WHO good practices for pharmaceutical
quality control laboratories

General considerations
Glossary
Part one. Management and infrastructure

1.
Organization and management
2.
Quality management system
3.
Control of documentation
4.
Records
5.
Data-processing equipment
6.
Personnel
7.
Premises
8.
Equipment, instruments and other devices
9. Contracts
Part two. Materials, equipment, instruments and other devices
10.
Reagents
11.
Reference substances and reference materials
12.
Calibration, verification of performance and
qualification of equipment, instruments and other devices
13. Traceability
Part three. Working procedures
14.
Incoming samples
15.
Analytical worksheet
16.
Validation of analytical procedures
17.
Testing
18.
Evaluation of test results
19.
Certificate of analysis
20. Retained samples
Part four. Safety
21. General rules
References
Appendix

Equipment for a first-stage and medium-sized pharmaceutical quality control laboratory

 General considerations

The WHO Expert Committee on Specifications for Pharmaceutical Products
adopted in 1999 the guidelines entitled WHO Good practices for national
pharmaceutical control laboratories, which were published as Annex 3 of
the WHO Technical Report Series, No. 902, 2002. As the other guidelines
related to laboratory quality assurance have been updated and subsequent
inspections for the compliance with the guidelines on good practices for
national pharmaceutical control laboratories indicated that some sections
were in need of improvement and clarification, it was considered necessary
to prepare a revised text.

These guidelines provide advice on the quality management system within
which the analysis of active pharmaceutical ingredients (APIs), excipients
and pharmaceutical products should be performed to demonstrate that
reliable results are obtained.

Compliance with the recommendations provided in these guidelines will
help promote international harmonization of laboratory practices and will
facilitate cooperation among laboratories and mutual recognition of results.

Special attention should be given to ensure the correct and effi cient
functioning of the laboratory. Planning and future budgets should ensure
that the necessary resources are available inter alia for the maintenance
of the laboratory, as well as for an appropriate infrastructure and energy
supply. Means and procedures should be in place (in case of possible supply
problems) to ensure that the laboratory can continue its activities.

These guidelines are applicable to any pharmaceutical quality control
laboratory, be it national, commercial or nongovernmental. However, they
do not include guidance for those laboratories involved in the testing of
biological products, e.g. vaccines and blood products. Separate guidance
for such laboratories is available.

These guidelines are consistent with the requirements of the WHO
guidelines for good manufacturing practices (1) and with the requirements
of the International Standard ISO/IEC 17025:2005 (2), and provide detailed
guidance for laboratories performing quality control of medicines. The
guidance specific to microbiology laboratories can be found in the draft
working document WHO guideline on good practices for pharmaceutical
microbiology laboratories (reference QAS/09.297).

The good practice outlined below is to be considered as a general guide
and it may be adapted to meet individual needs provided that an equivalent
level of quality assurance is achieved. The notes given provide clarifi cation
of the text or examples; they do not contain requirements which should be
fulfilled to comply with these guidelines.

Pharmaceutical quality control testing is usually a matter of repetitive testing
of samples of APIs or of a limited number of pharmaceutical products,
whereas national quality control laboratories have to be able to deal with a
much wider range of pharmaceutical substances and products and, therefore,
have to apply a wider variety of test methods. Specifi c recommendations
for national pharmaceutical quality control laboratories are addressed
in the following text. Particular consideration is given to countries with
limited resources wishing to establish a governmental pharmaceutical
quality control laboratory, having recently done so, or which are planning
to modernize an existing laboratory.

Quality control laboratories may perform some or all quality control
activities, e.g. sampling, testing of APIs, excipients, packaging materials and/
or pharmaceutical products, stability testing, testing against specifi cations
and investigative testing.

For the quality of a medicine sample to be correctly assessed:

• The submission of a sample of an API, excipient or pharmaceutical
product or a suspected counterfeit material to the laboratory, selected
in accordance with national requirements, should be accompanied by a
statement of the reason why the analysis has been requested.
• The analysis should be correctly planned and meticulously executed.
• The results should be competently evaluated to determine whether the
sample complies with the specifications or other relevant criteria.
National pharmaceutical quality control laboratories

The government, normally through the national medicines regulatory
authority (NMRA), may establish and maintain a pharmaceutical quality
control laboratory to carry out the required tests and assays to verify
that APIs, excipients and pharmaceutical products meet the prescribed
specifications. Large countries may require several pharmaceutical quality
control laboratories which conform to national legislation, and appropriate
arrangements should, therefore, be in place to monitor their compliance
with a quality management system. Throughout the process of marketing
authorization and postmarketing surveillance, the laboratory or laboratories
work closely with the NMRA.

A national pharmaceutical quality control laboratory provides effective
support for an NMRA acting together with its inspection services. The
analytical results obtained should accurately describe the properties of
the samples assessed, permitting correct conclusions to be drawn about
the quality of the samples of medicines analysed, and also serving as an
adequate basis for any subsequent administrative regulations and legal
action.

