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Guidance for Industry and FDA Review Staff: Collection of Platelets by Automated Methods

[PDF Printable Version - 219 KB]

Additional copies of this guidance are available from the Office of Communication, Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/cber/guidelines.htm.

For questions on the content of this guidance, contact the Division of Blood Applications, Office of Blood Research and Review at 301-827-3524.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research December 2007

Contains Nonbinding Recommendations


Table of Contents 
  1. INTRODUCTION
  1. DISCUSSION
    1. Background
    2. Definitions
  1. DONOR SELECTION AND MANAGEMENT
    1. Donor Selection
    2. Donor Management

      1. Platelet Count
      2. Donation Frequency
      3. RBC Loss Prior to a Collection of Platelets, Pheresis
      4. Total Plasma Volume Loss Per Collection Procedure
  1. INFORMATION PROVIDED TO THE DONOR
  2. COMPONENT COLLECTION
  3. VALIDATION OF THE COLLECTION PROCESS

    1. Equipment Installation Qualification
    2. Validation Protocol
    3. Process Performance Qualification (Operator)
    4. Product Performance Qualification for Component Collection Process
    5. Re-Qualification/Re-Validation
  1. QUALITY ASSURANCE AND MONITORING
    1. Standard Operating Procedures (SOPs) and Recordkeeping

      1. Requirements for SOPs
      2. Additional Provisions Applicable to SOPs
      3. Recordkeeping
    2. Donor Monitoring

      1. Platelet Counts
      2. Adverse Reactions in Donors
    3. Component Testing

      1. Component Specification Check
      2. QC Monitoring
    4. Equipment/Supplies
    5. Operator Training
    6. Quality Monitoring
  1. PROCESSING AND TESTING
    1. Processing
    2. Communicable Disease Testing
    3. Expiration Date
  1. LABELING
  1. REPORTING CHANGES TO AN APPROVED BIOLOGICS LICENSE APPLICATION (BLA)
    1. Prior Approval Supplement (PAS): Changes Requiring Supplement Submission and Approval Prior to Distribution of the Product Made Using the Change (Major Changes) (21 CFR 601.12(b))
    2. Changes Being Effected in 30 Days (CBE-30) Supplement: Changes Requiring Supplement Submission at Least 30 Days Prior to Distribution of the Product Made Using the Change (21 CFR 601.12(c))
    3. Submission Inclusion Documents
    4. Submission of Platelets, Pheresis Sample(s) to CBER
    5. Shipping Platelets, Pheresis Sample(s) to CBER
  1. CONTACT INFORMATION
  1. REFERENCES

Guidance for Industry and FDA Review Staff
Collection of Platelets by Automated Methods

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

  1. INTRODUCTION

This guidance provides you, blood establishments, and FDA staff with revised recommendations for the collection of Platelets by automated methods (plateletpheresis). This guidance is intended to help you ensure donor safety and the safety, purity, and potency of Platelets collected by an automated blood cell separator device. For the purpose of this document, Platelets collected by automated methods and resuspended in plasma will be referred to by the product name "Platelets, Pheresis." We consider the recommendations in this guidance document to provide appropriate criteria for a biologics license application or supplement for manufacturing Platelets, Pheresis, and provide guidance on preparing a manufacturing supplement for Platelets, Pheresis under Title 21 Code of Federal Regulations 601.12 (21 CFR 601.12).

This guidance applies only to the following Platelets, Pheresis components:

  • Platelets, Pheresis (single, double, and triple collections);
  • Platelets, Pheresis Leukocytes Reduced (single, double, and triple collections); and
  • Platelets, Pheresis or Platelets, Pheresis Leukocytes Reduced collected concurrently with Plasma, Red Blood Cells (RBCs), and/or Source Plasma.1

This guidance replaces FDA's "Revised Guideline for the Collection of Platelets, Pheresis" dated October 1988. Also, this guidance finalizes the draft guidance, "Guidance for Industry and FDA Review Staff: Collection of Platelets by Automated Methods" dated September 2005.

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA's guidances means that something is suggested or recommended, but not required.

If you have any questions about the effect of any portion of this guidance on a regulatory requirement, contact the Center for Biologics Evaluation and Research (CBER), Office of Blood Research and Review, Division of Blood Applications, at 301-827-3524.

Return to Table of Contents


  1. DISCUSSION
  1. Background

Plateletpheresis is the routine collection of platelets using an automated blood cell separator device, which results in the product Platelets, Pheresis manufactured from a high yield of platelets from a single donor. Transfusion of Platelets, Pheresis is effective for treating patients with platelet related insufficiencies, while limiting the recipient's exposure to platelets from multiple donors. In recent years, many improvements have been made in automated blood cell separator device technology, platelet storage stability, and blood cell counting methods, including:

  • collection process efficiency;
  • storage container characteristics; and
  • accuracy of methods for determining a donor's pre-donation platelet count and component yields.

Automated blood cell separator devices are now capable of various plateletpheresis collection procedures including but not limited to the following:

  • collection of double and triple platelet components obtained during a single procedure;
  • use of in-process leukocyte reduction (Ref. 1);
  • collection of concurrent plasma components (Ref. 2); and
  • collection of concurrent RBC components (Ref. 3).

This document includes the following recommendations:

  • Published research indicates that there is poor recovery of viable platelets stored at a pH of less than 6.2 (Refs. 4 and 5). Therefore, your process validation and quality control (QC) testing for Platelets, Pheresis should assure a pH at or above 6.2, to rule out a pH less than 6.2 on the date the product is issued or on the date the product expires (outdates). Note that we recommend that you adopt a stricter pH standard than that currently specified in 21 CFR 640.25(b)(2).
  • You should include additional deferral criteria for donors of Platelets, Pheresis who have taken certain medications (see section III.A.) (Refs. 6, 7, and 8).
  • To protect the safety of the donor, seven days should elapse after collection of a double or triple Platelets, Pheresis before the donor is eligible to donate Platelets, Pheresis again. In addition, first-time donors without a pre-donation platelet count should not undergo collection of a triple Platelets, Pheresis.
  • Because of similarities between plateletpheresis and Source Plasma donation, you should follow the donor weight provisions for Source Plasma donors under 21 CFR 640.63(c)(6) (see Section III.A.).
  • QC testing, as prescribed in 21 CFR 640.25(b)(1) through (3) requires that, each month, four units prepared from different donors be tested at the end of the storage period for platelet count, pH of not less than 6.0 when measured at the storage temperature of the unit, and volume. In addition, 21 CFR 211.160(b) requires that laboratory controls include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

We also note that bacterial contamination of blood components and associated transfusion risks is a continuing problem (Refs. 9 and 10). Bacterial contamination testing is a necessary part of process validation and quality assurance monitoring for Platelets, Pheresis.

  1. Definitions

For purposes of the terms used in this guidance, the following definitions apply:

Actual platelet yield - The total platelet yield in the component, calculated by multiplying the platelet count of the sample times the volume of the component (platelet count x component volume = actual platelet yield).

