2BLA SupplementsA 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 CFRThe regulation applies only to the manufacture and distribution of licensed products.
3Outline Regulations Reporting categories Examples of changes in each categoryDeficiencies identified during the CBE30, CBE, AR reviewComparability protocolsLabeling changesFailure to comply
421 CFRAn 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).
521 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.
6Three Reporting Categories Prior Approval Supplement (PAS)Changes Being Effected in 30 days Supplement (CBE30)- Changes Being Effected Supplement (CBE)Annual Report (AR)
7Prior 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 productReview and approval of supplement required before product made using change can be distributed
8Examples 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
9Examples 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
10Examples of PAS Changes (cont.) Revision of SOPsWhen the change is less restrictive than previously approvedWhen implementing a change for which FDA has not published a guidance documentImplementation of an immunization program for RBCs or unlicensed vaccineImplementation of Source Plasma collection program from disease state or high risk donorsImplementation of a physician substitute program
11Examples of PAS Changes (cont.) Request for comparability protocolUse of a new contract testing laboratory for infectious disease testing of blood componentsAddition of a new contractor to perform manufacturing stepsRelocation of a facility with change in core center personnel, SOP or equipmentRequest for an alternative procedure under CFR
12Changes 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 productSubmission of a supplement at least 30 days prior to the distribution of the product made using the changeInitial review of submission within 30 days for completeness and correctness
13Changes 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 distributeFDA will continue the review after 30 days- This is not a 30-day approvalWritten approval will be sent to applicant after review is completed and issues are adequately addressed
14Examples of CBE-30 Changes Implementation of a FDA-cleared computer- assisted self-interview systemCollection of plasma as a by-product in an approved apheresis RBC and/or platelet programImplementation of licensed vaccine immunization program following manufacturer’s instructions
15Examples of CBE-30 Changes (cont.) Use of registered contract donor testing laboratory for infectious disease testingUse of an off-site storage facilityRequest for alternative procedure with published guidance, e.g. implementation of an infrequent plasmapheresis collection program
16Changes 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 productFDA will communicate with applicant if supplement is incomplete or not submitted in correct categoryProduct 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
17Changes Being Effected Supplement (cont.) FDA will continue the review- This is not an immediate approvalWritten approval will be sent to applicant after review is completed and issues are adequately addressedExampleRequest to change annual report date
18Annual 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 productAll licensed facilities are required to submit an annual report each year describing minor changes made in the previous12 months within 60 days ofThe anniversary date of approval of the applicationThe date of approval of an alternative reporting period
19Annual Report (cont.)Annual report date determined by the date of the first product approvalAn applicant may request in writing an alternative date as the annual report dateContent of report- Cover letter and FDA form 356hInclude 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
20Annual 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
21Examples of AR ChangesRevision of approved SOP with more restrictive changesChanges or upgrades by the device manufacturer of automated apheresis equipment that does not affect the safety or effectiveness of the productImplementation of a pre-existing disease-associated Source Plasma collection program from normal donorsChange in “doing business as” name that does not affect the legal entity name of the license
22Examples 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
23Examples of AR Changes (cont.) Implementation of a blood establishment computer system (except CASI)Use of an approved back-up donor testing laboratoryUse of an accepted AABB donor history questionnaire without modificationAddition of tests not required or recommended by FDA
24Not Considered AR Changes Changes reported as supplementsInadvertent development of antibody in RBC immunization programs; keep on file at centerBiological product deviation reports(21 CFR )Changes in authorized official name, contact information and mailing addressSend to FDA as soon as possible to ensure uninterrupted effective communication
25Deficiencies Identified During the CBE30, CBE, AR Review Deficiencies identified during the reviewChange 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 productActions 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 submittedIf 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
26Comparability Protocol Described in 21 CFR (e)Submit as a PASSupplement 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 productChange is specificApproval may result in reduced reporting category for future changes
27Comparability 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.
28Comparability 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
29Changes 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
30Changes 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
31Failure to Comply Described in 21 CFR 601.12(g) Action is taken on repeated offensesApplicable laws and regulations will be enforcedAll changes may have to be submitted as supplements and receive approval prior to distribution of products
32Blood and Plasma Branch telephone number: For more informationPlease call if you have questions on how to submit a comparability protocolPlease call if you do not see your change listed in the guidance documentPlease call if you are unsure of the reporting category or the contents of your submissionBlood and Plasma Branch telephone number:
33Regulatory OversightThe 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 )
34References 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