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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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7342.002 - Inspection of Source Plasma Establishments, Brokers, Testing Laboratories, and Contractors

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Compliance Program Guidance Manual

Chapter 42 – Blood and Blood Products

 

Implementation Date:

April 1, 2011

Completion Date:

On-going

Product Codes:

57DI-44 Source Plasma

57DI-55 Source Leukocytes Human

57DI-65 Therapeutic Exchange Plasma (TEP)

Programs/Assignment Codes:

42002 F Source Plasma Level 1 Inspection (all systems)

42002 G Source Plasma Level 2 Inspection (two systems)
42002A Pre-License
42832 Pre-Approval
 


 FIELD REPORTING REQUIREMENTS

A. General

Policy Development or Clarification: Districts should send Establishment Inspection Reports (EIRs) that contain issues requiring policy development or clarification or questions concerning inspection issues to the Center for Biologics Evaluation and Research (CBER) for review. Send the EIR and relevant exhibits electronically, if possible, to cberinspections@fda.hhs.gov, or by mail to the following address:

Division of Inspections and Surveillance (HFM-650)
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200 N
Rockville, MD 20852-1448

Foreign Inspections: CBER acts as the “home district” for foreign inspections of CBER-regulated products. Send the complete original EIR, including exhibits, to OCBQ/DIS/HFM-650, regardless of classification. Send a copy of the EIR narrative and the FACTS coversheet with endorsement to your foreign trip coordinator at HFC-130.

B. Inspection Reporting - FACTS Coversheet of EIR

Include the following information within the FACTS Coversheet (Inspection Summary field) in addition to the information specified in the Investigations Operations Manual (IOM):

  1. Inspection Level - Level 1 or Level 2.
  2. Criteria used to determine which inspection level would be performed.
  3. If a Level 2 inspection was performed, specify each system inspected and the rationale for selecting these systems.
  4. Document when a planned Level 2 inspection is changed to Level 1 based on the finding of significant objectionable conditions.

C. Fatality Follow Up

Send a copy of the EIR with exhibits pertinent to the fatality to the Fatality Program Manager (HFM-650) at the general address above, or electronically to the point of contact that issued the inspection follow up assignment.

Report any blood collection or transfusion related fatality identified during an inspection, and not yet reported to FDA, to the Fatality Program Manager (HFM-650) at 301-827-6220.

D. Warning Letters

Add the final, unredacted, signed Warning Letter to the MARCS-CMS case file under the Final Outcome tab with the file type identified as PDF VERSION Non-Redacted Issued Violation Letter.  Once added, this copy becomes available to the full text DOC search within MARCS-CMS.  It also serves as an internal copy for FDA that is available through the system to anyone who may need a copy of the issued letter.

Copies of the Warning Letters may also be sent to an appropriate state agency. Refer to the Regulatory Procedures Manual, Chapter 4, Advisory Actions, for guidance on this issue.

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TABLE OF CONTENTS

Part I Background

Part II Implementation

  1. Objective
  2. Strategy
  3. Program Management Instructions
  4. Frequency and Scheduling of CGMP Inspections
  5. Assignment of Investigators and Compliance Personnel

Part III Inspection

  1. Strategy
  2. Inspection Options: Level 1 and Level 2
  3. FDA 483 Observations
  4. Inspection Instructions

Part IV Analytical

Part V Regulatory / Administrative Strategy

  1. Deficiencies
  2. Federal / State Relations

Part VI References, Attachments and Program Contacts

  1. Laws and Regulations
  2. ORA Inspection Manuals and Guides
  3. Guidance Documents and Memoranda
  4. Center for Biologics Evaluation and Research and Office of Regulatory Affairs Program Contacts

Part VII Center for Biologics Evaluation and Research Responsibilities

Attachments

  1. General Instructions for all inspections
  2. Quality Assurance System
  3. Donor Eligibility System
  4. Product Testing System
  5. Product Collection and Processing System
  6. Quarantine/Storage/Disposition System
  7. Special Source Plasma Collection Programs
  8. Specific Instructions for Source Leukocytes and TEP
  9. Brokers
  10. Contractors

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PART I - BACKGROUND

This Compliance Program covers Source Plasma, Source Leukocytes, and Therapeutic Exchange Plasma intended for further manufacture into injectable drug products (e.g. immune globulin, albumin) and non-injectable products (e.g. in-vitro devices such as blood bank reagents), which are biological products subject to the licensure provisions of Section 351 of the Public Health Service Act (PHS). For the purpose of this Compliance Program:

  • Source Plasma means the fluid portion of human blood (plasma) collected by plasmapheresis and intended as source material for further manufacturing use (21 CFR 640.60);
  • Source Leukocytes means human leukocytes (white blood cells) prepared manually from Whole Blood or collected by apheresis and intended as source material for further manufacturing use; and
  • Therapeutic Exchange Plasma (hereinafter TEP) means the fluid portion of human blood (plasma) usually collected by apheresis as part of a medical procedure that is carried out under a physician’s order and performed to treat a medical condition, and intended as source material for further manufacturing use.

Biologics License Applications (BLAs)

FDA issues biologics licenses for Source Plasma, Source Leukocytes, and TEP under the authority of Section 351(a) of the PHS Act. A biologics license must be in effect for a biological product prior to its introduction or delivery for introduction into interstate commerce.

Approval of a biologics license application or issuance of a biologics license shall constitute a determination that the establishment(s) and the product meet applicable requirements to ensure continued safety, purity, and potency (21 CFR 601.2). The license number is issued for both the manufacturing site and the first product licensed for that site at the time of original licensing. The applicant may submit separate supplements to the BLA to manufacture additional products, to change manufacturing methods, or to include additional locations. The establishment that manufactures Source Plasma, Source Leukocytes and TEP must be maintained in a manner that meets CGMP and other standards (21 CFR 601.2, 601.4, and 601.20). The license number must appear on the container label (21 CFR 606.121(c)).

Licensed manufacturers must notify FDA about each change in the product, production process, quality control, equipment, facilities, responsible personnel, or labeling included in the approved license application (See 21 CFR 601.12 and the Guidance for Industry, “Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture, August 2001).” See: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm076729.htm

Under the provisions of Section 351 of the PHS Act and the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA investigators conduct inspections of blood establishments, including those that manufacture or participate in the manufacture of Source Plasma, Source Leukocytes, and TEP for further manufacturing use. Under the FD&C Act, Source Plasma, Source Leukocytes or TEP may have the legal identity of either a drug or a device depending on its intended use. However, Source Plasma, Source Leukocytes, and TEP are not finished pharmaceuticals or finished devices. Therefore, the requirements in the Current Good Manufacturing Practice for Finished Pharmaceuticals regulations at 21 CFR Parts 210 and 211, and the Quality System Regulation at 21 CFR 820 do not apply to these products. Rather, manufacturers of Source Plasma, Source Leukocytes, and TEP must comply with the applicable statutory CGMP requirements, the Current Good Manufacturing Practice for Blood and Blood Components requirements in 21 CFR 606 and other applicable regulations in 21 CFR Parts 600-680.

Statutory CGMP

Source Plasma, Source Leukocytes, and TEP are subject to the adulteration provision of Section 501(a)(2)(B) of the FD&C Act, which requires all drugs to be manufactured in conformance with CGMP. No distinction is made between these products and a finished pharmaceutical in the FD&C Act and the failure of either to comply with statutory CGMP constitutes a violation of the FD&C Act.

FDA has long recognized that the CGMP requirements in the good manufacturing practice regulations for finished pharmaceuticals (21 CFR Parts 210 and 211) are valid and applicable in concept to products for further manufacture into drug products. These concepts include, among others, building quality into the drug by using suitable equipment and employing appropriately qualified and trained personnel, establishing adequate written procedures and controls designed to assure manufacturing processes and controls are valid, and establishing a system of in-process material tests.

FDA expects Source Plasma, Source Leukocyte, and TEP manufacturers to apply statutory CGMPs to the manufacturing process beginning with donor screening.

FDA began the inspection of Source Plasma establishments in 1973. This compliance program builds upon the knowledge gained during previous FDA inspections of the industry and recent scientific developments. It provides a risk-based approach to the CGMP inspection of these establishments with focus on the operating systems present.

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PART II - IMPLEMENTATION

A. Objective

The objective of this program is to ensure that Source Plasma, Source Leukocytes, and TEP for further manufacture into products for human use are safe, pure, and potent, and appropriately labeled. FDA compliance and surveillance activities also assess compliance with donor protection standards which are intended to ensure a continuous and healthy donor population.

The inspection instructions in this program apply to the manufacture of Source Plasma, Source Leukocytes, and TEP. Manufacturers must:

  • Meet the CGMP For Blood and Blood Components requirements in 21 CFR Part 606 and other applicable regulations and standards in 21 CFR Parts 600-680;
  • Meet any additional conditions of licensure included in the manufacturer’s approved Biologic License Application; and
  • Meet the applicable statutory CGMP requirements in 501(a)(2)(B) of the FD&C Act

B. Strategy

This compliance program outlines a systems-based approach to conducting a CGMP inspection. It identifies five systems in the establishment’s operation for inspection. The inspection is a comprehensive evaluation of the critical areas in each system used by the establishment. Problems in the critical areas may adversely compromise a donor’s safety and/or affect product quality if procedures are not performed properly or system controls are inadequate or function incorrectly. The following systems have been identified:

  1. Quality Assurance System – the system for managing quality that encompasses the organizational structure, written procedures, processes and resources, as well as activities to ensure confidence that the product will meet its intended specifications for safety, purity, and potency.
  2. Donor Eligibility System – the system that protects the donor’s safety and product quality, determines donor eligibility for blood collection (including donor deferral resulting from either medical history screening and/or testing), and notifies the donor of ineligibility for donation.
  3. Product Testing System – the system that includes properly testing products collected for further manufacture for evidence of communicable disease agents consistent with 21 CFR 610.40.
  4. Product Collection and Processing System – the system that controls the collection and processing, including issues of product quality and donor safety.
  5. Quarantine/Storage/Disposition System - the system that manages product quarantine, storage, and distribution, and prevents release of unsuitable products (release for use or destruction).

Each of the five systems is discussed in detail in Attachments B – F.

The inspection is based on a multi-layered set of safeguards (referred to as the “five layers of safety”) related to the collection, manufacture, and distribution of blood and blood components, including Source Plasma, Source Leukocytes, and TEP. The five layers of safety are:

  1. Donor Screening – written procedures to identify donors who have one or more defined risk factors for one or more communicable diseases or who are otherwise ineligible to donate.
  2. Donor Deferral – written procedures to identify ineligible donors and prevent the distribution of blood products collected from these donors unless the donors participate in a special collection program.
  3. Product Testing – written procedures to properly test products for further manufacture for evidence of infection by specific communicable disease agents.
  4. Quarantining – written procedures to ensure that blood products are quarantined until all tests and control procedures are acceptable and unsuitable products are removed from inventory and destroyed or appropriately labeled and distributed; e.g., for use in research, test kit controls, etc.
  5. Monitoring and Investigating Problems – written procedures to identify system problems, biological product deviations, and donor adverse reactions.

Table 1 – Relationship of Layers of Safety to Systems

Each system in the inspectional approach relates to one or more of the “five layers of safety” as follows:

Layer of Safety

System(s)

Donor Screening

Donor Eligibility, Quality Assurance

Donor Deferral

Donor Eligibility, Quality Assurance

Product Testing

Product Testing, Quality Assurance, Product Collection and Processing

Quarantining

Quarantine/Storage/Disposition, Quality Assurance, Product Collection and Processing

Monitoring and Investigating Problems

Quality Assurance, Product Collection and Processing

The inspection is conducted under a Level 1 or Level 2 inspection option. Select and report the correct PAC code based on the level of inspection selected either 42002 F for Level 1 inspections or 42002 G for Level 2. See Part III, Inspection for selection criteria for Level 1 and Level 2 inspections.

C. Program Management Instructions

This program covers the following establishment types.

  1. Source Plasma Establishment

This is a facility holding an approved biologics license application for Source Plasma, as defined in 21 CFR 640.60. There may be multiple Source Plasma establishments (locations) operating under a single license. The Source Plasma establishment may also collect other blood and blood components for further manufacture, e.g., Source Leukocytes, TEP. Source Plasma establishments are required to register and submit a list of each product in commercial distribution (21 CFR 607.20(a)).

  1. Plasma Broker

An establishment or person that arranges the sale of Source Plasma, Source Leukocytes or TEP between other entities is a broker. A broker that takes possession of Source Plasma, Source Leukocytes or TEP and/or engages in any manufacturing step (e.g., pooling or re-labeling products, or making aliquots) must register and maintain appropriate records of the activities performed (21 CFR 607.20, 606.160). A broker that only arranges the sale or shipment of products must maintain records of the arrangement of the sale but is not required to register.

  1. Testing Laboratory

A laboratory that performs testing for an establishment manufacturing Source Plasma, Source Leukocytes or TEP; i.e., (1) required testing for evidence of a communicable disease agents, (2) donor eligibility testing including testing for donor re-entry, and (3) testing to support labeling claims related to product quality, must register with FDA and be either certified by the Centers for Medicare and Medicaid Services (CMS) to perform such testing, or have met equivalent requirements as determined by CMS (21 CFR 610.40(f) and 21 CFR Part 607).

  1. Contractor

Any person or entity that performs part or all of the steps in the manufacture of a licensed product or that performs a manufacturing step under contract as a service to the product manufacturer must register (21 CFR 607.20).

  1. Off-Site Storage Facility

An off-site storage facility that performs manufacturing operations, such as culling and quarantining products prepared for distribution, repackaging or relabeling product must register (21 CFR 607.20), and maintain appropriate records of those operations.

An off-site facility that only stores products under specific controlled conditions, prior to shipment to a final user(s), e.g., temporary storage pending approval of a license application / supplement and distribution, is not required to register, but must still maintain records (21 CFR Part 606).

  1. Other Blood Establishments

Some licensed blood banks also manufacture Source Plasma, Source Leukocytes and or TEP for further manufacture. These blood establishments are required to register and list all products, including blood components for transfusion (e.g. Platelets) and for further manufacture (e.g. Source Plasma).

Investigators can review current registration information for active, inactive and pre-registered establishments by accessing the CBER Blood Establishment Registration database.