Apheresis - Automated blood collection in which a device continuously or intermittently removes a small volume of whole blood, separates the components, collects certain components, and returns to the donor the uncollected remainder.

Automated blood cell separator - A device that uses a centrifugal or filtration separation principle to automatically withdraw whole blood from a donor, separate the whole blood into blood components, and return to the donor the remainder of the whole blood and blood components. The automated blood cell separator device is intended for routine collection of blood and blood components for transfusion or further manufacturing use.

Bacterial contamination testing - Testing conducted to determine whether a product contains viable contaminating bacteria.

Component - A part of a single donor's blood, such as platelets, separated from whole blood by physical or mechanical means. For Platelets, Pheresis, a component is a transfusable product that may result from a single collection (resulting in one component), a double collection (resulting in two Platelets, Pheresis components), or a triple collection (resulting in three Platelets, Pheresis components).

Concurrent component - When a blood component, such as Platelets, is being collected during an apheresis procedure, a concurrent component is a different blood component (i.e., Plasma, RBCs) collected at the same time.

Dedicated donation - Platelets, Pheresis donated for a specific recipient.

Devices cleared or approved - Describes a device that has been cleared or approved by FDA pursuant to a 510(k) Premarket Notification (cleared device) or Premarket Approval Application (approved device). (See Title 21, United States Code, section 360c; Federal Food, Drug, and Cosmetic Act (FDCA), section 515 - Premarket Approval; and, FDCA, section 510(k)).

Donation frequency - Interval between a donor's collection procedures.

Process validation - Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.

Qualification - A part of process validation that establishes confidence that a manufacturing device is capable of operating consistently (equipment installation qualification) and can be performed effectively and reproducibly (process performance qualification), and that the finished product meets all of the release requirements for functionality and safety (product performance qualification).

Residual White Blood Cell (WBC) count - The number of WBCs remaining in a Leukocytes Reduced component, calculated by multiplying the WBC count from a sample of the component times the volume of the component. In this document:

  • references to residual WBC count testing apply when the Platelets, Pheresis will be labeled as Leukocytes Reduced.
  • references to percent platelet retention apply to leukocyte reduction by filtration, provided there is access to a pre-filtration sample.

Rolling 12-month period - Continual assessment of a donor over a 12-month period. This is not a set 12-month period (i.e., calendar year).

Target platelet yield - The intended platelet yield programmed into an automated blood cell separator device, which may be based on the donor's platelet count and other factors.

Tolerance values - Minimum and maximum values (i.e., container volume; platelet concentration) described by the manufacturer as being acceptable. These values may also be described as specifications.

Weight/volume conversion - The total weight of the component minus the tare weight of the empty container divided by the specific gravity of the component equals volume of the component.

Return to Table of Contents


  1. DONOR SELECTION AND MANAGEMENT
  1. Donor Selection

Under 21 CFR 640.21(c), plateletpheresis donors must meet donor suitability criteria described in the biologics license application or supplement. These typically conform to donor suitability requirements (21 CFR 640.3) and recommendations applicable to donors of Whole Blood. In addition, we recommend:

  • donor weight of at least 110 pounds (currently required for Source Plasma donors under 21 CFR 640.63(c)(6))
  • Prior to the first donation, collect a sample for a platelet count.
  • If you cannot test a sample for a platelet count prior to the first donation (for example, because the donor presents at a mobile collection site), you should collect a pre-donation sample and evaluate the donor's platelet count after the first collection.

You should not collect Platelets, Pheresis from donors who have ingested platelet inhibitory drugs recently enough to adversely affect platelet function in the product, or the safety of the donor. These recommendations include, but may not be limited to:

  • Aspirin (ASA)/ASA-containing drugs/Feldene - two full medication free days prior to donation (Refs. 6 and 7)
  • Plavix (Clopidogrel) and Ticlid (Ticlopidine) - 14 full medication free days prior to donation (Ref. 8).

    When the drugs listed in this section are taken for a specific medical condition, donors should not discontinue taking drugs prescribed or recommended by their physicians in order to be eligible2 to donate Platelets, Pheresis. However, we do not necessarily recommend deferral of such donors for all blood products, if the donors are in good health, and establishments may make eligibility determinations for donations of other products.

  1. Donor Management
  1. Platelet Count
  • You should collect a pre-donation sample from the donor for a platelet count. The device operator should enter that platelet count, or the one obtained immediately following initiation of the collection procedure, to more accurately set the target platelet yield parameters for each collection of Platelets, Pheresis. These steps should be consistent with the automated blood cell separator device manufacturer's directions for use.
  • For any collection facility that cannot test a pre-donation sample for a platelet count (for example, a mobile collection site), you may use an average of previous historic platelet counts (as specified by the device manufacturer), or a default platelet count (either as recommended by the automated blood cell separator device manufacturer, or determined by using blood center specific values), to set the target platelet yield. You should not collect a triple Platelets, Pheresis from first-time donors who do not have a pre-donation platelet count available either prior to or immediately following initiation of the collection procedure. Concurrent components may be drawn if the donor meets eligibility requirements for those components.
  • You should defer from donation donors whose platelet counts are less than 150,000 platelets/uL until a subsequent pre-donation platelet count indicates that the donor's platelet count is at least 150,000 platelets/uL.
  1. Donation Frequency

To protect the safety of the donor:

  • a donor should undergo no more than 24 Platelet, Pheresis collections in a rolling 12-month period.
  • the interval between each collection of Platelets, Pheresis should be at least two days with no more than two procedures in a seven-day period.
  • the interval between collection of a double or triple Platelets, Pheresis and any subsequent collection of Platelets, Pheresis should be at least seven days.
  • the automated blood cell separator device should be set with a post-donation platelet count target of no less than 100,000 platelets/uL.
  1. RBC Loss Prior to a Collection of Platelets, Pheresis

To protect the donor from significant RBC loss, we recommend that:

  • you not allow a donor who has donated a unit of Whole Blood, a single unit of Red Blood Cells by apheresis, or a single unit of Red Blood Cells by apheresis concurrent with Platelets, Pheresis or Plasma in the previous 8 weeks to donate Platelets, Pheresis, unless the extracorporeal red blood cell volume during the Platelets, Pheresis collection is expected to be less than 100 mL (Ref 3).
  • you not perform any collection procedure on a donor who has donated two units of Red Blood Cells by apheresis within the previous 16 weeks (Ref. 3).
  1. Total Plasma Volume Loss Per Collection Procedure

The total plasma volume (excluding anticoagulant) of all blood components retained per collection of Platelets, Pheresis should not exceed:

  • 500 mL (600 mL for donors weighing 175 lbs or greater), or
  • the volume described in the labeling for the automated blood cell separator device (this volume may be more or less than the 500 mL or 600 mL volume stated in the above bullet).

