QUALITY BY DESIGN - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 92

These are the attributes that impact patient safety and efficacy and therefore
it is important they are clearly established for the drug product. An experienced
company would normally use their prior knowledge to make an initial assess-
ment of the potential CQAs and then carry out a risk assessment to establish
whether these potential CQAs are critical to patient safety and efficacy, and
product quality. This prior knowledge could comprise clinical and preclinical
data, development records from similar compounds, manufacturing experience,
other published data, etc.
Many attributes may be well known—for example, for a small molecule oral
solid dosage product, dissolution can be considered as related to efficacy, whereas
degradant (impurity) level would be related to patient safety. Alternatively, for a
large molecule product, where there are usually many potential CQAs, viral load
would be an example of a patient safety attribute.
Normally, but not always, a specification is established for a CQA.
The intent of the early risk assessment is to establish whether experimental
work, such as DOE or other multivariate techniques, should be employed to
understand which unit operations' parameters and material attributes may impact
the CQAs.
For example, it may be known that blending in an oral solid dosage product,
lyophilization for a parenteral product, or micronizing for an inhalation product
are important unit operations that could affect particular product CQAs, but there
may not be sufficient data to assess the risk, and so a company will carry out
experimental work to investigate this. The attributes of raw materials (such as
nonactive excipients or drug substance) can impact CQAs and therefore these
should be included in the risk assessment.
On the basis of their experience, a company may have an initial idea of the
kind of manufacturing process envisaged and therefore the type and number of
unit operations expected, and choose to tailor their approach, for business reasons,
to align with, for example, their manufacturing capability within the company.
Its business strategy may favor one type of unit operation over another, such
as choosing roller compaction over wet granulation for granulating of a tablet
product.
A critical process parameter ( CPP) is defined in ICH Q8R2 [1] as “ apro-
cess parameter whose variability has an impact on a CQA and therefore should
be monitored or controlled to ensure the process produces desired quality .” It is
therefore important to establish which process parameters for a particular unit
operation impact the CQAs and the degree of this impact. An FMEA or FMECA
risk assessment approach is commonly used to establish which process param-
eters and material attributes are critical. An example of the output from a risk
assessment is shown in Figure 5.6. This illustrates both the initial risk assess-
ment and final risk assessment, where controls have been put in place to bring
the potential risks to an acceptable level, as shown by the dotted line.
Design Space is defined in Q8R2 [1] as, “ the multidimensional combination
and interaction of input variables (e.g., material attributes) and process parame-
ters that have been demonstrated to provide assurance of quality .”