1. Organization and management
1.1 The laboratory, or the organization of which it is part, must be an
entity that is legally authorized to function and can be held legally
responsible.
1.2 The laboratory must be organized and operate so as to meet the
requirements laid down in these guidelines.
1.3 The laboratory must:
(a) have managerial and technical personnel with the authority and
resources needed to carry out their duties and to identify the
occurrence of departures from the quality system or the procedures
for performing tests and/or calibrations, validation and
verification, and to initiate actions to prevent or minimize such
departures;
(b) have arrangements to ensure that its management and personnel
are not subject to commercial, political, financial and other pressures
or conflicts of interest that may adversely affect the quality
of their work;
(c) define, with the aid of organizational charts, the organization and
management structure of the laboratory, its place in any parent
organization, such as the ministry or the drug regulatory authority,
and the relationships between management, technical operations,
support services and the quality system;
(d) specify the responsibility, authority and interrelationships of all
personnel who manage, perform or verify work which affects
the quality of the tests and/or calibrations, validations and
verifications;
(e) provide adequate supervision of staff, including trainees, by
persons familiar with the test and/or calibration, validation and
verification methods and procedures, as well as their purpose and
the assessment of the results;
(f) have a technical manager who has overall responsibility for the
technical operations and the provision of resources needed to
ensure the required quality of laboratory operations; and
(g) have appropriate safety procedures (see Part Four).
1.4 The laboratory, regardless of whether it is small (without subunits)
or large (and possibly divided into subunits), must have a
central registry with the following functions:
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(a) receiving, distributing and supervising the consignment of the
samples to the specific units;
(b) keeping records on all incoming samples and accompanying
documents;
(c) ensuring the precise allocation of responsibilities, particularly
in the designation of specific units for particular types of drugs;
and
(d) maintaining a specifications archive (see Part Two, section 9)
containing an up-to-date collection of all quality specifications
and related documents.
1.5 In a large laboratory, communication and coordination must be
guaranteed between the staff involved in the testing of the same
sample in different units.
2. Quality system
2.1 The laboratory management establishes, implements and maintains
a quality system appropriate to the scope of its activities,
including the type, range and volume of testing and/or calibration,
validation and verification activities it undertakes. The laboratory
management must describe its policies, systems, programmes, procedures
and instructions to the extent necessary to enable the laboratory
to assure the quality of the test results that it generates. The
documentation used in this quality system must be communicated and
available to, and understood and implemented by, the appropriate
personnel. The elements of this system must be documented in a
quality manual, available to the laboratory personnel, which must
be maintained and updated by a nominated responsible member
of the laboratory personnel. The quality manual must contain as a
minimum:
(a) the structure of the laboratory (organizational chart);
(b) the operational and functional activities pertaining to quality, so
that each person concerned will know the extent and the limits of
his or her responsibilities;
(c) the general internal quality assurance procedures;
(d) references to specific quality assurance procedures for each test;
(e) information on participation in appropriate proficiency testing
schemes, use of reference materials, etc.;
(f) details of satisfactory arrangements for feedback and corrective
action when testing discrepancies are detected;
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(g) a procedure for dealing with complaints;
(h) a flow-chart for samples;
(i) details of audit and quality system review;
(j) information on the appropriate qualifications that personnel are
required to possess;
(k) information on initial and in-service training of staff;
(l) a quality policy statement, including at least the following:
(i) a statement of the laboratory management’s intentions with
respect to the standard of service it will provide;
(ii) the purpose of the quality system;
(iii) the laboratory management’s commitment to good professional
practice and quality of testing, calibration, validation
and verification, as a service to its clients;
(iv) the laboratory management’s commitment to compliance
with the content of these guidelines;
(v) a requirement that all personnel concerned with testing
and calibration activities within the laboratory familiarize
themselves with the documentation concerning quality and
the implementation of the policies and procedures in their
work.