Return to Table of Contents


  1. INFORMATION PROVIDED TO THE DONOR

Under 21 CFR 640.22(c), the collection procedure must be as described in the biologics license application or supplement. As part of the collection procedure, Platelets, Pheresis donors should receive information about the collection procedure and its associated risks. You should provide Platelets, Pheresis donors with the same information that is provided to a Whole Blood donor3, plus the following information specific to the platelet collection:

Under 21 CFR 640.22(c), the collection procedure must be as described in the biologics license application or supplement. As part of the collection procedure, Platelets, Pheresis donors should receive information about the collection procedure and its associated risks. You should provide Platelets, Pheresis donors with the same information that is provided to a Whole Blood donor3, plus the following information specific to the platelet collection:

  • a description of the procedure for collection of Platelets, Pheresis and its associated risks.
  • information about potential side effects of the procedure including possible effects as a result of solutions and/or treatment to reduce side effects such as treatment with a calcium replacement. Examples of side effects include anticoagulant effects (tingling and/or nausea), hypovolemia (decreased blood volume), fainting, and any other side effect as described by the automated blood cell separator device manufacturer.
  • information indicating that there are limitations to the number and types of components that can be donated per year.

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  1. COMPONENT COLLECTION

Improvements in collection of Platelets, Pheresis have enabled blood establishments to obtain from a single collection procedure one, two, or three Platelets, Pheresis component(s) (and concurrent collection of Plasma, Source Plasma and/or RBC components).

Under 21 CFR 640.22(c), the collection procedure must be as described in the biologics license application or supplement. In addition, the phlebotomy must be performed by a single uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's tissue (21 CFR 640.22(d)). A sterile connecting device may be used as described in the manufacturer's directions for the apheresis collection set. The automated blood cell separator device must perform in the manner for which it was designed (21 CFR 606.60(a)). Accordingly, your collection procedures should be consistent with the Operator's Manual, directions for use, and/or manufacturer's specifications. Specifications identified by the manufacturer may include, but not be limited to, the donor's platelet count, weight, height or hematocrit; the minimum/maximum volume of the storage container; platelet concentration per uL in the storage container, or actual platelet yield. In addition, supplies and reagents must be used in a manner consistent with instructions provided by the manufacturer (21 CFR 606.65(e)).

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  1. VALIDATION OF THE COLLECTION PROCESS

The Current Good Manufacturing Practice (CGMP) regulations described in 21 CFR Parts 210 and 211 contain the minimum requirements for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing or holding of a drug to assure that the drug meets the requirements of the FDCA as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess(21 CFR 210.1(a)). These CGMP regulations also apply to Whole Blood and blood components (21 CFR 210.2(a), 211.1(b)) and supplement the CGMP regulations for blood and blood components contained in 21 CFR Part 606. As an element of CGMP, process validation "establishes documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics" (Ref. 11).4 We recommend that establishing documentation of process validation include, but not be limited to, validation protocol development, installation qualification, process operator performance qualification, and product performance component qualification (Ref. 11).

Each device intended for the routine collection of Platelets, Pheresis must be cleared or approved by FDA for this purpose (see 21 CFR 864.9245). You should conduct validation of the collection process using each type of device used in your establishment prior to implementing routine collections.

In addition, your validation efforts should include the following manufacturing steps:

  • cell counting
  • pH measurement: we recommend that a pH meter or gas analyzer be routinely used rather than pH (nitrazine) paper.
  • component weighing
  • sterile connecting method (Ref. 12)
  • storage
  • shipping
  1. Equipment Installation Qualification

21 CFR 606.60(a) requires that equipment be observed, standardized and calibrated on a regularly scheduled basis as prescribed in the Standard Operating Procedures Manual and must perform in the manner for which it was designed. Upon initial installation, the automated blood cell separator device should be qualified as described in the Operator's Manual or manufacturer's directions for use.

  1. Validation Protocol

An integral element of the performance and documentation of process validation is the development of a validation protocol. You should refer to FDA's "Guideline on General Principles of Process Validation" (Ref. 11) as an outline for developing your validation protocol. The validation protocol should include at least the following:

  • a description of the equipment to be used
  • minimum/maximum acceptable values for the Platelets, Pheresis collection and/or component as specified by the automated blood cell separator device manufacturer
    • total volume (after removal of samples for hematological testing and bacterial contamination testing), including per component (container) from double and triple collections
    • actual platelet yield
    • residual WBC count (if Leukocytes Reduced) for the collection and components (if multiple components are collected), and percent platelet retention when applicable
    • concurrent component volume (Plasma or RBC), if applicable
    • pH measurement
  • manufacturer's specifications or recommendations for processing parameters (i.e., actual platelet yield and concentration, weight or volume collected)
  • description of supplies used in the collection (e.g., collection/storage containers, anticoagulants, etc.)
  • failure investigation criteria
  • personnel training criteria
  • standard operating procedures for performing each element of the collection process
  • documentation of the validation protocol criteria (all of the above)
  1. Process Performance Qualification (Operator)

Each person engaged in the collection of Platelets, Pheresis must have adequate education, training, or experience to assure competent use of the automated blood cell separator devices involved (21 CFR 211.25(a)). Establishments must maintain applicable proficiency test results (21 CFR 606.160(b)(5)(v)).

We recommend that personnel training include the successful, consecutive, performance under supervision of an appropriate number of procedures, as defined by your facility. These procedures should result in the collection of Platelets, Pheresis meeting relevant component specifications.

  1. Product Performance Qualification for Component Collection Process

Various mechanical and biological factors may influence the plateletpheresis collection process (i.e., the optical qualities of a donor's plasma, the donor's platelet count and platelet size, vascular access, and procedure duration) (Ref. 14). The objective of collection performance qualification is to verify that the automated blood cell separator device performs according to the manufacturer's claims when used, and through appropriate testing establishes confidence that the finished product produced by the specified process meets all release requirements for functionality and safety (Ref. 11). All components collected during the validation process can be released for transfusion provided that they meet minimum specifications as defined by the manufacturer, are labeled appropriately, and are otherwise suitable.

Process performance qualification should include testing for the actual platelet yield, pH, and volume; residual WBC count and percent platelet retention (for Leukocytes Reduced components) (See Table 1). We recommend that you assess the following at each collection site:

  • actual platelet yield (platelet count multiplied by the volume):
    • determine actual platelet yield at collection.
    • follow the platelet pre-donation count recommendations in section III.B.1., and set an appropriate target platelet yield as recommended by the automated blood cell separator device manufacturer to maximize the likelihood that each transfusable component contains > 3.0 x 1011 platelets and the target collection type (single, double, triple) is achieved.
  • pH as a measurement of quality after storage:
    • determine pH on the date the product is issued or on the date the product expires (outdates).
    • each transfusable component should have a pH > 6.2
  • percent platelet retention
    • perform when the automated blood cell separator device or filtration method is first put into use at an establishment and/or as recommended by the automated blood cell separator device manufacturer.
    • if leukocytes are reduced by filtration and there is access to both a pre-filtration and post-filtration sample, calculate percent platelet retention using pre- and post-filtration volume and cell content.
  • residual WBC count:
    • perform when the automated blood cell separator device or filtration method is first put into use at an establishment and/or as recommended by the automated blood cell separator device manufacturer.
    • perform within 48 hours of collection or per the manufacturer's directions for the cell counting methodology used (Ref. 15).
    • conduct testing on the collection (parent container) and on the individual components from double and triple collection
  • volume:
    • determine the volume after removal of samples for testing (i.e., cell count, bacterial contamination testing).
    • fill each storage container consistent with the manufacturer's minimum/maximum specifications.
    • equilibrate storage containers for double or triple collections + 10 mL, or per the manufacturer's directions if different.

