Contents

SUBCHAPTER 560 - BIOLOGICS

560 - DEFINITION

A "biological product" means any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or its derivatives (or any trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of diseases or injuries of man (Public Health Service Act Sec. 351(i)).  Additional interpretation of the statutory language is found in 21 CFR 600.3. Biological products are either drugs or devices, depending on their use and mode of action.

Veterinary biologicals are subject to the animal Virus, Serum, and Toxin Act which is enforced by USDA (21 U.S.C. 151-158).

561 - BIOLOGICS INSPECTIONS

FDA has developed a strategy known as "Team Biologics", a reinvention of the agency's approach to inspectional coverage of certain biological products. Team Biologics consists of the "Blood Bank Cadre" and the "Core Team." The periodic cGMP inspections and compliance operations of plasma fractionated products, allergenic products, vaccines, and biological in vitro diagnostic devices are now led by investigators and compliance officers in the Core Team. The investigators in the Cadre perform inspections of blood banks, plasmapheresis centers, tissue banks, and other blood establishments. The Cadre members report to their ORA District. The Core Team investigators report to ORO headquarters; Core Team compliance officers report to OE. Inspections of certain CBER-regulated medical devices are not covered by the Core Team (e.g., blood establishment software) are conducted by District investigators who may or may not be part of the Cadre. See IOM 701 for a discussion of statutory authority. CBER maintains the lead for pre-licensing inspections of biological products, while ORA customarily leads PMA/510(k) inspections.

Biological products are regulated under the authority of Section 351 of the Public Health Service Act and under the Food, Drug and Cosmetic Act, as drugs or devices. Blood and blood products for transfusion are prescription drugs under the FD&C Act. Recovered plasma and source plasma intended for manufacturing non-injectable products and in-vitro diagnostics, e.g., HIV home collection kits, are devices.

Section 351(a) of the PHS Act provides for licensure of biological products and inspection of the products covered is per 351(d). Most biological drugs are licensed. Radioactive biological products require NDAs (21 CFR 505) unless they have an unrevoked and unsuspended license issued prior to August 25, 1975.

The investigational new drug application regulations (21 CFR 312) also apply to biological products subject to the licensing provisions of the PHS Act. However, investigations of blood grouping serum, reagent red blood cells, and anti-human globulin in-vitro diagnostic products may be exempted (21 CFR 312.2(b)).

For blood bank and plasmapheresis center inspections (CP 7342.001 & 7342.002) use the CGMPs for Blood and Blood Components (21 CFR 606) as well as the general requirements for biological products (21 CFR Part 600), the general biological product standards (21 CFR Part 610), and the additional standards for human blood and blood products (21 CFR Part 640.) The drug GMPs (21 CFR 210/211) also apply to biologic drugs. In the event it is impossible to comply with both sets of regulations, the regulation specifically applicable to the product applies. This would generally be Parts 606 and 640 of the regulations in the case of blood banks or plasma centers.

FDA is in the process of revising the regulation of human tissues, cells, and cellular and tissue-based products. CBER currently regulates human tissue intended for transplantation under 21 CFR Part 1270. This regulation applies to tissue recovered, processed, stored, or distributed by methods which do not change tissue function or characteristics and is not currently regulated as a human drug, biological product, or medical device. Examples of such tissues include: bone, skin, corneas, ligament and tendon. Part 1270 requires tissue establishments to screen and test donors, to prepare and follow written procedures for the prevention of the spread of communicable disease, and to maintain records. Registration and Listing requirements for human cells, tissues, and cellular and tissue based products (HCT/Ps) are found in 21 CFR 1271.

Blood and human tissue establishments are sensitive to maintaining confidentiality of donor names. The mere reluctance to provide records is not a refusal. However, FDA has the authority under both the PHS and the FD&C Acts to make inspections and 21 CFR 600.22 (g) provides for copying records during a blood establishment inspection. For prescription drugs, section 704 of the FD&C Act specifically identifies records, files, papers, processes, controls, and facilities as being subject to inspection.