National pharmaceutical quality control laboratories usually encompass
essentially two types of activity:

—
compliance testing of APIs, pharmaceutical excipients and
pharmaceutical products employing “official” methods including
pharmacopoeial methods, validated analytical procedures provided by
the manufacturer and approved by the relevant government authority for
marketing authorization or validated analytical procedures developed by
the laboratory; and
—
investigative testing of suspicious, illegal, counterfeit substances or
products, submitted for examination by medicine inspectors, customs or
police.
To ensure patient safety, the role of the national pharmaceutical quality
control laboratory should be defined in the general pharmaceutical
legislation of the country in such a way that the results provided by it can, if
necessary, lead to enforcement of the law and legal action.

Glossary

The definitions given below apply to the terms as used in these guidelines.
They may have different meanings in other contexts.

acceptance criterion for an analytical result

Predefined and documented indicators by which a result is considered to be
within the limit(s) or to exceed the limit(s) indicated in the specifi cation.

accuracy

The degree of agreement of test results with the true value or the closeness
of the results obtained by the procedure to the true value (1).

Note: It is normally established on samples of the material to be examined
that have been prepared to quantitative accuracy. Accuracy should be
established across the specified range of the analytical procedure. It is
generally acceptable to use a “spiked” placebo which contains a known
quantity or concentration of a reference substance.

active pharmaceutical ingredient (API)

Any substance or mixture of substances intended to be used in the
manufacture of a pharmaceutical dosage form and that, when so used,
becomes an active ingredient of that pharmaceutical dosage form. Such
substances are intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment, or prevention of disease
or to affect the structure and function of the body (1).

analytical test report

An analytical test report usually includes a description of the test
procedure(s) employed, results of the analysis, discussion and conclusions
and/or recommendations for one or more samples submitted for testing (see
Part three, sections 18.7–18.11).

analytical worksheet

A printed form, an analytical workbook or electronic means (e-records) for
recording information about the sample, as well as reagents and solvents
used, test procedure applied, calculations made, results and any other
relevant information or comments (see Part three, section 15).

batch (or lot)

A defined quantity of starting material, packaging material or product
processed in a single process or series of processes so that it is expected
to be homogeneous. It may sometimes be necessary to divide a batch into
a number of sub-batches which are later brought together to form a fi nal
homogeneous batch. In the case of terminal sterilization the batch size is
determined by the capacity of the autoclave. In continuous manufacture
the batch should correspond to a defined fraction of the production,
characterized by its intended homogeneity. The batch size can be defi ned
either as a fixed quantity or as the amount produced in a fi xed time
interval (1).

batch number (or lot number)

A distinctive combination of numbers and/or letters which uniquely identifi es
a batch on the labels, its batch records and corresponding certifi cates of
analysis (1).

calibration

The set of operations that establish, under specified conditions, the
relationship between values indicated by an instrument or system for
measuring (especially weighing), recording and controlling, or the values
represented by a material measure, and the corresponding known values
of a reference standard. Limits for acceptance of the results of measuring
should be established (1).

certificate of analysis

The list of test procedures applied to a particular sample with the results
obtained and the acceptance criteria applied. It indicates whether or not the
sample complies with the specifi cation (3).

certified reference material

Reference material, characterized by a metrologically valid procedure for
one or more specified properties, accompanied by a certificate that provides

the value of the specified property, its associated uncertainty and a statement
of metrological traceability (4).

compliance testing

Analysis of active pharmaceutical ingredients (APIs), pharmaceutical
excipients, packaging material or pharmaceutical products according to
the requirements of a pharmacopoeial monograph or a specification in an
approved marketing authorization.

control sample

A sample used for testing the continued accuracy and precision of the
procedure. It should have a matrix similar to that of the samples to be
analysed. It has an assigned value with its associated uncertainty.

design qualification (DQ)

Documented collection of activities that define the functional and
operational specifications of the instrument and criteria for selection of the
vendor, based on the intended purpose of the instrument.

Note: Selection and purchase of a new instrument should follow a conscious
decision process, based on the needs of the technical management. When
designing a new laboratory facility, the design specification and the
requirements for services should be agreed between the management team
and the agreed suppliers and documented.

good manufacturing practice(s) (GMP)

That part of quality assurance which ensures that pharmaceutical
products are consistently produced and controlled to the quality standards
appropriate to their intended use and as required by the marketing
authorization (1).

installation qualification (IQ)

The performance of tests to ensure that the analytical equipment used in a
laboratory is correctly installed and operates in accordance with established
specifi cations.

management review

A formal, documented review of the key performance indicators of a quality
management system performed by top management.

manufacturer

A company that carries out operations such as production, packaging,
testing, repackaging, labelling and/or relabelling of pharmaceuticals (1).

marketing authorization (product licence, registration certificate)