D. Frequency and Scheduling of CGMP Inspections

CGMP inspections are statutory obligations that are generally conducted on a biennial schedule (based upon the previous date of inspection). ORA and CBER jointly develop the annual inspection workplan. District office staff schedule CGMP inspections of domestic establishments according to the ORA workplan.

The following are exceptions to the required biennial inspection:

  1. A firm or establishment location under a Notice of Intent to Revoke and/or other administrative action, or a compliance follow-up inspection to verify an establishment’s implementation of corrective action after any other regulatory action. Inspection frequency is determined by district compliance officer in these situations.
  2. Firms under a Consent Decree of Permanent Injunction
  3. A for-cause inspection.
  4. A facility that does not engage in manufacturing, e.g., a broker that only arranges the sale or shipment of products is inspected at the district’s discretion or for cause.
  5. An establishment that changes location should be inspected within 60-90 days of the change or as soon as district work plans permit.
  6. A Pre-License (PLI) or Pre-Approval inspection (PAI).*

* Note: CBER schedules all PLI and PAI inspections when appropriate. CBER and Office of Regulatory Affairs (ORA) often jointly conduct PLI and PAI inspections with CBER as the lead. On occasion, CBER may request that ORA conduct the PLI or PAI inspection. PLI and PAI inspections are part of the review of a biologics license application or supplement. CBER identifies the scope and content of the inspection.

E. Assignment of Investigators and Compliance Personnel

Whenever possible, only Investigators who completed the required Blood Banking and Plasmapheresis training course(s) should inspect establishments covered under this program.

Whenever possible, only Compliance Officers who completed the required Blood Banking and Plasmapheresis training course(s) should process compliance recommendations.

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PART III - INSPECTION

A. Strategy

This program provides two inspection options, Level 1 and Level 2. Both levels satisfy the biennial inspection requirement.

Inspect each system to the extent necessary to determine whether the establishment complies with applicable laws and regulations. The systems for coverage are Quality Assurance, Donor Eligibility, Product Testing, Product Collection and Processing, and Quarantine/Storage/Disposition. The inspection should extend to the critical areas of written procedures, personnel/training, facilities, equipment, records, and use of computers for each system inspected (see Attachment A for general instructions for all inspections). The inspection should include actual observation of the processes applicable to the system, whenever possible.

B. Inspection Options

  1. Level 1 Inspection Option .

The Level 1 Option is a comprehensive evaluation of an establishment's compliance and is a comprehensive inspection of all systems employed at the establishment. Select the Level 1 option for:

  • Initial inspection of an establishment by district investigators
  • Compliance follow up inspections
  • Establishments that have a history of inconsistent compliance
  • After conducting two previous inspections under a Level 2 option

If an establishment has less than 5 systems, inspection of all systems present will be considered a Level 1 inspection. For example, a testing laboratory may generally only have two systems present, quality assurance and testing. Inspections of these facilities will be considered comprehensive and will be reported as Level 1 inspections.

  1. Level 2 Inspection Option .

The Level 2 option is a streamlined evaluation of an establishment’s compliance and is a comprehensive inspection of two of the systems existing at the establishment. For example, most establishments collecting Source Plasma, Source Leukocytes and TEP do not perform their own communicable disease testing. Therefore, the systems selected for coverage would be selected from the four remaining systems. The district determines the two systems to be covered after reviewing the establishment's file, evaluating the inspection history and assessing biologic product deviation reports, product recalls and other available information pertaining to the establishment. District program managers and investigators should make certain that coverage of the two systems under the Level 2 option are rotated in successive inspections, unless otherwise indicated.

Select the Level 2 Option when all the following conditions are met:

  • The establishment has a satisfactory history of compliance (two successive NAI or VAI CGMP inspections), AND
  • One of the two previous routine inspections was a Level 1 inspection, AND
  • The inspection preparation revealed no specific trends that may have a significant impact on product or donor safety, as identified during reviews of previous EIRs, product recalls, complaints, biological product deviation reports, or fatality reports,

Finding significant objectionable conditions while conducting a Level 2 inspection may indicate a need to perform a comprehensive Level 1 inspection. Include in the EIR and in the FACTS coversheet the level of inspection (1 or 2) performed, for Level 2 include the systems selected for inspection. If the inspection level was changed from Level 2 to Level 1, include the reason the change was made.

C. FDA 483 Observations

In accordance with IOM section 5.2.3, reportable observations on an FDA 483 include factual observations of significant deviations from the FD&C Act (21 U.S.C. 301), PHS Act, 21 CFR, and other acts where FDA has enforcement authority. This includes observations where establishments fail to comply with regulations for CGMP at 21 CFR Part 606, the general requirements for biological products in 21 CFR Part 600, the general biological products standards in 21 CFR Part 610 and the additional standards for human blood and blood products in 21 CFR Part 640.

Source Plasma, Source Leukocytes and TEP are products which are not considered finished pharmaceuticals or finished devices; rather, they are source material for further manufacture into either injectable or non injectable products. Therefore, the requirements in 21 CFR Parts 210 and 211, and 21 CFR 820 do not apply to these products.

However, manufacturers of Source Plasma, Source Leukocytes, and TEP are expected to establish, document, and implement an effective system for managing quality, as well as adequate controls over computer systems, that ensure compliance with Section 501(a)(2)(B) of the FD&C Act “statutory CGMP.”

  • For inspectional observations relating to responsibilities of the quality control unit, refer to the FD&C Act, Section 501(a)(2)(B) (U.S.C.351(a)(2)(B)) if the observations are not specifically associated with provisions in 21 CFR Parts 600-680.
  • For inspectional observations relating to automatic, mechanical, and electronic equipment (including computer system observations), refer to the FD&C Act, Section 501(a)(2)(B) if the observations are not specifically associated with provisions in 21 CFR Parts 600-680.

NOTE: Turbo EIR should not be used to create a FDA 483 during an inspection where there are observations relating to the quality control unit or computer systems, because a statutory GMP cite module in Turbo EIR does not currently exist (and the relevant 21 CFR Part 211 Turbo cites cannot be used because 21 CFR Part 211 does not apply to these products). Investigators should approach observations relating to the quality control unit or computer systems in the same manner as they do for other program areas where Turbo EIR cannot be used to generate the 483, and describe the observation in accordance with IOM instructions (e.g. include significant objectionable conditions, relating to products and/or processes, or other violations of the FD&C Act and related Acts which were observed during the inspection (see IOM 5.2.3))

D. Inspection Instructions

Instructions for coverage within each of the five (5) systems for inspection are included in the following attachments:

  • Attachment A - General Instruction for All Inspections
  • Attachment B - Quality Assurance System (QA)
  • Attachment C - Donor Eligibility System
  • Attachment D - Product Testing System
  • Attachment E - Product Collection and Processing System
  • Attachment F - Quarantine/Storage/ Disposition System
  • Additional instructions for coverage of specific products or establishments are included in the following attachments:
  • Attachment G - Special Source Plasma Collection Programs
  • Attachment H - Specific Instructions for Donors of Source Leukocytes and Therapeutic Exchange Plasma
  • Attachment I - Brokers
  • Attachment J - Contractors

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PART IV - ANALYTICAL

No physical sample collections are planned under this program.

If sample collection is necessary, specific instructions will be provided. Consult with CBER program contacts identified in Part VI, and before collecting samples for agency analysis, except for documentary samples for interstate commerce (collect a documentary sample in accordance with IOM 4.1.4.2, “Documentary Samples” to support regulatory/administrative action).

Contact the CBER Sample Custodian (301-594-6517) before shipping any samples to CBER. No one is available to receive samples over the weekend. All samples collected under this program will be shipped to:

Center for Biologics Evaluation and Research
Attention: Sample Custodian, HFM-672
5516 Nicholson Lane, Building B, Room 113
Kensington, MD 20895

Collect any samples of a potentially bio-hazardous nature in accordance with IOM 1.5.5.

Original results of analyses will be forwarded to the home district of the involved facility, with a copy to CBER/OCBQ/DCM, HFM-610. Investigators should enter information into FACTS per IOM 4.4.10.3, Preparation of Collection Report, and designate in the collection remarks, to whom the sample results should be forwarded.

Copies of collection reports for physical samples must be submitted to CBER/OCBQ/DCM, HFM-610.

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PART V - REGULATORY/ADMINISTRATIVE STRATEGY

When inspection findings demonstrate that a manufacturer of Source Plasma, Source Leukocytes, or TEP is not operating in a state of control and/or the establishment’s management is either unwilling or unable to implement adequate corrections in a timely manner, districts should consider the advisory, administrative and/or judicial options currently available. A firm is considered to be operating in a state-of-control when it employs conditions and practices that ensure compliance with the intent of Section 501(a)(2)(B) of the FD&C Act, and the portions of the CGMP regulations that pertain to its systems. A firm in a state of control produces products for which there is an adequate level of assurance of quality, identity, purity and potency.

The district office should base all regulatory recommendations on significant deviations that are well documented. The quality of any action begins with the quality of evidence collected at the time of the inspection to support the observed objectionable conditions. The recognition, collection, and effective presentation of evidence are essential to successful advisory, administrative, and judicial actions. The identification of those responsible for violations is also a critical part of the inspection. Establish responsibility and identify persons to hold accountable for violations, and with whom the Agency must communicate to seek lasting corrections and/or to be the subject of enforcement actions. The decision on the type of action to recommend should be based on the seriousness of the documented deficiencies with regard to, and the most effective way to protect, public health.

A firm’s written corrective action, in response to the FDA-483, should not preclude the consideration of an advisory, administrative, or judicial action. Please refer to the FDA Regulatory Procedures Manual (RPM) Procedures for Clearing FDA Warning Letters and Untitled Letters dated March 2010, regarding the clearance process and review of a firm’s response to an FDA-483. Recommend such action, if the objectionable observations represent (a) a continuing pattern of non-compliance, (b) a failure to correct significant deficiencies noted during a previous inspection, or (c) the deficiencies pose a significant threat to the public health, and voluntary action is either not appropriate or can not be readily accomplished.

For products intended for further manufacture, the advisory, administrative, and judicial options available include:

Action

Among other things, consider if,

Warning Letter

Violations of regulatory significance that cause one or more systems to be considered not in a state of control.

License Revocation

21 CFR 601.5

Notice of Intent to Revoke with Opportunity for Correction:

  • Unable to gain access to the manufacturing facility for inspection.
  • Licensed products are not safe or effective for their intended use, or are misbranded with respect to any such use.
  • Manufacturer fails to report a change in accordance with 21 CFR 601.12.
  • Manufacturer fails to conform to applicable standards to ensure product safety, potency, and purity.
  • Licensed products are no longer manufactured.
Direct Revocation without Opportunity for Correction
  • Demonstration of willful disregard.
License Suspension 21 CFR 601.6

 

Reasonable grounds for revocation and a danger to health exist. It provides immediate withdrawal of the authorization to ship a biological product in interstate commerce.

Seizure

Manufacturer is unwilling or unable to retrieve violative products or products held for sale are unsuitable for safe use. U.S. Marshal takes possession of products through Court Order pursuant to Section 304 of the FD&C Act.

Injunction

A current health hazard exists, the establishment has a history of uncorrected deviations despite previous warnings, suspension of the firm’s license would result in an unacceptable shortage of products, and/or to halt intrastate distribution of products manufactured under violative conditions.

Prosecution

Fraud; gross, flagrant, intentional violations; or a continuous or repeated course of violative conduct.

Districts should initially consider an advisory action, such as a warning letter, if there is no previous violative history at the firm.

To determine the appropriate action, consult with CBER/Office of Compliance and Biologics Quality (OCBQ)/Division of Case Management (HFM-610), early in the inspection, and consult the RPM. This early consultation is especially critical when immediate action is indicated (e.g., license suspension or temporary restraining order (TRO)). See RPM Chapter 6, regarding TROs and an injunction to protect the public health. When inspection findings indicate the potential for fraud (e.g., falsification, counterfeiting, illegal importation, drug diversion), the investigator should notify his/her supervisor, who will notify CBER/OCBQ. District management will alert the appropriate Office of Criminal Investigations Office, as appropriate. The investigator should, however, continue to pursue any public health concerns, in coordination with CBER/OCBQ, concurrently.

Evidence of significant and /or a pattern of deficiencies (history) within a system covered could constitute failure of that system. The district should classify as Official Action Indicated, an inspection report that documents one or more systems as not in a state of control. The district should then consider a Warning Letter or other appropriate action. When deciding the type of action to recommend, follow the RPM and base the initial decision on the seriousness and /or frequency of the problem and the firm’s compliance history.

Districts may issue Warning Letters per RPM Chapter 4, to achieve voluntary compliance and establish prior notice. The RPM outlines the types of letters requiring CBER concurrence prior to issuance.

