Microbiological Quality 
Considerations in  
Non-sterile Drug 
Manufacturing 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Susan Zuk, 240-402-9133.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
September 2021 
Pharmaceutical Quality/Microbiology 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
   
Microbiological Quality 
Considerations in  
Non-sterile Drug 
Manufacturing 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
September 2021 
Pharmaceutical Quality/Microbiology 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ........................................................................................................ 2 
III.  STATUTORY AND REGULATORY FRAMEWORK............................................. 3 
IV.  MICROORGANISMS AND LIFECYCLE PRODUCT QUALITY.......................... 5 
A.  General  Microbiological Concerns Regarding NSDs..................................................... 5 
B.  Risk-Based Impact Assessment ...................................................................................... 7 
1. Product Specific Elements................................................................................................ 8 
2. Manufacturing Elements .................................................................................................. 9 
C.  Microbiological Concerns for Specific Dosage Forms and Special Cases...........................12 
1. Solid Dosage Forms.......................................................................................................12 
2. Non-Solid Dosage Forms................................................................................................13 
3. Microbiological Consideration  Special Cases .................................................................14 
D.  Updating Approved Drug Product Specifications ...........................................................17 
APPENDIX:  CASE STUDY EXAMPLES OF MICROBIOLOGICAL 
CONTAMINATION OF NSD PRODUCTS; IMPACT ON PRODUCT QUALITY AND 
MANUFACTURING PROCESS......................................................................................... 21 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Microbiological Quality Considerations in  
2  Non-sterile Drug Manufacturing 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance is intended to assist manufacturers in assuring the control of microbiological2 
17  quality of their non-sterile drugs (NSDs).3 The recommendations herein apply to solid non-
18  sterile dosage forms, as well as semi-solid, and liquid non-sterile dosage forms (e.g., topically 
19  applied creams, lotions and swabs, and oral solutions and suspensions). NSDs can be 
20  prescription or nonprescription drugs, including those marketed under approved new drug 
21  applications (NDAs) or abbreviated new drug applications (ANDAs), and nonprescription drugs 
22  without approved new drug applications which are governed by the provisions of section 505G 
23  of the FD&C Act (often referred to as over-the-counter (OTC) monograph drugs).4 These 
24  recommendations, if followed, will also assist manufacturers in complying with the current good 
25  manufacturing practice (CGMP) requirements for finished pharmaceuticals and active 
26  pharmaceutical ingredients (APIs).5  
27   
28  This guidance discusses product development considerations, risk assessments, and certain 
29  CGMPs that are particularly relevant to microbiological control in a manufacturing operation for 
30  a NSD. It also provides recommendations to help manufacturers assess the risk of contamination 
31  of their NSDs with objectionable microorganisms in order to establish appropriate specifications 
32  and manufacturing controls that prevent such contaminations and assure the safety, quality, 
33  identity, purity, and efficacy of the NSD.6 
34   
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration. 
2 For the purposes of this guidance, the terms microbiological and microbial are used interchangeably. 
3 For the purposes of this guidance, non-sterile drugs (NSDs) refers to non-sterile finished dosage forms. 
4 The term OTC monograph drug means a nonprescription drug without an approved new drug application which 
is governed by the provisions of section 505G. See FD&C Act section 744L(5).  
5 See 21 CFR parts 210 and 211, CGMP for Finished Pharmaceuticals, and FD&C Act section 501(a)(2)(B) for 
APIs.   
6 The term objectionable microorganisms as used here refers to organisms that are objectionable due to their 
detrimental effect on products or potential harm to patients or objectionable due to the total number of organisms.  
See 43 FR 45053 (Sep. 29, 1978). 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
35  For application products (i.e., NDAs, ANDAs) this guidance also explains how applicants should 
36  submit NSD controls in original submissions and report changes in microbiological 
37  specifications and testing programs to the FDA, in accordance with current Agency guidances 
38  regarding changes to an approved application. 
39   
40  To illustrate the importance of a microbiological risk assessment and control strategy, this 
41  guidance discusses incidents of Burkholderia cepacia complex (BCC) and other microorganism 
42  contamination in non-sterile dosage forms that resulted in adverse events and recalls of the drug 
43  products. The guidance describes proper prevention of and testing for BCC in aqueous dosage 
44  forms of NSDs. 
45   
46  The guidance describes the Agencys current thinking on microbiological contamination of 
47  topical antiseptic drugs intended for use by health care professionals in a hospital setting or other 
48  health care situations outside the hospital,7 which are used prior to medical procedures to reduce 
49  the number of bacteria on the skin and that in some cases are not manufactured as sterile 
50  products. 
51   
52  The contents of this document do not have the force and effect of law and are not meant to bind 
53  the public in any way, unless specifically incorporated into a contract.  This document is 
54  intended only to provide clarity to the public regarding existing requirements under the law.  
55  FDAs guidance documents should be viewed only as recommendations, unless specific 
56  regulatory or statutory requirements are cited. The use of the word should in Agency guidances 
57  means that something is suggested or recommended, but not required. 
58   
59  II.  BACKGROUND 
60   
61  This guidance was developed, in part, as a result of the Agencys review of FDA Adverse Event 
62  Reports (FAERs)8 and recalls involving contamination of non-sterile dosage forms. A review of 
63  FAERs that occurred between 2014 and 2017 revealed 197 FAERs associated with intrinsic9 
64  microbiological or fungal contamination, and of those, 32 reported serious adverse events. 
65  Because spontaneous reports10 in FAERs are voluntary by definition, the Agency anticipates a 
66  degree of underreporting. The actual number of incidents associated with microbiological 
67  contamination is likely significantly higher than the number of events reported.11 
 
7 Such products include health care personnel hand washes, health care personnel hand rubs, surgical hand scrubs, 
surgical hand rubs, and patient antiseptic skin preparations (i.e., patient preoperative and preinjection skin 
preparations). 
8 FDA Adverse Event Reporting System (FAERS) Latest Quarterly Data Files - 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082
193.htm. 
9 Intrinsic means the microbial or fungal contamination originated with the manufacture, packaging, shipping, or 
storage of the drug, not from extrinsic sources, (e.g., consumer or health care provider use errors). 
10 For definition of spontaneous report see FDAs The Publics Stake In Adverse Event Reporting -  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm179
586.htm. 
11 According to FDAs Question and Answers on FAERs, FDA does not receive reports for every adverse event or 
medication error that occurs with a product...There are also duplicate reports where the same report was submitted 
by the consumer and by the sponsor [drug manufacturer].  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
68   
69  The review of voluntary recall actions during the same time period revealed over 50 events 
70  associated with objectionable microbiologically contaminated NSDs.12 The recalls showed that a 
71  wide range of objectionable microorganisms were found in both aqueous and non-aqueous 
72  NSDs.13 
73   
74  The Agency is also aware of specific concerns regarding BCC and its association with 
75  contamination of aqueous-based NSDs that resulted in a number of serious adverse events, i.e., 
76  infections and deaths.14 In May 2017, FDA released a statement15 alerting drug manufacturers of 
77  the recent product recalls associated with the presence of BCC in NSDs. The statement also 
78  reminded drug manufacturers of their responsibilities to prevent objectionable microorganisms 
79  from adversely impacting their NSD manufacturing processes, as well as the products 
80  themselves. 
81   
82  Analysis of these events, combined with FDAs experience conducting microbiology 
83  assessments of non-sterile drugs for NDA and ANDA products and compliance actions, helped 
84  to inform the recommendations in this guidance.16 
85   
86  III.  STATUTORY AND REGULATORY FRAMEWORK 
87   
88  Under section 501(a)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act),17 a drug will 
89  be deemed adulterated if: 
90   
91  the methods used in, or the facilities or controls used for, its manufacture, processing, 
92  packing, or holding do not conform to or are not operated or administered in conformity 
93  with current good manufacturing practice to assure that such drug meets the requirements 
94  of this Act as to safety and has the identity and strength, and meets the quality and purity 
95  characteristics, which it purports or is represented to possess, or if it has been prepared, 
96  packed, or held under insanitary conditions whereby it may have been contaminated with 
97  filth, or whereby it may have been rendered injurious to health. 
98   
99  For finished pharmaceuticals, the CGMP regulations described in 21 CFR parts 210 and 211 
100  address prevention of objectionable microorganisms in non-sterile drug products, bioburden 
101  specifications, and in-process testing. Specifically: 
102   
 
