12.9
Procedures should include instructions for the safe handling, transport
and storage of measuring equipment. On reinstallation, requalifi cation
of the equipment is required to ensure that it functions properly.
12.10 Maintenance procedures should be established, e.g. regular servicing
should be performed by a team of maintenance specialists, whether
internal or external, followed by verification of performance.
12.11 Equipment, instruments and other devices, either subjected to
overloading or mishandling, giving suspect results, shown to be
defective or outside specified limits, should be taken out of service
and clearly labelled or marked. Wherever possible they should not be
used until they have been repaired and requalifi ed.

12.12 When the equipment, instruments and other devices are outside the
direct control of the laboratory for a certain period or have undergone
major repair, the laboratory should requalify the equipment to ensure
its suitability for use.
Note: For further guidance on calibration, verification of performance
and qualification of equipment refer to:

•
Procedures for verifying and calibrating refractometers,
thermometers used in determinations of melting temperatures
and potentiometers for pH determinations and methods for
verifying the reliability of scales for ultraviolet and infrared
spectrophotometers and spectrofluorometers in The International
Pharmacopoeia (19);
•
Specific guidelines for qualification of equipment elaborated by
the European Network of Official Medicines Control Laboratories
(OMCL) (20); and
•
General chapter of the US Pharmacopeia on Analytical instrument
qualifi cation (21).
13. Traceability
13.1
The result of an analysis should be traceable, when appropriate,
ultimately to a primary reference substance.
13.2
All calibrations or qualification of instruments should be traceable
to certified reference materials and to SI units (metrological
traceability).
Part Three. Working procedures

14. Incoming samples
Sections 14.1–14.3 are applicable to national pharmaceutical quality control
laboratories.

14.1
Samples received by a laboratory may be for compliance testing or for
investigative testing. Samples for compliance testing include routine
samples for control, samples suspected of not complying with the
specifications or samples submitted in connection with a marketing
authorization process. Close collaboration with the providers of the
samples is important. In particular it is important that the sample is
large enough to enable, if required, a number of replicate tests to be
carried out (see Part three, section 14.3) and for part of the sample to
be retained (see Part three, section 20).

14.2
Samples for investigative testing may be submitted by various
sources including customs, police and medicines inspectors. These
samples comprise suspicious, illegal or counterfeit substances or
products. Usually, the primary objective of investigative testing
is to identify the substance or the ingredient in the product and, if
sufficient substance or product is available, to estimate the purity or
content. Well-documented screening procedures should be in place
as well as confirmatory analytical procedures to positively identify
the substance or the ingredient(s). If an estimation of the content of
an identified ingredient is required then an appropriate quantitative
analytical procedure should be applied. The value obtained should
be reported with an indication of the uncertainty of measurement if
required (see Part three, section 18.10).
14.3
It is common for a sample to be taken and divided into three
approximately equal portions for submission to the laboratory:
— one for immediate testing;

— the second for confirmation of testing if required; and
— the third for retention in case of dispute.
14.4
If the laboratory is responsible for sampling of substances, materials
or products for subsequent testing then it should have a sampling
plan and an internal procedure for sampling available to all analysts
and technicians working in the laboratory. Samples should be
representative of the batches of material from which they are taken
and sampling should be carried out so as to avoid contamination
and other adverse effects on quality, or mix-up of or by the material
being sampled. All the relevant data related to sampling should be
recorded.
Note: Guidelines for sampling of pharmaceutical products and
related materials were adopted by the WHO Expert Committee on
Specifications for Pharmaceutical Preparations at its thirty-ninth
meeting (22).

