Current Good Manufacturing 
PracticeGuidance for Human 
Drug Compounding Outsourcing 
Facilities Under  
Section 503B of the FD&C Act 
 
Guidance for Industry 
 
   
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. 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. All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Marci Kiester 301-796-0600.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2020 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
 
Revision 2 
   
Current Good Manufacturing 
PracticeGuidance for Human 
Drug Compounding Outsourcing 
Facilities Under  
Section 503B of the FD&C Act 
 
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 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2020 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
 
Revision 2
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CGMP FOR OUTSOURCING FACILITIES................................................................ 3 
A.  Quality Assurance Activities ......................................................................................................... 3 
B.  Facility Design ................................................................................................................................ 5 
C.  Control Systems and Procedures for Maintaining Suitable Facilities ...................................... 7 
D.  Environmental and Personnel Monitoring ................................................................................ 10 
E.   Equipment .................................................................................................................................... 12 
F.  Containers and Closures ............................................................................................................. 12 
G.  Components .................................................................................................................................. 14 
1. Regulatory Policy Regarding Component Supplier Qualification Testing .................................... 17 
2. Regulatory Policy Regarding Testing for Finished Product To Be Used as a Source Material for 
Processing .......................................................................................................................................... 17 
H.  Production and Process Controls ............................................................................................... 18 
1. General Production and Process Controls .................................................................................... 19 
2. Drug Product Sterilization ............................................................................................................. 19 
I.  Release Testing ............................................................................................................................. 22 
J.  Laboratory Controls .................................................................................................................... 25 
K.  Stability/Expiration Dating for Compounded Drug Products ................................................. 26 
1. Stability Program and Beyond-Use Dating ................................................................................... 26 
2. Establishing an In-Use Time for Sterile Drug Products ................................................................ 29 
3. In-Use Time and BUDs for Sterile Drug Products ........................................................................ 30 
L.  Packaging and Labels .................................................................................................................. 31 
M.  Reserve Samples ........................................................................................................................... 31 
N.  Complaint Handling .................................................................................................................... 32 
IV.   REFERENCES ................................................................................................................ 32 
V.   GLOSSARY..................................................................................................................... 34 
APPENDIX A. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT 
INTEND TO TAKE REGULATORY ACTION REGARDING CERTAIN RELEASE 
TESTING REQUIREMENTS ................................................................................................... 37 
APPENDIX B. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT 
INTEND TO TAKE REGULATORY ACTION REGARDING STABILITY TESTING 
AND EXPIRATION DATE REQUIREMENTS ..................................................................... 43 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Current Good Manufacturing PracticeGuidance for Human Drug 
2  Compounding Outsourcing Facilities  
3  Under Section 503B of the FD&C Act  
4  Guidance for Industry1 
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
9  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.  
12   
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This guidance describes FDAs policies regarding compliance with current good manufacturing 
19  practice (CGMP) requirements for facilities that compound human drugs and register with FDA 
20  as outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act 
21  (FD&C Act). Under section 501(a)(2)(B) of the FD&C Act, a drug is deemed to be adulterated if 
22  it is not produced in accordance with CGMP. FDAs regulations regarding CGMP requirements 
23  for the preparation of drug products have been established in 21 CFR parts 210 and 211.2 FDA 
24  intends to promulgate more specific CGMP regulations for outsourcing facilities. Until these 
25  final regulations are promulgated, outsourcing facilities are subject to the CGMP requirements in 
26  parts 210 and 211. This guidance provides for conditions under which FDA generally does not 
27  intend to take regulatory action against an outsourcing facility regarding certain CGMP 
28  requirements in parts 210 and 211 during this interim period. This guidance applies to drugs 
29  compounded in accordance with section 503B. In addition, this guidance generally applies to 
30  drugs that outsourcing facilities repackage and biological products that outsourcing facilities 
31  mix, dilute, or repackage in accordance with relevant guidance for outsourcing facilities.3 
32   
33  This guidance reflects FDAs intent to recognize the differences between outsourcing facilities 
34  and conventional drug manufacturers, while maintaining the minimum standards necessary to 
                                                 
1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research and in 
cooperation with the Office of Regulatory Affairs at the Food and Drug Administration.  
2 Positron emission tomography (PET) drug products are subject to CGMP regulations at 21 CFR part 212 and are 
not covered by this guidance. 
3 See guidances for industry Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing 
Facilities and Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics 
License Application (Biologics guidance). To the extent that the policies in the Biologics guidance differ from this 
guidance (e.g., conditions concerning assigning a beyond-use date to repackaged biological products based on 
stability testing), the policies described in the Biologics guidance apply. FDA updates guidances periodically. For 
the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
35  protect patients from the risks of contaminated or otherwise substandard compounded drug 
36  products.  
37   
38  This guidance revises the draft guidance Current Good Manufacturing PracticeInterim 
39  Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the 
40  FD&C Act issued in July 2014. Revision 1 was developed to (1) include considerations for non-
41  sterile compounded drug products; (2) differentiate between requirements applicable to sterile 
42  compounded drug products and non-sterile compounded drug products where appropriate; (3) 
43  include changes regarding stability testing, including the assignment of a beyond-use date (BUD) 
44  as an expiration date, and release testing requirements; and (4) address reserve samples and 
45  provide guidance on in-use times. Revision 2 refines a description of antimicrobial 
46  effectiveness testing in section III.K. and clarifies that section C of appendix B does not apply to 
47  non-sterile unpreserved aqueous drug products. 
48   
49  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
50  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
51  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
52  the word should in Agency guidances means that something is suggested or recommended, but 
53  not required.  
54   
55   
56  II.  BACKGROUND 
57   
58  The Drug Quality and Security Act added a new section 503B to the FD&C Act.4 Under section 
59  503B(b), a compounder can register as an outsourcing facility with FDA. Drug products 
60  compounded in an outsourcing facility can qualify for exemptions from the FDA approval 
61  requirements in section 505 of the FD&C Act,5 the requirement to label drug products with 
62  adequate directions for use under section 502(f)(1) of the FD&C Act,6 and the drug supply chain 
63  security requirements in section 582 of the FD&C Act,7 if the conditions in section 503B are 
64  met. Outsourcing facilities are inspected by FDA according to a risk-based schedule and must 
65  comply with other provisions of the FD&C Act, including CGMP requirements under section 
66  501(a)(2)(B) (see section 503B).  
67   
68  Under section 501(a)(2)(B), a drug is deemed to be adulterated if: 
69   
70  [T]he methods used in, or the facilities or controls used for, its manufacture, processing, packing, 
71  or holding do not conform to or are not operated or administered in conformity with current good 
72  manufacturing practice to assure that such drug meets the requirements of this [Act] as to safety 
73  and has the identity and strength, and meets the quality and purity characteristics, which it 
74  purports or is represented to possess . . . . 
75   
                                                 
4 See Pub. L. No. 113-54,  102(a), 127 Stat. 587, 587588 (2013). 
5 21 U.S.C. 355. 
6 21 U.S.C. 352(f)(1). 
7 21 U.S.C. 360eee-1. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
76  Further, section 501 of the FD&C Act, as amended by the Food and Drug Administration Safety 
77  and Innovation Act,8 states: 
78   
79    For purposes of paragraph (a)(2)(B), the term current good manufacturing practice includes the 
80  implementation of oversight and controls over the manufacture of drugs to ensure quality, including 
81  managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of 
82  drugs, and finished drug products. 
83   
84  CGMP requirements for finished drug products, except PET drug products, are established in 21 
85  CFR parts 210 and 211. The primary focus of this guidance is on those aspects of part 211 that 
86  relate to sterility assurance of sterile drug products and the safety of both sterile and non-sterile 
87  compounded drug products more generally, including with respect to strength (e.g., subpotency, 
88  superpotency), and labeling or drug product mix-ups, because these aspects of outsourcing 
89  facility operations pose the highest risk to patient safety if not conducted properly.  
90   
91  The recommendations in this guidance are consistent with the principles of good manufacturing 
92  practice, which hold that quality is best assured by implementing appropriate controls throughout 
93  the manufacturing process, with end-product testing providing additional assurance. This 
94  guidance also provides a risk-based approach to CGMP requirements. Accordingly, this 
95  guidance focuses on control of raw materials, facility design and maintenance, production 
96  techniques and controls, and personnel practices as the most critical aspects of ensuring quality 
97  for all drug products. Other CGMP requirements, such as testing samples of the finished drug 
98  product before batch release and the collection of reserve samples, provide additional assurance 
99  of drug quality and are described with respect to higher risk outsourcing facility operations. For 
100  example, the guidance distinguishes, where applicable, between higher risk compounding 
101  activities (e.g., higher volume of production for a drug product, sterile production, manual 
102  manipulations) and lower risk compounding activities (e.g., lower volume of production, non-
103  sterile production, use of automated equipment).  
104   
105  Depending on the level of risk, the guidance describes certain conditions under which FDA 
106  generally does not intend to take regulatory action against an outsourcing facility regarding 
107  specific CGMP requirements. 
108   
109   
110  III.  CGMP FOR OUTSOURCING FACILITIES 
111   
112  A.  Quality Assurance Activities  
113   
114  Quality assurance activities are needed to ensure that procedures are followed and a quality drug 
115  product is produced (see, e.g.,  211.22, 211.180, 211.192, 211.198). Part 211 (see, e.g., 
116   211.22) requires that drug producers establish a quality control unit to oversee various aspects 
117  of production, including strength as well as sterility assurance activities for sterile products and 
118  microbiological quality for non-sterile products.  
119   
                                                 
8 Pub. L. No. 112-114, 126 Stat. 993 (2012). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
120  The quality control unit should be independent; that is, the quality control unit should not take on 
121  the responsibilities of other units of the outsourcing facilitys organization, such as those handled 
122  by production personnel, in order to preserve the integrity of the quality control units functions. 
123  FDA has found that quality control units that are independent from other operations are more 
124  likely to be able to fulfill their required functions.9 FDA recommends the staffing level be 
125  adequate to perform all quality assurance functions at a level commensurate with the scale of the 
126  compounding operation, including number and volume of drug products compounded. 
127   
128  Procedures describing the role and responsibilities of the quality control unit must be established 
129  and followed ( 211.22(d)). The following aspects of quality assurance and quality control are 
130  critical to ensuring the quality of compounded sterile and non-sterile drug products at 
131  outsourcing facilities. 
132   
133  The quality control unit is responsible for ensuring that each batch of finished drug product is 
134  sampled and tested to ensure that it meets appropriate specifications for release (see 
135   211.22(a), 211.165(d)). For sterile products, procedures should be established and followed to 
136  ensure that for each batch intended to be released without completed sterility testing (see section 
137  I and Appendix A), the results of the sterility testing, once available, are reviewed and added to 
138  the batch record (see  211.188). 
139   
140  The quality control unit must periodically (at least annually) review records of compounding 
141  operations to evaluate the quality standards for each drug product to determine the need for 
142  changes in specifications or control procedures ( 211.180(e)). As part of this review, the quality 
143  control unit should identify trends and evaluate quality indicators such as (where required by 
144  part 211): 
145   
146    Results of environmental monitoring. 
147   
148    Results of personnel monitoring. 
149   
150    Where water is used as a component in the drug product, results of water system testing 
151  for water that is purified/processed on-site, or if water is purchased as an incoming 
152  component, testing results from the supplier or results of testing conducted by the 
153  outsourcing facility.  
154   
155    Results of finished drug product testing. 
156   
157    All media fills/process simulations performed since the last review. 
158   
159    Periodic scrutiny of operations to ensure adherence to procedures and proper aseptic 
160  technique. 
                                                 
9 FDA inspection information indicates that most outsourcing facilities maintain personnel in a quality control unit 
that is fully separate from compounding operations. However, FDA recognizes that there may be an extraordinary 
circumstance in which an individual in the quality control unit may need to participate in another operation. In such 
circumstances, that person is still accountable for implementing all of the controls and reviewing compounding 
operations to ensure that facility, process, and product quality standards have been met. See  211.22.  
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
161   
162    Complaints, discrepancies, failures, and yield variation. 
163   
164  The quality control unit is responsible for discrepancy and failure investigations and the 
165  development and oversight of effective corrective actions, which also include changes necessary 
166  to prevent recurrence, regarding the following (see, e.g.,  211.192, 211.180(e)):  
167   
168    Results of tests and examinations, regardless of batch disposition, if applicable to 
169  evaluate the quality of components, containers, closures, in-process materials, and 
170  finished product. Examples of such tests and examinations include but are not limited to 
171  sterility testing, endotoxin levels, content assay, impurity assay, particulate matter, 
172  reconstitution time, content uniformity, preservative content testing, microbial 
173  enumeration, tests for specified microorganisms, and, weight, volume, or counts. 
174   
175    Unexpected results (e.g., potential defects) or trends. 
176   
177    Failures that occur during validation or revalidation. These could include process 
178  validation, sterilization, or depyrogenation processes, including media fill/process 
179  simulation failures, as applicable.  
180   
181    Stability failures, including failures of quality that are determined to have causes other 
182  than degradation of the drug product. 
183   
184    Environmental and personnel monitoring results that exceed alert or action limits. 
185   
186    Process deviations or equipment malfunctions that involve critical equipment, such as 
187  sterilizers, lyophilizers, pellet machines, capsule machines, mixers, and homogenizers. 
188   
189    Complaints that indicate possible drug product contamination or other potential risks to 
190  patients (e.g., hazy or cloudy drug product, foreign matter/particulates in injectable drug 
191  products, cracked or leaky containers, change in color or appearance, particles falling out 
192  of oral solutions). 
193   
194  B.  Facility Design  
195   
196  Part 211 sets out the requirements applicable to the design of facilities used in the manufacture, 
197  processing, packing, or holding of a drug product (see, e.g.,  211.42). The design of a facility 
198  should consider the products produced and must provide the necessary level of control to prevent 
199  mix-ups and contamination ( 211.42).  
200   
201  The production areas in which components, drug products, in-process materials, equipment, and 
202  containers or closures are prepared, held, or transferred must be designed to minimize the level 
203  of contaminants so as to prevent objectionable microorganisms in non-sterile drug products (see 
204   211.113(a)) and prevent microbiological contamination of drug products purporting to be 
205  sterile (see  211.113(b)). Processing and controlled areas must be clean and sanitary ( 211.56).  
206   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
207  Additional Considerations for Sterile Drug Products 
208   
209  Outsourcing facilities should meet the following elements:  
210   
211    Sterile drugs should be produced only in ISO 5 or better air quality as determined under 
212  dynamic conditions (see Table 1 for International Organization for Standardization (ISO) 
213  cleanroom classification standards).  
214   
215  Table 1. ISO Classification of Particulate Matter in Room Air*  
ISO Class Name  Particles/m3 
3  35.2 
4  352 
5  3,520 
6  35,200 
7  352,000 
8  3,520,000 
*Limits are in particles of 0.5 m and larger per cubic meter (current ISO) measured under dynamic 
conditions. Adapted from ISO 14644-1:2015, Cleanrooms and associated controlled environmentsPart 1: 
Classification of air cleanliness by particle concentration.  
216   
217    The facility should be designed and operated with cascading air quality (e.g., by proper 
218  air classification and air pressurization) to protect the ISO 5 zone (or critical area10). The 
219  facility layout, room separation, and process flow must be designed to prevent the influx 
220  of contamination from adjacent areas and rooms of lower air quality and to avoid any 
221  disruption of HEPA unidirectional flow ( 211.42). 
222    
223    The air cleanliness classification of the area surrounding the ISO 5 zone immediately 
224  adjacent to the aseptic processing line should, at a minimum, meet ISO 7 standards under 
225  dynamic conditions. 
226   
227    If an isolator11 is used, the surrounding area should, at a minimum, meet ISO 8 standards 
228  under dynamic conditions.  
229   
230    If a restricted access barrier12 is used (e.g., a glove box), the surrounding area should, at a 
231  minimum, meet ISO 7 standards under dynamic conditions. 
232   
233    Terminally sterilized drugs should be produced in ISO 8 or better air quality as 
234  determined under dynamic conditions. 
                                                 