2.2 The quality system must be reviewed systematically and periodically
(internal and external audits) by, or on behalf of, the management
to ensure the continued effectiveness of the arrangements and
apply any necessary corrective measures. Such reviews must be recorded,
together with details of any corrective action taken.
2.3 The laboratory management must appoint a member of the staff
as quality manager, who, irrespective of other duties and responsibilities,
should have defined responsibilities and authority for ensuring
that the quality system is implemented and followed at all times.
The quality manager must have direct access to the highest level of
management at which decisions are taken on laboratory policies or
resources.
3. Control of documentation
3.1 Documentation is an essential part of the quality system. The
laboratory must establish and maintain procedures to control and
review all documents (both internally generated and from external
sources) that form part of the quality documentation.
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4. Records
4.1 The laboratory must establish and maintain procedures for the
identification, collection, indexing, retrieval, storage, maintenance
and disposal of, and access to, all quality documentation and technical
records.
4.2 All original observations, calculations and derived data, calibration,
validation and verification records, etc., and final results must be
retained on record for an appropriate period of time in accordance
with national regulations. Ideally, they should be kept for the whole
length of time that the drug concerned is on the market. The records
for each test must contain sufficient information to permit the tests to
be repeated. The records must include the identity of the personnel
involved in the sampling, preparation and testing of the samples. The
records of samples to be used in legal proceedings should be kept
according to the legal requirements applicable to them.
4.3 All records must be legible, readily retrievable, stored and
retained, using facilities that provide a suitable environment that will
prevent modification, damage or deterioration and/or loss. The conditions
under which all original records are stored must be such as to
ensure their security and confidentiality. Quality records must include
reports from internal (and external, if performed) audits and management
reviews, including records of possible corrective and preventive
actions.
4.4 Authorized written standardized operating procedures (SOPs)
are required, including, but not limited to, instructions for administrative
and technical operations, such as:
(a) the purchase and receipt of consignments of materials (e.g.
samples, reference materials, reagents);
(b) the internal labelling, quarantine and storage of materials;
(c) the appropriate installation of each instrument and item of
equipment;
(d) sampling and inspection;
(e) the testing of materials, with descriptions of the methods and
equipment used;
(f) the qualification of equipment;
(g) the calibration of analytical apparatus;
(h) maintenance, cleaning and sanitation;
(i) safety measures;
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( j) actions relating to personnel matters, including qualifications,
training, clothing and hygiene;
(k) environmental monitoring;
(l) the preparation and control of reference materials.
5. Data-processing equipment
5.1 For computers, automated tests or calibration equipment, and the
collection, processing, recording, reporting, storage or retrieval of test
and/or calibration data, the laboratory must ensure that:
(a) calculations and data transfers are systematically subject to
appropriate verifications;
(b) computer software developed by the user is documented in
sufficient detail and appropriately validated or verified as being
adequate for use;
(c) procedures are established and implemented for protecting the
integrity of data. Such procedures must include, but are not
limited to, measures to ensure the integrity and confidentiality of
data entry or collection, and the storage, transmission and processing
of data;
(d) computers and automated equipment are maintained so as to
function properly, and are provided with the environmental and
operating conditions necessary to ensure the integrity of test and
calibration data;
(e) procedures are established and implemented for making, documenting
and controlling for changes to information maintained in
computerized systems; and
(f) procedures exist to protect and keep back-up data on computers
or other means (e.g. magnetic tapes, diskettes and CD-ROMs) at
all times, and to prevent unauthorized access or amendments to
the data.
6. Personnel
6.1 The laboratory must have sufficient personnel with the necessary
education, training, technical knowledge and experience for their
assigned functions. They should be free from any conflict of interest
and not subject to any pressure that would interfere with the quality
of the results.
6.2 The laboratory management must ensure the competence of all
persons operating specific equipment, instruments or other devices,
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who are performing tests and/or calibrations, validations or verifications.
