lution can detect a morphological change outside of additional
characterization tools, such as X-Ray Powder Diffraction (XRPD).
This is another way dissolution provides important information
for scientists making decisions. Regulatory agencies continue to
place more emphasis on dissolution testing from concept of design to validity of the procedure.
While stability indication of an assay and the impurities procedure is scrutinized during Chemistry, Manufacturing and Controls (CMC) review, dissolution continues to gain focus to ensure
the optimal procedure is developed. Indeed, many regulatory
guidance documents have been published requiring a gradual
progression of dissolution throughout the phases of drug development or in support of Scale-Up and Post-Approval Changes
Dissolution can remain “king” as compared to other testing
procedures only if the right dissolution procedure is developed.
The dissolution procedure should evolve over time as a product
matures from early-phase development to post-approval as part
of life-cycle management.
Platforms need to be developed to efficiently identify an optimal dissolution procedure. Here are some attributes to consider:
• What is the purpose of the product and how will it be designed (e.g. targeted selection)?
• What is the phase of development and how will the data be
used to define the product’s performance?
• What do we know about the classification (BCS) of the drug
substance? What if that information is not available?
• What information can we learn from the characterization of
the drug substance such as pH solubility?
• What is the current and proposed particle size of the drug
substance? Is there a robust milling or micronization step
in the process?
As these key attributes are discussed and verified, designing
a dissolution testing procedure to meet the desired target profile—appropriate for the current phase of drug development—is
For example, Metrics Contract Services has been given late-phase dissolution methods to redevelop or optimize and often,
there is no justification to the selection of dissolution medium, apparatus type and speed. There is no doubt that the industry favors
certain surfactants, such as sodium lauryl sulphate, and“1%” is a
well-documented, standard concentration used for many poorly
soluble drugs. Furthermore, paddle speeds at or above 100 rpms
also are selected without much justification and adequate discrimination. While these parameters can be selected, the current regulatory environment requires the product-specific, data-driven justification of them; reliance on industry standards is not sufficient.
Regulatory agencies seem to agree by applying high standards
when it comes to selecting parameters so that the desired op-
timal dissolution procedure is achieved. There appears to be an
increase in the level of questions surrounding the development
and suitability of a dissolution procedure. An effective dissolution
procedure can ensure a true“baseline” is established for a newly
registered product that will enable comparability for potential
changes in the manufacturing process, site transfers or even for-
mulation changes. It is clear by reviewing agency guidance docu-
ments that dissolution testing for non-BCS Class 1 drugs is key
to establishing acceptability for proposed changes.
Even in early-phase development, when the formulation can
change, it is still critical to establish a suitable dissolution method
to allow for predictive modeling. Pharmacological pH solubility,
pKa data, thermodynamics, morphology, particle size and other
characterization data should be well understood.
Also, when you shift through the various development phas-
es, the dissolution method should shift as well. Prior to initiation
of Phase III clinical studies, the dissolution procedure should be
optimized to represent your final registered method. The method
should have been challenged by formulation designs designed to
produce failures (if applicable) as part of formulation Quality by
Design (QbD) activities.
After the dissolution procedure has been optimized, there
should be a clearly documented pathway regarding how the dis-
solution procedure was developed. Statistical design approaches
from the various activities should be utilized, such QbD analyses,
during drug development.
A good way to challenge a dissolution procedure that will be
used to support a future commercial product is to determine if
the following criteria can be answered:
• What is the purpose of drug product? Specifically, what is
targeted release profile of the drug?
• Does the dissolution medium selection concur with the
pharmacological relevance of the drug? And how does the
selection of the dissolution medium compare to the solubility and stability of the drug substance?
• Is disintegration or diffusion the rate-limiting step in the
dissolution process or is it solubility of the drug substance?
• If there were deviations from the drug substance and drug
product manufacturing process, is the method specific
enough to detect these changes?
• Can you justify the selection of other key dissolution parameters such as speed and apparatus type? Are the parameters optimized?
While CAPA merits attention, dissolution is a key analysis tool for pharmaceutical drug products. Perhaps dissolution
should be King. CP
As Vice President of Analytical Services at Metrics Contract Services,
KEITH MOORE is responsible for the day-to-day leadership of the
company’s analytical services team, comprising some 100 chemists. His division helps clients determine and ensure the identity,
purity, potency and performance of drug products by conducting
analytical chemistry and microbiology tests, method development and validation,
and stability studies in compliance with international standards. Moore also is
responsible for laboratory operational teams, as well as quality-control functions
that involve raw materials, cleaning verification, quality control-finish product, and
the microbiological laboratory. Moore joined Metrics Contract Services in 1998
as a laboratory analyst and consistently took on roles of increasing responsibility
to become senior manager of analytical services by 2012. Prior to his current
appointment, he served as senior manager of technical operations at Salix Pharmaceuticals, where he managed R&D and commercial activities at numerous