10 A critical area is an area designed to maintain sterility of sterile materials. See guidance for industry Sterile Drug 
Products Produced by Aseptic ProcessingCurrent Good Manufacturing Practice.  
11An isolator is a decontaminated unit supplied with ISO 5 or higher air quality that provides uncompromised, 
continuous isolation of its interior from the external environment. For further information, see also guidance for 
industry Sterile Drug Products Produced by Aseptic ProcessingCurrent Good Manufacturing Practice. 
12 See guidance for industry Sterile Drug Products Produced by Aseptic ProcessingCurrent Good Manufacturing 
Practice.  
 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
235   
236  The ISO 5 zone or critical area must be qualified (i.e., shown to meet the specifications; see 
237   211.42, 211.113(b)). Qualification should include at least the following studies and tests, 
238  which must be documented as having been conducted (see  211.113(b)), including the particular 
239  conditions under which the studies and tests were conducted:13  
240   
241    Airflow studies (e.g., an in-situ smoke study) should be conducted under simulated 
242  operational conditions to evaluate airflow patterns because of the risk for contamination 
243  of exposed product in the critical area. These studies should be conducted at the critical 
244  area to demonstrate unidirectional flow and sweeping action over and away from the 
245  product under dynamic conditions and should be repeated when any changes are made to 
246  the critical area that might affect airflow.14 Because proper control of airflow is necessary 
247  to prevent contamination, any indication of poor air control (e.g., non-unidirectional, 
248  turbulent) must be corrected before use (see  211.42, 211.113(b)). 
249   
250    HEPA periodic testing/recertification should be performed at least twice a year to ensure 
251  that appropriate airflow and quality are maintained. These tests should include integrity 
252  testing of the HEPA filters, particle counts, and air velocity checks. 
253   
254    Velocities of unidirectional air should be measured 6 inches from the HEPA filter face 
255  and at a defined distance close to the work surface in the ISO 5 area. 
256   
257    If any portable ISO 5 units are moved from one location to another, requalification of the 
258  unit should be performed before resuming sterile compounding.  
259   
260  C.  Control Systems and Procedures for Maintaining Suitable Facilities 
261   
262  To prevent contamination or mix-ups during the course of operations,  211.42 requires separate 
263  or defined areas or other similar control systems for a facilitys operations.15 Section 211.56 
264  requires that procedures be established and followed that assign responsibility for sanitation and 
265  describe in detail the cleaning schedules, methods, equipment, and materials to be used in 
266  cleaning buildings and facilities.  
267   
268  For multiuse facilities and nondedicated equipment, changeover and cleaning procedures for 
269  equipment and utensils must be established and followed to prevent contamination, including 
270  cross-contamination between products (see  211.42, 211.67). 
271   
272  Procedures for cleaning and disinfecting must also be established (see  211.42, 211.56, 
273  211.67). Equipment surfaces that come in contact with drug products, containers, or closures 
274  must be cleaned at appropriate intervals to prevent contamination (see  211.67). The suitability 
                                                 
13 In addition to documenting these tests and studies, the CGMP regulations generally require that other key 
activities be documented (see part 211, subpart J: Records and Reports). 
14 Additional information may be found in NSF/ANSI 492014 Biosafety Cabinetry: Design, Construction, 
Performance, and Field Certification. 
15 For example, this would be especially critical when using powders because powder particles can become airborne 
and contaminate other areas unless airflow is designed to contain such particles. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
275  and efficacy of the cleaning agents and cleaning methods should be evaluated, and the cleaning 
276  agents compatibility with applicable work surfaces should be assessed. Published literature and 
277  supplier certificates of analysis (COAs) can be relied on when initially determining the 
278  effectiveness of agents used to clean and disinfect, as necessary, the facility and equipment 
279  surfaces, provided that the suppliers cleaning procedures are followed. The expiration dates of 
280  cleaning and disinfection agents should be closely monitored and expired solutions should be 
281  discarded. 
282   
283  For non-sterile drug production, water used as a final rinsing agent for any equipment or utensils 
284  that come in direct contact with the drug product should meet the requirements for Purified 
285  Water, USP, or higher quality standards.16  
286   
287  If powder drugs are handled, procedures must be established and followed to appropriately 
288  manage cross-contamination risk (see  211.100). This is particularly important if the powder is 
289  cytotoxic or highly sensitizing. FDA recommends the physical segregation of areas in which 
290  powder drugs are exposed to the environment. For penicillin products, a separate facility is 
291  required (see  211.42(d)). However, FDA has clarified that separate buildings may not be 
292  necessary, provided that the manufacturing operation involving penicillin is isolated (i.e., 
293  completely and comprehensively separated) from the areas in which non-penicillin products are 
294  manufactured.17 For non-penicillin beta-lactam products, FDA recommends complete and 
295  comprehensive separation from other products.18 Additionally, appropriate controls related to 
296  movement of equipment, product, and personnel should be established to prevent cross-
297  contamination of non-beta-lactam products.  
298   
299  In general, processes and procedures at an outsourcing facility should minimize contamination 
300  risks posed by, for example, the number and complexity of manipulations, number of 
301  simultaneous operations and workstations, and staging of materials used in the process. 
302   
303  Additional Considerations for Sterile Drug Products 
304   
305  HEPA filters should be qualified to provide appropriate air quality and be periodically 
306  maintained and tested to ensure intended air quality. Discolored, dirty, or damaged HEPA filters 
307  should be repaired or replaced.  
308   
309  Temperature and humidity must be maintained in cleanroom areas; such controls are critical to 
310  reduce microbiological growth (see  211.46). A specification for humidity should be established 
311  considering that higher humidity supports microbial growth, while too little humidity can cause 
312  problems with static electricity (which may be particularly problematic when working with 
313  powders) and may lead to increased particulates. Cleanroom temperature and humidity 
314  specifications should be maintained solely through the facilitys central heating, ventilation, and 
                                                 
16 See FDAs Guide to Inspections of High Purity Water Systems at https://www.fda.gov/inspections-compliance-
enforcement-and-criminal-investigations/inspection-guides/high-purity-water-system-793. 
17 Preamble to the final rule, Current Good Manufacturing Practice in Manufacture, Processing, Packing, or 
Holding. 43 FR 45014, at 45038 (September 29, 1978).  
18 See guidance for industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-
Contamination. 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
315  air conditioning (HVAC); peripheral devices such as stand-alone (de-)humidifiers and air 
316  conditioners should not be used because they generate airborne particles, are water sources, and 
317  may harbor microorganisms. As a scientific matter, a system for environmental monitoring must 
318  include the establishment of pressure differential limits (see  211.42), and control systems 
319  should include built-in alarms to detect excursions. An adequate control system includes 
320  monitoring for pressure differentials, humidity, and temperature during production and taking 
321  prompt action to correct adverse conditions, which are necessary activities to prevent 
322  contamination during aseptic processing (see  211.42, 211.46, 211.58). If a problematic 
323  condition cannot be immediately corrected, production should stop until it has been corrected. 
324  Regardless of whether production is stopped or allowed to continue, the impact of any 
325  excursions on product that is already in process should be evaluated. Among other requirements 
326  in  211.192, any unexplained discrepancy must be investigated, the results of which must be 
327  documented.  
328   
329  Monitoring procedures should require documentation and investigation of any instances in which 
330  there is a loss of positive pressure in the cleanroom during actual production and documentation 
331  of the batches affected and the corrective action taken. These checks should be conducted 
332  regularly on a schedule that considers the environment, such as use of an isolator versus a less 
333  protected process, and the results should be recorded in logs and evaluated against prespecified 
334  alert and action limits at each check. 
335   
336  In addition to the requirements in  211.42 and 211.56, FDA recommends that outsourcing 
337  facilities ensure that air vents and airflow are not obstructedby large equipment, for example
338  in such a way that could potentially compromise aseptic operations. Equipment that is not 
339  needed for the specific cleanroom operations conducted should not be stored in the cleanroom. 
340   
341  Procedures for cleaning and disinfecting ISO 5 areas/units should include detailed instructions 
342  for consistently and properly cleaning and disinfecting surfaces that are difficult to access. A 
343  system for cleaning and disinfecting all critical areas to produce aseptic conditions includes 
344  sporicidal and other sterile disinfectants and lint-free sterile wipes (see  211.42). Procedures 
345  must describe the methods and schedule for cleaning (see  211.42, 211.56, 211.67, 211.182) 
346  and should include the use of sporicidal disinfectants in the ISO 5 area and other classified areas 
347  on a regular basis.  
348   
349  Water used as a cleaning or rinsing agent for any equipment or utensils that will not be 
350  subsequently disinfected or sterilized and depyrogenated must be sterile (see  211.113(b)). 
351  Purified Water, USP, is considered acceptable for use with equipment or utensils that will be 
352  sterilized and depyrogenated. 
353    
354  Based on the results of environmental monitoring (see section D below), the disinfection 
355  program must be revised if there are indications that the frequency of disinfection or the methods 
356  or type of disinfectant(s) used are inadequate to ensure appropriately clean surfaces (see 
357   211.42, 211.56, 211.67, 211.113). Conducting disinfectant effectiveness testing may be useful 
358  in guiding revision of the disinfection program in such cases. 
359   
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Draft  Not for Implementation 
360  Critical equipment surfaces that come in contact with sterile drug products, containers, and 
361  closures must be sterilized at appropriate intervals (see  211.67); disinfection alone is not 
362  sufficient (see section E below). Single-use disposable equipment and supplies that are purchased 
363  presterilized and depyrogenated and are discarded after one use need not be resterilized. 
364   
365  D.  Environmental and Personnel Monitoring 
366   
367  The frequency and methods of environmental and personnel control and monitoring should be 
368  commensurate with the risk to product quality. For example, for non-sterile drugs, aqueous-
369  based drugs present the highest microbiological risk to patients. Consequently, water system and 
370  environmental monitoring for aqueous non-sterile drug production should be performed more 
371  frequently than for non-aqueous non-sterile drugs. During aqueous non-sterile drug production, 
372  temperature and humidity should be monitored daily and air (viable19 and nonviable particles) 
373  and surfaces (viable particles) should be monitored periodically (e.g., at least quarterly). Aseptic 
374  sterile drug production environments should be monitored at least daily during production. Also, 
375  monitoring of product residue may be necessary to ensure that the cleaning program is effective 
376  or containment is maintained, with an increased frequency of monitoring and sensitivity of 
377  methods when contamination poses a higher risk, such as when producing cytotoxic or highly 
378  sensitizing materials.  
379   
380  Additional Considerations for Sterile Drug Products 
381   
382  21 CFR 211.42(c)(10)(iv) requires establishing a system for monitoring environmental 
383  conditions in aseptic processing areas, and  211.113(b) and 211.28(a) require personnel 
384  sanitation practices and gowning to be both acceptable and qualified for the operations they 
385  perform. For example, gowning procedures should ensure that there is no exposed skin on 
386  personnel involved in any production activities in, or that can directly affect, the ISO 5 area.20 
387  Procedures for monitoring the environment and personnel for the presence of viable particles and 
388  nonviable particles should be established and followed as described here. 
389    
390  Operations and appropriate written procedures designed to prevent microbial contamination 
391  include a well-defined and documented program for environmental monitoring that evaluates the 
392  potential routes of microbial contamination of the human drug that could arise from the air, 
393  surfaces, process, operation, and personnel practices (see  211.42(c)(10)(iv), 211.100, 
394  211.113(b)). The program should contain an appropriate detection component(s) to verify state 
395  of control of the environment. However, environmental monitoring equipment should not 
396  interfere with aseptic operations (e.g., instruments should not interfere with validated and 
397  appropriate airflow patterns). In particular, the program should: 
398   
399    Cover all production shifts and include monitoring during normal production conditions.  
400   
401    Include at least daily monitoring of the ISO 5 zone during operations. 
                                                 
