Post approval changes USFDA

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Post Approval Changes: Best Practices and
Strategies
Paul Schwartz, PhD
Director, Division of Post Marketing Activities II
Office of Life Cycle Drug Products
Office of Pharmaceutical Quality
Center for Drug Evaluation and Research
Olugbenga “Gbenga” Okubadejo, PharmD
Branch Chief (Post Marketing Activities)
Office of Program and Regulatory Operations
Office of Pharmaceutical Quality
Center for Drug Evaluation and Research

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A quality product of any kind consistently
meets the expectations of the user.
Pharmaceutical Quality
www.fda.gov

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A quality product of any kind consistently
meets the expectations of the user.
Pharmaceutical Quality
Drugs are no different.
www.fda.gov

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Patients expect safe and effective
medicine with every dose they take.
www.fda.gov

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Pharmaceutical quality is
assuring every dose is safe and
effective, free of contamination
and defects.
www.fda.gov

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It is what gives patients confidence
in their next dose of medicine.
www.fda.gov

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Post-Approval Change Regulations
• 21 CFR 314.70- Supplements and other changes to an approved
application.
• 314.70(a)(1)(i):…the applicant must notify FDA about each
change in each condition established in an approved application
beyond the variations already provided for in the application. The
notice is required to describe the change fully.
• 314(a)(2): The holder of an approved application must assess the
effects of the change before distributing a drug product made
with a manufacturing change.

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Common Post-Approval Changes
• Manufacturing Sites
• Manufacturing Process
• Specifications (tests, acceptance criteria)
• Container Closure System
• Components and Composition
• Miscellaneous
- Change in the approved stability protocol
- Change in the expiration date

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I. a. Post-Approval Changes
• The quality evaluation of supplements (PAS, CBE-30, CBE-0) involves:
1. An assessment of the effects of the change
- Conformance to the approved or acceptable specifications
- Additional testing, when appropriate, of the post-change drug product or material directly
affected by the change.
2. An assessment of equivalence
- Comparing test results from pre- and post- change material and determining if the test results
are equivalent
- For some changes the comparator for equivalence may be the RLD
3. An assessment of potential adverse effects
- Evaluating the risk of the change and the impact on drug product safety and effectiveness

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Guidances
1. Changes to an approved NDA or ANDA (CANA, 2004)
-Reporting categories with examples
2. SUPAC Guidances (1995, 1997)
- Specific to dosage form type (IR,MR, and SS)
- Change categories and supporting data
3. CMC Post-Approval Manufacturing Changes to be Documented in Annual Reports
(2014)
4. PAC-ATLS: Analytical Testing Laboratory Sites (1998)

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Guidances (cont’d)
5. MAPP 5015.6: Review of Grouped Supplements (2016)
6. Tablet Scoring Guidance (2013)
- Data to be provided for Level 2 and Level 3 changes in SUPAC
7. Comparability Protocol CMC Draft Guidance (2016)
- CP submitted as PAS, but allows for reduced filling category for reporting the
proposed change(s).

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Supplement Review Process
Assigned to reviewer by RBPM
No
Yes
YES
IR issued if needed
Supplement Received
Is filing category appropriate?
Review
Action Letter
(Approval or CR)
Applicant Notified
* If CBE downgraded to AR, applicant
told to withdraw supplement.
* If CBE elevated/denied to PAS,
notification letter sent to applicant.
Applicant resubmits as PAS.
*An applicant may ask FDA to expedite
its PAS review for public health reasons
(e.g., drug shortage, extraordinary
hardships on applicant, etc.)

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Examples of AR Changes
1. Elimination or reduction of an overage from the drug product
manufacturing batch formula that was previously used to compensate
for manufacturing losses.
2. Extensions of drug product expiry based on an approved stability
protocol.
3. Any change made to comply with the official compendium, except
relaxation of an acceptance criterion or deletion of a test.
4. Change in the supplier of an excipient, where the technical grade and
specification for the excipient remain the same.
5. A change in the order of addition of ingredients for solution dosage
forms.
6. Tightening of acceptance criteria.