You also should qualify devices and perform failure investigations as follows:

  • Devices:
    • complete product performance qualification for apheresis devices from different manufacturers, and for each model.
    • obtain data from all automated blood cell separator devices at each site for initial product performance qualification. If additional devices of the same model are added at the facility after qualification, include qualification data in monthly QC only.
  • Failure investigation: Conduct an investigation for all component qualification failures, and when appropriate, initiate corrective action and follow-up measures (see 21 CFR 211.192; 606.100(c)). We understand that some failures may occur due to conditions not resulting from a failure of the process (e.g., automated blood cell separator device failures, donor reactions). In addition, you should:
    • investigate as qualification failures residual WBC counts that exceed the following:
      • single collection: > 5.0 x 106 (collection)
      • double collection: > 8.0 x 106 (collection), and > 5.0 x 106 (either or both components)
      • triple collection: > 1.2 x 107 (collection), and > 5.0 x 106 (one, two or all three components).
    • However, each transfusable component from a double or triple collection of Platelets, Pheresis may be labeled as Leukocytes Reduced provided the residual WBC count on the component is found to be < 5.0 x 106. investigate collections that fail to meet the percent platelet retention, if performed. However, the component may be transfused if the actual platelet yield is determined subsequent to filtration, and the component is labeled appropriately.

Variation in the actual platelet count might be due to the platelet counter used and the type of platelet count used at the time of collection (pre-donation or historic average). However, you should select a statistically sound sample size, based on 95% confidence that 75% of components (platelet yield) will meet the recommended results (see Table 1). For pH and recommended residual WBC count, you should select a statistically sound sample size, based on 95% confidence that 95% of components (pH) or collections (residual WBC count) will meet the recommended results. Using the binomial statistic for example, a minimum of 60 components/collections should be tested, with zero process failures (93 tested with one process failure, 124 tested with two process failures, etc.) to qualify the process. Determine the sample size selection before starting the qualification process. For example, if you test 60 samples and encounter a failure, you should not continue with the testing of an additional 33 components. If you select a sample size of 93 and encounter a failure during testing, you may continue to test but there should be no additional failures. Similarly, if you select a sample size of 124 and encounter two failures, you may continue to test, but there should be no additional failures.

Table 1. Product Performance Qualification Criteria for the Platelet Component Collection Process

TestRecommended ResultsTarget1Allowable Process Failures2 to achieve recommended results for a set of N tests3
Actual platelet yield of transfusable component≥ 3.0 x 101195%/75% *N=11 **N=18 **N=23 **
012
pH≥ 6.295% / 95% ***N=60N=93N=124
012
Percent component retention> 85% component retention if performed ****95%/95%N=60N=93N=124
012
Residual WBC count *****Single collection: < 5.0 x 10695%/95%N= 60 collectionsN=93 collectionsN=124 collections
012
Double collection: Collection: < 8.0 x 106 or Components: < 5.0 x 10695%/95%N=60 collectionsN=93 collectionsN=124 collections
012
Triple collection: Collection: < 1.2 x 107 or Components: < 5.0 x 10695%/95%N=60 collectionsN=93 collectionsN=124 collections
012

1, 2 Process failures only; non-process failures should be excluded.
3 Corrective actions for exceeding allowable process failures

  • if you select a sample size of 11 and find one failure, 17 additional samples would need to be tested with no additional failures.
  • if you select a sample size of 60 and find one failure, 91 additional samples would need to be tested with no additional failures. If you select a sample size of 93 and find two failures, 157 additional samples should be tested with no failures. If you select a sample size of 124 and find three failures, 127 additional samples should be tested with no failures.

    * 95% confidence that greater than 75% of the components meet the standard.
    ** The sample size numbers can be used in a sampling plan that should be representative of products collected on each machine type in each facility.
    *** 95% confidence that greater than 95% of the components meet the standard.
    **** Or per the container/automated blood cell separator device manufacturer's specifications
    ***** The stratified recommended results should ensure that the individual transfusable units will be < 5.0 x 106 even with a 25% error in equilibration of the volume for double and triple collections.

  1. Re-Qualification/Re-Validation
  • Exceeding the allowable process failures of the collection process qualification may indicate that the process is not in control. You must investigate and correct the source of this failure (see 21 CFR 211.192, 606.100(c)) and should repeat validation.
  • The manufacturer may provide re-qualification requirements for the automated blood cell separator device to be followed.

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  1. QUALITY ASSURANCE AND MONITORING

Quality assurance (QA) is the sum of activities planned and performed to provide confidence that all systems and system elements that influence the quality of the component are functioning as expected (Ref. 13). When this is demonstrated, the process is considered to be in a state of control. Whether a process is operating in a state of control is determined by analyzing the day-to-day process and the data for conformance with the manufacturer's specifications and for variability.

You must have a quality control (QC) unit that has the responsibility and authority to approve or reject all components, containers, closures, in-process materials, packaging material, labeling and drug products and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)). Thus, the QC unit's responsibilities include the review of production records, and the review of complaints involving the possible failure of a product to meet its specifications. (See, for example, 21 CFR 211.22, 211.192, 211.198, 606.100(c)). Please refer to FDA's "Guideline for Quality Assurance in Blood Establishments" (Ref. 13) for developing a QA and Monitoring program.