A legal document issued by the competent medicines regulatory authority
that authorizes the marketing or free distribution of a pharmaceutical
product in the respective country after evaluation for safety, effi cacy and
quality. In terms of quality it establishes inter alia the detailed composition
and formulation of the pharmaceutical product and the quality requirements
for the product and its ingredients. It also includes details of packaging,
labelling, storage conditions, shelf-life and approved conditions of use.

measurement uncertainty

Non-negative parameter characterizing the dispersion of quantity values
being attributed to a measurand (analyte), based on the information used
(4).

metrological traceability

Property of a measurement result whereby the result can be related to a
reference through a documented, unbroken chain of calibrations, each
contributing to the measurement uncertainty (4).

operational qualification (OQ)

Documented verification that the analytical equipment performs as intended
over all anticipated operating ranges.

out-of-specification (OOS) result

All test results that fall outside the specifications or acceptance criteria
established in product dossiers, drug master files, pharmacopoeias or by the
manufacturer (5).

performance qualification (PQ)

Documented verification that the analytical equipment operates consistently
and gives reproducibility within the defi ned specifications and parameters
for prolonged periods.

pharmaceutical excipient

A substance, other than the active pharmaceutical ingredient (API), which
has been appropriately evaluated for safety and is included in a medicines
delivery system to:

—
aid in the processing of the medicines delivery system during its
manufacture;
—
protect, support or enhance stability, bioavailability or patient
acceptability;
—
assist in pharmaceutical product identifi cation; or
—
enhance any other attribute of the overall safety and effectiveness of the
medicine during its storage or use (6, 7).

pharmaceutical product

Any material or product intended for human or veterinary use, presented in
its finished dosage form or as a starting material for use in such a dosage
form, which is subject to control by pharmaceutical legislation in the
exporting state and/or the importing state (1).

precision

The degree of agreement among individual results when the procedure
is applied repeatedly to multiple samplings of a homogeneous sample.
Precision, usually expressed as relative standard deviation, may be
considered at three levels: repeatability (precision under the same operating
conditions over a short period of time), intermediate precision (within
laboratory variations — different days, different analysts or different
equipment) and reproducibility (precision between laboratories).

primary reference substance (or standard)

A substance that is widely acknowledged to possess the appropriate qualities
within a specified context, and whose assigned content is accepted without
requiring comparison with another chemical substance (8).

Note: Pharmacopoeial chemical reference substances are considered to be
primary reference substances. In the absence of a pharmacopoeial reference
substance, a manufacturer should establish a primary reference substance.

qualification of equipment

Action of proving and documenting that any analytical equipment complies
with the required specifications and performs suitably for its intended
purpose (see Part two, section 12).

quality control

All measures taken, including the setting of specifications, sampling, testing
and analytical clearance, to ensure that raw materials, intermediates, packaging
materials and finished pharmaceutical products conform with established
specifications for identity, strength, purity and other characteristics.

quality management system

An appropriate infrastructure, encompassing the organizational structure,
procedures, processes and resources, and systematic actions necessary to
ensure adequate confidence that a product or service will satisfy given
requirements for quality (see Part one, section 2).

quality manager

A member of staff who has a defined responsibility and authority for
ensuring that the management system related to quality is implemented and
followed at all times (see Part one, section 1.3(j)).

quality manual

A handbook that describes the various elements of the quality management
system for assuring the quality of the test results generated by a laboratory
(see Part one, sections 2.1–2.2).

quality unit(s)

An organizational unit, independent of production, which fulfi ls
both quality assurance and quality control responsibilities. This can
be in the form of separate quality assurance and quality control or a
single individual or group, depending on the size and structure of the
organization.

reference material

Material sufficiently homogeneous and stable with respect to one or more
specified properties, which has been established to be fit for its intended use
in a measurement process (4).

reference substance (or standard)

An authenticated, uniform material that is intended for use in specifi ed
chemical and physical tests, in which its properties are compared with those
of the product under examination, and which possesses a degree of purity
adequate for its intended use (8).

secondary reference substance (or standard)

A substance whose characteristics are assigned and/or calibrated
by comparison with a primary reference substance. The extent of
characterization and testing of a secondary reference substance may be less
than for a primary reference substance (8).

Note: Often referred to as an “in-house” working standard.

signature (signed)

Record of the individual who performed a particular action or review.
The record can be initials, full handwritten signature, personal seal or
authenticated and secure electronic signature.

specifi cation

A list of detailed requirements (acceptance criteria for the prescribed test
procedures) with which the substance or pharmaceutical product has to
conform to ensure suitable quality.

standard operating procedure (SOP)

An authorized written procedure giving instructions for performing
operations both general and specifi c.

standard uncertainty

Uncertainty of the result of a measurement expressed as a standard deviation
(4, 9, 10).

system suitability test

A test which is performed to ensure that the analytical procedure fulfi ls the
acceptance criteria which had been established during the validation of the
procedure. This test is performed before starting the analytical procedure
and is to be repeated regularly, as appropriate, throughout the analytical
run to ensure that the system’s performance is acceptable at the time of
the test.

validation of an analytical procedure

The documented process by which an analytical procedure (or method) is
demonstrated to be suitable for its intended use.

verification of an analytical procedure

Process by which a pharmacopoeial method or validated analytical
procedure is demonstrated to be suitable for the analysis to be performed.

verification of performance

Test procedure regularly applied to a system (e.g. liquid chromatographic
system) to demonstrate consistency of response.

