Early-phase methods requiring validation
During discussions held to develop this approach to early-phase method validation, it was evident that the context of the
terms "validation" and "qualification" was not universally used within all the IQ member companies. To facilitate a common
understanding of this approach, the authors will therefore refer to "validated methods" as those methods which perform as
expected when subjected to the series of analytical tests described in this approach. "Qualified methods" are considered to
be analytical methods which are subjected to less stringent testing to demonstrate that they are scientifically sound for
their intended use. In the following sections, the authors recommend which types of methods typically employed in early development
require either validation or qualification.
Methods for release testing and to support GMP manufacturing. In early development, specifications are used to control the quality of APIs and drug products. Consideration of specifications
places great emphasis on patient safety since knowledge of the API or drug product process is limited due to the low number
of batches produced at this stage of development. Specifications typically contain a number of different analytical tests
that must be performed to ensure the quality of the API or drug product. Typical material attributes, such as appearance,
potency, purity, identity, uniformity, residual solvents, water content, and organic/inorganic impurities, are tested against
established acceptance criteria. The API and drug-product specific methods for potency, impurity, uniformity, and others should
be validated as described above and demonstrated to be suitable for their intended use in early phase development prior to
release. If compendial methods are used to test against a specification (e.g., FTIR for identification and Karl Fischer titration
[KF] for water content), they should be evaluated and/or qualified to be suitable for testing the API or drug product prior
to use without validation. Materials used in the manufacture of GMP drug substance and drug product used for early-phase clinical
studies for which specifications are not outlined in a regulatory filing (e.g., penultimates, starting materials, isolated
intermediates, reagents, and excipients) need only to be qualified for their intended use. Method transfer is less rigorous
at this early stage of development and may be accomplished using covalidation experiments or simplified assessments.
As mentioned, method qualification is often differentiated from method validation. The experiments to demonstrate method qualification
are based on intended purpose of the method, scientific understanding of the method gained during method development and method
type. It is an important step in ensuring that reliable data can be generated reproducibly for investigational new drugs in
early development stages. The qualified methods should not be used for API or drug product release against specifications
and concurrent stability studies. However, reference material characterization may be done with qualified methods.
Generation of process knowledge in early development is rapidly evolving. Numerous samples are tested during early development
to acquire knowledge of the product at various stages of the process. The results from these samples are for information only
(FIO) and methods used for this type of testing are not required to be validated or qualified. However, to ensure the accuracy
of the knowledge being generated, sound scientific judgment should be used to ensure the appropriateness of any analytical
method used for FIO purposes.
"Generic" or "general" methods. A common analytical strategy often employed in early development is the use of fit-for-purpose generic or general methods
for a specific test across multiple products (e.g., gas chromatography for residual solvents). These methods should be validated
if they are used to test against an established specification. The suggested approach to validating these methods in early
development is typically performed in two stages. Stage 1 involves validating the parameters that are common for every product
with which the method can be used. Linearity of standard solutions and injection repeatability belong to this stage. Stage
2 of the validation involves identifying the parameters that are specific to individual product, such as accuracy. Specificity
may be demonstrated at Stage 1 for nonproduct related attributes and at Stage 2 for product related attributes. Stage 1 validation
occurs prior to GMP testing. Stage 2 validation can happen prior to or concurrent with GMP testing. This approach to validation
of fit-for-purpose methods can provide efficiency for drug development by conserving resources in the early phases of development
and can ensure reliability of the method's intended application.
Methods for GTI and tox batch qualification. The need for analytical methods to demonstrate the control of genotoxic impurities (GTI) has developed recently because of
expectations and guidances provided by regulatory authorities (8, 9). Often, these methods require high sensitivity with limits
of quantitation in the parts-per-million (ppm) range. Although the control levels for GTIs (referred to as the threshold of
toxicological concern) is less stringent for early clinical studies (e.g., patient intake < 50 ug/day for clinical studies
< 30 days vs 1.5 ug/day for longer clinical studies), regulatory authorities expect that GTI control is demonstrated during
early development. Depending on when a GTI is potentially generated during an API synthesis, GTIs may be listed in specifications.
Validation of these methods is again dependent upon the intended use of the method. Methods used for assessment may be qualified
unless they are used to test against a specification as part of clinical release. Method qualification is also considered
appropriate if the method is intended for characterization or release of test articles for a toxicology study.