  1. Standard Operating Procedures (SOPs) and Recordkeeping
  1. Requirements for SOPs
  • An automated blood cell separator device must "perform in the manner for which it was designed" (21 CFR 606.60(a)) during the collection or processing of apheresis components. Written SOPs must be maintained and must include all steps to be followed in the collection, processing, compatibility testing, storage, and distribution of blood and blood components (21 CFR 606.100(b)). Therefore, you must have written SOPs for each step in the collection of Platelets, Pheresis.
  1. Additional Provisions Applicable to SOPs
  • Adverse reactions: You must have a written SOP for investigating adverse donor and recipient reactions (21 CFR 606.100(b)(9)). In addition, you should have a written SOP for managing a cardiopulmonary emergency or any other adverse reactions associated with donation, containing steps for contacting physicians, obtaining an emergency rescue squad response, and transporting the donor to the hospital.
  • Hematocrit: If the final platelet collection contains more than 2 mL of packed RBCs, you should attach a sample of donor blood to the platelet storage container for compatibility testing to prevent the possibility of an adverse reaction during transfusion. In addition, you should hold the Platelets, Pheresis collection prior to distributing as Leukocytes Reduced until a residual WBC count of the transfusable component can be determined and found to be < 5.0 x 106.
  • Component volume: You should describe how to process components in the event the volume exceeds the automated blood cell separator device manufacturer's specifications. In addition, the volume in the storage containers from double or triple collections should be within +10 mL of each other or per the manufacturer's directions if different.
  • Samples for QC: Containers for QC samples should be attached to the component/collection set using a sterile connecting device, to ensure the maintenance of the closed system.
  • Actual platelet yield: The platelet yield from each collection of Platelets, Pheresis should be available to provide to the transfusion facility.
  • pH measurement: Accurate pH measurement is time dependent, and samples should be tested within 1 hour of sampling, or as suggested by the manufacturer of the pH measurement system. We recommend that a pH meter or gas analyzer be routinely used rather than pH (nitrazine) paper. However, if you choose to determine pH measurements with nitrazine paper, the selected paper should read in increments of one-tenth units, or it may provide inaccurate measurements.
  • RBC loss: You must have a written SOP for your collection procedure, including in-process precautions to measure accurately the quantity of blood removed from the donor (21 CFR 606.100(b)(5)). You should calculate the donor's RBC loss, which may include the residual RBCs remaining in the apheresis collection set after a collection of or discontinued collection of Platelets, Pheresis; the extracorporeal RBCs remaining in event of no RBC rinseback; the RBC loss from collection of tubes for testing; and/or collection of a concurrent RBC. You should record such RBC loss in the donor's record, in a manner that allows tracking of cumulative RBC loss over time.
  • Bacterial contamination testing: You must maintain written SOPs and include all steps to be followed in the testing of blood and blood components (21 CFR 606.100(b)). Bacterial contamination testing should be performed using a culture based methodology, and using your established procedures.
  • QC failures: You must thoroughly investigate any unexplained discrepancy or the failure of a batch to meet any of its specifications (21 CFR 211.192). You should define appropriate criteria for retesting of components, testing of additional components, final labeling, and disposition of components that fail to meet specifications.
  • Failure investigations: (see 21 CFR 211.192; 606.100(c)) The criteria to assess in the performance of a thorough failure investigation (including the conclusions and followup) should include, but not be limited to: donor characteristics or specifications; operation and or performance of the collection device; adherence to SOPs; lot numbers of reagents or supplies; sample collection, handling, storage or shipping; operator performance, training or competency; and cell counting instrument performance including shifts or trends in controls.
  • Manufacturer's performance specifications: You should state the acceptable tolerance specifications for the volumes, platelet concentration, and/or actual platelet yield for each storage container as described by the manufacturer. You should have a procedure addressing the handling of components that do not meet the manufacturer's performance specifications (e.g., use in research or further manufacture).
  • Labeling:
    • The final component volume stated on the label should be determined after removal of samples for platelet count determination, QC, and/or bacterial contamination testing.
    • Platelets, Pheresis for transfusion should routinely contain > 3.0 x 1011 platelets. When special circumstances warrant their use, Platelets, Pheresis components containing less than 3.0 x 1011 platelets should be labeled with the actual platelet content.
  • Component Storage:
    • If Platelets, Pheresis are stored at 20 to 24 oC, you must maintain a continuous gentle agitation throughout the storage period (21 CFR 640.25(a)). You should describe how temperature and agitation will be monitored, and the disposition of platelet components that are not stored properly.
    • You must follow the automated blood cell separator device manufacturer's directions for use (21 CFR 606.60(a)). If sterile connecting an additional container(s) is necessary, use a container(s) designed to achieve and protect a sterile conduit. Because of differences in container specifications, you should use containers from the same manufacturer.
  1. Recordkeeping

All recordkeeping requirements of 21 CFR Part 606, Current Good Manufacturing Practice for Blood and Blood Components, Subpart I (Records and Reports); Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, Subpart J (Records and Reports); and applicable provisions of 21 CFR 640.20 through 640.27, must be met.

  1. Donor Monitoring
  1. Platelet Counts

If the platelet count is known, you should notify your Medical Director when a donor has a post collection platelet count less than 100,000/uL, and you should defer the donor until his/her platelet count has returned to at least 150,000/uL.

Transient decreases in platelet counts have been reported in donors undergoing multiple collections of Platelets, Pheresis (Ref. 16). You should periodically review a donor's records to monitor platelet counts.

  1. Adverse Reactions in Donors

    Records must be maintained of any reports of complaints of adverse reactions regarding each unit of blood or blood product arising as a result of blood collection or transfusion and a thorough investigation of each reported adverse reaction must be made (21 CFR 606.170(a)).

  2. Red Blood Cell Loss
  • Per collection:
    • If the collection procedure needs to be discontinued for any reason before completion, and if the Operator's Manual allows, you should attempt to return RBCs to the donor.
    • Donor eligibility based on RBC loss (with or without RBC rinseback, and including all other types of donation) is described in Table 2.

Table 2: Recommendations for donor eligibility based on RBC loss per collection

Donor's Initial packed RBC lossDonor's Second packed RBC loss within 8 weeksEligibility
Less than 200 mLNo donation or total from initial and second loss less than 200 mLNo deferral of donor for packed RBC loss; frequency of donation of Platelets, Pheresis as discussed in section III.B.2
Less than 200 mLMore than 200 mL but less than 300 mL totalDonor is not eligible to donate for 8 weeks from 2nd loss
More than 200 mL but less than 300 mLNADonor is not eligible to donate for 8 weeks from initial loss
Less than 200 mLTotal loss from initial and second loss of more than 300 mLDonor is not eligible to donate for 16 weeks from the 2nd loss
300 mL or moreNADonor is not eligible to donate for 16 weeks from initial loss.
  • Per 12 months:

Under 21 CFR 640.3(b), a person may not serve as a source of Whole Blood more than once in 8 weeks. In any such assessment, and in assessing a donor's RBC loss during the past rolling 12-month period, the RBC loss associated with the collection of Platelets, Pheresis, and including any other donation type (i.e., Whole Blood, RBC by apheresis), should also be considered.

  • Total plasma volume loss per 12 months:

The maximum volume (excluding anticoagulant) collected from a donor during a rolling 12-month period, and including any other donation type (i.e. Whole Blood, plasmapheresis) should not exceed:

  • 12 liters (12,000 mL) for donors weighing 110 - 175 lbs
  • 14.4 liters (14,400 mL) for donors weighing more than 175 lbs (Ref. 2).
  1. Component Testing
  1. Component Specification Check
  • Actual platelet yield (volume x platelet count) must be determined after each collection (21 CFR 211.103).
  • Weight/volume conversion is necessary to determine the volume of each collection. To convert weight to volume, divide the weight of the collection (the total weight minus the weight of the bag) by the specific gravity (1.03).
  • Bacterial contamination testing: You should perform bacterial testing as specified by the storage container manufacturer (i.e., 7-day storage of Platelets, Pheresis, Leukocytes Reduced).
  1. QC Monitoring

Under 21 CFR 211.160(b), laboratory controls must include the establishment of scientifically sound and appropriate specifications, standards, sampling plans and test procedures to assure that components and products conform to appropriate standards. One example of a scientifically sound statistical sampling and analytic plan is based on a binomial approach (see Table 1: Product Performance Qualification Criteria for the Platelet Component Collection Process). The sampling sizes described in Table 1 will confirm with 95% confidence a < 5% non-conformance rate for pH and residual WBC count, and < 25% non-conformance rate for actual platelet yield.

