1. Scope Clarifications (Introduction)
- The final guidance explicitly states it now also covers regulatory submissions to FDA for these systems, not just development recommendations.
- A new carve-out has been added: the guidance does not apply to blood establishments that already intend to manufacture components using the BC method with already-approved or cleared systems. This narrows the guidance's applicability to new/developmental systems.
2. Background Section Update
- The draft noted that no collection/processing/storage systems were yet approved or cleared for the BC method in the U.S. This statement has been removed in the final version.
- The final version adds that, once such systems are approved or cleared, licensed blood establishments could submit BLA supplements to FDA to begin using them — a concrete regulatory pathway not spelled out in the draft.
3. Recommendation 1 (Regulatory Pathway)
- Largely unchanged, but the final version adds an explicit encouragement for manufacturers to contact FDA to discuss their planned submission and supporting data before filing (cross-referencing what is now Recommendation 4).
4. Recommendation 2 — Substantively Rewritten
This is one of the most important changes for industry:
- Draft (2024): Recommended that manufacturers developing anticoagulant/additive solutions use solutions already approved by FDA.
- Final (2026): Replaces this entirely with new language supporting the industry shift toward DEHP-free collection/processing/storage systems, explicitly acknowledging this may require new, not-yet-approved additive/storage solutions, and encouraging manufacturers to engage FDA on supporting data for such novel solutions.
- Practical impact: The final guidance is notably more open to novel (non-approved) materials and solutions than the draft, provided manufacturers bring supporting data — a meaningful shift for companies pursuing DEHP-free product lines.
5. New Recommendation 3 — Overnight Hold (Not Present in Draft)
- An entirely new recommendation addresses holding Whole Blood up to 24 hours before separation ("overnight hold").
- Clarifies that FDA regulations (21 CFR 640.4(h), 640.16(a), 640.24(b), 640.34(a) and (c)) do not restrict the timeframe for separating components from Whole Blood — the allowable timeframe is instead whatever is specified in the system's directions for use.
- Manufacturers are now explicitly told to include data supporting the specific separation timeframe(s) claimed (e.g., 4, 8, or 24 hours) for the BC method.
- Practical impact: This gives manufacturers a clearer regulatory basis to seek broader (or different) hold-time claims, as long as they generate supporting data.
6. Renumbering of Submission Content Requirements
- Because of the new Recommendation 3, the detailed list of what submissions should include (design, biocompatibility, sterility, shelf life, in vitro study results, etc.) shifts from Recommendation 3 in the draft to Recommendation 4 in the final. The substance of items (a) through (h) is the same, with the additions noted below.
7. Platelet Study Acceptance Criteria — Added Flexibility and Detail
- Control arm definition (new): The final guidance specifies that the control arm should consist of platelets manufactured using already approved or cleared systems, and requires manufacturers to justify their choice of control product — including if they choose to use historical control data. None of this appeared in the draft.
- Sample size flexibility (new): While both versions recommend a sample size of at least 60 single units or 60 pools, the final version explicitly allows manufacturers to propose an alternative, statistically justified sample size with supporting data, rather than treating 60 as a fixed requirement.
8. RBC Study Acceptance Criteria — Handling of Hemolysis Failures
- The final guidance adds new language acknowledging that donor-related factors can cause variable hemolysis results and potential failures against the ≤1.0% hemolysis criterion.
- It directs manufacturers to investigate and describe any failures in their submission, and states that FDA will consider the identified reason (e.g., donor-related factors) during review.
- This gives manufacturers a documented path to address/explain outlier hemolysis results rather than treating any failure as a hard rejection.
9. Plasma Criteria
- No substantive change — the final version only reorders the sentences describing sample size and comparability thresholds; the underlying 30-day frozen storage comparison, 20% difference threshold, and 60-unit sample size recommendation are unchanged.
10. Unchanged Sections
- Communication with FDA (Section IV): Identical between both versions — engage CBER's Office of Blood Research and Review (OBRR) early, using pre-submission meetings (devices) or Type C meetings (NDAs).
- References: Identical list of 9 references in both versions.
- Appendix (in vitro parameters for platelets, plasma, RBCs): Identical parameter lists in both versions (only the appendix label changes from "Appendix A" in the draft to simply "Appendix" in the final).
Manufacturers currently developing submissions based on the 2024 draft should revisit their control arm justification, sample size rationale, and any DEHP-free or novel solution strategy in light of these final-guidance changes.
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