Changes to An approved NDA and ANDA Regulatory considerations for manufacturing, Packaging and labeling of pharmaceuticals in USA and CANADA

1. CHANGES TO AN APPROVED NDA/ANDA
BY:
BHAVIKA A. PATEL
ROLL NO: 28
SUBJECT: 201
M.PHARM RA SEM II

2. • Once an ANDA as an NDA has been approved, any significant changes
in the conditions described in the application must first be approved
via a supplemental NDA/ANDA.
• Any substantive modifications proposed for the formulation may
require the submission of additional data assuring the bioavailability
of the drug.
• Certain minor changes, however, as permitted by specific regulations,
may be made without the filing of supplemental applications.
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SUPPLEMENTAL NEW DRUG APPLICATION

3. • The changes occurs in chemistry, manufacture of
drug, use, labeling, safety, effectiveness, identity,
strength, quality or purity of the drug or the
adequacy of the manufacturing methods,
facilitation, and controls to preserve these
elements.
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DEFINITION

4. RECOMMENDATIONS ARE PROVIDED FOR POST APPROVAL
CHANGES IN
(1) components and composition,
(2) manufacturing sites,
(3) manufacturing process,
(4) specifications,
(5) container closure system, and
(6) labeling, as well as
(7) miscellaneous changes and
(8) multiple related changes
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REPORTING CATEGORIES FOR CHANGES TO NDA/ANDA
REPORTING CATEGORIES FOR CHANGES TO NDA/ANDA
MAJOR CHANGE MODERATE CHANGE MINOR CHANGE
SUPLLEMENT- CHANGES
BEING EFFECTED
SUPLLEMENT- CHANGES
BEING EFFECTED
ANNUAL REPORT

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MAJOR CHANGES
Ø A major change is a change that has a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or potency of a
drug product as these factors may relate to the safety or effectiveness of
the drug product.
Ø A major change requires the submission of a supplement and approval
by FDA prior to distribution of the drug product made using the
change.
Ø This type of supplement is called, and should be clearly labeled, a Prior
Approval Supplement

7. • Manufacturer changes to manufacturing site that is different from those
specified in the approved application
• A move to a different manufacturing site, except one used to manufacture or
process a drug substance intermediate, when the new manufacturing site has
never been inspected by FDA or had a cGMP inspection for the type of
operation that is being moved .
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MAJOR CHANGES

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MAJOR CHANGES
q A move to a different manufacturing site for
• the manufacture, processing, or primary packaging of drug products when the
primary packaging components control the dose delivered to the patient.
E.g. oral and nasal metered-dose inhalers (MDIs), dry powder inhalers (DPIs),
and nasal spray pumps
• the manufacture or processing of in-process materials with modified-release
characteristics.
E.g. modified-release solid oral dosage forms, transdermal systems, liposomal
drug products, depot drug products

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MAJOR CHANGES
q Transfer of the manufacture of an aseptically processed sterile drug substance or
product to
• a newly constructed aseptic processing facility or area or
• an existing aseptic processing facility or area that does not manufacture similar
(including container types and sizes) approved drug products.
Eg. transferring the manufacture of a lyophilized drug product to an existing aseptic
process area where no approved lyophilized drug products are manufactured or
where the approved lyophilized drug products being manufactured have different
container types and/or sizes
q Transfer of the manufacture of a finished drug product sterilized by terminal
processes to a newly constructed facility at a different manufacturing site.

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MODERATE CHANGES
• This types of changes requires the submission of a supplement to FDA at least 30 days before the
distribution of the drug product made using the change. This type of supplement is called, and
should be clearly labeled, (CBE -30)
• The drug product made using a moderate change cannot be distributed if FDA informs the applicant
within 30 days of receipt of the supplement that a prior approval supplement is required.
Moderate change /
Supplement – Changes
Being Effected in 30 Days
• For certain moderate changes distribution can occur when FDA receives the supplement.
• This type of supplement is called, and should be clearly labeled, a Supplement - Changes Being
Effected (CBE-0)
Moderate change /
Supplement – Changes Being
Effected
q A moderate change is a change that has a moderate potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the drug product as
these factors may relate to the safety or effectiveness of the drug product. There
are two types of moderate change
q 2 types of moderate changes
q If, after review, FDA disapproves a CBE-30 or CBE-0, FDA may order the
manufacturer to cease distribution of the drug products made using the disapproved
change.

