Inspections, Compliance, Enforcement, and Criminal Investigations

SUBCHAPTER 5.7 - BIOLOGICS

Table of contents

 5.7.1 - DEFINITION

A "biological product" means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings (Public Health Service Act Sec. 351(i)). Additional interpretation of the statutory language is found in 21 CFR 600.3. Biological products also meet the definition of either a drug or device under Sections 201(g) and (h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).

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

 5.7.2 - 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. The periodic CGMP inspections and compliance operations of plasma fractionated products, allergenic products, vaccines, gene and cell therapy products, and biological in vitro diagnostic devices are led by investigators and compliance officers on  Team Biologics. Team Biologics investigators and its compliance officers report to DMPTPO.Inspections of unlicensed CBER-regulated medical devices are not covered by the Team (e.g., blood establishment software) but are conducted by District investigators who may or may not be part of the Biologics Cadre. See IOM 2.2 for a discussion of statutory authority. CBER maintains the lead for pre-licensing and pre-approval inspections of biological products, while ORA customarily leads PMA/510(k) inspections.

 5.7.2.1 - Authority

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, with the exception of certain human cells, tissues, and cellular and tissue-based products (HCT/Ps) regulated solely under Section 361 of the Public Health Service Act (see 21 CFR 1271.10). Blood and blood products for transfusion are prescription drugs under the FD&C Act.  Under the FD&C Act, source plasma and recovered plasma may have the legal identity of either a drug or device depending on its intended use. 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. 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)).

 5.7.2.1.1 - BLOOD AND SOURCE PLASMA INSPECTIONS

The investigators in the Biologics Cadre perform inspections of blood and plasma establishments. For blood bank and source plasma establishment 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 biological 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 bank and source plasma establishments.

 5.7.2.1.2 - HUMAN TISSUE INSPECTIONS

In February 1997, FDA proposed a new, comprehensive approach to the regulation of human cellular and tissue-based products (now called human cells, tissues, and cellular and tissue-based products or HCT/Ps). The agency announced its plans in two documents entitled, "Reinventing the Regulation of Human Tissue" and "A Proposed Approach to the Regulation of Cellular and Tissue-based Products" (62 FR 9721, March 4, 1997).

Since that time, the agency has published three final rules and one interim final rule to fully implement the proposed approach. On January 19, 2001, FDA finalized regulations to create a new, unified system for registering HCT/P establishments and for listing their HCT/Ps (registration final rule, 66 FR 5447). Part of the definition of "human cells, tissues, or cellular or tissue-based products" became effective on January 21, 2004. On January 27, 2004 (69 FR 3823), we issued an interim final rule to except human dura mater and human heart valve allografts from the scope of that definition until all of the tissue rules became final. On May 25, 2004, FDA finalized regulations requiring most cell and tissue donors to be tested and screened for relevant communicable diseases (donor-eligibility final rule, 69 FR 29786). On November 21, 2004, FDA finalized regulations requiring HCT/P establishments to follow current good tissue practice (CGTP), which governs the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps; recordkeeping; and the establishment of a quality program. The new CGTP regulations also contain certain labeling and reporting requirements, as well as inspection and enforcement provisions (GTP final rule, 69 FR 68612). The donor eligibility and CGTP rules became effective May 25, 2005.

Part 1271 contains six subparts:

  1. Subpart A of part 1271 - general provisions
  2. Subpart B of part 1271 - registration
  3. Subpart C of part 1271 - screening and testing of donors to determine eligibility
  4. Subpart D of part 1271 - provisions on CGTP
  5. Subpart E of part 1271 - certain labeling and reporting requirements
  6. Subpart F of part 1271 - inspection and enforcement provisions.

The subparts apply as follows:

Subparts A through D apply to all HCT/Ps, i.e., to those HCT/Ps described in Sec. 1271.10 and regulated solely under section 361 of the PHS Act, and to those regulated as drugs, devices, and/or biological products. Subparts E and F, which pertain to labeling, reporting, inspection, and enforcement, apply only to those HCT/Ps described in Sec. 1271.10 and regulated solely under section 361 of the PHS Act. However, with the exception of two provisions (Sec. 1271.150(c) and 1271.155) subparts D and E are not being implemented for reproductive HCT/Ps described in 21 CFR 1271.10 and regulated solely under section 361 of the PHS Act.

HCT/Ps subject to the provisions of 21 CFR Part 1271 include, but are not limited to, bone, ligaments, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.

For HCT/P inspections, use the CP 7341.002, “Inspections of Human Cells, Tissues, and Cellular and Tissue-Based Products.”

 5.7.2.2 - Donor Confidentiality

Blood bank, source plasma, 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) and 1271.400(d) provides for copying records during an 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 5.2.5 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 5.3.8.6.

 5.7.2.3 - Inspectional Objectives

The inspectional objective for biological products is to assure the products are safe, effective, and contain the quality and purity they purport to possess, and are properly labeled. The inspectional objective for HCT/Ps is to assure that HCT/Ps are recovered, processed, stored, labeled, packaged and distributed, and the donors are screened and tested, in a way that prevents the introduction, transmission, or spread of communicable diseases. Facilities will be inspected for conformance with:

  1. Provisions of the PHS Act and FD&C Act,
  2. Applicable regulations in 21 CFR 210-211600-680, and 820.
  3. HCT/P regulations in 21 CFR 1270 and 1271.
  4. FDA Policies, which include guidance to the industry, and the Compliance Policy Guides Chapter 2.

