General European OMCL Network (GEON)

QUALITY MANAGEMENT DOCUMENT

PA/PH/OMCL (13) 82 R5

Validation/Verification of Analytical Procedures

Full document title and Validation/Verification of Analytical Procedures

reference PA/PH/OMCL (13) 82 R5
Document type Guideline

Legislative basis Council Directive 2001/83/EC and 2001/82/EC, as amended

Date of first adoption October 1999

Date of original entry February 2000

into force
Date of entry into force July 2020
of revised document
Previous titles/other Last adopted version PA/PH/OMCL (13) 82 2R
references / last valid
version
Custodian Organisation The present document was elaborated by the OMCL Network / EDQM of
the Council of Europe
Concerned Network GEON

N.B. This OMCL Quality Management System document is applicable to members of the European
OMCL Network only. Other laboratories might use the document on a voluntary basis. However,
please note that the EDQM cannot treat any questions related to the application of the documents
submitted by laboratories other than the OMCLs of the Network.
 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Note: Mandatory requirements in this guideline are defined using the terms “shall” or
“must”. The use of “should” indicates a recommendation. For these parts of the text
otherappropriately justified approaches are acceptable. The term “can” indicates a possibility
or an example with non-binding character.

INTRODUCTION

The ICH Guideline on “Validation of Analytical Procedures: Text and Methodology” (Q2)
constitute a discussion of the validation characteristics that should be considered during the
validation of an analytical procedure (the guideline has also been adopted for veterinary
products during VICH discussion). They are primarily addressed to pharmaceutical industry
indicating which validation data need to be provided in an application file. These data should
demonstrate that the proposed testing and acceptance criteria are sufficiently under control
to guarantee reproducible quality of the products at release and adequate control during
shelf-life (stability).

As the circumstances under which an OMCL works are different from those of a
pharmaceutical company – in most cases no routine analysis, but often responses to be
made in a short period of time - the extent of analytical validation/verification requested
before performing an analysis needs to be reconsidered. On the other hand, it has in all
cases to be guaranteed that the result submitted is reliable. It should also be emphasised
here, that adequate reference materials are an important factor in both the performance of
the validation/verification studies and the analysis itself. The use of widely accepted
reference preparations can in certain circumstances avoid the consideration of some
validation characteristics, mainly in the field of biological products: this has then to be
justified on a case by case basis. The OMCL may decide the extent required considering the
risk factors.

The scope of this document – specifically addressed to OMCLs - is to give guidance on the
extent of validation/verification needed, depending on various circumstances i.e. objective of
the analysis (e.g. screening for non-compliance), amount of validation data already available
(e.g. in case of a method transfer), experience or historical data already available in the
individual OMCL (e.g. recovery from a complex matrix; routine use of a standard titration
even if different substances are titrated), etc. This document is equally applicable to
products of synthetic and of biological origin. It does not address common laboratory
practice: for instance guidance concerning the use of the equipment, calibration etc.

This document is a note for guidance, which provides detailed recommendations of the
extent of the validation/verification exercise dependent on the category of the analytical
procedure; it should be noted that other approaches are always possible. With respect to
the new Directive 2010/63/EU on ethical animal use for scientific and educational purposes
and the European Convention for the Protection of Vertebrate Animals used for Experimental
and Other Scientific Purposes (Council of Europe) special attention is needed for the use of
in vivo methods as analytical procedures. All efforts should be made to rationalise and
restrict animal use to a necessary minimum based on a thorough analysis of the situation. It
should be stressed that this document cannot provide detailed advice for all possible cases
where in vivo tests are used. The purpose of this document is to provide general guidance.

In all cases a short description and/or justification of the approach chosen, including the
methods, should be described in the internal documentation of the analysis. Validation data

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

of validated methods (compendial, marketing authorisation dossier) should be available.

Modifications from the original validated method shall be justified. Depending on the nature
of the modifications and the outcome of the risk assessment, supplementary validation or
verification activities may be undertaken.

The same definitions as in the ICH document apply.

