5460-3 Shargel Ch12 R2 102504

12
Scale-up, Post-approval Changes, and
Post-marketing Surveillance

Sadie M. Ciganek, Aruna J. Mehta,

Frank J. Mellina, and Leon Shargel

1. INTRODUCTION
Approval of an Abbreviated New Drug Application (ANDA) is only the
beginning of a generic drug product’s history. Frequently, changes are
made to the chemistry and manufacturing controls of an ANDA following
approval and continue throughout the life of the product. A pharmaceutical
manufacturer may make changes in the drug formulation, batch size, pro-
cess, equipment, or manufacturing site, which a¡ects the identity, strength,
quality, purity, and potency of the ¢nished product. Therefore, any change
must be fully evaluated prior to implementation to determine its impact on
the ¢nished product as they may relate to safety or e¡ectiveness.
Changes to an approved ANDA can be initiated for a number of rea-
sons, i.e., revised market forecast a¡ecting batch size requirements, quali¢-
cation of a new active pharmaceutical ingredient source, optimization of the
manufacturing process, upgrade of the container=closure system, or
enhancement of the analytical test methods and speci¢cations to name a line.
A change within a given parameter can have varied adverse e¡ects
depending on the type or dosage form of the product. For example, a change
in the container=closure system of a solid oral dosage form will have less
impact on the drug product than it would for a semisolid or oral liquid dosage
281

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 5460-3 Shargel Ch12 R2 112204

282 Ciganek et al.

form where the primary packaging component becomes critical for the
shelf life of the ¢nished product. To illustrate further, a small change in the
concentration ratio of an inactive ingredient may have less impact on an
immediate release drug product than it would for a modi¢ed release product,
where that same ingredient may adversely a¡ect the release rate, thereby
impacting [Link] such circumstances, the reporting require-
ments for one will di¡er from those for the other depending on the dosage
form and route of administration.
Single or multiple changes within the same ANDA over time can have
an impact and must be considered in the overall life of the drug product as
well. Numerous changes to the manufacturing parameters occurring over
time may render the drug product approved in the original ANDA substan-
tially di¡erent than the one on the market. Therefore, data submitted in an
application to support most changes should include a comparison to the
original exhibit batch or bio-batch wherever possible.
Pharmaceutical manufacturers are also required to ¢le periodic Post-
Market Reports for an approved ANDA to FDA through the Post-Marketing
Surveillance System, which will be described in greater detail in this chapter.

2. HISTORY AND BACKGROUND

2.1. FDAMA
On November 21, 1997, the Food and Drug Administration Modernization
Act (FDAMA) was signed into law. The FDAMA initiative was directed at
providing more de¢nite language to the current Food, Drug, and Cosmetic
(FD&C) Act and further de¢ning the statutory requirements for marketing
approved drugs in the United States. FDAMA added section 506A
(21U.S.C. 356a) to the FD&C Act, which provided speci¢c language for
manufacturing changes to an approved application, and reporting require-
ments for those changes. Following FDAMA, and further decodifying
the statutory requirements for post-approval changes, the FDA issued
a Guidance for Industry: Changes to an Approved NDA or ANDA in Novem-
ber 1999 (1). This guidance is the current standard used in the pharma-
ceutical industry to assess and report manufacturing changes.
FDAMA was e¡ectively a rewrite for Title 21 Code of Federal
Regulation (CFR) part 314.70, which had previously de¢ned post-approval
changes, but not to the extent that FDAMA considered. FDAMA also
relaxed certain requirements for changes that were determined to have little
or no impact on the ¢nished [Link] was intended to lessen the regula-
tory burden for FDA and industry alike. In addition to relaxing certain
change requirements, FDAMA also provided a new reporting category

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Scale-up, Post-approval Changes, Surveillance 283

known as Supplement
Changes Being Effected in 0 Day (CBE 0 day). The

CBE 0 day enabled sponsors to implement changes immediately after ¢rst
notifying FDA without a waiting period. In e¡ect, the current CBE 30 days
reporting category already provided for in (CFR) part 314.70 was expanded
to include another level of noti¢cation less stringent than what existed.
In summary, FDAMA provided for four reporting categories as
follows:
1. Prior Approval Supplement: Major changes that require FDA
approval before implementation
2. Supplement
Changes Being Effected (30 Days): Moderate
changes that require 30 days’ notice before implementation
3. Supplement
Changes Being Effected (0 Day): Moderate changes
that can be implemented immediately
4. Annual Report: Minor changes that can be implemented immedi-
ately and ¢led in the next Periodic Report

