Mixing, Diluting, or 
Repackaging Biological 
Products Outside the 
Scope of an Approved 
Biologics License 
Application 
Guidance for Industry  
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
January 2018 
Compounding and Related Documents 
   
  Mixing, Diluting, or 
Repackaging Biological 
Products Outside the 
Scope of an Approved 
Biologics License 
Application 
Guidance for Industry  
 
Additional copies are available from: 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Building 51, Room 2201, Silver Spring, MD 20993  
Phone: 301-796-3400; Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
and/or 
Office of Communication, Outreach, and Development 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Building 71, Room 3128 
Silver Spring, MD 20993 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
January 2018 
Compounding and Related Documents   
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION AND SCOPE .................................................................................... 1 
II.  BACKGROUND ............................................................................................................... 3 
A.  Biological Products ........................................................................................................................ 3 
B.  Legal Framework for FDAs Regulation of Biological Products ............................................... 5 
C.  Sections 503A and 503B of the FD&C Act Do Not Exempt Biological Products from the 
Premarket Approval Requirements of the PHS Act or from Provisions of the FD&C Act ............ 5 
III.  POLICY ............................................................................................................................. 6 
A.  General Conditions ........................................................................................................................ 6 
B.  Mixing, Diluting, or Repackaging Licensed Biological Products .............................................. 7 
C.  Licensed Allergenic Extracts for Subcutaneous Immunotherapy ........................................... 14 
IV.  PAPERWORK REDUCTION ACT .............................................................................. 18 
Appendix A - Assigning a BUD for Repackaged Biological Products Based On Stability 
Testing ........................................................................................................................................... 19 
Appendix B - Release Testing for Biological Products Mixed, Diluted, or Repackaged by 
Outsourcing Facilities .................................................................................................................. 23  Contains Nonbinding Recommendations 
 
Mixing, Diluting, or Repackaging Biological Products Outside the 
Scope of an Approved Biologics License Application 
Guidance for Industry1 
 
 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION AND SCOPE 
 
This guidance sets forth FDAs policy regarding the mixing,2 diluting, and repackaging3 of 
certain types of biological products that have been licensed under section 351 of the Public 
Health Service Act (PHS Act) when such activities are not within the scope of the products 
approved biologics license application (BLA) as described in the approved labeling for the 
product. This guidance describes the conditions under which FDA does not intend to take action 
for violations of section 351 of the PHS Act and section 502(f)(1), section 582, and, where 
specified, section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 
U.S.C. 352(f)(1), 21 U.S.C. 360eee-1, and 21 U.S.C. 351(a)(2)(B), respectively), when a state-
licensed pharmacy, a federal facility, or an outsourcing facility4 dilutes, mixes, or repackages 
certain biological products outside the scope of an approved BLA.    
    
                                                 
1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research (CDER), in 
cooperation with the Center for Biologics Evaluation and Research (CBER) and the FDA Office of Regulatory 
Affairs.
 
2 For purposes of this guidance, mixing means combining an FDA-licensed biological product with one or more 
ingredients.  
 
3 For purposes of this guidance, repackaging means taking a licensed biological product from the container in which 
it was distributed by the original manufacturer and placing it into a different container without further manipulating 
the product.  As used in this guidance, the terms mixing, diluting, and repackaging describe distinct sets of activities 
with respect to a biological product.  
 
4 Outsourcing facility refers to a facility that meets the definition of an outsourcing facility under section 503B(d)(4) 
of the FD&C Act (21 U.S.C. 353b(d)(4)).  See guidance for industry Guidance for Entities Considering Whether to 
Register As Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act (August 
2015), available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434171.pdf. 
 
All FDA guidances are available on the Agencys guidance website at 
http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234622.htm.  FDA updates guidances regularly.  To 
ensure that you have the most recent version, please check this web page.  
 
1 
  Contains Nonbinding Recommendations 
 
This guidance does not address the following:5 
 
  Biological products not subject to licensure under section 351 of the PHS Act (i.e., 
biological products for which a marketing application could properly be submitted under 
section 505 of the FD&C Act (21 U.S.C. 355) (see section 7002(e) of the Affordable 
Care Act)).6 
 
  Radioactive biological products.  It is the Agencys understanding that pharmacists do 
not manipulate radioactive biological products outside the scope of the products 
approved labeling. 
 
  Mixing, diluting, or repackaging biological products (other than allergenic extracts) by 
entities that are not state-licensed pharmacies, federal facilities, or outsourcing facilities 
(e.g., repackers registered with FDA under section 510 of the FD&C Act (21 U.S.C. 
360)); and preparation of allergenic extracts by entities that are not state-licensed 
pharmacies, federal facilities, outsourcing facilities, or physicians. 
 
  Removing a biological product from the original container at the point of care (e.g., 
patients bedside) for immediate administration to a single patient after receipt of a valid 
patient-specific prescription or order for that patient (e.g., drawing up a syringe to 
administer directly to the patient).  FDA does not consider this to be repackaging for 
purposes of this guidance. 
 
  Diluting or mixing a biological product at the point of care for immediate administration 
to a single patient after receipt of a valid patient-specific prescription or order for that 
patient (e.g., diluting or mixing into a syringe to administer directly to the patient). 
 
  Mixing, diluting, or repackaging a licensed biological product when the product is being 
mixed, diluted, or repackaged in accordance with the approved BLA as described in the 
approved labeling for the product.  FDA considers this to be an approved manipulation of 
the product. 
 
  Mixing, diluting, or repackaging of blood and blood components for transfusion,7 
vaccines, cell therapy products, or gene therapy products.  This guidance does not alter 
FDAs existing approach to regulating the collection and processing of blood and blood 
components for transfusion.  In addition, FDA intends to consider regulatory action if 
licensed vaccines, cell therapy products, and gene therapy products are subject to 
additional manufacturing, including mixing, diluting, or repackaging, in ways not 
                                                 
5 FDA is considering the applicability of the policies described in this guidance to hospitals and health systems and 
intends to address these issues in separate guidance. 
6
 The repackaging of biological products approved under section 505 of the FD&C Act is addressed in a separate 
guidance for industry, Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities 
(January 2017), available at https://www.fda.gov/downloads/Drugs/Guidances/UCM434174.pdf. 
 
7 This guidance does apply to licensed, plasma-derived biological products, including recombinant and transgenic 
versions of plasma derivatives that are mixed, diluted, or repackaged outside the scope of an approved BLA. 
2 
  Contains Nonbinding Recommendations 
 
specified in the products approved BLA as described in the approved labeling for the 
product.    
 
  Investigational new drugs being studied under an investigational new drug application.  
This guidance does not alter FDAs existing approach to regulating investigational new 
drugs. 
 
As stated above, this guidance does not address the mixing, diluting, or repackaging of a 
biological product for which a marketing application could properly be submitted under section 
505 of the FD&C Act (see section 7002(e) of the Affordable Care Act).  Accordingly, in this 
guidance, the term biological product does not include products for which a marketing 
application can be or has been submitted under section 505 of the FD&C Act.    
 