19 A viable particle consists of, or supports, one or more live microorganisms (see ISO 14644-6:2007, Cleanrooms 
and associated controlled environmentsPart 6: Vocabulary). 
20 See guidance for industry Sterile Drug Products Produced by Aseptic ProcessingCurrent Good Manufacturing 
Practice for further recommendations regarding gowning. 
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
402   
403    Establish alert and action limits and appropriate responses when excursions occur. 
404   
405    Describe the use of sampling (e.g., contact plates, swabs, active air samplers), alert and 
406  action limits and responses, and testing methods (e.g., media, plate exposure times, 
407  incubation times and temperatures) that are designed to detect environmental 
408  contaminants, including changes in microflora type and amount, and the scientific 
409  justification for the testing methods selected. 
410   
411    Be supported by a scientific justification for sampling locations, based on risk, and 
412  sampling methods, which may be based on risk and peer-reviewed literature.  
413   
414    Investigate results that exceed established limits or demonstrate adverse trends; determine 
415  product impact; and execute appropriate actions.  
416   
417  Personnel monitoring should:  
418   
419    Include a routine program for daily/shift monitoring of operators gloves and an 
420  appropriate schedule for monitoring other critical sites of the gown (e.g., gown sleeves 
421  for hood work) during or immediately after completion of aseptic operations. Monitoring 
422  should take place before planned disinfection so that actual operating conditions are 
423  being assessed. 
424   
425    Establish and justify limits that are based on the criticality of the operation relative to the 
426  contamination risk to the product. 
427   
428    Call for an investigation of results that exceed the established levels or demonstrate an 
429  adverse trend, a determination of the impact on the sterility assurance of finished 
430  products intended to be sterile, and the development and execution of appropriate 
431  corrective actions. 
432   
433  If microbiological media used in performing tests, including environmental and personnel 
434  monitoring, are not purchased from a qualified supplier,21 the outsourcing facility or contract 
435  laboratorys procedures should establish the validity of each medium, including its growth 
436  potential. The quality control unit of an outsourcing facility that opts to rely on a contract 
437  laboratory for any of the duties described in this section of the guidance must ensure the 
                                                 
21 A supplier could be qualified by following the recommendations for component supplier qualification in section 
III.G.1. of this guidance. Specifically, the outsourcing facility should have a quality agreement with each supplier 
and make the quality agreement available for review upon request by FDA. Each quality agreement should include, 
at a minimum: a description of the testing performed before a lot is released and shipped to the outsourcing facility 
and the specific quantitative (or qualitative, if applicable) results of a representative lot that would be provided on 
each COA; examples of testing records (such as growth promotion) that the supplier generates in performing release 
testing before shipping each lot to the outsourcing facility; a description of packaging, labeling, tamper-evident 
seals, and other features used to ensure package integrity while the purchased media is in distribution; and a 
commitment that the supplier will notify the outsourcing facility if there is identification of a problem with the 
quality of the media already shipped to the outsourcing facility. 
  11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
438  existence, appropriateness, and implementation of contract laboratory procedures (see  200.10, 
439  211.22, 211.160). 
440   
441  E.   Equipment 
442   
443  Several provisions of part 211 address controls over the equipment used to compound (see 
444   211.63, 211.65, 211.67, 211.68).  
445   
446  Equipment (mechanical, electronic, or automated) must be qualified as capable of performing its 
447  intended functions or operations before first use, and procedures for routine calibration and 
448  maintenance must be established and followed (see  211.68). Equipment surfaces that come in 
449  contact with components, in-process materials, or drugs must not be reactive, additive, or 
450  absorptive so as to alter the quality of the drug (see  211.65). Equipment needs to be designed 
451  and located to facilitate operations, cleaning, and maintenance, and equipment may require 
452  sanitization or sterilization to prevent contamination (see  211.63, 211.67).  
453   
454  Outsourcing facilities may choose to use single-use disposable equipment (e.g., transfer tubing 
455  and temporary holding vessels), which reduces the need for cleaning between different batches 
456  and the potential for contamination (see  211.67). Single-use disposable equipment should be 
457  inspected for damage or contamination following use. The suitability of single-use disposable 
458  equipment for its use in processing may be determined by the use of a valid COA from the 
459  supplier in lieu of testing or examination by the outsourcing facility (see  211.65, 211.113). In 
460  addition, the integrity of the packaging of the single-use disposable equipment should be verified 
461  upon receipt before use.  
462   
463  Additional Considerations for Sterile Drug Products 
464   
465  Equipment that comes into contact with the drug product must be evaluated to ensure adequacy 
466  for intended use, including to ensure sterility and cleanliness at time of use (see  211.65, 
467  211.67(a)). For sterility and endotoxin limits, a valid COA may be used in lieu of testing by the 
468  outsourcing facility for single-use disposable equipment (see  211.65, 211.113). 
469   
470  If the outsourcing facility does not use presterilized and depyrogenated single-use disposable 
471  equipment (e.g., filters, transfer tubing, temporary holding vessels), the equipment must be 
472  sterilized and depyrogenated before use through processes that have been validated22 (see 
473   211.65, 211.67(a) and (b), 211.100, 211.113). 
474   
475  F.  Containers and Closures 
476   
477  Controls for the containers and closures in which the compounded drug product is packaged are 
478  critical to ensuring the quality of compounded drug products and are expected to be implemented 
479  by outsourcing facilities (see  211.80, 211.82, 211.84, 211.87, 211.94, 211.113).  
                                                 
22 A process has been validated if it has been demonstrated and documented to consistently achieve the desired 
result when performed under defined conditions. 
 
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Draft  Not for Implementation 
480   
481  Scientifically sound and appropriate criteria23 for containers and closures must be established to 
482  ensure that drug product containers and closures used for compounded drug products are suitable 
483  for each particular drug product for which they will be used (see  211.160(b)). As part of the 
484  selection process, testing of the drug product container-closure system under the proposed 
485  storage conditions for the finished product must be performed to verify its ability to meet 
486  established quality specifications of the finished drug product over the expiry period (see  
487  211.94, 211.166). Testing must be performed again if the manufacturers specification of the 
488  container or closure is changed (see  211.94, 211.166). Appropriate procedures must be 
489  established for testing or verifying the testing, as applicable, of the containers and closures 
490  before use to determine whether they meet the criteria for use; the tests and results must be 
491  documented (see  211.84(d)(3), 211.184). Each lot of containers and closures must be 
492  examined to verify identity and tested to ensure conformity with appropriate specifications 
493  before use (see  211.84(d)).  
494   
495  Containers and closures must be handled and stored to protect them from risk of contamination 
496  and must be examined and cleaned to prevent introduction of contamination (see  211.80, 
497  211.82, 211.84, 211.94). 
498   
499  If containers or closures are stored for long periods in the absence of a suppliers expiration date 
500  or established in-use period, or if they are exposed to air, heat, or other conditions that might 
501  adversely affect the drug product container or closure, the containers and closures must be 
502  retested or re-examined for integrity and fitness for use before they are used (see  211.87).  
503   
504  Additional Considerations for Sterile Drug Products 
505   
506  Containers and closures that come into contact with the drug product must be evaluated to ensure 
507  adequacy for intended use, including to ensure sterility and cleanliness at time of use (see 
508   211.80, 211.84(d)(6)).  
509   
510  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
511  the identification or testing of each lot of containers and closures if (1) for a finished drug 
512  product intended to be sterile, the supplier certifies and labels the material as ready-to-use, 
513  sterile, and nonpyrogenic; (2) the suppliers packaging integrity is verified upon receipt before 
514  use; and (3) the valid COA provided by the supplier is reviewed to verify that the product is 
515  represented to meet the required specifications established by the outsourcing facility, including 
516  sterility and depyrogenation. Any container or closure not meeting acceptance requirements must 
517  be rejected or not used until rendered suitable for use (see  211.84(d) and (e)). 
518   
519  If the outsourcing facility does not use presterilized and depyrogenated containers and closures 
520  (e.g., vials, syringes), the containers and closures must be sterilized and depyrogenated before 
521  first use through processes that have been validated (see  211.94(c)). 
522   
                                                 
23 For sterile drug products, see guidance for industry Sterile Drug Products Produced by Aseptic Processing
Current Good Manufacturing Practice for recommended test methods and criteria.  
  13  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
523  Procedures for storage, if appropriate, of sterilized containers or closures must be established in a 
524  manner to prevent contamination and to maintain sterility (see  211.80(a) and (b)). For 
525  example, safeguards must be in place to ensure that containers and closures are not contaminated 
526  when held for use in areas where other materials are received, unpacked, and stored. 
527    
528  Containers or closures that are purchased as sterile must not be used after the suppliers 
529  expiration date without testing or examination to verify that container or closure integrity has 
530  been maintained (see  211.87). Once the presterilized primary package has been breached, it 
531  should remain under the hood or in the ISO 5 area until the containers or closures are used. 
532  Where appropriate, any containers or closures removed from the ISO 5 area may be used for 
533  sterile production after resterilization using a validated process (which must also establish that 
534  the integrity of the container or closure is maintained) or used for drug products that do not 
535  require a sterilized container or closure ( 211.84, 211.87, 211.94).  
536   
537  G.  Components 
538   
539  Controls over the source and quality of components are required ( 211.82, 211.84, 211.87, 
540  211.113). When producing sterile drug products, one aspect of such controls is the 
541  consideration of whether the incoming components are non-sterile. The following controls are 
542  considered critical to ensuring the quality of compounded drug products and are expected to 
543  be implemented by outsourcing facilities. 
544   
545  Scientifically sound and appropriate specifications must be established for the components used 
546  in each drug product (see  211.160(b)). Scientifically sound and appropriate specifications 
547  include those that address the attributes necessary to ensure the quality of the finished drug 
548  product and are appropriate for the intended use of the drug product, including the route of 
549  administration, as specified in the directions for use. A specification should generally conform to 
550  the model described in the ICH guidance for industry Q6A Specifications: Test Procedures and 
551  Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. A 
552  specification should minimally include those tests described in ICH Q6As section 3.2, 
553  Universal Tests/Criteria. Other dosage form-specific attributes may also be considered (see 
554  ICH Q6A section 3.3, Specific Tests/Criteria). Attributes can include identity, strength, purity, 
555  particle size, sterility, bacterial endotoxin level, content uniformity, microbial enumeration, tests 
556  for specified microorganisms, or other characteristics that could affect the quality of the final 
557  drug product.  
558   
559  To be eligible for the exemptions provided in section 503B of the FD&C Act, each bulk drug 
560  substance used in compounding must be accompanied by a valid certificate of analysis (section 
561  503B(a)(2)(D)). FDA interprets this provision to mean that each lot of a bulk drug substance is 
562  accompanied by a valid COA.24 FDA recommends that the COA conform to the model described 
563  in ICH Q6A.25 In addition, to be eligible for the exemptions provided in section 503B of the 
                                                 
24 Under certain conditions, a valid COA may be relied upon to minimize testing of incoming components (see  
211.84). 
25 The COA should be in English or should be translated into English to facilitate use by the outsourcing facility and 
review by FDA on inspection if needed. 
  14  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
564  FD&C Act, the bulk drug substance must be manufactured by an establishment that is registered 
565  under section 510 of the FD&C Act (section 503B(a)(2)(C) of the FD&C Act).  
566   
567  Each shipment of each lot of components must be tested to verify identity and evaluated for 
568  conformity with appropriate specifications before use (see  211.84). Components should not be 
569  used beyond the suppliers labeled expiration (or re-test) date. If the component does not have an 
570  expiration date, the supplier should provide the date or testing should be conducted to establish 
571  an expiration date. 
572   
573  Components that are not approved finished drug products (both active pharmaceutical 
574  ingredients (APIs) and inactive ingredients) must be tested to verify identity and evaluated for 
575  conformity with appropriate specifications and, if necessary and depending on intended use, 
576  tested for endotoxin level and bioburden before use in compounding (see  211.84). As described 
577  in  211.84(d)(2), in lieu of testing each shipment of each ingredient, a suppliers COA can be 
578  accepted and evaluated to determine whether the lot can be used, provided that the following 
579  conditions are met (see also Figure 1 below): 
580   
581    The reliability of the suppliers analyses has been established at appropriate intervals and 
582  through appropriate steps to: 
583   
584    Confirm the suppliers test results for those tests relevant to the specifications 
o
585  established for the compounded drug product. 
586   
587    Confirm that the ingredient meets the applicable United States Pharmacopeia (USP) 
o
588  or National Formulary (NF) monograph, if one exists.26  
589   
590  Such steps may include, but are not limited to, confirmatory testing and remote audit of 
591  the suppliers procedures. 
592   
593  FDA recommends that these steps be carried out no less frequently than annually for 
594  APIs and every 2 years for other components. 
595   
596    At least one specific identity test has been conducted before use to confirm that the 
597  component is the one specified in the purchase order. 
598   
599  In addition, as required by  211.82(a): 
600   
601    Each container or grouping of containers of components must be examined to verify 
602  appropriate labeling regarding contents. 
603   
604    The shipments package integrity must be verified upon receipt before use. 
605     
                                                 
26 Components, both bulk drug substances and other ingredients, used in compounding must comply with the 
standards of the applicable USP or NF monograph, if such monograph exists, to qualify for the exemptions provided 
in section 503B of the FD&C Act (see sections 503B(a)(2)(B) and (a)(3)). 
  15  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
606   
607  Figure 1. Using a Suppliers COA in Lieu of Testing*  
608   
At appropriate intervals (e.g., annually for API and every 2 years for other 
components): 
 Confirm the suppliers test results for tests relevant to the product 
specifications. 
Verify supplier 
analyses  Confirm that the component meets the applicable USP or NF 
monograph, if one exists. 
 
 Exa mine each  con tainer or g roup  ing of  con taine rs to ver ify  app ropriate  
labeling regarding c ontents. 
Examine   Verify the package integrity of each container or grouping of containers. 
shipments                          
     
 Conduct at least one specific identity test before use to confirm that the 
 
component is the one specified in the purchase order.  
                       