A. Deficiencies

The following, although not all-inclusive, are examples of deficiencies that may be indicative of the firm’s state-of-control:

1. General

  1. Any practice or pattern of practices that poses a danger to public health and warrants grounds for license revocation (21 CFR 601.6(a))
  2. Failure to provide adequate facilities and to maintain them in a clean and orderly manner (21 CFR 606.40)
  3. Failure of a licensed establishment to notify CBER of any change that has a substantial potential to have an adverse effect on the product as it relates to the safety or effectiveness of the product (21 CFR 601.12(b))
  4. Falsifying, changing or altering product labels or records (42 U.S.C. 262(b) 21 CFR 606.160; 640.70; 640.72)
  5. Any failure to completely identify the container or laboratory samples so they can be correlated to the individual donor (21 CFR 606.140(c); 606.160(c); 640.72(a)(2))
  6. Failure of the physician to be physically on premises during red blood cell immunizations (21 CFR 640.62)
  7. Personnel lacking educational background, experience, or training in the operations they perform to such an extent that a danger to the health of the donor or safety of the product exists (21 CFR 606.20 and 640.64(a))
  8. Failure to maintain, standardize, calibrate, and follow established written procedures for equipment used in the collection, processing, testing, storage, and distribution of Source Plasma (21 CFR 606.60)
  9. Inadequate supervision (21 CFR 640.62)

2. Quality Assurance System

  1. Failure to thoroughly investigate and incorporate appropriate corrections concerning any unexplained discrepancy or the failure of a lot or a unit to meet specifications that may affect the safety, purity, or potency of the product (21 CFR 606.100(c))
  2. Unapproved major changes in manufacturing methods (21 CFR 601.12)

3. Donor Eligibility System

  1. Failure to establish a donor identification system that confirms donor identity and correlates medical records, test results, and components to the donor record (21CFR 640.65(b)(3); 640.72(a)(2))
  2. Any personnel or system failure that causes the establishment to accept or inappropriately re-enter ineligible donors (21 CFR 610.41(a) and (b))
  3. Failure to establish or repeated failure to follow SOPs for donor eligibility determinations (21 CFR 606.100(b)(1) and (2); 640.63)
  4. Failure to explain hazards or risks of procedure by a physician or designee, to obtain a signed informed consent form, or implement appropriate safeguards to minimize the potential for transmission of unexpected infectious agents (21 CFR 606.160(b)(1)(v), 606.100(b), 640.61 and CPG 250.100)
  5. Failure to properly determine the suitability of the donor (e.g., routine physical examinations, medical history questions, hemoglobin, blood pressure, temperature, total protein, plasma or serum protein electrophoresis or quantitative immuno-diffusion or equivalent test to determine immunoglobulin composition) (21 CFR. 640.63, 640.65(b)(1)(i), 640.65(b)(2)(i), and 606.20(b))
  6. Failure to perform and adequately document physician’s review of laboratory and collection records (21 CFR 640.65(b)(2))
  7. Failure to have a licensed physician perform physical examinations for immunization, unless approved as an alternative procedure under 21 CFR 640.120 (21 CFR 640.63 (b)(2)(i))
  8. Failure to maintain accurate records that identify unsuitable donors so that the establishment will not distribute products from such individuals (21 CFR 606.160 (b)(1) and (e))
  9. Pattern of failure to make a reasonable attempt to notify donors of deferral status (21 CFR 630.6)
  10. A physician substitute (PS) supervising an immunization program prior to receiving appropriate training and / or an individual performing the duties of a PS prior to CBER approval of a Source Plasma establishment’s PS training program (21 CFR 606.20(b) and 640.66)
  11. Duplicate, discrepant, or invalid records existing in the computer's donor deferral files that could lead to the acceptance of unsuitable donors and release of unsuitable products. (21 CFR 606.160(b), 606.100(c))
  12. Failure to immunize donors by acceptable procedure(s) and/or use approved antigens (21 CFR 640.66)
  13. Failure to establish written procedures and maintain adequate records for an immunization program (21CFR 606.160(a)(1); 640.66; CPG 250.100)

4. Product Testing System

  1. Any failure to perform communicable disease testing (21 CFR 610.40 and 640.65 and 640.67)
  2. Failure to perform tests or interpret results according to manufacturers' instructions and specifications; e.g., use of outdated reagents or mixing of reagents from different master lots; failure to run the proper number of controls concurrently with the test; inappropriate invalidation of test results; calculations incorrectly determined resulting in reactive results being interpreted as nonreactive; interpreting reactive test results as nonreactive; and failure to conduct necessary retests. (21CFR 610.40, and 606.65(e))
  3. Communicable disease tests not performed using an approved or licensed test kit or otherwise allowed in 21 CFR 610.40.
  4. Incomplete or inaccurate testing records, including all records associated with invalidated test runs (21 CFR 606.160(b)(2)(i); 640.72(a)(2))

5. Quarantine/Storage/Disposition System

  1. Source Plasma and/or other products for further manufacture not stored at proper temperature (21 CFR 610.53, 640.69(b), 640.74)
  2. Failure to maintain temperature records when Source Plasma is in storage or shipped. (21 CFR 606.160(b)(3)(iii); 640.72(a)(1))
  3. Failure to utilize final containers that adequately protect against external factors that may cause deterioration or contamination (21 CFR 640.68(b))
  4. Failure to establish or follow a system that prevents the distribution of any products not suitable for use (606.100(b); 606.160(e); and 610.40 (h))
  5. Failure to obtain CBER approval to ship product that is not tested for communicable disease agents required in 21 CFR 610.40.
  6. Failure to establish or follow a system by which receipt and distribution of each unit of Source Plasma can be readily determined to facilitate recall, if necessary (21 CFR 606.165(a))
  7. Failure to quarantine unsuitable products or to notify consignees in accordance with 21 CFR 610.46(a)

6. Product Collection and Processing System

  1. Failure to collect Source Plasma by methods that protect against contamination of the returned red blood cells (21 CFR 640.64(b) and (e))
  2. Failure to follow equipment manufacturer’s instructions for plasmapheresis procedures (21 CFR 640.65, 606.60)
  3. Failure to use approved containers for the collection of Source Plasma (21 CFR 640.68(b))
  4. Failure to maintain complete and accurate processing records (21 CFR 606.160(a)(1), (b)(2); 640.72)
  5. Failure to properly label blood components (21 CFR 610.62 and 640.70)
  6. Failure to record whole blood weights in manual collection and to recognize and/or correct overbleeding in manual or automated collection procedures (21 CFR 640.65(b)(4)(5)(6) and (8) and 606.160(a)(1)
  7. Failure to prevent the infusion of one donor’s red blood cells into another donor (21 CFR 640.65(b)(3) and 606.100(b)(17))
  8. Failure to recognize, adequately respond to, and investigate adverse reactions and document and maintain appropriate records (21 CFR 606.170(a) and 606.100(b)(9))
  9. Failure to advise CBER of fatalities resulting from complications related to blood collection and failure to investigate (21 CFR 606.170(b))

B. Federal / State Relations

Currently FDA has no formal cooperative program with state or local jurisdictions to inspect or regulate Source Plasma, Source Leukocyte, or TEP establishments. Nonetheless, districts should cooperate with these authorities, especially if the state or local jurisdiction has a regulatory program. Whenever possible, districts should exchange information with all levels of government consistent with information disclosure procedures. Provide a copy of a warning letter to the appropriate state agency or agencies. If a state official requests a copy of the Form FDA-483, redact the document according to FOI procedures prior to release. For additional assistance, contact the Office of Regulatory Affairs/Division of Federal State Relations (HFC-150) at (301) 796-5955).

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PART VI REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS

A. Laws and Regulations

Federal Food, Drug, and Cosmetic Act as Amended and Related Laws.
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/default.htm

Public Health Service Act, Subpart I - Biological Products
 

Title 21, Code of Federal Regulations, Parts 600-680. http://www.gpoaccess.gov/cfr/index.html

B. ORA Inspection Manuals and Guides

FDA Investigations Operations Manual, March 2010 or latest edition. Sections 500-529, 560-565, 590-595, 635, 773, 921, 924, 927-928, 1026 http://www.fda.gov/ora/inspect_ref/iom

FDA Regulatory Procedures Manual (RPM), March 2010 or latest edition. Chapter 4 – Advisory Actions, Chapter 5- Administrative Actions, Chapter 6 – Judicial Actions, Chapter 7 – Recall and Emergency Procedures, Chapter 9 – Import Operations/Actions. http://www.fda.gov/ora/compliance_ref/rpm

FDA Compliance Policy Guides, August 2000 or latest edition, Chapter 1 - General and Chapter 2 – Biologics.
http://www.fda.gov/ora/compliance_ref/cpg/default.htm

C. Guidance Documents and Memoranda

Note: This list is not all-inclusive. Agency guidance may be updated at any time. Consult CBER’s web page for a complete and current listing of guidance documents.

Donor Eligibility

Guidance for Industry: Implementation of Acceptable Full-Length Donor History Questionnaire and Accompanying Materials for Use in Screening Donors of Blood and Blood Components (October 2006)

FEDERAL REGISTER NOTICE: Guidance for Industry: Discontinuation of Donor Deferral Related to Recent Fever with Headache as a Symptom of West Nile Virus Infection; Withdrawal of Guidance, June 30, 2005, 70 FR 37864, (see: http://www.gpoaccess.gov/fr/browse.html)

Guidance for Industry: Revised Recommendations for the Assessment of Donor Suitability and Blood Product Safety in Cases of Suspected Severe Acute Respiratory Syndrome (SARS) or Exposure to SARS, September 16, 2003

Guidance for Industry: Recommendations for the Assessment of Donor Suitability and Blood Product Safety in Cases of Suspected Severe Acute Respiratory Syndrome (SARS) or Exposure to SARS, April 2003

Question and Answer on FDA Guidance Entitled “Recommendations for The Assessment of Donor Suitability and Blood and Blood Product Safety in Cases of Suspected and Probable Severe Acute Respiratory Syndrome (SARS) or Exposure to SARS,” June 5, 2003.

Guidance for Industry: Recommendations for Deferral of Donors and Quarantine and Retrieval of Blood and Blood Products in Recent Recipients of Smallpox Vaccine (Vaccinia Virus) and Certain Contacts of Smallpox Vaccine Recipients, December 30, 2002.

Questions and Answers on FDA Guidance Entitled “Recommendations for Deferral of Donors and Quarantine and Retrieval of Blood and blood Products in Recent Recipients of Smallpox Vaccine (Vaccinia Virus) and Certain Contacts of Smallpox Vaccine Recipients”

Guidance for Industry: Recommendations for Assessment of Donor Suitability and Blood Product Safety in Cases of Possible Exposure to Anthrax, October 17, 2001.

Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products, January 2002.

Donor Deferral Due to Red Blood Cell Loss During Collection of Source Plasma by Automated Plasmapheresis, December 4, 1995.

Recommendations for the Deferral of Current and Recent Inmates of Correctional Institutions as Donors of Whole Blood, Blood Components, Source Leukocytes, and Source Plasma, June 8, 1995.

Deferral of Blood and Plasma Donors Based on Medications, July 28, 1993.

Revised Recommendations for the Prevention of Human Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products, April 23, 1992.

Source Plasma Collection and Special Programs

Revised Recommendations for Red Blood Cell Immunization Programs for Source Plasma Donors, March 14, 1995.

Revision of FDA Memorandum of August 27, 1982: Requirements for Infrequent Plasmapheresis Donors, March 10, 1995.
 

Volume Limits for Automated Collection of Source Plasma, November 4, 1992.

Revisions to 26 October 1989 Guideline for Collection of Blood or Blood Products from Donors with Positive Tests for Infectious Disease Markers (“High Risk” Donors), April 17, 1991.

Guideline for Collection of Blood or Blood Products from Donors with Positive Tests for Infectious Disease Markers (“High Risk” Donors), September 1989.

Extension of Dating Period for Storage of Red Blood Cells, Frozen, December 4, 1987.

Plasma Derived from Therapeutic Plasma Exchange, December 14, 1984.

Guidelines for the Collection of Human Leukocytes for Further Manufacturing (Source Leukocytes), January 28, 1981.

Guidelines for Immunization of Source Plasma (Human) Donors with Blood Substances, June 1980.

Infectious Diseases

Guidance for Industry: Requalification Method for Reentry of Blood Donors Deferred Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (Anti-HBc) (May 2010)

Guidance for Industry: Adequate and Appropriate Donor Screening Tests for Hepatitis B; Hepatitis B Surface Antigen (HBsAg) Assays Used to Test Donors of Whole Blood and Blood Components, Including Source Plasma and Source Leukocytes (11/21/07 – Updated July 2007)

Guidance for Industry: “Lookback” for Hepatitis C Virus (HCV): Product Quarantine, Consignee Notification, Further Testing, Product Disposition, and Notification of Transfusion Recipients Based on Donor test Results Indicating Infection with HCV (8/24/07) http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073170.htm

Guidance for Industry: Use of Nucleic Acid Tests on Pooled and Individual Samples from Donors of Whole Blood and Blood Components (including Source Plasma and Source Leukocytes) to Adequately and Appropriately Reduce the Risk of Transmission of HIV-1 and HCV, October 21, 2004.

Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (CJD) by Blood and Blood Products, January 9, 2002. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm074089.htm

Questions and Answers on FDA Guidance Entitled Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob (CJD) Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products. Last updated 1/22/04.

Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV -1) Group O Infection, August 2009

Additional Recommendations for Testing Whole Blood, Blood Components, Source Plasma and Source Leukocytes for Antibody to Hepatitis C Virus Encoded Antigen (Anti-HCV), May 16, 1996.

Clarification of the Use of Unlicensed Anti-HCV Supplemental Test Results in Regard to Donor Notification, August 19, 1993.

Revised Recommendations for Testing Whole Blood, Blood Components, Source Plasma and Source Leukocytes for Antibody to Hepatitis C Virus Encoded Antigen (Anti-HCV), August 5, 1993.

Revised Recommendations for the Prevention of Human Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products, April 23, 1992.

Use of Fluorognost HIV-1 Immunofluorescent Assay (IFA), April 23, 1992.

Use of Genetic Systems HIV-2 EIA, June 21, 1990.

HTLV-1 Antibody Testing (to Licensed Source Plasma Manufacturers Approved for Immunization with Red Blood Cells) July 6, 1989.

Recommendations for the Management of Donors and Units that are Initially Reactive for Hepatitis B Surface Antigen (HBSAG), December 2, 1987.

Inspections

Discontinuance of Pre-License Inspection of Immunization Using Licensed Tetanus Toxoid and Hepatitis B and Rabies Vaccine, July 7, 1988.

Control of Unsuitable Blood and Blood Components, April 6, 1988.

Labeling

Guidance for Industry: Recognition and Use of a Standard for Uniform Blood and Blood Component Container Labels (9/22/06)

Guidance for Industry: United States Industry Consensus Standard for the Uniform Labeling of Blood and Blood Components Using ISBT 128 (9/22/06)

Miscellaneous

Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics (12/4/08)

Guidance for Industry: Informed Consent Recommendations for Source Plasma Donors Participating in Plasmapheresis and Immunization Programs (6/20/07)

Guidance for Industry: Biological Product Deviation Reporting for Blood and Plasma Establishments (10/18/06)

Guidance for Industry: Implementing a Collection Program for Source Plasma Containing Disease-Associated and Other Immunoglobulin (IgG) Antibodies (8/8/06)

Guidance for Industry and FDA Staff: Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, May 12, 2005.

Guidance for Industry: Notifying FDA of Fatalities Related to Blood Collection or Transfusion, September 22, 2003.

Guidance for Industry: Streamlining the Donor Interview Processes: Recommendations for Self-Administered Questionnaires, July 3, 2003.

Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture, August 7, 2001.

Guidance for Industry: Revised Recommendations Regarding Invalidation of Test Results of Licensed and 510(k) Cleared Bloodborne Pathogen Assays Used to Test Donors, July 11, 2001.

FDA Guidance for Industry: Exports Under the FDA Export Reform and Enhancement Act of 1996, July 23, 2007.

Revised Recommendations for Red Blood Cell Immunization Programs for Source Plasma, March 14, 1995.

Guidance Regarding Post Donation Information Reports, December 10, 1993.

Physician Substitutes, August 15, 1988.

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, May 10, 1999.

Computers

Draft Guidance for Industry: Blood Establishment Computer System Validation in the User’s Facility October 2007

Guidance for Industry: Part 11, Electronic Records; Electronic Signatures – Scope and Application, August 2003.

General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 11, 2002.

Reviewer Guidance for a Pre-market Notification Submission for Blood Establishment Computer Software, January 13, 1997.

Guidance for Industry Process Validation: General Principles and Practices, January 2011.  

PART VI- REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS

D. CENTER FOR BIOLOGICS EVALUATION AND RESEARCH AND OFFICE OF REGULATORY AFFAIRS PROGRAM CONTACTS

OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY, HFM-600

1. Immediate Office of the Director, HFM-600

Anita Richardson, 301-827-6190, FAX 301-827-3381
General Policy Issues

2. Division of Case Management, HFM-610

Robert Sausville,Director, 301-827-6201, FAX 301-594-0940

Advertising and Promotional Labeling; Application Integrity; Biological Product Recalls; Certificates of Export; Citations; Civil Money Penalties; Compliance Status Checks; Debarment; Import/Export Programs; Injunctions; License Suspensions; Prosecutions; Revocations and Denials; Seizures; Tissue Recall Orders; Warning Letters

Blood and Tissue Compliance Branch, HFM-614

Stephany Wesley, Branch Chief 301-827-6201, FAX 301-594-0940

3. Division of Inspections and Surveillance, HFM-650

Gilliam Conley, Director 301-827-6220, FAX: 301-827-6748
Program Surveillance Branch, HFM-654

Janet Ishimoto, Chief, 301-827-9094

Sharon O’Callaghan
Susan Cannon
Biological Product Deviations Fatality Program

Transfusion/Donation Fatality Reporting
Email: fatalities2@fda.hhs.gov
Voice Mail: 301-827-6220
FAX: 301-827-6748 
 

OFFICE OF BLOOD RESEARCH AND REVIEW, HFM-300

1. Division of Blood Applications, HFM-370

Director, 301-827-3524, FAX: 301-827-3535

Deputy Director, 301-827-3524, FAX: 301-827-3535

Blood Registration Coordinator
Janet O’Brien 301-827-3546
bloodregis@fda.hhs.gov

Registration, Licensing, Labeling, Variances, Approvals for Changes

Blood and Plasma Branch, HFM-375

Leslie Holness, MD, BranchChief, 301-827-3543, FAX: 301-827-3534

OFFICE OF REGIONAL OPERATIONS (ORO)/OFFICE OF REGULATORY AFFAIRS (ORA) CONTACTS

ORO/ORA/Division of Domestic Field Investigations, DDFI, HFC-130

David Glasgow, Director, 301-796-5403
Mary Carden, National Expert, 716-541-0352
Gail Katz, (Biologics Group) 301-796-5410

ORO/ORA/Division of Foreign Field Investigations, DFFI, HFC-130
Ann Marie Montemurro, Director, 301-796-5521

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PART VII - CENTER FOR BIOLOGICS EVALUATION AND RESEARCH RESPONSIBILITIES

The Center for Biologics Evaluation and Research (CBER), through its Office of Compliance and Biologics Quality (OCBQ)/Division of Inspections and Surveillance (DIS), works cooperatively with the Office of Regulatory Affairs (ORA) Biological Products Field Committee to monitor the inspection and compliance accomplishments under this compliance program, and the status of the establishments inspected under this program. The ORA annual workplan, developed by CBER and ORA, provides overall resource allocations and anticipated numbers of inspections. However, current industry practices encountered during an inspection, the past compliance history of an establishment, or other compliance developments, may necessarily result in unplanned inspections or in individual CGMP inspections taking more or less time than estimated in the workplan.

ORA continues to have the primary responsibility for ensuring (1) that the program strategies, priorities, and procedures articulated in this compliance program are followed by the ORA Field staff and (2) that potential problems or needs for policy/program clarification are brought to CBER's attention. CBER and ORA jointly coordinate activities to achieve industry compliance with applicable laws, regulations, and court orders (e.g., Consent Decrees of Permanent Injunction).

CBER/OCBQ will continue to use accomplishment data from the ORA Field Accomplishment and Compliance Tracking System (FACTS), legal or administrative action recommendations, requests for policy decisions/clarification received from the public or the blood industry, and input from CBER scientific and product experts to provide overall direction to FDA's blood safety initiatives that are supported by this risk-based compliance program.

CBER/OCBQ will send to the appropriate district Director of Investigation Branch email attachments containing approved changes to biologic license applications.

The Biological Products Field Committee and the OCBQ/DIS intend to have periodic conference calls concerning this program and an annual meeting, with other ORA and CBER units (e.g., CBER Office of Blood Research and Review) participating as necessary.

CBER/OCBQ will carefully evaluate the experience with this systems-based inspection program through inspection reports and other compliance data to determine its effectiveness and to continually assess and improve the quality of the CBER products inspection program. CBER/OCBQ also will carefully review and monitor industry compliance, product developments within industry, and the safety and quality of Source Plasma.

CBER’s Office of Blood Research and Review (OBRR) reviews applications and related documents and will advise on the establishment's licensure status. OBRR also provides advice, as needed, on technical and scientific issues. Upon request, OBRR carefully evaluates donor safety and/or product quality deviations and provides written Health Hazard Evaluations (HHEs) for violative products and practices.

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ATTACHMENT A

GENERAL INSTRUCTIONS FOR ALL INSPECTIONS

Evaluate the following critical areas of Current Good Manufacturing Practice for each system selected for inspection:

  1. Standard Operating Procedures (SOPs)

The establishment shall maintain written SOPs that include all steps to be followed in the collection, processing, labeling, storage and distribution of products. SOPs shall be available to personnel in the areas where they perform such operations (21 CFR 606.100).

  1. Training and Personnel

The personnel responsible for the collection, processing, storage, or distribution of Source Plasma, Source Leukocytes and TEP shall be adequate in number, educational background, training and experience, including professional training as necessary, or a combination thereof, to ensure competent performance of assigned functions and to ensure that the final product has the safety, purity, potency, identity, and effectiveness it purports or is represented to possess (21 CFR 606.20).

  1. Facilities

Facilities shall be maintained in a clean and orderly manner and shall be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The facility must comply with the requirements of 21 CFR 606.40, including providing adequate space for private and accurate examinations of individuals to determine their suitability as donors.

  1. Equipment, Supplies, and Reagents

Equipment used in the collection, processing, storage, and distribution of Source Plasma, TEP and Source Leukocytes shall be maintained in a clean and orderly manner and located so as to facilitate cleaning and maintenance. The equipment shall be observed, standardized and calibrated on a regularly scheduled basis, as prescribed in the SOP manual. The equipment shall also perform in the manner for which it was designed so as to ensure compliance with the official requirements for Source Plasma manufacture (21 CFR 606.60). All supplies and reagents used in the collection, processing, compatibility testing, storage and distribution of blood and blood components must be stored in an orderly manner and used in a manner consistent with the instructions provided by the manufacturer (21 CFR 606.65).

  1. Records

The establishment must maintain records concurrently with the performance of each significant step in collecting, processing, quarantining, storing, and distributing each unit of blood and blood components so that all steps can be clearly traced (21 CFR 606.160). All records shall be legible and indelible and shall identify the person performing the work, including dates of the various entries, test results as well as interpretation of the result; the expiration date assigned to the specific product; and shall be as detailed as necessary to provide a complete history of the work performed (21 CFR 606.160). Each donor must have a separate and complete record that is cross-referenced to the Source Plasma, Source Leukocyte or TEP units collected from the donor (21 CFR 640.72). The establishment may maintain records as hard copies or electronic documents, or a combination of both.

  1. Changes to an Approved Application

For every inspection, assess any major or minor changes (e.g. significant change to manufacturing processes or manufacture of a new product) since the prior routine inspection.

  • Biological Product Deviations (BPD)

Prior to conducting an inspection, investigators should review the establishment’s BPD submissions in CEARS. ORA investigators have direct access to BPD information through CEARS (CBER Error and Accident Reporting System). Instructions for accessing the system are posted on the CEARS Intranet web page. Deviation codes may indicate systems that the investigator will want to examine more closely for patterns or trends. Otherwise, evaluate all BPD relevant to the systems selected for inspection and determine the adequacy of the firm’s reporting and corrective action.

Under 21 CFR 606.171, a manufacturer of blood and blood components, including Source Plasma, Source Leukocytes and TEP must report to CBER any event, and information relevant to the event, associated with the manufacturing, to include testing, processing, packing, labeling, or storage, or with the holding or distribution of blood or blood components, if the event meets all of the following criteria:

Either:

represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity or potency of that product; or

represents an unexpected or unforeseeable event that may affect the safety, purity or potency of that product, and

occurs in the facility or another facility under contract with the establishment, and involves a distributed blood or blood component.

Events are required to be reported to CBER/OCBQ as soon as possible, but no later than 45 days from the date of discovery reasonably suggesting that a reportable event occurred. Under 21 CFR 606.171, the manufacturer who had control over the product when the deviation or unexpected or unforeseen event occurred must report a BPD.

If a manufacturer contracts out any manufacturing step, that manufacturing step is performed under the manufacturer’s control under the regulation. Thus, under 21 CFR 606.171(a), the manufacturer must establish a procedure for receiving information from that contract manufacturing facility of all deviations, complaints, and adverse events that may affect the product.

During the inspection,

  1. Determine if the establishment submitted all reportable biological product deviations. (Contact OCBQ/DIS if clarification regarding BPD reporting is needed.)
  1. Computers

Establishments may use computer systems for a variety of purposes within the operation. They may utilize a complex, integrated computer system with a donor software module or they may use a single software module. Computerized operations may include:

  • Storing, updating, and accessing donor history information, donor deferral records and distribution records.
  • Accepting, storing, and interpreting test results, including making determinations of donor eligibility and product acceptability. Results may be entered manually or by electronic file transmission from the test instrument or laboratory data management system.
  • Releasing Source Plasma for distribution.

Determine which operations are computerized and how the user validated the computer system to demonstrate that it performs the intended functions accurately and reliably.

  1. Requirements for Source Plasma Establishment Computer Software

 All software, including software developed in-house, used to manufacture blood and blood components (including Source Plasma), to maintain data for making decisions about donor (suitability) eligibility, or to release products for further manufacture are medical devices under Section 201(h) of the FD&C Act. The device provisions such as: registration as a device manufacturer, product listing, medical device reporting, compliance with the quality system regulation, and pre-market notification 510(k) or application, apply to the device software manufacturer. Only blood establishment computer software that is 510(k) cleared or has pre-market approval (PMA) should enter interstate commerce. FDA has previously advised blood establishments to transition to a cleared software device.

Source Plasma establishments that developed software for their own use and that do not distribute it interstate or access or transmit any data across state lines are still considered medical device manufacturers. The finished device is subject to the Quality System Regulation (21 CFR Part 820).

 Use of computer software developed by a Source Plasma establishment by outside consignees (not under the same license number), constitutes commercial distribution and interstate commerce, and requires a 510(k). Also use of software/data by sites under the same license number may require submission of a 510(k) if the software / data crosses state lines.

The actual use of software in Source Plasma establishments is subject to statutory CGMP and the CGMP regulations for Blood and Blood Components (21 CFR 606). Establishments should perform user validation to ensure that the software meets its intended use.

  • During the inspection,
  • Determine if the Source Plasma establishment uses only 510(k) cleared software.Contact CBER / OBRR / DBA / Devices Review Branch, HFM-390, for guidance regarding computer software. A list of 510(k) cleared blood bank software is posted at http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/SubstantiallyEquivalent510kDeviceInformation/ucm134987.htm

 Review records and written procedures the Source Plasma manufacturer used to determine if:

  • Computer systems used in manufacturing comply with 21 CFR 606.60.
  • Computers, software, and interfaces used in the manufacture of Source Plasma are validated prior to implementation, qualified at the location where used, and revalidated as necessary.
  1. Inspection of Source Plasma Establishments that are also Medical Device Manufacturers

Use the following Compliance Program and medical device reporting codes when conducting inspections of Source Plasma establishments that also manufacture medical devices such as computer software:

Compliance Program Guidance Manual, Inspection of Medical Device Manufacturers – 7382.845
Establishment Type - MW
Product Code - 81M
PAC Codes: 42845A – Level 1; 42845B – Level 2; 42845C – Level 3 inspections

  1. Programs and Computer Functions to Include in the Inspection
    •  Criteria to consider when deciding which functions of the system to inspect:
    • The criticality of the functions controlled by the computer, (e.g. determination of product suitability for release)
    • Computer problems revealed by reviewing computer problem reports and biologic product deviation reports
    • Areas suggested for inspection after reviewing computer system change control records.
During the inspection,
  1. Review the computer system operator’s manual.
  2. Observe the use of the computer system. For example, observe manual data input, screen messages, error checking, etc.
  3. Review the overall validation plan and written procedures and the validation of critical programs and reports critical to the establishment’s operations. Validation may be conducted or overseen at the corporate location.
  4. Determine if the Source Plasma establishment validated the system prior to implementation. Determine if the establishment followed the manufacturers’ instructions regarding installation and validation of upgrades.
  5. Be alert to user customization of vendor supplied software systems. Customization is normally accomplished by a user setting certain parameters which affect how the software functions. Check the vendor’s recommended configuration and review the validation of all deviations from the vendor recommended parameters.
  6. Determine if the Source Plasma establishment includes changes to software under written change control procedures and if it documents changes to the system, including the potential impact the changes will have on the system. The establishment should document the change (who made the change, who authorized the change, and the effective date of the change).
  7. Review the use of “work-arounds.Establishments may implement work-arounds when the system does not perform exactly the way the user requires and the software vendor recommends and/or the user develops procedures to circumvent the system’s limitation. Determine the reason the work-around was created, whether it adequately addressed the situation and whether the work-around created any other problems.
  8. Determine if the Source Plasma establishment monitors the functioning of the computerized system for errors and if it documents them and assesses their impact on operations and/or records.
  9. The Source Plasma establishment should have written procedures for continuing operations when the computer system is not functional, in addition to procedures for data and system recovery in the case of system failure. It should periodically back up data and systems files and store them in a secure location.
  10. Review the Source Plasma establishment’s written policies for computer security and determine if the firm follows them. Source Plasma establishments that maintain electronic records must maintain the integrity of those records as required by 21 CFR Part 11. System access must be controlled to limit access to only authorized individuals.