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MODERATE CHANGES
q A move to a different manufacturing site for the manufacture or
processing of any drug product, in-process material, or drug substance
q For aseptically processed sterile drug substance or aseptically
processed sterile drug product, a move to an aseptic processing facility
or area at the same or different manufacturing site
q A move to a different manufacturing site for the primary packaging of
1. any drug product that is not otherwise listed as a major change
2. modified-release solid oral dosage form drug products.

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MINOR CHANGES
Ø A minor change is a change that has minimal potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the drug
product as these factors may relate to the safety or effectiveness of the
drug product.
Ø No need of taking approval from FDA
Ø Must be described in the next Annual Report.
Ø An applicant can submit one or more protocols (i.e., comparability
protocols) describing tests, studies, and acceptance criteria to be
achieved to demonstrate the absence of an adverse effect from specified
types of changes.

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MINOR CHANGES
Ø A move to a different manufacturing site for secondary packaging.
Ø A move to a different manufacturing site for labeling.
Ø A move to a different manufacturing site for the manufacture or processing of
drug substance intermediates other than the final intermediate.
Ø A change in the contract sterilization site for packaging components when the
process is not materially different from that provided for in the approved
application
Ø A transfer of the manufacture of a finished product sterilized by terminal
processes to a newly constructed building or existing building at the same
manufacturing site.
Ø A move to a different manufacturing site for the ink imprinting of solid oral
dosage form drug products.

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• Changes in the qualitative or quantitative
formulation, including inactive ingredients –
Major change
• Requires submission of PAS
• The deletion or reduction of an
ingredient intended to affect only the
color of the drug product may be
reported in an annual report
Change in
Components
and
Composition

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• Manufacturer changes to manufacturing site that is
different from those specified in the approved
application
• Sites can include those used by an applicant to
• manufacture or process drug products, in-process
materials, drug substances, or drug substance
intermediates,
• package drug products,
• label drug products,
• test components, drug product containers, closures,
packaging materials, in-process materials, or drug
products.
• Sites include those owned by the applicant or contract
sites used by an applicant.
Change in
Manufacturing
sites

16. 1. CORRECTIVE AND PREVENTIVE ACTION (CAPA)
Managing a quality event requires understanding exactly what documents, which
product lines, and which processes are impacted by the event throughout the
organization; identifying what needs to be modified to solve the problems; and
following through on corrective action
2. DESIGN CONTROLS
o FDA requires that companies’ design control processes provide visibility across all projects
and related design activities. Mandatory scheduled periodic management reviews to verify
the project status and confirm that requirements have been achieved with documented
evidence
o FDA risk management stipulation requires that processes be in place to determine how post
release changes or corrective actions impact original design specifications and controls
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17. CONCLUSION
ü Automate compliance and quality processes to address the FDA’s QSIT
requirements
ü PLM is the ideal solution for companies seeking to address all FDA expectations
with regard to QSIT
ü By streamlining quality and compliance processes, PLM enables medical device
enterprises to reduce “time to market”, strengthen product quality, reduce cost,
and improve response to customer needs
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• http://www.regulatoryone.com/2012/02/changes-
to-approved-nda-or-anda.html
References

19. REGULATORY CONSIDERATIONS FOR
MANUFACTURING, PACKAGING AND LABELING
OF PHARMACEUTICALS IN USA.

20. • Manufacturing pharmaceuticals approved by CDER
• CDER mission to oversee research, development, manufacture, and marketing of
drugs.
• FDA ensures the quality of drug products by carefully monitoring drug manufacturers'
compliance with its Current Good Manufacturing Practice (CGMP) regulations.
• The CGMP regulations for drugs contain minimum requirements for the methods,
facilities, and controls used in manufacturing, processing, and packing of a drug
product.
• The approval process for new and generic drug marketing applications includes a
review of the manufacturer's compliance with the CGMPs.
• Manufacturing/marketing approval is necessary
– It is necessary to collect the data related to drug quality, safety and efficacy and have
those reviewed and approved by FDA
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21. • The regulations enable a common understanding of the regulatory process
by describing the requirements to be followed by drug manufacturers,
applicants, and FDA.
– 21 CFR 314 For FDA approval to market a new drug.
– 21 CFR 210 Current Good Manufacturing Practice in Manufacturing Processing,
packing, or Holding of Drugs.
– 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals.
• Owners or operators of drug manufacturing establishments are required to register their
establishments with FDA.
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22. • FDA ensures the quality of drug products by carefully monitoring of drug
manufacturers adhere to pharmaceutical regulatory compliance as per the cGMP.
• Packaging is also the part of cGMP.
• The terms packaging and packaging materials as used in this article refer to the
packaging of industrially manufactured finished pharmaceutical products
• The most important function of such packaging is to protect the tested and approved
product until it reaches the end user and to ensure that it conforms, within the defined
limits, to the product specification until the expiry date.
• In addition, the packaging materials must correspond at all times to the specification
reported and submitted to the authorities (authorization). Any deviation from this
specification must be reported to the authorities and in serious cases will lead to a
recall of the product from the market concerned.
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The following characteristics are common
requirements of most regulatory agencies:
1. Product or
preparation
related
requirements:
• Protection of the
product
• Protection of the
consumer
• Control of doses
2. Label related
requirements:
• Information to
the receive
• Legal control of
the product
3. Environmental
aspects:
• Packaging
wastage
• Ozone depletion
4. Consumer
protection:
• Child resistant
Closures
• Tamper evident
packaging