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Examples of PAS Changes
1. Addition of a new API supplier
2. Change in the route of synthesis of drug substance
3. Relaxing acceptance criteria to accommodate failing data (e.g.,
impurity levels) or deleting tests (e.g., antimicrobial effectiveness
testing)
4. Equipment of different operating principles (e.g., oven tray dryer vs.
fluid bed dryer)
5. Add new flavor or color
6. Adding a new strength
7. Sterile drug product- a change from a glass ampule to a glass vial
with an elastomeric closure.

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Case Study 1:
CBE-30 Elevated to PAS
• Proposed Change: Alternate drug product manufacturing site for an IR product
- Supplement submitted as CBE-30 (VI.C.1.a in CANA guidance)
• Decision: Supplement was denied to PAS by FDA
• Reason: Proposed site did not have a satisfactory cGMP inspection (PAS per VI.B.2 in CANA
guidance)
Modified release (MR) solid oral dosage forms include both delayed and extended release drug
products.
Per SUPAC-MR, alternate drug product manufacturing site is a PAS (Level 3 change), with
bioequivalence study.
A move to a different manufacturing site, except one used to
manufacture or process a drug substance intermediate, when the new
manufacturing site does not have a satisfactory CGMP inspection for the
type of operation being moved.

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Case Study 2:
CBE-30 Elevated to PAS
• Proposed Change: Delete blend uniformity analysis (BUA) testing for a
low dose drug (0.5 mg)
- Supplement submitted as CBE-30
• Decision: Supplement elevated to PAS by FDA
• Reason: Active drug represents 0.5 mg or only 0.6% of total tablet
weight of 80 mg. Deletion of BUA is high risk. (PAS per VIII. B.2 in
CANA guidance.)
*Deleting any part of a specification except as otherwise provided for in
this guidance (e.g., section VIII.D.2).

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Common Deficiencies in Supplements
1. Comply with current USP monograph for DS and/or DP
- e.g., Assay, and Specified Impurities
2. Demonstrate method equivalency to USP
3. DMF is inadequate; provide revised API specification and method
validation/verification
4. Provide tablet splitability data for scored tablets for Level 2/3 changes in
SUPAC IR/MR
- e.g., Change in equipment to a different design and different operating
principles; alternate drug product manufacturing site, etc.

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Tips to Submit Better Supplements & Avoid
These Common Deficiencies
1. Use regulations and guidances to determine the appropriate
reporting category for the change and provide sufficient supporting
data (e.g., per SUPAC, Tablet scoring guidance’s)
✓Do not rely on data to justify classification, but instead justify
reporting category based on cited guidance applicable sections and
nature of proposed change(s). If multiple related changes, most
restrictive filing category will apply.
✓Clearly list all proposed changes in the cover letter.
2.Keep track of USP updates
3. Work with your DMF holder closely

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Conclusion
• Use science-based and risk-based approach to assess product
quality impact as a result of the proposed change
• Demonstrate good product and process understanding of your
supplement (e.g., QbD, CQA, CPP, CMA, control strategy)

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FDA/Industry Communication
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www.fda.gov

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Notable
Common
Issues
• Ambiguous Cover Letters
• Incomplete 356h form
• Insufficient information submitted to eCTD
modules
• Unfamiliarity with filing and assessment
timelines
• Incorrect filing category for addition of
analytical testing sites
• Drug Substance manufacturing process
changes – No Drug Product Manufacturer
CoA included in submission
• Incorrectly Grouped Supplements

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Supplement
Cover Letter
• State the proposed change(s) [Itemized list
of changes]
• Include filing category for each change
• Any referenced Drug Master File (DMF)?
Include the DMF #
• Is submission based on a specific DMF
amendment? Reference the DMF
amendment letter to the agency or
submission date in the cover letter
• Are there other pending submissions or
approved applications with the same/similar
proposed change(s)? Include the information
• For PAS submission based on CBE denied to
PAS reference the FDA communication

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Example of Cover Letter

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Example of Cover Letter (Cont.)

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Example of Cover Letter (Cont.)

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Establishment Information
• Form 356h Updated version (08/18) -
https://www.fda.gov/media/72649/download
• Common received questions:
– What facility Information should be included when submitting a new
supplement or resubmissions?
– How should withdrawn facilities be documented?
– Is the FDA Establishment Identifier (FEI) number and Data Universal
Numbering System (DUNS) required on the form?
– Should facilities (Manufacturing/Packaging/Testing) used by the
referenced Drug Master File (DMF) be included on the form?
– Where else should establishment information be provided in the
submission?