12 See footnote 6. 
13 FDA Recalls, Market Withdrawals, & Safety Alerts - https://www.fda.gov/Safety/Recalls/default.htm. 
14 Glowicz J et al, 2018, A multistate investigation of health careassociated Burkholderia cepacia complex 
infections related to liquid docusate sodium contamination, January-October 2016, Am J Infection Control, Vol 46: 
649-665, https://www.ajicjournal.org/article/S0196-6553(17)31287-7/fulltext. 
15 FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, 
water-based drug products, May 2017, https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm. 
16 CDER began chemistry, manufacturing and controls (CMC) microbiology reviews of NSD in the mid-1990s with 
a focus on aqueous based NSDs. 
17 See 21 U.S.C. 351(a)(2). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
103  21 CFR 211.113(a), Control of microbiological contamination, states that appropriate 
104  written procedures, designed to prevent objectionable microorganisms in drug products 
105  not required to be sterile, shall be established and followed. 
106   
107  21 CFR 211.110(a)(6), (b), (c), Sampling and testing of in-process materials and drug 
108  product, requires (where appropriate) in-process bioburden testing and valid in-process 
109  specifications to assure the drug product meets its microbiological specifications. In-
110  process testing shall occur during the product process, e.g., at commencement or 
111  completion of significant phases or after storage for long periods. 
112   
113  21 CFR 211.84(d)(4) and (6), When appropriate, components shall be microscopically 
114  examined. Each lot of a component, drug product container, or closure with potential for 
115  microbiological contamination that is objectionable in view of its intended use shall be 
116  subjected to microbiological tests before use.  
117   
118  To assure the microbiological quality of NSDs subject to premarket approval, applicants must 
119  propose appropriate drug substance and product specifications (i.e., tests, analytical procedures, 
120  and acceptance criteria) in their submissions in accordance with 21 CFR 314.50(d)(1) [NDAs] 
121  and 21 CFR 314.94(a)(9) [ANDAs].18 
122   
123  In general, a drug with a name recognized in an official compendium must comply with the 
124  United States Pharmacopeia (USP) compendial standards for identity, strength, quality, and 
125  purity, or be deemed adulterated, misbranded, or both.19 If USP has established a monograph for 
126  a drug, the USP monograph will identify the official tests, procedures, acceptance criteria, and 
127  other requirements. When USP monographs include a test or specification referencing 
128  Applicable General Chapters,20 the applicant should ensure that their monograph product 
129  complies with the testing requirement, or it could be deemed adulterated. Some of the USP 
130  General Chapters that are more commonly referenced in drug monographs, as they apply to 
131  controlling microbiological activity in NSDs, include, for example: 
132   
133    USP <60> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS 
134  TESTS FOR BURKHOLDERIA CEPACIA COMPLEX     
135    USP <61> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  
136  Microbial Enumeration Tests  
137    USP <62> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: 
138  Tests for Specified Microorganisms  
139   
 
18 For the definition of specification, see 21 CFR 314.3(b) and also ICH guidance for industry Q6A Specifications: 
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 
(December 2000). 
19 FD&C Act 501(b) and 502(e)(3)(B) and (g); also 21 CFR 299.5. 
20 See USP, Conformance to Standards, 3.10, Applicable general chapters means general chapters numbered 
below 1000 or above 2000 that are made applicable to an article through reference in General Notices, a monograph, 
or another applicable general chapter numbered below 1000. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
140  In addition to USP monograph requirements, further microbiological tests are often performed as 
141  part of batch release requirements as described in 21 CFR part 211.21 
142   
143  Objectionable microorganisms and bioburden in non-sterile APIs should be controlled. FDA 
144  guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical 
145  Ingredients (September 2016) states: 
146   
147  Appropriate specifications should be established for APIs in accordance with accepted 
148  standards and consistent with the manufacturing process. The specifications should 
149  include control of impurities (e.g., organic impurities, inorganic impurities, and residual 
150  solvents). If the API has a specification for microbiological purity, appropriate action 
151  limits for total microbial counts and objectionable microorganisms should be established 
152  and met. 
153   
154  IV.  MICROORGANISMS AND LIFECYCLE PRODUCT QUALITY 
155   
156  A. General  Microbiological Concerns Regarding NSDs 
157   
158  Prevention, control, and monitoring of the microbiological population in non-sterile drug 
159  components and drug products are necessary to minimize the risk of: 
160   
161    patient exposure to significant numbers or harmful species of microorganisms, especially 
162  in immunocompromised patients22  
163    patient exposure to harmful microbial metabolites and/or toxins  
164    drug spoilage or degradation 
165   
166  The statutory and regulatory framework described in section III above, coupled with sound 
167  scientific rationale, provides the foundation for establishing a program to monitor and control the 
168  manufacturing process to prevent objectionable microorganisms from affecting the quality of a 
169  NSD.  
170   
171  To ensure product quality and patient safety, it is essential to limit the level and type of 
172  microorganisms in NSDs during manufacturing and over product shelf life. While a NSD is not 
173  required to be sterile, there is a threshold of microbiological content above which safety and 
174  efficacy of a given NSD may be adversely impacted. 
175   
176  The CGMP regulations require that components are sampled, tested, or examined prior to release 
177  by the manufacturers quality control unit.23 Naturally-derived components (e.g., plant or animal 
178  derived ingredients, and naturally occurring ingredients such as water) may contribute 
179  significantly to the total bioburden of the drug product and must be subjected to microbiological 
 
21 CGMPs are not limited to drugs marketed under approved applications. See FD&C Act section 501(a) and 21 
CFR parts 210 and 211.  
22 For the purposes of this guidance, we define immunocompromised patients as those who have a weakened 
immune system, which may be due to trauma, surgery, illness, or chronic disease. It also includes vulnerable 
populations, such as infants and the elderly. 
23 See 21 CFR 211.84.  
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
180  testing in accordance with established procedures.24 For instance, water is a common component 
181  used in NSD manufacturing. However, water system control deviations can be difficult to detect 
182  due to limitations of sampling.25 These deviations may lead to the formation of biofilms and 
183  have been shown to have a profound impact on microbial quality of an aqueous-based drug. 
184  Consequently, proper water system design and control, appropriate microbial action limits,26 and 
185  routine water quality testing is critical to assuring that microbial levels are below established 
186  limits, and that the water is free of objectionable microorganisms.27 Therefore, it is important for 
187  manufacturers to have a robust design for water systems, including controls designed to prevent 
188  objectionable microorganisms and procedures for monitoring, cleaning, and maintenance.28 
189   
190  Aqueous non-sterile products, which may support microbial growth during the product shelf life 
191  due to their water activity (a ),29 should be designed to prevent microbial proliferation of 
w
192  intrinsic microorganisms or those inadvertently introduced during use. While the potential for 
193  microbial growth during the manufacturing process or over storage through the shelf life can be 
194  partially mitigated by a properly designed preservative system or formulation, antimicrobial 
195  preservatives can provide a false sense of product safety regarding the presence or growth of 
196  microorganisms. Two purposes of a preservative are to counteract possible incidental microbial 
197  contamination during multiple uses of a product by a consumer and maintain microbial control 
198  over the shelf life of the product. Preservatives are not a substitute for a comprehensive approach 
199  to preventing objectionable microorganisms from contaminating NSDs, and should not be 
200  presumed to reduce in-process bioburden during manufacturing. Certain microorganisms have 
201  been found to degrade commonly used preservatives, despite the drug having previously met 
202  antimicrobial effectiveness testing acceptance criteria. Consequently, non-sterile drug 
203  manufacturers should be aware of the potential for the development of preservative resistance. 
204  This potential decrease in preservative effectiveness should be investigated (root cause analysis 
205  and corrective action to eliminate the source of contamination) in cases of objectionable 
206  microbes or an upward trend in total microbial enumeration counts. This issue is discussed as a 
207  special case study regarding Burkholderia cepacia complex and Aqueous Drug Products in 
208  section IV.C.3.a Microbial Considerations  Special Cases of this guidance.   
209   
210  In contrast, many non-sterile liquid products that are not aqueous-based, such as those containing 
211  high percentages of alcohol or other non-aqueous solvents, can potentially pose lower risk of 
212  microbial proliferation during processing, holding of in-process materials, and storage over shelf 
 