Test request

14.5
A standard test request form should be filled out and should
accompany each sample submitted to the laboratory. In the case of a
pharmaceutical manufacturer’s laboratory the requirements may be
given in the master production instructions.
14.6
The test request form should provide or leave space for the following
information:
(a) the name of the institution or inspector that supplied the sample;
(b) the source of the material;

(c)
a full description of the medicine, including its composition,
international nonproprietary name (INN) (if available) and
brand name(s);
(d) dosage form and concentration or strength, the manufacturer,
the batch number (if available) and the marketing authorization
number;
(e)
the size of the sample;
(f)
the reason for requesting the analysis;
(g)
the date on which the sample was collected;
(h) the size of the consignment from which it was taken, when
appropriate;
(i)
the expiry date (for pharmaceutical products) or retest date (for
APIs and pharmaceutical excipients);
(j)
the specification to be used for testing;
(k)
a record of any further comments (e.g. discrepancies found or
associated hazard); and
(l)
the required storage conditions.
14.7
The laboratory should review the test request to ensure that:
(a)
the requirements are adequately defined and the laboratory has
the capability and resources to meet them; and
(b) the appropriate tests and/or methods are selected and are capable
of meeting customers’ requirements.
Any issue should be resolved with the originator of the request for
analysis before testing starts and a record of the review should be
kept.

Registration and labelling

14.8
All newly delivered samples and accompanying documents (e.g.
the test request) should be assigned a registration number. Separate
registration numbers should be assigned to requests referring to two
or more medicines, different dosage forms, or different batches of the
same medicine or different sources of the same batch. If applicable, a
unique registration number should also be assigned to any incoming
retained sample (see Part three, section 20).
14.9
A label bearing the registration number should be affixed to each
container of the sample. Care should be taken to avoid obscuring any
other markings or inscriptions.
14.10 A register should be kept, which may be a record book, a card fi le
or data-processing equipment, in which the following information is
recorded:

(a) the registration number of the sample;
(b) the date of receipt; and
(c) the specific unit to which the sample was forwarded.
Visual inspection of the submitted sample

14.11 The sample received should be visually inspected by laboratory staff
to ensure that the labelling conforms with the information contained
in the test request. The findings should be recorded, dated and signed.
If discrepancies are found, or if the sample is obviously damaged,
this fact should be recorded without delay on the test request form.
Any queries should be immediately referred back to the provider of
the sample.
Storage

14.12 The sample prior to testing, the retained sample (see Part three,
section 20) and any portions of the sample remaining after
performance of all the required tests should be stored safely, taking
into account the storage conditions (22, 23) specified for the sample.
Forwarding to testing

14.13 The specific unit to which the sample is sent for testing is determined
by the person responsible.
14.14 The examination of a sample should not be started before the relevant
test request has been received.
14.15 The sample should be properly stored until all relevant documentation
has been received.
14.16 A request for analysis may be accepted verbally only in emergencies.
All details should immediately be placed on record pending the
receipt of written confi rmation.
14.17 Unless a computerized system is used, copies or duplicates of all
documentation should accompany each numbered sample when sent
to the specifi c unit.
14.18
Testing should be performed as described under Part three, section 17.
15. Analytical worksheet
15.1
The analytical worksheet is an internal document to be used by the
analyst for recording information about the sample, the test procedure,
calculations and the results of testing. It is to be complemented by
the raw data obtained in the analysis.

Purpose

15.2
The analytical worksheet contains documentary evidence either:
—
to confirm that the sample being examined is in accordance with
the requirements; or
—
to support an OOS result (see Part three, sections 18.1–18.3).
Use

15.3
A separate analytical worksheet should usually be used for each
numbered sample or group of samples.
15.4
Analytical worksheets from different units relating to the same
sample should be assembled together.
Content

15.5
The analytical worksheet should provide the following information:
(a)
the registration number of the sample (see Part three,
section 14.9);
(b) page numbering, including the total number of pages (and
including annexes);
(c)
the date of the test request;
(d)
the date on which the analysis was started and completed;
(e)
the name and signature of the analyst;
(f)
a description of the sample received;
(g) references to the specifications and a full description of test
methods by which the sample was tested, including the limits;
(h) the identification of the test equipment used (see Part two,
section 12.1);
(i)
the identification number of any reference substance used (see
Part two, section 11.5);
(j)
if applicable, the results of the system suitability test;
(k) the identification of reagents and solvents employed;
(l)
the results obtained;
(m) the interpretation of the results and the final conclusions (whether
or not the sample was found to comply with the specifi cations),
approved and signed by the supervisor; and
(n)
any further comments, for example, for internal information (see
Part three, section 17.1), or detailed notes on the specifi cations
selected and the methods of assessment used (see Part three,
section 15.9), or any deviation from the prescribed procedure,
which should be approved and reported, or whether and when
portions of the sample were forwarded to other units for special
tests and the date on which the results were received.