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Form 356h

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Form 356h –
Establishment
Information
• Complete
entirety of the
establishment
information

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Form 356h
Include complete
information on the
locations of all existing
and proposed
manufacturing, packaging
and control sites for both
drug substances and drug
product

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Establishment
Information
• Update the form with every new
submission (Important with change in
status of facility information)

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Establishment (Status) Information
Pending: Introducing a new facility to the application
Active: Already approved for use for that application
Inactive: Approved for use to manufacture the drug under
the application but is not currently being utilized
Withdrawn: Any facility withdrawn from the current, pending,
original, or supplemental submission

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Facility Addition Related Supplements
• List the proposed facility in the cover letter, form 356h, and
module 3
• If facility was added in a previous supplement and that
supplement remains pending when submitting your next
supplement:
• If the supplement was previously approved, the next
supplement:

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Facility Addition Related Supplements
If a Complete Response (CR) Letter was issued in the
supplement where you proposed the addition of a
facility all subsequent supplements until approval of
the facility should state:

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Withdrawal of Approved Facility
• Preferred communication for withdrawal of approved
Manufacturing/Packaging/Testing sites should be via a new
supplement and not a General Correspondence
• This may also be included in new supplements with other
proposed changes

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Withdrawal of Unapproved Facilities
• When withdrawing a supplement which is in Complete
Response status

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FEI & DUNS NUMBER
• Include the FDA Establishment Identifier (FEI) Number and Data
Universal Numbering System (DUNS) for each facility
• Section 510 of the Food, Drug, and Cosmetic Act requires that each
initial and annual drug establishment registration include a Unique
Facility Identifier (UFI) (21 U.S.C. 360(b), (c), and (i)). The Agency’s
preferred UFI for a drug establishment is the DUNS number,
assigned and managed by Dun & Bradstreet.
• 21 CFR 207.21(a) states that “Registrants must register each
domestic establishment no later than 5 calendar days after
beginning to manufacture, repack, relabel, or salvage a drug…”

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FEI & DUNS NUMBER
• 21 CFR 207.21(b) states that “Registrants must register each
foreign establishment before a drug …manufactured,
repacked, relabeled, or salvaged at the establishment is
imported or offered for import into the United States.”

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FEI NUMBER
To obtain an FEI number for a GDUFA-
related facility, email
FDAGDUFAFEIRequest@fda.hhs.gov.
Note: An FEI number is a facility specific
identifier. Thus, if a particular facility has
already been assigned an FEI number
(through registration of any commodity,
GDUFA, PDUFA, BsUFA, etc.), you
should not request a second FEI number
for that location.

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DUNS
NUMBER
DUNS numbers can be obtained, or
DUNS information modified,
through Dun & Bradstreet’s
website:
https://www.dnb.com/solutions/go
vernment/duns-number-request-
guide.html

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FEI/DUNS
NUMBER
To find or verify a previously
obtained FEI or DUNS number go
to FDA’s registration site for drug
establishments:
https://www.accessdata.fda.gov/s
cripts/cder/drls/default.cfm

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DRUG MASTER FILE FACILITIES
The facility information
contained within a DMF properly
incorporated by reference
should be included on both Form
FDA 356h and in Module 3 of the
application, as appropriate
The Agency will consider all
facilities that are listed in a DMF
apply to the referencing ANDA
application unless explicitly
stated in the DMF Letter of
Authorization (LOA) that only
certain facilities will be used by
the referencing application

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DRUG MASTER FILE FACILITIES
The DMF LOA, which permits the Agency to review the DMF and permits
the authorized party (i.e., the company or individual who submits an
application or another DMF) to incorporate information from the DMF into
an application or another DMF by reference, should specify which facilities
will be utilized in the commercial manufacturing. If the LOA specifies a
subset of facilities that will be utilized in commercial manufacturing, then
only these facilities should be listed in Form FDA 356h and in Module 3 of
the application. Absent this specificity, all facilities that could be potential
sources of the materials for which the DMF is being referenced by the
NDA/ANDA should be listed in the application.