24 See 21 CFR 211.84(d) and 211.113(a). 
25 An effective and ongoing monitoring program is important in determining if water used to support batch 
manufacture continues to meet predetermined quality characteristics. For products that include water in 
manufacturing operations, more sensitive water sampling strategies are generally appropriate, and should include 
use of larger sample sizes (e.g., 100 mL) with membrane filtration.  
26 Microbial action limits should be established based on the risk-based impact assessment, as described in section 
IV.B.   
27 See 21 CFR 211.84(d). 
28 See 21 CFR 211.63, 211.67, 211.100. 
29 It is important to note that water activity is different from water content. USP <1112> defines water activity as the 
ratio of the vapor pressure of water in the drug, when in a completely undisturbed balance with the surrounding air 
media, to the vapor pressure of distilled water under identical conditions. See USP <1112> APPLICATION OF 
WATER ACTIVITY IN DETERMINATION TO NONSTERILE PHARMACEUTICAL PRODUCTS. In contrast, 
water content is the amount of moisture in the drug. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
213  life.30 Also, non-sterile solid drug products, such as tablets and capsules, have a low water 
214  activity that usually does not allow for microbial growth during product shelf life. However, it 
215  should be noted that although microorganisms that are present in a non-sterile drug product with 
216  low water activity will not proliferate, they can persist in non-aqueous liquids and dry products 
217  throughout the shelf life of the product. The CGMP regulations require that written procedures 
218  be established to prevent introduction of objectionable microbiological contamination in the 
219  manufacture of drug products not required to be sterile, and that a program be designed to assess 
220  the stability characteristics of drug products, including NSD.31 Consequently, it is important to 
221  provide for appropriate microbiological control of the components (e.g., excipients and APIs) of 
222  non-sterile drug products, even if the components possess a low water activity. 
223   
224  Non-sterile solid drug products also can be at risk for microbial proliferation through 
225  contamination during manufacturing. For example, extended in-process hold times of aqueous 
226  solutions or slurries at various points in the manufacturing process of a solid drug product could 
227  allow for microbial proliferation exceeding the appropriate levels for such dosage forms. 
228  Consequently, procedures that establish time limits are essential to assure product quality, 
229  including control of microbiological quality, at each process step used in the manufacture of both 
230  liquid and solid NSDs to prevent objectionable microorganisms.32  
231   
232  While not exhaustive, the USP provides a widely accepted set of microbiological test methods 
233  for non-sterile drug products.33 USP also recommends the establishment of acceptance criteria 
234  regarding total numbers of microorganisms, in addition to selected specified microorganisms in 
235  NSDs.34 However, the USP does not provide a comprehensive list of objectionable 
236  microorganisms; therefore, firms should identify any additional controls and acceptance criteria 
237  that are necessary. The need for additional controls of objectionable microorganisms should be 
238  determined for each product. For example, the presence of BCC in aqueous non-sterile drug 
239  products may lead to both drug product degradation and patient infection. The intended patient 
240  population, drug product indication, and route of administration should be considered when 
241  establishing a microbial specification and determining if a specific microorganism is 
242  objectionable in the drug product. 
243   
244  B.  Risk-Based Impact Assessment 
245   
246  The controls necessary to prevent objectionable microorganisms will depend on the risk 
247  (probability and hazard potential) of microbiological contamination in the NSD, including the 
248  characteristics of the NSD (e.g., formulation, component selection, conditions of use, and route 
249  of administration), the NSD manufacturing process, and the impact of the manufacturing 
250  environment. Well-designed and appropriately controlled manufacturing processes present fewer 
251  opportunities for introducing objectionable microorganisms and their proliferation or growth. For 
252  certain low-risk manufacturing operations (e.g., tablet manufacture), reduction in 
 
30 There have been recalls in alcohol based products. Refer to Appendix, Case 6. 
31 See, e.g., 21 CFR 211.113 and 211.166(a). 
32 See 21 CFR 211.111 and 211.113(a). 
33 USP <61> MICROBIAL ENUMERATION TESTS and USP <62> TESTS FOR SPECIFIED ORGANISMS. 
34 USP <1111> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  ACCEPTANCE 
CRITERIA FOR PHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL 
USE. 
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253  microbiological monitoring and testing may be justified using a risk assessment (see section C 
254  below). 
255   
256  A risk-based impact assessment helps manufacturers identify product-specific characteristics and 
257  manufacturing process elements that are more likely to introduce bioburden or objectionable 
258  microorganisms into the NSD. Systems designed to mitigate risks based on this risk-based 
259  impact assessment are more likely to prevent objectionable microorganisms in NSDs. The 
260  elements listed below, while not an exhaustive list, should be considered in the risk management 
261  plan to reduce objectionable microorganisms, where relevant.  
262   
263  1.  Product Specific Elements 
264   
265    Dosage Form 
o
266    Liquid products typically have a higher potential for microbial growth 
267  than other types, and semi-solids typically have a higher potential for 
268  microbial growth than solids.35 
269   
270    Water Activity36 
o
271    Water activity of non-aqueous NSDs should be low enough to inhibit 
272  microbial growth. 
273    When NSDs have a higher water activity, there is higher potential for 
274  microbial growth and additional manufacturing controls may be needed. 
275   
276    Proposed Use  
o
277    Consider the patient populationthe spectrum of patients that could be 
278  exposed to the drug and disease state of the most vulnerable patients 
279  taking the drug. 
280    Consider the route of administration. 
281    Consider the body site to which the NSD may be administered (e.g., the 
282  skin, the respiratory tract, the gastrointestinal tract, or the urinary tract), 
283  and whether the tissue may be injured or diseased, and therefore more 
284  susceptible to infection. 
285    Consider the setting in which the product is used (e.g., operating room, 
286  NICU). 
287   
288     
 
35 Dosage form will dictate the type of and extent to which microbial enumeration testing should be performed on 
the finished product. General enumeration testing is described in USP <61> and USP <62>. For solid dosage forms, 
ICH Q6A Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical 
Substances includes recommendations for conditions under which periodic or skip testing with regard to microbial 
enumeration testing may be considered. 
36 USP <1112> APPLICATION OF WATER ACTIVITY DETERMINATION TO NONSTERILE 
PHARMACEUTICAL PRODUCTS - Reduced water activity (a ) will greatly assist in the prevention of microbial 
w
proliferation in pharmaceutical products; the formulation, manufacturing steps, and testing of nonsterile dosage 
forms should reflect this parameter. 
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289    Packaging 
o
290    Ensure container/closure provides adequate protection from foreseeable 
291  external factors that can lead to microbial contamination (e.g., water or 
292  microbial ingress).37  
293    Consider the appropriateness of a single-dose versus a multiple-dose 
294  container-closure when selecting the NSD packaging.38 For certain dosage 
295  forms, a single-dose container/closure might provide superior safety with 
296  respect to preventing extrinsic microbial ingress into the finished product.  
297   
298    Product Components and Composition 
o
299    Consider selection of appropriate preservatives that assure effectiveness to 
300  prevent microbiological proliferation throughout the shelf life. 
301    Assure all incoming lots of raw materials are suitable for their intended 
302  use, including acceptable microbiological quality.39 
303   
304    Microbiological TestingProduct Specific Considerations 
o
305    Establish appropriate microbial limits for components, in-process 
306  materials, and finished products.40 
307    Ensure the sampling plan detects variation within a batch.41 
308    Ensure appropriate sensitivity of methods for detecting a variety of 
309  microbes that could be in components or the finished product and that 
310  could pose a risk to patients or product stability.42 
311    Implement appropriate action limits and test methods for water that is used 
312  as a component, including use as a processing aid.43 Purified water, USP, 
313  that does not exceed 100 CFU/ml is recommended for use in solid oral 
314  dosage forms. More stringent microbiological quality standards may be 
315  appropriate for other dosage forms.44 
316   
317  2.  Manufacturing Elements 
318   
319    Manufacturing Process Steps: Certain processing steps may have a greater impact 
o
320  than others in either promoting or reducing bioburden. 
321    Bulk storage steps, especially those that are aqueous-based in the 
322  manufacturing process, may create conditions in which microorganisms 
323  can proliferate, particularly during extended in-process holding periods 
324  (i.e., time between different unit operations). Other manufacturing steps 
325  might introduce objectionable microorganisms. Therefore, extended 
326  holding of aqueous in-process materials (e.g., coating 
327  suspensions/solutions, liquid mixtures prior to the addition of a 
 