Conduct identity 
test on shipment  
                         
609   
     
610  * See  211.84(d)(2) and 211.82(a). 
611   
 
612  Acceptance of incoming lots of non-sterile components (including water) for use in sterile drug 
613  products must include microbial and endotoxin testing and meet limits appropriate for the drug 
614  products intended use (see  211.84(d)(6)). FDA generally does not intend to take regulatory 
615  action against an outsourcing facility regarding the absence of such testing for water if it is 
616  purchased and certified as sterile and nonpyrogenic and if it is accompanied by a valid COA; 
617  however, the type of water purchased must be appropriate for its intended use (e.g., Sterile Water 
618  for Injection, USP) ( 211.84). The quality of water produced on-site and used as an ingredient 
619  or processing aid must be tested regularly, using validated methods, at point of use to verify 
620  acceptable microbial quality, chemical quality, and endotoxin limits ( 211.84, 211.160). 
621  Acceptance criteria should be in agreement with those specified in the respective USP 
622  monograph and be appropriate for the intended use of the product.  
623   
624  Any component not meeting acceptance requirements must be rejected (see  211.84(e)). 
625   
626  Components must be retested or re-examined for identity, strength, quality, and purity after 
627  storage for long periods or after exposure to air, heat, or other conditions that might adversely 
628  affect the component (see  211.87). However, additional testing is unnecessary if each lot of 
629  components is stored under the suppliers labeled storage conditions, used within the established 
630  (i.e., as labeled, as provided by the supplier, or as determined by the outsourcing facility) retest 
631  or expiration date, and protected from contamination when portions of the lot are removed (see  
632  211.187). 
633     
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Draft  Not for Implementation 
634  1.  Regulatory Policy Regarding Component Supplier Qualification Testing 
635   
636  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
637  additional testing to confirm the suppliers COA under  211.84(d)(2) if the outsourcing facility 
638  enters into a quality agreement with each supplier of each component, makes the quality 
639  agreement available for review upon request by FDA, and each quality agreement includes, at a 
640  minimum: 
641   
642    A description of the testing performed before a component lot is released and shipped to 
643  the outsourcing facility and the specific quantitative (or qualitative, if applicable) results 
644  of a representative lot that would be provided on each COA. 
645    
646    Examples of testing records, such as chromatograms and spectrograms, that the 
647  component supplier generates in performing release testing before shipping each lot of 
648  the component to the outsourcing facility.  
649   
650    A description of packaging, labeling, tamper-evident seals, and other features used to 
651  ensure package integrity while the purchased component is in distribution. 
652   
653    A commitment that the component supplier will notify the outsourcing facility if any 
654  testing performed to generate the release COA is significantly modified (e.g., change in 
655  principle of operation for a test method). 
656   
657    A commitment that the component supplier will notify the outsourcing facility under 
658  specified circumstances, including but not limited to a change in specifications or 
659  identification of a problem with the quality of a component already shipped to the 
660  outsourcing facility. 
661   
662    A commitment that the supplier, if not the original component manufacturer, ensures the 
663  components pedigree to the outsourcing facility, including:  
664   
665    A description of the suppliers qualification and audit requirements for each 
o
666  manufacturer from which the supplier purchases components.  
667   
668    A description of the supply chain authentication controls that the supplier has 
o
669  implemented to verify that before receipt, each component is transported through 
670  known and pre-established channels. 
671   
672  2.  Regulatory Policy Regarding Testing for Finished Product To Be Used as a 
673  Source Material for Processing 
674   
675  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
676  the identification or testing of each lot of a product under  211.84 that is to be used as a source 
  17  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
677  material and is an approved human finished drug product if all of the following conditions are 
678  met:  
679   
680    The product was purchased directly from a manufacturer registered and listed with FDA 
681  under section 510 of the FD&C Act and has not been repacked or otherwise altered since 
682  initial manufacture, or the product was purchased from a distributor that certifies that it 
683  has not been repacked or otherwise altered since initial manufacture. 
684    
685    The label of each lot of the product has been examined to verify that the product meets 
686  required specifications before use. 
687   
688    No portion of the lot has been subject to a recall for reasons that would make it unsuitable 
689  for use. 
690   
691    The shipments package integrity has been verified upon receipt before use. 
692   
693  H.  Production and Process Controls  
694   
695  Production and process controls are required when producing any drug product (see, e.g., 
696   211.22, 211.25, 211.28, 211.100, 211.111, 211.113, 211.188, 211.192).  
697   
698  Written procedures for production and process controls must be designed and followed to ensure 
699  the consistent production of a drug that meets the applicable standards of identity, strength, 
700  quality, and purity (see  211.100). These controls are intended to ensure consistent yields; 
701  batches failing to meet the theoretical yield must be investigated (see  211.186, 211.192). The 
702  degree of batch-by-batch control over product attributes or process parameters should be 
703  commensurate with the risk of those attributes and parameters to the process and product. These 
704  procedures should ensure documentation that all key process parameters are controlled and that 
705  any deviations from the procedures are justified. 
706   
707  Before use in production, equipment, components, containers, and closures should be visually 
708  examined for indications of damage, degradation, or contamination.  
709   
710  Batch records must provide complete documentation of the production of each batch of a drug 
711  product (see  211.188).27 The actual batch output (yield) must be compared to the projected 
712  (calculated) output for each drug product (see  211.103). If the actual output is different than 
713  expected after accounting for sampling and known process loss, this finding should be 
714  considered an indicator of a potential problem with production and must be investigated 
715  ( 211.192). An acceptance level for actual output should be established that ensures batch-to-
716  batch consistency. Failure to meet the acceptance criteria and production standards must be 
717  investigated before making the batch disposition decision and may require that the batch be 
718  rejected (see  211.165, 211.192). 
719   
                                                 
27 For aseptic operations that occur in a hood, a contemporaneous recording to the batch record is one that occurs as 
soon as possible after completion of that unit operation. 
  18  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
720  Additional Considerations for Sterile Drug Products 
721   
722  1.  General Production and Process Controls 
723   
724  If a drug product intended to be sterile is not terminally sterilized, there must be a validated 
725  sterilization step such as sterile filtration (see  211.113(b)), and it is critical that the sterilization 
726  step occur as close to filling into the final product container as is feasible.  
727   
728  The microbiological content (bioburden) of articles and components that are subsequently 
729  sterilized should be controlled. If materials are stored or held during processing (e.g., before 
730  sterilization, after sterilization, before container fill), storage or holding times must be 
731  established (see  211.110(c), 211.111). Production phase hold times for a drug product should 
732  be limited, verified by testing, and based on an understanding of the associated risk of increased 
733  bioburden and endotoxin. Hold time assessments can be performed as part of the process for 
734  validating sterility assurance (see  211.111, 211.113(b), 211.160). In addition, in-process 
735  materials such as bulk stock solutions must be stored in equipment that is protective and does not 
736  affect the quality of the drug beyond its established specifications (see  211.65, 211.113(b)). 
737   
738  2.  Drug Product Sterilization 
739     
740  a.  Terminal sterilization 
741   
742  For sterile drug products that are terminally sterilized, at least a 10-6 sterility assurance level 
743  should be demonstrated in validation studies during process development using an appropriate 
744  sterilization load monitor, such as biological indicators and thermocouples.28 Validation studies 
745  should be performed for each load size (container closure and number of vials) intended for 
746  sterilization. For terminally sterilized drug products that are not subjected to an overkill terminal 
747  sterilization cycle, presterilization bioburden limits should be established (i.e., determining the 
748  number of microorganisms that can be reliably killed) and measured before sterilization. The 
749  selected sterilization method should both sterilize and maintain the strength, purity, quality, and 
750  package integrity of the sterile product.29  
751   
752  b.  Aseptic processing 
753   
754  If a drug product intended to be sterile is not terminally sterilized, the finished drug product 
755  should be sterilized immediately before filling into the final product container. This is typically 
756  done by filtration; however, other validated sterilization methods may be used. If a finished drug 
                                                 
28 See guidance for industry Submission Documentation for Sterilization Process Validation in Applications for 
Human and Veterinary Drug Products. For products such as pellets or powders, validation studies should be 
conducted using a biological indicator placed inside the product (i.e., inside the powder or pellets in their marketed 
containers) and spaced throughout the load to verify that the sterilization cycle results in sterility of the entire batch. 
Pellets should be placed in a defined and specified pattern in the sterilization chamber to demonstrate that 
appropriate lethality is delivered to each unit of the batch. Refer to ISO 11137-1:2006, Sterilization of health care 
productsRadiationPart 1: Requirements for the development, validation and routine control of a sterilization 
process for medical devices; and ISO 11137-2:2013, Sterilization of health care products RadiationPart 2: 
Establishing the sterilization dose. See PDA Technical Report No.1 (Parenteral Drug Association 2007).  
29 See also USP General Chapters  1211  Sterility Assurance and <1229> Sterilization of Compendial Articles. 
< >
  19  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
757  product cannot be filtered (e.g., certain suspensions), components should be sterilized (e.g., 
758  filter) at the last possible step (e.g., before forming the suspension). Manipulations following the 
759  component sterilization step must use aseptic practices to maintain sterility (see  211.113). 
760   
761  Introductory training on microbiology, aseptic technique, cleanroom behavior, gowning, and 
762  procedures covering aseptic manufacturing area operations must be established and conducted 
763  before an individual is permitted to enter the aseptic manufacturing area or conduct operations in 
764  a laminar flow hood (see  211.25(a)). Once introductory training outside of the aseptic 
765  manufacturing area is completed, further training based on department-specific requirements and 
766  individual job descriptions should be conducted. Individuals would be considered qualified to 
767  conduct aseptic operations after passing at least three successful, successive media fill 
768  simulations based on a scientifically sound protocol designed to verify the adequacy of their 
769  technique and behavior. Production simulations should be conducted in the same area where 
770  production occurs. 
771   
772  Techniques intended to maintain sterility of items and surfaces should include the following: 
773   
774    Sterile materials should be handled only with sterile instruments. 
775   
776    After initial gowning, sterile gloves should be regularly sanitized (e.g., using sterile 70 
777  percent isopropyl alcohol) during production or, when needed, changed. 
778   
779    Sterile and non-shedding gowning components should be used. Gowning components 
780  should be stored such that their sterility is not compromised. 
781   
782    Torn or defective gowns should be changed immediately. 
783   
784    Sterile products, the product-contacting surfaces of containers or closures, or other 
785  critical surfaces should not directly touch any part of the gown or gloves. 
786   
787    Personnel should move slowly and deliberately within the cleanroom or hood. 
788   
789    Personnel should keep their bodies and objects out of the path of unidirectional flow 
790  above open containers and products being filled. 
791   
792  Procedures for aseptic processing should address the following considerations: 
793   
794    The design of equipment used in aseptic processing should limit the number and 
795  complexity of aseptic manipulations and should be suitable for its intended use.  
796   
797    Personnel, material, and process flow should be optimized to prevent unnecessary 
798  activities that could increase the potential for introducing contaminants to exposed 
799  product, containers or closures, or the surrounding environment.  
800   
801    In-process material, including intermediates such as stock solutions, should be placed in 
802  containers or closures that protect the material from the cleanroom environment. 
  20  Contains Nonbinding Recommendations 
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803  Containers or closures holding sterile in-process material should not be breached in an 
804  environment less than ISO 5. 
805   
806    Products should be transferred under appropriate cleanroom conditions. For example, 
807  transfer, loading, and unloading of aseptically filled product to and from the lyophilizer 
808  should occur only in classified areas that provide ISO 5 or better protection to the 
809  partially sealed containers.  
810   
811    All aseptic manipulations, including processing of sterile materials, filling, and closing 
812  (e.g., placement and sealing of stoppers on vials), should be performed under 
813  unidirectional flow that is ISO 5 or better. 
814   
815    Appropriate steps to prepare equipment for sterilization should be established, such as 
816  cleaning and use of wrapping that ensures protection while still allowing penetration of 
817  the sterilizing agent. 
818   
819    The validation of sterilization operations for equipment associated with aseptic 
820  processing (e.g., holding vessels, filling equipment, lyophilizer) and periodic verification 
821  activities and results must be documented (see  211.113(b)).  
822   
823    For sterile drug products that are filter-sterilized, prefiltration bioburden limits should be 
824  established and measured before sterile filtration, unless all components consist of FDA-
825  approved sterile drug products and/or components purchased and certified to be sterile 
826  and nonpyrogenic. A sterile pharmaceutical sterilizing-grade filter appropriate for the 
827  drug product (e.g., chemically compatible) should be used. The filter must be compliant 
828  with  211.72 and filter integrity testing should be conducted after each filtration or 
829  production run. 
830   
831  For aseptic processing of sterile drug products (i.e., not subjected to terminal sterilization), the 
832  process for ensuring sterility must be validated ( 211.113(b)), for example by conducting media 
833  fills simulating the production process. Validation should be performed semi-annually. Media fill 
834  studies should closely simulate aseptic manufacturing operations incorporating, as appropriate, 
835  worst-case activities and conditions that are challenging to aseptic operations. The media fill 
836  program should address applicable issues such as the following:  
837   
838    Factors associated with the longest permitted run of the aseptic processing operation that 
839  can pose contamination risk (e.g., operator fatigue, quality of processing environment). 
840   
841    Representative number, type, and complexity of normal interventions that occur with 
842  each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, 
843  equipment adjustments). (The maximum number of expected interventions should be 
844  included to simulate worst-case conditions.30) 
                                                 
30 When the possibility of contamination is higher based on the process design (e.g., manually intensive filling 
lines), a larger number of units, generally at or approaching the full production batch size, should be used. In 
contrast, a process conducted in an isolator can have a low risk of contamination because of the lack of direct human 
intervention and can be simulated with a lower number of units as a proportion of the overall operation. 
  21  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
845   
846    Lyophilization, when applicable. 
847   
848    Aseptic assembly of equipment (e.g., at start-up, during processing). 
849   
850    Number of personnel and their activities. (The maximum expected number of personnel 
851  should be included to simulate worst-case conditions.) 
852   
853    Representative number of aseptic additions (e.g., filling containers and closures as well as 
854  sterile ingredients) or transfers. 
855   
856    Shift changes, breaks, and gown changes (when applicable). 
857   
858    Type of aseptic equipment disconnections/connections. 
859   
860    Aseptic sample collections. 
861   
862    Operational configurations in the ISO 5 zone and line speeds (when applicable). 
863   
864    Weight checks. 
865   
866    Container-closure systems (e.g., size, type, compatibility with equipment). 
867   
868    Specific provisions in written procedures related to aseptic processing (e.g., conditions 
869  beyond which discarding of exposed materials in the ISO 5 area or line clearance is 
870  mandated). 
871   
872  I.  Release Testing 
873   
874  Sections 211.165 and 211.167 require that finished drug products be tested to determine whether 
875  they meet final product specifications before their release for distribution. Section 211.22 
876  establishes that the quality control unit is responsible for ensuring that the finished drug product 
877  is not released until this testing is conducted and the results confirm that the finished drug 
878  product meets specifications. Procedures for final release testing should be established and 
879  followed as outlined here. 
880   
881  Appropriate specifications must be established for each drug product (see  211.160(b)). 
882  Specifications must address those attributes necessary to ensure the quality of the finished drug 
883  product and must include, at a minimum ( 211.160(b), 211.165, 211.167): 
884   
885    Identity and strength of the API.31  
                                                 
31 If the API is known (from literature or other scientific information) to have the potential to form genotoxic 
degradants as discussed in ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk, the presence of the impurity or impurities 
should be evaluated as part of the assay or, if the assay method is not sufficiently sensitive, using a different test. 
 