15.6
All values obtained from each test, including blank results, should
immediately be entered on the analytical worksheet and all graphical
data, whether obtained from recording instruments or plotted by
hand, should be attached or be traceable to an electronic record fi le
or document where the data are available.
15.7
The completed analytical worksheet should be signed by the responsible
analyst(s), verified and approved and signed by the supervisor.
15.8
When a mistake is made in an analytical worksheet or when data
or text need to be amended, the old information should be deleted
by putting a single line through it (it should not be erased or made
illegible) and the new information added alongside. All such
alterations should be signed by the person making the correction and
the date of the change inserted. The reason for the change should
also be given on the worksheet (suitable procedures should be in
place for amending electronic worksheets).
Selection of the specifications to be used

15.9
The specification necessary to assess the sample may be that
given in the test request or master production instructions. If
no precise instruction is given, the specification in the offi cially
recognized national pharmacopoeia may be used or, failing this, the
manufacturer’s officially approved or other nationally recognized
specification. If no suitable method is available:
(a)
the specification contained in the marketing authorization or
product licence may be requested from the marketing authorization
holder or manufacturer and verified by the laboratory; or
(b) the requirements may be set by the laboratory itself on the basis
of published information and any procedure employed is to be
validated by the testing laboratory (see Part three, section 16).
15.10 For
offi cial specifications the current version of the relevant
pharmacopoeia should be available.
Filing

15.11 The analytical worksheet should be kept safely together with any
attachments, including calculations and recordings of instrumental
analyses.
16.
Validation of analytical procedures
16.1
All analytical procedures employed for testing should be suitable for
the intended use. This is demonstrated by validation (24). Validation

also serves to establish acceptance criteria for system suitability
tests which are subsequently employed for the verification of the
analytical procedure before analysis.

16.2
Validation should be performed according to a validation protocol,
which includes analytical performance characteristics to be verifi ed
for various types of analytical procedures. Typical characteristics
which should be considered are listed in Table 1 (in the development
phase of an analytical procedure, robustness, i.e. the ability of the
procedure to provide results of acceptable accuracy and precision
under a variety of conditions should also be considered). The results
are to be documented in the validation report.
Table 1

Characteristics to consider during validation of analytical procedures

Type of analytical
Procedure
Identification Testing for impurities Assay
Quantitative
tests
Limit
tests
• dissolution
(measurement
only)
• content/potency
Characteristics
Accuracy
Precision
Repeatability
Intermediate
precisiona
Specifi city
Detection limit
Quantitation limit
Linearity
Range
–
–
–
+
–
–
–
–
+ –
+ –
+ –
+ +
–b +
+ –
+ –
+ –
+
+
+
+
–
–
+
+

– Characteristic is normally not evaluated; + characteristic should normally be evaluated.
a

In cases where a reproducibility study has been performed, intermediate precision is not needed.
b May be needed in some cases.

16.3
Pharmacopoeial methods are considered to be validated for the
intended use as prescribed in the monograph(s). However, the
laboratory should also confirm that, for example, for a particular
finished pharmaceutical product (FPP) examined for the fi rst time,
no interference arises from the excipients present, or that for an API,
impurities coming from a new route of synthesis are adequately
differentiated. If the pharmacopoeial method is adapted for another
use then it should be validated for such a use to demonstrate that it is
fi t-for-purpose.