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DRUG MASTER
FILE FACILITIES
• Facility withdrawals submitted in an
amendment to the DMF should also be
submitted on Form FDA 356h for
referencing applications if the facilities
were included on the applicant’s Form
FDA 356h
• A facility referenced in a DMF to be
utilized for research and development
or testing, is considered part of the
commercial control strategy and should
be included in your application. If you
intend to accept an LOA from a DMF
testing facility, we recommend that this
facility be listed in your application

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Quality Data
• Submit all quality data
for assessment to the
corresponding module

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MODULE 3
• Should contain all facilities listed on Form FDA 356h, as well as research
and development manufacturing and testing sites that generated data
in support of the application. This includes facilities that manufactured
or tested any lots of the product.
• Should also contain testing labs that perform functions integral to the
control strategy, including but not limited to characterization and
comparability of molecules and analytical similarity. This includes any
testing sites that generate release data, stability testing to support the
application, and commercial testing sites

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Timelines (CBE 0/30)
Inquiry of Grant
Status for CBE 0/30:
30 days
Complete Assessment of
CBEs: generally 6-10 months
depending on complexity,
facility inspectional
assessment, etc.

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TIMELINES
(PAS)
Generally Issue Acknowledgement Letter within 30 days
Submission Type General Expected Completion
Standard PAS or PAS
Major Amendments
6-10 months depending on
preapproval inspection
requirements
Priority PAS or PAS
Major Amendments
4-10 months depending on
preapproval inspection
requirements, submission of
complete and accurate Pre-
Submission Facility
Correspondence (PFC)
Standard and Priority
PAS Minor Amendments
3 months

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PAC-ATLS
Submissions
PAC-ATLS: Postapproval
Changes – Analytical Testing
Laboratory Sites:
– At a minimum such
changes should be
submitted as CBE-30
– If no inspectional history
this should be submitted
as a PAS
– Inquire from business
partners about current
cGMP history of the
facility prior to
submission

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Grouped Supplements
• Identical CMC post-approval changes that affect multiple approved
applications
• Two or more supplements reviewed and processed using the
procedures and assigned to same assessment team
• The supporting data necessary for the review of the CMC changes
should be the same for each of the grouped supplements
• Any supplement that provides for the same CMC changes but
necessitates the review of data that is unique to that supplement (e.g.,
product specific data) should not be grouped – However, should be
mentioned in the cover letter
• The cover letter for the supplements should clearly state the purpose of
the proposed CMC changes and indicate that the supplement is one of
multiple submissions for the same change

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Grouped Supplements
• Supplements are grouped at the discretion of the Center for the
purpose of ensuring review efficiency and consistency

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Drug Substance
Manufacturing
Process
Changes
• Submissions should include
Certificate of Analysis (CoA) for
both the Drug Substance and
Drug Product Manufacturer
• If either is missing an Information
Request will be issued and this
may potentially delay filing
classification

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CORRESPONDENCE
TO THE AGENCY
• Supplements: Contact the Project Owner
OGD RPM or OPQ RBPM who issued the
Acknowledgement Letter
• Controlled Correspondence: Inquiries
concerning post-approval submission
requirements that are not covered by
CDER post-approval changes guidance
and are not specific to an abbreviated
new drug application (ANDA) should be
submitted via a Standard Controlled
Correspondence

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CORRESPONDENCE
TO THE AGENCY
• Other: Inquiries about post-approval
submission requirements which do not
qualify as controlled correspondence and not
covered under any of the CDER post-
approval guidance. CDER-OPQ-
Inquiries@fda.hhs.gov

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PRIMARY POINTS OF CONTACT
Depends on the type of Supplement Submitted
• Office of Pharmaceutical Quality, Regulatory Business Process Manager
(RBPM) manages changes solely related to chemistry, manufacturing
and controls (CMC), including facility and product quality issues
• Office of Generic Drugs Regulatory Project Manager (RPM) manages
submissions which are inclusive of the above and any
labeling/Bioequivalence changes - genericdrugs@fda.hhs.gov
• ANDA Transfer of Ownership, Withdrawal and Consolidation are
managed by the Office of Generic Drugs - genericdrugs@fda.hhs.gov

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Thank you!
www.fda.gov