1. License Supplements under 21 CFR 601.12
Hoi-may Wong, BS, MT(ASCP)SBB
Consumer Safety Officer
CBER, OBRR, DBA
September 15, 2009

2. BLA Supplements
A manufacturer may make a change in the product, labeling, production process, quality controls, equipment, or facilities that has been described in the approved license application(s).
The requirements for making a change are prescribed in 21 CFR
The regulation applies only to the manufacture and distribution of licensed products.

3. Outline Regulations Reporting categories
Examples of changes in each category
Deficiencies identified during the CBE30, CBE, AR review
Comparability protocols
Labeling changes
Failure to comply

4. 21 CFR
An applicant must inform the FDA about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s).

5. 21 CFR (cont.)
Before distributing a product made using a change, an applicant must assess the effects of the change and demonstrate through appropriate validation….. the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.

6. Three Reporting Categories
Prior Approval Supplement (PAS)
Changes Being Effected in 30 days Supplement (CBE30)
- Changes Being Effected Supplement (CBE)
Annual Report (AR)

7. Prior Approval Supplement
Described in 21 CFR (b)
Change that has a substantial potential to have an adverse effect on the safety or effectiveness of the product
Review and approval of supplement required before product made using change can be distributed

8. Examples of PAS Changes
Implementation of new manufacturing processes, such as
- additional product, e.g. Fresh Frozen Plasma
- leukocyte reduction
- washing / rejuvenating
- freezing / deglycerolizing
- irradiation
- change from manual to automated collection

9. Examples of PAS Changes (cont.)
Addition of the following SOPs
- Donor suitability, including donor deferral
- Blood collection, including arm preparation
- High risk behavior questions and AIDS information
- Donor history forms, including informed consent
- Product manufacturing for licensed products
- Quarantine and disposition of unsuitable product

10. Examples of PAS Changes (cont.)
Revision of SOPs
When the change is less restrictive than previously approved
When implementing a change for which FDA has not published a guidance document
Implementation of an immunization program for RBCs or unlicensed vaccine
Implementation of Source Plasma collection program from disease state or high risk donors
Implementation of a physician substitute program

11. Examples of PAS Changes (cont.)
Request for comparability protocol
Use of a new contract testing laboratory for infectious disease testing of blood components
Addition of a new contractor to perform manufacturing steps
Relocation of a facility with change in core center personnel, SOP or equipment
Request for an alternative procedure under CFR

12. Changes Being Effected in 30 Days Supplement
Described in 21 CFR (c)
Change that has a moderate potential to have an adverse effect on the safety or effectiveness of the product
Submission of a supplement at least 30 days prior to the distribution of the product made using the change
Initial review of submission within 30 days for completeness and correctness

13. Changes Being Effected in 30 Days Supplement (cont.)
FDA will communicate with applicant within 30 days if supplement is incomplete or not submitted in correct category (21 CFR (c)(4))
Product may be distributed 30 days after FDA receipt of supplement, unless FDA has communicated with the applicant and informed them not to distribute
FDA will continue the review after 30 days
- This is not a 30-day approval
Written approval will be sent to applicant after review is completed and issues are adequately addressed

14. Examples of CBE-30 Changes
Implementation of a FDA-cleared computer- assisted self-interview system
Collection of plasma as a by-product in an approved apheresis RBC and/or platelet program
Implementation of licensed vaccine immunization program following manufacturer’s instructions

15. Examples of CBE-30 Changes (cont.)
Use of registered contract donor testing laboratory for infectious disease testing
Use of an off-site storage facility
Request for alternative procedure with published guidance, e.g. implementation of an infrequent plasmapheresis collection program

16. Changes Being Effected Supplement
Described in 21 CFR (c)(5)
Change that has a moderate potential to have an adverse effect on the safety or effectiveness of the product
FDA will communicate with applicant if supplement is incomplete or not submitted in correct category
Product made using the change may be distributed immediately upon FDA receipt of the supplement unless FDA has communicated with the applicant and informed them not to distribute

17. Changes Being Effected Supplement (cont.)
FDA will continue the review
- This is not an immediate approval
Written approval will be sent to applicant after review is completed and issues are adequately addressed
Example
Request to change annual report date