 5.7.2.4 - 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 the Centers for Medicare and Medicaid Services (CMS) on transfusion services;
  2. Correspondence from the firm depicting any changes since the last inspection;
  3. Firm's registration and product listing information;
  4. DMPTPO Guide to Inspections of Source Plasma Establishments 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).

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 (CP) available on the CBER internet site at (CBER CP Website).

The OSHA regulation 29 CFR 1910.1030 dated December 6, 1991, was intended to protect health care workers from blood borne 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) and (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 OO, OMPTO, Division of Medical Products and Tobacco Program Operations or see CBER's web site.

 5.7.2.5 - Inspectional Approach

Use the Compliance Program Guidance Manuals (CP) and Guides to Inspection of Source Plasma Centers and Infectious Disease Marker Testing Facilities for inspectional instructions. 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 the 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.

For blood banks and source plasma establishments, refer to CP 7342.001 and 7342.002 for a discussion of the systems approach to inspection. The CP incorporates a systems-based approach to conducting an inspection and identifies five (5) systems in a blood bank and source plasma establishment operation for inspection. Each system may not be in a particular establishment operation; therefore, the inspection should focus on the systems present. The CP directs an in-depth audit of the critical areas in each system. A multi-layered system of safeguards has been built into the blood collection, manufacturing and distribution system to assure a safe blood supply.

For HCT/P establishments, refer to CP 7341.002.

For Biological Drug Products, refer to CP 7345.848.

For Licensed Viral Marker Test Kits, refer to CP 7342.008.

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

 5.7.2.6 - Regulations, Guidelines, Recommendations

Guidance documents for industry are made available to the public in accordance with good guidance practice regulations at 21 CFR 10.115. The contents of most of these documents are incorporated into the establishment's SOPs and/or license applications or supplements. In addition, DMPTPO has issued Source Plasma Establishment and Infectious Disease Marker Testing Facility Inspectional Guides to be used by investigators during inspections.

Deviations from guidance documents 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 is not aware of any of these documents, provide the telephone number of CBER's Office of Communication, Outreach and Development, Division of 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 or the appropriate CBER product office.

 5.7.2.7 - Technical Assistance

Several FDA regions and 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/ OO/OMPTO/DMPTPO, 301-796-0358, are available for telephone or on-site consultation and assistance in problem areas.Highlighted to denote updated text

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

 5.7.2.8 - CBER Bioresearch Monitoring

Bioresearch monitoring (BIMO) assignments for biological products will generally be issued by the Center for Biologics Evaluation and Research (CBER) (see IOM 5.5.6).

 5.7.3 - REGISTRATION, LISTING AND LICENSING.

 5.7.3.1 - Registration and Listing

See IOM 2.9.3.1.

 5.7.3.1.1 - TRANSFUSION SERVICES

Most transfusion services are exempt from registration under 21 CFR 607. This includes facilities that are certified under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR Part 493 to perform the FDA-required tests on blood or has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services, and are 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.

 5.7.3.1.2 - HCT/PS

Establishments manufacturing HCT/Ps (human cells, tissues, or cellular or tissue-based products) as defined in 21 CFR 1271.3(d) must register and list using form FDA 3356.  Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, cornea, hematopoietic stem cells derived from peripheral and cord blood, manipulated autologous chondrocytes, and semen or other reproductive tissue. Establishments manufacturing HCT/Ps regulated as medical devices, drugs or biological drugs must also register and list with the FDA pursuant to 21 CFR 1271 using form FDA 3356.

 5.7.3.1.3 - LABORATORIES

Laboratories performing infectious disease testing of donors of blood or blood components or HCT/P 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 and HCT/P testing operations.

 5.7.3.1.4 - MILITARY BLOOD BANKS

Inspection of military blood banks is an ORA responsibility. 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.

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

 5.7.3.2 - MOUs

Under the 1983 Memorandum of Understanding (MOU) between the FDA and the Centers for Medicare and Medicaid Services (CMS, formerly Health Care Financing Administration - HCFA), CMS agreed to survey these facilities that engage in minimal manufacturing in order to minimize duplication of effort and reduce the burden on the affected facilities while continuing to protect transfusion recipients. However, no transfer of statutory functions or authority is made under the MOU and the FDA retains legal authority to inspect these unregistered transfusion services whenever 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 under the MOU, you should terminate the inspection and report as such. See Federal Cooperative Agreements Manual - FDA/HCFA Memorandum of Understanding.

 5.7.3.3 - Biologic License

See IOM 2.9.3.2. A biologics license application (BLA) shall be approved only after inspection of the establishment(s) listed in the application and upon a determination that the establishment complies with the standards established in the BLA and the requirements prescribed in applicable regulations (21 CFR 601.20(d)). CBER is responsible for conducting all pre-license (PLI) and pre-approval (PAI) inspections of CBER-regulated products. These inspections are part of the review of a BLA or BLA supplement. CBER identifies the scope of the inspection and invites ORA to participate in the inspections. Copies of CBER's PLI and PAI inspection reports are forwarded to the districts and should be part of the firm's file.

 5.7.3.4 - 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 pre-license inspection (PLI). 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.

 5.7.4 - 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.

 5.7.5 - TESTING LABORATORIES

Blood bank, source plasma, and HCT/P  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. Certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR part 493, or has met equivalent requirements as determined by CMS.

Laboratories performing required testing for HCT/Ps must:

  1. Test using approved FDA-licensed, approved or cleared donor screening tests according to the manufacturers instructions, and
  2. Be either certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR part 493, or has met equivalent requirements as determined by CMS.

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

 5.7.6 - 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.

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