Changes
to an
Approved
Product
Chemistry, Manufacturing
and Controls
By Khandan Baradaran, PhD and Peggy Berry, MBA, RAC
I
t is a huge achievement for any company
to obtain licensing rights to an approved
pharmaceutical product. Postapproval
challenges are inherent in the marketing
and distribution process. Of these, foreseen and
unforeseen changes to the manufacturing process
top the list. Sponsors of newly licensed products
may encounter issues that were not fully realized
during development, such as long-term stability
issues, which only come to light within the first
two years postapproval. Such unforeseen issues
require corrective actions that usually impact
the approved manufacturing process in one or
more ways. At the same time, there are likely to
30 April 2008
be foreseen, legitimate needs to make changes
to the approved product or production process.
Postapproval changes can be relatively minor,
such as like-for-like changes to manufacturing
equipment; or they can be more critical, such as
a change to the drug product container closure.
The latter is common for products that undergo
lifecycle management. For example, the compa-
ny may, develop and obtain approval for the drug
supplied in a vial, then plan to obtain approval
for a prefilled syringe presentation for ease of
patient use.
Certain changes must be reported to regu-
latory authorities, and in some instances, the
sponsor may be prevented from distributing the
drug manufactured with a particular change
until the regulatory authority has reviewed and
approved the change. In the US, manufactur-
ing changes can be reported to FDA in supple-
ments to the marketing/license application and
in annual reports. The four reporting categories
are: prior-approval supplement (PAS), changes
being effected (CBE), changes being effected in
30 days (CBE-30) and annual report (AR) (Table
1). Some changes are transparent to the license1
and do not need to be reported. It is the regula-
tory professionals job to determine whether a
change needs to be reported, and whether the
regulatory agency needs to approve the change
before distribution. This can be a complex task,
involving extensive oversight, reporting and
control within a company to identify a change,
assess the impact to the drug product, tag out
the impacted drug product lots until approval is
obtained, and report the change to the relevant
authorities. The complexity increases with more
products in the manufacturing plant that may
require changes, and marketing rights in mul-
tiple countries.
In the US, licensed pharmaceutical drug
manufacturers pay a postmarketing user fee to
market the drug (see Prescription Drug User Fee
Regulatory Focus 31
Table 1. Impact Assessment and Reporting of CMC Changes
Degree of Change Impact Assessment Reporting Category
Major change substantial potential to have an adverse effect prior-approval supplement (PAS)
Moderate change moderate potential to have an adverse event changes being effected in 30 days (CBE-30)
moderate potential to have an adverse event and
Certain moderate changes FDA concurrence obtained for product distribution changes being effected (CBE or CBE-0)
when supplement received
Minor change minimal potential to have an adverse event annual report

Act (PDUFA)).2 Fees are collected from licensed
pharmaceutical companies on a per-product (each
approved dosage form) basis. Annual establish-
ment fees and fees required for supplements with
clinical information also apply. In return, FDA is
required to review certain supplements within a
specified time frame (four months for most PAS,
30 days for CBE-30); some supplements have no
time constraints.
Impact Assessment
Each change must be assessed to determine
whether it needs to be reported. Changes
that must be reported include changes to the
product, production process, quality con-
trols, equipment or facilities established in
the approved license application.3,4 To assess
a change, the regulatory professional must
determine what potential adverse effects it
could have on the products identity, strength,
quality, purity or potency as related to the
products safety or effectiveness. Which of the
four reporting categories applies depends upon
this product impact assessment.
In addition to determining which submis-
sion type to file (based upon potential effect on
product quality attributes), the impact assess-
ment must include any repercussions for vali-
dation; equipment, the manufacturing process
step, analytical methods or any combination

Table 2. Major Changes (Substantial Potential of AE) Requiring Prior-approval Supplement Filing
Process Changes
Changes to
Analytical Methods
Other Major Changes
Triggers for Additional
Clinical or
Nonclinical Studies
change to validated sterilization process (sterile products)
new/revised recovery procedures
new/revised purification process, including column change
change in process solution chemistry or formulation
change in processing step sequence or processing step addition, deletion or substitution
reprocessing a product without a previously approved protocol
scale-up requiring larger fermenter, bioreactor or purification equipment (biologics)
replacing an existing analytical method with a new one (e.g., RP-HPLC to replace ELISA)
establishing wider specification limits
deleting a specification or analytical method
eliminating tests from the stability protocol
assay transfer to another QC laboratory
change in product composition or dosage form or ancillary components
expiration dating period extension or change in storage temperature
container/closure change
change in manufacturing site
conversion from single- to multi-product manufacturing area(s)
culture growth time extension resulting in significant increase in cell doublings beyond validated
parameters (biologics)
cell line change or new MCB (biologics)
formulation or excipient changes
multiple simultaneous changes (e.g., scale-up, media components impacting titer, change in
purification resin type, container closure)
any change resulting in an observed change in activity assay (e.g., out-of-specification or trend
regarding licensed specifications and manufacturing history)
significant impurity profile increase