Their duties also involve the evaluation of results as well as
signing test reports (see Appendix 1) and calibration certificates.
6.3 Staff undergoing training must be appropriately supervised, and
a formal assessment after training is recommended. Personnel performing
specific tasks must be appropriately qualified in terms of
their education, training, experience and/or demonstrated skills, as
required.
6.4 The laboratory personnel must be permanently employed or
under contract. The laboratory must ensure that additional technical
and key support personnel who are under contract are supervised
and sufficiently competent and motivated, and that their work is in
accordance with the good practice of the laboratory.
6.5 The laboratory must maintain current job descriptions for managerial,
technical and key support personnel involved in tests and/or
calibrations, validations and verifications. The laboratory must also
maintain records of all technical personnel, including those under
contract, describing their areas of competence, educational and professional
qualifications, training, skills and experience. This information
must be readily available and must include the date on which
authorization and/or competence was confirmed. The criteria on
which the authorization is based must also be given, together with the
name of the confirming authority.
6.6 The laboratory must have the following managerial and technical
personnel:
(a) a head of laboratory (supervisor), who must be of high professional
standing with extensive experience in drug analysis and
laboratory management in a pharmaceutical control laboratory in
the regulatory sector or in industry. The head of laboratory also
takes final responsibility for recommending any regulatory action
in the event of non-compliance of a tested sample. The person’s
function is to ensure that:
(i) all key members of the laboratory staff have the requisite
competence and are given grades matching their
responsibilities;
(ii) standard samples are analysed periodically;
(iii) the adequacy of existing staffing, management and training
procedures is reviewed periodically;
(iv) “self-checking” procedures for instrument operators are
devised;
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(v) regular in-service training programmes to update and extend
the skills of both professionals and technicians are arranged;
(vi) the safe keeping of any narcotics (see Part One, sections
7.10–7.12) kept in the workplace is under the supervision of
an authorized person;
(b) a head of central registry, who must have wide experience in drug
analysis and be responsible for:
(i) receiving and keeping records of all incoming samples and
accompanying documents;
(ii) supervising their consignment to the specific units concerned;
(iii) monitoring the progress of analyses and the dispatch of
completed reports (see also Part One, section 1.4);
(iv) if required, collating and evaluating the test results for each
analysis;
(c) analysts, who must be graduates in pharmacy, analytical chemistry,
microbiology or other relevant subjects with the requisite
knowledge, skills and ability to adequately perform the tasks
assigned to them by management and to supervise technical staff;
(d) technical staff, who should hold diplomas in their subjects
awarded by technical or vocational schools;
(e) a storekeeper (see Part Two, section 10.13), who is responsible
for keeping the central store and must have appropriate competence
and be trained to handle reagents and materials with the
necessary care and safety;
(f) a quality manager (see Part One, section 2.3).
6.7 In large laboratories with subunits, the following additional personnel
are necessary:
(a) heads of various subunits;
(b) a reference material coordinator (see Part Two, section 11.8).
6.8 The more routine analyses performed, the greater the proportion
of technicians required. Non-routine work, and particularly the
review of test methods for newly registered drugs, requires a higher
proportion of fully qualified specialists. In general, the ratio of technicians
to analysts in a routine testing environment has been shown to
be 3: 1 in a chemical or physicochemical unit, and 5 : 2 in a biological
or microbiological laboratory.
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7. Premises
7.1 The laboratory should be of a suitable size, construction and
location. Safety requirements should be taken into consideration in
the design (see Part Four).
7.2 The design of the laboratory should be such as to provide an
adequate degree of separation of any activity which may interfere
with the proper conduct of each study.
7.3 The laboratory should have a sufficient number of rooms or areas
to ensure that test systems are isolated from one another.
7.4 The premises must have suitable testing and safety equipment.
The necessary energy sources should be available; if the line voltage
is variable, suitable voltage stabilizers should be installed.
