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Post Approval Changes: Best Practices and Strategies

Paul Schwartz, PhDDirector, Division of Post Marketing Activities IIOffice of Life Cycle Drug ProductsOffice of Pharmaceutical QualityCenter for Drug Evaluation and Research

Olugbenga “Gbenga” Okubadejo, PharmDBranch Chief (Post Marketing Activities)Office of Program and Regulatory OperationsOffice of Pharmaceutical QualityCenter for Drug Evaluation and Research

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A quality product of any kind consistently meets the expectations of the user.

Pharmaceutical Quality

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A quality product of any kind consistently meets the expectations of the user.

Pharmaceutical Quality

Drugs are no different.

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

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Pharmaceutical quality is

assuring every dose is safe and effective, free of contamination and defects.

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

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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 supplier2. Change in the route of synthesis of drug substance3. 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 color6. Adding a new strength7. 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 updates3. 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

21www.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/government/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/scripts/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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TIM

ELI

NE

S (

PA

S)

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 andDrug 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!

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