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ATTACHMENT B

QUALITY ASSURANCE SYSTEM

A. Quality Management Principles

NOTE: The requirements in the Current Good Manufacturing Practice for Finished Pharmaceuticals regulations at 21 CFR Parts 210 and 211, and the Quality System Regulation at 21 CFR 820 do not apply to these products. Rather, manufacturers of Source Plasma, Source Leukocytes, and TEP must comply with the applicable statutory CGMP requirements, the CGMP for Blood and Blood Components requirements in 21 CFR 606 and other applicable regulations in 21 CFR Parts 600-680.

Quality is the responsibility of all persons involved in manufacturing. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

The system for managing quality should encompass the organizational structure, written procedures, processes and resources, as well as activities to ensure confidence that the Source Plasma, Source Leukocytes and TEP will meet the established specifications for safety, purity and potency. The quality management principles established by the firm should include:

  1. All quality-related activities should be defined and documented.
  2. There should be a quality control unit(s) that is independent of production and that fulfills quality control (QC) responsibilities. The quality control unit can be in the form of a single individual or group, depending upon the size and structure of the organization.
  3. The persons authorized to release Source Plasma, Source Leukocytes, and TEP should be specified.
  4. All quality-related activities should be recorded at the time they are performed.
  5. Any departures from established written procedures should be documented and explained. Critical departures should be investigated, and the investigation and its conclusions should be documented.
  6. No incoming materials (e.g. collection kits, anticoagulants, bottles, solutions) should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine).
  7. Written procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious CGMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).

B. Responsibilities of the Quality Control Unit(s)

The quality control unit(s) should be involved in all quality-related matters. The quality unit(s) should review and approve all appropriate quality-related documents.

The main responsibilities of the independent quality control unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to:

  1. Releasing or rejecting all Source Plasma, Source Leukocytes, and TEP (21 CFR 606.100(c)).
  2. Establishing a system to release or reject supplies (e.g. soft goods, anticoagulants, containers), packaging, and labeling materials.
  3. Reviewing completed production records (e.g. donor record files, pheresis machine logs) and laboratory control records of critical process steps before release of the product for distribution.
  4. Making sure that all deviations are investigated and resolved.
    1. Making sure events that meet all the criteria in 21 CFR 606.171(b) are reported to FDA as product deviations.
  5. Approving all specifications and all procedures affecting the quality of products.
  6. Approving contract manufacturers (e.g. contract test laboratories)
  7. Approving changes that potentially affect product quality
  8. Making sure that reports of complaints of adverse reactions arising as a result of blood/plasma collection are investigated and documented pursuant to 606.170(a).
  9. Making sure that complications of blood/plasma collection confirmed to be fatal are investigated, documented, and reported to CBER in accordance with 21 CFR 606.170(b).
  10. Making sure that quality-related complaints are investigated and resolved.
  11. Making sure that effective systems are used for maintaining and calibrating critical equipment. Ensuring that written procedures include:
    1. Appropriate calibration, cleaning and preventative maintenance of equipment according to manufacturer’s recommendations and/or SOPs;
    2. Qualification of equipment, as necessary, including after repairs, ensure that equipment functions properly.
  12. Making sure that effective systems are in place for fulfilling all applicable Lookback requirements, in accordance with 21 CFR 610.46, 610.47, and 610.48.
  13. Performing annual product quality reviews.

C. Product Quality Review

Regular quality-reviews should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:

  1. A review of critical in-process control and critical Source Plasma, Source Leukocytes, and TEP test results
  2. A review of all units of Source Plasma, Source Leukocytes, and TEP that failed to meet established specification(s) (including reactive/positive infectious disease testing)
  3. A review of all deviations, departures, or nonconformances and related investigations (including those reported to FDA and those that were not reported)
  4. A review of any changes carried out to the processes or analytical testing methods;
  5. A review of all quality-related recalls, complaints and returns
  6. review of adequacy of corrective actions
     

The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.

During the inspection,

  1. Evaluate whether the quality unit fulfills its responsibility to review and approve all written procedures related to the quality of the product.
  2. Evaluate deviations (both reportable and non-reportable events) or problem reports and determine the adequacy of any investigation and corrective action implemented by the establishment.
  3. Determine if there are any trends in deviations (reportable or non reportable) identified by the establishment. Note: A pattern of recurring problems may indicate an incomplete investigation or inadequate correction.
  4. Determine if product quality reviews are conducted annually.

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ATTACHMENT C

DONOR ELIGIBILITY SYSTEM

This system includes the Source Plasma, Source Leukocytes or TEP establishment’s written procedures intended to protect the donor’s health and ensure product safety. Donor eligibility requirements for manufacture of Source Plasma are found in 21 CFR 640.63 and 640.65. Part VI of this compliance program lists guidance documents, memoranda, and other references relating to donor eligibility determinations for Source Plasma donors.

A. Medical Supervision

Source Plasma regulations require that a qualified licensed physician be on the premises when donor eligibility is determined, immunizations are occurring, whole blood is being collected, and red blood cells are being returned to the donor (21 CFR 640.62). An establishment may have an approved physician substitute (PS) training program as an alternative procedure to 21 CFR.640.62 approved under 21 CFR 640.120, and may train a qualified individual to perform some of the duties of a physician.

Duties of PS often include the following: initial medical and physical examinations of new donors; annual physical examinations of repeat donors; evaluation of donor reactions and providing appropriate therapy as prescribed by the Source Plasma establishment’s SOPs; performing immunizations; counseling donors; and reviewing collection records and accumulated laboratory data to determine a donor’s continued suitability for plasmapheresis. For immunization programs, a PS must not perform the selection and scheduling of the injection, and the evaluation of a donor’s clinical response, unless specifically approved as an exception or alternative procedure under 21 CFR 640.120 (21 CFR 640.66). The PS operates under the supervision of the establishment’s physician.

Even if the establishment has a PS trained under an approved PS program, the physician is still responsible for: reentry of donors; reviewing adverse donor reactions; overseeing Red Blood Cell immunization, disease state and high risk donor programs; approving RBC immunizations; and being on the premises during RBC immunizations.

During the inspection,

  1. Verify that the physician is qualified and licensed.
  2. If the establishment uses a PS, determine if
    1. The establishment has a CBER-approved PS program.
    2. The PS meets the criteria identified in the approved program.
    3. Each PS received training for the duties performed in each Source Plasma establishment.

B. Obtaining Informed Consent

The Source Plasma establishment must obtain written informed consent for Source Plasma collection after a qualified, licensed physician or PS has clearly explained the hazards of each procedure in which the prospective donor will participate: manual collection, automated plasmapheresis, immunization with an antigen, and participation in special collection programs approved by CBER; e.g., collection of Source Plasma from coagulant factor-deficient donors (21 CFR 640.61).

The Source Plasma establishment should explain the donation process in a confidential manner sodonors may make an intelligent and informed decision regarding whether to participate in the donation procedure. The informed consent process must provide the donor with an opportunity to refuse the procedure (21 CFR 640.61). The method should ensure comprehension of the information presented and confidentiality. Source Plasma establishment should have appropriate written procedures if collecting Source Plasma from hearing or vision-impaired donors, from donors who speak English as a second language, or from donors who may have a reading difficulty. (See guidance document, “Informed Consent Recommendations for Source Plasma Donors Participating in Plasmapheresis and Immunization Programs,” June 2007)

During the inspection,

  1. Review the informed consent process to determine if it contains a simple explanation of the plasmapheresis procedure and the risks involved, such as infiltration, infection, and loss of red blood cells.
  2. For automated operations, the informed consent may include the risk of possible anticoagulant reactions.
  3. For manual operations, the informed consent must include the risk of inadvertently receiving another donor’s red blood cells and the possibility of experiencing a hemolytic transfusion reaction (21 CFR 640.61).
  4. For immunization programs that use licensed vaccines, the informed consent must explain the risks associated with receiving the vaccine (21 CFR 640.61).
  5. The Source Plasma establishment should also inform donors immunized with red blood cells that they may develop atypical or unexpected red cell antibodies that may interfere with obtaining a compatible blood, organ or tissue transplant in the future.
  6. Determine if the donor is given an opportunity to ask questions and to decline participation (21 CFR 640.61).

C . Donor Screening

The establishment must implement written procedures that positively identify all donors (usually a photograph) and that relates the donor directly to the products collected and to the donor’s accumulated records and laboratory data (21 CFR 606.100(b), 640.65). The method used should prevent conditions that allow a prospective donor to impersonate another person or donate when not eligible, e.g. missing or poor quality photos, duplicate files, or acceptance of a deferred donor under a different name or social security number.

Firms may present donor screening questions to the donor by several methods. These include direct oral questioning of the donor by firm personnel and self-administered donor questionnaires, using either printed forms or by a computer-assisted interactive interview.

In the self-administered computer-assisted interactive interview procedure, the donor reviews the questions on a computer screen and enters the answers electronically into the software program managing the interview process. The computer software may or may not make decisions on the suitability of the donors based on the responses to the questions. The computer system used in the computer-assisted interactive interview procedure includes any hardware and software needed to perform the process. It may be a stand-alone system, used solely to conduct the donor interview, or it may interface with other computer systems at the same or other locations. It may be a desktop or laptop computer or a handheld device. The software may have data storage capabilities or may send data to a printer for hardcopy printout. In addition, the computer system may be accessible from a remote location. The user interface may present both video and audio data to the user via monitors, headphones, etc. Donors and collection personnel may input data or responses via keyboard, microphone, or a pointing device such as a mouse, touch screen, or stylus. The system may use pictures or drawings to illustrate the topic of the displayed questions. Also see Attachment A, 7, “Computers.” The establishment should have a method at each donation to ensure that the donor understands the questions (e.g., additional verbal or written questions). This should include an evaluation of the donor's ability to read and understand the language of the self-administered questionnaire, regardless of its medium (written, audio, or visual).

The Source Plasma manufacturer must determine donor eligibility, to include physical examinations, and medical screening, according to applicable FDA requirements and its SOPs (21 CFR 640.63 and 640.65).

  1. Identify yourself to the donor and explain that observing the screening process is part of a routine inspection. Ask the donor’s permission to observe the screening process and give the donor a clear opportunity to refuse. If the donor refuses, make the request of another donor.

Note: If management questions FDA’s authority to observe donor screening, explain to management that observing the screening process is part of conducting the inspection of a Source Plasma establishment in a manner that is reasonable under the circumstances and, therefore, authorized by law. Follow the procedures in IOM (Inspection Refusal) if management refuses to permit observation.

  1. A third party; e.g., a language translator or sign interpretermay assist in the interview process. To ensure confidentiality and full disclosure of information by the donor, CBER recommends that the establishments not use the donor’s friends or relatives as the third party. This third party should understand the confidential nature of the information discussed and agree not to disclose it to anyone. The third party may not complete the questionnaire.

The Source Plasma establishment must maintain written standard operating procedures for all aspects of donor screening (21 CFR 606.100(b), 640.63), including criteria for use of a third party. Donor records should indicate participation of a third party in the donor screening process, when utilized.

  1. Under 21 CFR 640.65(b), a sample of blood shall be drawn from each donor on the day of the first medical examination or plasmapheresis, whichever comes first and at least every 4 months thereafter. A serologic test for syphilis and a serum protein electrophoresis shall be performed on the sample. A repeat donor who does not return at the time the 4-month sample is due to be collected may be plasmapheresed on the day he appears provided no longer than 6 months has elapsed since the last sample was collected, and the physician (or PS) on the premises approves the plasmapheresis procedure and so indicates by signing the donor’s record before such a procedure is performed. The sample for the 4-month tests shall be collected on the day of the donor’s return. A repeat donor from whom the plasmapheresis center is unable to obtain a sample for testing, for the total period exceeding 6 months shall be processed as a new donor.

During the inspection,

  1. Observe one or more medical examinations.
  2. Determine if medical examinations and physicals are conducted according to the SOPs and applicable FDA requirements and at the proper intervals (21 CFR 640.63(a), (b) ).
  3. Personnel should adequately respond to donor questions or refer questions to the appropriate medical personnel, as necessary.
  4. Review the Source Plasma establishment’s procedure for determining a donor’s eligibility on the day of donation for consistency with the requirements in 21 CFR 640.63.
  5. If the computer-assisted interactive screening process is used, determine if SOPs describe the process and the computer system has been adequately validated for its intended use.
  6. Determine if the physician / PS reviews a total plasma or serum protein determination and serum protein electrophoresis or equivalent test to determine immunoglobulin composition, syphilis test results, and the donor’s accumulated laboratory data within 21 days of collection of the initial and 4-month test samples.

Each donor must be certified to be in good health by the examining physician or PS on a form supplied by Source Plasma establishment. The certification applies to the eligibility of the individual to be a plasmapheresis donor and, when applicable, an immunized donor (21 CFR 640.63(b)(3)).

  1. The Source Plasma establishment should provide AIDS educational material, including information about high-risk activities, to donorsat each donation.
  2. Determine if the Source Plasma establishment performs all required screening tests (temperature, pulse, blood pressure, total serum or plasma protein and hematocrit or hemoglobin) in determining donor eligibility (21 CFR 640.63(c)). The establishment’s SOPs may require additional tests not specifically required by FDA, such as urine glucose or urine protein.
  3. Determine if the Source Plasma establishment calibrates and maintains all equipment used in donor screening according to the device manufacturer’s instructions and its SOPs and runs proper quality control according to the equipment manufacturer’s instructions.
  4. Determine if Source Plasma donors weight at least 110 pounds (21 CFR 640.63(c)).
  5. The donor’s weight determines the amount of Source Plasma the manufacturer may collect.
  6. Determine if the Source Plasma establishment collects Source Plasma from infrequent donors no more often than once every 4 weeks. For additional discussion of infrequent plasmapheresis, see Attachment G.
  7. Review the Source Plasma establishment’s procedure to prevent cross donation.

