License Submission Checklist for Red Blood Cells Collected by Apheresis

Purpose: To provide guidance when submitting documentation to FDA in support of a BLA or a license supplement.

Definitions and Abbreviations ...... 2 Cover Letter ...... 3 Labeling Requirements ...... 4 General Chemistry, Manufacturing and Controls...... 5 Critical Control Points for Red Blood Cells Collected by Apheresis...... 8 Sterile Connecting Device ...... 15 Miscellaneous Information ...... 16

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Definitions and Abbreviations

The table below lists the abbreviations that are used throughout this document.

Abbreviation/Term Definition BLA Biologics License Application CBE Supplement – Changes being effected (30 days waived) CBE 30 Supplement – Changes being effected in 30 days CBER Center for Biologics Evaluation and Research Collection Site Fixed or mobile location that collects the pheresis product CMC Chemistry, Manufacturing and Controls Form 2567 Transmittal of Labels and Circulars Form 356h Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use Infrequent Plasmapheresis Every four weeks or less frequently IQ Installation Qualification OQ Operational Qualification PAS Prior Approval Supplement PQ Performance Qualification STCD Sterile Connecting Device

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Cover Letter

FDA continues to encourage applicants to use a cover letter to introduce and summarize the application.

It is recommended that the following topics be covered in the cover letter to the FDA for license submission:

Statement/purpose of submission – included in first paragraph Full facility name, FDA registration and license numbers Product(s) requested for licensure Manufacturing site(s) or area(s) affected and their CFN/FEI (includes off-site donor or QC testing) Collection device(s) in use at the blood center(s) – (only those associated with the products included in the license submission) Anticoagulant used Description of operator’s training List of all attachments included in the submission Contact information for questions, concerns or requests for additional information Statement clarifying whether this is the facility’s comparability protocol for use with future submissions

Note: The Form FDA 356h should be included with each submission to FDA relating to a BLA. It is the “cover sheet” that allows proper identification, routing and filing of the attached information. Examples of how to complete Form FDA 356h are:

ƒ Product Description – indicate “see cover letter” for established and chemical name; refer to COI” for indications; all else in this section is “N/A. ƒ Application Description – check the “BLA” and “CMC” boxes; we check “PAS” or “CBE-30” boxes appropriately. Briefly describe the reason for the submission, e.g., “Prior Approval submission for Platelets, Pheresis using the Amicus cell separator.” ƒ Establishment Information – indicate “see cover letter.” ƒ Cross-references – list any applicable previously approval STNs/approval dates or applicable Comparability Protocol STNs/approval dates. ƒ Page 2 of the 356h – check boxes 4, 4A, and 20 (”see cover letter”).

To obtain the FDA form, go to http://www.fda.gov/opacom/morechoices/fdaforms/cber.html. Instructions for completing Form FDA 356h are found in “Guidance for Industry for the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Blood and Blood Components Intended for Transfusion or for Further Manufacture and for the Completion of the form FDA 356h ‘Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use.’” The guidance can be obtained at http://www.fda.gov/cber/gdlns/cmcblood.pdf.

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Labeling Requirements

Each label submitted for review should be submitted with the items listed below.

SOP/ Reference to Items Required for Licensure Attachment # Policy # Prior Submission If a label has been previously approved and is to be used without change, do not submit for another review. Instead, reference the label review number to identify the previously approved label. One copy of the current Circular of Information that includes the facility identification information. One original and one copy (labeling set) of each label. (Indicate if it is a printer’s proof or final printed labeling for the product). A single Form FDA 2567, completed and signed by an authorized official, should accompany each label set and/or Circular of Information that is submitted for review.

Note: Labels and Form FDA 2567 should be detached from the rest of the submission. The FDA form can be obtained at http://www.fda.gov/opacom/morechoices/fdaforms/_cber.html.

“Apheresis” must be indicated on the label in the product name or attributes. Consult the FDA guidance document, “Recognition and Use of a Standard for Uniform Blood and Blood Component Container Labels” - Sep 2006, “Guideline for the Uniform Labeling of Blood and Blood Components” – Aug 1985, and/or consult the FDA Consumer Safety Officer who will perform the review of your submitted labels.

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General Chemistry, Manufacturing and Controls

The table below lists the common CMC contents for blood products collected by apheresis that should be submitted, or referenced from prior FDA submissions, for all apheresis blood product license submissions. The products may be leukoreduced or non- leukoreduced. The table does not include requirements for additional products collected, including concurrent plasma.

Note: • Listing of applicable SOPs may be substituted if SOPs have been previously submitted and approved and there will be no significant changes. • Ensure that data on submitted records are complete, acceptable and documented as reviewed.