Section II of this guidance provides background on biological products and the legal framework 
for FDAs regulation of these products and explains that sections 503A and 503B of the FD&C 
Act (21 U.S.C. 353a and 21 U.S.C. 353b, respectively) do not provide exemptions for mixing, 
diluting, or repackaging of biological products.  Section III describes FDAs policy on mixing, 
diluting, or repackaging of certain licensed biological products that is not within the scope of the 
products approved BLA as described in the approved labeling for the product. 
   
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
A.  Biological Products  
 
The term biological product is defined in section 351(i)(1) of the PHS Act as 
 
a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or 
derivative, allergenic product, protein (except any chemically synthesized polypeptide), 
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. 
 
Biological products can be complex chains or combinations of sugars, amino or nucleic acids, or 
living entities such as cells and cellular therapies.  Biological products include therapeutic 
proteins, monoclonal antibodies, allergenic extracts, blood and blood derivatives, cell therapy 
products, gene therapy products, preventive vaccines, and therapeutic vaccines.  Generally, 
biological products have a complex set of structural features (e.g., amino acid sequence, 
glycosylation, folding) essential to their intended effect and are very sensitive to changes to their 
manufacturing process, including but not limited to any manipulation outside of their approved 
container-closure systems.  In addition, many biological products are particularly sensitive to 
3 
  Contains Nonbinding Recommendations 
 
storage and handling conditions and can break down or aggregate if exposed to heat or light, if 
dropped, or if shaken during storage and handling. Accordingly, in the absence of manufacturing 
controls, diluting or mixing a biological product with other components or repackaging a 
biological product by removing it from its approved container-closure system and transferring it 
to another container-closure system is highly likely to affect the safety or effectiveness of the 
biological product.  Biological products are also particularly susceptible to microbial 
proliferation in a short period of time if contaminated.   
 
Nevertheless, to meet the needs of a specific patient, certain licensed biological products are 
sometimes mixed or diluted in a way not described in the products approved labeling .  For 
example, some biological products have no licensed pediatric strength or dosage form, so the 
product is diluted for use in pediatric patients.  There also may be certain circumstances where a 
person would repackage a licensed biological product by removing it from its original container 
and placing it into different containers in a manner that is not within the scope of the approved 
BLA as described in the approved labeling for the product.  Like other drugs, biological products 
are sometimes repackaged for various reasons, including for pediatric or ophthalmic use.  For 
example, a pediatric dialysis unit may repackage a larger quantity of a product into smaller 
aliquots so that the optimal dose may be administered to each pediatric dialysis patient being 
treated at that particular time.   
 
Repackaging a drug or biological product could change its characteristics in ways that have not 
been evaluated during the approval process and that could affect the safety and effectiveness of 
the product.  Improper repackaging of drugs and biological products can cause serious adverse 
events.  Of particular concern is the repackaging of sterile drugs, which are susceptible to 
contamination and degradation.  For example, failure to properly repackage a sterile drug (such 
as a biological product) under appropriate aseptic conditions could introduce contaminants that 
could cause serious patient injury or death.  Repackaging practices that conflict with approved 
product labeling have led to product degradation, resulting in adverse events associated with 
impurities in the product or lack of efficacy because the active ingredient has deteriorated.  These 
risks are often even more acute for biological products due to their complex composition and 
sensitivity to variations in storage and handling conditions.   
    
Cell and gene therapy products often contain viable cells or intact/active viral vectors.  The 
manufacturing process for these products is complex and includes multiple controls to assure the 
products safety, purity, and potency.  Many cell therapy products are cryopreserved, and the 
procedures for thawing and handling in preparation for administration described in the approved 
labeling must be followed to maintain the safety and effectiveness of the product.  Because these 
products are frequently implanted or administered intravenously and are not typically amenable 
to terminal sterilization, their microbiological safety is dependent largely on facility design, 
aseptic technique, and manufacturing protocols that are best controlled by robust quality systems. 
 
Vaccines are manufactured using biological systems and supplied by manufacturers in single- or 
multi-dose presentations.  Unlike most other drugs and biological products, vaccines are 
administered to healthy individuals, including infants, to prevent disease.  Vaccines may contain 
live attenuated organisms, inactivated organisms, or components of bacteria or viruses such as 
polysaccharides, inactivated toxins, or purified proteins.  The manufacturing process for vaccines 
4 
  Contains Nonbinding Recommendations 
 
is complex and includes multiple controls to assure safety and effectiveness.  Each single dose of 
a vaccine is formulated to deliver the correct quantity of an active ingredient to the recipient.  
 
Because of the particularly sensitive nature of these products as described above, the policies in 
this guidance do not cover cell therapy products, gene therapy products, and vaccines.   
 
The policies in this guidance also do not cover or alter FDAs existing approach to regulating the 
collection and processing of blood and blood components for transfusion.  These activities are 
currently conducted in FDA-licensed or -registered blood collection establishments and in 
hospital-based transfusion services regulated in part by the Centers for Medicare & Medicaid 
Services under the Clinical Laboratory Improvement Amendments of 1988.  In all instances, the 
collection and processing of blood and blood components for transfusion is already subject to 
current good manufacturing practice (CGMP) requirements under the existing statutory and 
regulatory framework for blood and blood components and will not be subject to the policies 
described here. 
 
B.  Legal Framework for FDAs Regulation of Biological Products 
 
Section 351(a)(1) of the PHS Act prohibits the introduction into interstate commerce of any 
biological product unless a biologics license . . . is in effect for the biological product.  For 
FDA to approve a BLA, the BLA must contain data to demonstrate that the biological product is 
safe, pure, and potent and that the facility in which the biological product will be manufactured, 
processed, packed, or held meets standards designed to assure that the biological product 
continues to be safe, pure, and potent (see section 351(a)(2)(C) of the PHS Act).  Because 
manufacturing controls are so important to ensuring the safety and effectiveness of biological 
products, FDA licensing of a biological product is based in part on an extensive review of 
chemistry and manufacturing controls data submitted by the applicant.  This includes a thorough 
evaluation of the raw materials, drug substance, and drug product to ensure consistency in 
manufacturing and continued safety and effectiveness.  In addition, other data are submitted and 
reviewed (e.g., stability and compatibility testing results) to establish the storage and handling 
conditions appropriate to ensure the safety, purity, and potency of the biological product.   
 
A biological product that is mixed, diluted, or repackaged outside the scope of an approved BLA 
is an unlicensed biological product under section 351 of the PHS Act.  For example, if a licensed 
biological product is diluted or mixed with components other than those described in the 
approved labeling for the product, or if it is removed from its original container-closure system 
and placed in a new container-closure system that is not described in the approved labeling for 
the product, these additional manufacturing steps would create a new, unlicensed biological 
product.  To be legally marketed, the new biological product would have to be licensed on the 
basis of an approved BLA that includes, among other things, chemistry and manufacturing 
controls data. 
 