2.2. SUPAC
Prior to FDAMA, the basis for revision of the FD&C Act was the Guidance
for Industry: Immediate Release Solid Dosage Forms
Scale-Up and Post-
Approval Changes (SUPAC ) (2). This guidance was a ¢rst attempt beyond
the Case of Federal Regulation (CFR) to provide industry with clear and
de¢nitive language regarding the regulatory noti¢cation process and
requirements for post-approval changes. It also attempted to reduce the reg-
ulatory burden for industry. SUPAC classi¢ed changes according to ‘‘levels’’
and provided requirements to support each level. The reporting category
for the change was determined by the ‘‘level’’ classi¢cation, which will be
described in greater detail below. When SUPAC was ¢rst introduced, it
became a milestone for the pharmaceutical industry. The criteria for the dif-
ferent level changes and the documentation required to support the change
were based on three independent studies: (a) research conducted by the Uni-
versity of Maryland in Association with the FDA, (b) results from a
workshop between the American Association Pharmaceutical Scientists
(AAPS), US Pharmaceutical Convention, and FDA, and (c) research
conducted at the University of Michigan and the University of Uppsala.
In summary, the SUPAC guidance expanded 21 CFR part 314.70 and
de¢ned in much greater detail the types of changes and reporting category
required. The guidance describe the following areas where change is likely:
 Components and composition of the drug product
 Manufacturing site change
 Scale-up of the drug product

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 5460-3 Shargel Ch12 R2 102504

284 Ciganek et al.

 Manufacturing equipment
 Packaging

The SUPAC guidance describes three levels of change and the recom-
mended chemistry, manufacturing and controls tests, in vitro dissolution
tests, and bioequivalence tests for each level. It also describes the documents
required to support the change. The three level changes as described by
FDA are provided below.

Level Definition

1 Changes that are unlikely to have any detectable impact on formulation

quality and performance
2 Changes that could have a significant impact on formulation quality and
performance
3 Changes that are likely to have a significant impact on formulation quality and
performance

A level 1 change such as a small change in the excipient amount (e.g.,

starch, lactose) is unlikely to alter the quality or performance of the drug
product, whereas a level 3 change where the qualitative or quantitative
change in the excipients is outside an allowable range, particularly for drug
products with a narrow therapeutic range, may require an in vivo
bioequivalence study to demonstrate that the drug quality and performance
were not altered by the change.
A manufacturing change must be assessed for its e¡ect on the identity,
strength, quality, purity, and potency of the product, as these factors may
relate to the safety or e¡ectiveness of the product (506A(b)). The assessment
of the e¡ect of a change should include a determination that the drug sub-
stance, in-process materials, and=or drug product a¡ected by the change
conforms to specifications, which are provided in the approved application.
Moreover, the manufacturer must con¢rm the quality of drug substance,
drug product, and in-process materials. If a speci¢cation needs to be revised
as a result of the change, this is considered a multiple change. Additional
testing such as chemical and physical behavior, microbiological, biological,
bioavailability, and=or stability may also be required in order to ensure that
the identity, strength, quality, purity, or potency of the product is not
changed. The type of additional testing that an applicant should perform
depends on the type of manufacturing changes, the type of drug substance
and=or drug product, and the e¡ect of the change on the quality of the

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Scale-up, Post-approval Changes, Surveillance 285

product, e.g.,
 Evaluation of changes in the purity or degradant pro¢le
 Toxicology tests to qualify a new impurity or degradant or to qualify
an impurity that is above a previously quali¢ed level
 Evaluation of the hardness or friability of a tablet
 Assessment of the e¡ect of a change on bioequivalence, which may
include multipoint and=or multimedia dissolution pro¢ling and=or
an in vivo bioequivalence study
 Evaluation of extractables from new packaging components or
moisture permeability of a new container=closure system
If an assessment concludes that a change has adversely a¡ected the
identity, strength, quality, purity, or potency of the drug product, the change
should be ¢led in a Prior Approval Supplement, regardless of the reporting
category of the change.
Following the publication of the SUPAC-IR, FDA issued numerous
other SUPAC guidances speci¢c for modi¢ed release drug products, active
pharmaceutical ingredients, analytical equipment, etc. The same principles
of assessment of changes, i.e., level 1, 2, or 3, are used in these guidances. This
discussion will focus mainly on the original SUPAC Immediate Release
Drug Products guidance.