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v FDA packaging guidelines defines the types of containers to
be used, dividing them into
Ø Parenteral containers (glass/plastic)
Ø Non parenteral containers (glass, plastic& metal)
Ø Pressurized containers
Ø Bulk containers of API & drug products
Ø Also listed are closures including child resistant & tamper
evident closure, liner, seal & elastomers when used for
closure.

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v According to FDA guidelines, for submitting documents for packaging
for human drugs and biological the following are required.
1. PURPOSE
Ø Package must maintain standards, identity, strength, quality & purity
for intended shelf life
o Full information needed
o Type of container/closure
o Suitability for intended use
o Submission of packaging information & date.

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2. ENVIRONMENTAL CONCERN
v With increased environmental concerns there has been a considerable
pressure to reduce contamination of environment with particular
concern on amount of packaging & its disposal. Ozone depletion is
also of concern with the use of pressurized containers. Regarding this
aspects the increase in concerns has led to the European E Commission
packaging waste directive whichrequires:
o Reduction in quantity of waste
o Reduction in harmfulness of waste
o Increase in reuse of packaging
o Recycling & recovery of packaging waste &
o Reduction of the total packaging to be disposed of.

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Ø Labeling for prescription medicines is FDA’s primary tool for communicating
drug information to healthcare professionals, and patients and their caregivers.
Ø Labeling for prescription medicines includes:
o Prescribing Information (labeling for healthcare professionals),
o Carton and container labeling (cartons and containers are outside packaging
that contain information about prescription medicines), and
o Labeling for patients or caregivers (e.g., Medication Guides, Patient Package
Inserts, and Instructions for Use).
Ø Labeling for prescription medicines is required for all FDA-approved prescription
medicines. Such labeling is:
o Proposed by the drug company,
o Reviewed by the FDA, and
o If acceptable, approved by the FDA. If the labeling for a new medicine is
found to be unacceptable by the FDA, the medicine will not be approved by
the FDA.

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Ø FDA Medicine Labeling Requirements
o Brand name
o Description
o Indication and Usage
o Contraindication
o Warnings and Precaution
o Storage
o Adverse reaction
o Overdosage
o Dosage and administration
o How supplied
o Mfg date
o Expiry date
Ø The label shall contain information about the name and address of the manufacturer,
packer, or distributor.

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Carton and Container Labeling

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ØWritten procedures should be established to ensure that correct
labels, labeling packaging materials are used for APIs. Such
procedures should be followed and documented.
ØPhysical or spatial separation from other API operations should be
provided to prevent mix-ups and contamination.
ØPackaging and labeling facilities should be inspected immediately
before use to ensure that all materials not required for the next
packaging run have been removed.
ØThis Inspection should be documented.

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Ø Each API should be identified with a lot or control number that permits
determination of the history of its manufacture and control. Packaged and labeled
APIs should be examined to ensure that containers and packages in the lot bear the
correct label.
Ø API containers that are shipped outside of the manufacturer's control should be
sealed in a manner that alerts the recipient of possible tampering if the seal is
breached or missing.