37 CFR 211.94(b). 
38 USP <659> PACKAGING AND STORAGE REQUIREMENTS. 
39 See 21 CFR 211.84(d)(6). 
40 See 21 CFR 211.113(a). 
41 See 21 CFR 211.110(a). 
42 See 21 CFR 211.160(b). 
43 See 21 CFR 211.84(d)(6).  
44 USP <1231> WATER FOR PHARMACEUTICAL PURPOSES. 
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328  preservative) is not advisable. Holding time limits must be established to 
329  preserve product quality.45 
330    Inadequate equipment cleaning processes, such as extended hold times 
331  before cleaning and insufficient drying after equipment has been cleaned, 
332  may also promote microbiological contamination. 
333    Inadequate environmental controls, such as production areas open to a 
334  natural, uncontrolled, or insufficiently controlled environment when 
335  product or product contact surfaces are exposed may promote 
336  microbiological contamination. 
337    Some manufacturing steps (e.g., those that involve filtration, high 
338  temperature, extreme pH, or organic solvents) might result in an in-
339  process material that has a reduced bioburden. 
340   
341    Components: Non-sterile components can be a source of objectionable 
o
342  microorganisms in the manufacturing process. Appropriate specifications46 for 
343  these components, as well as strategies for monitoring, controlling, preventing 
344  objectionable microorganisms must be established.47 Special attention should be 
345  given to purified water48 and naturally-derived components due to their intrinsic 
346  risk for contamination.  
347   
348    Water System: Water used as a component (or as a processing aid) must be, as for 
o
349  any other component, of appropriate quality for its intended use in processing and 
350  in the formulation.49,50 When water used as a component is processed in-house, 
351  the purification system must be well-designed and rigorously controlled and 
352  maintained.51 Maintenance and control of water purification systems should 
353  include proactive replacement of parts to prevent deterioration and routine 
354  monitoring to assure the system can consistently produce water meeting its 
355  predetermined quality characteristics. The procedure for monitoring should 
356  incorporate appropriate action and alert limits and include timely sampling after 
357  key water processing steps and equipment used in the water processing and 
358  delivery system, including all points-of-use. Water used as a cleaning agent, 
359  depending on conditions of use and equipment, should be monitored to ensure it 
360  meets appropriate quality for its intended use.  
361   
362    Environment: Manufacturers must ensure that facilities, equipment, and 
o
363  environmental conditions are adequate to ensure control of air quality for 
364  manufacture, such as preventing introduction of microbiological contaminants or 
365  bioburden that would be objectionable to the particular NSD being produced.52 
 
45 See 21 CFR 211.111. 
46 See 21 CFR 211.160(b). 
47 See 21 CFR 211.100(a), 211.113(a). 
48 USP <1231> WATER FOR PHARMACEUTICAL PURPOSES. 
49 See 21 CFR 211.80, 211.84, 211.160(b). 
50 USP <1231> WATER FOR PHARMACEUTICAL PURPOSES classifies different water quality grades to 
indicate relative purity and absence of microorganisms. 
51 See 21 CFR 211.63, 211.67. 
52 See 21 CFR 211.46(b), 211.56. 
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
366  Manufacturers should periodically identify microorganisms present in the 
367  manufacturing facility which might lead to contamination of the NSD, and ensure 
368  that their controls effectively mitigate the impact of these microorganisms on their 
369  NSD. 
370   
371    Equipment: It is important to maintain the sanitary condition of equipment by 
o
372  limiting bioburden through proper design (e.g., vessels, piping), maintenance, 
373  cleaning, and sanitization. 
374   
375    Cleaning and Sanitizing Agents: Manufacturers must use cleaning/sanitizing 
o
376  agents appropriate to assure that buildings and facilities are maintained in a clean 
377  and sanitary manner, which should include ensuring that they do not harbor 
378  objectionable microorganisms.53 Appropriate equipment cleaning is essential to 
379  prevent objectional microbiological contamination of components, containers, 
380  closures, packaging materials, and drugs.54 
381   
382    Personnel: Manufacturers should take steps to establish and maintain appropriate 
o
383  practices to minimize the potential impact of personnel introducing objectionable 
384  microorganisms into the manufacturing process. They must ensure that personnel 
385  follow good hygiene practices.55 
386   
387    In-Process Testing: Manufacturers are required to establish procedures to assure 
o
388  the quality of in-process materials is consistent with the finished products 
389  established specifications, which includes evaluating whether microbial attributes 
390  are met during processing.56  
391   
392    Microbiological Release Testing (as appropriate): 
o
393    Total microbial content (microbiological enumeration testing)57 
394    Specified organism testing and identification program to identify other 
395  objectionable microorganisms58 
396   
397     
 
53 See 21 CFR 211.56. 
54 See 21 CFR 211.56, 211.67. 
55 See 21 CFR 211.28(b). 
56 See 21 CFR 211.110(a)(6). 
57 USP <61> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  MICROBIAL 
ENUMERATION TESTS. 
58 USP <62> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  TESTS FOR SPECIFIED 
MICROORGANISMS. 
  11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
398  C. Microbiological Concerns for Specific Dosage Forms and Special Cases 
399   
400  1.  Solid Dosage Forms 
401   
402  Compared to other NSDs, solid dosage forms represent a lower microbiological risk to patients 
403  due to their low water activity.  Therefore, the microbiological controls associated with their 
404  manufacture are generally not expected to be as stringent as those associated with the 
405  manufacture of other NSDs. 
406   
407  The microbiological quality of the finished solid dosage form is also monitored through finished 
408  product testing.59 Microbial enumeration testing of the finished drug product can be performed 
409  by methods described in the USP for Total Aerobic Microbial Counts (TAMC), Total Combined 
410  Yeast and Mold Count (TYMC), and specified organisms, as appropriate.60,61 If testing is 
411  performed using compendial methods, method suitability testing should be performed using the 
412  drug product. Other test methods, including rapid microbiological methods, may be used for 
413  product testing, but will require validation to demonstrate their suitability and equivalence to the 
414  compendial methods.62 
415   
416  Although the USP contains recommended acceptance criteria for microbial control, and specifies 
417  the absence of certain objectionable microorganisms,63 manufacturers may develop alternative 
418  approaches to microbiological control, including limits/release criteria. For example, many 
419  finished solid oral dosage forms have a water activity that does not permit growth or persistence 
420  of many vegetative cells. Therefore, it is possible that water activity determination during 
421  product development, in conjunction with in-process controls designed to limit objectionable 
422  microorganisms, can serve as justification for the reduction or elimination of microbiological 
423  testing for release of certain types of solid oral finished products. If there are sufficient data to 
424  demonstrate that in-process microbiological controls are successful, finished product water 
425  activity is acceptable, and component lot bioburden test results remain  consistently in control, 
426  the microbial enumeration testing of the finished product may be reduced or eliminated (see 
427  section below titled Potentially Reducing Microbiological Release Testing for Solid Dosage 
428  Forms Based on Risk-Based Impact Assessment). If such surrogate criteria are used in lieu of a 
429  product release test, it is important to establish and document appropriate process and facility 
430  controls, including testing of incoming component lots and controls in the manufacturing 
431  process, as these controls serve to limit the bioburden in the final product. 
432   
433     
 
59 See 21 CFR 211.165(b). 
60 USP <61> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  MICROBIAL 
ENUMERATION TESTS. 
61 USP <62> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  TESTS FOR SPECIFIED 
MICROORGANISMS. 
62 See 21 CFR 211.194(a)(2). 
63 USP <1111> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  ACCEPTANCE 
CRITERIA FOR PHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL 
USE. 
 
