Regulatory Issues in Transfusion Medicine

Regulation Versus Accreditation

Regulation and accreditation are not the same thing. Regulation involves laws (rules) that must be followed, while accreditation is a seal of approval from an independent accrediting body, such as AABB or The Joint Commission, certifying that an organization or individual has met specific standards. Accreditation is voluntary; regulation is law. Both accreditation and regulation are drivers of safety in transfusion medicine. It is interesting to note that in transfusion medicine, accreditation is frequently so essential that many accreditation requirements have the same effect as regulations, but accreditation is based on standards, which are not legally binding.

The Food and Drug Administration

The FDA’s objective is to ensure a safe and effective blood supply and to provide regulatory oversight of the blood supply in the United States. This agency regulates blood establishments under the authority of Title 21 of the CFR, Parts 211 through 226 and Parts 600 through 680. These sections include good manufacturing practices for drugs and biologics. The descriptor blood establishment includes blood banks and hospital transfusion services as well as other facilities, such as plasma collectors and laboratories that perform testing on donor blood. Blood establishments that manufacture medical devices such as blood establishment computer software (BECS) are also regulated under Title 21 Part 820, but these regulations are not discussed in this chapter.

The FDA has three major functions:

• 1.

  Development and promulgation of regulations

• 2.

  Registration and licensure of blood establishments

• 3.

  Inspection and compliance actions

The FDA’s Center for Biologics Evaluation and Research (CBER) works closely with other parts of the Public Health Service (PHS) to establish blood regulations and to identify and respond to potential threats to blood safety or supply. Regulations promulgated by the FDA are binding both on the agency and the blood establishment industry. The FDA also issues guidance documents that, while not laws, do represent the FDA’s current thinking on the handling of a particular subject.

FDA oversight reflects and supports five overlapping layers of safety in the manufacture of blood and blood products: donor screening; testing of the blood for transfusion transmissible agents; maintenance of donor deferral lists; quarantine to prevent the distribution of unsuitable blood and blood products; and investigation of breaches in safety with required and appropriate corrective action.

Registration and Licensure

Section 510 of the Federal Food, Drug, and Cosmetic Act (the Act) requires drug and device manufacturers, including manufacturers of biological products, to register with the FDA. Title 21 CFR Part 607 lists and describes the registration requirements for manufacturers of human blood and blood products. Transfusion services are commonly registered, as opposed to being licensed, while most blood banks in which blood is collected are both licensed and registered. This has changed somewhat as transfusion services have adopted methodologies to test platelets on day 4 and 5 or to extend platelet life to 6 or 7 days. These transfusion services must now register with the FDA as a manufacturer. Unless a product crosses states lines, licensure is not required. Some transfusion services are exempt from registration if they do not engage in activities that the FDA has defined as requiring registration. Activities that are exempt include routine compatibility testing, product pooling, product thawing, and transfusion. Activities generally requiring registration include, but are not limited to, collection, processing (including product manipulations), testing, storage, and distribution.

Section 351 of the PHS Act requires specific licensure for some biological products, specifically those involved in interstate commerce. Blood banks that participate in interstate commerce must be licensed with the FDA, and licensure applies to both facilities and products. To obtain a license, a blood bank must submit a Biologics License Application (BLA). This may require the submission of data for agency review. The FDA will also conduct an inspection of the requesting facility before issuing a license. Once a license is granted, the FDA will routinely inspect the facility to ensure continued compliance with cGMPs.

Once approved, changes to a BLA require FDA notification and, in some cases, the changes may require FDA approval before an organization can implement them. The FDA considers changes in three broad categories. Those that have a substantial potential to adversely affect the final product are known as prior approval supplement changes; the FDA may take up to 12 months to act on such changes. Changes with a moderate potential to adversely impact the final product can be submitted in the second category, CBE 30. This is shorthand to describe a change to be effective not less than 30 days from submission to the FDA. Minor changes, such as a modification to standard operating procedures (SOPs) that do not affect a major manufacturing step, can be implemented immediately and must be described in the organization’s annual report to the FDA.

Inspections and Compliance Actions

The Food, Drug, and Cosmetic Act provides authority for the FDA to inspect blood banks and transfusion services. Through a memorandum of understanding issued in 1980, hospital transfusion services that are exempt (as above) are covered by and may be inspected by the Center for Medicaid and Medicare Services (CMS), but the FDA reserves the right to also inspect these facilities. Under the oversight of the Office for Regulatory Affairs, FDA investigators, also known as consumer safety officers, inspect blood banks and transfusion services. The inspections are typically unannounced, but they are typically performed at reasonable times of day and in a reasonable manner. The FDA presents Form 482, Notice of Inspection, on arrival at a facility. This form provides information about the inspection, including the legal authority by which the inspection is authorized. If the investigator sees evidence of noncompliance with FDA regulations, a written statement of the noncompliance, referred to as an observation, is provided on Form 483 and reviewed with facility leadership at the conclusion of the inspection. Although a written response it not required by law, most blood banks and transfusion services will respond to the Form 483 by writing a corrective action plan. Once an inspection is completed, the FDA issues an Establishment Inspection Report, which is a narrative that provides a detail about a particular inspection. Routine inspections usually occur every two years, although the FDA can choose to inspect more frequently. The FDA may also conduct inspections to follow up on an issue from a prior inspection or as the result of a complaint.