If you encounter problems accessing records, explain FDA's authority to copy these records. IOM 514 should be followed if a refusal is encountered. When donor names or other identifiers are necessary, they may be copied, but the information must be protected from inappropriate release. See IOM 527.06.

The inspectional objective is to ensure biological products are safe, effective, and contain the quality and purity they purport to possess, and are properly labeled. Facilities will be inspected for conformance with:

1. Provisions of the PHS Act and FD&C Act,
2. GMPs in 21 CFR 210-211, 600-680, and 820,
3. FDA Policies, which include guidance to the blood and blood products industry, and the Compliance Policy Guides Chapter 2.

561.01 - Preparation

Review the district files of the facility to be inspected and familiarize yourself with its operation and compliance history. Review:

1. Appropriate Compliance Programs and related Compliance Policy Guides (CPG), Chapter 2.
   NOTE: Federal Cooperative Agreements Manual; MOU with the Department of Defense, and MOU with Health Care Financing Administration (HCFA) on transfusion services;
2. Correspondence from the firm depicting any changes since the last inspection;
3. Firm's registration and product listing information;
4. DFI's Guide to Inspections of Source Plasma Establishments, Guide to Inspections of Blood Banks, and Guide to Inspections of Infectious Disease Marker Testing Facilities.
5. Biological Product Deviation Reports, Adverse Reaction Reports, complaints, and recalls;
6. Guideline for Quality Assurance in Blood Establishments, (July 14, 1995).
7. Draft Guideline for the Validation of Blood Establishment Computer Systems (September 28, 1993).

Through guidance documents, CBER sets forth its inspection policy and regulatory approach. A list of these documents is attached to the current Compliance Program Guidance Manuals (CPGM).

The OSHA regulation 29 CFR 1910.1030 dated December 6, 1991, was intended to protect health care workers from bloodborne pathogens, including those involved in the collection and processing of blood products. The regulation defines expectations for the use of gloves, hand washing facilities, decontamination of work areas, waste containers, labeling and training of employees and exemptions for volunteer blood donor centers. FDA Investigators should adhere to these safety guidelines during inspections or related activities in establishments that process biologically hazardous materials.

Become familiar with the OSHA regulations and their applicability to 21 CFR 606.40(d)(1) & (2), which require the safe and sanitary disposal for trash, items used in the collection and processing of blood and for blood products not suitable for use. Consult your district biologics monitor for copies of the above references. Additional copies may be obtained from ORO, Division of Field Investigations (DFI), Biologics Group, HFC-130, (301) 827-5653 or see CBER's web site at http://www.fda.gov/cber.

561.02 - Inspectional Approach

Use the Compliance Program Guidance Manuals (CPGM) and Guides to Inspection of Blood Banks, Source Plasma Centers and Infectious Disease Marker Testing Facilities for inspectional guidance. The EIR must clearly identify the areas covered. The report should include a summary of the inspection, the FDA 482, the FDA 483, if issued, and required FACTS EI Record.

Particular attention should be given to biological products deviation reports indicative of problematic areas or processes, adverse reactions, transfusion associated AIDS (TAA), transfusion or donation associated fatalities and hepatitis and HIV lookback procedures. For additional information regarding TAA, see CP 7342.001. The follow-up investigations to such reports should also be covered.

Complaints, in particular those involving criminal activity, must be promptly investigated and coordinated with other agency components as needed.

A multi-layered system of safeguards has been built into the blood collection, manufacturing and distribution system to assure a safe blood supply.

Refer to CPGM 7342.001 and 7342.002 for a discussion of the systems approach to inspection. The CPGM incorporates a systems-based approach to conducting an inspection and identifies five (5) systems in a blood establishment operation for inspection. Each system may not be in a particular blood establishment operation; therefore, the inspection should focus on the systems present. The CPGM directs an in-depth audit of the critical areas in each system.