3. CURRENT REQUIREMENTS FOR POST-APPROVAL

CHANGES
3.1. Components=Composition
In general, changes to the qualitative=quantitative composition of the
formulation are considered major changes. Therefore, these changes must
be considered carefully before implementation. Such changes require a Prior
Approval Supplement unless otherwise exempted by regulation or guidance
documents. The current guidance for industry, Changes to an Approved
ANDA or NDA, does not address components=composition in detail; there-
fore, the SUPAC guidance remains in e¡ect for de¢ning components and
composition changes and the reporting category thereof.
The addition or deletion of an ingredient can have an adverse e¡ect on
the dissolution pro¢le of the ¢nished product and on the in vivo bioequiva-
lence to the reference listed drug. In general, any addition or deletion of an
ingredient must be ¢led as a Prior Approval Supplement. The exception to
this applies to colors,which can be removed or reduced from the formulation
and ¢led in an annual report. Only in certain circumstances can changes to
the components=composition be made with a less stringent reporting cate-
gory. These instances are de¢ned in SUPAC and summarized in Table 1.

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TABLE 1 Components=Composition Change

286
Level Definition Category and example Test documentation Filing documentation

1 (Minor Changes unlikely to have i. Deletion=partial dele- i. Chemistry: Compen- Annual Report (all
changes) any detectable impact tion of color or flavor dial release and stabi- information including
on formulation quality or change in the ingre- lity testing long-term stability data)
and performance dient of the printing Stability: Long-term
ink stability testing on one
ii. Changes in excipient batch in annual report

5460-3 Shargel Ch12 R2 102504

(% w=w) of total for ii. Dissolution: None
mulation not greater beyond application=
than 5% compendial require-
ment
iii. In vivo BE: None
2 (Moderate Changes could have Changes in technical i. Chemistry: Compendial Changes Being Effected
changes) significant impact on grade of an excipient or release, batch record (CBE) Supplement
formulation quality and changes in excipient Stability: one batch with long-term
performance as a amount greater than with 3 months’ stability data
result of change in expressed in level 1, accelerated stability
therapeutic range, but total additive effect datain supplement
solubility, and of all excipients should andone batch on
permeability (low not be greater long-term stability
or high) than 10% ii. Dissolution: Using
case A, B, and C

Ciganek et al.
as described in the
guidance
iii. InVivo BE: None if
situation does not
meet above dissolu-
tion description
Copyright © 2005 by Marcel Dekker, Inc.
 Scale-up, Post-approval Changes, Surveillance
3 (Major Changes likely to have a i. Qualitative and quan- i. Chemistry: Compen- Prior Approval
changes) significant impact on titative changes to a dial release and batch Supplement on all
formulation quality and narrow therapeutic records information including
performance as a drug beyond the Stability: (a) 3 months’ accelerated stability
result of change in ranges of excipients accelerated stability and long-term stability
therapeutic range, noted in level 1 testing on one batch in Annual Report
solubility, and ii. High solubility and in supplement and long-
permeability (low permeability drug, term stability data on one
or high) low permeability and batch in Annual
high solubility drug Report if significant

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and high permeability body of information
and low solubility is available; (b) 3
drugs not meeting the months’accelerated
dissolution criteria as (supplement) and
stipulated in the gui- long-term stability
dance (Annual Report) on
iii. Changes in the excipi- up to three batches
ent ranges of low ii. Dissolution: Multi-
solubility, low perme- point dissolution pro-
ability drugs listed file in compendial
under level 1 medium at 15, 30, 45,
60, and 120 min or
until asymptote is
reached
iii. InVivo BE: Full BE
study except for the
cases when in vitro=
in vivo correlation is

287
established

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 5460-3 Shargel Ch12 R2 102504

