that have the potential to impact the final product’s CQAs. In
the case of biological drug substances, any knowledge regarding mechanism of action and biological characterization,
such as studies that evaluate structure-function relationships,
can contribute to the assessment of risk for some product
Drug substance CQAs typically include those properties or characteristics that affect identity, purity, biological
activity, and stability of the final drug product. In the case of
biotechnological/biological products, most of the CQAs of
the drug product are associated with the drug substance and
thus are a direct result of the design of the drug substance or
its manufacturing process. When considering CQAs for the
drug substance, it is important to not overlook the impact of
impurities because of their potential impact on drug product
safety. For chemical entities, these include organic impurities (including potentially mutagenic impurities), inorganic
impurities such as metal residues, and residual solvents.
For biotechnological/biological products, impurities
may be process-related or product-related (see ICH Q6B).
Process-related impurities include: cell substrate-derived
impurities (e.g., Host Cell Proteins [HCP] and DNA); cell
culture-derived impurities (e.g., media components); and
downstream-derived impurities (e.g., column leachable).
Determining CQAs for biotechnology/biological products should also include consideration of contaminants,
as defined in Q6B, including all adventitiously introduced
materials not intended to be part of the manufacturing process (e.g., viral, bacterial, or mycoplasma contamination).
Defining the design space and establishing a control strategy
ICH Q8 describes a tiered approach to establishing final processing conditions that consists of moving from the knowledge
space to the process design space and finally the control space.
ICH Q8 and Q11 define the Design Space as “the multidimensional combination and interaction of input variables
(e.g., material attributes) and process parameters that have
been demonstrated to provide assurance of quality.” In the
drug product world the terminology typically applied to the
design space is the Proven Acceptable Range (PAR) that used
to equate to the validated range.
Here is why this is important: the ability to accurately
assess the significance and effect of the variability of material
attributes and process parameters on drug substance CQAs,
and hence the limits of a design space, depends on the extent
of process and product understanding. The challenge with
drug substance processes is where to apply the characterization. ICH Q7A recognizes that upstream of the RSM does
not require GMP control. The design space can be developed
based on a combination of prior knowledge, first principles,
and/or empirical understanding of the process. A design
space might be determined per unit operation (e.g., reaction,
crystallization, distillation, purification), or a combination of
selected unit operations should generally be selected based on
their impact on CQAs.
In developing a control strategy, both upstream and downstream factors should be considered. Starting material characteristics, in-process testing, and critical process parameters
variation control are the key elements in a defensible control
strategy. For in-process and release testing criteria the resolution of the measurement tool should be considered before
making any conclusions.
ICH Q11’s description of process validation mimics the
same description in ICH Q7A but offers up an alternative
for continuous verification that mirrors the concepts in ICH
Q8 and the new process validation guidance. As mentioned,
the enforcement of the new guidance by the FDA has been
uneven, but positioning the process validation to satisfy the
new guidance requires the drug substance manufacturer to
formally implement characterization and validation standards,
just as a drug product manufacturer would be required to do.
The quality system elements and management responsibilities described in ICH Q10 are intended to encourage the
use of science-based and risk-based approaches at each
lifecycle stage, thereby promoting continual improvement
across the entire product lifecycle. There should be a systematic approach to managing knowledge related to both drug
substance and its manufacturing process throughout the
lifecycle. This knowledge management should include but
not be limited to process development activities, technology
transfer activities to internal sites and contract manufacturers, process validation studies over the lifecycle of the drug
substance, and change management activities.
The new ICH Q11 guidance represents the most recent
example of the FDA’s commitment to the principles of QbD
to define an integrated framework for implementing the
principles of ICH Q6-Q10. Although the guidance does not
mandate adopting ICH Q8, the considerations required to create a defensible control strategy require a much higher level
of process understanding than the conventional approach of
sample and test, once the foundation of product development.
Defining the requirements is another example of where the
FDA is going in terms of expectations for drug substance and
drug product understanding. If effectively enforced, this can
be a significant step forward, pushing the industry toward a
QbD philosophy for process and product development.
Bikash Chatterjee has been involved in the biopharmaceutical, pharmaceutical, medical device, and diagnostics industry
for over 30 years. His expertise includes site selection, project
management, design, and validation of facilities for U.S. and
European regulatory requirements.