If Investigators encounter products not specifically referenced in the regulations, they should contact CBER/OCBQ/ Division of Inspections and Surveillance for guidance.

561.03 - Regulations, Guidelines, Recommendations

Guidance documents for industry are sent directly from CBER or made available on the CBER web site or via CBER's FAX Information System. The contents of most of these documents are incorporated into the establishment's SOPs and/or license applications or supplements. Also, DFI has issued Blood Bank, Source Plasma Establishment and Infectious Disease Marker Testing Facility Inspectional Guides to be used by investigators during inspections.

Deviations from the guides must not be referenced on a FDA 483. However, since these documents are often related to specific GMP requirements, in most cases deviations can be referenced back to the GMP. If a deviation is observed during an inspection and the investigator relates it to the regulations or law, then the item may be reported on the FDA 483. During the discussion with management, the relationship of the deviation to the regulation or law, or accepted standard of industry, should be clearly explained.

If an establishment indicates it has not received any of these documents, provide the CBER web site and the telephone number of CBER's Office of Communication, Training, and Manufacturers Assistance, 301-827-2000.

If a firm claims approval for an alternative procedure, verify by reviewing the firm's written approval letter. Approved alternative procedures may be verified by contacting CBER/Division of Blood Applications.

561.04 - Technical Assistance

Several regions and some districts have biologics specialists who are available for technical assistance and consultation. Do not hesitate to avail yourself of their services.

The services of expert investigators in ORA/ORO/ Division of Field Investigations (DFI), Biologics Group, HFC-130, (301) 827-5653, are available for telephone or on-site consultation and assistance in problem areas.

CBER/OCBQ, Division of Inspections and Surveillance (HFM-650), (301) 827-6220, can provide technical assistance on blood banking principles, testing issues, and can coordinate assistance with other CBER offices.

561.05 - CBER Bio-research Monitoring

Bio-research monitoring (BiMO) assignments for biological products will generally be issued by the Center for Biologics Evaluation and Research (CBER) (see IOM 545).

562 - REGISTRATION, LISTING AND LICENSING

See IOM 773.01.

Registration and Listing - Most transfusion services are exempt from registration under 21 CFR 607. This includes facilities approved for Medicare reimbursement and engaged in the compatibility testing and transfusion of blood and blood components, but which neither routinely collect nor process blood and blood components. Such facilities include establishments:

1. Collecting, processing and shipping blood and blood components under documented emergency situations,
2. Performing therapeutic phlebotomy and therapeutic plasma exchange after which the product is discarded,
3. Preparing recovered human plasma and red blood cells,
4. Pooling products/platelets for in-house transfusion,
5. Thawing frozen plasma or cryoprecipitate for transfusion.

Although FDA transferred the routine inspection responsibility for these establishments to the Centers for Medicare and Medicaid Services (CMS, formerly Health Care Financing Administration - HCFA), the FDA retains legal authority to inspect them if warranted. When appropriate, Districts should conduct inspections jointly with the CMS regional liaison. If you determine during a routine inspection an establishment is a CMS obligation, you should terminate the inspection and report as such. See Federal Cooperative Agreements Manual - FDA/HCFA Memorandum of Understanding.

Tissue establishments manufacturing HCT/Ps (Human Cellular and Tissue-Based Products) currently regulated under 21 CFR Part 1270 must register and list. Establishments manufacturing HCT/Ps currently regulated under 21 CFR 1270 (e.g., bone, skin, corneas, and fascia) must have registered and listed by May 4, 2001. Manufacturers of HCT/Ps not currently regulated under this part (e.g., reproductive cells, and tissue and hematopoietic stem cells) must register when all of 21 CFR part 1271 is finalized and effective. These manufacturers may voluntarily register before then, but will not be subject to the regulations or inspections until such time as the regulations are final. Establishments manufacturing HCT/Ps currently regulated as medical devices, drugs or biological drugs registered with the FDA using forms FDA 2891 or 2656 will begin to register and list with FDA using Form FDA 3356 when Part 1271 is finalized.