Part One. Management and infrastructure

1.
Organization and management
1.1
The laboratory, or the organization of which it is part, should be an
entity that is legally authorized to function and can be held legally
responsible.
1.2
The laboratory should be organized and operate so as to meet the
requirements laid down in these guidelines.
1.3
The laboratory should:
(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 management 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)
have a policy and procedure in place to ensure confi dentiality of
— information contained in marketing authorizations,
— transfer of results or reports,
— and to protect data in archives (paper and electronic);
(d) 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 NMRA in the case
of a national pharmaceutical quality control laboratory), and
the relationships between management, technical operations,
support services and the quality management system;
(e)
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
verifi cations;
(f)
ensure the precise allocation of responsibilities, particularly in
the designation of specific units for particular types of medicines;
(g) nominate trained substitutes/deputies for key management and
specialized scientifi c personnel;
(h)
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;
(i)
have management which has overall responsibility for the
technical operations and the provision of resources needed to
ensure the required quality of laboratory operations;
(j)
designate a member of staff as quality manager who,
irrespective of other duties he/she may have, will ensure
compliance with the quality management system. The
nominated quality manager should have direct access to the
highest level of management at which decisions are taken on
laboratory policies or resources;
(k) ensure adequate information flow between staff at all levels.
Staff are to be made aware of the relevance and importance of
their activities;
(l)
ensure the traceability of the sample from receipt, throughout
the stages of testing, to the completion of the analytical test
report;
(m) maintain an up-to-date collection of all specifications and related
documents (paper or electronic) used in the laboratory; and
(n)
have appropriate safety procedures (see Part four).

1.4
The laboratory should maintain a registry with the following
functions:
(a)
receiving, distributing and supervising the consignment of the
samples to the specific units; and
(b)
keeping records on all incoming samples and accompanying
documents.
1.5
In a large laboratory, it is necessary to guarantee communication and
coordination between the staff involved in the testing of the same
sample in different units.
2.
Quality management system
2.1
The laboratory or organization management should establish,
implement and maintain a quality management system appropriate
to the scope of its activities, including the type, range and volume
of testing and/or calibration, validation and verifi cation activities
it undertakes. The laboratory management should ensure that its
policies, systems, programmes, procedures and instructions are
described 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 management system should be communicated,
available to, and understood and implemented by, the appropriate
personnel. The elements of this system should be documented, e.g.
in a quality manual, for the organization as a whole and/or for a
laboratory within the organization.
Note: Quality control laboratories of a manufacturer may have this
information in other documents than a quality manual.

2.2
The quality manual should contain as a minimum:
(a)
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)
a commitment to establishing, implementing and
maintaining an effective quality management system,
(iii) the
laboratory management’s commitment to good
professional practice and quality of testing, calibration,
validation and verifi cation,
(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;

(b)
the structure of the laboratory (organizational chart);
(c) the operational and functional activities pertaining to quality, so
that the extent and the limits of the responsibilities are clearly
defi ned;
(d)
outline of the structure of documentation used in the laboratory
quality management system;
(e)
the general internal quality management procedures;
(f)
references to specific procedures for each test;
(g)
information on the appropriate qualifications, experience and
competencies that personnel are required to possess;
(h)
information on initial and in-service training of staff;
(i)
a policy for internal and external audit;
(j)
a policy for implementing and verifying corrective and
preventive actions;
(k) a policy for dealing with complaints;
(l)
a policy for performing management reviews of the quality
management system;
(m) a policy for selecting, establishing and approving analytical
procedures;
(n) a policy for handling of OOS results;
(o) a policy for the employment of appropriate reference substances
and reference materials;
(p)
a policy for participation in appropriate proficiency testing schemes
and collaborative trials and the evaluation of the performance
(applicable to national pharmaceutical quality control laboratories,
but may be applied by other laboratories); and
(q) a policy to select service providers and suppliers.
2.3
The laboratory should establish, implement and maintain authorized
written SOPs including, but not limited to, administrative and
technical operations, such as:
(a)
personnel matters, including qualifications, training, clothing
and hygiene;
(b) the change control;
(c) internal audit;
(d) dealing with complaints;
(e)
implementation and verification of corrective and preventive
actions;
(f)
the purchase and receipt of consignments of materials (e.g.
samples, reagents);