C.  Sections 503A and 503B of the FD&C Act Do Not Exempt Biological 
Products From the Premarket Approval Requirements of the PHS Act or 
From Provisions of the FD&C Act 
 
5 
  Contains Nonbinding Recommendations 
 
Section 503A of the FD&C Act exempts compounded drugs from sections 505 (concerning new 
drug approval of human drug products), 502(f)(1) (concerning labeling of drug products with 
adequate directions for use), and 501(a)(2)(B) (concerning CGMP) of the FD&C Act, provided 
that certain conditions are met, including that the drug is compounded pursuant to a prescription 
for an individually identified patient from a licensed practitioner.   
 
The Drug Quality and Security Act added a new section 503B to the FD&C Act.  Under section 
503B(b) of the FD&C Act, a compounder can register with FDA as an outsourcing facility.  
Drug products compounded under the direct supervision of a licensed pharmacist in an 
outsourcing facility can qualify for exemptions from the FDA approval requirements in section 
505 of the FD&C Act and the requirement to label drug products with adequate directions for use 
under section 502(f)(1) of the FD&C Act if the conditions in section 503B are met.  Drugs 
compounded in outsourcing facilities are not exempt from the CGMP requirements of section 
501(a)(2)(B).    
 
Although sections 503A and 503B provide an exemption for certain compounded drugs from the 
requirement to obtain premarket approval under section 505 of the FD&C Act, they do not 
provide an exemption from the requirement to obtain premarket approval under section 351 of 
the PHS Act.  Manufacturers of biological products must obtain an approved license under 
section 351(a) or (k) of the PHS Act.  Thus, for purposes of sections 503A and 503B, a drug 
does not include any biological product that is subject to licensure under section 351 of the PHS 
Act.  Accordingly, such biological products are not eligible for the exemptions for compounded 
drugs under sections 503A and 503B of the FD&C Act.  In other words, the FD&C Act does not 
provide a legal pathway for marketing biological products that have been prepared outside the 
scope of an approved BLA. 
 
 
III.  POLICY  
 
Because biological products are sometimes mixed, diluted, or repackaged in ways not addressed 
in labeling approved for the product under section 351 of the PHS Act, but do not qualify for the 
exemptions in sections 503A or 503B of the FD&C Act, FDA has developed this guidance to 
explain the conditions under which FDA does not intend to take action when certain biological 
products are mixed, diluted, or repackaged in a manner not described in their approved labeling. 
 
A.  General Conditions 
 
This guidance addresses the mixing, diluting, or repackaging of a licensed biological product, not 
a biological product licensed for further manufacturing use only or a bulk drug substance.  The 
policies expressed in this guidance do not extend to any person or entity that mixes, dilutes, or 
repackages a biological product from any other starting material.  For example, a licensed 
biological product mixed with a bulk drug substance would not be subject to the policies in this 
guidance.  Consistent with section 351 of the PHS Act, an entity seeking to mix, dilute, or 
repackage a biological product licensed for further manufacturing use only, or a bulk drug 
substance, or to mix a licensed biological product with a bulk drug substance must first submit a 
BLA and obtain a license for the product.   
6 
  Contains Nonbinding Recommendations 
 
 
Furthermore, the policies expressed in this guidance apply only to the mixing, diluting, or 
repackaging of certain licensed biological products in accordance with the conditions specified in 
section III of this guidance.  Except as described in section III, the Agency intends to consider 
regulatory action if a licensed biological product is subject to additional manufacturing outside 
of the conditions specified in the approved labeling for the licensed product, including mixing, 
diluting, or repackaging.   
 
As described in section II.B, a biological product that is mixed, diluted, or repackaged outside 
the scope of an approved BLA is an unlicensed biological product under section 351 of the PHS 
Act.  To be legally marketed, the new biological product would have to be the subject of an 
approved BLA and made in accordance with all other requirements applicable to biological 
products, including CGMP requirements.   
 
B.  Mixing, Diluting, or Repackaging Licensed Biological Products8  
 
FDA does not intend to take action for violations of section 351 of the PHS Act or sections 
502(f)(1) or 582 of the FD&C Act if a state-licensed pharmacy, a f 
ederal facility, or an outsourcing facility mixes, dilutes, or repackages a biological product in 
accordance with the conditions described below, and any applicable requirements.9  In addition, 
FDA does not intend to take action for violations of section 501(a)(2)(B) of the FD&C Act when 
a state-licensed pharmacy or a Federal facility mixes, dilutes, or repackages a biological product 
in accordance with the conditions described below, and any applicable requirements.10  
 
The conditions referred to in the preceding paragraph are as follows: 
 
1.  The FDA-licensed biological product is a biological product that is mixed, diluted, or 
repackaged, not a biological product licensed for further manufacturing use only or a bulk 
drug substance.  Additionally, a licensed biological product is not combined with a biological 
product licensed for further manufacturing use only or with a bulk drug substance.  Any 
materials used in mixing or diluting are sterile, pharmaceutical grade,11 and otherwise 
appropriate for such use.  
 
                                                 
8 Section III.B does not apply to allergenic extracts.  For FDAs policy concerning the preparation of prescription 
sets for subcutaneous immunotherapy, refer to section III.C of this guidance.
 
9 Applicable requirements include, for example, the requirement that manufacturers not adulterate a biological 
product by preparing, packing, or holding the drug under insanitary conditions. See section 501(a)(2)(A) of the 
FD&C Act.  
 
10 For purposes of the applicability of the conditions in this guidance document, references to a state-licensed 
pharmacy or federal facility do not include a facility that is registered as an outsourcing facility under section 503B 
of the FD&C Act.
 
11 For purposes of this guidance, pharmaceutical grade refers to materials that are suitable for administration in 
humans.
 
 
7 
  Contains Nonbinding Recommendations 
 
2.  The biological product is mixed, diluted, or repackaged in a state-licensed pharmacy, a 
federal facility, or an outsourcing facility. 
 
3.  The biological product is mixed, diluted, or repackaged by or under the direct supervision of 
a licensed pharmacist.  
 
4.  If the biological product is mixed, diluted, or repackaged in a state-licensed pharmacy or a 
federal facility, it is distributed12 only after the receipt of a valid prescription for an 
individually identified patient (including a written order or notation in a patients chart in a 
health care setting) directly from the prescribing practitioner or patient. This condition does 
not apply to biological products mixed, diluted, or repacked in an outsourcing facility.13 
 
5.  Except as provided below, the biological product is mixed, diluted, or repackaged, then 
stored and shipped in a way that does not conflict with the approved labeling for the licensed 
biological product.14   
 
o  For a biological product packaged in a single-dose vial that is mixed, diluted, or 
repackaged, the biological product is mixed, diluted, or repackaged in a way that does 
not conflict with the approved labeling, except for the statements designating the 
product as a single-dose or single-use product, and related language (e.g., discard 
remaining contents).15 
 
o  For a biological product repackaged by an outsourcing facility that assigns a beyond 
use date (BUD) to the product in accordance with Appendix A of this guidance, the 
biological product is repackaged in a way that does not conflict with the approved 
labeling, except for the statements regarding the products labeled in-use time (and 
any statements designating the product as a single-dose or single-use product, as 
described immediately above). 
 