  12  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
434  Potentially Reducing Microbiological Release Testing for Solid Dosage Forms Based on Risk-
435  Based Impact Assessment  
436   
437  Solid dosage forms with a water activity that will not support vegetative microbial growth are 
438  excellent candidates for reduced microbial testing for product release and stability. ICH Q6A 
439  Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: 
440  Chemical Substances includes recommendations for conditions under which periodic or skip 
441  testing with regard to microbial enumeration testing may be considered. The recommendations 
442  in ICH Q6A are based on product characteristics and provide a logical approach to determining 
443  an appropriate microbiological testing schedule. To support the reduction or elimination of 
444  microbiological release testing for solid dosage forms, manufacturers should conduct a risk-
445  based impact assessment, as recommended in section IV.B of this guidance. 
446   
447  Microbiological testing in a stability program may be reduced or eliminated for lower risk solid 
448  dosage forms with appropriate justification, including the manufacturers historical experience in 
449  manufacturing the NSD, such as the amount of microbiological release and stability data, any 
450  adverse findings, and the extent of process, facility, and component bioburden controls. Note that 
451  some solid dosage forms that contain growth-supporting components, such as proteinaceous 
452  components,64 should undergo a risk assessment to determine if they are candidates for reducing 
453  or eliminating the need for microbiological testing in stability protocols. 
454   
455  2.  Non-Solid Dosage Forms 
456   
457  Typically, non-solid dosage forms (e.g., solutions, suspensions, lotions, creams, and some 
458  ointments) have higher water activity than solid dosage forms and thus a higher risk of 
459  supporting microbial growth. The capacity of non-solid dosage forms to support microbial 
460  growth is largely dependent on the water activity of the drug product components. Many 
461  contamination events have been associated with products with water activity levels that support 
462  microbial growth, and therefore we recommend that non-solid dosage form manufacturers focus 
463  on microbiological quality when evaluating the overall manufacturing process. Understanding a 
464  products water activity throughout the manufacturing process can aid in decisions related to 
465  manufacturing, in-process holding times, and storage conditions. For products, components, and 
466  in-process materials with water activities that are known to support microbial proliferation, 
467  greater scrutiny should be placed on process controls throughout the operation. This includes in-
468  process and finished product microbiological monitoring methods and acceptance criteria, 
469  validation of in-process holding periods,65 and any manufacturing step that is vulnerable to 
470  microbial proliferation. For example, naturally occurring ingredients with low water activity may 
471  have high intrinsic bioburdens and require special attention. Also, the presence of objectionable 
472  microorganisms in the manufacturing steps for topical drugs has resulted in microbial 
473  contamination of such products, which typically have low water activity. Additionally, 
474  suspensions can present an additional challenge in managing objectionable microorganisms.66 
475  Product stability studies should take into account that suspensions may separate into different 
 
64 Solid oral dosage forms with certain naturally-derived active ingredients (e.g., pancreatic enzymes) and soft 
gelatin capsules have a higher likelihood of harboring objectionable contamination. 
65 See 21 CFR 211.111. 
66 See footnote 6. 
  13  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
476  phases, during storage and distribution, that may result in the segregation of formulation 
477  ingredients and cause an unequal distribution of preservatives. The phase with insufficient 
478  preservatives may have high water activity resulting in microbial growth.  
479   
480  In addition to evaluating the overall manufacturing process, it is also important to ensure that 
481  manufacturing equipment is cleaned and maintained such that water residue does not remain on 
482  equipment while it is stored, unused, or unprotected.67 Water residue can promote microbial 
483  growth. Equipment surfaces, including those that may not contact product directly, should be 
484  dried or stored in manner that permits rapid drying as soon as possible after cleaning and 
485  sanitization. 
486   
487  Non-solid products with low water activities nonetheless can harbor objectionable contamination 
488  due to introduction of contamination during manufacturing or from raw materials. However, 
489  microbial proliferation during shelf-life is less common. For non-solid products with synthetic 
490  components and water activities that are well below those that are known to support microbial 
491  proliferation, less frequent microbiological testing conducted in the finished product stability 
492  program may be supportable. Batches placed in a stability testing program are typically sampled 
493  and tested at multiple time points over their labeled shelf life, including beginning and end and 
494  several interim points. To support reduced (i.e., fewer stability time points) microbiological 
495  testing of finished product lots in the stability program, a risk-based impact assessment should be 
496  performed that includes water activity data, microbiological monitoring information related to 
497  the manufacturing process, bioburden potential of the components, manufacturing history (with 
498  attention to any failures and deviations), and an understanding of the processing steps that may 
499  contribute positively or negatively to microbiological quality (see previous subsection on 
500  Potentially Reducing Microbiological Release Testing for Solid Dosage Forms Based on Risk-
501  Based Impact Assessment). 
502   
503  3.  Microbiological Consideration  Special Cases 
504   
505  This section discusses examples of NSD product formulations and intended uses that inherently 
506  pose greater relative risk for objectionable microorganisms or bioburden to harm the patient 
507  population (e.g., administration of NSD to skin prior to medical procedures that break the skin). 
508  This example demonstrates that more rigorous identification and assessment of the bioburden in 
509  these products is critical to understand product hazard. Appropriate laboratory methods must be 
510  used, and qualified staff must review the results to determine if the product is contaminated with 
511  objectionable microorganisms.68,69 These methods should differentiate and identify objectionable 
512  microorganisms. Such batch quality information is critical to prevent distribution of an 
513  objectionably contaminated product that poses a hazard to consumers, and to facilitate an 
514  investigation of the cause(s) to correct or prevent a quality problem. 
515   
516     
 
67 See 21 CFR 211.67. 
68 See 21 CFR 211.160(b). 
69 See 21 CFR 211.25(a). 
  14  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
517  a.  Burkholderia cepacia Complex and Aqueous Drug Products 
518   
519  Non-sterile aqueous drug products have the potential to be contaminated with BCC organisms 
520  because of the potential for these microorganisms to be present in pharmaceutical water systems. 
521  (Refs. 2, 18, 19, 21). Burkholderia cepacia is now considered part of a complex of at least 17 
522  genomovars, or closely related species (Refs. 2, 8, 14).
 
523   
524  These organisms are opportunistic human pathogens that can cause severe life-threatening 
525  infections (Refs. 2, 14, 24). It is important that non-sterile aqueous drug products not contain 
526  BCC organisms because of their unique characteristics and the safety risk they pose. BCC strains 
527  have a well-documented ability to utilize a wide variety of substrates as energy sources, many of 
528  which are traditional preservative systems (Refs. 1-4, 12, 13). Thus, despite the presence of an 
529  otherwise adequate preservative system in a non-sterile drug product, BCC strains can survive 
530  and proliferate in a non-sterile product over its shelf life. While microbial enumeration testing 
531  for finished product release may demonstrate an acceptable level for the total aerobic microbial 
532  count, BCC can proliferate to unsafe levels by the time the product reaches the patient. In May 
533  2016, the FDA was notified by the Centers for Disease Control and Prevention (CDC) of severe 
534  illnesses and deaths associated with BCC in patients in 13 hospitals across 9 states. This 
535  prompted the recall of a non-sterile OTC liquid stool softener due to BCC contamination (Ref. 
536  17). In a series of cases from 2000 to 2002, involving a medical device (an ultrasound gel), 
537  intrinsic contamination by BCC led to serious blood infections after the gel was used in 
538  association with transrectal prostate biopsies (Ref. 6).  
539   
540  Pharmaceutical water and naturally-derived components used in the manufacturing process are 
541  the most likely sources of BCC in drug products. Therefore, a robust implementation of the 
542  CGMPs is essential to ensure product quality and patient safety, including: 
543   
544    establishing a risk management program for the design and control of operations to 
545  prevent BCC contamination70 
546    using robust water systems71 
547    ensuring components meet appropriate specifications for bioburden72 
548    appropriately sanitizing and cleaning equipment,73 and  
549    validated sampling procedures74 to routinely perform in-process monitoring and finished 
550  product testing for the presence of BCC  
551   
552  Unless a manufacturer performs validated manufacturing steps (e.g., microbial retentive filtration 
553  of the bulk product formulation with a sterilizing filter right before filling) that render a drug 
554  product free from BCC, release testing is essential as the last in a series of controls that helps 
555  demonstrate that the non-sterile aqueous drug product is free from BCC (Ref. 7). 
556   
 