However, other statistical plans may also be appropriate, such as the use of scan statistics.

As part of your QC protocol you should:

  • define a plan for non-selectively identifying collections to be tested. This should ensure testing of components collected on each individual automated blood cell separator device, each collection type, and each location.
  • define sampling schemes for actual platelet yield (including volume determination) and pH, and residual WBC. We recognize that these sampling schemes may be mutually exclusive. However, the platelet yield of the collection (and designation of single, double or triple) should be made prior to performing the residual WBC count QC.
  • test actual platelet yield (platelet count times the volume) and pH at the maximum allowable storage time for the container system used (or representing the dating period). Title 21 CFR 640.25(b) specifies that QC testing, including platelet count and measurement of actual plasma volume, be performed at the end of the storage period. We believe that such testing may be conducted "at issue" or within 12 hours after expiration. In addition, actual platelet yield and pH testing may be conducted on one storage container of a double or triple collection.
  • include the residual WBC count (Ref. 1) for Leukocytes Reduced collections, if manufacturing leukocytes reduced products.
    • Perform the residual WBC count on the collection. For the purpose of labeling as Leukocytes Reduced (see 21 CFR 606.121(c)(1)), you may also perform a residual WBC count on the transfusable units for double and triple collections that fail the collection acceptance criteria listed (see below in this section).
    • Test for the residual WBC count within 48 hours after collection (Ref. 15), or per the manufacturer's directions for the cell counting methodology, to reduce aberrant results due to cellular deterioration and clumping.
    • Test for percent platelet retention, if leukocytes reduced by filtration.
  • describe the criteria for investigation of failures during QC, including the factors to consider in categorizing a failure as process or non-process.
  • have a method to document all calculations and test results.

We recommend that you consider the following QC results to be acceptable:

  • pH > 6.2. If one component from a double or triple collection is found to have a pH < 6.2, the corresponding component(s) from the collection should be retrieved and/or quarantined until they are tested and found to be acceptable.
  • transfusable Platelets, Pheresis components > 3.0 x 1011 platelets.
  • residual WBC count:
    • Single collection: < 5.0 x 106 WBC
    • Double collection: < 8.0 x 106 WBC
      Note: If > 8.0 x 106, but each transfusable component is < 5.0 x106, this is not considered a collection failure.
    • Triple collection: <1.2 x 107
      Note: If > 1.2 x 107, but each transfusable component is < 5.0 x106, this is not considered a collection failure.
  • percent platelet retention should be > 85% or per the manufacturer's specifications. Components with <85% platelet retention may be distributed, but a failure investigation should be performed.
  • negative for bacterial contamination testing, when performed.
  1. Equipment/Supplies

Equipment must be observed, standardized, and calibrated on a regularly scheduled basis as prescribed in the Standard Operating Procedures Manual (21 CFR 606.60(a)). Such equipment includes, but may not be limited to, the automated blood cell separator device, cell counting instrument(s), pH meter, scales and sterile connector.

All supplies (including containers) and reagents must meet all of the requirements described in 21 CFR 606.65.

  1. Operator Training

Operators must have adequate training, education and experience, or combination thereof, to assure competent performance of their assigned functions (21 CFR 606.20(b)). We recommend that assessment of operators include scheduled competency assessment and proficiency testing. In addition, we recommend that you develop and document appropriate training on component preparation and/or machine maintenance as updated information becomes available (Ref. 12).

  1. Quality Monitoring

You should assess the following:

  • total component volume and equal distribution of volume in double and triple component collection containers. This assessment should include checking the performance of the scale; the use of the tare weight of the empty containers/tubing; and the weight/volume conversion.
  • component bacterial contamination testing: Rates of bacterial contamination of plateletpheresis should be monitored, and bacterial contamination rates that exceed 1:3000 (Refs. 10 and 12) should be investigated.

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  1. PROCESSING AND TESTING
  1. Processing

Platelets, Pheresis must be processed as described in 21 CFR 640, Subpart C - Platelets (21 CFR 640.20-640.27).

  1. Communicable Disease Testing

Donations of Platelets, Pheresis must be tested for communicable diseases (21 CFR 610.40, 640.5(a) through (c), 640.23). Platelets, Pheresis may be released or shipped prior to completion of communicable disease testing in accordance with 21 CFR 610.40(g).You must test donations of human blood and blood components from a donor whose donations are dedicated to and used solely by a single identified recipient except that, if the donor makes multiple donations for a single identified recipient, you may perform such testing only on the first donation in each 30-day period (21 CFR 610.40(c)(1)(i)).

You must test donations of human blood and blood components from a donor whose donations are dedicated to and used solely by a single identified recipient except that, if the donor makes multiple donations for a single identified recipient, you may perform such testing only on the first donation in each 30-day period (21 CFR 610.40(c)(1)(i)).

  1. Expiration Date

The dating period for Platelets, Pheresis collected using an FDA cleared or approved collection container under a closed or functionally closed system will be specified by the collection container manufacturer.

In accordance with such instructions and our recommendation, Platelets, Pheresis collected in an open system expire 24 hours from the termination of the procedure if the integrity of the hermetic seal is broken during processing.

If the integrity of the hermetic seal is broken after collection, the Platelets, Pheresis expire 4 hours from the time of the integrity violation, or at the original expiration date, whichever is earlier (21 CFR 606.122(l)(2)).

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  1. LABELING

An instruction circular must be available for distribution if the product is intended for transfusion (21 CFR 606.122).

Your container labels must comply with 21 CFR 606.121 and 610.60.

In addition:

  • The label should include the estimated amount of anticoagulant in the component container.
  • Platelets, Pheresis components for transfusion, containing less than 3.0 x 1011 platelets per storage container, should be labeled with the actual platelet content.
  • A component from a double or triple Platelets, Pheresis may accurately be labeled as Leukocytes Reduced when the residual WBC count of the collection is > 8.0 x 106 (double) or > 1.2 x 107 (triple) IF the transfusable component is tested and found to have a residual WBC count < 5.0 x 106.
  • Platelets, Pheresis may be labeled (i.e., tie-tag) with the residual WBC count if counted and found to contain < 1.0 x 106.

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  1. REPORTING CHANGES TO AN APPROVED BIOLOGICS LICENSE APPLICATION (BLA)

Licensed establishments must report changes to their approved application(s) in accordance with 21 CFR 601.12. For assistance in reporting your changes see FDA's "Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture." The information below is intended to assist you in determining which reporting mechanism is appropriate for a change to your approved BLA, as it applies to the manufacture of Platelets, Pheresis. You should prominently label each submission with the reporting category under which you are reporting your change, e.g., "Prior Approval Supplement;" "Supplement - Changes Being Effected in 30 Days;" "Supplement - Changes Being Effected;" or "Annual Report."

