Quality Considerations for 
Topical Ophthalmic Drug 
Products  
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Ranjani Prabhakara 240-402-4652. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
December 2023 
Pharmaceutical Quality/CMC 
 
 
Revision 1
 
   
Quality Considerations for 
Topical Ophthalmic Drug 
Products  
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) 
 
December 2023 
Pharmaceutical Quality/CMC 
 
Revision 1 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  MICROBIOLOGICAL CONSIDERATIONS ............................................................... 2 
A.  Product Sterility ............................................................................................................................. 2 
B.  Multidose Drug Products .............................................................................................................. 3 
III.  VISIBLE PARTICULATE MATTER ............................................................................ 4 
IV.   EXTRACTABLES AND LEACHABLES ...................................................................... 5 
A.  Extractables Studies....................................................................................................................... 5 
B.  Leachables Studies ......................................................................................................................... 6 
C.   Safety Thresholds ........................................................................................................................... 6 
V.   IMPURITIES AND DEGRADATION PRODUCTS .................................................... 7 
A.   NDA, ANDA, and OTC Monograph Drugs ................................................................................. 7 
B.   BLAs ................................................................................................................................................ 8 
VI.  IN VITRO DRUG RELEASE/DISSOLUTION TESTING FOR QUALITY 
CONTROL .................................................................................................................................... 9 
VII.  CCS DESIGN AND DELIVERY AND DISPENSING CHARACTERISTICS ......... 9 
A.  CCS Design ..................................................................................................................................... 9 
1. Tamper-Evident Packaging ............................................................................................................. 9 
2. Tips................................................................................................................................................. 10 
3.  Torque Specifications..................................................................................................................... 10 
4. Color Coding ................................................................................................................................. 10 
B.   Delivery and Dispensing Characteristics ................................................................................... 10 
1.  Unit Dose Containers .................................................................................................................... 10 
2.  Multidose Containers ..................................................................................................................... 10 
VIII.   STABILITY ..................................................................................................................... 11 
A.  Container Orientation During Storage ...................................................................................... 11 
B.  Water Loss .................................................................................................................................... 12 
C.  Freeze/Thaw Study for Emulsions and Suspensions ................................................................ 12 
D.   In-Use Stability Studies ............................................................................................................... 13 
IX.  GLOSSARY..................................................................................................................... 13 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Quality Considerations for Topical Ophthalmic Drug Products 
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
7  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.  
10   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance discusses certain quality considerations for ophthalmic drug products2 (i.e., gels, 
17  ointments, creams, and liquid formulations such as solutions, suspensions, and emulsions) 
18  intended for topical delivery in and around the eye. Specifically, the guidance discusses: 
19   
20    Microbiological considerations. 
21   
22    Approaches to evaluating visible particulate matter, extractables and leachables, and 
23  impurities and degradation products. 
24   
25    Use of in vitro drug release/dissolution testing as an optional quality control strategy for 
26  certain ophthalmic dosage forms. 
27    
28    Recommendations for design, delivery, and dispensing features of container closure 
29  systems (CCSs).3 
30   
31    Recommendations for stability studies. 
32   
 
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 The term drug product, as used in this guidance, refers to drugs approved pursuant to new drug applications 
(NDAs) and abbreviated new drug applications (ANDAs) under section 505 of the Federal Food, Drug, and 
Cosmetic Act (FD&C Act; 21 U.S.C. 355); biological products licensed under section 351(a) or (k) of the Public 
Health Service Act (PHS Act; 42 U.S.C. 262(a) or (k)) that are regulated as drugs; and other drugs that, while also 
subject to CGMP requirements, are not marketed pursuant to an approval or licensure, including products marketed 
pursuant to section 505G of the FD&C Act (often referred to as over-the-counter (OTC) monograph drugs) and 
drugs compounded by outsourcing facilities pursuant to section 503B of the FD&C Act. The term also encompasses 
such drugs or biological products when they are included as a constituent part of a combination product, as defined 
in FDA regulations at 21 CFR 3.2(e). 
3 Some ophthalmic products that are the subject of this guidance may be combination products (see 21 CFR 3.2). 
See section VII for more information. Contact the Office of Combination Products at Combination@fda.hhs.gov 
with questions regarding the classification of a specific product. 
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33  This guidance provides information regarding quality considerations for ophthalmic drug 
34  products consistent with the current good manufacturing practice (CGMP) requirements outlined 
35  in section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 
36  parts 210 and 211 for all drug products, part 601 for biological products, and part 4 for 
37  combination products.4 For ophthalmic drug products with a United States Pharmacopeia (USP) 
38  monograph, this guidance provides information about applicable criteria from the USP.5 This 
39  guidance also provides recommendations to industry on the documentation that should be 
40  submitted in the chemistry, manufacturing, and controls (CMC) section of new drug applications 
41  (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications 
42  (BLAs), including BLAs for biosimilar and interchangeable biosimilar products.6 The CMC 
43  section of NDAs, ANDAs, and BLAs must be included as required by 21 CFR 314.50, 21 CFR 
44  314.94, and 21 CFR part 601, respectively. Relevant records and other information that 
45  demonstrate compliance with CGMP requirements must be made available for FDA review 
46  during an inspection conducted under section 704(a)(1) of the FD&C Act or when requested by 
47  FDA in advance or in lieu of an inspection as described in section 704(a)(4) of the FD&C Act.7 
48  This guidance does not apply to biological products regulated by the Center for Biologics 
49  Evaluation and Research. 
50   
51  This guidance revises the draft guidance of the same name issued in October 2023. This revision 
52  adds microbiological considerations related to product sterility for all ophthalmic drug products 
53  and the prevention of contamination of ophthalmic drug products packaged in multidose 
54  containers. 
55   
56  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
57  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
58  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
59  the word should in Agency guidances means that something is suggested or recommended, but 
60  not required. 
61   
62   
63  II.  MICROBIOLOGICAL CONSIDERATIONS 
64   
65  A.  Product Sterility 
66   
67  Product sterility is a critical quality attribute (CQA) for ophthalmic drug products.8 Recent cases 
68  of microbially contaminated ophthalmic drug products leading to serious injury and death, as 
 