Cross donation occurs when (a) an individual donates at more than one Source Plasma establishment or blood collection facility in a geographic area concurrently, (b) donates at one establishment although permanently or temporarily deferred at another, or (3) donates at a frequency that would be injurious to the donor’s health (no more than twice in a 7 day period with two days between donations (21 CFR 640.65(b) and CPG 256.100)).

Review sufficient records to determine if the Source Plasma establishment’s written procedures are adequate to identify donors and to prevent cross donation.

D. Records

Records must be maintained concurrently with the performance of each significant step in the collection, processing, storage and distribution of each unit of blood and blood components so that all step`s can be clearly traced (21 CFR 606.160 ). Records may be maintained as hard copies or electronic records.

Establishments must have separate and complete donor records (referred to as a donor record file) of all initial and periodic examinations, tests, laboratory data, interviews, etc. related to donor eligibility, product collection, immunization, and laboratory testing (21 CFR 640.72).

During the inspection,

Review a sufficient number of the records to determine if the establishment collects Source Plasma from donors with acceptable health history and screening test results. Determine if the records contain the following information:

  1. Initial and annual physical examinations and consent for plasmapheresis and immunization, as applicable (21 CFR 640.72) Note: See Attachment G - Infrequent Plasmapheresis Collection program.
  2. Donor screening test results, e.g., hematocrit, temperature, blood pressure, pulse, donor weight, total protein, and donor medical history interviews (21 CFR 640.63).
  3. Tests for communicable diseases and results of 4-month syphilis and serum protein electrophoresis testing and review (21 CFR 610.40 and 640.65).
  4. Records of immunization, if applicable (21 CFR 640.66).
  5. A cross-reference to unit(s) of Source Plasma collected from the donor (21 CFR 640.72).
  6. Reason(s) for donor deferral, including red blood cell loss (21 CFR 606.160 and 640.72(c)).
  7. The reason Source Plasma was determined unsuitable (21 CFR 640.72(c)).
  8. Donor reactions that occurred on or after leaving the premises (21 CFR 640.72(d)).
  9. Collection volume and donor weight (21 CFR 640.72(a)).

E. Donor Eligibility for Special Collection Programs - Also see Attachment G

An establishment must have an approved BLA supplement to collect Source Plasma from special donor populations. Special collection programs include,

  • Pre-Existing Antibody Collection Programs
  • Pre-Existing Disease-Associated Collection Programs
  • Disease State Collection Programs
  • High-Risk Donor Collection Programs
  • Immunization Programs
  • Infrequent Plasmapheresis Collection Programs

F. Donor Eligibility for Source Leukocyte / Therapeutic Exchange Plasma- See Attachment H

G. Donor Deferral

The establishment must have specific written procedures to defer donors who are determined ineligible for collection due to (a) medical history, (b) physical examination, or (c) a positive screening test(s) for evidence of a communicable disease agent(s) identified in 21 CFR 610.40 (HIV-1 and 2, hepatitis B virus, hepatitis C virus and syphilis). (21 CFR 606.100(b)(20), 610.41) Note: Be aware that under special collection programs, manufacturers may collect Source Plasma from ineligible donors. See Attachment G.

The establishment must keep a record of deferred or ineligible donors so that products from such donor are not distributed (21 CFR 606.160(e)). Most establishments determine the deferral status of new or returning donors prior to collection.

Establishments may ship Source Plasma collected prior to a donor’s reactive syphilis serologic test result and donations determined to have a biologic false-positive syphilis test result. A donor with a reactive serologic test for syphilis shall not be plasmapheresed again until the donor’s serum is tested and found to be non-reactive (21 CFR 640.65). See also, Compliance Policy Guide 7134.15, Section 245.100, “Use of Units from Donors Subsequently Found to be Reactive to a Serologic Test for Syphilis.”

During the inspection,

  1. Review the establishment’s written procedures and criteria for donor deferral for compliance with 21 CFR 606.160(e) and 610.41.
  2. Review records and observe operations to determine if the establishment accurately records donor screening deferrals, testing deferrals, and post donation information.
  3. Determine if the establishment accurately records, either electronically or manually, all causes of temporary or permanent deferrals.
  4. The establishment should have written procedures/computer programs to identify discrepant and/or duplicate donor information and written procedures to prevent release of unsuitable products.
  5. Determine if the establishment appropriately corrects and/or merges discrepant or duplicate records according to its SOPs.
  6. Review records to determine if the establishment inappropriately released unsuitable Source Plasma.

H. Notifying Deferred Donors

An establishment must make reasonable attempts to notify any donor who has been deferred based on the results of tests for evidence of infection with a communicable disease agent as required by 21 CFR 610.41, or who has been determined not to be suitable as a donor based on suitability criteria under 21 CFR 640.63 (21 CFR Part 630). An establishment must have written procedures for such notifications in accordance with 21 CFR 606.100. The SOPs must include the method for notifying the donor, including follow-up if the initial attempt at notification fails (21 CFR 606.100(b)(20 )).

During the inspection,

Review a sampling of records with repeat reactive test results to determine if the establishment performs supplemental testing and notification to donors as required in 21 CFR 630.6.

I. Donor Re-Entry Algorithms

An establishment may re-enter donors previously deferred because of a positive test result for a required communicable disease agent after it finds the donor is otherwise eligible by a re-qualification method or process acceptable to FDA and the donor is otherwise suitable. Most Source Plasma establishments, however, do not re-enter donors.

During the inspection,

If re-entry is performed, identify donors that the Source Plasma establishment re-entered and determine if the establishment performed donor re-entry according to the acceptable methods or processes found acceptable for such purposes by FDA (21 CFR 610.41(b)).

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ATTACHMENT D

PRODUCT TESTING SYSTEM

Establishments that collect blood or blood components must test each Source Plasma and TEP donation for evidence of infection due to the following communicable disease agents (21 CFR 610.40):

  • Human Immunodeficiency Virus, types 1 & 2
  • Hepatitis B Virus
  • Hepatitis C Virus

Source Leukocyte donations must be tested for all communicable disease agents listed in 21 CFR 610.40, including anti-HTLV, types I and II

Establishments must also test donors for syphilis, total plasma or serum protein, and immunoglobulin composition of plasma or serum, initially and every four months (21 CFR 640.65(b)).

Further testing of each reactive donation, using screening and supplemental tests approved by FDA for such use is also required (21 CFR 610.40(e)). Establishments may contract part or all of the communicable disease testing to an outside testing laboratory. The contract, testing laboratory must register with FDA and be certified by the Centers for Medicare and Medicaid Services (CMS) or has met equivalent requirements as determined by CMS to perform infectious disease testing (21 CFR 607.20, 610.40(f)). The establishment must ensure that the contract laboratory is registered with FDA and that laboratory testing complies with 21 CFR 610.40 (a), (b), (e) and (f).

The laboratory must perform required testing for communicable disease agents using screening and supplemental test kits FDA has approved for such use. Serological tests for syphilis should be labeled for use in donor screening. A list of currently licensed HIV and hepatitis test kits is on the Internet at

http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm080466.htm

An establishment that does its own testing for evidence of a communicable disease agent must retain testing records as required in 21 CFR 606.160(d). A manufacturer that sends such testing to an outside laboratory must have test results; i.e., reactive, nonreactive, positive, negative or indeterminate in written form (hard copy or available electronically) prior to releasing Source Plasma for further manufacture.

A. Communicable Disease Testing - Testing Performed at the Establishment

This section applies to inspection of establishments that perform on-site testing for required communicable disease agents.

During the inspection

  1. Observe actual testing practices and procedures whenever feasible. Ensure that testing is performed in accordance with the manufacturer’s instructions. Determine if appropriate controls are used, that samples and controls are diluted properly, that the time and temperature of incubation are accurate and that instrument and equipment settings are correct during testing.
  2. Determine if the establishment performs equipment maintenance according to the manufacturer’s recommendations and the firm’s SOPs.
  3. Determine if all testing problems are adequately investigated, resolved, and documented.
  4. If unable to observe infectious disease testing, then at a minimum, compare the establishment’s test procedures with the test kit manufacturer’s package inserts, test equipment user manuals, and reagent inserts.

Review the package inserts for the lot of test kits and reagents in current use instead of those on file. Investigate any noncompliance noted between inserts or manuals and the firm's written procedures. Discuss any questions with CBER/ Division of Emerging Transfusion Transmitted Diseases (301-827-3008).

  1. Review as many required infectious disease test records as the inspection permits, extending the review as necessary depending on findings.

Consider both the size of the firm and its compliance history. If possible, select records from a time period when problems are more likely to occur, such as holidays, on evening shift, at installation of new equipment, or when there is new management or personnel. Investigate unusual test results, such as low values and invalidated test results.

  1. Select a representative number of reactive test results for each required disease agent. Track the units from donor screening, product collection, donor deferral, product quarantine, storage, and disposition to determine appropriate handling of products and required recordkeeping.
  2. Observe procedures for handling samples. Assess whether the procedures are adequate to prevent sample mix-ups. The laboratory must store samples as specified in the test kit manufacturer's instructions.
  3. Ensure that the sample requirements (anticoagulant, age of sample, quantity, storage temperature, especially if testing is delayed, etc.) are met.

The establishment must qualify automated sampling equipment and positive identification systems to ensure proper identification of samples and test results.

  1. Evaluate the establishment’s laboratory quality control program. Determine if all laboratory equipment is qualified, calibrated and maintained as required by user manuals, maintenance manuals and the establishment’s standard operating procedures (21 CFR 606.60).

B. Communicable Disease Testing - Testing Performed at Another Location

Most establishments contract with another establishment for communicable disease testing or centralize communicable disease testing at another location operating under the same license. The Source Plasma, Source Leukocyte, or TEP establishment remains responsible for releasing products that meet the applicable requirements and product standards. The off-site testing laboratory is responsible for complying with the CGMP requirements applicable to the manufacturing steps they perform.

During the inspection

  1. Determine if the laboratory performing the communicable disease testing is CLIA certified or the equivalent and is registered with FDA.
  2. Determine if there is a written contract or agreement which specifically identifies which tests will be performed and which establishment will be responsible for the SOPs.
  3. Determine if the contract testing laboratory has been audited by the establishment or how the establishment determines the laboratory is complying with regulations.
  4. If necessary, obtain the product inserts from the testing laboratory via fax or other means to determine if the test kits used meet FDA regulations for testing donors of Source Plasma, Source Leukocytes, or TEP.
  5. Determine if the sample criteria in the product insert are being met such as sample type, collection container, sample storage, shipment and sample age.
  6. Determine how test results are received and reviewed at the establishment.
  7. Determine how the firm determines all tests have been completed and who is responsible for review of test results and the release of finished product.

C. Invalidation of Test Results

Evaluate the establishment's written procedures for invalidating a test result for consistency with the recommendations in the document, “Guidance for Industry: Revised Recommendations Regarding Invalidation of Test Results of Licensed and 510(k) Cleared Bloodborne Pathogen Assays Used to Test Donors,” dated July 2001 (see http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm062869.pdf). This guidance incorporates provisions of the Clinical Laboratory Improvement Act of 1988 (CLIA) for invalidation of test results based on CLIA external control requirements and only applies to some communicable disease testing. Invalidation of NAT testing must be performed in accordance with the manufacturer’s directions for use.

Laboratories or facilities that perform testing may invalidate a reactive test result ONLY IF the assay run in which a sample is tested either fails to meet test kit manufacturer’s instructions acceptance criteria OR the firm failed to do testing according to the test kit manufacturer’s instructions; e.g., using compromised reagents or faulty equipment. If test kit manufacturer’s instructions are met, but CLIA control requirements are not met, the laboratory may invalidate only non-reactive results, but MAY NOT invalidate any reactive results. If an initially reactive specimen tests reactive on one or both of the two repeat duplicate tests, the sample is reactive and the testing laboratory should manage the results as indicated in the guidance document. When a negative or non-reactive test result is legitimately invalidated, re-test the sample singly and that result, if valid, is the test of record.

The testing facility should document all incidents of invalidation including:

  • The basis for invalidation
  • The details of an investigation
  • The outcome of the investigation, and
  • If indicated, any corrective action taken

During the inspection,

Review all records of invalidation of test results for consistency with test kit manufacturer’s instructions for use and CBER recommendations. Notify CBER/Division of Inspection and Surveillance at 301-827-6220 if questions arise regarding invalidation of test results.

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ATTACHMENT E

PRODUCT COLLECTION AND PROCESSING SYSTEM

This system covers the operations from collection through labeling.

CBER may approve an application or application supplement for a Source Plasma establishment to collect Source Plasma by manual or automated apheresis methods under various Source Plasma collection programs. The Source Plasma establishment may collect Source Plasma from donors only twice in a 7-day period, and at a 2-day interval (21 CFR 640.65(b)(8)). Donors who participate in an infrequent plasmapheresis collection program may donate no more frequently than once every four weeks. Infrequent plasmapheresis donors should meet Whole Blood donor suitability requirements and weigh at least 110 pounds. Currently, CBER approves infrequent plasmapheresis programs as an exception or alternative procedure under 21 CFR 640.120.

The collection procedures must ensure that the appropriate volume of Source Plasma is collected and that the maximum feasible volume of red blood cells is returned to the donor (21 CFR 640.65). Overbleeding donors during manual collection and/or failure to return red blood cells due to technical difficulties during automated plasmapheresis may require temporary deferral of donors (21 CFR 640.63).

Written SOPs must be maintained and shall include all steps to be followed in the collection, processing, compatibility testing, storage, and distribution of the blood component for further manufacturing purposes (21 CFR 606.100). Source Plasma collection must meet the requirements in 21 CFR 640.64 and 640.65.