                                                 
12 Distributed means that the mixed, diluted, or repackaged biological product has left the facility in which it was 
mixed, diluted, or repackaged. 
 
13 Note, however, that drugs produced by outsourcing facilities, including drugs that are also biological products, 
remain subject to the requirements in section 503B of the FD&C Act.  Therefore, a prescription drug, including a 
biological product, cannot be dispensed to a patient without a prescription.
 
14 For example, if the approved labeling for the licensed biological product contains instructions for handling or 
storage of the product, the mixing, diluting, or repackaging is done in accordance with those instructions.  
Otherwise, it would be considered to be in conflict with the approved labeling for the licensed biological product. 
15 For example, Avastin (bevacizumab) is packaged in a single-dose vial.  This condition could be satisfied even if 
Avastin is repackaged into multiple single dose syringes despite the fact that the label of the approved product states, 
Single-use vial . . . Discard unused portion.  However, this condition would not be satisfied if Avastin is mixed, 
diluted, or repackaged in a manner that conflicts with other language in the approved labeling (e.g., regarding the 
appropriate diluent and storage conditions).   
 
 
8 
  Contains Nonbinding Recommendations 
 
6.  The container-closure system16 (e.g., syringe) into which the mixed, diluted, or repackaged 
biological product is placed is suitable for storage of the biological product through its 
BUD17 and the primary packaging is sterile. 
 
7.  If the labeling for the licensed biological product includes storage or handling instructions 
(e.g., protect from light, do not freeze, keep at specified storage temperature), the labeling for 
the biological product that is mixed, diluted, or repackaged specifies the same storage 
conditions.18 
 
8.  If the biological product is mixed, diluted, or repackaged in a state-licensed pharmacy or 
federal facility, the duration of time from beginning (i.e., when the original biological 
product to be repackaged or to be used for mixing or diluting is punctured or otherwise 
opened) to end of mixing, diluting, or repackaging is no more than four hours. 
 
9.  As described in section II of this guidance, biological products are very susceptible to 
product quality concerns when mixed, diluted, or repackaged.  For example, because 
biological products provide a rich media for microbial growth, they are particularly 
susceptible to microbial proliferation over time if contaminated.  Therefore, the mixed, 
diluted, or repackaged biological product is given a BUD19 that is not longer than the 
applicable BUD specified below.  The BUD timeframes in this condition begin from the time 
in which the container of the original biological product to be repackaged or to be used for 
mixing or diluting is punctured or otherwise opened. 
 
a.  If the biological product is mixed, diluted, or repackaged by a state-licensed 
pharmacy or a federal facility, it is given a BUD that:   
 
-  does not exceed the time frame within which the opened product is to be used 
as specified in the approved labeling of the licensed biological product for any 
manipulation (in-use time) or the expiration date of the biological product 
being mixed, diluted, or repackaged, whichever is shorter;  20 or 
                                                 
16 A container-closure system is the sum of packaging components that together contain and protect the dosage 
form. This includes primary packaging components and secondary packaging components, if the latter are intended 
to provide additional protection to the drug product.
 
17 For example, for state-licensed pharmacies and federal facilities, information provided by the containers 
manufacturer could indicate that the container is suitable for biological products mixed, diluted, or repackaged in 
accordance with this condition.  CGMP requirements address container suitability and drug stability for outsourcing 
facilities.  
18 See section IV of this guidance.
 
19 The BUD is the date beyond which a biological product should not be used.
 
20 For example, the approved labeling for Avastin states that diluted Avastin solutions may be stored at 2-8oC (36-
46oF) for up to 8 hours.  Store in the original carton until time of use.  Therefore, assigning a BUD to repackaged 
Avastin of 8 hours, provided that the repackaged Avastin is stored between 2oC and 8oC, would be consistent with 
conditions 5 and 9.  Although the approved labeling refers to diluted Avastin, FDA believes that this BUD is also 
appropriate for repackaged Avastin because of the potential for time-related product quality problems at a longer 
BUD.  For example, FDA is concerned about the potential for microbial proliferation if Avastin is inadvertently 
 
9 
  Contains Nonbinding Recommendations 
 
 
-  if the approved labeling does not specify an in-use time and the product is 
refrigerated, the in-use time is not longer than 24 hours, or the expiration date 
of the biological product being mixed, diluted, or repackaged, whichever is 
shorter. 
 
b.  Regarding outsourcing facilities: 
 
i.  If the biological product is mixed or diluted, it is given a BUD that  
 
-  does not exceed the in-use time specified in the approved labeling of 
the biological product or the expiration date of the biological product 
being mixed or diluted, whichever is shorter; or 
 
-  if the approved labeling does not specify an in-use time and the 
product is refrigerated, the in-use time is not longer than 24 hours, or 
the expiration date of the biological product being mixed or diluted, 
whichever is shorter. 
 
ii.  If the biological product is repackaged by an outsourcing facility that does not 
perform the testing described in Appendix A for that product, it is given a 
BUD that21:  
 
-  does not exceed the in-use time specified in the approved labeling of 
the biological product or the expiration date of the biological product 
being repackaged, whichever is shorter; or 
 
-  if the approved labeling does not specify an in-use time and the 
product is refrigerated, the in-use time is not longer than 24 hours or 
the expiration date of the biological product being repackaged, 
whichever is shorter.  
 
iii.  If the biological product is repackaged by an outsourcing facility that 
performs the testing described in Appendix A for that product, the BUD is 
assigned based on a stability program conducted in accordance with Appendix 
A for each container closure system to be used, the BUD does not exceed the 
expiration date of the biological product being repackaged, and the 
                                                 
contaminated while being repackaged, particularly because condition 9.a applies to facilities that likely do not 
comply with CGMP requirements.  Furthermore, the approved labeling for Avastin states, Store in the original 
carton until time of use, which means it should be stored in the original carton until it is opened and diluted.  At a 
longer BUD, the Avastin could interact with the container in which it is repackaged, which may result in 
degradation. 
21 See condition 5, which states that the biological product is mixed, diluted, or repackaged in a way that does not 
conflict with the approved labeling for the licensed biological product.  This means, for example, that the 
repackaged biological product is stored in accordance with labeled storage conditions, including temperature.
 