(g) the procurement, preparation and control of reference substances
and reference materials (8);
(h)
the internal labelling, quarantine and storage of materials;
(i)
the qualification of equipment (11);
(j)
the calibration of equipment;
(k)
preventive maintenance and verification of instruments and equipment;
(l)
sampling, if performed by the laboratory, and visual inspection;
(m) the testing of samples with descriptions of the methods and
equipment used;
(n) atypical and OOS results;
(o)
validation of analytical procedures;
(p)
cleaning of laboratory facilities, including bench tops, equipment,
work stations, clean rooms (aseptic suites) and glassware;
(q) monitoring of environmental conditions, e.g. temperature and
humidity;
(r)
monitoring storage conditions;
(s)
disposal of reagents and solvent samples; and
(t)
safety measures.
2.4
The activities of the laboratory should be systematically and
periodically audited (internally and, where appropriate, by external
audits or inspections) to verify compliance with the requirements
of the quality management system and to apply corrective and
preventive actions, if necessary. The audits should be carried out by
trained and qualifi ed personnel, who are independent of the activity
to be audited. The quality manager is responsible for planning and
organizing internal audits addressing all elements of the quality
management system. Such audits should be recorded, together with
details of any corrective and preventive action taken.
2.5
Management review of quality issues should be regularly undertaken
(at least annually), including:
(a)
reports on internal and external audits or inspections and any
follow-up required to correct any defi ciencies;
(b)
the outcome of investigations carried out as a result of complaints
received, doubtful (atypical) or aberrant results reported in
collaborative trials and/or proficiency tests; and
(c)
corrective actions applied and preventive actions introduced as
a result of these investigations.
3.
Control of documentation
3.1
Documentation is an essential part of the quality management
system. The laboratory should establish and maintain procedures

to control and review all documents (both internally generated and
from external sources) that form part of the quality documentation.
A master list identifying the current version status and distribution
of documents should be established and readily available.

3.2
The procedures should ensure that:
(a)
each document, whether a technical or a quality document, has
a unique identifier, version number and date of implementation;
(b) appropriate, authorized SOPs are available at the relevant
locations, e.g. near instruments;
(c)
documents are kept up to date and reviewed as required;
(d)
any invalid document is removed and replaced with the
authorized, revised document with immediate effect;
(e)
a revised document includes references to the previous
document;
(f)
old, invalid documents are retained in the archives to ensure
traceability of the evolution of the procedures; any copies are
destroyed;
(g)
all relevant staff are trained for the new and revised SOPs; and
(h) quality documentation, including records, is retained for a
minimum of fi ve years.
3.3
A system of change control should be in place to inform staff of new
and revised procedures. The system should ensure that:
(a)
revised documents are prepared by the initiator, or a person who
performs the same function, reviewed and approved at the same
level as the original document and subsequently released by the
quality manager (quality unit); and
(b)
staff acknowledge by a signature that they are aware of applicable
changes and their date of implementation.
4.
Records
4.1
The laboratory should establish and maintain procedures for the
identification, collection, indexing, retrieval, storage, maintenance
and disposal of and access to all quality and technical/scientifi c
records.
4.2
All original observations, including calculations and derived data,
calibration, validation and verification records and fi nal results,
should be retained on record for an appropriate period of time in
accordance with national regulations and, if applicable, contractual
arrangements, whichever is longer. The records should include the
data recorded in the analytical worksheet by the technician or analyst

on consecutively numbered pages with references to the appendices
containing the relevant recordings, e.g. chromatograms and spectra.
The records for each test should contain sufficient information to
permit the tests to be repeated and/or the results to be recalculated,
if necessary. The records should 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.

 Note: The generally accepted retention period of shelf-life plus one
year for a pharmaceutical product on the market and 15 years for an
investigational product is recommended, unless national regulations
are more stringent or contractual arrangements do not require
otherwise.

4.3
All quality and technical/scientific records (including analytical test
reports, certificates of analysis and analytical worksheets) should
be legible, readily retrievable, stored and retained within facilities
that provide a suitable environment that will prevent modifi cation,
damage or deterioration and/or loss. The conditions under which
all original records are stored should be such as to ensure their
security and confidentiality and access to them should be restricted
to authorized personnel. Electronic storage and signatures may also
be employed but with restricted access and in conformance with
requirements for electronic records (12–16).
4.4
Quality management records should include reports from internal
(and external if performed) audits and management reviews, as
well as records of all complaints and their investigations, including
records of possible corrective and preventive actions.
5.
Data-processing equipment
5.1
Detailed recommendations are provided in Appendix 5 to Annex 4 of
the Fortieth report of the WHO Expert Committee on Specifications
for Pharmaceutical Preparations: Supplementary guidelines in
good manufacturing practice: validation. Validation of computerized
systems (12).
5.2
For computers, automated tests or calibration equipment, and the
collection, processing, recording, reporting, storage or retrieval of
test and/or calibration data, the laboratory should ensure that:
(a)
computer software developed by the user is documented in
sufficient detail and appropriately validated or verified as being
suitable for use;

(b) procedures are established and implemented for protecting the
integrity of data. Such procedures should include, but are not
limited to, measures to ensure the integrity and confi dentiality
of data entry or collection and the storage, transmission and
processing of data. In particular, electronic data should be
protected from unauthorized access and an audit trail of any
amendments should be maintained;
(c)
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;
(d) procedures are established and implemented for making,
documenting and controlling changes to information stored in
computerized systems; and
(e)
electronic data should be backed up at appropriate regular intervals
according to a documented procedure. Backed-up data should be
retrievable and stored in such a manner as to prevent data loss.
Note: For further guidance on validation of data-processing equipment,
refer to documents published by the International Society for
Pharmaceutical Engineering (13, 14), US Food and Drug Administration
(15), European Commission (16) and the Official Medicines Control
Laboratories Network of the Council of Europe (17).

