Compliance Policy Guide  
CPG Sec. 280.110:  Microbiological 
Control Requirements - Licensed Anti-
Human Globulin & Blood Grouping 
Reagents 
 
 
Guidance for FDA Staff 
 
 
This guidance is for immediate implementation. 
 
 
 
FDA is issuing this guidance for immediate implementation in accordance with  
21 CFR 10.115(g)(4)(i).  Submit one set of either electronic or written comments on this 
guidance at any time.  Submit electronic comments to https://www.regulations.gov/.  Submit 
written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.  You should identify all comments with 
docket number FDA-2014-D-0428.   
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or 
from the Internet at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/biologics-guidances. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
 July 2020  Contains Nonbinding Recommendations 
Table of Contents 
 
I.  INTRODUCTION: ............................................................................................................ 1 
II.  BACKGROUND: ............................................................................................................... 1 
III.  POLICY: ............................................................................................................................. 2 
IV.  REGULATORY ACTION GUIDANCE: ........................................................................ 2 
 
 
 
i  Contains Nonbinding Recommendations 
Compliance Policy Guide 
CPG Sec. 280.110:  Microbiological Control Requirements - 
Licensed Anti-Human Globulin & Blood Grouping Reagents 
 
 
Guidance for FDA Staff 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
 
 
I.  INTRODUCTION:  
 
The purpose of this Compliance Policy Guide (CPG) is to provide guidance to FDA staff on the 
microbiological control requirements for Anti-Human Globulin (AHG) and Blood Grouping 
Reagents (BGR) licensed by the Center for Biologics Evaluation and Research (CBER).  
 
In general, FDAs guidance documents, including this guidance, do not establish legally 
enforceable responsibilities.  Instead, guidances describe the FDAs current thinking on a topic 
and should be viewed only as recommendations unless specific regulatory or statutory 
requirements are cited.  The use of the word should in FDAs guidances means that something 
is suggested or recommended but not required.  
 
 
II.  BACKGROUND:  
 
The Quality System Regulation found at Title 21 of the Code of Federal Regulations Part 820 (21 
CFR Part 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 
Parts 600-660. 
 
IVDs are classified into three major categories based on 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.  The level of microbiological control 
necessary for the manufacture of a specific IVD is established by the manufacturer's design 
controls (21 CFR 820.30) and 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. 
1  Contains Nonbinding Recommendations 
III.  POLICY:  
 
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(h)(1)).  The 
biologics regulations describe additional standards for licensed BGR (21 CFR 660.20) and AHG 
(21 CFR 660.50).  CBER amended the regulations for BGR and AHG on December 12, 2000 
(65 FR 77497), to remove the requirements that these products be sterile or aseptically processed 
because:  (1)  the manufacturers do not claim these products as sterile on the product labels; (2) 
quality checks are required for the end users of licensed IVDs (21 CFR 606.65(c)); (3) all BGR 
and AHG contain preservatives; and (4) historically, CBER has not requested sterility 
requirements during the license application review of these products.  Therefore, unless specified 
in the license application, CBER does not expect AHG and BGR to be manufactured under 
aseptic conditions; however, they should be manufactured under conditions such that the 
microbial level will not adversely impact product performance. 
 
 
IV.  REGULATORY ACTION GUIDANCE:  
 
Investigators should not cite a manufacturer of BGR or AHG on the Form FDA 483 for not 
following aseptic processing procedures unless:  (1) the product is labeled as sterile; (2) aseptic 
processing is required as part of its license; or (3) the firm is not following its own manufacturing 
standard operating procedures (SOPs) (e.g., 21 CFR 820.70 (production and process control); 21 
CFR 820.30 (design control)).  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 control of those environmental conditions that could have an adverse effect 
on product quality.  If investigators have any questions regarding the requirements for a 
particular product, they should consult with CBER's Office of Compliance and Biologics Quality 
using the email CBERInspections@fda.hhs.gov. 
 
Issued:  8/14/2000 
Revised:  5/2014, 07/31/2020 
 
 
 
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