License Supplements under 21 CFR 601.12

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 601.12. • 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 601.12 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 601.12 (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 601.12(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 21 CFR 640.120

12. Changes Being Effected in 30 Days Supplement • Described in 21 CFR 601.12(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 601.12(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 601.12(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 606.171) • 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 601.12(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 601.12(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 601.12(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. 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: 301-827-3543

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 600.21)

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 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm076729.htm