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REFERENCE
Ø https://www.slideshare.net/prreeem/fda-regulations-for-pharmaceutical-
packaging
Ø https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-
good-manufacturing-practice-cgmp-regulations

33. LEGISLATION AND REGULATIONS FOR IMPORT,
MANUFACTURE, DISTRIBUTION AND SALE OF COSMETICS
IN USAAND CANADA.

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The FD&C Act defines cosmetics by their intended use, as
"articles intended to be rubbed, poured, sprinkled, or
sprayed on, introduced into, or otherwise applied to the
human body...for cleansing, beautifying, promoting
attractiveness, or altering the appearance" (FD&C Act, sec.
201(i)). Among the products included in this definition are
skin moisturizers, perfumes, lipsticks, fingernail polishes,
eye and facial makeup, cleansing shampoos, permanent
waves, hair colors, and deodorants, as well as any
substance intended for use as a component of a cosmetic
product. It does not include soap.
What is
cosmetics
?

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v The law does not require cosmetic products and
ingredients, other than color additives, to have FDA
approval before they go on the market, but there are laws
and regulations that apply to cosmetics on the market in
interstate commerce.
v The two most important laws pertaining to cosmetics
marketed in the United States are:
o the Federal Food And Cosmetics Act (FD&C Act) and
o the Fair Packaging and Labelling (FP&L) Act,
v Under this law, cosmetics must not be adulterated or misbranded.

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v Fair Packaging and Labelling Act
o To ensure that packages and their labels provide
consumers with accurate information about the
quantity of contents and facilitate value comparisons.
v FDA does not require pre-approval of cosmetic products and
ingredients other than color additives to have FDA approval
before place on market
v It is the responsibility of cosmetic manufacturer to ensure,
before marketing their products, that the products are safe
when used as directed in their label or under customary
condition of

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v VOLUNTARY COSMETIC REGISTRATION
Ø FDA voluntary cosmetics registration program is reporting system
for use by manufacturer, packers , and distributors of cosmetic
products that are in commercial distribution in the US
Ø There are two parts to the VCRP filing, described in detail in
the sections below.
Ø You may participate in both parts of the program or only one
part.
Ø The VCRP regulations can be found in 21 CFR, parts 710 and
720.
Ø The VCRP applies only to cosmetic products being sold to
consumers in the United States.

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v VOLUNTARY COSMETIC REGISTRATION
Ø We are FDA Consultants and US Agent for Foreign
facilities. We provide GMP, FDA Registration and Listing
service along with FDA Pre- Inspection Service.
o VCRP Registration : 649 USD (5 days)
o Cosmetic Label Review : 749 USD ( 20 days)
o Ingredient Statement Filling : 649 USD (2 days)

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Ø Under the law, manufacturers are not required to register their
cosmetics establishment or file their product no registration
number required to import cosmetics into the US.

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LABELING REQUIREMENT
ØThe FD&C Act prohibits the marketing
of adulterated or misbranded cosmetics in interstate
commerce.
ØA cosmetic is considered misbranded if.....
• labeling is false or misleading
• label does not state Cosmetic Labeling Guide
• the name and address of the manufacturer, packer, or
distributor o the net quantity of contents

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ØThe term "label" is defined in the FD&C Act and the FP&L Act.
The definitions differ in that under the FD&C Act definition a label
is "a display of written, printed or graphic matter upon the
immediate container," and under the FP&L Act definition "written,
printed or graphic matter affixed to any consumer commodity or
affixed to or appearing upon a package containing any consumer
commodity.”
ØThis includes labels, inserts, risers, display packs, leaflets,
promotional literature or any other written or printed information
distributed with a product.
LABELING REQUIREMENT

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ØA label may consist of more than one panel. It may consist of a
front panel, side panels and a back panel.
ØBack and side panels are generally called information panels.
ØThe FP&L Act also defines for consumer commodities, or
packages containing a consumer commodity, the term "principal
display panel," otherwise known for short as PDP.
ØThe "principal display panel" is that part of a panel that is most
likely to be shown or examined under customary conditions of
display for retail sale. Usually, it is the front panel of the label of
the outer package.
LABELING REQUIREMENT

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ØPlacement of information on label
o Outer container (or label of single container product)
Principal Display Panel Name of product
Identity §
740.10 warning
Net quantity of contents
Information Panels
Directions for safe use Warnings
Name and place of business
Ingredient declaration
Any other required information
Ø The information above must appear on the label of the outer container
which usually is a box, folding carton, wrapper etc. holding the inner
(immediate) container.
LABELING REQUIREMENT

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ØThe information above must appear on the label of the
outer container which usually is a box, folding carton,
wrapper etc. holding the inner (immediate) container.
ØPlease note that only the label of an outer container has a
PDP.
ØStatement of the brand name of the product is not a
regulatory requirement under the FD&C or FP&L Act.
LABELING REQUIREMENT