CATEGORIES OF ANALYSIS

This chapter defines the different analytical situations (categories) which might occur in an
OMCL and the corresponding validation characteristics which should be considered. Refer to
the current version of the ICH guideline on “Validation of Analytical Procedures: Text and
Methodology” (Q2).

Formal validation studies, according to the ICH requirements, must be performed for a new
developed method or when for an existing method the validation data must be completed.
According to ISO 17025, validation is required for non-standard methods. In the OMCL
context, pharmacopoeial methods and validated methods from a Marketing Authorisation are
considered to be standard methods.

Verification of Method must be done to show that under actual conditions of use in the
individual laboratories the (validated) method is adequate (fit for use). This may be achieved
by carrying out the system suitability tests (e.g. resolution in a chromatographic method),
controlling sensitivity at the reporting threshold, controlling the completeness of a reaction
step (e.g. extraction, hydrolysis reaction) before the actual determination can be performed,
verifying the precision of the method etc. This may also be achieved by carrying out a
method transfer exercise, in the laboratory that has established the method and the OMCL
and the results compared to show equivalence.

In all cases, a short note, explaining the rationale for the chosen approach - depending on
the complexity of the analysis required -, should be provided in the internal documentation
of the analysis. Deviation from this guideline shall be justified.

Several categories of analysis are considered in Tables 1 – 8:

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Table 1: Method published in the European Pharmacopoeia

Analytical procedures described in a monograph are considered validated. The OMCL must verify that all reference materials needed are
available and the required system suitability tests are performed. For related substances tests, specificity for any known impurities not listed in
the monograph (e.g. Ph Eur transparency list) should be verified.
For finished product monographs, the OMCL should verify that any excipients do not interfere in the analysis of the active substance, unless
addressed in the monograph.

Note: To fall under this category, the procedures must be described in detail, not for instance as in some cases for biologicals where there is
only a general description of the method. The details may come from the published report of the collaborative study (e.g. BSP study reports in
Pharmeuropa Bio & Scientific notes)

Test Samples Method Checks required by the OMCL

Active Substance Identification No formal validation required
Related Substances No formal validation required
Assay No formal validation required
Medicinal Product Identification No formal validation required
Related Substances Specificity: no interference from excipients;
Reporting threshold (at least the quantitation limit)
Assay Specificity
Accuracy: mainly recovery, minimum 1 determination.
Precision (repeatability): around the target test concentration (minimum 2
independent determinations)
Linearity at three measuring points in the range around the target value.

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Table 2: Validated method from a Manufacturer (1st MAH)

Analytical procedures taken from a marketing authorisation are fully validated by the company.

Test Samples Method Checks required by the OMCL

1st MAH Active Substance Any No formal validation required
1st MAH Medicinal Product Any No formal validation required
2nd MAH Active Substance Identification No formal validation required
Related Substances Specificity (impurity profile)
(if the impurity profile is different, further validation data might be necessary)
Assay No formal validation required in case of a titration
Stability indicating: see testing for related substances
2nd MAH Medicinal Product Identification No formal validation required
Related Substances Specificity (interference of excipients)
Comparable formulations (matrix) Reporting threshold (quantitation limit)
If matrices identical, see 1st MAH Precision over range
Product above) Assay Specificity: no interference from excipients
Accuracy: around the target concentration
Repeatability: around the target concentration (minimum 2 independent
determinations)
Linearity at three measuring points in the range around the target value.

1st MAH = product made by the MAH who validated the original method used. 2nd MAH = a product made by a different manufacturer for
which the original method used has not been specifically validated

Where methods are from old application file(s) with no or insufficient validation data, the supervising Competent Authority should be informed.
For the validation characteristics to be considered see Tables 2, 5.