16.4
System suitability testing is an integral part of many analytical
procedures. The tests are based on the fact that the equipment,
electronics, analytical operations and samples to be analysed
contribute to the system. Which system suitability tests are to be
applied depends on the type of procedure to be used. System
suitability tests are employed for the verification of pharmacopoeial
methods or validated analytical procedures and should be performed
prior to the analysis. Provided the system suitability criteria are
fulfilled the method or procedure is considered to be suitable for the
intended purpose.
Note: If a large number of samples is being analysed in sequence, then
appropriate system suitability tests are to be performed throughout
the sequence to demonstrate that the performance of the procedure
is satisfactory.

 Verification is not required for basic pharmacopoeial methods such
as (but not limited to) pH, loss on drying and wet chemical methods.

16.5
A major change to the analytical procedure, or in the composition
of the product tested, or in the synthesis of the API, will require
revalidation of the analytical procedure.
Note: Further guidance on validation of analytical procedures is
available in the following:

•
Guideline elaborated by the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) (25);
•
Guideline elaborated by the European Network of Official
Medicines Control Laboratories (OMCL) (26);
•
General chapters of the US Pharmacopeia on Validation of
compendial procedures and on Verification of compendial
procedures (27).
17. Testing
17.1
The sample should be tested in accordance with the work plan of
the laboratory after completion of the preliminary procedures. If
this is not feasible the reasons should be noted, e.g. in the analytical
worksheet (see Part three, section 15), and the sample should be stored
in a special place which is kept locked (see Part three, section 14.12).
17.2
Specific tests required may need to be carried out by another unit or
by a specialized external laboratory (see Part one, section 9). The
responsible person should prepare the request and arrange for the

transfer of the required number of units (bottles, vials or tablets) from
the sample. Each of these units should bear the correct registration
number. When the analytical test report contains results of tests
performed by subcontractors, these results should be identifi ed as
such.

17.3
Detailed guidance on official pharmacopoeial requirements is
usually given in the general notices and specific monographs of the
pharmacopoeia concerned. Test procedures should be described in
detail and should provide sufficient information to allow properly
trained analysts to perform the analysis in a reliable manner. Where
system suitability criteria are defined in the method they should be
fulfilled. Any deviation from the test procedure should be approved
and documented.
18.
Evaluation of test results
18.1
Test results should be reviewed and, where appropriate, evaluated
statistically after completion of all the tests to determine whether
they are mutually consistent and if they meet the specifi cations used.
The evaluation should take into consideration the results of all the
tests (all test data). Whenever doubtful (atypical) results are obtained
they should be investigated. The complete testing procedure needs
to be checked according to the internal quality management system
(see also Part one, section 2).
18.2
When a doubtful result (suspected OOS result) has been identifi ed, a
review of the different procedures applied during the testing process
is to be undertaken by the supervisor with the analyst or technician
before retesting is permitted. The following steps should be followed:
(a) confirm
with the analyst or technician that the appropriate
procedure(s) was (were) applied and followed correctly;
(b)
examine the raw data to identify possible discrepancies;
(c)
check all calculations;
(d) check that the equipment used was qualified and calibrated, and
that system suitability tests were performed and were acceptable;
(e)
ensure that the appropriate reagents, solvents and reference
substances were used;
(f) confirm that the correct glassware was used; and
(g) ensure that original sample preparations are not discarded until
the investigation is complete.
18.3
The identification of an error which caused an aberrant result will
invalidate the result and a retest of the sample will be necessary.

Doubtful results can be rejected only if they are clearly due to an
identified error. Sometimes the outcome of the investigation is
inconclusive — no obvious cause can be identified — in which case
a confirmatory determination is to be performed by another analyst
who should be at least as experienced and competent in the analytical
procedure as the original analyst. A similar value would indicate an
OOS result. However, further confirmation using another validated
method, if available, may be advised.