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886   
887    Purity of the drug product. 
888   
889    For drug products purporting to be sterile and/or nonpyrogenic, sterility32 and a limit for 
890  bacterial endotoxins. 
891   
892    Antimicrobial effectiveness for sterile drug products labeled as multiple dose and for 
893  aqueous non-sterile drug products labeled as multiple dose.33 If antimicrobial 
894  effectiveness testing was previously performed using the subject formulation and 
895  container-closure system, preservative content testing may be used in lieu of a full 
896  antimicrobial effectiveness study. Appropriate specifications for aqueous drug products 
897  labeled as multiple dose include assurances that the product is adequately self-preserving 
898  or contains appropriate preservative content to limit microbial proliferation of 
899  microorganisms and assure that the product maintains its quality and purity for each 
900  dose.34 
901   
902  The product must also meet any other specifications included in an applicable USP monograph 
903  (see, e.g., section 501(b) of the FD&C Act). In addition, FDA recommends consideration of the 
904  following specifications: 
905   
906    Color, clarity. 
907   
908    pH, if applicable (e.g., for aqueous formulations). 
909   
910    For drug products that are not solutions, content uniformity.35 
911   
912    For drug products that are non-sterile, microbial testing (i.e., microbial enumeration, tests 
913  for specified microorganisms).  
914   
                                                 
32 Sterility testing should be conducted using USP General Chapter <71> Sterility Tests. Any other method used for 
sterility testing should be validated. See, for example, USP General Chapter <1223> Validation of Alternative 
Microbiological Methods or PDA Technical Report No. 33 (see Parenteral Drug Association 2013) for 
recommended validation methods. 
33 See USP General Chapter <51> Antimicrobial Effectiveness Testing for more information. 
34 Unsafe injection practices, including the improper use of needles, syringes, and vials for more than one patient, 
threaten patient safety and have resulted in multiple blood borne bacterial and viral infection outbreaks. Bacterial 
infections have been transmitted to patients when single-dose containers were used improperly, the contents became 
contaminated, and these contents were then administered to multiple patients. Therefore it is critical that drug 
products that are not adequately self-preserving and do not contain appropriate preservative content be labeled as 
single-dose to prevent such risks to health.  
35 For oral solid dosage forms (e.g., tablets and capsules), content should be assessed between dosage units. For 
nonsolid oral products (e.g., suspensions), the content should be assessed within the container (e.g., from the top and 
bottom of the container). 
 
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915    For drug products that are solutions purporting to be sterile, a limit for visible particles36 
916  and subvisible particles (10m-100m).37 
917   
918  Other appropriate specifications for generally recognized attributes for the dosage form, such as 
919  those described in ICH Q6A, should also be considered. For example, the specification for 
920  immediate release solid oral dosage forms typically includes disintegration testing, while non-
921  immediate release dosage forms include dissolution testing as a measure of the release rate of 
922  drug substance from the drug product (see  211.167). 
923   
924  Procedures for release must be established that ensure that each batch of a drug product is not 
925  released until the following have been completed (see  211.22, 211.165, 211.167, 211.192): 
926    
927    An appropriate laboratory determination has been conducted to ensure that each batch of 
928  a drug product conforms to specifications. 
929   
930    A review of environmental and personnel monitoring data, if applicable, has been 
931  conducted to ensure that manufacturing conditions were acceptable during production of 
932  the batch. 
933    
934    Associated laboratory data and documentation have been reviewed by the quality control 
935  unit, and they demonstrate that the drug product meets specifications. 
936   
937    A designated qualified individual from the quality control unit has authorized final 
938  release. 
939   
940  Under certain conditions described in Appendix A, FDA generally does not intend to take action 
941  against an outsourcing facility regarding the release testing requirements described immediately 
942  above and in the appendix.  
943   
944  Additional Considerations for Sterile Drug Products 
945   
946  Finished product sterility testing provides additional verification of sterility, even for those 
947  products compounded from sterile starting materials, because an unexpected event posing a risk 
948  to sterility may have occurred but may not have been detected. Appendix A describes the 
949  conditions under which FDA generally does not intend to take regulatory action against an 
950  outsourcing facility regarding finished product sterility testing based on mitigating factors, such 
951  as the use of a validated terminal sterilization method and the use of other approaches to evaluate 
952  sterility of the finished product before release.  
953   
                                                 
36 Such a limit may be established for any solution by following USP General Chapter <790> Visible Particulates in 
Injections. 
37 Applicable only to parenteral preparations. See USP General Chapters <788> Particulate Matter in Injections and 
<789> Particulate Matter in Ophthalmic Solutions for additional information. 
 
  24  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
954  For finished products purporting to be nonpyrogenic, the product must meet endotoxin limits38 
955  before release ( 211.167). For finished products compounded from starting materials that are 
956  sterile and nonpyrogenic, endotoxin testing can be conducted on all starting materials (through 
957  testing of the starting materials, or reliance on a statement of the limit met on a valid COA, or 
958  where specified in an applicable USP monograph) or through testing of samples of the finished 
959  product. The fact that a starting material is labeled nonpyrogenic does not necessarily ensure that 
960  the finished product will meet the appropriate endotoxin limit because starting materials, 
961  including FDA-approved products, may have been tested against different endotoxin limits, 
962  depending on the intended dose and the route of administration.39 
963   
964  J.  Laboratory Controls 
965   
966  When testing components, in-process materials, and finished drug products, laboratories must 
967  use controls to ensure the reliability of the tests ( 211.160). Each laboratory used to test 
968  components, in-process materials, or finished drug productswhether in-house or external to the 
969  outsourcing facilitymust employ the following critical aspects of laboratory controls to ensure 
970  the quality of non-sterile and sterile drug products compounded by the outsourcing facility (see 
971   211.160, 211.194): 
972    
973    Follow appropriate written procedures for the conduct of each test and document the 
974  results. 
975   
976    Design sampling and testing procedures to ensure that components, in-process materials, 
977  and drug products conform to the specifications set for the drug product. 
978   
979    Use analytical methods and equipment that are suitable for their intended use and are 
980  capable of producing valid results. If using a validated or an established compendial test 
981  procedure in a specification, the test has been verified and documented to work under the 
982  conditions of actual use. 
983   
984    Keep complete records of all tests performed to ensure compliance with established 
985  specifications and standards, including examinations and assays. 
986   
987  When an outsourcing facility seeks the services of a contract facility to perform all or part of the 
988  testing of a drug, the outsourcing facilitys quality control unit is responsible for approving and 
989  rejecting drugs tested by the contractor. See  200.10(b) and 211.22(a) and guidance for 
990  industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. In addition, 
991  FDA recommends that contract facilities performing testing of a drug be ISO 17025 accredited.  
992   
                                                 
38 Typically, endotoxin testing is not required for topically administered ophthalmic products. See USP General 
Chapter <771> Ophthalmic ProductsQuality Tests. 
39 See also guidance for industry Pyrogens and Endotoxins Testing: Questions and Answers. 
  25  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
993  K.  Stability/Expiration Dating for Compounded Drug Products 
994   
995  1.  Stability Program and Beyond-Use Dating 
996   
997  A stability program must be established to assess the stability characteristics of finished drug 
998  products, and the results of stability testing must be used to determine appropriate storage 
999  conditions and expiration dates ( 211.166). Stability testing is used to ensure that a drug product 
1000  will retain its quality (e.g., strength) and remain sterile, if applicable, through the labeled 
1001  expiration date. A stability program for compounded drug products should use past experiences, 
1002  available literature, and fundamental scientific principles to establish the parameters for the 
1003  program. An expiration date is established through the conduct of a stability program that 
1004  includes testing to assess the products performance against specifications after aging to the 
1005  desired expiration date ( 211.137); the conditions outlined in ICH guidance for industry 
1006  Q1A(R2) Stability Testing of New Drug Substances and Products are recommended. 
1007   
1008  FDA understands that a compounded drugs batch size may be small and the frequency of batch 
1009  production may vary considerably. The policies regarding stability testing and expiration dating 
1010  in this guidance recognize these potential aspects of compounded drug production while 
1011  addressing concerns regarding the quality of these products using a risk-based approach. 
1012   
1013  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1014  stability testing requirements if all of the following apply:  
1015   
1016    The drug product is compounded solely by combining two or more drug products 
1017  approved under section 505 of the FD&C Act. 
1018   
1019    The approved drug product labeling of at least one of the components specifies how to 
1020  assign an in-use time. 
1021    
1022    The compounded drug product has been prepared and labeled with an in-use time in 
1023  accordance with the approved product labeling.  
1024   
1025    The in-use time is used as the expiration date, provided the in-use time does not exceed 
1026  the expiration date of any of the approved drug products used to compound the drug. If 
1027  two or more approved drug products with in-use times are used in the compounded drug 
1028  product, the shortest in-use time is used as the expiration date for the compounded drug 
1029  product.  
1030   
1031  In addition, taking into account the unique aspects of compounding, FDA generally does not 
1032  intend to take regulatory action against an outsourcing facility under the conditions described in 
1033  the remainder of this section and in Appendix B, such as using a BUD established through 
1034  limited stability testing or, for certain lower risk situations, using a default BUD as the expiration 
  26  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1035  date, in lieu of establishing an expiration date through the conduct of a full stability program 
1036  required under part 211,40 if all of the following apply: 
1037   
1038    The compounded drugs BUD does not exceed appropriately established expiration or 
1039  retest-by dates for any of the components used to compound the drug.  
1040   
1041    If the drug is compounded from an approved drug product, and the approved product 
1042  labeling recommends one type of storage (e.g., refrigeration through the expiry date, such 
1043  as 18 months), but also provides for storage at another condition (e.g., stable at room 
1044  temperature for a time frame shorter than the expiry date, such as up to 14 days), the 
1045  compounded drug product is not labeled with a BUD that is longer than the relevant 
1046  storage time frame in the approved product labeling (e.g., the BUD of the compounded 
1047  drug does not exceed 14 days for room temperature).  
1048   
1049  In addition, for repackaged products, FDA generally does not intend to take regulatory action 
1050  against an outsourcing facility under the conditions described in the remainder of this section and 
1051  in Appendix B, in lieu of establishing an expiration date through the conduct of a full stability 
1052  program, if (1) the BUD does not exceed the expiration date of the drug product that is being 
1053  repackaged; and (2) if the approved product labeling for the drug product being repackaged 
1054  recommends one type of storage (e.g., refrigeration through the expiry date, such as 18 months) 
1055  but also provides for storage at another condition (e.g., stable at room temperature for a time 
1056  frame shorter than the expiry date, such as up to 14 days), the repackaged product is not labeled 
1057  with a BUD that is longer than the relevant storage time frame in the approved product labeling 
1058  (e.g., the BUD does not exceed 14 days for room temperature). For more information on 
1059  repackaging, see the guidance for industry Repackaging of Certain Human Drug Products by 
1060  Pharmacies and Outsourcing Facilities. 
1061   
1062  Whether you use an expiration date or BUD to be used as an expiration date according to the 
1063  provisions outlined below and in Appendix B, the two studies below are required to be 
1064  completed before a batch is released (see  211.166, 211.167). Each study only needs to be 
1065  conducted once for each formulation and container-closure system, and a bracketing or matrixing 
1066  approach can be considered to minimize the amount of testing. See Appendix B for more 
1067  information regarding bracketing approaches. 
1068   
1069    Container-closure integrity testing is conducted on samples aged to or beyond the 
1070  desired BUD or expiration date to ensure that sterility is maintained over that time 
1071  period.41  
1072   
                                                 
40 To meet the conditions under section 503B of the FD&C Act, the compounded drug product must be labeled with 
an expiration date (see section 503B(a)(10)(A)(iii)(VI)). 
41 See USP General Chapter <1207> Package Integrity EvaluationSterile Products for more information on 
container-closure integrity testing. 
 
  27  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1073    Antimicrobial effectiveness testing for drug products labeled or intended to be multiple 
1074  dose is conducted on samples aged to the proposed BUD or expiration date. (Note that 
1075  antimicrobial effectiveness testing is container-closure specific.)42  
1076   
1077  Tables 2 and 3 highlight the conditions under which FDA generally does not intend to take 
1078  regulatory action against an outsourcing facility for assigning a BUD to be used as an expiration 
1079  date in lieu of conducting full stability studies required under part 211.  
1080   
1081  a.  Non-sterile limited stability testing 
1082   
1083  For small batches (5,000 units43 in an aggregate batch44), FDA generally does not intend to take 
1084  regulatory action if the relevant default BUDs provided in Appendix B are used for the 
1085  expiration date and the conditions set forth in Appendix B are met. Alternatively, for small 
1086  batches, FDA generally does not intend to take regulatory action if limited stability testing is 
1087  conducted to support a BUD longer than the relevant default BUDs in accordance with Appendix 
1088  B, and that BUD is used as an expiration date in lieu of conducting full stability studies required 
1089  under part 211. For larger batches (>5,000 units in an aggregate batch), FDA generally does not 
1090  intend to take regulatory action regarding stability testing if the relevant conditions for the 
1091  limited stability testing outlined in Appendix B are met. If, at any time during a 6-month 
1092  reporting period, the total number of units compounded exceeds the 5,000-unit limit, the 
1093  conditions applicable to small batches (i.e., 5,000 units) do not apply. 
1094   
1095  Table 2. BUDs for Non-Sterile Compounded Drug Products, by Aggregate Batch Size  
Aggregate Batch Size 
BUD Based on Limited 
(over 6-month  Default BUD (no testing) 
Stability Testing 
reporting period) 
Default BUD, which may be  Data-driven stability program. 
further limited by literature or  See Appendix B for the 
5,000 units  other scientific information.  conditions that must be met. 
See Appendix B for the 
conditions that must be met. 
N/A. Default BUDs are not  Data-driven stability program. 
>5,000 units  applicable to large aggregate  See Appendix B for the 
batch sizes.  conditions that must be met. 
1096     
                                                 