SOP/ Reference Items Required for Licensure Attachment # Policy # to prior submission Standard Operating Procedures SOP that describes donor suitability requirement (donor selection) and donor educational material (pre-donation). SOP that describes the donor consent process. SOP that describes the collection of the product for which license is being requested. SOP that describes donor deferral procedure on red cell and plasma loss. SOP that describes the management of donor complications and reactions (adverse events). SOP that addresses Medical Director review of charts. SOP that describes product acceptability (needs to be consistent with device operator’s manual) and failure investigation. SOP that describes the handling of the products (components), to include storage requirements and leukoreduction procedures when appropriate. SOP that describes the quarantine of potentially unsuitable products and subsequent evaluation and disposition.

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SOP/ Reference Items Required for Licensure Attachment # Policy # to Prior Submission SOP that describes the labeling process for the product to include the method to accurately track multiple units collected from each donation (as needed). SOP that describes packing instructions for the shipment and distribution of the product. SOP that describes the quality control on the product and failure investigation. SOP that describes Equipment QC/ Preventive Maintenance (include cleaning). SOP that describes the use of STCD (if appropriate).

Note: See the section on Sterile Connecting Device for procedural specifics. SOP/job description that describes the responsibilities of the collection device operator SOP/checklist that describes training SOP/checklist that describes competency SOP for validation process

Records to Submit Submit two months of QC data for products collected after validation process. • Include products from all collection protocols performed on all devices in use. • Include data for each site for which licensure is being requested. • Identify facility where QC is performed. Submit relevant validation protocol and data. Complete Form FDA 356h for each product type, for each type of device, by collection site. Include name(s) of the anticoagulant(s) and device(s) that will be used to manufacture the product, and list the manufacturing site(s) that will be collecting the apheresis products.

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SOP/ Reference Items Required for Licensure Attachment # Policy # to Prior Submission Submit QC sheets that contain the following information: • Facility [21 CFR 211.194(a)(1)] • Device manufacturer and type [21 CFR 211.194(a)(2)] • Blood Unit Number [21 CFR 606.140(c)] • Date of collection [21 CFR 211.194(a)(1)] • Date of testing [21 CFR 211.194 (a)(7); 600.12(a); 606.160 (a)(1)] • Appropriate collection types (single, double, triple, autologous if applicable) • Interpretation of results [21 CFR 211.194(a)(6); 606.160 (a)(1); 606.160 (a)(2)(i)] • Interpretation of month • Yield [21 CFR 211.103; 211.186(b)(7)] • Acceptable criteria [21 CFR 211.165(d)] • Initials [21 CFR 211.194 (a)(7); 600.12(a); 606.160 (a)(1)] • Evidence of review [21 CFR 211.194(a)(8; 211.103)] • Records of calculations [21 CFR 211.194 (a)(5)]

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Critical Control Points for Red Blood Cells Collected by Apheresis

The table below lists some critical control points, by procedure, for the collection of red blood cells by apheresis.

SOP/Policy # Items Required for Licensure Attachment # SOP CCPs SOP that describes donor suitability to include the following criteria the donor must meet: • All FDA criteria for allogeneic whole blood donation (21 CFR 640.3 and 640.12). o If donor is near the minimum weight, the donor should be further evaluated (e.g., weighed, physician assessment, etc.). • Specific hemoglobin/hematocrit requirements for the device cleared by FDA: o Method needs to be a quantitative method to determine pre-donation hematocrit/hemoglobin for double red cells. o Use of copper sulfate is not recommended. • Single unit donor: o Donor who donates a single unit of RBC plus platelets and/or plasma must wait 8 weeks before donating any additional products. o Donor who donates a single unit of RBC may donate a platelet and/or plasma product (apheresis) within 8 weeks if the extracorporeal RBC volume during the procedure is less than 100 mL. • Donor must wait 16 weeks after undergoing a double RBC collection procedure before donating any additional products (manual or apheresis collection procedures). • All additional criteria outlined in the device operator’s manual.

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SOP/Policy # Items Required for Licensure Attachment # SOP for the consent process should: • Describe how and by whom the consent is obtained. • Include and provide to the donor: o A description of the procedures to be followed, in language understandable to the donor. o A description of any reasonable foreseeable risks or discomforts that may occur, including side effects of the procedure and the hazards of solutions and/or drugs the donor will receive. o Donation frequency. o Presentation in such a manner that a clear opportunity to refuse is given. o A statement that participation is voluntary and the donor may withdraw his/her consent at any time. o A statement informing the donor of his/her right to ask questions of and discuss the procedure with a physician. o A statement that the donor has reviewed and understands the information provided to him/her regarding the spread of the AIDS virus by donated blood and plasma. It should also state that if the donor considers him/herself to be at risk for spreading the virus known to cause AIDS, he/she will agree to not donate blood or plasma products for transfusion to another person or further manufacturing. o Statement that long term effects of lymphocyte reduction are unclear. SOP that describes the collection of the product should be consistent with device operator’s manual and include: • Donor preparation (e.g., arm prep). • Name and manufacturer of equipment used to collect the product. • Use of STCD (if appropriate). • Management of alarms.

