocol.

b) The TNP in force at the time of the study.

(c) Books of record, notebooks of laboratory notes, files, work sheets, computer listings, etc.

d) Check the calculations, where appropriate.

e) The final report.

In studies where animals (such as rodents or other mammals) are used, inspectors should monitor a certain percentage of specimens from their arrival to the laboratory to the necropsy, with special attention to records relating to:

1. Animal body weight, amount of water and food ingested, preparation and administration of doses, etc.

2. ° Clinical observations and conclusions resulting from necropsy.

3. Biological Examinations.

4. Pathology.

6. Conclusion of inspections or study audits.-After completion of a laboratory inspection or study verification, the inspector shall be willing to discuss his findings with the laboratory representatives in a final meeting and you will need to prepare a written report, called "Inspection Report".

A laboratory inspection is likely to reveal a number of slight deviations from the GLP principles, but these deviations will generally not be sufficiently important to affect the validity of the tests. studies from the laboratory. In such cases, it is reasonable for the inspector to indicate in the report that the laboratory develops its activities in accordance with the GLP principles established by the control body of the GLP. However, the inspector must inform the laboratory in detail of the shortcomings or defects identified and ask the management of the same guarantees that measures will be taken to correct them.

The inspector may need to revisit the laboratory after a certain period of time to verify that the necessary measures have been taken.

If, in the course of a study verification or laboratory inspection, a serious deviation is detected with respect to the GLP principles which, in the opinion of the inspector, may have affected the validity of that study or of the studies carried out at the facility, the inspector shall give an account to the body responsible for the GLP compliance programme. The actions taken by that authority and/or by the regulatory authority, as appropriate, shall depend on the nature and severity of the breaches and the legal and/or administrative provisions of the GLP compliance programme.

When a study verification has been carried out at the request of a regulatory authority, a full report shall be drawn up with the conclusions to be sent to that authority through the national control body of the GLP. corresponding.