18.4
An SOP should be in place for the conduct of an investigation of
an OOS test result. The SOP should give clear guidance on the
number of retests allowed (based on sound statistical principles). All
investigations and their conclusions should be recorded. In the event
of an error, any corrective action taken and any preventive measure
introduced should be recorded and implemented.
18.5
All individual results (all test data) with acceptance criteria should
be reported.
18.6
All conclusions should be entered on the analytical worksheet (see
Part three, section 15) by the analyst and signed by the supervisor.
Note: Further guidance on evaluation and reporting of test results is
available in the following:

•
Guideline elaborated by the US Food and Drug Administration (5);
•
Guideline elaborated by the European Network of Official
Medicines Control Laboratories (OMCL) (28).
Analytical test report

18.7
The analytical test report is a compilation of the results and states the
conclusions of the examination of a sample. It should be:
(a) issued by the laboratory; and
(b) based on the analytical worksheet (see Part three, section 15).
18.8
Any amendments to the original analytical test report will require the
issue of a new corrected document.
18.9
Pharmacopoeial content limits are set taking into account the
uncertainty of measurement, and the production capability and
acceptance criteria for an analytical result should be predefi ned.
Under presently applicable rules neither the pharmacopoeias nor the
NMRAs require the value found to be expressed with its associated
expanded uncertainty for compliance testing. However, when
reporting the results of investigative testing, although the primary
objective is to identify a substance in the sample, a determination of

its concentration may be also requested, in which case the estimated
uncertainty should also be given.

18.10 Measurement uncertainty can be estimated in a number of ways,
e.g.:
(a) by
preparing an uncertainty budget for each uncertainty
component identified in an analytical procedure (bottom-up
approach);
(b)
from validation data and control charts (29); and
(c)
from the data obtained from proficiency tests or collaborative
trials (top-down approach).
Note: Further guidance can be found in various guidelines (9, 10, 30,
31, 32).

Content of the analytical test report

18.11 The analytical test report should provide the following information:
(a)
the laboratory registration number of the sample;
(b)
the laboratory test report number;
(c)
the name and address of the laboratory testing the sample;
(d) the name and address of the originator of the request for analysis;
(e)
the name, description and batch number of the sample, where
appropriate;
(f)
an introduction giving the background to and the purpose of the
investigation;
(g) a reference to the specifications used for testing the sample or
a detailed description of the procedures employed (sample for
investigative testing), including the limits;
(h) the results of all the tests performed or the numerical results with
the standard deviation of all the tests performed (if applicable);
(i)
a discussion of the results obtained;
(j)
a conclusion as to whether or not the sample(s) was (were)
found to be within the limits of the specifi cations used, or for a
sample for investigative testing, the substance(s) or ingredient(s)
identifi ed;
(k)
the date on which the test(s) was (were) completed;
(l)
the signature of the head of the laboratory or authorized person;
(m) the name and address of the original manufacturer and, if
applicable, those of the repacker and/or trader;
(n)
whether or not the sample(s) complies (comply) with the
requirements;
(o)
the date on which the sample was received;
(p)
the expiry date or retest date, if applicable; and

(q) a statement indicating that the analytical test report, or any
portion thereof, cannot be reproduced without the authorization
of the laboratory.
19.
Certificate of analysis
19.1
A certificate of analysis is prepared for each batch of a substance or
product and usually contains the following information:
(a)
the registration number of the sample;
(b) date of receipt;
(c)
the name and address of the laboratory testing the sample;
(d) the name and address of the originator of the request for analysis;
(e)
the name, description and batch number of the sample where
appropriate;
(f)
the name and address of the original manufacturer and, if
applicable, those of the repacker and/or trader;
(g) the reference to the specification used for testing the sample;
(h) the results of all tests performed (mean and standard deviation,
if applicable) with the prescribed limits;
(i)
a conclusion as to whether or not the sample was found to be
within the limits of the specifi cation;
(j)
expiry date or retest date if applicable;
(k)
date on which the test(s) was (were) completed; and
(l)
the signature of the head of laboratory or other authorized person.
Note: The Guideline on model certificate of analysis was adopted by
the WHO Expert Committee on Specifications for Pharmaceutical
Preparations at its thirty-sixth meeting (3).

20.
Retained samples
20.1
Samples should be retained as required by the legislation or by the
originator of the request for analysis. There should be a suffi cient
amount of retained sample to allow at least two re-analyses. The
retained sample should be kept in its fi nal pack.
Part four. Safety

21.
General rules
21.1
General and specific safety instructions refl ecting identifi ed risk,
should be made available to each staff member and supplemented
regularly as appropriate (e.g. with written material, poster displays,
audiovisual material and occasional seminars).