42 See USP General Chapter <51> Antimicrobial Effectiveness Testing for more information. 
43 Units are individual tablets or capsules for solid oral dosage forms and suppositories, inserts, or immediate 
containers (e.g., vial, syringe, IV bag, tube) for other dosage forms. 
44 For the purposes of this guidance, batch size has been considered by defining aggregate batch as the sum of all 
units produced from any number of batches over the 6-month period for which a drug product report is submitted. 
For more information about product reports, see the guidance for industry Electronic Drug Product Reporting for 
Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic 
Act.  
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Draft  Not for Implementation 
1097  b.  Sterile limited stability testing 
1098   
1099  For small batches (1,000 units in an aggregate batch), FDA generally does not intend to take 
1100  regulatory action if the relevant default BUDs provided in Appendix B are used for the 
1101  expiration date and the conditions set forth in Appendix B are met. Alternatively, for small 
1102  batches, FDA generally does not intend to take regulatory action if limited stability testing is 
1103  conducted to support a BUD longer than the relevant default BUDs in accordance with Appendix 
1104  B, and that BUD is used as an expiration date in lieu of conducting full stability studies required 
1105  under part 211. For larger batches (>1,000 units in an aggregate batch), FDA generally does not 
1106  intend to take regulatory action regarding stability testing if the relevant conditions for the 
1107  limited stability testing outlined in Appendix B are met. If, at any time during a 6-month 
1108  reporting period, the total number of units compounded exceeds the 1,000-unit limit, the 
1109  conditions applicable to small batches (i.e., 1,000 units) do not apply.  
1110   
1111  Table 3. BUDs for Sterile Compounded Drug Products, by Aggregate Batch Size  
Aggregate Batch Size 
BUD Based on Limited 
(over 6-month  Default BUD (no testing) 
Stability Testing 
reporting period) 
Default BUD, which may be  Data-driven stability program. 
further limited by literature or  See Appendix B for the 
1,000 units  other scientific information.  conditions that must be met. 
See Appendix B for the 
conditions that must be met. 
N/A. Default BUDs are not  Data-driven stability program. 
>1,000 units  applicable to large aggregate  See Appendix B for the 
batch sizes.  conditions that must be met. 
1112   
1113  2.  Establishing an In-Use Time for Sterile Drug Products 
1114   
1115  To be eligible for the exemptions under section 503B of the FD&C Act, the container for the 
1116  compounded drug product must include directions for use, including, as appropriate, dosage and 
1117  administration (section 503B(a)(10)(B) of the FD&C Act). If the compounded drug product 
1118  requires additional manipulation before administration (e.g., reconstitution and/or dilution), FDA 
1119  interprets the directions for use requirement to include an in-use time because the health care 
1120  practitioner who manipulates or administers the drug would need to know how long it is 
1121  expected to retain its quality after being manipulated. Furthermore, stability studies (as required 
1122  by  211.166) would be needed to support the stated in-use time. However, FDA generally does 
1123  not intend to take regulatory action regarding the requirement to have data to support the stated 
1124  in-use time, such as microbial challenge and stability studies, if the sterile product has directions 
1125  for use that include an in-use time less than 4 hours at room temperature or less than 24 hours 
1126  refrigerated.45 
1127   
                                                 
45 For a description of methods and acceptance criteria for microbial challenge studies, see Metcalfe 2009. 
  29  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1128  Under  211.160 and 211.165(b), appropriate laboratory testing of products required to be free 
1129  of objectionable microorganisms are required, and laboratory controls must include scientifically 
1130  sound and appropriate specifications and test procedures designed to provide assurance that the 
1131  product conforms to appropriate standards of identity, strength, quality, and purity. For multiple 
1132  dose products, appropriate laboratory tests and specifications include ones for antimicrobial 
1133  effectiveness, whether the product contains a preservative or antimicrobial activity is inherent in 
1134  the formulation. See USP General Chapter <51> for antimicrobial effectiveness test methods and 
1135  acceptance criteria. If the acceptance criteria described in USP General Chapter <51> are met, 
1136  labeling up to a 28-day in-use period is considered to be appropriate for multiple-dose products, 
1137  subject to the conditions regarding stability testing discussed below.  
1138   
1139  In addition to microbial challenge studies, the stability of the manipulated product must be 
1140  assessed (see  211.166). FDA generally does not intend to take regulatory action regarding the 
1141  requirement to conduct full stability studies to assess the stability of the manipulated product if 
1142  the tests conducted as part of the limited stability testing described in Appendix A are conducted 
1143  on samples aged to at least 2/3 of the labeled BUD (if longer than the default BUDs outlined in 
1144  Appendix B), manipulated (e.g., reconstituted or diluted) as described in labeling, and then held 
1145  for the desired in-use time (up to 28 days). 
1146   
1147  The labeled directions for use46 should include instructions to the health care provider or patient 
1148  that the time in storage plus the administration phase should not exceed the BUD. Consider, for 
1149  example, a sterile powder formulation in a vial that must be reconstituted with Sterile Water for 
1150  Injection, USP, before patient administration with a label that includes an in-use-time of within 4 
1151  hours at room temperature or within 24 hours if refrigerated. The in-use time begins when the 
1152  sterile powder vial is entered and reconstituted with Sterile Water for Injection, USP. The 
1153  reconstituted solution should be administered to the patient within 4 hours if the solution is held 
1154  at room temperature or within 24 hours if it is stored in the refrigerator.  
1155   
1156  3.  In-Use Time and BUDs for Sterile Drug Products 
1157   
1158  The outsourcing facility should establish the BUD placed on a compounded drug products label, 
1159  taking into consideration that the BUD is the date/time after which the product is to be discarded. 
1160  The labeled directions for use should include instructions to the health care provider or patient 
1161  accordingly. If the product does not require any manipulation (e.g., dilution or reconstitution) 
1162  before administration, the directions for use should advise that administration to the patient 
1163  should be completed before reaching the BUD. For example, if an IV bag containing a 
1164  compounded drug product with a BUD of 24 hours is to be infused to the patient over a period of 
1165  4 hours, the infusion should begin by 20 hours to ensure that administration will be complete 
1166  before reaching the BUD, at which point the compounded drug product should be discarded. 
1167     
                                                 
46 Section 503B(a)(10)(B) of the FD&C Act provides the following: The container from which the individual units 
of the drug are removed for dispensing or for administration . . . shall include . . . directions for use, including, as 
appropriate, dosage and administration.  
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Draft  Not for Implementation 
1168  L.  Packaging and Labels 
1169   
1170  Packaging of non-sterile and sterile drugs must be appropriate to the product and capable of 
1171  ensuring the sterility, if applicable, and integrity of the product until it is administered to a 
1172  patient (see  211.94, 211.122). Labels must contain required information, and labeling 
1173  operations must include controls to prevent mix-ups; furthermore, procedures must be developed 
1174  to ensure these requirements are met ( 211.122, 211.125, 211.130, 211.134).  
1175   
1176  The following aspects of packaging and labeling are critical to ensure the quality of compounded 
1177  drug products and must be implemented by outsourcing facilities:  
1178   
1179    The container, closure, and packaging systems provide adequate protection against 
1180  foreseeable external factors in storage, shipment, and use that could cause contamination 
1181  or deterioration of the finished drug product (e.g., cracked vials, leaks in bags) 
1182  ( 211.94).  
1183   
1184    Adequate controls have been established for issuing labels, examining issued labels, and 
1185  reconciliation of used labels to prevent mix-ups ( 211.125). 
1186   
1187    There is adequate separation between the labeling and packaging operations of different 
1188  products, including ones with different strengths or containers or closures, to prevent 
1189  mix-ups ( 211.130).  
1190   
1191    Adequate controls have been established to ensure proper identification of any filled 
1192  containers of non-sterile or sterile drug products that will be stored unlabeled for any 
1193  period of time ( 211.130).  
1194   
1195    Packaging records include results of examinations of labels used ( 211.134) and 
1196  specimens or copies of all labeling used ( 211.188).  
1197   
1198    The labeled finished drug product has been examined for accuracy before release 
1199  ( 211.134).  
1200   
1201  M.  Reserve Samples 
1202   
1203  An appropriately identified reserve sample that is representative of each lot or batch of drug 
1204  product must be retained and stored under conditions consistent with product labeling 
1205  ( 211.170). FDA generally does not intend to take regulatory action against an outsourcing 
1206  facility regarding reserve sample requirements if all of the following apply: 
1207   
1208    Once >10,000 units are produced of a given drug product formulation and container-
1209  closure system in a 6-month reporting period, an appropriately identified and 
1210  representative reserve sample is collected each time 1,000 units of that specific 
1211  formulation and container-closure system is produced for the remainder of the current 
1212  reporting period and for the entire subsequent 6-month reporting period. 
1213   
  31  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1214    The reserve sample is retained and stored under the labeled storage conditions and in the 
1215  same immediate container-closure system in which the drug product is marketed or in 
1216  one that has essentially the same characteristics (e.g., same material, same headspace for 
1217  liquids).  
1218   
1219    The reserve sample is held for at least 30 days following the expiration date. 
1220   
1221    The reserve sample consists of at least the quantity of drug product necessary for all tests 
1222  required at release, except for sterility and pyrogen testing. 
1223   
1224  N.  Complaint Handling 
1225   
1226  Outsourcing facilities must have procedures for handling complaints that they receive about their 
1227  compounded drug products ( 211.198). Written and oral complaints concerning the quality or 
1228  purity of a drug product must be reviewed by the quality control unit, which must determine the 
1229  need to investigate the complaint in accordance with  211.192 ( 211.198). If an investigation is 
1230  needed, in addition to the quality control unit, personnel appropriate to evaluate the complaint 
1231  should be involved. Complaint handling procedures must include provisions for review to 
1232  determine whether the complaint represents an adverse event that must be reported to FDA (see 
1233   211.198, section 301(ccc)(3) of the FD&C Act, and the guidance for industry Adverse Event 
1234  Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and 
1235  Cosmetic Act).  
1236   
1237   
1238  IV.   REFERENCES 
1239   
1240  Literature 
1241   
1242  FDA, 1993, Guide to Inspections of High Purity Water Systems, Silver Spring, MD. 
1243   
1244  Metcalfe, JW, 2009, Microbiological Quality of Drug Products After Penetration of the 
1245  Container System for Dose Preparation Prior to Patient Administration, American 
1246  Pharmaceutical Review. 
1247   
1248  Parenteral Drug Association, 2007, Validation of Moist Heat Sterilization Processes: Cycle 
1249  Design, Development, Qualification and Ongoing Control, PDA Technical Report No. 1 (TR1), 
1250  Bethesda, MD. 
1251   
1252  Parenteral Drug Association, 2013, Evaluation, Validation and Implementation of Alternative 
1253  and Rapid Microbiological Methods, PDA Technical Report No. 33 (TR33), Bethesda, MD. 
1254   
1255  Guidances for Industry 
1256   
1257  Guidance for industry Adverse Event Reporting for Outsourcing Facilities Under Section 503B 
1258  of the Federal Food, Drug, and Cosmetic Act 
1259   
  32  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1260  Guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements 
1261   
1262  Guidance for industry Electronic Drug Product Reporting for Human Drug Compounding 
1263  Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act 
1264   
1265  Guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical 
1266  Production 
1267   
1268  Guidance for industry Mixing, Diluting, or Repackaging Biological Products Outside the Scope 
1269  of an Approved Biologics License Application  
1270   
1271  Guidance for industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing 
1272  Cross-Contamination 
1273   
1274  Guidance for industry Pyrogens and Endotoxins Testing: Questions and Answers 
1275   
1276  Guidance for industry Repackaging of Certain Human Drug Products by Pharmacies and 
1277  Outsourcing Facilities 
1278   
1279  Guidance for industry Sterile Drug Products Produced by Aseptic ProcessingCurrent Good 
1280  Manufacturing Practice 
1281   
1282  Guidance for industry Submission Documentation for Sterilization Process Validation in 
1283  Applications for Human and Veterinary Drug Products 
1284   
1285  Guidance for industry Submission of Documentation in Applications for Parametric Release of 
1286  Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes 
1287   
1288  ICH Guidances for Industry 
1289   
1290  ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
1291  Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk 
1292   
1293  ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products 
1294   
1295  ICH guidance for industry Q1D Bracketing and Matrixing Designs for Stability Testing of New 
1296  Drug Substances and Products 
1297   
1298  ICH guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for 
1299  New Drug Substances and New Drug Products: Chemical Substances 
1300   
1301  ISO Standards 
1302   
1303  ISO 11137-1:2006, Sterilization of health care productsRadiationPart 1: Requirements for 
1304  the development, validation and routine control of a sterilization process for medical devices 
1305   
  33  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1306  ISO 11137-2:2013, Sterilization of health care productsRadiationPart 2: Establishing the 
1307  sterilization dose 
1308   
1309  ISO 14644-1:2015, Cleanrooms and associated controlled environmentsPart 1: Classification 
1310  of air cleanliness by particle concentration 
1311   
1312  ISO 14644-6:2007, Cleanrooms and associated controlled environmentsPart 6: Vocabulary 
1313   
1314   
1315  V.   GLOSSARY 
1316   
1317  Action Limit: An established microbial or airborne particle level that, when exceeded, should 
1318  trigger appropriate investigation and corrective action based on the investigation. 
1319   
1320  Active Pharmaceutical Ingredient (API): Any substance that is intended for incorporation into 
1321  a finished drug product and is intended to furnish pharmacological activity or other direct effect 
1322  in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or 
1323  any function of the body. API does not include intermediates used in the synthesis of the 
1324  substance. 
1325   
1326  Aggregate Batch: The sum of all units produced from any number of batches over the 6-month 
1327  period for which a drug product report is submitted. 
1328   
1329  Alert Limit: An established microbial or airborne particle level giving early warning of potential 
1330  drift from normal operating conditions and triggering appropriate scrutiny and follow-up to 
1331  address the potential problem. Alert limits are always lower than action limits.  
1332   
1333  Aseptic: Free from germs that cause disease; sterile. 
1334   
1335  Aseptic Manufacturing Area: The classified part of a facility that includes the aseptic 
1336  processing room and ancillary cleanrooms. 
1337   
1338  Aseptic Process: The process by which a sterile product is packaged in a sterile container in a 
1339  manner that maintains sterility. 
1340   
1341  Batch: A specific quantity of a drug or other material that is intended to have uniform character 
1342  and quality, within specified limits, and is produced according to a single compounding order 
1343  during the same cycle of production. 
1344   
1345  Beyond-Use Date (BUD): A date beyond which a compounded drug product should not be used. 
1346  A BUD notifies the user of the period during which a compounded drug products required 
1347  quality characteristics (e.g., sterility, strength, purity, freedom from particulate matter) can be 
1348  ensured. 
1349   
1350  Bioburden: The total number of microorganisms associated with a specific item before sterilization. 
1351   
  34  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1352  Biological Indicator (BI): A population of microorganisms inoculated onto a suitable medium 
1353  (e.g., solution, container or closure) and placed within appropriate sterilizer load locations to 
1354  determine the sterilization cycle efficacy of a physical or chemical process. The challenge 
1355  microorganism is selected based on its resistance to the given process. Incoming lot D-value and 
1356  microbiological count define the quality of the BI. 
1357   
1358  Bulk Drug Substance: See definition for active pharmaceutical ingredient.  
1359   
1360  Cleanroom: A room designed, maintained, and controlled to prevent particle and 
1361  microbiological contamination of drug products. Such a room is assigned a classification based 
1362  on reproducibly meeting appropriate air cleanliness limits. 
1363   
1364  Component: Any ingredient intended for use in the manufacture of a drug product, including 
1365  ingredients that may not appear in the final drug product.  
1366   
1367  Critical Area: An area designed to maintain sterility of sterile materials. 
1368   
1369  Critical Surface: Surfaces that may come into contact with or directly affect a sterilized product 
1370  or its containers or closures.  
1371   
1372  Depyrogenation: A process used to destroy or remove pyrogens (e.g., endotoxins). 
1373   
1374  Disinfection: A process by which surface bioburden is reduced to a safe level or eliminated.  
1375   
1376  Endotoxin: A pyrogenic product (e.g., lipopolysaccharide) present in the bacterial cell wall. 
1377  Endotoxins can lead to reactions ranging from fever to death in patients receiving injections. 
1378   
1379  Expiration Date: A date on the drug product label that indicates how long the drug can meet 
1380  applicable standards of identity, strength, quality, and purity under labeled storage conditions 
1381  before it is used. Expiration dates are determined based on product-specific stability studies 
1382  evaluating the specific formulation of a drug product, in the specific container in which it is to be 
1383  stored, and under the conditions to which it may be exposed. Temperature, humidity, and light 
1384  are some of the factors that can affect whether and how much a drug product degrades over time.  
1385   
1386  HEPA Filter: A high-efficiency particulate air filter with minimum 0.3 m particle retaining 
1387  efficiency of 99.97 percent.  
1388   
1389  In-Use Time: The maximum amount of time that can be allowed to elapse between penetration 
1390  of a container-closure system once the drug product has been sterilized, or after a lyophilized 
1391  drug product has been reconstituted, and before patient administration. 
1392   
1393  Intervention: An aseptic manipulation or activity that occurs in the critical area. 
1394   
  35  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1395  Isolator: A decontaminated unit supplied with ISO 5 or higher air quality that provides 
1396  uncompromised, continuous isolation of its interior from the external environment (e.g., 
1397  surrounding cleanroom air and personnel).47  
1398   
1399  Lot: A batch, or a specific identified portion of a batch, having uniform character and quality 
1400  within specified limits; or, in the case of a drug product produced by continuous process, a 
1401  specific identified amount produced in a unit of time or quantity in a manner that provides 
1402  assurance of its having uniform character and quality within specified limits. 
1403   
1404  Operator: Any individual participating in the aseptic processing operation, including line set-up, 
1405  filler, or maintenance, or any other personnel associated with aseptic line activities. 
1406   
1407  Pyrogen: A substance that induces a febrile reaction in a patient. 
1408   
1409  Terminal Sterilization: The application of a lethal agent (e.g., heat) to sealed, finished drug 
1410  products for the purpose of achieving a predetermined sterility assurance level (SAL) of usually 
1411  less than 10-6 (i.e., a probability of a non-sterile unit of greater than one in a million). 
1412   
1413  Unidirectional Flow: An airflow moving in a single direction, in a robust and uniform manner, 
1414  and at sufficient speed to reproducibly sweep particles away from the critical processing or 
1415  testing area.  
1416   
1417  Viable Particle: A particle that consists of, or supports, one or more live microorganisms.  
1418 
                                                 
