Imagine that you were about to embark

on making a biopharmaceutical.
How do you begin?
Many biomanufacturers use a recently developed approach
to pharmaceutical development called Quality by Design,
or QbD, to focus their work.
The premise of Quality by Design is
that quality is designed into the product
rather than tested for after the product is made.
There are at least three important elements of QbD.
First, understanding the critical quality
attributes of your product including
how changes and process parameters or material
attributes may impact them.
Second, developing a design space.
And finally, developing a control strategy.
Critical quality attributes, or CQAs,
are physical, chemical, biological,
or microbiological properties of a biopharmaceutical that
should be within an appropriate limit, range, or distribution
to ensure the desired product quality, activity, or efficacy.
So how do we determine what the CQAs are?
We don't always have significant clinical data when we start,
so we often rely on in vitro biological activity
assays, toxicology assays, and animal studies.
We also use prior knowledge about the product
or similar products.
We might even synthesize product-related impurities,
such as partially oxidized protein to use in a bioassay.
These surrogate measures show how product related variants
might impact biological activity in vivo.
Our understanding in the relative importance of CQAs
naturally evolves during product development
as we gain more product knowledge.
Once we understand our CQAs, a risk assessment
can help identify which material attributes and process
parameters might impact them.
To do this, most manufacturers will bring together expertise
from across the manufacturing organization
to determine the severity of potential failures,
both at the process level and the patient level, how
frequently failures might occur, and the probability
of timely detection and correction.
For those parameters that have more risk than is acceptable,
we use DOE, or Design of Experiments,
to help us identify the process parameter
boundaries that affect the critical quality attributes.
The analysis of DOE data, which are often
multivariate in nature, help us identify the design space.
The design space is a multi-dimensional combination
and interaction of input variables and process
parameters.
When the process operates within it,
these variables and parameters have
been demonstrated to provide assurance of quality.
For a bioreactor unit operation, it
might include a range of kLa, agitation, and sparge rate.
For a low pH viral clearance step,
the design space might be the range where
there are acceptable limits for both viral clearance
and aggregation with respect to time and pH.
While these examples involve a single unit operation,
a design space can cover multiple unit operations
or even an entire process.
Typically, the design space is larger than the manufacturing
operating space so that a control system
can act as an early warning system
rather than indicating that a manufacturing process is out
of control.
Now that we identified the design space,
we need a control strategy to ensure
we stay within this space.
A control strategy is a planned set of controls
that ensures product quality and process performance.
These should minimally include the following-- controls
for raw materials, such as qualifications
and specifications for media, excipients, and buffer
components; procedural controls like qualifications
and specifications for equipment, water,
and air handling systems, or other facility operations
and process parameter controls for CPPs;
a strategy for and limits on the outputs of inprocess testing,
lot release, and stability testing;
a plan for how changes to the manufacturing process
will be shown to be comparable; and a protocol and limits
associated with monitoring select process
parameters for trends.
So what we have just learned is that QbD
is a systematic approach to development that
begins with predefined objectives,
emphasizes product and process understanding and process
control, and is based on sound science and quality risk
management.
There are several other elements to QbD,
and if you would like to learn more,
you can find these in the ICH Q8 documents.