Laboratories performing infectious disease testing on blood or blood components are an FDA obligation and required to register. Clinical laboratories were previously exempted from registration by 21 CFR 607.65(g), but FDA revoked this regulation. Your inspections should focus on activities relevant to blood product testing operations.

Inspection of military blood banks is a responsibility of the field. These facilities are required to meet the same standards as other blood banks although military emergencies may require deviations from the standards. A separate license is held by each branch of the service; although each individual establishment may be licensed or unlicensed, all are required to register. Districts should notify the appropriate military liaisons 30 days before inspection of a military facility. For additional information on inspection of government establishments, see Compliance Program Guidance Manual 7342.001, the Federal Cooperative Agreements Manual, and the MOU with Department of Defense Regarding Licensure of Military Blood Banks.

Field Management Directive 92, Agency Establishment Registration and Control Procedures, details the registration process within the agency. Refer to FDA Compliance Policy Guides (CPG), Chapter 2, Sub-chapter 230 (230.110), for additional information on registration.

Ensure the firm's current registration forms reflect actual operations.

Biologic License - See IOM 773.02. Prior to granting a license, field personnel and CBER jointly conduct a pre-license inspection of the firm for compliance with the firm's license application and regulations. Copies of CBER's pre-license inspection reports are forwarded to the districts and should be part of the firm's file.

Approval of Biological Devices - There must be a pre-approval inspection (PAI) of the establishment for compliance with the QS/GMP regulation and the firm's PMA. For licensed devices, CBER conducts the PAI. Devices used in the collection and testing of blood for transfusion are approved/cleared through the PMA/510(k) authorities. ORA Investigators customarily inspect the CBER regulated devices, which are subject to PMA/510(k) applications.

563 - RESPONSIBLE INDIVIDUALS

In licensed establishments, the applicant or license holder may designate an authorized official(s) to represent the applicant to the FDA in matters of compliance. The FDA 482 and any 483 should be issued to the most responsible person on the premises at the time of inspection. An exact copy of the FDA 483 should also be forwarded to the top official of the firm if that person did not receive the FDA 483. The designation as authorized official does not necessarily mean that individual is the most responsible for any non-compliance of the firm. In licensed or unlicensed facilities, establish and document all individuals responsible for violations and their reporting structure in the organization.

564 - TESTING LABORATORIES

Blood establishments may use outside testing laboratories to perform required testing. Laboratories conducting testing for licensed blood banks are usually licensed. CBER may approve the use of a non-licensed laboratory to do required testing, provided the lab is capable of performing the tests and the lab registers with CBER prior to CBER approving the licensing arrangement. Laboratories performing required testing for Source Plasma manufacturers must either be (1) licensed or (2) meet the standards of the Clinical Lab Improvement Act (CLIA) and be qualified to perform the required testing. Clinical laboratories are specifically exempted from registration, but are encouraged to voluntarily register. Laboratories performing testing for manufacturers of blood and blood components are FDA inspectional obligations whether or not they are exempt from registration.

Guidance for inspecting testing laboratories is included in the appropriate Compliance Program Guidance Manuals. Coordinate the inspection of non-registered laboratories with HCFA regional office contacts. If a testing laboratory is located outside of the district, request an inspection by the appropriate district office.

565 - BROKERS

Blood establishments may use brokers to locate buyers for products such as recovered plasma or expired red blood cells. These articles are used for further manufacture into products such as clinical chemistry controls and in-vitro diagnostic products not subject to licensure. Fractionators also use brokers to locate suppliers of plasma under the short supply provisions (21 CFR 601.22). During inspections, determine if the facility is selling products to any brokers. If brokers are used, determine if the brokered products are shipped to a facility operated by the broker or directly to the consignee.

Brokers who take physical possession of blood products and engage in activities considered manufacturing or labeling are required to register and are included in the OEI for routine inspection under the blood bank compliance program. Brokers who only arrange sales of or store blood and blood components, but do not engage in manufacturing activities are not required to register.