 
10 
  Contains Nonbinding Recommendations 
 
outsourcing facility maintains records of the testing performed in accordance 
with Appendix A.22   
 
10. The biological product is mixed, diluted, or repackaged in accordance with the following: 
 
a.  If the biological product is mixed, diluted, or repackaged in a state-licensed pharmacy 
or a federal facility, it is done in accordance with the United States Pharmacopeia 
(USP) Chapter <797>,23 except the BUD is as specified in condition 9. 
 
b.  If the biological product is mixed, diluted, or repackaged in an outsourcing facility, it 
is done in accordance with CGMP requirements, except the BUD is as specified in 
condition 9.24 
 
For purposes of condition 10.b, FDA intends to apply the policies described in the 
guidance, Current Good Manufacturing Practice  Interim Guidance for Human 
Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act 
(July 2014),25 once that guidance is finalized, except for the following:     
 
o  See condition 9 and Appendix A of this guidance for FDAs policies 
concerning expiration dating or BUDs and stability testing for biological 
products mixed, diluted, or repackaged by outsourcing facilities. 
 
o  See Appendix B of this guidance for FDAs policies concerning release 
testing requirements for biological products mixed, diluted, or repackaged by 
outsourcing facilities.  Appendix B describes the circumstances under which 
FDA does not intend to take action against outsourcing facilities for failing to 
conduct batch release testing required under 21 CFR part 211 of mixed, 
diluted, or repackaged biological products.  
   
11. The biological product is not sold or transferred by an entity other than the entity that mixed, 
diluted, or repackaged the biological product.  For purposes of this condition, a sale or 
transfer does not include administration of a biological product in a health care setting.  
 
                                                 
22 See section IV of this guidance with respect to the maintenance of testing records.
 
23 For purposes of this condition, reference to the USP Chapter <797> means USP 40-NF 35 (2017).  USP has 
proposed revisions to USP Chapter <797> that would affect biological products.  Once USP has considered the 
public comments that it received and finalized the revised Chapter <797>, FDA intends to evaluate whether to revise 
the reference in condition 10.a.  
 
24 FDA does not intend to take action against an outsourcing facility for assigning a BUD to be used as an expiration 
date in lieu of conducting stability studies required under 21 CFR part 211 if the BUD is assigned in accordance 
with condition 9.b.
 
25 When final, this guidance will represent FDAs current thinking on this topic. For the most recent version of a 
guidance, check the FDA Drugs guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
 
11 
  Contains Nonbinding Recommendations 
 
12. The mixed, diluted, or repackaged biological product is distributed only in states in which the 
facility mixing, diluting, or repackaging the biological product meets all applicable state 
requirements. 
 
13. If the biological product is mixed, diluted, or repackaged by an outsourcing facility:26 
 
a.  The label on the immediate container (primary packaging, e.g., the syringe) of the 
mixed, diluted, or repackaged biological product includes the following:  
 
i.  The statement This biological product was mixed/diluted by [name of 
outsourcing facility] or This biological product was repackaged by [name of 
outsourcing facility], whichever is appropriate 
 
ii.  The address and phone number of the outsourcing facility that mixed, diluted, 
or repackaged the biological product 
 
iii.  The proper name of the licensed biological product that was mixed, diluted, or 
repackaged 
 
iv.  The lot or batch number assigned by the outsourcing facility for the mixed, 
diluted, or repackaged biological product 
 
v.  The dosage form and strength of the mixed, diluted, or repackaged biological 
product  
 
vi.  A statement of either the quantity or the volume of the mixed, diluted, or 
repackaged biological product, whichever is appropriate 
 
vii.  The date the biological product was mixed, diluted, or repackaged 
 
viii.  The BUD of the mixed, diluted, or repackaged biological product 
 
ix.  Storage and handling instructions for the mixed, diluted, or repackaged 
biological product 
 
x.  The National Drug Code (NDC) number for the mixed, diluted, or repackaged 
biological product, if available27 
 
xi.  The statement Not for resale and, if the biological product is distributed by 
an outsourcing facility other than pursuant to a prescription for an individual 
identified patient, the statement Office Use Only 
 
                                                 
26 See section IV of this guidance with respect to sections 13.a.i-x and xii, sections 13.b.i-ii, and section 13.c. 
27 The NDC number for the original licensed biological product should not be placed on the mixed, diluted, or 
repackaged biological product. 
12 
  Contains Nonbinding Recommendations 
 
xii.  If included on the label of the FDA-licensed biological product from which 
the biological product is being mixed, diluted, or repackaged, a list of the 
active and inactive ingredients in the FDA-licensed biological product, unless 
such information is included on the label for the container from which the 
individual units of the mixed, diluted, or repackaged biological product are 
removed, as described below in 13.b.i; and, if the biological product is mixed 
or diluted, a list of any ingredients that appear in the mixed or diluted product 
in addition to those ingredients that are on the label of the original FDA-
licensed biological product.   
 
b.  The label on the container from which the individual units are removed for 
administration (secondary packaging, e.g., the bag, box, or other package in which the 
mixed, diluted, or repackaged biological products are distributed) includes:  
 
i.  The active and inactive ingredients included on the label of the original FDA-
licensed biological product, if the immediate product label is too small to 
include this information 
 
ii.  Directions for use, including dosage and administration, as appropriate 
 
iii.  The following information to facilitate adverse event reporting: 
www.fda.gov/medwatch and 1-800-FDA-1088. 
 
c.  The mixed, diluted, or repackaged biological product is included on a report 
submitted to FDA each June and December identifying the drug products made by the 
outsourcing facility during the previous 6-month period, including the active 
ingredient; the source of the active ingredient; NDC number of the source ingredient, 
if available; strength of the active ingredient per unit; the dosage form and route of 
administration; the package description; the number of individual units mixed, 
diluted, or repackaged;28 and the NDC number of the mixed, diluted, or repackaged 
biological product, if assigned.29 
 
d.  The outsourcing facility reports serious adverse events to FDA that are associated 
with its mixed, diluted, or repackaged biological products.30 
                                                 
28 Currently, FDAs electronic drug reporting system is not configured to accept additional information that is 
specific to biological products, such as license number.  In the future, FDA intends to modify the system to accept 
this information.
 
29 FDA has issued a guidance for industry, Electronic Drug Product Reporting for Human Drug Compounding 
Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act (December 2016), 
available at https://www.fda.gov/downloads/drugs/newsevents/ucm424303.pdf.  This guidance describes how 
outsourcing facilities submit drug product reports to FDA.  Although that guidance addresses reporting of 
compounded drug products, outsourcing facilities should follow the same procedure to electronically report the 
biological products they mixed, diluted, or repackaged.
 