47 See Appendix 1 in guidance for industry Sterile Drug Products Produced by Aseptic ProcessingCurrent Good 
Manufacturing Practice. 
  36  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1419  APPENDIX A. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT 
1420  INTEND TO TAKE REGULATORY ACTION REGARDING CERTAIN RELEASE 
1421  TESTING REQUIREMENTS 
1422   
1423  Procedures for release must be established that ensure that each batch of a drug product is not 
1424  released until the following have been completed (see  211.22, 211.165, 211.167(a), 211.192): 
1425    
1426    An appropriate laboratory determination has been conducted to ensure that each batch of 
1427  a drug product conforms to specifications. 
1428   
1429    A review of environmental and personnel monitoring data, if applicable, has been 
1430  conducted to ensure that manufacturing conditions were acceptable during production of 
1431  the batch. 
1432   
1433    Associated laboratory data and documentation have been reviewed by the quality control 
1434  unit, and they demonstrate that the drug product meets specifications. 
1435   
1436    A designated qualified individual from the quality control unit has authorized final 
1437  release. 
1438   
1439  A.  Non-Sterile Drug Products 
1440   
1441  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1442  these release requirements under the conditions described in Table A, which is at the end of 
1443  Appendix A. For any given product, consider which conditions in Table A apply. If multiple 
1444  conditions apply, choosing the least stringent option for each individual batch release test among 
1445  the applicable conditions would be consistent with the enforcement policy set forth in this 
1446  appendix.  
1447   
1448  Example 1: All of the following conditions apply: 
1449   
1450    The batch size is >60 units. 
1451   
1452    The water activity is 0.6 (it is not a solid dosage form). 
1453   
1454    The product is tested for strength by a method that is highly specific (e.g., high 
1455  performance liquid chromatography (HPLC)) and uses a reference standard. 
1456   
1457  From Table A, conditions 2b and 3 apply; under those conditions, FDA generally does not intend 
1458  to take regulatory action against an outsourcing facility regarding batch release tests for identity, 
1459  AET/preservative content, microbial enumeration, or tests for specified microorganisms if the 
1460  outsourcing facility assessed strength, content uniformity, pH, appearance, and the other 
1461  appropriate specifications for that product. 
1462   
1463  Example 2: All of the following conditions apply: 
1464   
  37  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1465    The batch size is 30 units each month. 
1466   
1467    The starting material is a bulk drug substance. 
1468   
1469    The product is a solid dosage form. 
1470   
1471    The product is tested for strength by a method that is highly specific (e.g., HPLC) and 
1472  uses a reference standard. 
1473   
1474  From Table A, conditions 1b and 3 apply for the first batch of 30 units; conditions 2c and 3 apply 
1475  for the second batch of 30 units (i.e., when a total of 60 units has been produced); conditions 1b 
1476  and 3 apply for the third batch of 30 units; and so on. Under those conditions, FDA generally 
1477  does not intend to take regulatory action against an outsourcing facility regarding batch release 
1478  testing for identity, content uniformity, pH, AET/preservative content, microbial enumeration, 
1479  tests for specified microorganisms, or the other appropriate specifications if the outsourcing 
1480  facility assessed strength and appearance for every batch and also assessed content uniformity 
1481  and the other appropriate specifications for that product for every other batch. 
1482   
1483  B.  Sterile Drug Products 
1484   
1485  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1486  these release requirements as they apply to sterility testing if sterility testing is initiated before 
1487  batch release (see also Table D in Appendix B for BUDs for products released without a 
1488  completed sterility test) and established procedures specify that if the drug product fails to meet a 
1489  criterion for sterility:  
1490   
1491    All facilities that received the drug product are notified immediately of the test results 
1492  and provided with any appropriate information and recommendations to aid in the 
1493  treatment of patients.  
1494   
1495    The notification is documented.  
1496   
1497    FDA is notified in writing within 5 working days.48  
1498   
1499  In addition, FDA generally does not intend to take regulatory action against an outsourcing 
1500  facility regarding the release requirements for sterility testing under the conditions described in 
1501  Table B, which is at the end of Appendix A. For any given product, consider which conditions in 
1502  Table B apply. If multiple conditions apply, choosing the least stringent option for each 
1503  individual batch release test among the applicable conditions would be consistent with the 
1504  enforcement policy set forth in this appendix. 
1505   
1506  Example 1: All of the following conditions apply: 
1507   
1508    The batch size is 30 units each month.  
                                                 
48 Reports should be emailed to FDA at OFAlertReport@fda.hhs.gov.  
  38  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1509   
1510    The product is a solution or total parenteral nutrition (TPN) and the bulk solution but not 
1511  the finished drug product is tested for identity and strength immediately before filling 
1512  into the final and prelabeled drug product containers. 
1513   
1514    The product is terminally sterilized using a validated sterilization cycle that uses physical, 
1515  chemical, or biological indicators. 
1516   
1517  From Table B, conditions 2, 5, and 6 apply to the first batch of 30 units; conditions 1, 5, and 6 
1518  apply to the second batch of 30 units (i.e., when a total of 60 units has been produced); and so 
1519  on. Under those conditions, FDA generally does not intend to take regulatory action against an 
1520  outsourcing facility regarding batch release testing for identity, strength, sterility, pH, visible 
1521  particulates, subvisible particulates (where applicable), or other appropriate specifications, 
1522  including USP monograph specifications, if the outsourcing facility conducted testing for 
1523  endotoxin, color, and clarity on that product for each batch and also conducted testing on pH, 
1524  visible particulates, subvisible particulates (where applicable), and other appropriate 
1525  specifications, including USP monograph specifications on every other batch.  
1526   
1527  Example 2: Both of the following conditions apply: 
1528   
1529    The batch size is >60 units. 
1530   
1531    Drug product is a multicomponent injectable drug product (e.g., total parenteral nutrition 
1532  product, cardioplegia solution) compounded from APIs produced only by FDA-registered 
1533  manufacturers, the finished product is compounded using automated equipment with 
1534  validated software, and the equipment is calibrated immediately before and after each 
1535  personnel shift. 
1536   
1537  From Table B, conditions 1 and 5 apply; under those conditions, FDA generally does not intend 
1538  to take regulatory action against an outsourcing facility regarding batch release testing for 
1539  identity and strength if the outsourcing facility conducted testing for sterility, endotoxin, pH, 
1540  color, clarity, visible particulates, subvisible particulates (where applicable), and other 
1541  appropriate specifications, including USP monograph specifications. 
1542   
1543  C.  Additional Considerations 
1544   
1545  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1546  the requirement to test the finished product before release (see  211.165, 211.167) if the drug 
1547  product is aseptically filled into secured, sterile cartridges or cassettes that are designed to 
1548  prevent misuse through a locking mechanism that prevents the outsourcing facility from testing 
1549  the finished product, and all testing/examinations are conducted on a sample from the container 
1550  that holds the pooled, compounded drug product (e.g., pump reservoir) after all final containers 
1551  are filled.49 
                                                 
49 See Table 2 in USP General Chapter <71> Sterility Tests for more information regarding the volume to be 
sampled. 
  39  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1552   
1553  To reduce the need for the manufacturing of additional units to meet the sterility testing 
1554  requirement (see  211.167) by following the procedures in USP General Chapter <71> Sterility 
1555  Tests, FDA generally does not intend to take action against an outsourcing facility regarding the 
1556  number of units tested if: 
1557   
1558    For batch sizes up to and including 10 units that do not also meet conditions 3 or 6 in 
1559  Table B, at least 1 unit is tested; and  
1560   
1561    For batch sizes of greater than 10 units and fewer than 40 units, the sterility test is 
1562  conducted using a number of containers that equals 10 percent rounded up to the next 
1563  whole number.  
  40  Contains Nonbinding Recommendations; Draft  Not for Implementation 
1564  Table A. Conditions Regarding Batch Release Tests for Non-Sterile Drug Products  
Batch Release Test 

 Test for which FDA generally does not intend to take regulatory action under the 
conditions listed 

 Test expected to be performed, if applicable 
d 
nt n 
Conditions  Identity  Strength  cContent Uniformity  pH  Appearance  T/Preservative Conte Microbial Enumeratioe (bacteria and fungi) Tests for Specified e Microorganisms Other Appropriate fSpecifications 
E
A
 
Tests are conducted according to these conditions ... 
1. Batch size <60 units,a if omitted tests are performed once 60 units are producedb 
1a. Starting from FDA-approved product                    
1b. Starting from bulk drug substance                   
2. Batch size 60 units or once 60 units are producedb and considering the following characterizations of water activity: 
2a. Water activity >0.6                   
2b. Water activity 0.6 (other than solid dosage 
                 
forms) 
2c. Solid dosage forms                    
... unless conditions 3 or 4 also apply. If so, choosing the least stringent option for each test among applicable conditions would 
 
be consistent with the enforcement policy set forth in this appendix.
3. Product tested for strength by method that is highly 
                 
specific (e.g., HPLC) and uses a reference standard 
4. Compounded drug product is single dilution of 
FDA-approved drug product, or is made from one or 
more dilutions of FDA-approved drug product 
                 
performed per labeling dilution instructions and using 
automated equipment calibrated immediately before 
and after production 
a Individual tablets or capsules for solid oral dosage forms and suppositories, inserts, or containers (e.g., vial, syringe, IV bag, tube) for other dosage 
forms. 
b Omitted tests under these conditions need only be performed one time after a single batch of 60 or more units has been produced or once 60 or more 
units have been produced in more than 1 batch within a year of the time the first batch is produced, and resets once testing has been performed or at 1 
year from the time the first batch is produced if a minimum of 60 units was not produced. For example, if the batch size is consistently 30 units (e.g., 
tubes) of a particular volume of drug, the omitted tests are conducted on every second batch produced. Or, if the first, second, and third batches in the 
year include 25, 30, and 10 units respectively, the omitted tests are performed on the third batch because the minimum of 60 units has been met. 
c FDA generally does not intend to take regulatory action if content uniformity testing is not performed on solutions. 
d If the drug product is self-preserving, then either test for the API/excipient that is providing the preserving effect or conduct antimicrobial 
effectiveness testing (AET). For products with a preservative, conduct preservative content testing. Nonetheless, AET should be performed at least 
one time on a formulation using the lowest preservative concentration for the subject formulation and container-closure system. 
e See, for example, USP General Chapter <1111>. 
 
f These include generally recognized attributes for each dosage form such as those described in ICH Q6A or USP monographs or general chapters.
1565 
  41  Contains Nonbinding Recommendations; Draft  Not for Implementation 
1566  Table B. Conditions Regarding Batch Release Tests for Sterile Drug Products  
Batch Release Test 

 Test for which FDA generally does not intend to take regulatory action 
under the conditions listed 

 Test expected to be performed 
 
Conditions  Identity  Strength  Sterility  cEndotoxin  pH  Color  Clarity  Visible Particulates  Subvisible Particulates  Other Appropriate dpecifications 
S
Tests are conducted according to these conditions ...  
                  
