Chemistry Reference
In-Depth Information
supplement is recommended. In the guidance, the FDA provided reporting categories
depending on the type of change, or the potential to have an adverse effect on the iden-
tity, strength, quality, purity, or potency of a drug product.
A
major change
is a change that has a substantial potential to have an adverse
effect. In the case of a major change, a
Prior Approval Supplement
(PAS) is required.
As the name implies, FDA approval is necessary prior to distribution of the drug
product made using the change. A
moderate change
has a moderate potential for an
adverse effect, and requires the submission of a supplement called a
Supplement-
changes being effected in 30 days
, often referred to as a CBE-30. For changes in this
category, the drug product cannot be distributed if the FDA informs the applicant
within 30 days that a PAS is required. CBE supplements are also used without the
30-day window for some moderate changes that do not relax acceptance criteria or
for those that provide the same or increased assurance of identity, strength, quality,
purity, or potency of a drug product. There have been cases where the FDA has not
been able to complete a CBE-30 review within 30 days. If a firm were to implement
the procedure after 30 days without FDA review, they are within the regulation, but
at risk. There have also been cases where the FDA has notified firms that a review
will not be completed within 30 days, and has asked the firm not to implement the
method. Each of these cases is an example of where it is important to have a good
dialog with the FDA.
A
minor change
is a change that has minimal potential for an adverse effect, and
these changes are described in the applicant's next
annual report
.
A supplemental or Annual Report must include a list of the detailed descrip-
tion for all the changes; for supplements, the information must be summarized in
the cover letter; in annual reports, included in the summary section. Applicants
are also encouraged to submit a comparability protocol that describes test, studies,
and acceptance criteria used to demonstrate the absence of any adverse effects, and
guidance on this topic has appeared in draft form [5]. However, if a comparability
protocol was not included in the original application, then it must be submitted as a
PAS. The type of supplement is also dictated somewhat by the types of sample, for
example, drug product versus intermediate. Verification (see Section 9.4.1) data and
any statistical evaluation of equivalence should be included in the annual report.
9.3 WHAt constItutes A cHAnge to A metHod?
Adjustments to USP methods have always been allowed to satisfy system suitability
requirements and are often noted in individual monographs. However, at what point
does an adjustment become a change? After all, a change in the method triggers a
revalidation, and at least some level of reporting as outlined previously (and more on
this later!). Historically, as long as adjustments to the method are made within the
boundaries of any robustness studies performed, no further actions are warranted.
However, any adjustment outside the bounds of the robustness study constitutes a
change to the method, thus requiring a revalidation.
In 1998, Furman et al. proposed a way to classify allowable adjustments [6]. But it
was not until 2005 that guidance appeared on the topic [3, 7, 8]. The FDA Office of
Regulatory Affairs (ORA) has had guidance in place for a number of years [3], and