  1. Prior Approval Supplement (PAS): Changes Requiring Supplement Submission and Approval Prior to Distribution of the Product Made Using the Change (Major Changes) (21 CFR 601.12(b))

Under 21 CFR 601.12(b), changes that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product must be reported to FDA in a Prior Approval Supplement (PAS). Under this standard, the following kinds of manufacturing changes would fall within this category, warranting submission of your request to implement the following changes to your approved BLA as a PAS:

  • if you currently hold an unsuspended, unrevoked BLA to manufacture blood components other than Platelets, Pheresis, and you intend to manufacture and distribute Platelets, Pheresis under that license.
  • if you are currently approved to manufacture Platelets, Pheresis at a specific facility, and you intend to manufacture Platelets, Pheresis at a different facility, not under an approved Comparability Protocol. To submit a request for a Comparability Protocol see below.
  • if you are approved to manufacture Platelets, Pheresis, but intend to change your manufacturing process in a manner that presents a substantial potential for an adverse effect on the product. FDA believes that such manufacturing changes include: change in storage conditions; change in anticoagulant; leukocyte reduction; and collection of an additional or different product.
  • if you intend to collect Platelets, Pheresis using an automated blood cell separator device new to the market or new to your establishment.
  • if you are requesting approval for a Comparability Protocol. The Comparability Protocol described in 21 CFR 601.12(e) is a supplement that describes the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. A new Comparability Protocol, or a change to an existing one, requires approval from FDA prior to distribution of the product which, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect (21 CFR 601.12(e)).

A Comparability Protocol is appropriate, but not required, if you wish to add multiple collection facilities under your direction and control, using the same process to manufacture Platelets, Pheresis. If you request approval for a Comparability Protocol, you should describe the procedures and processes that each new collection facility will implement to ensure conformance with the Comparability Protocol. You may identify one or more collection facilities for the purpose of validation and submission of the Comparability Protocol and supporting data to CBER for review. Approval of such a Comparability Protocol for future collection facilities justifies a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect.

If you are using an approved Comparability Protocol, you should routinely review the procedures and specifications in the Comparability Protocol to assure that they remain current and consistent with the applicable application and current guidance. If modifications are required, you should contact FDA to discuss the change and to determine the appropriate reporting category.

  • We consider the recommendations in this guidance document to provide appropriate criteria for a biologics license application or supplement for Platelets, Pheresis. You may use an alternative approach if such approach satisfies the requirements of the applicable statutes and regulations. Your alternative procedure(s) may be acceptable if you demonstrate that the resulting Platelets, Pheresis components meet applicable standards. We have determined that it may be adequate to determine the actual platelet yield at collection, and that re-determination of the actual platelet yield at issue or outdate is unlikely to provide additional relevant information. If you choose to discontinue determining the platelet count for QC testing as described under 21 CFR 640.25(b)(1), you must submit a request for an alternative procedure under 21 CFR 640.120.

You must not distribute in interstate commerce blood components made using a changed manufacturing process requiring a PAS until you have received our approval of your PAS (21 CFR 601.12(b)(3)).

  1. Changes Being Effected in 30 Days (CBE-30) Supplement: Changes Requiring Supplement Submission at Least 30 Days Prior to Distribution of the Product Made Using the Change (21 CFR 601.12(c))

Under 21 CFR 601.12(c), changes that have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product must be reported to FDA in a Changes Being Effected in 30 days (CBE-30) supplement.

You must submit your request to implement manufacturing changes with a moderate potential for an adverse effect to your approved BLA as a CBE-30 supplement under 21 CFR 601.12(c). The manufacturing changes described below are examples of changes that we believe fall within this category:

  • certain software and hardware upgrades provided by the manufacturer to your cleared or approved automated blood cell separator device
  • addition of concurrent plasma collection
  • implementation of a new collection facility under an approved Comparability Protocol

You may distribute your blood components made using the change requested in your CBE-30 supplement in interstate commerce 30 days after we receive your supplement, unless we notify you otherwise (21 CFR 601.12(c)(4)).

  1. Submission Inclusion Documents
  1. PAS: To comply with the requirements in 21 CFR 601.12(b)(3), the following must be included in the supplement:
  • identification of the components involved (e.g., single plateletpheresis component, double plateletpheresis components, and/or triple plateletpheresis components) and manufacturing site(s) or area(s) affected, and a detailed description of the manufacturing change (including device collection technology and the collection protocol(s)) (21 CFR 601.12(b)(3)(i) through (iii)). We recommend that this information be documented in a cover letter and FDA Form 356h. To permit assessment of the manufacturing change we recommend including copies of the following SOPs: 
    • collection
    • informed consent
    • labeling including labels
    • donor qualification, deferral and adverse event follow-up
    • a description of training (or an example of training documents)
    • component manufacturing
    • monitoring donor RBC and plasma loss
    • failure investigation
    • quality control including sampling scheme, sample handling, tracking and trending
    • equipment standardization/calibration
    • quarantine and disposition of unsuitable products
    • Additionally, we recommend that the following SOPs, if already approved for other blood collection activities and unrevised, would not need to be submitted:
      • sample preparation
      • component storage and shipping
      • donor arm preparation
  • product labeling for each component, if changed (21 CFR 601.12(f)). We recommend submitting a Form FDA 2567 including Circular (unless already on file at FDA)
  • a reference list of relevant SOPs (21 CFR 601.12(b)(3)(vii))
  • relevant validation protocols and data (21 CFR 601.12(b)(3)(vi)). We recommend a summary of the validation protocol, including failure investigations.
  • a description of the methods used and studies performed to evaluate the effect of the change and the data derived from such studies (21 CFR 601.12(b)(3)(iv) through (v)). We recommend submitting the following information and data:
    • the device manufacturer
    • the device type
    • blood unit number
    • component description (i.e., leukocytes reduced)
    • date of collection
    • date of testing
    • result interpretation(s)
    • the identity of the person performing the testing
    • the identity of the collection facility
    • evidence of QA oversight, and
    • expected component specifications.

Additionally, we recommend two months of QC data for actual platelet yield and volume, pH, and residual WBC count (if requesting approval for Leukocytes Reduced platelets).

We further recommend that you provide an agreement to summarize bacterial contamination testing results for the first two hundred and fifty (250) Platelets, Pheresis collections in your Annual Report.

