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WHO Technical Report Series No. 981, 2013
WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report
API-related considerations such as use of semi-synthetic and fermentation
products, complex routes of synthesis, polymorphism, isomerism and potential
genotoxic impurities; and product-related considerations such as the use of
novel excipients, the complexity of the formulation, single-ingredient versus
xed-dose combinations, and special delivery systems (e.g. modied release,
transdermal products, and inhalation products). Once risk factors have been
identied, resources should be allocated to minimize risk. For example, assessors
with expertise related to the product-related risk identied should be assigned to
assess the dossier whenever possible. When resources allow, the assessors may
be organized according to specialization, assigning assessors to various product
categories (e.g. generic products, sterile products, solid oral dosage forms, or
special delivery systems). is can facilitate the development of expertise in
key areas and promote consistency of review, as well as ensuring that products
requiring specialized knowledge are identied and assessed by those with the
appropriate expertise. Where a high level of risk is identied for a dossier, the
more experienced assessors need at least to be available on a consultation basis.
e risk level associated with a dossier may change during the course
of assessment. For example, rejection of the bioequivalence study will result in
additional time required to conduct and assess additional studies and associated
additional quality information. In such a scenario the risk relates both to the use
of additional resources and to an increased risk that the overall product quality
may be poor.
Allocation of resources to various aspects or sections of the dossier is an
important QRM consideration, in order to ensure that the resources used are
commensurate with the risk level. An understanding of the relative criticality of
dossier sections or aspects is necessary for ecient use of resources. All aspects of
the dossier are important to achieve overall quality, safety and ecacy; however
some areas are inherently more critical from a risk perspective and warrant
more attention in the assessment process. Examples include the clinical reviews,
bioavailability reviews, API synthesis, specications and stability studies, FPP
manufacturing details, pharmaceutical development studies including biowaiver
justication, process validation, specications and stability studies. An example
applicable to most simple solid oral products is that more time should be allocated
to the review of manufacturing steps prior to packaging than to reviewing the
packaging process.
During the assessment process there should be a standard procedure
for communicating to the inspectors those issues identied which may require
consideration during inspection. Aer approval of a product, QRM principles
should be applied to evaluate the impact of proposed variations or changes. Clear
guidelines that outline possible post-approval changes and assign an associated
risk level are an eective means to achieve this.