288 Ciganek et al.

3.2. Site Changes

The sponsor of an ANDA must include in its application the site of manufac-
ture, where the drug product will be produced, tested, packaged, and=or
labeled. A change in any of these sites can adversely a¡ect the identity,
strength, quality, purity, or potency of the ¢nished product. Therefore, any
site change under SUPAC-IR calls for the new site to be in compliance with
good manufacturing practice (cGMP) regulations. A stand-alone packaging
operation site change, utilizing container(s)=closure(s) in the approved
application, may be submitted as a Change Being E¡ected Supplement. The
facility should also have a current and satisfactory cGMP compliance pro¢le
with FDA for the type of packaging operation in question before submission
of the supplement. If the facility has not received a satisfactory cGMP
inspection within the previous two years for the type of packaging operation
involved, a Prior Approval Supplement with the same commitment for stabi-
lity is recommended. The supplement should also contain a commitment to
place the ¢rst production batch of the product on long-term stability studies
using the approved protocol in the application and to submit the resulting
data in annual reports. Likewise, a stand-alone analytical testing laboratory
site change may also be submitted as a Change Being E¡ected Supplement
if the new facility has a current and satisfactory cGMP compliance pro¢le
with the FDA for the type of testing operation in question.
Di¡erent levels and the regulatory requirements for site changes are
discussed in Table 2.

3.3. Change in Batch Size

Change in batch size from pivotal=pilot scale bio-batch to larger or smaller
production batches tends to change the operating parameters. Therefore, all
the parameters, such as mixing time, speed, etc., are adjusted according to
the equipment (large or small) used in the process. This requires proper vali-
dation of the batches before submission of additional information in the appli-
cation. Any change in the production batch for which the operating
parameter falls within the range established for the ANDA batch and valida-
tion batches will be regarded as a level1change. If it falls outside the validation
ranges, the change would be permitted under SUPAC-IR as a level 2 change.
Regardless, SUPAC-IR does not address scale-down below 100,000 units.
Changes in batch size are characterized in two levels as cited inTable 3.

3.4. Manufacturing
This includes any change made in equipment and the process used in
manufacturing a drug product.

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TABLE 2 Site Change

Scale-up, Post-approval Changes, Surveillance

Level Definition Test documentation Filing documentation

1 (Minor changes) Site change within facility and i. Chemistry: Compendial release Annual Report
using same equipment, ii. Dissolution: Compendial release
SOPs, environment iii. In-vivo BE: None
conditions (temperature and
humidity), and controls, no
changes made in manu-
facturing batch records

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2 (Moderate changes) Site change within a i. Chemistry: Updated batch records, com- Changes Being
contiguous campus or pendial release, Stability: Long-term sta- Effected (CBE)
between facilities in adjacent bility on one batch reported in Annual Report Supplement,
city blocks using same equip ii. Dissolution: Compendial release Annual Report
ment, SOPs, environment
iii. InVivo BE: None
conditions (temperature and
humidity), and controls, no
changes made to manu-
facturing batch records
3 (Major changes) Changes in manufacturing site i. Chemistry: Updated batch records, com- Changes Being
to a different campus. Same pendial release, Stability: 3 months’ Effected (CBE)
equipment, SOPs, environment accelerated stability data reported in Supplement,
conditions and controls should supplement, long-term stability data on Annual Report
be used at the new site. No
up to three batches in Annual Report
changes in the manufacturing
batch records
ii. Dissolution: Case B of the guidance,
multipoint profile in compendial medium
at 15, 30, 45, 60, and 120 min or until an
asymptote is reached. Dissolution profile
should be similar at both current and pro
posed site

289
iii. InVivo BE: None

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TABLE 3 Batch Size Change

290
Level Definition Test documentation Filing documentation

1 (Minor changes) Change in batch size by i. Chemistry: Compendial Annual Report including long-
10 times the pilot=bio-batch release, notification of term stability data
using equipment having the changes, and updated
same design and operating batch records in annual
principles as that used to report, Stability: Long-
produce the test batch. The term stability on one batch

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batch should be manufac- ii. Dissolution: Compendial
tured under full compliance release
with cGMPs and SOPs using iii. In vivo BE: None
the same formulation and
manufacturing procedures
2 (Moderate changes) Change in batch size beyond a i. Chemistry: Compendial Changes Being Effected
factor of 10 times the size of release, notification of Supplement, Annual Report
the pilot= bio-batch using change, and updated including long-term
equipment having the same batch records, Stability: stability data
design and principles. The 3 month’accelerated stabi-
batch should be manufac- lity and long-term stability
tured under full compliance on one batch
with cGMPs and SOPs using ii. Dissolution: Case B of the
the same formulation and guidance, multiple point
manufacturing procedures profile in compendial med-