18. Annual Report Described in 21 CFR 601.12(d)
Change that has a minimal potential to have an adverse effect on the safety or effectiveness of the product
All licensed facilities are required to submit an annual report each year describing minor changes made in the previous12 months within 60 days of
The anniversary date of approval of the application
The date of approval of an alternative reporting period

19. Annual Report (cont.)
Annual report date determined by the date of the first product approval
An applicant may request in writing an alternative date as the annual report date
Content of report
- Cover letter and FDA form 356h
Include U.S. License Number, time period covered in the report, current organization chart, licensed products, list of all facilities, including contracted facilities and their functions

20. Annual Report (cont.) Content of report (cont.)
Full description of minor changes
- List products affected by each change
- List all facilities where changes were implemented
- Describe SOP or process affected by the change
- Date changes became effective

21. Examples of AR Changes
Revision of approved SOP with more restrictive changes
Changes or upgrades by the device manufacturer of automated apheresis equipment that does not affect the safety or effectiveness of the product
Implementation of a pre-existing disease-associated Source Plasma collection program from normal donors
Change in “doing business as” name that does not affect the legal entity name of the license

22. Examples of AR Changes (cont.)
Changes of previously approved equipment or collection sets used according to manufacturer’s instructions
- irradiation equipment
- blood collection set or leukocyte reduction filters
- donor screening equipment
- automated equipment for ABO/Rh, syphilis and infectious disease testing on donor samples
- Infectious disease testing methodology

23. Examples of AR Changes (cont.)
Implementation of a blood establishment computer system (except CASI)
Use of an approved back-up donor testing laboratory
Use of an accepted AABB donor history questionnaire without modification
Addition of tests not required or recommended by FDA

24. Not Considered AR Changes
Changes reported as supplements
Inadvertent development of antibody in RBC immunization programs; keep on file at center
Biological product deviation reports
(21 CFR )
Changes in authorized official name, contact information and mailing address
Send to FDA as soon as possible to ensure uninterrupted effective communication

25. Deficiencies Identified During the CBE30, CBE, AR Review
Deficiencies identified during the review
Change reported in wrong category (e.g., sent in as CBE30 but should have been a PAS)
Submission does not contain sufficient information to determine the effect of the change on the product
Actions taken (21 CFR (c)(4 & 6))
FDA will communicate with the applicant and inform them to not distribute product until the supplement has been approved or the additional information has been submitted
If no deficiencies are identified during the preliminary review but deficiencies that may adversely impact the product are identified during the in-depth review, FDA may order the manufacturer to cease distribution of the product

26. Comparability Protocol
Described in 21 CFR (e)
Submit as a PAS
Supplement includes protocols describing specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect on the safety or effectiveness of the product
Change is specific
Approval may result in reduced reporting category for future changes

27. Comparability Protocol (cont.)
Content of CP supplement
- Description of change
- SOPs
- Validation protocol, including acceptance criteria
- Training program
- QA plan
- Implementation plan
- Label(s) if applicable.

28. Comparability Protocol (cont.)
Uses of comparability protocol
- Implementation of a single change in multiple facilities under the same license
- Implementation of a single change with a long planning stage and short implementation timetable

29. Changes in Labeling PAS - Described in 21 CFR 601.12(f)(1):
- Contain additional claims
- Change in volume of Whole Blood container (e.g., 450 mL to 500 mL)
- Injectable <-> Noninjectable Source Plasma
- Conversion from Codabar to ISBT 128 labels

30. Changes in Labeling (cont.)
CBE - Described in (f)(2):
Change in legal name of applicant (new license number will be issued)
Change in FDA-approved additive/anticoagulant for Whole Blood collections

31. Failure to Comply Described in 21 CFR 601.12(g)
Action is taken on repeated offenses
Applicable laws and regulations will be enforced
All changes may have to be submitted as supplements and receive approval prior to distribution of products

32. Blood and Plasma Branch telephone number:
For more information
Please call if you have questions on how to submit a comparability protocol
Please call if you do not see your change listed in the guidance document
Please call if you are unsure of the reporting category or the contents of your submission
Blood and Plasma Branch telephone number:

33. Regulatory Oversight
The blood component manufacturer is responsible for compliance with regulations and good manufacturing practices when collecting, processing, labeling, testing, storing, and distributing blood components (21 CFR 600.3(t))
Documentation of the manufacturing process changes are reviewed during FDA inspections (21 CFR )

34. References Regulations 21 CFR 601.12
Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture, July 2001