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v Inner Container (If Packaged in an Outer Container)
Front Panel Information Panels Information Panels
Directions for safe use
Warnings
Name of Product Name and Place of Business
Net Quantity of Contents
Any Other Required Information
Ø The information above must appear on the label of the inner (immediate)
container holding the cosmetic product.
Ø The inner container is packaged and displayed in a non-transparent box,
folding carton etc.
LABELING REQUIREMENT

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Prominence and Conspicuousness
1. Panel display: The required information must be on a panel which is
presented or displayed under customary conditions of purchase. This
eliminates placement of required information on a bottom panel of a
cosmetic unless it is very small and customarily picked up by hand
where inspected for possible purchase.
2. Panel Size: The label must be large enough to provide sufficient space
for prominent display of the required information.
3. Style and Size of Letters: The type must be of such size, and at least of
the required minimum size, and of such style that the required label
statements are easily readable.
LABELING REQUIREMENT

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Ø Background Contrast: The contrast must be sufficient to make the required
label statements conspicuous and easily readable.
Ø Obscuring Designs, Vignettes: The required statements must not be obscured
by vignettes or other designs or by crowding with other printed or graphic
matter.

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REFERENCE
• https://www.fda.gov/media/88234/download
• https://www.google.com/search?q=fda+cosmetic+regulations&oq=
fda+cosme&aqs=chrome.2.35i39i650j69i57j0i67i650j0i512j0i20i2
63i512j0i67i650j69i60l2.4947j0j7&sourceid=chrome&ie=UTF-8
• https://cosmetic.chemlinked.com/new-webinar/understanding-
cosmetic-regulations-in-the-united-states
• https://www.slideshare.net/RichaPatel76/richa-usa-seminar

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Ø All cosmetics sold in Canada must be safe to use and must not pose any
health risk.
Ø They must meet the requirements of the Food and Drugs Act and the
Cosmetic Regulation
Ø Under the Food and Drugs Act, a cosmetic includes "any substance or mixture
of substances, manufactured, sold or represented for use in cleansing,
improving or altering the complexion, skin, hair or teeth and includes
deodorants and perfumes." This includes:
• cosmetics used by professional esthetic services
• bulk institutional products such as hand soap in school rest rooms
• "handmade" cosmetics sold through home-based businesses or craft sales

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Ø The Cosmetic Regulations and the Food and Drugs Act require that cosmetics
sold in Canada are manufactured, prepared, preserved, packed and stored under
sanitary conditions. The manufacturer and importer must:
• provide a list of the product's ingredients
• notify Health Canada that they are selling the product
Ø Requirements under two law Consumer Packaging And Labeling Act
(CPLA), the Canadian Environmental Protection Act 1999, (CEPA) and the
Cannabis Act,

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Ø Notification of product :
o It is mandatory notification of product name and function, qualitative and
quantitative ingredients list to be notified10 days at least after place on
market
o The completed cosmetic notification form provides specific information
to Heath Canada, including
ü Address and contact information of the manufacturer ,distributors and
formulators
ü Function of the cosmetics
ü Form of cosmetics ( ex. Cream, gel )
ü Ingredients of cosmetics
ü Concentration of each ingredients

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Ø Manufacturers and importer are responsible for making sure their products
meets requirements of the food and drug act and its cosmetics regulation.
LABELING REQUIREMENTS
The labelling of cosmetics is governed by two Acts and their associated
Regulations:
o the Food and Drugs Act and the Cosmetic Regulations, and
o the Consumer Packaging and Labelling Act and the Consumer Packaging
and Labelling Regulations

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LABELING REQUIREMENTS
ØThe Food and Drugs Act and the Cosmetic Regulations govern the
classification and labelling of cosmetic products with regard to the:
o expression of the product's identity on its label,
o name and address of the principal place of business of the
manufacturer (see definition) indicated on the label,
o listing of ingredients on the label, and
o avoidable hazards presented by the cosmetic.

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LABELING REQUIREMENTS
Ø The Consumer Packaging and Labelling Act and Regulations prescribe the
mandatory information that must appear on the label of a pre-packaged
cosmetic product which includes the:
o product's identification in English and French,
o declaration of the product's net quantity in metric units of measure in
English and French, and
o Identity and principal place of business of the dealer (see definition) in
English or French.
The Act and Regulations also address false or misleading representation of the
product and the standardization of container size.

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REFERENCE
https://www.canada.ca/en/health-canada/services/consumer-product-
safety/reports-publications/industry-professionals/labelling-cosmetics.html

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