Ciganek et al.
ium at 15, 30, 45, 60, and
120 min or until an asymp-
tote is reached
iii. In vivo BE: None

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Scale-up, Post-approval Changes, Surveillance 291

3.4.1. Equipment Change

Any change in manufacturing equipment other than that used in the
approved application requires appropriate validation studies to demon-
strate that the new equipment is similar to the original equipment. Equip-
ment within the same class and subclass would be considered to have the
same design and operating principal under SUPAC-IR. For example, a
change inV-blender from one manufacturer to another manufacturer would
not represent a change in operating principle, and hence be considered to
be the same under SUPAC-IR,whereas a change in equipment from one class
(V-blender) to a di¡erent class (ribbon blender) would be considered a
change in design and operating principle and would be considered di¡erent
under SUPAC-IR. A guidance for industry, SUPAC-IR=MR: Immediate
Release and Modified Solid Oral Dosage Forms
Manufacturing Equipment
Addendum, 1999 (3), explains in detail about various changes in equipment
and the regulatory requirements.
The two di¡erent levels of change and regulatory requirements on
change in equipment are summarized in Table 4.

3.4.2. Process Change

Change in manufacturing process or technology from that currently used by
the applicant may have the potential for adverse e¡ects on the identity,
strength, quality, purity, or potency of a drug [Link] safety or e¡ective-
ness of the product depends on the type of the manufacturing process and
the changes being instituted for the drug substance or drug product. Any fun-
damental change in the manufacturing process, e.g., dry to wet granulation
or change from one type of drying process to another (e.g., oven tray, £uid-
bed) is considered a major change,whereas change in mixing time, operating
speed, etc., within an approved range is considered a minor change. The
guidance de¢nes three levels of in-process change, as indicated in Table 5.

3.5. Specifications
Speci¢cations are the standards a drug product must meet to ensure confor-
mance to predetermined criteria for consistency, reproducibility, and quality.
Such changes generally require a PriorApproval Supplement unless the speci¢-
cation is tightening or otherwise exempted by regulation guidance documents.
Prior approval is required on the following major changes in speci¢ca-
tion except as provided in the SUPAC-IR guidance:
 Relaxing an acceptance criterion

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 TABLE 4 Equipment Change

292
Level Definition Test documentation Filing documentation

1 a. Changes from nonautomated i. Chemistry: Notification of change, compendial Annual Report including long-
to automated equipment to release, and Updated batch records Stability: Long- term stability data
move ingredients term stability on one batch
b. Changes to alternative equip ii. Dissolution: Compendial release
ment of the same design and iii. In vivo BE: None
operating principles (same or

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different capacity)
2 Changes in equipment to a dif i. Chemistry: Compendial release, notification of Prior Approval Supplement
ferent design and Different change, updated batch records with justification for change,
operating principles. Stability: (a) Significant body of data available, which Annual Report including
includes 3 months’accelerated stability data in sup- long-term stability data
plement and long-term stability on one batch reported
in Annual Report; (b) significant body of data not
available,Which includes 3 months’accelerated stabi-
lity on up to three batches in supplement and long-
term stability on up to three batches reported in annual
report
ii. Dissolution: Case C dissolution profile of the gui-
dance, which is multipoint dissolution, provides in
water, 0.1N HCl, and USP buffer media at pH 4.5, 6.5,
and 7.5 for the proposed and currently accepted for-

Ciganek et al.
mulation
iii. In vivo BE: None

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TABLE 5 Process Change

Scale-up, Post-approval Changes, Surveillance

Level Definition Test documentation Filing documentation

1 Changes such as mixing times i. Chemistry: Compendial release Annual Report

and operating speeds within ii. Dissolution: Compendial release.
application=validation iii. In vivo BE: None
changes
2 Any changes outside of appli- i. Chemistry: Compendial release, notification of change, Changes Being Effected
cation=validation ranges updated batch records (CBE) Supplement,