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SOP/Policy # Items Required for Licensure Attachment # SOP that describes donor deferral with regard to cumulative red blood cell loss: • If a donor has an RBC loss of <200mL, the donor may return to donate within 8 weeks if all other donor suitability criteria are met. • If a donor has a second RBC loss of <100mL within an 8-week time period, defer the donor for 8 weeks from the second RBC loss (total RBC loss within 8 weeks <300mL). • If a donor has a total absolute RBC loss of >= 300mL, then defer the donor for 16 weeks from last date of RBC loss. • If a donor has a total absolute RBC loss of >200mL but <300mL, then defer the donor for 8 weeks. • If a procedure is discontinued before completion and a total absolute RBC loss of >= 300 mL, then defer the donor for 16 weeks. • Donor needs to meet all additional criteria outlined in the device operator’s manual. SOP that describes the management of donor complications and reactions (adverse events) should address: • The documentation for recording these events. • The results of investigation and follow-up. • The management of a cardiopulmonary emergency, including steps for contacting the physician, transport of donor, etc. • Medical attendance in the event of donor adverse reactions or physician available within 15 mins. SOP that describes the Medical Director’s review of charts should address the following: • Time frames for review. • Which adverse finding needs to be reviewed prior to allowing the donor to return. SOP that describes product acceptability should be consistent with the device operator’s manual and include instructions for management of units that do not meet product specification.

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SOP/Policy # Items Required for Licensure Attachment # SOP that describes handling of the product (components), including storage requirements, should address: • Specifications for each component to be prepared. • Leukocyte reduction methods (when appropriate). • Storage requirements during processing and storage. SOP that describes the quarantine of potentially unsuitable products and subsequent evaluation and disposition should address: • Responsibility for review and authority for disposition of the products, including authority to return the product to inventory. • The process for identification, quarantine, retrieval and recall of unsuitable products. • Segregation of unsuitable products. • The process to prevent unintended distribution or use of unsuitable products. • Criteria for release of units later found to be suitable. • Record keeping processes and review of such records at appropriate steps. • Define documentation that will indicate final disposition of unsuitable units. SOP that describes the labeling process for the product should include the method for accurately tracking multiple units collected from each donation. SOP that describes packing instructions for shipment and distribution of the product should include: • Specification of shipping containers. • Specification of the coolant material. • Time allowed out of the storage environment. • Verification record checks. • Shipping records. • Labeling of outer box to meet transportation rules.

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SOP/Policy # Items Required for Licensure Attachment # SOP that describes the quality control on the product needs to ensure: • Instructions for sample handling are included. • 50 total units per site; at least one single. • Mean hemoglobin of >=60g or 180mL per unit and at least 95% of the units sampled have >50g of hemoglobin (or 150 mL packed red cell volume) per unit (AABB standard). • At least 95% of leukoreduced units sampled have >42.5g of hemoglobin (or 128 mL packed red cell volume) per unit (AABB standard). • At least 95% of units sampled meet product specifications described in the device operator’s manual or on the product labeling (e.g. percent recovery). • Quality control review is under the oversight of qualified staff: o Results are tracked. o Trends are identified and failures are investigated. o Corrective action implemented is reviewed for effectiveness. o Instructions are available for appropriate disposition of the unit(s) involved. SOP that describes equipment QC/preventive maintenance, including cleaning, should describe: • The required process(es). • Personnel assigned to perform the process. • When the process is to be performed. • Records should be readily available with evidence of concurrent documentation and review. • What to do when equipment is not in compliance.