70 See 21 CFR 211.100(a), 21 CFR 211.113(a). 
71 See 21 CFR 211.42(a). 
72 See 21 CFR 211.80(a), 211.84(d)(6). 
73 See 21 CFR 211.67(a). 
74 See 21 CFR 211.110(a), 21 CFR 211.165(a). 
  15  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
557  The USP provides a compendial test for BCC that became official on December 1, 2019, entitled 
558  60  MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTSTESTS FOR 
559  BURKHOLDERIA CEPACIA COMPLEX. FDA recommends that manufacturers use the USP 
560  m ethod described in this USP chapter to test drug products for the presence of BCC. If a 
561  manufacturer chooses to develop an alternative in-house method, the alternative method or 
562  procedure must be fully validated and must produce comparable results to the compendial 
563  method.75 Additionally, any applicant choosing to develop an alternative method should be 
564  aware that test methods can be complicated by the fact that BCC are highly adaptable and 
565  variable in their ability to survive and grow in a variety of environments (Refs. 1, 8). There can 
566  be difficulties detecting and correctly identifying and classifying BCC (Refs. 1, 15) and, 
567  consideration of the diverse phenotypes exhibited by BCC members is essential for recovery 
568  method development (Ref. 3).  
569   
570  b.  Preoperative Skin Preparation Drug Products (Topical 
571  Antiseptics) 
572   
573  Patient preoperative skin preparations are topical antiseptic drug products used to reduce the 
574  number of microorganisms on the skin prior to medical procedures or injections, as the skin is 
575  typically covered with microorganisms (Ref. 16). Some of these products are not manufactured 
576  as sterile products (Ref. 16). However, there have been a number of published reports of 
577  infection outbreaks associated with antiseptic products due to microbial contamination (Refs. 9, 
578  10, 11, 21). Notably, contaminated antiseptic products made up a majority of non-sterile product 
579  recalls that occurred between 2009 and 2013. There were eight recalls due to microbial 
580  contamination of alcohol or povidone-iodine prep pads.  
581   
582  The product indication alone (application to a body surface that is about to be surgically 
583  compromised), as well as recent infection outbreaks and product recalls, suggest that the sterility 
584  of the product may be an important risk mitigation or have an important impact on clinical 
585  outcomes. In 2011, the FDA published a news release reminding health care professionals to 
586  check the labeling on alcohol prep pads to determine if they are sterile or non-sterile due to 
587  recent contamination events.76 FDA recommended that only sterile pads be used for procedures 
588  requiring strict sterility measures (Ref. 19). FDA encourages manufacturers of patient pre-
589  operative antiseptic products to explore manufacturing processes for these products that render 
590  them sterile, whether the product is under development or currently marketed. FDA welcomes 
591  questions regarding development of sterilization processes for these products, and is committed 
592  to working with applicants and other stakeholders on options for sterilization of pre-operative 
593  antiseptic products.77  
594   
 
75 See 21 CFR 211.194(a)(2), 21 CFR 211.194(a)(6), USP <1223>.  
76 FDA Press Announcement FDA reminds health care professionals about safe use of non-sterile alcohol prep 
pads, February 1, 2011, https://wayback.archive-
it.org/7993/20170113073826/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm241750.htm. 
See also FDA Drug Safety Communication: FDA requests label changes and single-use packaging for some over-
the-counter topical antiseptic products to decrease risk of infection, November 13, 2013, 
https://www.fda.gov/Drugs/DrugSafety/ucm374711.htm.  
77 Requests not associated with a specific application can be sent to CDER-OPQ-Inquiries@fda.hhs.gov. 
  16  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
595  c.  Transdermal Products 
596   
597  Traditional transdermal and topical delivery systems (collectively TDS) pose limited microbial 
598  risk when used on intact skin.78 However, as the technology for these products continues to 
599  evolve, the potential risk to patients should be re-assessed to determine the need for additional 
600  manufacturing controls. 
601   
602  TDS designed with a physical mechanism to abrade or penetrate the skin increase the potential 
603  for infections, especially given that skin thickness varies across individuals, body sites, and by 
604  patient age. During development manufacturers of such TDS should consider the risks and 
605  determine whether the TDS should be manufactured as sterile or with a bioburden level below 
606  that normally seen with TDS designs that rely on chemical permeation enhancers.79 The FDA 
607  encourages these manufacturers to contact the Agency in the early phase of planning and product 
608  development.80  
609   
610  D. Updating Approved Drug Product Specifications 
611   
612  FDA does not expect application holders of approved drug products to amend the product 
613  specification in cases where it is inconsistent with the recommendations discussed in this 
614  guidance. If a new supplemental application proposing a manufacturing change that may impact 
615  the risk of increased microbiological growth (e.g., new manufacturing process, relaxation of 
616  critical process parameters) is submitted, FDA assessors may request that application holders 
617  update the microbiological testing information in the product specification during assessment 
618  and before approval. Application holders may wish to consider updating a given drug product 
619  specification as recommended in this guidance. This could help to expedite approval of future 
620  supplements for other manufacturing changes.81 Table 1 provides guidance regarding the filing 
621  category for submission of supplements that propose changes to the microbiological testing 
622  program of non-sterile drug products.  
623   
624     
 