5460-3 Shargel Ch12 R2 102504

(mixing time, operating Stability: Long-term stability on one batch Annual Report includ-
speed) ii. Dissolution: Case B dissolution profile of the guidance, mul- ing long-term stability
tipoint dissolution in the application=compendial medium at data
15, 30, 45, 60, and 120 min or until an asymptote is reached
iii. In vivo BE: None
3 Any change in process such as i. Chemistry: Compendial release, notification of change, Prior Approval Supple-
wet-granulation to direct updated batch records ment with justification,
compression Stability: (a) Significant body of data available, which is 3 Annual Report
months’accelerated stability on one batch in supplement including long-term
and long-term stability on one batch reported in Annual stability data
Report; and (b) significant body of data not available 3 this
includes 3 months’accelerated stability on up to three
batches in supplement and long-term stability on up to three
batches reported in Annual Report.
ii. Dissolution: Case B dissolution profile of the guidance, mul-
tipoint dissolution profile in the application=compendial
medium at 15, 30, 45, 60, and 120 min or until an asymptote
is reached
iii. InVivo BE: Full BE study. BE study may be waived if IVIVC is

293
established

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 5460-3 Shargel Ch12 R2 112304

294 Ciganek et al.

 Deleting any part of a speci¢cation

 Changing or establishing a new regulatory analytical procedure
that does not provide the same or increased assurance of the iden-
tity, strength, quality, purity, or potency of the material being tested
as the analytical procedure described in the approved application
A 30 days’ Changes Being E¡ected Supplement needs to be ¢led in case
of moderate changes in speci¢cations, e.g.,
 Change in regulatory analytical procedures other than editorial or
identi¢ed as major
 A change in analytical procedure or deletion of a test for raw materi-
als used in drug substance manufacturing or in-process materials
prior to the ¢nal intermediate
The following include changes in speci¢cations that are considered to
have minimal potential for an adverse e¡ect on the identity, strength, quality,
purity, or potency of a product as they may relate to the safety or e¡ectiveness
of the product, and therefore can be submitted in an annual report:
 Change in speci¢cation made to comply with an o⁄cial
compendium
 Change in analytical procedure for testing raw material, drug
substance or drug product that provides the same or increased
assurance of identity, strength, purity, or potency of the material
being tested as the analytical procedure described in the approved
application
 Tightening of acceptance criteria

3.6. Packaging
A container=closure system for a solid oral dosage form tends to be low risk
and will have little impact on the shelf life of the ¢nished [Link],
under the new guidance for industry, and the stability guidance, the require-
ments for packaging changes have been relaxed signi¢cantly.

4. COMPARABILITY PROTOCOLS
A comparability protocol is a plan for anticipated future CMC changes. FDA
recently published a draft guidance, Comparability Protocols
Chemistry,
Manufacturing, and Controls Information, to provide recommendations on
preparing and using comparability protocols for post-approval changes in
the CMC section of an NDA or ANDA (4). Although applications for protein

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Scale-up, Post-approval Changes, Surveillance 295

products are not included in the guidance, well-characterized synthetic

peptides are included within the scope of this guidance.
According to the guidance,‘‘A comparability protocol is a well de¢ned,
detailed, written plan for assessing the e¡ect of speci¢c CMC changes in the
identity, strength, quality, purity, and potency of a speci¢c drug product as
these factors relate to the safety and e¡ectiveness of the product. A compar-
ability protocol describes the changes that are covered under the protocol
and speci¢es the tests and studies that will be performed, including analyti-
cal procedures that will be used, and acceptance criteria that will be
achieved to demonstrate that speci¢ed CMC changes do not adversely a¡ect
the product.’’
A comparability protocol may be submitted with an ANDA or NDA
application or as a Prior Approval Supplement (post-approval). The bene¢t
of the comparability protocol is that an FDA request for additional informa-
tion to support a change is less likely when the change is covered under an
approved protocol. Thus, the sponsor could implement a CMC post-
approval change as described in the comparability protocol. This would
allow the sponsor to place the product in distribution sooner.