A. Venipuncture

Personnel must prepare the skin at the site of phlebotomy thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. (21 CFR 640.64(e))

During the inspection,

Observe several phlebotomists as they prepare the venipuncture site. Determine if each phlebotomist prepares the venipuncture site consistent with the establishment’s SOPs. Critical steps in preparing the skin for venipuncture include:

  • Sufficient time and vigor of scrubbing - key factors in removing superficial microbes.
  • Applying a bactericidal agent according to the reagent manufacturer’s instructions.
  • No touching of the prepared area with fingers or other non-sterile object, including donors bending their arms.

B. Collection Methods

As part of the application review process, CBER reviews certain SOPs for collection of Source Plasma. Manufacturers should have a procedure to identify and prevent overbleeds. Overbleeding occurs when the amount of Source Plasma exceeds what may be collected at one time from a donor or the donor donates more frequently than twice in a 7-day period.

  1. Automated Collection

Under Section 510(k) of the FD&C Act, FDA has cleared several fully automated, stand-alone or concurrent plasma collection systems for plasma collection. Devices cleared to collect plasma products as a by-product of plateletpheresis or red blood cell apheresis are used in blood bank or blood center operations. Many Source Plasma establishments use the following stand-alone devices

  • Baxter/Fenwal - Autopheresis-C Plasmapheresis System
  • Haemonetics – PCS2 Plasma Collection System

During the inspection,

  1. Review the SOPs for automated collection of Source Plasma. Determine if the Source Plasma establishment collects Source Plasma according to its written procedures approved as part of the license application, and the collection device manufacturer’s instructions.
  2. Observe Source Plasma collection to assess the adequacy of employee training. The staff should be able to explain error messages and take appropriate action.

Note: CBER recommends the following operator to device ratio: 1 trained operator may operate 6 devices and 1 trainee operator may operate 4 devices under the supervision of a trained operator. The trainee’s 4 devices should be included within the trained operator’s 6 devices so that the trained operator does not exceed the number of devices that the operator may safely oversee.

  1. Become familiar with device safety alarms. Ensure that employees do not override or bypass the alarms without taking corrective action as indicated in the device manual(s).
  2. Review each collection device record or log to identify any problems with the device. The record or log should include all warning alarms and problems in returning red blood cells. The record or log often identifies problems with disposable collection sets.
  3. Determine if the Source Plasma establishment performs and records routine maintenance according to the device manufacturer’s instructions.
  4. Determine if the Source Plasma establishment has written procedures to ensure that collection devices operate properly after software changes and following repairs (21 CFR 606.60). Note: Computer software in collection devices can frequently be changed using manufacturer upgrades.
  5. Review donor record files to determine if the Source Plasma establishment collects the appropriate volume of plasma specifically approved for the device (21 CFR 640.65(b)).

The establishment may use a device-specific approved nomogram or plan to determine the amount of plasma to collect.

A nomogram may use several criteria to determine the collection volume; e.g., the donor’s gender, weight, height, and hematocrit. CBER developed a simplified nomogram that determines the maximum collection volume or weight of plasma based only on the weight of the donor.

Note: The CBER-developed, simplified nomogram is intended to be adopted as a complete set of limits. The simplified nomogram and the equipment manufacturer's nomogram should not be used simultaneously in the same center. Consult the CBER Blood Memorandum, “Volume Limits for Automated Collection of SourcePlasma, November 4, 1992”

The Source Plasma establishment should have a procedure to track red blood cell loss. Determine if the employees appropriately defer donors who failed to have their red blood cells returned, unless exempt under 21 CFR 640.63.

Note: Any person who has donated one unit or more of Whole Blood (or who has lost the equivalent amount of red blood cells due to technical difficulties during an automated plasmapheresis procedure) must not serve as a donor of Source Plasma for 8 weeks (21 CFR 640.63(e)).

2. Manual Collection

A Source Plasma establishment that uses a manual method must collect and process Whole Blood for Source Plasma according to the requirements in 640.65(b)(4) – (7), 640.68 and the establishment’s SOPs. The SOPs should describe in detail the collection procedures, including:

  • Donors should participate in the identification procedure for returning red blood cells.
  • Personnel should adequately mix the contents of the collection bag during collection.

During the inspection,

  1. Review donor record files to determine if the interval between donations is consistent with regulations (21 CFR 640.65).
  2. Review the Source Plasma establishment’s written procedures for returning the maximum amount of red blood cells to the donor (21 CFR 640.65(b)(7)). Observe as many employees as possible collect Source Plasma to ensure that staff is following the establishment’s written procedures.
  3. Ensure that ”double bagging” (collection of the second bag of whole blood prior to the return of the red blood cells from the first bag collected) does not occur.
  4. Determine if the Source Plasma establishment has a procedure to identify and prevent overbleeding; e.g., monitoring scales after adjustments or repairs, as necessary. Note: Review Whole Blood weight records to determine the number of overbleeds by volume.
  5. Determine if appropriate written procedures exist for plasma pooling to prevent cross-pooling (21 CFR 640.69).
  6. Investigate any incidents of incorrect red blood cell infusion. Any incident of incorrect red blood cell infusion is a serious departure from the Source Plasma establishment’s SOPs.

The Source Plasma establishment should have written procedures to provide the donor who received the incorrect red blood cells appropriate emergency medical attention.

  1. If any incorrect red blood cell infusions occurred, determine if the Source Plasma establishment properly deferred each donor involved in incident. The manufacturer must defer donors who did not receive any red blood cells from further collection for eight weeks (21 CFR 640.63(e)). Donors who received incorrect red blood cells are not suitable and must be deferred for 1 year because such donors received a blood transfusion (21 CFR 640.63(b)(13).

C. Adverse Reactions

The Source Plasma establishment must maintain a record of any donor reaction it receives and must conduct a complete investigation and document the investigation findings (21 CFR 606.170, 640.72(d)). The extent of the investigation should be based on the seriousness of the adverse donor reaction.

During the inspection,

Review records of adverse donor reactions to ensure the records contain a full explanation of the reaction, including the measures taken to assist the donor and the outcome of the incident.

D. Donor Fatalities

An establishment must report to CBER as soon as possible any complication of blood collection that results in a donor fatality. Within 7 days, the establishment must submit a written report of its investigation of the fatality to the Director, Office of Compliance and Biologics Quality. The Fatality Program Manager (HFM-650) usually receives initial notice within 24 hours of the fatality or, at least, by the next business day (21 CFR 606.170 (b), 640.73).

If an investigator becomes aware of an unreported fatality during an inspection, contact the Fatality Program Manager, Division of Inspections and Surveillance 301-827-6220 as soon as possible to discuss the circumstances surrounding the incident and to determine if the Source Plasma establishment should report the fatality.

Determine if the establishment conducted an adequate and complete investigation.

During the inspection,

Fatality follow up

  1. Review the establishment’s investigation.
  2. Review donor records and if the establishment does automated collection, also review the device records, maintenance log, and other relevant records.
  3. Review both the initial notification to CBER and the 7-day written report. Often the fatality investigation is not completed in 7 days, so also review any report relevant to the investigation of the case that later became available. Determine if the firm reported accurate information to the Fatality Program Manager.
  4. Review any corrective action and procedure to monitor its effectiveness.
  5. Obtain a copy of the relevant records as indicated in the guidance document, “Notifying FDA of Fatalities Related to Blood Collection or Transfusion, September 2003.”

Send a copy of the EIR with exhibits to the Fatality Program Manager. Refer to the cover page of this document for the address.

E. Labeling

Product labels must meet the requirements of 21 CFR 640.70 and 640.74. While CBER reviews product labels during the application review process, it is also the investigator's responsibility to examine the labels during the inspection to assure they meet the requirements in 21 CFR 640.70 and 640.74. Investigators should call CBER’s Office of Blood Evaluation and Research at 301-827-3543 if they have questions about the information on the labels or to confirm if the establishment is using approved labels.

F. Source Plasma Collection Programs (See Attachment G)

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ATTACHMENT F

QUARANTINE/ STORAGE/DISPOSITION SYSTEM

A. Quarantine

Control over the Quarantine/Storage/Disposition System is necessary to prevent the distribution of any unsuitable products. The establishment must not ship or use human blood or blood components that have a reactive screening test for evidence of infection due to a communicable disease agent designated in the regulations, or that are collected from a donor with a previous record of a reactive screening test, except as specifically provided under 21 CFR 610.40, 610.46, or 610.47. Establishments must also maintain records from which unsuitable donors may be identified so that products from such individuals will not be distributed (21 CFR 606.160(e)).

During the inspection,

  1. Examine records to determine if the Source Plasma manufacturer quarantined Source Plasma products appropriately (21 CFR 606.160).
  2. Evaluate the firm’s procedure for removing products from quarantine; e.g., returning product to inventory after performing additional testing.
  3. Determine if records identify the individual who removed products from quarantine, the date removed, and the reason for the removal (21 CFR 606.160).
  4. Determine if after collection, the establishment immediately stores and maintains Source Plasma at the appropriate temperature and that the Source Plasma establishment documents the temperature (21 CFR 610.53, 640.69, 640.74).

Intended for further manufacture into injectable products: -20º C or colder

Intended for further manufacture into noninjectable products: temperature appropriate for the intended use

Source Plasma Liquid: 10º C or colder, unless otherwise approved by CBER

  1. If Source Plasma intended for further manufacture into injectable products was not stored or shipped at appropriate temperatures, determine if the Source Plasma establishment re-labeled the product “Source Plasma Salvaged” consistent with 21 CFR 640.76(a)(1) or (b), unless an exception under 21 CFR 640.76(a)(2) applied or CBER determined that no re-labeling was required.
  2. Review the establishment’s distribution records to determine traceability of all Source Plasma products and maintenance of records according to 21 CFR 606.165 and 640.72.
  3. Determine if the establishment releases Source Plasma for distribution only after it receives and reviews written or computerized test results for the Source Plasma products (21 CFR 606.100(c)).

Notes:

  • CBER approval is not required to ship products under quarantine, prior to completion of PCR or NAT testing, to other locations operating under the same license (Source Plasma establishments, fractionators, or off-site storage locations).
  • CBER approval is required to ship products prior to completion of PCR or NAT testing to Source Plasma establishments, fractionators, or off-site storage facilities operating under a different license.
  • CBER approval is required to ship products under quarantine pending PCR or NAT testing, to an independently owned, unlicensed, off-site storage location.

B. Equipment

All equipment used in the manufacture must meet the requirements of 21 CFR 606.60.

During the inspection,

Determine if all storage and temperature monitoring equipment is calibrated and maintained per manufacturer’s instructions.

Note: After installation and qualification of a central temperature monitoring system, CBER may permit an alternate procedure from the daily comparison of the internal thermometer to the recording chart/device.

C. Shipment

The Source Plasma establishment shall ship Source Plasma at a temperature appropriate for manufacture of the final product: (21 CFR 600.15, 640.76(b))

  • Intended for further manufacture into injectable products: at –5ºC or colder
  • Intended for further manufacture into noninjectable products: at 10ºC or colder or as indicated in an approved BLA supplement

Source Plasma for injectable use kept under continuous temperature monitoring requires no inspection for evidence of thawing prior to issue, provided temperature records indicate appropriate storage temperatures at –20°C or colder (21 CFR 640.69(c)).

Source Plasma Liquid shall meet the requirements of 21 CFR 640.74. Prior to issue, the Source Plasma establishment must immediately inspect each container for abnormal color, physical appearance or indication of microbial contamination (21 CFR 640.74(b)(5)).

The Source Plasma manufacturer shall re-label Source Plasma intended for manufacture into injectable products that is inadvertently exposed to unacceptable temperature as “Source Plasma Salvaged,” except as provided in 21 CFR 640.76(a)(2). The manufacturer must also maintain appropriate records identifying the units involved, their disposition and an explanation of the conditions that caused the unacceptable temperature exposure (21 CFR 640.76(a)-(c), 640.70(b)).

During the inspection,

Determine if the Source Plasma establishment ships products according to regulations.

D. Imported Blood and Blood Components

During the inspection,

  1. Determine if the establishment received imported products.
  2. Determine if the establishment received imported products identified as “import for export.” Contact HFM-610 to determine if CBER approved the ”import for export” shipment pursuant to Section 801(d)(4) of the FD&C Act.
  3. Determine if the establishment received any returns from outside the United States.

For further information, see Compliance Program 7342.007, “Imported CBER-Regulated Products.”

E . Lookback

New regulations for HCV lookback and revised regulations for HIV lookback became effective February 20, 2008 (72 FR 48766). Under 21 CFR 610.46, 610.47, and 610.48, FDA requires establishments collecting blood or blood components, including Source Plasma and Source Leukocytes, to establish, maintain, and follow an appropriate system for identifying blood and blood components previously donated by a donor who tests reactive for evidence of hepatitis C or HIV infection on a subsequent donation. For HCV, the evidence of infection may be identified on a subsequent donation identified either by current testing or after a review of historical testing records, or when the collecting establishment is made aware of other reliable test results or information indicating evidence of HCV infection. Such collections may be at increased risk of transmitting HCV or HIV infections. The regulations require collecting establishments to:

  • Identify and quarantine prior in-date blood and blood components from such donors;
  • Notify consignees of prior in-date blood and blood components from such donors for quarantine purposes and to perform further testing on the donor;

The regulations also require consignees to notify transfusion recipients of blood and blood components from such donors, as appropriate. In addition, under 21 CFR 610.48, establishments must perform a review of historical testing records for HCV performed before February 20, 2008. (See also “Guidance for Industry: Lookback for Hepatitis C Virus (HCV): Product Quarantine, Consignee Notification, Further Testing, Product Disposition, and Notification of Transfusion Recipients Based on Donor Test Results Indicating Infection with HCV” August 2007)

During the inspection,

  1. Review the SOPs to determine that lookback procedures comply with current regulations.
  2. Determine if, within 3 calendar days after a donor tests reactive for evidence of HIV or HCV infection, or when made aware of other reliable test results or information indicating evidence of infection, the establishment reviews all records to identify blood and blood components previously donated by such a donor.
  3. Determine if the establishment quarantines all previously collected in-date blood and blood components identified.
  4. Determine if the establishment notifies consignees to quarantine Source Plasma, Source Leukocytes and TEP collected within 12 months and less before the donor’s most recent nonreactive screening tests, or 12 months and less before the donor’s reactive direct viral detection test (e.g. NAT) except pooled components intended solely for further manufacture into products that are manufactured using validated viral clearance procedures.