78 Technical considerations (beyond microbiological aspects) for traditional transdermal systems are addressed in 
FDAs draft guidance for industry Transdermal and Topical Delivery Systems - Product Development and Quality 
Considerations (November 2019). When final, this guidance will represent the FDAs current thinking on this topic. 
79 See FDAs guidance for industry Chronic Cutaneous Ulcer and Burn Wounds  Developing Products for 
Treatment (June 2006). 
80 When the submission is for an NDA, contact the specific drug products review division with questions. When the 
product under development is an ANDA, the Office of Pharmaceutical Quality (OPQ) and Office of Generic Drugs 
(OGD) may be contacted through general correspondence, controlled correspondence, or request for a Pre-ANDA 
Meeting, as applicable. 
81 FDA also recommends that non-application drug products consider updating drug product specifications as 
maintained by the pharmaceutical quality system as recommended in this guidance. 
  17  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
625  Table 1. Regulatory Filing Strategy for Proposed Changes to the Microbiological Testing of 
626  Non-Sterile Drugs 
627   
Proposed Testing Change  Regulatory  Related Guidance 
Filing 
Currently not performing  Annual Report  Guidance for industry on CMC 
microbial enumeration testing.   Postapproval Manufacturing Changes To 
Proposing to add testing  Be Documented in Annual Reports 
according to USP General 
Chapters <61> and <62> with 
criteria consistent with USP 
General Chapter <1111>. 
Currently performing microbial  Annual Report  Guidance for industry on CMC 
enumeration testing with less  Postapproval Manufacturing Changes To 
stringent acceptance criteria than  Be Documented in Annual Reports 
that suggested in USP General 
Chapter <1111>. Proposing to 
tighten acceptance criteria to USP 
recommended levels. 
Currently performing microbial  Prior Approval  Guidance for industry on Changes to an 
enumeration testing. Proposing to  Supplement  Approved NDA or ANDA 
delete microbial enumeration  (PAS) 
testing based on submission of a 
risk assessment. This type of 
proposal would only be 
appropriate for testing and 
evaluation of certain solid dosage 
forms with a low water activity. 
Currently testing according to  Changes Being  Guidance for industry on Changes to an 
USP General Chapters <61> and  Effected (CBE- Approved NDA or ANDA 
<62> with criteria consistent with  0) 
USP General Chapter <1111>. 
Proposing to add BCC test, but 
currently not performing testing 
for BCC. 
628   
629     
  18  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
630  References (as related to case studies in lines 509-579) 
631   
632  1.  Halls N, 2006, Burkholderia (Pseudomonas) cepacia-A brief profile for the pharmaceutical 
633  microbiologist, Eur J Parenteral and Pharm Sci, 11(2):53-57. 
634  2.  Vial L, A Chapalain, MC Groleau, and E Desiel, 2011, The various lifestyles of the 
635  Burkholderia cepacia complex species: a tribute to adaptation, Environ Microbiol, 13(1):1-
636  12. 
637  3.  Zani F, A Minutello, L Maggi, P Santi, and P Mazza, 1997, Evaluation of preservative 
638  effectiveness in pharmaceutical products: the use of a wild strain of Pseudomonas cepacia, J 
639  Appl Microbiol, 83(3):322-326. 
640  4.  Amin A, S Chauhan, M Dare, and AK Bansal, 2010, Degradation of parabens by 
641  Pseudomonas beteli and Burkholderia latens, Eur J of Pharm and Biopharm, 75:206-212.  
642  5.  Hutchinson J, W Runge, M Mulvey, G Norris, M Yettman, N Valkova, R Villemur, and F. 
643  Lapine, 2004, Burkholderia cepacia infections associated with intrinsically contaminated 
644  ultrasound Gel: The role of microbial degradation of parabens, Infect Cont Hosp Epid, 
645  25:291-296. 
646  6.  Torbeck L, D Raccasi, DE Guilfoyle, RL Friedman, D Hussong, 2011, Burkholderia cepacia: 
647  This Decision is Overdue, PDA J Pharm Sci Tech, 65(5):535-43. 
648  7.  Ahn Y, JM Kim, H Ahn, Y-J Lee, JJ LiPuma, D Hussong, and CE Cerniglia, 2014, 
649  Evaluation of liquid and solid culture media for the recovery and enrichment of Burkholderia 
650  cenocepacia from distilled water, J Indus Micro and Bio, 41(7):1109-1118. 
651  8.  Chang CY and LA Furlong, 2012, Microbial Stowaways in Topical Antiseptic Products, N 
652  Engl J Med, 367(23):2170-2173. 
653  9.  Notes from the Field: Contamination of Alcohol Prep Pads with Bacillus cereus Group and 
654  Bacillus speciesColorado, 2010, MMWR Morb Mortal Wkly Rep 2011 60(11):347. 
655  10. Sutton S and L Jimenez, 2012, A Review of Reported Recalls Involving Microbiological 
656  Control 2004-2011 with Emphasis on FDA Considerations of Objectionable Organisms, Am 
657  Pharm Rev, Jan/Feb:42-56. 
658  11. Burdon DW and JL Whitby,1967, Contamination of hospital disinfectants with Pseudomonas 
659  species, Brit Med J, 2:153-155. 
660  12. Geftic SG, H Heymann, and FW Adair, 1979, Fourteen-Year Survival of Pseudomonas 
661  cepacia in a Salts Solution Preserved with Benzalkonium Chloride, App and Env Micro, 
662  37(3):505-510. 
663  13. Mahenthiralingam, E, TA Urban, and JB Goldberg, 2005, The multifarious, multireplicon 
664  Burkholderia cepacia complex, Nature Reviews Microbiology, 3(2):144156. 
665  14. Lowe P, C Engler, and R Norton, 2002, Comparison of Automated and Nonautomated 
666  Systems for Identification of Burkholderia pseudomallei, J Clin Micro, 40(12):4625-4627. 
667  15. Federal Register/Vol 77, No 225/Wednesday, November 21, 2012/Notices FDA-2012-N-
668  1040, https://www.govinfo.gov/content/pkg/FR-2012-11-21/pdf/2012-28357.pdf. Antiseptic 
669  Patient Preoperative Skin Preparation Products; Public Hearing. 
670  16. FDA Updates on Multistate Outbreak of Burkholderia cepacia Infections, October 12, 2016, 
671  http://www.fda.gov/Drugs/DrugSafety/ucm511527.htm. 
672  17. Carson LA, MS Favero, WW Bond, and NJ Petersen, 1973, Morphological, Biochemical, 
673  and Growth Characteristics of Pseudomonas cepacia from Distilled Water, App Micro, 
674  25(3):476-483. 
  19  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
675  18. Jimenez L, 2007, Microbial Diversity in Pharmaceutical Products Recalls and Environments, 
676  Parenteral Drug Association J of Pharm Sci and Tech, 61(5):383-399. 
677  19. FDA News Release, FDA Reminds Healthcare Professionals about Safe Use of Non-Sterile 
678  Alcohol Prep Pads, February 1, 2011.  
679  20. Halls N, Burkholderia (Pseudomonas) cepacia  A brief profile for the pharmaceutical 
680  microbiologist, EJ Parenteral & Pharmaceutical Sci, 11(2):53-57. 
681  21. Webber D, W Tutella, E Sickbert-Bennet, Outbreaks associated with contaminated 
682  antiseptics and disinfectants, Antimicrobial Agents and Chemotherapy, Dec 2007. 
683  22. Micronase Tablets Recalled Fungal Organisms Found In Anti-Diabetic Medication (traced to 
684  a raw material used in the formulation. Micronase is an oral antidiabetic medication used to 
685  treat type 2 diabetes). https://www.fda.gov/inspections-compliance-enforcement-and-
686  criminal-investigations/warning-letters/ctx-lifesciences-private-ltd-577416-07122019. 
687  23. Nationwide recall for 2 lots Relpax 40 Mg Tablets Due to Potential Microbiological 
688  Contamination of Non-Sterile Products   https://www.fda.gov/safety/recalls-market-
689  withdrawals-safety-alerts/pfizer-inc-issues-voluntary-nationwide-recall-2-lots-relpaxr-
690  eletriptan-hydrobromide-40-mg-tablets. 
691  24. Glowicz J, M Crist, C Gould, H Moulton-Meissner, J Noble-Wang, T de Man, A Perry, Z 
692  Miller, W Yang, S Langille, J Ross, B Garcia, J Kim, E Epson, S Black, M Pacilli, J LiPuma, 
693  R Fagan, 2018, A multistate investigation of healthcare-associated Burkholderia cepacia 
694  complex infections related to liquid docusate sodium contamination, January - October 2016, 
695  Am J Infect Control. 2018 Jun; 46(6): 649655. https://pubmed.ncbi.nlm.nih.gov/29329922/ 
696   
697     
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698  APPENDIX:  Case Study Examples of Microbiological Contamination of NSD Products; 
699  Impact on Product Quality and Manufacturing Process 
700   
701  The following seven case studies summarize incidents of NSDs contaminated with 
702  microorganisms leading to infections, and ultimately product recalls. In each of the cases below, 
703  the manufacturer of the product initiated voluntary recall actions to mitigate the impact of the 
704  contaminated product on patients and end-users, and instituted new processes and corrective 
705  measures to prevent future microbial contamination of their product. Of particular significance 
706  are the root cause analyses and corrective/preventative strategies that manufacturers took to 
707  address microbiological contamination. These examples suggest that risk assessments should be 
708  an integral part of strategies to prevent the microbiological contamination of NSDs. 
709   
710  Case 1:  Contamination of an oral solution with Burkholderia cepacia complex (BCC) 
711   
712  In 2016, an OTC product (oral liquid docusate sodium) indicated for constipation was contract 
713  manufactured for a customer who marketed the products under its own label. FDA investigated a 
714  multistate outbreak of serious BCC infections in 108 patients, including multiple associated 
715  patient deaths. Testing by FDA and CDC revealed that more than 10 lots of oral liquid product 
716  were contaminated with BCC. The BCC clinical isolates matched with the product isolates. The 
717  investigation also detected BCC in the water system used by the firm to manufacture the product. 
718  FDA and CDC identified the contract manufacturer as the source of the outbreak. The poorly 
719  designed water system (cold system; not continuously circulating), inadequate monitoring of the 
720  system, poor manufacturing controls, and inadequate microbiological testing methods all 