5. POST-MARKETING SURVEILLANCE
Once the FDA approves a generic drug product, manufacturers are respon-
sible for conducting post-marketing surveillance. Post-marketing reporting
requirements for an approved ANDA are set forth in the US Federal Code
of Regulations, 21 CFR 314.80 (5) and 314.98. The main component of this
requirement is the reporting of adverse drug experiences(ADEs). According
to 21 CFR 314.80(a), an adverse drug experience is de¢ned as ‘‘any adverse
event associated with the use of a drug in humans,whether or not considered
drug related’’ (6). The de¢nition continues by stating that adverse events
include those that occur in the course of the use of a drug product in profes-
sional practice, occur from drug overdose (accidental or intentional), abuse,
or withdrawal, or involve failure of expected pharmacological action.
According to the de¢nition, it is irrelevant whether or not an event is con-
sidered drug related. A known or proven cause and e¡ect relationship
between the drug and the event is not required. The fact that an adverse
event occurred while a person was using a drug product is reason enough to
consider it an adverse drug experience.
It is important to examine who is involved in the process of ADE
reporting. Generally, there are three members that take part in this process:
a reporter, a manufacturer, and the FDA. Essentially anyone can report an
[Link] reporter can be a patient, doctor, pharmacist, nurse, or anyone else
aware of such an event. This person can report it to either the manufacturer

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296 Ciganek et al.

of the drug product or directly to the FDA. If the manufacturer receives the
report ¢rst, the manufacturer is responsible for investigating the ADE and
reporting it to the FDA. If the FDA is noti¢ed directly by the reporter, the
agency informs the manufacturer so that the ADE can be investigated. Part
of investigating an ADE may include, but is not limited to, contacting the
patient’s physician, the prescriber (if di¡erent from the physician), and the
pharmacy that ¢lled the prescription. Other investigations include perform-
ing all required testing of the retain sample from the lot of the product that
was used by the patient. Of course, there are many times when the lot number
is not known and therefore, this testing cannot be conducted. Once an
investigation is complete, the manufacturer is responsible for submitting
the information in a report to the FDA.
There is certain information that must be known, though, before a
report is submitted to the FDA. Among this information are four elements:
an identi¢able patient, an identi¢able reporter, a suspect drug=biological
product, and an adverse event or fatal outcome. If any of these basic
elements remain unknown after being actively sought by the applicant=
manufacturer, a report on the incident should not be submitted to the
FDA, because reports without this information make interpretation of
their signi¢cance di⁄cult, if not impossible. In these cases, the appli-
cant=manufacturershould track the steps taken to acquire the additional
information in their safety ¢les for the product. To facilitate the reporting
process, FDA created the MedWatch program (7). MedWatch is the FDA
Medical Products Reporting Program. It was originally designed to
emphasize the responsibility of healthcare providers to identify and report
ADEs. Through the MedWatch program, healthcare professionals can
report ADEs with the use of FDA Form 3500 (6) (MedWatch Form). How-
ever, this reporting is done on a voluntary basis. Currently, there are no reg-
ulations that require healthcare professionals to report adverse drug
experiences to the FDA or the manufacturer. In contrast, a manufacturer
aware of an ADE is required by law to report it to the FDA (provided the
four elements noted earlier are known). The FDA= MedWatch Form
3500A is used for mandatory reporting by manufacturers. It is interesting
to point out that on the bottom portion of both MedWatch forms there is
a note that reads: ‘‘Submission of report does not constitute an admission
that the product caused or contributed to the event.’’ This is a reiteration
of what was stated earlier in the CFR de¢nition of an ADE.
After an adverse event is reported to a manufacturer, two classi¢ca-
tions must be made. First, the adverse event must be categorized as either
serious or nonserious. Second, it must be determined whether the ADE is
expected or unexpected. Again, these terms are de¢ned in 21 CFR 314.80.
A serious adverse drug experience is ‘‘any ADE occurring at any dose that

Copyright © 2005 by Marcel Dekker, Inc.