  1. Comparability Protocol: If you are an establishment with multiple manufacturing sites and wish to submit a comparability protocol to justify a reduced reporting category for a manufacturing change at multiple sites (see Section X.C.4 below), you must submit that protocol as a PAS (21 CFR 601.12(e)). In addition to the information listed in Section X.C.1 above , we recommend that you include the following:
  • implementation plan
  • proposed reporting category for changes made under proposed Comparability Protocol
  1. CBE-30 submissions (excluding new facilities under an approved Comparability Protocol): Under 21 CFR 601.12(c)(3) and 601.12(b)(3)(i) through (vii), the following information must be included in your CBE-30 submission:
  • identification of the Platelets, Pheresis components involved (e.g., single plateletpheresis component, double plateletpheresis components, and/or triple plateletpheresis components) and manufacturing site(s) or area(s) affected, and a detailed description of the proposed manufacturing change (including device collection technology and the collection protocol(s)). We recommend that you document this information in a cover letter and FDA Form 356h. To permit assessment of the documented manufacturing change, we recommend that you include copies of any new or revised SOPs.
  • relevant validation protocols and data. We recommend that you submit a summary of the validation protocol, including failure investigation.
  • the data derived from such studies. We recommend two months of QC data for actual platelet yield and volume, pH, and residual WBC count (if requesting approval for Leukocytes Reduced platelets).
  1. CBE-30 submissions for new facilities under an approved Comparability Protocol: To comply with 21 CFR 601.12(c)(3) and 601.12(b)(3)(i) through (vii), the following information must be included:
  • identification of the components involved (e.g., single plateletpheresis component, double plateletpheresis components, and/or triple plateletpheresis components) and new manufacturing site(s) or areas(s) affected, and a detailed description of the proposed implementation plan (manufacturing change including device collection technology and the collection protocol(s)). Additionally, we recommend that this information be documented in a cover letter and FDA Form 356h.
  • relevant validation protocols and data. We recommend a summary of the validation protocol, including failure investigations to meet the requirement.
  • the data derived from studies. We recommend two months of QC data for actual platelet yield and volume, pH, and residual WBC count (if requesting approval for Leukocytes Reduced platelets).

In addition, you should include the submission tracking number (STN) of the approved Comparability Protocol, or the STN(s) of changes to the SOPs associated with an approved Comparability Protocol.

  1. Submission of Platelets, Pheresis Sample(s) to CBER

To obtain a biologics license under Section 351 of the Public Health Service Act for any biological product, the manufacturer must submit an application to CBER, and sample(s) presentative of the product must be listed in the application (21 CFR 601.2(a)).

We recommend that:

  • applicants with no prior experience in the collection of Platelets, Pheresis schedule submission of Platelets, Pheresis products to CBER.
  • applicants who submit a CBE-30 for an additional facility under an approved Comparability Protocol generally would not need to submit Platelets, Pheresis products to CBER.

CBER may request the submission of product samples by other applicants, as necessary, during the review process or at any other time (21 CFR 610.2(a)).

  1. Shipping Platelets, Pheresis Sample(s) to CBER

If CBER has requested you to submit a Platelets, Pheresis sample(s) to CBER, you should contact CBER Division of Hematology, Laboratory of Cellular Hematology at (301) 496-2577 to schedule delivery of the products to arrive prepaid. Platelets, Pheresis sample(s) should be shipped to the following address between 8:30 a.m. and 4:00 p.m. Monday through Friday, excluding Federal holidays:

Center for Biologics Evaluation and Research (CBER)

Food and Drug Administration

8800 Rockville Pike

Building 29, Room 323

Bethesda, Maryland 20892

We recommend that you enclose a pre-paid, self-addressed shipping label to allow return of shipping boxes and coolants, if desired.

We recommend that you ensure that the Platelets, Pheresis sample(s) arrives at CBER prior to the expiration time. The Platelets, Pheresis sample(s) should not expire on Friday or Saturday at midnight, or at midnight on the day before a Federal holiday.

Labeling and processing, including required testing for evidence of infection due to communicable disease agents (21 CFR 610.40), should be complete prior to shipment.

When shipping to us, you should follow your SOPs for collection, processing, storage and distribution of blood components intended for transfusion.

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  1. CONTACT INFORMATION

You may direct questions specific to Platelets, Pheresis application submissions to the Division of Blood Applications. You may also direct questions to the Office of Communications, Training, and Manufacturers Assistance (OCTMA) as an initial general point of contact. Submit all registration forms (Form FDA 2830) and licensure applications/supplements to the Director, CBER.

Table 3: FDA Contact Information

Submissions:

˜ Registrations

˜ License Applications

Director, Division of Blood Applications

Center for Biologics Evaluation and Research, HFM-370, Food and Drug Administration, c/o Document Control Center, HFM-99, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448.

General Questions

Director, OCTMA, HFM-40, Food and Drug Administration, c/o Document Control Center, HFM-99, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, Voice (301) 827-2000; Fax (301) 827-3843.

Application Submission

Director, Division of Blood Applications,

Center for Biologics Evaluation and Research, HFM-370, Food and Drug Administration, c/o Document Control Center, HFM-99, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, Voice (301) 827-3543; Fax (301) 827-3534.

Platelets, Pheresis Samples to

CBER

Center for Biologics Evaluation and Research (CBER)

Food and Drug Administration

8800 Rockville Pike

Building 29, Room 323

Bethesda, Maryland 20892

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  1. REFERENCES

1. FDA Recommendations and Licensure Requirements for Leukocyte-Reduced Blood Products, May 29, 1996.

2. FDA Memorandum to Registered Blood and Source Plasma Establishments, Revision of FDA Memorandum of August 27, 1982: Requirements for Infrequent Plasmapheresis Donors - 3/10/1995.

3. FDA Guidance for Industry: Recommendations for Collecting Red Blood Cells by Automated Apheresis Methods - Technical Correction February 2001 - 2/13/2001.

4. Murphy S. Platelet storage for transfusion. Seminars in Hematology 1985 July; 22(3):165-77.

5. Dumont LJ, VandenBroeke T. Seven-day storage of apheresis platelets: report of an in vitro study. Transfusion. 2003 Feb; 43(2):143-50.

6. Sonksen JR, Kong KL, Holder R. Magnitude and time course of impaired primary haemostatis after stopping chronic low and medium does aspirin in healthy volunteers. British Journal of Anaesthesia. 1999 Mar; 82(3):360-5.

7. Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scandinavian Journal of Haematology. 1984 Aug; 33(2):155-9.

8. Quinn MJ, Fitzgerald DJ. Ticlopidine and Clopidogrel. Circulation. 1999(100):1667-72.

9. Blajchman MA. Incidence and significance of the bacterial contamination of blood components. Developmental Biology 2002; 108: 59-67.

10. Hillyer CD, Josephson CD, Blajchman, MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: Joint ASH and AABB Educational Session in Transfusion Medicine. Hematology 2003; 575-89.

11. FDA Guideline on General Principles of Process Validation, May 1987, reprinted February 1993.

12. FDA Guidance for Industry: Use of Sterile Connecting Devices in Blood Bank Practices - 11/22/2000.

13. FDA Guideline for Quality Assurance in Blood Establishments, July 11, 1995.

14. Dumont LJ, Dzik WH, Rebulla P, et al. Practical guidelines for process validation and process control of white-cell reduced blood components: report of the Biomedical Excellence for Safer Transfusion (BEST) working party of the International Society of Blood Transfusion (ISBT). Transfusion 1996; 36: 11-20.

15. Dzik WH, Ragosta A, Cusack WF. Flow-cytometric method for counting very low numbers of leukcoytes in platelet products. Vox Sang. 1990; 59:153-9.

16. Lazarus EF, Browning J, Norman J, Oblitas J, Leitman SF. Sustained decreases in platelet count associated with multiple, regular plateletpheresis donations. Transfusion. 2001 June; 41:756-761.

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Contact FDA

(800) 835-4709
(240) 402-8010
Manufacturers Assistance and Technical Training Branch (CBER)

Division of Manufacturers Assistance and Training

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002