30 FDA has issued a guidance for industry, Adverse Event Reporting for Outsourcing Facilities Under Section 503B 
of the Federal Food, Drug, and Cosmetic Act (October 2015), available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434188.pdf, 
 
13 
  Contains Nonbinding Recommendations 
 
 
C.  Licensed Allergenic Extracts for Subcutaneous Immunotherapy31 
 
FDA recognizes that there are circumstances in which licensed allergenic extracts would be 
mixed and diluted to provide subcutaneous immunotherapy to an individual patient, even though 
these allergenic extract combinations are not specified in the approved BLAs for the licensed 
biological products.  Such combinations are commonly referred to as prescription sets.32  For the 
purpose of this guidance, a prescription set is defined as a vial or set of vials of premixed 
licensed standardized and non-standardized allergenic extracts for subcutaneous immunotherapy 
diluted with an appropriate diluent prepared by a licensed physician for an individual patient 
according to instructions from a valid prescription (including a chart order in a health care 
setting).   
 
FDA does not intend to take action for violations of section 351 of the PHS Act or sections 
502(f)(1) or 582 of the FD&C Act if a physician, state-licensed pharmacy, federal facility, or 
outsourcing facility prepares prescription sets of allergenic extracts in accordance with the 
conditions described below, and any applicable requirements.    
 
In addition, FDA does not intend to take action for violations of section 501(a)(2)(B) of the 
FD&C Act when the prescription set is prepared by a physician, state-licensed pharmacy, or a 
federal facility that is not registered with FDA as an outsourcing facility if the prescription set is 
prepared in accordance with the conditions described below, and any applicable requirements.  
 
The conditions referred to in the preceding two paragraphs are as follows: 
 
1.   The prescription set is prepared from FDA-licensed allergenic extracts and diluents that are 
sterile, pharmaceutical grade, and otherwise appropriate for such use.   
 
2.  The prescription set is prepared in a physicians office, state-licensed pharmacy, federal 
facility, or outsourcing facility.  
 
                                                 
which describes how outsourcing facilities submit adverse event reports to FDA and the content and format of the 
reports that they are required to submit.  Although that guidance addresses reporting of adverse events associated 
with compounded drug products, outsourcing facilities should follow the procedure described in that guidance to 
electronically report adverse events associated with the biological products they mixed, diluted, or repackaged. 
31 Allergenic extracts are subject to FDAs BLA and investigational new drug application requirements. The policies 
described in this guidance only apply to allergenic extracts for subcutaneous immunotherapy; they do not apply to 
allergenic extracts for use in cutaneous diagnostic testing.
 
32 Under 21 CFR 610.17, licensed biological products must not be combined with other licensed products, either 
therapeutic, prophylactic or diagnostic, except as covered by a license obtained for the combined product.  All mixes 
of allergenic extracts that are not prescription sets must be the subject of an approved BLA or have in effect an 
investigational new drug application.  
 
 
14 
  Contains Nonbinding Recommendations 
 
3.  Each prescription set is distributed33 only after the receipt of a valid prescription for an 
identified, individual patient (including a written order or notation in a patients chart in a 
health care setting) directly from the prescribing practitioner or patient.   
 
4.  The prescription set is prepared in a way that does not conflict with approved labeling of the 
licensed biological products that are part of the prescription set.34  
 
5.  The BUD for the prescription set is no later than the earliest expiration date of any allergenic 
extract or any diluent that is part of the prescription set, and the BUD does not exceed one 
year from the date the prescription set is mixed or diluted.35 
 
6.  The prescription set is prepared in accordance with the following: 
 
a.  If the prescription set is prepared in a State-licensed pharmacy or Federal facility, or 
in a physicians office, it is prepared in accordance with USP Chapter <797>,36 
except the BUD is as specified in condition 5. 
 
b.  If the prescription set is prepared in an outsourcing facility, it is prepared in 
accordance with applicable CGMP requirements, except the BUD is as specified in 
condition 5.    
 
For purposes of condition 6.b, FDA intends to apply the policies described in the 
guidance, Current Good Manufacturing Practice  Interim Guidance for Human 
Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, 
once that guidance is finalized, except for the following:   
 
o  See condition 5 of this guidance for FDAs policies concerning expiration 
dating/BUDs for prescription sets prepared by outsourcing facilities. 
 
o  See Appendix B of this guidance for FDAs policies concerning release 
testing requirements for prescription sets prepared by outsourcing facilities.  
Appendix B describes the circumstances under which FDA does not intend to 
take action against outsourcing facilities for failing to conduct batch release 
testing of prescription sets.  
                                                 
33 Distributed means that the prepared prescription set has left the facility in which it was prepared.
 
34 See note 14. 
35 FDA does not intend to take action against an outsourcing facility for assigning a BUD to be used as an expiration 
date in lieu of conducting stability studies required under 21 CFR part 211, so long as the outsourcing facility 
assigns a BUD in accordance with this condition. 
36 For purposes of this condition, the reference to the USP Chapter <797> means in USP 40-NF 35 (2017).  USP has 
proposed revisions to USP Chapter <797> that would affect biological products.  Once USP has evaluated the public 
comments that it received and finalized the revised Chapter <797>, FDA intends to consider whether condition 7 
should refer to the updated chapter, or conditions should be adopted that are different than those included in final 
Chapter <797>.   
 
15 
  Contains Nonbinding Recommendations 
 
 
7.  The prepared prescription set is not sold or transferred by an entity other than the entity that 
prepared the prescription set. For purposes of this condition, a sale or transfer does not 
include administration of a prescription set in a health care setting.    
 
8.  The prescription set is distributed only in states in which the facility preparing the 
prescription set meets all applicable state requirements.   
 
9.  If the prescription set is prepared by an outsourcing facility:37 
 
a.  The label on any immediate containers (primary packaging) of the prescription set 
includes the following:  
 
i.  The patients name as identified on the prescription or order 
 
ii.  The statement This prescription set was prepared by [name of outsourcing 
facility]  
 
iii.  The address and phone number of the outsourcing facility that prepared the 
prescription set 
 
iv.  The identity of each allergenic extract in the prescription set and the quantity 
of each 
 
v.  The dilution of each dilution vial 
 
vi.  The lot or batch number of the prescription set 
 
vii.  The date the prescription set was prepared  
 
viii.  The BUD as the expiry date for the prescription set 
 
ix.  Storage and handling instructions for the prescription set 
 
x.  The statement Not for resale  
 
b.  The label of the container from which the individual units of the prescription set are 
removed for administration (secondary packaging) includes the following information 
to facilitate adverse event reporting: www.fda.gov/medwatch and 1-800-FDA-1088. 
 
c.  Each prescription set also is accompanied by instructions for use.    
 
d.  The prescription set is included in a report submitted to FDA each June and 
December identifying the drug products made by the outsourcing facility during the 
                                                 
37 With respect to sections 9.a.i-ix; section 9.c; and section 9.d., see section IV of this guidance. 
16 
  Contains Nonbinding Recommendations 
 
previous 6-month period, including the active ingredients; source of the active 
ingredients; NDC number of the source ingredients, if available; strength of the active 
ingredients per unit; the dosage form and route of administration; the package 
description; the number of individual units produced; and the NDC number of the 
final product, if assigned.38  
 
e.  The outsourcing facility reports serious adverse events to FDA that are associated 
with its prescription sets.39 
 