1. Batch size 60 unitsa or once 60 units are producedb   
2. Batch size <60 units, if omitted tests are performed once 60       
           
units are producedb     
3. Batch <10 units compounded pursuant to prescription for   
   
single patient and label bears BUD per Table D in Appendix B, if                  
omitted tests are performed once 60 units are producedb 
... unless conditions 4, 5, or 6 also apply. If so, choosing the least stringent option for each test among applicable conditions would 
be consistent with the enforcement policy set forth in this appendix. 
4. Product tested for strength (potency) by method that is highly                     
specific (e.g., HPLC) and uses a reference standard  
5. For solutions or total parenteral nutrition (TPN) only: 
- Compounded drug product is single dilution of FDA-approved 
drug product, or is made from one or more dilutions of FDA-
approved drug product performed per labeling dilution 
instructions and using automated equipment calibrated 
immediately before and after production 
- OR - 
- Bulk solution but not finished drug product is tested for identity 
               
   
and strength immediately before filling into final and prelabeled 
drug product containers 
- OR   
- Drug product is multicomponent injectable drug product (e.g., 
TPN product, cardioplegia solution) compounded from APIs 
produced only by FDA-registered manufacturers, finished 
product is compounded using automated equipment with 
validated software, and equipment is calibrated immediately 
before and after each personnel shift 
6. Product is terminally sterilized using validated sterilization                   
 
cycle that uses physical, chemical, or biological indicators 
a Individual tablets or capsules for solid oral dosage forms and suppositories, inserts, or containers (e.g., vial, syringe, IV bag, tube) for other dosage forms. 
b Omitted tests under this condition need only be performed one time after a single batch of 60 or more units has been produced or once 60 or more units 
have been produced in more than 1 batch within a year from the time the first batch is produced, and resets once testing has been performed or at 1 year 
from the time the first batch is produced if a minimum of 60 units was not produced. For example, if the batch size is consistently 35 units (e.g., vials) of a 
particular volume of drug, testing is conducted on every second batch produced. Or, if the first, second, and third batches in the year include 25, 20, and 30 
units respectively, testing is performed on the third batch because the minimum of 60 units has been met. 
c For finished products compounded from starting materials that are sterile and nonpyrogenic, see section I, Release Testing, for more information on 
endotoxin testing.   
d These include generally recognized attributes for each dosage form such as those described in ICH Q6A or USP monographs or general chapters.
1567    42  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1568  APPENDIX B. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT 
1569  INTEND TO TAKE REGULATORY ACTION REGARDING STABILITY TESTING 
1570  AND EXPIRATION DATE REQUIREMENTS  
1571   
1572  A.  Default BUD (No Testing) for Non-Sterile Drug Products: Aggregate Batch 
1573  Size 5,000 Units 
1574   
1575  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1576  the requirements for stability studies and expiration dates for non-sterile drug products under 
1577   211.166 and 211.137 if (1) a BUD has been assigned according to Table C; (2) water activity 
1578  testing is conducted as described below, if applicable, to determine the type of product for 
1579  assigning the BUD; (3) literature or other scientific information, including relevant commercially 
1580  available product labeling for a similar drug (e.g., components, dosage form, route of 
1581  administration, primary container-closure type), does not indicate that the drug product may not 
1582  be physicochemically stable over the time period listed; and (4) the BUD is used as the 
1583  expiration date.50  
1584   
1585  The default BUDs in Table C are based on the likelihood of microbial proliferation as 
1586  determined by water activity testing. Products with a water activity >0.6 are of greater concern 
1587  microbiologically because there is potential for proliferation of microorganisms in the product. 
1588  Use of a validated preservative strategy51 can greatly reduce the likelihood of microbial 
1589  proliferation in finished drug products.  
1590   
1591  Water activity testing is conducted as follows to determine the type of product for assigning the 
1592  default BUD: 
1593   
1594    Solid dosage forms (i.e., tablets and capsules): No water activity testing is necessary. 
1595   
1596    Products with water activity >0.6: No water activity testing is necessary if the product is 
1597  known or assumed to have a high water activity (e.g., liquid oral solution) and the 
1598  applicable default BUD for products with water activity >0.6 is used. 
1599   
1600    Products with suspected low water activity (other than solid dosage forms) (e.g., 
1601  suppository): Water activity testing is conducted once for each non-sterile drug product 
1602  formulation according to validated test procedures such as those described in USP 
1603  General Chapter <1112>. Depending on the results of the water activity test, the BUD 
1604  should be set according to Table C. 
1605   
                                                 
50 To be eligible for the exemptions provided under section 503B of the FD&C Act, the compounded drug product 
must be labeled with an expiration date (see section 503B(a)(10)(A)(iii)(VI)). 
51 See USP General Chapter <51>. 
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Draft  Not for Implementation 
1606  Table C: Default BUDs for Non-Sterile Drug Products With Aggregate Batch Size 5,000 
1607  Units  
Storage Conditions 
Type of Product  Controlled Room Temperature  Refrigerator (2 to 8C) 
(20 to 25C) 
Solid dosage forms   180 days  N/A 
Preserved: 30 days  Preserved: 30 days 
Water activity >0.6  
Unpreserved: Not applicable  Unpreserved: 14 days 
Water activity 0.6   90 days  N/A 
1608   
1609  B.  Default BUD (No Testing) for Sterile Drug Products: Aggregate Batch Size 
1610  1,000 Units 
1611   
1612  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1613  the requirements for stability studies and expiration dates under  211.166 and 211.137 if (1) a 
1614  BUD has been assigned according to the criteria based on processing conditions in Table D; (2) 
1615  literature or other scientific information, including relevant commercially available product 
1616  labeling for a similar drug (e.g., components, dosage form, route of administration, primary 
1617  container-closure type), does not indicate that the drug product may not be physicochemically 
1618  stable over the time period listed; and (3) the BUD is used as the expiration date.52  
1619   
1620  Table D. Default BUDs for Aggregate Batch Size 1,000 Units With Given Processing and 
1621  Storage Conditions 
Storage Conditions 
Controlled 
Contains a 
Processing Conditions  Room  Refrigerator  Freezer 
Preservative? 
Temperature  (2 to 8C)  (-25 to -10C) 
(20 to 25C) 
  Finished drug product is 
aseptically processed; and   No  6 days  9 days  45 days 
  A sterility test has not been 
completed before release 
Yes  28 days  42 days  45 days 
  Finished drug product is 
terminally sterilized;  
No  14 days  28 days  45 days 
  A validated sterilization 
cycle that uses physical, 
                                                 
52 To be eligible for the exemptions provided under section 503B of the FD&C Act, the compounded drug product 
must be labeled with an expiration date (see section 503B(a)(10)(A)(iii)(VI)). 
  44  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
chemical, or biological 
indicators is employed; and  
Yes  28 days  42 days  45 days 
  A sterility test has not been 
completed before release  
  Finished drug product is 
No  28 days  42 days  45 days 
aseptically processed or 
terminally sterilized and has 
a completed, passing sterility 
Yes  42 days  42 days  45 days 
test before release 
1622   
1623  C.  Enforcement Policy Regarding the Use of Limited Stability Testing To 
1624  Assign a BUD 
1625   
1626  Stability testing is intended to confirm the stability performance of a non-sterile or sterile 
1627  compounded drug product held under the labeled storage conditions for the duration of the BUD. 
1628  Procedures established for assessing the stability of drug products compounded by outsourcing 
1629  facilities must achieve the following ( 211.122, 211.160, 211.166):  
1630   
1631    Incorporate stability-indicating test methods that are reliable, meaningful, and specific. 
1632   
1633    Evaluate samples of the drug product in the same container-closure system and with the 
1634  same or representative label and adhesive that will be affixed to the container in which 
1635  the drug product is marketed. 
1636   
1637    Evaluate samples for stability that are representative of the batch from which they were 
1638  obtained and are stored under suitable conditions. 
1639   
1640    Incorporate testing to evaluate antimicrobial effectiveness for drug products labeled or 
1641  intended to be multiple dose. If antimicrobial effectiveness has been previously 
1642  established for the formulation and container-closure system, a test for preservative 
1643  content may be used in lieu of a full antimicrobial effectiveness study. 
1644   
1645  FDA generally does not intend to take regulatory action against an outsourcing facility regarding 
1646  stability testing and expiration date requirements if the outsourcing facility uses the approach 
1647  outlined below describing a number of lots and a set of testswhich should be conducted at lot 
1648  release as part of normal operationsto be performed at the time of the desired BUD. This 
1649  section C does not apply to non-sterile unpreserved aqueous drug products because of the higher 
1650  risk of microbiological proliferation. 
1651   
1652  The following conditions apply: 
1653   
1654    Samples are evaluated following aging under the long-term storage conditions (i.e., 
1655  temperature and humidity) in ICH Q1A(R2). 
1656   
1657    The data from each time point are evaluated against the established specifications for the 
1658  compounded drug product. 
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Draft  Not for Implementation 
1659    The BUD is not longer than 12 months. 
1660   
1661    If the data for any test fall outside of the established specifications, the BUD is restricted 
1662  to the last time point at which the data remained within specifications, or the default BUD 
1663  (described above) is used.  
1664   
1665  Because of the possibility that a sample may not meet specifications at the final time point, FDA 
1666  strongly recommends the inclusion of testing at at least one interim time point. If the data at the 
1667  final time point do not confirm the stability of the product at the desired BUD (e.g., some 
1668  measurements fall outside of the established specifications), but the data at the interim time point 
1669  are acceptable (i.e., measurements meet the established specifications), a BUD equal to the 
1670  interim time point meets the second condition above. 
1671   
1672  Under this policy, samples from one lot are tested. Each unit subjected to one or more tests that 
1673  compromise the integrity of the primary container-closure is only tested at a single time point 
1674  (i.e., not at additional time points). If a single unit is to be used for multiple discrete tests to 
1675  minimize destructive testing, the unit dosage is subdivided into multiple aliquots that are not held 
1676  longer than the time to complete the testing (typically not longer than 48-72 hours) and the 
1677  aliquots are placed into appropriate testing containers (e.g., high performance liquid 
1678  chromatography vials or sample tubes) that protect the sample from being compromised (e.g., 
1679  from exposure to air, light, evaporation). 
1680   
1681  1.  Non-sterile 
1682   
1683  a.  Nondestructive tests 
1684   
1685  The following test is conducted: 
1686   
1687    Appearance. 
1688   
1689  b.  Destructive chemical tests  
1690   
1691  The tests to be conducted include: 
1692   
1693    pH, if applicable (e.g., for aqueous formulations). 
1694    Assay.53 
1695    Appropriate specifications. 
1696     
                                                 
53 See note 31. 
  46  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1697  c.  Microbiological tests, if water activity >0.6  
1698   
1699  The tests to be conducted include: 
1700   
1701    Antimicrobial effectiveness testing/preservative content testing at expiry. 
1702    Microbial enumeration54 (USP General Chapter <61>). 
1703    Test for specified organisms55 (USP General Chapter <62>). 
1704   
1705  2.  Sterile 
1706   
1707  a.  Nondestructive tests 
1708   
1709  The following tests are conducted: 
1710   
1711    Appearance. 
1712    Color and clarity. 
1713    Visible particulates. 
1714   
1715  b.  Destructive chemical tests  
1716   
1717  The tests to be conducted include: 
1718   
1719    pH, if applicable (e.g., for aqueous formulations). 
1720    Assay.56 
1721    Subvisible particles (10m100m).57 
1722   
1723  c.  Sterility or container-closure integrity tests 
1724   
1725  To confirm that sterility is maintained over the proposed BUD, container-closure integrity testing 
1726  (such as described in USP General Chapter <1207>) or a sterility test (see USP General Chapter 
1727  <71>) is conducted. When performed, container-closure integrity testing is conducted on a 
1728  number of units that is suitable for the chosen test method. 
1729   
1730  D.  Bracketing 
1731   
1732  Use of bracketing in stability studies allows for more streamlined evaluation of drug products for 
1733  which there are multiple strengths or volume presentations produced. Bracketing assumes that 
1734  the stability of intermediate strengths (or intermediate fill volumes) is adequately represented by 
                                                 
54 See, for example, USP General Chapter <1111>. 
55 Ibid.  
56 See note 31. 
57 Applicable only to intrathecal, intravenous, intra-arterial, ophthalmic, intramuscular, sterile otic, and subcutaneous 
preparations. 
 
  47  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1735  the extremes tested.58 For multiple drug products to be eligible for bracketing stability studies, 
1736  the candidate formulations should vary only in strength (or concentration) or fill volume. 
1737  Although individual excipient amounts may vary, all excipients (in worst-case amounts) should 
1738  be in all bracketed formulations. Proportional formulations are not required. The same container-
1739  closure system must be used ( 211.166). If three or more strengths, concentrations, or volume 
1740  presentations exist, intermediate cases for stability studies as follows may reflect an appropriate 
1741  use of bracketing: 
1742   
1743    If 3 or 4 drug product strengths, concentrations, or volume presentations are produced, 
1744  test the high and low extremes (e.g., if available strengths include 2.0 mg/mL, 3.5 
1745  mg/mL, 5.0 mg/mL, and 10.0 mg/mL, test 2.0 mg/mL and 10.0 mg/mL).  
1746   
1747    If 5-10 drug product strengths, concentrations, or volume presentations are produced, test 
1748  the high and low extremes and 1 intermediate case. 
1749   
1750    If more than 10 drug product strengths, concentrations, or volume presentations are 
1751  produced, test the high and low extremes and 2 intermediate cases. 
1752   
1753  It is critical that determination of the extremes be done with care. For example, with respect to 
1754  volume fill, the appropriate extremes are not necessarily always the highest and lowest 
1755  fluid volume fills. Rather, the head space-to-fluid volume ratio may better represent the 
1756  appropriate extreme depending on the container volume used in the various presentations. 
1757   
1758  Bracketing as described in this section does not apply to microbial testing of sterility, endotoxins, 
1759  or bioburden. Bracketing may be appropriate for water activity testing and antimicrobial 
1760  effectiveness testing when used in conjunction with a preservative content testing strategy. 
                                                 
58 See ICH guidance for industry Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug 
Substances and Products for more information on bracketing and matrixing. 
  48