Note: Source Leukocytes are processed within 24 hours of collection. Source Plasma is usually pooled within 6 months of collection.

  1. Determine if the establishment performed by February 19, 2009, a review of historical testing records for HCV and took appropriate actions, as required under 21 CFR 610.48.
  2. Determine if the establishment identified any deviations in testing procedures or donor deferral associated with a lookback case. If the event(s) were reportable, determine if the manufacturer notified CBER.

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ATTACHMENT G

SPECIAL SOURCE PLASMA COLLECTION PROGRAMS

An establishment may supplement its BLA to include the manufacture of various Source Plasma products. This attachment contains information related to a number of Source Plasma collection programs. To obtain additional information about these collection programs, consult the guidance documents referenced or contact CBER, Division of Blood Applications, 301-827-3543.

A. Pre-existingAntibody Collection Program

An establishment may collect Source Plasma from donors who have a pre-existing antibody; e.g., antibody to Duffy red blood cell antigen (anti-Fya) or antibody to human leukocytes. Donors must meet all Source Plasma eligibility criteria (21 CFR 640.63).

During the inspection,

  1. Determine if the establishment collects Source Plasma from donors with pre-existing antibodies according to its SOPs.
  2. Determine if the establishment has notified CBER of various pre-existing antibody collection programs in its annual report of minor changes (21 CFR 601.12).

B. Pre-existing Disease-Associated Collection Program

An establishment may collect Source Plasma from donors who have pre-existing, disease-associated antibodies because of a previous exposure to certain diseases or cellular antigens; e.g., IgG antibody to Cytomegalovirus or anti-hepatitis A virus. Donors must meet all Source Plasma donor eligibility criteria (21 CFR 640.63). The manufacturer should inform donors that their participation in a special collection program depends on the level of antibody. A donor may immediately return to Source Plasma collection if the Source Plasma establishment no longer desires to collect the antibody. The manufacturer must notify CBER of the implementation of such programs in the establishment’s annual report of minor changes (21 CFR 601.12). (See also “Guidance for Industry: Implementing a Collection Program for Source Plasma Containing Disease-Associated and Other Immunoglobulin (IgG) Antibodies” August 2006)

During the inspection,

  1. Determine if the establishment collects Source Plasma from donors with pre-existing disease-associated antibodies according to its SOPs.
  2. Determine if the establishment has notified CBER of various pre-existing antibody collection programs in its annual report of minor changes (21 CFR 601.12).

C. Disease-State Collection Program

This program allows Source Plasma collection from donors who may not meet all Source Plasma eligibility requirements. These donors are generally feeling well and are not experiencing any active symptoms on the day of donation. The disease conditions under this programrequire physician’s authorization for collection. Some examples of disease state collections are antibody to Lyme disease or antibody to coagulation factors. The plasma is generally used for further manufacturing into in vitro diagnostic reagents.

Prior to implementing a disease-state collection program, the manufacturer must submit a supplement to the BLA (21 CFR 601.12). The supplement should include SOPs that define the donor selection criteria, labeling, quarantine procedures, and Source Plasma disposition.

The manufacturer should collect, handle, store, and distribute reagents, samples, and Source Plasma according to current biosafety guidelines established by FDA, Centers for Disease Control and Prevention (CDC) and /or Occupational Safety and Health Administration (OSHA).

During the inspection,

  1. Determine if the establishment follows its approved procedures.
  2. Determine if the establishment collects Source Plasma only from the disease-state donors covered in the BLA.
  3. Determine if the products are appropriately labeled in accordance with 21 CFR 640.70.

D. “High-Risk” Donor Collection Program

This program allows establishments to collect Source Plasma from donors who have a positive test result for a communicable disease agent. The product may be used in research, or for in vitro tests, or development of therapeutic products. The SOPs and labeling for this program must be submitted to CBER as a Pre-Approval Supplement under 21 CFR 601.12. Product collection, handling, storage, and disposition of samples and Source Plasma should be in accordance with current biosafety guidelines established by FDA, CDC and /or OSHA. For additional information, consult the following document.

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM062849.pdf

During the inspection,

  1. Determine if the establishment collects Source Plasma according to its SOPs and only from “high-risk” donors covered in the BLA.
  2. Determine if the products are appropriately labeled in accordance with 21 CFR 640.70(a).

E. Vaccine and Red Blood Cell (RBC) Immunization Programs

  1. Vaccine Immunization Programs

A Source Plasma manufacturer may immunize donors using licensed vaccines; e.g., tetanus or rabies vaccines, for collection of high titer antibody. If use of the vaccine is consistent with the approved prescribing information (or “package insert”), the manufacturer may submit a CBE-30 supplement and distribute Source Plasma within 30 days of CBER notification (21 CFR 601.12(c)). Immunization of Source Plasma donors using unlicensed vaccines must be conducted under an Investigational New Drug application (see 21 CFR Part 312). The administration of the vaccine may be performed by a licensed physician or a trained person under his supervision (21 CFR 640.66) (e.g. a physician substitute). Some establishments have received CBER approval under 21 CFR 640.120 for the physician substitute to perform the scheduling of the injection and the evaluation of the donor’s clinical response.

  1. Red Blood Cell (RBC) Immunization Programs

Immunization programs involving qualified red blood cells from a source approved by CBER require approval in the BLA or a pre-approval supplement (PAS) (21 CFR 601.12(b)). A pre-approval inspection is needed for implementation of red blood cell immunization programs in Source Plasma establishments.

Donors who have not been previously immunized (also known as “de Novo donors”) should be immunized only against Rho(D). Immunizations with other RBC antigens should be limited to donors with the corresponding preexisting alloantibodies. Only RBCs that have been qualified should be used to immunize Source Plasma donors. The qualification process includes, among other things, testing for all communicable disease agents as required and recommended by FDA, and cryopreservation and storage under quarantine for at least 12 months.

During the inspection,

  1. Determine if the establishment has the appropriate CBER approval for each immunization program.
  2. Determine if Source Plasma donors meet eligibility requirements in 21 CFR 640.63 and that the immunization complies with 21 CFR 640.66.
  3. Determine if the establishment’s process for obtaining consent for immunization informs donors of the hazards of immunization appropriate to the immunizing agent used (21 CFR 640.61).

Note : CBER recommends that only males or females who are incapable of bearing children participate in RBC immunization programs.

CBER recommends that donors not participate in more than one immunization program at a time.

  1. For red blood cell immunizations, determine if only a licensed qualified physician selects and schedules the antigen injection and evaluates the donor’s clinical response. (21 CFR 640.66)

A physician must be on the premises when RBC cell immunizations are performed (21 CFR 640.62). A PS or other trained individual under a physician’s supervision may administer immunizing agents (21 CFR 640.66).

Donors who participate in a RBC immunization program should receive required and CBER recommended testing, initially and at periodic intervals.

An immunized donor may return to normal Source Plasma collection (following a 12-month deferral period or an alternate deferral period approved by CBER under 21 CFR 640.120) if the donor fails to meet the titer requirement of the immunization program.

  1. Determine if the establishment uses only approved antigens or immunizing substances and that it handles and stores them appropriately. Determine if donors whose RBCs are used for immunization meet the eligibility requirements in 21 CFR 640.3.

Promptly notify CBER, Division of Inspections and Surveillance (HFM-650) at 301-827-6220 if a Source Plasma manufacturer uses red blood cells that were not qualified.

  1. If the establishment prepares RBCs for immunization, review all Whole Blood donor and recipient Source Plasma donor manufacturing records.
  2. Review the system for tracking RBCs from the Whole Blood donor to the red blood cell recipient / Source Plasma donor. Usually a lot numbering system is devised.
  3. Review both the Whole Blood donor and recipient Source Plasma donor communicable disease test records for any reactive or positive test results.
  4. Review records of donors who developed unexpected red blood cell antibodies.
  5. Determine if the products are labeled with the immunizing agent in accordance with 21 CFR 640.70(a).

Consult the following guidance documents for additional information.

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/
MemorandumtoBloodEstablishments/UCM062645.pdf

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/
MemorandumtoBloodEstablishments/UCM062818.pdf

F. Infrequent Plasmapheresis Collection Program

An establishment may collect Source Plasma from donors who meet whole blood donor suitability requirements, other than donation frequency, every four weeks or less frequently. The donor must weigh a minimum of 110 lbs. Note: If infrequent donors donate no more frequently than every four weeks, they do not require a new physical examination or a total plasma or serum protein or immunoglobulin composition. The maximum annual number of Source Plasma collections from a donor and the volume collected at each donation are described in the following document:

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/
MemorandumtoBloodEstablishments/UCM062648.pdf

NOTE: Immunized donors and donors in other special collection programs may be infrequent donors. Donors should participate in only one special collection program at a time.

If an infrequent donor returns for donation in less than 4 weeks or donates more than the maximum annual volume of Source Plasma, the Source Plasma establishment should follow all Source Plasma donor eligibility requirements, including medical examination and plasma or serum protein tests prior to considering the donor eligible for another donation (21 CFR 640.63).

During the inspection,

Determine if the establishment has an infrequent plasmapheresis collection program for Source Plasma. Determine if the establishment maintains and follows its SOPs.
 

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ATTACHMENT H

SPECIFIC INSTRUCTIONS FOR DONORS OF SOURCE LEUKOCYTES AND THERAPEUTIC EXCHANGE PLASMA (TEP)

Source Plasma establishment or blood banks may collect Source Leukocytes or Therapeutic Exchange Plasma (TEP) for further manufacture. Collection of these products is subject to the licensure provisions of Section 351(a) of the Public Health Service Act. Manufacturers must test each product for evidence of communicable disease agents as required in 21 CFR 610.40. Lookback requirements in 21 CFR 610.46 to 610.48 and recommendations also apply to these products. The SOPs and labeling for these programs must be submitted to CBER as a Pre-Approval Supplement under 21 CFR 601.12(b).

A. Source Leukocytes Collection Program

A blood bank, blood center or a Source Plasma manufacturer may collect Source Leukocytes as a by-product of Whole Blood collection, by manual plasmapheresis or automated apheresis. Donors must meet the eligibility requirements for Whole Blood donation or Source Plasma donation, as appropriate to the collection method (21 CFR 640.3, 640.63). Due to the short expiration period, manufacturers often ship Source Leukocytes under quarantine, prior to completing the testing required by 21 CFR 610.40. Manufacturers are expected to send the test results to consignees when testing is completed. As part of the review process, CBER approves the standard operating procedures and labels for Source Leukocytes. Collection methods include the following:

  1. By-product of Whole Blood Collection.
    • Donors must meet Whole Blood donor eligibility requirements. (21 CFR 640.3)
    • Collection frequency - no more frequent than once every eight weeks.
  2. Manual Apheresis
    1. Single unit as a by-product of manual apheresis with no additional monitoring of the donor
      1. Donors must meet Source Plasma donor eligibility requirements. (21 CFR 640.63)
      2. Collection frequency - no more frequent than once every eight weeks
      3. Manufacturers may collect Source Leukocytes only from the first unit of the 2-unit plasmapheresis collection.
    2. Single unit as a by-product of manual apheresis with additional monitoring of donor
      1. Donors must meet Source Plasma donor eligibility requirements (21 CFR 640.63)
      2. Collection frequency:
        1. No more frequently than once in 48 hours or twice in a 7-day period
        2. Total Source Leukocytes donations in one year should not exceed 32 units.
    3. Donors should have a white blood cell count of > 4000 per cubic millimeter on a blood sample tested within 7 days prior to each collection.
    4. The manufacturer may collect Source Leukocytes from one or both units of whole blood in a 2-unit plasmapheresis collection.

     

  3. Automated Apheresis

Currently, only the Haemonetics PCS-2 is approved for automated collection of Source Leukocytes. Licensing criteria for collection of Source Leukocytes using the automated device include, but are not limited, to the following:

  • Donor must meet Source Plasma donor eligibility criteria (21 CFR 640.63).
  • Collection frequency – should be no more frequent than once in a 7-day period and no more than 16 collections from a donor in one year.
  • Donor should have a white blood cell count of > 4000 per cubic millimeter on a blood sample tested within 7 days prior to each collection.

During the inspection,

  1. Review the establishment’s SOPs.
  2. Determine if the firm is following its written procedures for Source Leukocyte manufacture.

B. Therapeutic Exchange Plasma (TEP) Collection Program

Therapeutic plasmapheresis is a medical procedure for treatment of certain diseases and is carried out under a physician’s order. The manufacturer removes plasma incrementally and infuses other fluids to replace the plasma. The plasma derived from these procedures is limited to the manufacture of specific in vitro diagnostic reagents for which there are no alternate source materials.

During the inspection,

  1. Determine if personnel follow the establishment’s written procedures, particularly criteria for selection of donors and the initial quarantine of product until tested for agents of communicable diseases as required by 21 CFR 610.40.
  2. Donors may have a disorder that is transmissible or that is of unknown etiology. TEP is potentially hazardous; therefore, many facilities choose to quarantine it in a secure storage area.
  3. Determine if disposition records indicate the disposition or destruction of each container of TEP collected.

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ATTACHMENT I

BROKERS

Brokers are generally inspected only if the broker takes possession of products and performs a manufacturing operation; e.g., culling out unsuitable Source Plasma units, relabeling, or repackaging.

During the inspection,

At a minimum, evaluate the broker’s compliance with the following regulations: 21 CFR 606.100(b)(10), 606.160(b)(2) and (3), 606.165, 607, and 640.70. These regulations pertain to storage, records of product receipt, product pooling, labeling, distribution and registration.

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ATTACHMENT J

CONTRACTORS

A manufacturer may contract with another establishment to perform one or more manufacturing steps. Both the manufacturer and contractor are responsible for product quality. The Source Plasma, Source Leukocytes, or TEP manufacturer, as the license holder, remains responsible for compliance with applicable product and establishment standards. The contractor is responsible for complying with applicable CGMP. Inspect contractors that perform services, such as testing, pooling, culling, and/or preparing and supplying Red Blood Cells for immunization to a manufacturer.

During the inspection,

  1. Determine the extent of services provided.
  2. Determine each party’s responsibility for the product or operations performed.
  3. Determine who prepared the SOPs used by the contractor.
  4. Determine who performed product quality control tests
  5. Determine if the establishment holding the approved BLA has a system for approving and monitoring contractors.

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