D.  Establishment Registration and Drug Listing 
 
Under section 510(b)(1) of the FD&C Act, between October 1 and December 31 of each year, 
every person who owns or operates any establishment in any State engaged in the manufacture, 
preparation, propagation, compounding, or processing of a drug or drugs (including biological 
products) is required to register with FDA, and under section 510(j) of the FD&C Act, every 
person who registers with FDA under section 510(b) must list its drugs manufactured, prepared, 
propagated, compounded, or processed for commercial distribution with the Agency.  A drug is 
misbranded under section 502(o) of the FD&C Act (21 U.S.C. 352(o)) if it was manufactured, 
prepared, propagated, compounded, or processed in an establishment that is not registered under 
section 510, or if it was not included on a list required by section 510(j).  Pharmacies that mix, 
dilute, or repackage biological products may qualify for an exemption from registration and 
therefore also not be required to list their drugs with FDA.  Specifically, under section 510(g)(1), 
the registration requirement of section 510 does not apply to 
 
pharmacies which maintain establishments in conformance with any applicable local laws 
regulating the practice of pharmacy and medicine and which are regularly engaged in 
dispensing prescription drugs or devices, upon prescriptions of practitioners licensed to 
administer such drugs or devices to patients under the care of such practitioners in the 
course of their professional practice, and which do not manufacture, prepare, propagate, 
compound, or process drugs or devices for sale other than in the regular course of their 
business of dispensing or selling drugs or devices at retail. 
   
With respect to entities that do not qualify for the exemptions from registration under section 510 
of the FD&C Act,40 FDA does not intend to take action against outsourcing facilities for 
                                                 
38 FDA has issued a guidance for industry, Electronic Drug Product Reporting for Human Drug Compounding 
Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act.  This guidance describes 
how outsourcing facilities submit drug product reports to FDA.  Although that guidance addresses reporting of 
compounded drug products, outsourcing facilities should follow the same procedure to electronically report the 
prescription sets that they prepared. 
39 FDA has issued a guidance for industry, Adverse Event Reporting for Outsourcing Facilities Under Section 503B 
of the Federal Food, Drug, and Cosmetic Act, which describes how outsourcing facilities submit adverse event 
reports to FDA and the content and format of the reports that they are required to submit.  Although that guidance 
addresses reporting of adverse events associated with compounded drug products, outsourcing facilities should 
follow the procedure described in that guidance to electronically report adverse events associated with the 
prescription sets they prepared. 
40 See also, 21 CFR 207.13.  
 
17 
  Contains Nonbinding Recommendations 
 
violations of section 502(o) of the FD&C Act for failure to register and list under section 510 
biological products that are mixed, diluted, or repackaged in accordance with this guidance.41    
 
 
IV.  PAPERWORK REDUCTION ACT 
 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520).  See footnotes 18, 22, 26, and 37.  These provisions require review and are not in 
effect until they display a currently valid OMB control number.  The information collection 
provisions in this guidance have been submitted to OMB for review as required by section 
3507(d) of the Paperwork Reduction Act of 1995. FDA will publish a notice in the Federal 
Register announcing OMBs decision regarding the information collection provisions in this 
guidance.  
   
                                                 
41 Outsourcing facilities that mix, dilute, or repackage biological products under this guidance are registered with 
FDA under section 503B of the FD&C Act and report mixed, diluted, or repackaged biological products to FDA in 
accordance with condition 13.c  in section III.B or, for licensed allergenic extracts for subcutaneous immunotherapy, 
condition 9.d in section III.C. 
18 
  Contains Nonbinding Recommendations 
 
Appendix A 
 
Assigning a BUD for Repackaged Biological Products Based On Stability Testing42 
 
As noted above, outsourcing facilities are subject to CGMP requirements.  For example, an 
outsourcing facility that repackages biological products must have a written stability testing 
program that includes:43 
 
  Sample size and test intervals based on statistical criteria for each attribute examined 
to assure valid estimates of stability; 
 
  Storage conditions for samples retained for testing; 
 
  Stability-indicating test methods that are reliable, meaningful, and specific; 
 
  Evaluation of samples of the biological product in the same container closure system 
as that in which the product is to be marketed by the outsourcing facility; and    
 
  Testing of biological products for reconstitution at the time of dispensing (as directed 
in the labeling) and after reconstitution. 
 
The initial time point for the tests described below is the time at which the outsourcing facility 
conducts this testing on the initial source material (i.e., licensed biological product) used for 
repackaging.   
 
Stability testing is intended to confirm certain quality attributes of a repackaged biological 
product held under the labeled storage conditions for the duration of the BUD.  To assign a BUD 
beyond 24 hours44 for a repackaged biological product and remain eligible for the policies 
described in this guidance, the outsourcing facility would conduct a series of tests, described 
below.  Samples evaluated for stability must be representative of the batch from which they were 
obtained (see 21 CFR 211.160 and 211.166).  The data from each time point would be evaluated 
against specifications that the outsourcing facility established for the repackaged product prior to 
beginning the stability program.  Specifications should be meaningful for the specific product 
being tested, and the outsourcing facility should have scientific justification for each 
specification.  
 
                                                 
42 Appendix A applies only to biological products repackaged by outsourcing facilities, and it does not apply to 
prescription sets of allergenic extracts.  BUDs for biological products mixed, diluted, or repackaged by state-
licensed pharmacies or Federal facilities that are not outsourcing facilities are addressed in section III.B.9, and 
BUDs for prescription sets of allergenic extracts are addressed in section III.C.5. 
43 See 21 CFR 211.166. 
44 See condition III.B.9 of this guidance. Note that under this condition, the BUD does not exceed the expiration date 
of the licensed biological product being repackaged, even if the BUD is assigned on the basis of stability testing 
under this appendix. 
 
19 
  Contains Nonbinding Recommendations 
 
After specifications have been established, the outsourcing facility would conduct the testing 
described below on one lot of a particular biological product in the container into which it will be 
repackaged to establish the BUD for that product, and then the outsourcing facility would 
conduct these tests on one lot annually and whenever the formulation of the biological product 
being repackaged or the container into which it is being repackaged may have changed.45 In lieu 
of performing the testing itself, the outsourcing facility may contract with a testing facility to 
perform this testing.46   
 
When establishing the BUD for a repackaged biological product, if the data for any test does not 
meet the established specifications, the BUD is limited to the time point at which all of the data 
remained within specifications.47  For this reason, FDA recommends testing at one or more 
interim time points.  If the data at the last time point do not confirm the stability of the product at 
the desired BUD (e.g., some measurements fall outside of the established specifications) but the 
data at the interim meet the established specifications, assigning a BUD equal to the interim time 
point would be consistent with the policies in this guidance. 
 