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Scale-up, Post-approval Changes, Surveillance 297

results in any of the following outcomes: death, a life-threatening adverse

drug experience, inpatient hospitalization or prolongation of existing
hospitalization, a persistent or signi¢cant disability=incapacity, or a conge-
nital anomaly=birth defect.’’ In addition, the regulations include an ‘‘impor-
tant medical event’’ that may endanger the patient and may require medical
involvement to prevent one of the outcomes listed above. A nonserious
ADE is one that does not result in any outcome listed in the de¢nition of a
serious ADE.
In regards to the expected and unexpected designation, the labeling of
the product is used to determine the type of ADE. If the product labeling lists
a particular adverse event, it is considered expected. If not, it is considered
unexpected. This classi¢cation of ADEs is not always clear. Unexpected
ADEs also include events that may be symptomatically and pathophysiologi-
cally related to an event listed in the labeling, but di¡er from the event
because of greater severity or speci¢city. For example, if a report is received
that a patient experienced complete loss of vision while using a marketed
product and the labeling of the product lists visual disturbances in the
adverse e¡ects section, the manufacturer may consider this an expected
event. However, since complete loss of vision is more severe than the descrip-
tion in the labeling, this ADE would be classi¢ed as unexpected rather than
expected. The key here is that manufacturers should not give the FDA the
impression that reports or details of reports are being hidden or glossed over.
It is important to note that by submitting an ADE report to the FDA, manu-
facturers are simply notifying FDA. As discussed earlier, it is not an admis-
sion of guilt or even agreement that the product caused the event.
It is important to correctly classify an ADE as either serious or nonser-
ious and either expected or unexpected. The classi¢cation of the ADE will
determine the type of report that is submitted to the FDA. ADEs that are
considered both serious and unexpected must be submitted to the FDA in
an expedited manner and are known as 15-Day Alert Reports. Manufac-
turers must submit these reports to the FDA as soon as possible, but in no
case later than 15 calendar days of the initial receipt of the information. All
other ADEs (those that are serious and expected, nonserious and expected,
or nonserious and unexpected) should be reported to the FDA as Periodic
Reports. Periodic Reports must be submitted at quarterly intervals for three
years from the date of FDA approval of the product, and then annually. Any
follow-up information received after the initial submission to the FDA
should be submitted to the FDA and should follow the same rules depending
on whether the original ADE report was classi¢ed as a 15-Day Alert Report
or Periodic Report.
During the investigation and submission of the ADE report to the
FDA, patient privacy should be maintained. The manufacturer should

Copyright © 2005 by Marcel Dekker, Inc.

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298 Ciganek et al.

not identify patients by name or address in the reports. Instead, the

manufacturer should assign a unique code (e.g., patient’s initials or a
tracking number) to each report. In addition, names of patients, healthcare
professionals, hospitals, and geographical identi¢ers in adverse drug
experience reports are not releasable to the public under FDA’s public
information regulations.
Although there is some complexity at times, the ADE reporting system
is e⁄cient and straightforward. The main goal of the requirement is to iden-
tify new or previously unrecognized adverse events that are caused by drug
products. This often results in the addition of safety information to a pro-
duct’s labeling, but can also lead to more severe actions like product recalls
or withdrawals. In any case, the objective is to expand the information avail-
able to the medical community and the public regarding a product’s adverse
event pro¢le and therefore increase public safety.

REFERENCES
1. Guidance for Industry. Changes to an Approved NDA or [Link] Department
of Health and Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER), November 1999, CMC.
2. Guidance for Industry. Immediate Release Solid Oral Dosage Forms
Scale-Up
and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro
Dissolution Testing, and In Vivo Bioequivalence Documentation. Center for
Drug and Research (CDER), November 1995, CMC 5.
3. Guidance for Industry. SUPAC-IR=MR: Immediate Release and Modi¢ed
Release Solid Oral Dosage Forms
Manufacturing Equipment Addendum. US
Department of Health and Human Services, Food and Drug Administration,
Center for Drug Evaluation and Research (CDER), January 1999, CMC9
(Revision 1).
4. Guidance for Industry. Comparability Protocols
Chemistry, Manufacturing,
and Controls Information. FDA, Center for Drug Evaluation and Research
(CDER), February 2003, [Link]
5. O⁄ce of the Federal Register. 21 CFR 314.80. Revised as of April 1, 2002:
119^122.
6. Guidance for Industry. Postmarketing Adverse Experience Reporting for
Human Drug and Licensed Biological Products: Clari¢cation of What to
Report. Food and Drug Administration, August 1997.
7. Food and Drug Administration. MedWatch FDA Form 3500=3500A.
http:==[Link]=cder=guidance=[Link], June 1993.

Copyright © 2005 by Marcel Dekker, Inc.