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Table 3: Non-compendial published method

The validation characteristics to be considered will always depend on the amount of validation data provided. If the method has been fully
validated and data published in the literature, then see Table 1. If not, the following should be considered

Test Samples Method Checks required by the OMCL

Active Substance Identification No formal validation required
Related Substances Specificity (impurity profile)
Reporting threshold (quantitation limit)
Precision over range
Assay Specificity
Accuracy: around the target concentration
Repeatability: around the target concentration (minimum 2 independent
determinations)
Linearity at three measuring points in the range around the target value.
Medicinal Product Identification No formal validation required
Related Substances Specificity (interference of excipients)
Reporting threshold (quantitation limit)
Precision over range
Assay Specificity: no interference from excipients
Accuracy: around the target concentration
Repeatability: around the target concentration (minimum 2 independent
determinations)
Linearity at three measuring points in the range around the target value.

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Table 4: Active Substance method used for a Medicinal Product

The main factor to be considered here is the influence of the matrix on the analysis including interference from the excipients.

Test Samples Method Checks required by the OMCL

Medicinal Product Identification No formal validation required
Related Substances Specificity (interference of excipients)
Reporting threshold (quantitation limit)
Precision: over the range
Accuracy: over the range
Assay Specificity: no interference from excipients
Accuracy: around the target concentration
Repeatability: around the target concentration (minimum 2 independent
determinations)
Linearity at three measuring points in the range around the target value.

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Table 5: Methods validated to reduce, refine or replace animal use (3Rs)

Test Samples Method Checks required by the OMCL

Active Substance Any In these cases, the verification will generally involve methods validated
Medicinal Product through collaborative trials, validated by the manufacturer for a particular
product, or validated and published by another laboratory. The validation
characteristics to be considered will always depend on the amount of
validation data provided.
If the method has been fully validated and data is published in the literature
or available in the MA dossier, then Table 1 applies (active substance and
medicinal product). Elements highlighted in Table 2 may also be relevant in
these situations.
The OMCL should identify the key parameter(s) which should ensure the
precision of the test procedure. Wherever possible the same protocols and
reference material should be used in all labs.
When a laboratory participated in a collaborative study to develop a method,
data generated during the study can also be used in the validation package
for regular lab use.

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Table 6: Screening for non-compliance

Screening for non-compliance means that the target of the analysis is to detect potential non-compliance of the product with the specifications.
This type of screening would be performed when a rapid analysis is requested and/or when no validation data of the method are available. The
procedure must in all cases be documented.

If non-compliance is detected, the extent of validation must be expanded, for example by considering to switch to a well-recognised method
(compendial method or MAH dossier method).

Test Samples Method Checks required by the OMCL

Medicinal Product Identification Specificity
Testing for Related Specificity
substances Reporting threshold (quantification limit)
Precision over range
Assay Specificity: no interference from excipients and related substances
Precision: around the target test concentration (minimum 2 independent
determinations)

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Table 7: Screening for unknown product/contaminants

In these cases, there is a lack of information on the product which must be tested with respect to its label claim (presence or absence of certain
substances) or to clarify other aspects asked by the Inspectorate.
Testing to be considered: identification, assay and perhaps purity testing. The first important step is to identify the major components of the
product.

Test Samples Method Checks required by the OMCL

Active Substance Identification Specificity
Assay Specificity
Linearity at three measuring points in the range around the determined
value.
Repeatability: around the determined concentration (minimum 2 independent
determinations)
Contaminants Specificity, detection limit and quantitation limit.
Medicinal Product Identification Specificity
Assay Specificity: no interference from excipients
Accuracy: around the target concentration
Repeatability: around the target concentration (minimum 2 independent
determinations)
Contaminants Specificity, detection limit and quantitation limit.

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 PA/PH/OMCL (13) 82 R5 – Validation and Verification of Analytical Procedures

Table 8: Development of a new method

This is mainly the case where a product is tested in routine testing conditions and/or where an in-house analytical procedure is used.

Test Samples Method Checks required by the OMCL

Active Substance Any The analytical procedures should be validated according to the ICH guideline.
Medicinal Product When tests involve animals, the advice provided by Ph. Eur., ECVAM and EMA
on the reduction of animals used in validation of new procedures/test
methods should be used, wherever available.
Validation of the new assay should not require (re)validation of an
established in vivo test, even if the original test is not validated according to
current validation procedures.
Use may be made of any data already available (own/other lab(s) and/or
literature).

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