The stability studies are performed for each container-closure system to be used.   
 
FDA does not intend to take action against an outsourcing facility for non-compliance with 21 
CFR 211.166 when it repackages biological products in accordance with the conditions set forth 
in this guidance provided that it conducts a stability program that includes, at minimum, the 
following tests.  The outsourcing facility conducts these tests at each time point, except where 
specified: 
 
1.  Nondestructive Tests48 
 
The following tests are conducted to assure consistency with the biological product being 
repackaged and its approved labeling: 
 
  Appearance 
 
  Color and clarity 
                                                 
45 This is intended to assure that the product remains stable under labeled storage conditions for the duration of the 
BUD in the event of a change in the formulation of the biological product being repackaged or in the container into 
which it will be repackaged that the outsourcing facility is not aware of.  
46 When an outsourcing facility seeks the services of a contract facility to perform all or part of the testing of a 
biological product, the outsourcing facilitys quality control unit is responsible for approving and rejecting 
biological products tested by the contractor, and the outsourcing facility is responsible for assuring the stability of 
the repackaged biological product.  See 21 CFR 200.10(b) and 211.22(a). See also guidance for industry, Contract 
Manufacturing Arrangements for Drugs: Quality Agreements. We recommend that the testing facility be ISO 17025 
accredited. 
47 If the outsourcing facility receives failing results, it decreases the BUD to the time point at which all data 
remained within specifications and notifies its customers who received the product of the failing results and provides 
an alternate date by which the product should be used or discarded. 
48 If the container occludes visible determination of appearance, color, particulates, these tests are conducted without 
the container as part of the destructive tests (e.g., subvisible particulates). 
20 
  Contains Nonbinding Recommendations 
 
 
  Visible particulates 
 
2.  Destructive chemical tests 
 
The tests to be conducted include: 
 
  pH  
 
  Subvisible particles 
 
o  (See e.g., USP Chapter <788> Particulate Matter in Injections or USP 
Chapter <789> Particulate Matter for Ophthalmic Solutions, as appropriate, 
for the route of administration.  When the repackaged biological product being 
tested amounts to less than 1 mL, the outsourcing facility may complete this 
test by pooling a minimum of 10 units of the product and increasing the 
volume with particle free water in accordance with USP Chapter <788>. 
 
  Protein content 
 
o  See USP Chapter <1057> Biotechnology-Derived Articles  Total Protein 
Assay). 
 
  Product-related impurities including, at a minimum, protein aggregation, and variants 
in the size and charge of the protein49   
 
  Potency 
 
o  See Q6B Specifications: Test Procedures and Acceptance Criteria for 
Biotechnological/Biological Products (ICH Q6B validated assay) for 
developing a validated assay or purchasing a kit containing a validated assay. 
It is the outsourcing facilitys responsibility to select an appropriate kit and to 
demonstrate that it is using the kit properly and obtaining repeatable data. 
 
3.  Sterility and container closure integrity tests 
 
  The outsourcing facility conducts a sterility test at the time when the product is 
repackaged 
 
o  See 21 CFR 610.12 and USP Chapter <71> Sterility Tests.50  
 
                                                 
49 In general, these impurities can be characterized by standard biochemical methods, including but not limited to 
SE-HPLC or SDS PAGE. 
50 Sterility testing should be conducted using USP General Chapter <71> Sterility Tests.  Any other method used for 
sterility testing should be validated. 
21 
  Contains Nonbinding Recommendations 
 
  The outsourcing facility conducts either a sterility test or a container closure integrity 
test  
 
o  See USP Chapter <1207> Sterile Product PackagingIntegrity Evaluation) at 
additional time points.   
 
4.  Shipping  
 
The outsourcing facility ensures that the biological product remains stable and maintains 
appropriate package integrity during shipping.  For example, the outsourcing facility ensures that 
the temperature throughout the shipping period does not deviate from the recommended storage 
temperature range set forth in the approved product labeling for the licensed biological product.  
   
22 
  Contains Nonbinding Recommendations 
 
Appendix B 
 
Release Testing for Biological Products Mixed, Diluted, or Repackaged by Outsourcing 
Facilities 
 
21 CFR 211.165 and 211.167 require that finished drug products be tested to determine whether 
they meet final product specifications before their release for distribution.  21 CFR 211.22 
requires the establishment of a quality control unit, which is responsible for ensuring that the 
finished drug product is not released until this testing is conducted and the results confirm that 
the finished drug product meets specifications.   
 
  FDA does not intend to take action against an outsourcing facility for failing to 
conduct batch51 release testing under 21 CFR 211.165 and 211.167 for mixed, diluted, 
or repackaged biological products that are assigned a BUD that does not exceed the 
in-use time of the licensed biological product or 24 hours (in accordance with 
condition III.B.9 herein) and that are mixed, diluted, or repackaged in accordance 
with all of the other conditions of this guidance and any applicable requirements. 
 
  FDA does not intend to take action against an outsourcing facility for failing to 
conduct batch release testing under 21 CFR 211.165 and 211.167 for biological 
products that the outsourcing facility repackaged in accordance with the conditions of 
this guidance and that are assigned a BUD in accordance with Appendix A, provided 
that the outsourcing facility conducts the following release tests on each batch of 
biological products that it has repackaged and, except with respect to sterility testing, 
receives passing results prior to distribution: 
 
o  Sterility (the outsourcing facility initiates sterility testing before release and 
notifies customers of any failing results) 
o  Endotoxin52 
o  Color 
o  Clarity 
o  Visible particulates 
o  Subvisible particulates 
 
  FDA does not intend to take action against an outsourcing facility for failing to 
conduct batch release testing under 21 CFR 211.165 and 211.167 for prescription sets 
                                                 
51 See definition of batch at 21 CFR 210.3(b)(2). 
52 For finished products repackaged from starting materials that are sterile and nonpyrogenic, endotoxin testing can 
be conducted on all starting materials (through testing of the starting materials, reliance on a statement of the limit 
met on a certificate of analysis, or where specified in an applicable USP monograph) or through testing of samples 
of the finished product.  An outsourcing facility should not rely on the fact that a starting material is labeled 
nonpyrogenic to ensure that the finished product will meet the appropriate endotoxin limit because starting 
materials, including FDA-licensed products, may have been tested against different endotoxin limits, depending on 
the intended dose and the route of administration.  See also the guidance for industry Pyrogens and Endotoxin 
Testing: Questions and Answers (June 2012), available at 
https://www.fda.gov/downloads/drugs/guidances/ucm310098.pdf. 
23 
  Contains Nonbinding Recommendations 
 
that the outsourcing facility prepared in accordance with the conditions described in 
this guidance, provided that the outsourcing facility conducts the following release 
tests on each prescription set (at minimum, the first vial) that it has prepared, and it 
receives passing test results prior to distribution: 
 
o  Sterility 
o  Color 
o  Visible particulates 
 
24