7.5 Storage rooms or areas should be available, as needed, for supplies
and materials, and should be conveniently located. These rooms
should be separated from those areas housing the test systems and
should provide adequate protection against infestation, contamination
and/or deterioration.
7.6 To prevent contamination or mix-ups, separate rooms or areas
for the receipt and storage of test and reference items should be
available, as well as for the mixing of test items with a vehicle.
7.7 Storage rooms or areas for test items should be separate from
those containing the test systems. They should be constructed in such
a way as to preserve the identity, concentration, purity and stability of
the test item, and ensure safe storage of hazardous substances. All
storage areas must be located and equipped in accordance with fire
regulations. For safety reasons, and to reduce contamination of the
laboratory environment, flammable reagents, fuming and concentrated
acids and bases, volatile amines, etc., must never be kept in the
laboratory without good reason.
Central store
7.8 Separate central storage facilities must be maintained for the
secure storage of samples, retained samples (see Part Three, section
18), and reagents, laboratory accessories (see Part Two, sections
10.12–10.14) and reference materials (see Part Two, section 11).
Storage facilities must be equipped to store material, if necessary,
under refrigeration and securely locked. Access must be restricted to
designated personnel.
7.9 The central store should be organized in such a way so as to
accommodate incoming and outgoing samples, reagents, equipment,
instruments and other devices.
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7.10 Appropriate safety regulations must be drawn up and rigorously
implemented wherever toxic or flammable reagents are stored or
used.
7.11 Reagents subject to poison regulations or to the controls applied
to narcotic and psychotropic substances must be clearly marked as
“Poison”. They must be kept separately from other reagents in locked
cabinets.
7.12 The designated responsible member of staff must maintain a
register of these substances. The head of each unit must accept personal
responsibility for the safe keeping of any of these reagents kept
in the workplace (see Part One, section 6.6).
7.13 Archive facilities should be provided to ensure the secure
storage and retrieval of all documents (internally generated or from
external sources), samples of test items and specimens. The design
and condition of the archives should be such as to protect the
contents from untimely deterioration. Access to the archives must be
restricted to designated personnel.
7.14 The handling and disposal of wastes should be carried out in
such a way as not to jeopardize the integrity of studies and the
environment. Appropriate facilities for the collection, storage and
disposal of wastes should be available, as well as a means of decontamination,
where applicable, and transportation.
7.15 The environment in which the tests are undertaken must not be
such as to invalidate the test results or adversely affect the required
accuracy of measurements. This applies particularly to sites other
than permanent laboratory premises. Testing premises must be protected,
as required, from conditions such as heat, cold, dust, moisture,
steam, noise, vibration and electromagnetic disturbance or interference.
Devices to monitor the environmental conditions must be installed,
if required by the nature of the testing. Access to, and use of,
all test areas must be controlled and limited to the minimum necessary
for their designated purpose. Persons external to the laboratory
must satisfy the specified conditions of entry. Adequate measures
must be taken to ensure good housekeeping in the test laboratory.
8. Equipment, instruments and other devices
8.1 Equipment, instruments and other devices must be designed, constructed,
adapted, located, calibrated, qualified, verified and maintained
as required by the operations to be carried out in the local
environment. The user should purchase the equipment from an
agent capable of providing full technical support and maintenance
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when necessary. Documentation should be written in the language
employed in the laboratory.
8.2 To ensure proper sampling and measurement, the laboratory
must have the required test equipment, instruments and other devices
for the correct performance of the tests and/or calibrations, validations
and verifications (including the preparation of test and/or
calibration items, and the processing and analysis of test and/or
calibration data). As a guide, a list of basic equipment, instruments
and other devices is given in Appendix 2.
8.3 Equipment, instruments and other devices, including those used
for sampling, must meet the laboratory’s requirements, and comply
with the relevant standard specifications, as well as be verified and/or
calibrated (see Part Two, section 12).
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