Validation and Validation Data CCPs Facility Instrument information should include: • Manufacturer • Model • Software version • Serial # • Facility unique ID # (as appropriate) • Date installed and placed into service

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SOP/Policy # Items Required for Licensure Attachment # Equipment qualification/validation plan should include: • Scope • Purpose • Responsibility • Summary of changes • IQ/OQ/PQ requirements and acceptance criteria • Validation test cases, if applicable • Management of discrepancies include a description of whether the discrepancy was included in the acceptance/failure decision or if it was excluded with rationale. • Management of product that fail to meet validation release criteria and failure investigation. • Description of training to include trainer, program, requirements for passing, competency assessment. Validation: Evaluate 100 consecutive1 RBC units as follows: • Determine the expected or target RBC volume.2 • Determine any additional target parameters as specified in the device operator’s manual. • Calculate the total RBC product volume or absolute RBC mass and other parameters using a method determined by the device operator’s manual or locally validated method. • Compare the target values and actual values to determine product acceptability (use the product acceptability ranges in the operator’s manual). • If product acceptability ranges are not listed in the operator’s manual, then the products must meet the volume ranges in 21 CFR 606.121 (c)(6). Retrospective data accumulated from prior units may be used to qualify the collection process, but the data should represent consecutively collected units. If the evaluation of the data collected during validation indicates that at least 95% of the units meet the product specification described in the device operator’s manual or on the product label, then proceed to Product Quality Control.

1 The 100 consecutive units should represent units collected from each device in use at the collection center and from all collections procedures (e.g., single RBC and double RBC). Both units collected during a double RBC collection protocol should be included and may count as two units in the QC process. 2 Either total RBC product volume or absolute RBC mass volume (as determined by the device operator’s manual)

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SOP/Policy # Items Required for Licensure Attachment # If data indicate that <95% of the units tested meet the product specifications described in the device operator’s manual, then investigate the cause of the deviations and correct as part of the overall quality assurance program and repeat the validation qualification. Product Quality Control: • Each month, test a minimum of 50 units at each collection center for the total RBC product volume or absolute RBC mass volume (as determined by the device operator’s manual) and any other parameters described in the device operator’s manual. • If fewer than 50 units were manufactured at the center during the month, all units should be tested. Include RBC products from all collection protocols performed on all devices in use at the center. • Include at least one unit from the single RBC protocol and both units from the double RBC protocol collected on each device in use at the center, regardless of the manufacturer of the device, in the Product Quality Control sampling. • At least 95% of the product tested in the sampling should meet the product specifications described in the operator’s manual or on the product labeling. • If data indicate that <95% of the units tested meet the product specifications described in the device operator’s manual, then investigate the cause of the deviations and correct as part of the overall quality assurance program and repeat Product Quality Control.

Note: Units that are not acceptable as specified in the device operator’s manual or in the product labeling should be evaluated to determine their suitability for distribution.

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Sterile Connecting Device

Using a STCD to pool, mix or remove cellular components represents a change in the product that requires submission and approval of a license application or supplement.

The table below lists the critical control points when using STCD.

SOP/Policy # Items Required for Licensure Attachment # SOP CCPs A STCD may be used to: • Add a new or smaller needle to a blood collection set. • Prepare components (add an extra bag, filter, additive solution). • Pool blood products. • Make aliquots for pediatric use or divided units of WB, RBCs or FFP or Platelets, Pheresis. • Attach processing solutions (glycerol, saline). • Remove samples from blood products for testing. SOP must reflect changes in the assembly of collection and storage containers and in processing steps that involve the STCD for every product made. Records must reflect the date of the sterile connections, the lot numbers of the original containers and needles (and of those being added), the lot numbers of the STCD wafers, the initials of the individual preparing the containers, and a record of each STCD weld inspection and any corrective action taken. Techniques for the detection of leakage or air bubbles and specific instructions for handling the products with faulty welds should be described in SOP. Final product labeling may need to be revised to reflect different product volumes, and SOP should describe the minimum volume of split products as well as the expiration date of the final product(s). Procedures for labeling the aliquots or split products should be clearly stated in the SOP. Record keeping should be adequate to permit tracking and recall of all components.

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Miscellaneous Information

Pursuant to FDA regulations, all blood establishments must maintain the following records. These records do not need to be submitted, but should be available for review during FDA inspections.

• Records related to instrument and disposable equipment failures and reporting of failures to device manufacturers. Establishments should follow the device operator’s manual for corrective action for any adverse or unexpected event, e.g., evidence of product hemolysis.

• Documentation of observations, standardization and calibration of the automated equipment on a regularly scheduled basis, consistent with the device operator’s manual.

• Documentation of installation, operation and performance qualification tests, as applicable, performed on the automated device prior to implementing routine collections, in accordance with the device operator’s manual.

• Documentation of a thorough investigation, including the conclusions and follow- up, of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications.

• Records of any donor adverse reaction complaints and reports, including results of all investigations and follow-up.

• Personnel training for the collection of RBC by automated apheresis. FDA recommends that complete product QC testing be performed on all RBC units collected by an operator during the training period.

References: 21 CFR 606.60, 606.65, 606.100, 606.160 and 606.170

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