6.
Personnel
6.1
The laboratory should have sufficient personnel with the necessary
education, training, technical knowledge and experience for their
assigned functions.
6.2
The technical management should ensure the competence of all
personnel operating specific equipment, instruments or other
devices, who are performing tests and/or calibrations, validations or
verifications. Their duties also involve the evaluation of results as
well as signing analytical test reports and certificates of analysis (see
Part three, sections 18.7–18.11 and 19).
6.3
Staff undergoing training should be appropriately supervised
and should be assessed on completion of the training. Personnel
performing specific tasks should be appropriately qualified in terms
of their education, training and experience, as required.
6.4
The laboratory personnel should be permanently employed or under
contract. The laboratory should ensure that additional technical and
key support personnel who are under contract are supervised and

suffi ciently competent and that their work is in accordance with the
quality management system.

6.5
The laboratory should maintain current job descriptions for all
personnel involved in tests and/or calibrations, validations and
verifications. The laboratory should also maintain records of all
technical personnel, describing their qualifications, training and
experience.
6.6
The laboratory should have the following managerial and technical
personnel:
(a)
a head of laboratory (supervisor), who should have
qualifications appropriate to the position, with extensive
experience in medicines analysis and laboratory management
in a pharmaceutical quality control laboratory in the regulatory
sector or in industry. The head of laboratory is responsible for
the content of certificates of analysis and analytical testing
reports. This person is also responsible for ensuring that:
(i)
all key members of the laboratory staff have the requisite
competence for the required functions and their grades
reflect their responsibilities,
(ii)
the adequacy of existing staffing, management and training
procedures is reviewed periodically,
(iii) the technical management is adequately supervised;
(b) the technical management who ensure that:
(i)
procedures for performing calibration, verification and (re-)
qualification of instruments, monitoring of environmental
and storage conditions are in place and are conducted as
required,
(ii)
regular in-service training programmes to update and
extend the skills of both professionals and technicians are
arranged,
(iii) the safekeeping of any materials subject to poison
regulation or to the controls applied to narcotic and
psychotropic substances (see Part one, section 7.12) kept
in the workplace is under the supervision of an authorized
person,
(iv) national
pharmaceutical quality control laboratories
regularly participate in suitable proficiency testing schemes
and collaborative trials to assess analytical procedures or
reference substances;
(c)
analysts, who should normally 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; and
(e)
a quality manager (see Part one, section 1.3(j)).
7.
Premises
7.1
The laboratory facilities are to be of a suitable size, construction
and location. These facilities are to be designed to suit the functions
and operations to be conducted in them. Rest and refreshment rooms
should be separate from laboratory areas. Changing areas and toilets
should be easily accessible and appropriate for the number of users.
7.2
The laboratory facilities should have adequate safety equipment
located appropriately and measures should be in place to ensure good
housekeeping. Each laboratory should be equipped with adequate
instruments and equipment, including work benches, work stations
and fume hoods.
7.3
The environmental conditions, including lighting, energy sources,
temperature, humidity and air pressure, are to be appropriate to the
functions and operations to be performed. The laboratory should
ensure that the environmental conditions are monitored, controlled
and documented and do not invalidate the results or adversely affect
the quality of the measurements.
7.4
Special precautions should be taken and, if necessary, there should
be a separate and dedicated unit or equipment (e.g. isolator, laminar
flow work bench) to handle, weigh and manipulate highly toxic
substances, including genotoxic substances. Procedures should be in
place to avoid exposure and contamination.
7.5
Archive facilities should be provided to ensure the secure storage and
retrieval of all documents. The design and condition of the archives
should be such as to protect the contents from deterioration. Access
to the archives should be restricted to designated personnel.
7.6
Procedures should be in place for the safe removal of types of waste
including toxic waste (chemical and biological), reagents, samples,
solvents and air fi lters.
7.7
Microbiological testing, if performed, should be contained in an
appropriately designed and constructed laboratory unit. For further
guidance see the draft working document WHO guideline on good

practices for pharmaceutical microbiology laboratories (reference
QAS/09.297).