21.2
General rules for safe working in accordance with national regulations
and SOPs normally include the following requirements:
(a)
safety data sheets should be available to staff before testing is
carried out;
(b) smoking, eating and drinking in the laboratory should be
prohibited;
(c)
staff should be familiar with the use of fi re-fi ghting equipment,
including fire extinguishers, fire blankets and gas masks;
(d)
staff should wear laboratory coats or other protective clothing,
including eye protection;
(e)
special care should be taken, as appropriate, in handling, for
example, highly potent, infectious or volatile substances;
(f)
highly toxic and/or genotoxic samples should be handled in a
specially designed facility to avoid the risk of contamination;
(g)
all containers of chemicals should be fully labelled and include
prominent warnings (e.g. “poison”, “fl ammable”, “radioactive”)
whenever appropriate;
(h) adequate insulation and spark-proofing should be provided for
electrical wiring and equipment, including refrigerators;
(i)
rules on safe handling of cylinders of compressed gases should
be observed and staff should be familiar with the relevant colour
identifi cation codes;
(j)
staff should be aware of the need to avoid working alone in the
laboratory; and
(k) first-aid materials should be provided and staff instructed in
first-aid techniques, emergency care and the use of antidotes.
21.3
Protective clothing should be available, including eye protection,
masks and gloves. Safety showers should be installed. Rubber suction
bulbs should be used on manual pipettes and siphons. Staff should be
instructed in the safe handling of glassware, corrosive reagents and
solvents and particularly in the use of safety containers or baskets to
avoid spillage from containers. Warnings, precautions and instructions
should be given for work with violent, uncontrollable or dangerous
reactions when handling specific reagents (e.g. mixing water and
acids, or acetone–chloroform and ammonia), fl ammable products,
oxidizing or radioactive agents and especially biologicals such as
infectious agents. Peroxide-free solvents should be used. Staff should
be aware of methods for the safe disposal of unwanted corrosive or
dangerous products by neutralization or deactivation and of the need
for safe and complete disposal of mercury and its salts.
21.4
Poisonous or hazardous products should be singled out and labelled
appropriately, but it should not be taken for granted that all other

chemicals and biologicals are safe. Unnecessary contact with
reagents, especially solvents and their vapours, should be avoided.
The use of known carcinogens and mutagens as reagents should
be limited or totally excluded if required by national regulations.
Replacement of toxic solvents and reagents by less toxic materials
or reduction of their use should always be the aim, particularly when
new techniques are developed.

References

 1.
Quality assurance of pharmaceuticals. A compendium of guidelines and
related materials. Vol. 2, 2nd updated edition. Good manufacturing practices
and inspection. Geneva, World Health Organization, 2007.
2. International Organization for Standardization. General requirements for the
competence of testing and calibration laboratories. ISO/IEC 17025:2005.
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for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health
Organization, 2002, Annex 10 (WHO Technical Report Series, No. 902).
4.
International vocabulary of metrology — Basic and general concepts and
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(JCGM) 200:2008 (http://www.bipm.org/utils/common/documents/jcgm/
JCGM_200_2008.pdf).
5.
Guidance for industry — Investigating out-of-specification test results for
pharmaceutical production. US Food and Drug Administration, Center for
Drug Evaluation and Research (CDER), October 2006 (http://www.fda.gov/
downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM070287.pdf).
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Committee on Specifications for Pharmaceutical Preparations. Thirty-fifth
report. Geneva, World Health Organization, 1999, Annex 6 (WHO Technical
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World Health Organization, 1999, Annex 5 (WHO Technical Report Series,
No. 885).
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repeatability, reproducibility and trueness estimates in measurement
uncertainty estimation. 2004 (ISO Guide 21748).
10. International Organization for Standardization/International Electrotechnical
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of uncertainty in measurement (GUM:1995) 2008 (ISO/IEC Guide 98-3).