32 April 2008
Table 3. Moderate Change Examples (moderate potential of AE) Requiring CBE Supplement Filing
addition of duplicated process change (e.g., fermentation) or unit process (e.g., purification column)
Changes Being with no change in process parameters
Effected in 30 Days (CBE-30)
manufacture of an additional product in previously approved multiple-product manufacturing area
with same equipment/personnelif no changes in validated cleaning and changeover procedures
additional release tests and/or tightening of specifications
Changes Being Effected (CBE-0) changing from one compendial test method to another
replacing an in-house reference standard

of quality systems may need to be revalidated.
Validation data may need to be included in the
submission package with the data that demon-
strate comparability before and after the change.
Submissions
In the US, the waiting period when reporting
can be reduced if a protocol for assessing and
determining comparability is submitted and
approved prior to any changes being made.
The comparability protocol should describe the
change or possible changes, planned testing and
revalidation studies and conformance to prespeci-
fied acceptance criteria. This, in effect, allows a
sponsor to obtain FDA agreement on what stud-
ies are expected when certain changes are made,
and acceptable comparability outcomes.
A comparability protocol should be filed
with the initial marketing application or as a
PAS. It allows FDA and the sponsor to agree on
methods to be used to demonstrate compara-
bility between the old and new manufacturing
process, including:
analytical methods and acceptance
criteria
stability data requirements5
statistical tools
nonclinical studies, if needed
clinical studies, if needed
Table 2 gives examples of major changes.
Significant process changes, formulation
changes, widening acceptance criteria, replacing
analytical methods, scale-up and container
closure changes typically require PAS. Triggers
for additional clinical or nonclinical studies
may include formulation changes or new
excipients, significant changes to activity or
impurity levels and, for biologics, cell line
changes. Regulators are especially concerned
about the potential immunogenicity impact of
formulation or cell line changes for biologics.
Certain moderate changes can be reported
as CBEs. Sponsors may submit a CBE-0 or
CBE-30, depending in part upon the impact
assessment as well as discussions with FDA in
advance of the submission to obtain concur-
rence on the filing strategy and timing of the
change (Table 3). Some examples are the addi-
tion of a duplicate process chain or operation
unit that does not impact licensed/approved
process parameters, the addition of new prod-
ucts in the licensed manufacturing areas, chang-
es to compendial test methods and the replace-
ment of reference standards. CBE reporting is a
rather gray area, and the reporting category may
change depending upon the availability (or lack
thereof ) of agreements with FDA and internal
strategic needs.
Changes with the least potential for
impacting product quality attributes should
be submitted in the Annual Report (Table
4). These can include additional or more-
stringent release or stability specifications,
more-stringent stability test parameters or
time points, and modifications to analytical
test procedures that do not change the basic
test methodology or acceptance criteria. Drug
substance and drug product stability trends and
data are also included in the AR.
Summary
Postapproval changes to manufacturing pro-
cesses and quality controls present unique chal-
lenges to licensed drug companies and must be
assessed for their potential impact. The regula-
tory professional plays a pivotal role in assessing
the change, obtaining feedback from regulatory
authorities, and acting as the liaison between
Table 4. Minor Change Examples (Minimal Potential for AEs)
to File in Annual Report
modification in analytical procedures with no change in basic
Annually test methodology or release specifications
reportable additional release tests and/or tightening of specifications
replacing an in-house reference standard
more-stringent stability test parameters or time points
report of drug substance and drug product trend analyses
(release and stability data)

Regulatory Focus 33
 the regulatory agencies and the in-house quality,
manufacturing and supply chain groups. F

REFERENCES
1. Sufficiently described in the license, such as a like-for-
like equipment change.
2. For more information and to see the updated PDUFA
2007. Accessed 4 January 2008.
www.fda.gov/oc/initiatives/advance/fdaaa.html.
3. Labeling change reporting requirements are beyond the
scope of this article and are not discussed herein.
4. 21 CFR 314.70 and 21 CFR 601.12.
5. Stability data may be required for both API/drug sub-
stance and final drug product, depending upon the
potential impact of the change to either.

Additional Bibliographic Material

1. International Conference on Harmonization (ICH)
Q5E: Comparability of Biotechnological Products
Subject to Changes in their Manufacturing Process
November 2004.
2. 21 CFR 314.70 (New Drug)
3. 21 CFR 601.12 (Biologic)
4. Changes to an Approved NDA or ANDA. FDA CBER/
CDER, April 2004.
5. Changes to an Approved Application for Specified
Biotechnology and Specified Synthetic Biological Products.
FDA CBER/CDER, July 1997.
6. Comparability Protocols Protein Drug Products
and Biological Products. FDA CBER/CDER, Draft
September 2003.
7. Demonstration of Comparability of Human Biological
Products, Including Therapeutic Biotechnology Derived
Products. FDA CBER/CDER, April 1996.

AUTHORS
Khandan Baradaran, PhD, is a Senior Manager of
Regulatory Affairs at Dyax Corp. Prior to joining Dyax,
she held management positions in analytical development,
quality control, quality assurance and regulatory affairs at
Biogen Idec.
Peggy J. Berry, MBA, RAC, is Senior Vice President,
Quality and Regulatory Affairs at Dyax Corp., responsible
for the strategic management and oversight of the quality
and regulatory affairs departments. Previously she was
director of regulatory affairs at AstraZeneca and managed
the regulatory and clinical departments at Dey Laboratories.
Berry also has worked for ILEX Oncology and Cato
Research Ltd.) and in FDA review divisions.

34 April 2008