This is a new Compliance Policy Guide (CPG) concerning the requirements for microbiological control in Anti-Human Globulin (AHG) and Blood Grouping Reagents (BGR). It is an update to the Compliance Policy Guides Manual (August 1996), and will be included in the next printing of the manual. It is intended for FDA personnel and will be added to the electronic version of the CPG manual available on the Internet.
This document represents the Agency's current thinking on the microbiological control requirements for An-Human Globulin and Blood Grouping Reagents. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
The Quality System Regulation found at 21 CFR 820 applies to the manufacturing process for in vitro diagnostic products (IVDs). IVD products regulated by CBER, including AHG and BGR, may have additional manufacturing requirements as a condition of licensure based on the biologics regulations found in 21 CFR 600-680.
IVDs fall into three categories relative to microbiological control: (1) IVDs labeled as sterile; (2) IVDs that are microbiologically controlled, but are not labeled as sterile; and (3) IVDs that are not microbiologically controlled. An in-depth discussion of these three types of IVDs can be found in the Guideline for the Manufacture of In Vitro Diagnostic Products, January 10, 1994, issued by CDRH, which applies to products regulated under the Public Health Service Act and/or the Federal Food, Drug, and Cosmetic Act. The level of microbiologic control necessary for the manufacture of a specific IVD is established by the manufacturer's process validation studies in accordance with 21 CFR 820.75. Most, if not all, IVDs regulated by CBER fall into the category of microbiologically controlled products, including BGR and AHG.
The requirement for sterility for biological products is found in 21 CFR 610.12; however, there is a specific exception to the test for sterility for AHG and BGR [21 CFR 610.12(g)(4)(i)]. The biologics regulations describe additional standards for BGR (21 CFR 660.20) and AHG (21 CFR 660.50). Sections 660.20(a) and 660.50(a) state that BGR and AHG, respectively, must "...be prepared by a method to yield consistently a sterile product." Historically, for purposes of the manufacture of BGR and AHG, CBER has interpreted this to mean that the manufacturing process should include a sterile filtration step and that the products must pass the thioglycolate test, unless otherwise approved through the licensing process. Unless specified in the license application, CBER does not expect AHG and BGR to be manufactured under aseptic conditions.
CBER recognizes that the additional standards for Blood Grouping Reagents and Anti-Human Globulin are confusing in that they may be interpreted to require these products to be manufactured under aseptic processing conditions. CBER intends to amend these regulations to delete the phrase "...be prepared by a method to yield consistently sterile product" for BGR and AHG because: (1) the original intent of the standard did not include aseptic processing; (2) the manufacturers do not claim these products as sterile on the product labels; (3) quality checks are required for the end users of licensed IVDs [21 CFR 606.65(c)]; (4) all BGR and AHG contain preservatives; and (5) historically, CBER's product and establishment experts have not requested sterility requirements during the license application review of these products.
REGULATORY ACTION GUIDANCE:
Investigators should not cite a manufacturer of BGR or AHG on the FDA Form-483 for not following aseptic processing procedures unless: (1) the product is labeled as sterile; (2) aseptic processing is required as part of their license; or (3) the firm is not following its own manufacturing SOPs. Manufacturers should develop the process control procedures necessary to ensure the product meets its specifications. Investigators should verify that the manufacturer has established appropriate specifications and validated the process control procedures, including those environmental conditions that could have an adverse effect on product quality. Investigators should consult with CBER's Office of Compliance and Biologics Quality, Program Inspection Branch (HFM-604) if they have any questions regarding the requirements for a particular firm.