7.8
If in vivo biological testing (e.g. rabbit pyrogen test) is included in
the scope of the laboratory activities then the animal houses should
be isolated from the other laboratory areas with a separate entrance
and air-conditioning system. The relevant guidance and regulations
are to be applied (18).
Laboratory storage facilities

7.9
The storage facilities should be well organized for the correct storage
of samples, reagents and equipment.
7.10
Separate storage facilities should be maintained for the secure
storage of samples, retained samples (see Part three, section 20),
reagents and laboratory accessories (see Part two, sections 10.13–
10.14), reference substances and reference materials (see Part two,
section 11). Storage facilities should be equipped to store material,
if necessary, under refrigeration (2–8°C) and frozen (-20°C) and
securely locked. All specified storage conditions should be controlled,
monitored and records maintained. Access should be restricted to
designated personnel.
7.11
Appropriate safety procedures should be drawn up and rigorously
implemented wherever toxic or flammable reagents are stored or
used. The laboratory should provide separate rooms or areas for
storing flammable substances, fuming and concentrated acids and
bases, volatile amines and other reagents, such as hydrochloric
acid, nitric acid, ammonia and bromine. Self-igniting materials,
such as metallic sodium and potassium, should also be stored
separately. Small stocks of acids, bases and solvents may be kept
in the laboratory store but the main stocks of these items should
preferably be retained in a store separate from the laboratory
building.
7.12
Reagents subject to poison regulations or to the controls applied to
narcotic and psychotropic substances should be clearly marked as
required by national legislation. They should be kept separately from
other reagents in locked cabinets. A designated responsible member
of staff should maintain a register of these substances. The head of
each unit should accept personal responsibility for the safekeeping
of any of these reagents kept in the workplace.
7.13
Gases also should be stored in a dedicated store, if possible isolated
from the main building. Wherever possible gas bottles in the
laboratory are to be avoided and distribution from an external gas

store is preferred. If gas bottles are present in the laboratory they
should be safely secured.

Note: Consideration should be given to the installation of gas generators.

8. Equipment, instruments and other devices
8.1
Equipment, instruments and other devices should be designed,
constructed, adapted, located, calibrated, qualifi ed, verifi ed 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
when necessary.
8.2
The laboratory should 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
samples and the processing and analysis of test and/or calibration data).
8.3
Equipment, instruments and other devices, including those used for
sampling, should meet the laboratory’s requirements and comply
with the relevant standard specifications, as well as being verifi ed,
qualified and/or calibrated regularly (see Part two, section 12).

9. Contracts
Purchasing services and supplies

9.1
The laboratory should have a procedure for the selection and
purchasing of services and supplies it uses that affect the quality of
testing.
9.2
The laboratory should evaluate suppliers of critical consumables, supplies
and services which affect quality of testing, maintain records of these
evaluations and list approved suppliers, which have been demonstrated to
be of a suitable quality with respect to the requirements of the laboratory.
Subcontracting of testing

9.3
When a laboratory subcontracts work, which may include specifi c
testing, it is to be done with organizations approved for the type
of activity required. The laboratory is responsible for periodically
assessing the competence of a contracted organization.
9.4
When a laboratory performs testing for a customer and subcontracts
part of the testing, it should advise the customer of the arrangement
in writing and, if appropriate, gain his or her approval.

9.5
There should be a written contract which clearly establishes the
duties and responsibilities of each party, defines the contracted
work and any technical arrangements made in connection with it.
The contract should permit the laboratory to audit the facilities and
competencies of the contracted organization and ensure the access of
the laboratory to records and retained samples.
9.6
The contracted organization should not pass to a third party any
work entrusted to it under contract without the laboratory’s prior
evaluation and approval of the arrangements.
9.7
The laboratory should maintain a register of all subcontractors
that it uses and a record of the assessment of the competence of
subcontractors.
9.8
The laboratory takes the responsibility for all results reported,
including those furnished by the subcontracting organization.
Part two. Materials, equipment,
instruments and other devices

10.
Reagents
10.1
All reagents and chemicals, including solvents and materials used in
tests and assays, should be of appropriate quality.
10.2
Reagents should be purchased from reputable, approved suppliers
and should be accompanied by the certificate of analysis, and the
material safety data sheet, if required.
10.3
In the preparation of reagent solutions in the laboratory:
(a)
responsibility for this task should be clearly specified in the job
description of the person assigned to carry it out; and
(b) prescribed procedures should be used which are in accordance
with published pharmacopoeial or other standards where
available. Records should be kept of the preparation and
standardization of volumetric solutions.
10.4
The labels of all reagents should clearly specify:
(a) content;
(b) manufacturer;
(c)
date received and date of opening of the container;
(d) concentration, if applicable;
(e)
storage conditions; and
(f)
expiry date or retest date, as justifi ed.