11. Supplementary guidelines in good manufacturing practice: validation.
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Specifications for Pharmaceutical Preparations. Fortieth report. Geneva,
World Health Organization, 2006, Annex 4, Appendix 6 (WHO Technical
Report Series, No. 937).
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13.
Good automated manufacturing practice (GAMP) Good Practice Guides:
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14.
Good automated manufacturing practice (GAMP) Good Practice Guides:
Electronic data archiving. International Society for Pharmaceutical
Engineering (ISPE),2007.
15.
Title 21 Code of Federal Regulations (21 CFR Part 11): Electronic records;
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status of 21 CFR Part 11 Guidance is located under Regulations and
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http://www.fda.gov/OHRMS/DOCKETS/98fr/03-4312.pdf
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pdfs-en/anx11en.pdf).
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of computerised systems — core document (http://www.edqm.eu/site/
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and its annexes:
—
PA/PH/OMCL (08) 87 2R — Annex 1: Validation of computerised
calculation systems: example of validation of in-house software
(http://www.edqm.eu/site/NEW_Annex_1_Validation_of_computerised_
calculationpdf-en-8391-2.html),
—
PA/PH/OMCL (08) 88 R — Annex 2: Validation of Databases (DB),
Laboratory Information Management Systems (LIMS) and Electronic
Laboratory Notebooks (ELN) (http://www.edqm.eu/site/NEW_Annex_2_
Validation_of_Databases_DB_Laboratory_pdf-en-8392-2.html),
—
PA/PH/OMCL (08) 89 R — Annex 3: Validation of computers as part of
test equipment (http://www.edqm.eu/site/NEW_Annex_3_Validation_
of_computers_as_part_of_tespdf-en-8393-2.html).
18.
Guidelines for good laboratory practice and guidelines for the testing
of chemicals. Organisation for Economic Co-operation and Development
(OECD), Environment Directorate, Chemical Safety. (http://www.oecd.org/
document/63/0,3343,en_2649_34381_2346175_1_1_1_1,00.html).
19.
The International Pharmacopoeia, Fourth Edition (including First Supplement).
Vol. 2. Methods of analysis. Geneva, World Health Organization, 2008
(http://www.who.int/phint).

20. Official Medicines Control Laboratories Network of the Council of Europe,
Quality Assurance Documents:
—
PA/PH/OMCL (08) 73 — Qualification of equipment (http://www.edqm.eu/
medias/fi chiers/NEW_Qualifi cation_of_equipment_core_document.pdf),
—
PA/PH/OMCL (07) 17 DEF –Annex 1: Qualification of HPLC equipment
(http://www.edqm.eu/medias/fi chiers/Annex_1_Qualifi cation_of_HPLC_
Equipment.pdf),
—
PA/PH/OMCL (06) 86 DEF — Annex 2: Qualification of GC Equipment
(http://www.edqm.eu/medias/fi chiers/Annex_2_Qualifi cation_of_GC_
equipment.pdf),
—
PA/PH/OMCL (07) 11 DEF CORR — Annex 3: Qualification of UV-visible
spectrophotometers (http://www.edqm.eu/medias/fichiers/Annex_3_
Qualifi cation_of_UV_Visible_spectrophotometers.pdf),
—
PA/PH/OMCL (07) 12 DEF CORR - Annex 4: Qualification of IR
spectrophotometers (http://www.edqm.eu/medias/fichiers/Annex_4_
Qualifi cation_of_IR_spectrophotometers.pdf),
—
PA/PH/OMCL (07) 108 3R — Annex 5: Qualification of automatic titrators
(http://www.edqm.eu/medias/fi chiers/NEW_Annex_5_Qualifi cation_of_
Automatic_Titrators.pdf).
21.
US Pharmacopeia, 32nd ed. General chapters: <1058> Analytical instrument
qualification. Rockville, MD, 2009.
22. WHO guidelines for sampling of pharmaceutical products and related
materials. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005,
Annex 4 (WHO Technical Report Series, No. 929).
23. Stability testing of active pharmaceutical ingredients and finished
pharmaceutical products. In: WHO Expert Committee on Specifications
for Pharmaceutical Preparations. Forty-third report. Geneva, World Health
Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953).
24. Supplementary guidelines in good manufacturing practice: validation.
Analytical method validation. In: WHO Expert Committee on Specifications
for Pharmaceutical Preparations. Fortieth report. Geneva, World Health
Organization, 2006, Annex 4, Appendix 4 (WHO Technical Report Series,
No. 937).
25. Guid eline of the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
Q2(R1): Validation of analytical procedures: text and methodology (http://
www.ich.org/LOB/media/MEDIA417.pdf).
26. Official Medicines Control Laboratories Network of the Council of Europe,
Quality Assurance Documents: PA/PH/OMCL (05) 47 DEF — Validation of
analytical procedures (http://www.edqm.eu/medias/fichiers/Validation_of_
Analytical_Procedures.pdf).
27.
The US Pharmacopeia, 32nd ed. General chapters: <1225> Validation of
compendial procedures and <1226> Verification of compendial procedures.
Rockville, MD, 2009.
28. Official Medicines Control Laboratories Network of the Council of Europe,
Quality Assurance Documents: PA/PH/OMCL (07) 28 DEF CORR —