721  contributed to severe risks to the consumer. All lots of liquid products made by the contract 
722  manufacturer were ultimately recalled. 
723   
724  Case 2:  Contamination of aqueous-based throat spray and liquid antacid with Escherichia 
725  coli 
726   
727  In 2014, a manufacturer of an aqueous-based, non-sterile spray to relieve throat dryness and to 
728  restore throat comfort was determined to be contaminated with Escherichia coli (E.coli). The 
729  contamination was discovered when a microbial assay of the product returned results that 
730  indicated the bacterial count to be too numerous to count (TNTC). Although the root cause was 
731  not fully determined by the firm, several manufacturing practices were corrected as a result of 
732  the event, including new processes and procedures for cleaning and storage of equipment, and 
733  physical separation between used equipment and equipment that had been sanitized. Over 20,000 
734  units of this product were distributed nationally. 
735   
736  A separate case of E.coli contamination of an antacid liquid occurred in 2013, in which over 
737  10,000 units of the contaminated product were distributed nationally prior to completion of 
738  quality assurance testing. When the microbial assay for the product returned with E.coli counts 
739  greater than 3000 CFU/g, the product was immediately recalled by the manufacturer. After the 
740  manufacturers investigation, the quality assurance procedures were updated and employee 
741  training was conducted. However, the root cause of the contamination was not determined. In 
742  this instance, there were no reported injuries or illnesses that were attributed to the contaminated 
743  product. 
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744   
745  A review of FDAs recall database between 2012 and 2017 demonstrates that at least four other 
746  separate events have occurred with non-sterile aqueous based products resulting in E. coli 
747  contamination. 
748   
749  Case 3:  Contamination of moisturizing cream with Pseudomonas and Staphylococcus 
750   
751  In 2017, a manufacturer of a baby eczema moisturizing cream reported that their product was 
752  contaminated with Pseudomonas aeruginosa and Staphylococcus aureus. Over 15,000 units of 
753  the product were distributed nationally. The microbial assay determined that the bacterial load in 
754  the products was 87,500 CFU/g, despite presence of a preservative in the formulation. The root 
755  cause for the microbiological contamination appeared to be a raw material of natural origin that 
756  became contaminated due to improper storage at the firm, and apparently resulted in 
757  microbiological growth in finished product. 
758   
759  Similarly, in 2015, a distributor of a liquid antacid determined that over 100,000 units of their 
760  nationally distributed product was objectionably contaminated. Product contamination included 
761  Pseudomonas aeruginosa, as well as high yeast and mold counts. The recall scope was based on 
762  assessment of retention samples spanning 12 months. The root cause of the contamination 
763  appeared to be related to issues in the contract manufacturing process, but the ultimate root cause 
764  was not identified. 
765   
766  Case 4:  Excessive contamination of a non-aqueous-based cream indicated for infants 
767   
768  In 2018, a zinc oxide diaper rash cream, indicated for infants, was imported by a US distributor 
769  who intended to market it as an OTC product. When tested, it was found to be objectionably 
770  contaminated. Although the product was not aqueous-based, and had a low intrinsic water 
771  activity, it contained excessive numbers of bacteria and fungi. Samples included units with 
772  several very high aerobic microbial counts including values such as 3.5 million CFU Total 
773  Aerobic Microbial Count (TAMC)/mL and 27,000 CFU TAMC/mL. Many of the bacteria were 
774  spore formers of the Bacillus, spp. Yeast and mold count levels were also very high, including 
775  2700 Total Combined Yeast and Mold Count (TYMC)/mL, 39000 TYMC/mL, and 200 
776  TYMC/mL. The manufacturer recalled all lots of the product and ceased shipping to the US. 
777   
778  Case 5:  Topical cream contaminated with Enterobacter, sp. 
779   
780  In 2018 a manufacturer of a topical cream-based drug became aware that several lots of their 
781  product were contaminated with Enterobacter, sp. The product was inadvertently shipped prior 
782  to the completion of the microbial assay, which resulted in a microbial count that was TNTC. In 
783  addition to the assay, there was an unusually strong odor not typically associated with the 
784  product. After the recall was initiated, the manufacturer received customer complaints regarding 
785  a strong odor from the product. The potential root cause for the microbiological contamination 
786  was suspected to be improper changeover cleaning of the filling equipment. Several corrective 
787  actions were taken to prevent future microbial contamination of product, including revision of 
788  preventative maintenance and release testing procedures and employee re-training. 
789   
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790   
791  Case 6:  Alcohol antiseptics contaminated with Bacillus cereus 
792   
793  In 2011, an alcohol-based antiseptic product was produced under poor manufacturing conditions 
794  and the product was found to be contaminated with Bacillus, spp., including Bacillus cereus. 
795  Adverse events were reported to be associated with the contaminated antiseptics. Inspection of 
796  the firm found lack of appropriate controls to prevent contamination during formulation, filling, 
797  and storage of the drug products. Equipment was also observed to be insufficiently cleaned. 
798  These deficient conditions likely contributed to the contamination events. The manufacturer 
799  issued a voluntary nationwide recall of all lots of alcohol prep pads, alcohol swabs, and alcohol 
800  swab sticks, due to confirmed and potential microbial contamination. 
801   
802  Case 7:  Contamination of an API with Aspergillus, sp. and Enterobacter, sp. 
803   
804  In 2016, a manufacturer of an API that is further utilized by other manufacturers to derive oral 
805  and injectable finished pharmaceuticals became aware of customer complaints that their API 
806  contained TNTC/g levels of fungal contamination by various Aspergillus species. The root cause 
807  for this microbiological contamination appeared to be related to parts of the drying equipment 
808  used to dry the API. As corrective action, the API manufacturer replaced defective drying 
809  equipment ductwork to prevent trapped moisture from collecting within it, and revised existing 
810  preventive maintenance/monitoring procedures to enable a more robust control against 
811  microbiological contamination. The API manufacturer initiated a voluntary recall that impacted 
812  several API lots over the course of one year, and several manufacturers of finished drug 
813  products. There were no reported injuries or illnesses associated with the contaminated product. 
814   
815  In 2014, another manufacturer of a bulk cream base used to compound topical drugs recalled 
816  several lots of its bulk cream due to high counts of mold and bacteria, and specifically high 
817  counts of Aspergillus, sp. and Penicillium, sp. (among other microorganisms). The root cause of 
818  the microbial growth was insufficient manufacturing instructions that resulted in personnel 
819  adding lower amounts of preservatives than needed to ensure uniform distribution throughout 
820  each of the affected batches. When the final products were manufactured, enclosing the cream in 
821  its final container/closure resulted in the development of moisture as the product cooled. The 
822  moisture enabled mold to grow. Microbial assays of impacted lots all demonstrated mold growth, 
823  and corresponding microbial identity testing demonstrated lower preservative amounts in 
824  impacted batches. To mitigate future errors, the bulk cream manufacturer modified their 
825  manufacturing procedures and processes to ensure uniform distribution of the preservatives in 
826  each bulk cream batch.  
827   
828  Case 8: Fungal contamination traced to excipient 
829   
830  In 2001, a manufacturer recalled 45 lots of Glyburide tablets for fungal contamination. The 
831  source of the contamination was traced to a filler/binder excipient used in the formulation. A 
832  subsequent FDA Warning Letter cited the firm for not conducting an adequate investigation to 
833  determine the sources of the fungal contaminants and identify other Glyburide tablet lots 
834  manufactured which used the same excipient lots as well as the failure to appropriately sample 
835  and test the excipient. Additional investigation found that the air used in the drying process of 
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836  the excipient was contaminated with seasonal fungal spores during the chemical synthesis of 
837  excipient at the excipient manufacturing facility. 
838   
839  Case 9: Contamination of eletriptan hydrobromide with Pseudomonas, sp. and 
840  Burkholderia, sp.  
841   
842  In 2019, a firm recalled two lots of eletriptan hydrobromide because these product lots failed 
843  microbiological specifications for the potential presence of Pseudomonas, sp. and Burkholderia, 
844  sp. For the general population these risks are low, and may include temporary gastrointestinal 
845  distress without serious infection.  However, for certain vulnerable patient populations (such as 
846  patients with compromised immune systems, cystic fibrosis and chronic granulomatous disease) 
847  this objectionable contamination may pose the potential for serious adverse events including life-
848  threatening infections.  
849   
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