10.5
The labels of reagent solutions prepared in the laboratory should
clearly specify:
(a) name;
(b) date of preparation and initials of technician or analyst;
(c)
expiry date or retest date, as justifi ed; and
(d) concentration, if applicable.
10.6
The labels for volumetric solutions prepared in the laboratory should
clearly specify:
(a) name;
(b) molarity (or concentration);
(c)
date of preparation and initials of technician/analyst;
(d) date of standardization and initials of technician/analyst; and
(e) standardization factor.
Note: The laboratory should ensure that the volumetric solution is
suitable for use at the time of use.

10.7
In the transportation and subdivision of reagents:
(a)
whenever possible they should be transported in the original
containers; and
(b)
when subdivision is necessary, clean containers should be used
and appropriately labelled.
Visual inspection

10.8
All reagent containers should be visually inspected to ensure that the
seals are intact, both when they are delivered to the store and when
they are distributed to the units.
10.9
Reagents that appear to have been tampered with should be rejected;
however, this requirement may exceptionally be waived if the
identity and purity of the reagent concerned can be confi rmed by
testing.
Water

10.10 Water should be considered as a reagent. The appropriate grade for a
specific test should be used as described in the pharmacopoeias or in
an approved test when available.
10.11 Precautions should be taken to avoid contamination during its supply,
storage and distribution.
10.12 The quality of the water should be verified regularly to ensure that
the various grades of water meet the appropriate specifi cations.

Storage

10.13 Stocks of reagents should be maintained in a store under the
appropriate storage conditions (ambient temperature, under
refrigeration or frozen). The store should contain a supply of clean
bottles, vials, spoons, funnels and labels, as required, for dispensing
reagents from larger to smaller containers. Special equipment may
be needed for the transfer of larger volumes of corrosive liquids.
10.14 The person in charge of the store is responsible for looking after
the storage facilities and their inventory and for noting the expiry
date of chemicals and reagents. Training may be needed in handling
chemicals safely and with the necessary care.
11. Reference substances and reference materials
11.1
Reference substances (primary reference substances or secondary
reference substances (8)) are used for the testing of a sample.
Note: Pharmacopoeial reference substances should be employed when
available and appropriate for the analysis. When a pharmacopoeia
reference substance has not been established then the manufacturer
should use its own reference substance.

11.2
Reference materials may be necessary for the calibration and/or
qualification of equipment, instruments or other devices.
Registration and labelling

11.3
An identification number should be assigned to all reference
substances, except for pharmacopoeial reference substances.
11.4
A new identification number should be assigned to each new batch.
11.5
This number should be marked on each vial of the reference
substance.
11.6
The identification number should be quoted on the analytical
worksheet every time the reference substance is used (see Part three,
section 15.5). In the case of pharmacopoeial reference substances the
batch number and/or the batch validity statement should be attached
to the worksheet.
11.7
The register for all reference substances and reference materials
should be maintained and contain the following information:
(a) the identification number of the substance or material;
(b) a precise description of the substance or material;
(c) the source;

(d) the date of receipt;
(e)
the batch designation or other identifi cation code;
(f)
the intended use of the substance or material (e.g. as an infrared
reference substance or as an impurity reference substance for
thin-layer chromatography);
(g) the location of storage in the laboratory, and any special storage
conditions;
(h)
any further necessary information (e.g. the results of visual
inspections);
(i)
expiry date or retest date;
(j)
certificate (batch validity statement) of a pharmacopoeial
reference substance and a certified reference material which
indicates its use, the assigned content, if applicable, and its
status (validity); and
(k)
in the case of secondary reference substances prepared and
supplied by the manufacturer, the certificate of analysis.
11.8
A person should be nominated to be responsible for reference
substances and reference materials.
11.9
If a national pharmaceutical quality control laboratory is required to
establish reference substances for use by other institutions, a separate
reference substances unit should be established.
11.10 In addition a file should be kept in which all information on the
properties of each reference substance is entered including the safety
data sheets.
11.11 For reference substances prepared in the laboratory, the fi le should
include the results of all tests and verifi cations used to establish the
reference substances and expiry date or retest date; these should be
signed by the responsible analyst.
Retesting (monitoring)

11.12 All reference substances prepared in the laboratory or supplied
externally should be retested at regular intervals to ensure that
deterioration has not occurred. The interval for retesting depends
on a number of factors, including stability of the substance, storage
conditions employed, type of container and extent of use (how often
the container is opened and closed). More detailed information on
the handling, storage and retesting of reference substances is given
in the WHO General guidelines for the establishment, maintenance
and distribution of chemical reference substances (8).
11.13 The results of these tests should be recorded and signed by the
responsible analyst.

11.14
In the case that the result of retesting of a reference substance is noncompliant,
a retrospective check of tests performed using this reference
substance since its previous examination should be carried out. For
evaluation of outcomes of retrospective checks and consideration of
possible corrective actions, risk analysis should be applied.
11.15 Pharmacopoeial reference substances are regularly retested and the
validity (current status) of these reference substances is available
from the issuing pharmacopoeia by various means, e.g. web sites
or catalogues. Retesting by the laboratory is not necessary, provided
the reference substances are stored in accordance with the storage
conditions indicated.