Evaluation and reporting of results (http://www.edqm.eu/medias/fichiers/
Evaluation_Reporting_of_Results.pdf).

29.
Shewhart control charts. International Organization for Standardization, 1991
(ISO 8258).
30. Official Medicines Control Laboratories Network of the Council of Europe,
Quality Assurance Documents:
— PA/PH/OMCL (05) 49 DEF CORR — Uncertainty of measurement — Part
1: General OMCL policy for implementation of measurement uncertainty
in compliance testing (http://www.edqm.eu/medias/fichiers/Uncertainty_
of_Measurements_Part_I_Compliance_testing.pdf),
— PA/PH/OMCL (07) 106 DEF — Uncertainty of measurement — Part
2: OMCL policy on the estimation and application of uncertainty
in analytical measurement (http://www.edqm.eu/medias/fichiers/
Uncertainty_of_Measurements_Part_II_Other_than_compliance_testing.
pdf).
31. EURACHEM/Cooperation on International Traceability in Analytical Chemistry
(CITAC) Guides. Quantifying uncertainty in analytical measurement, 2nd ed,
EURACHEM/CITAC, 2000.
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(CITAC) Guides. Use of uncertainty information in compliance assessment,
EURACHEM/CITAC, 2007 (http://www.measurementuncertainty.org/).

A ppendix

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

A list of equipment considered by the Committee to be adequate either for
a first-stage or medium-sized pharmaceutical quality control laboratory is
given in the table. In the case of a medium-sized laboratory, specifi c sections
are devoted to a microbiology unit and pharmacognosy/phytochemistry
unit. For a first-stage laboratory testing herbal medicines, the additional
equipment recommended is specified in the table.

This list does not represent any requirements which should be fulfi lled
to comply with these guidelines. NMRAs or laboratories wishing to
perform pharmaceutical analyses may consider the following list in the
establishment or upgrading of their testing facilities. For budgetary reasons
it is necessary, besides the cost of equipment, to take into consideration the
cost of reference materials, reagents, solvents, glassware, other laboratory
commodities and personnel. Experience has shown that for sustainability,
a laboratory should allow a margin of 10–15% per year of the purchasing
expenditure on equipment to cover the cost of maintenance.

Table

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

First-stage laboratory
Equipment and major instruments Quantity
Top-loading balance
Analytical balance (5 digits)
Melting-point apparatus
pH meter (with assorted electrodes)
Microscope
Polarimeter
High-performance liquid chromatograph with ultraviolet detector
Ultraviolet/visible spectrophotometer
Infrared spectrophotometer with pellet press
Karl Fischer titrator (semi-micro determination of water)
Agate mortar with pestle
Equipment for thin-layer chromatography
Thin-layer chromatography spotter
Developing chambers