4 In addition, applicants, manufacturers, and outsourcing facilities should ensure that drug products subject to this 
guidance comply with other applicable provisions of the FD&C Act, including sections 501(a)(2)(A), 501(a)(1), 
501(c), 502(a), and 502(j). 
5 See section 501(b) of the FD&C Act. 
6 For topical ophthalmic biological products, including biosimilars and interchangeable products, we recommend 
that applicants consult with FDA before submitting their application. 
7 See also 21 CFR 211.180(c). 
8 See 21 CFR 200.50(a)(1). 
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69  well as recent recalls, highlight the importance of product sterility.9 Manufacturers10 of sterile 
70  drug products must comply with CGMP requirements to ensure product sterility.11 Failure to 
71  comply with these requirements will cause affected products to be deemed adulterated under 
72  section 501(a)(2)(B) of the FD&C Act.  
73   
74  For recommendations on how to meet CGMP requirements for product sterility, see guidances 
75  for industry Sterile Drug Products Produced by Aseptic ProcessingCurrent Good 
76  Manufacturing Practice (September 2004) and Submission Documentation for Sterilization 
77  Process Validation in Applications for Human and Veterinary Drug Products (November 
78  1994).12 
79   
80  B.  Multidose Drug Products 
81   
82  Ophthalmic drug products should be appropriately designed and controlled to prevent harmful 
83  microbial contamination throughout their shelf life and in-use period, which must be supported 
84  by stability data.13 Unit-dose CCSs prevent the hazards associated with in-use contamination and 
85  growth of microorganisms between doses that can occur with multidose CCSs that are opened 
86  multiple times over the course of their shelf life. Liquid ophthalmic drug products packaged in 
87  multidose containers should contain one or more suitable substances that will preserve the 
88  product and minimize the hazard of injury resulting from incidental contamination during use.14 
89  If a multidose drug product does not possess inherent antimicrobial activity adequate to preserve 
90  the formulation, it should be formulated with an appropriate preservative.15 Preservatives are 
91  critical to ensuring that the multidose drug product remains free from harmful contamination 
92  following potential microbial ingress. Such ingress could occur, for example, if surrounding air 
93  is introduced into the multidose drug product following administration, if the tip of a dropper is 
94  contaminated by a nonsterile surface (i.e., the fluid path is contaminated), or if a contaminated 
95  drop returns to the product reservoir. Regardless of whether a multidose drug product possesses 
96  inherent antimicrobial activity or contains one or more added preservatives, manufacturers 
 
9 See FDAs alerts and warnings about eye drops at https://www.fda.gov/drugs/buying-using-medicine-safely/what-
you-should-know-about-eye-drops. 
10 For the purposes of this guidance, we use the term manufacturer to refer to entities that produce the drug products 
defined in footnote 2. Where applicable, this guidance uses the term applicant to refer to manufacturers and other 
parties who are NDA, ANDA, and BLA applicants or application holders. 
11 See, e.g., 21 CFR 211.22(a), 211.94(b), 211.113(b), 211.160, 211.165, 211.166, and 211.167. 
12 Although the latter guidance on sterilization process validation is intended for the submission of documentation 
for application products, its principles are also instructive for OTC monograph drugs. We update 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.  
13 See 21 CFR 211.137 and 211.166. 
14 See 21 CFR 200.50(b)(1). If such substance(s) are not included in the drug product, other packaging and labeling 
recommendations apply. See 21 CFR 200.50(b)(2). 
15 For further discussion about the use of preservatives, see draft guidance for industry Microbiological Quality 
Considerations in Non-Sterile Drug Manufacturing (September 2021) at page 6. When final, this guidance will 
represent the FDAs current thinking on this topic. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
97  should implement a well-designed and rigorous antimicrobial effectiveness testing program that 
98  covers the products shelf life.16 
99   
100  FDA does not recommend using silver sulfate or other silver-containing compounds as a 
101  preservative in ophthalmic drug products because of the significant safety concerns associated 
102  with applying silver directly to the eye, including argyria (an irreversible discoloration of the 
103  skin and eyes) and granular deposits of silver in the conjunctiva and cornea.17 
104   
105  Some manufacturers have sought to use a preservative-free formulation for a multidose liquid 
106  drug product in conjunction with a CCS design intended to eliminate the potential for in-use 
107  microbial contamination.18 These formulations and associated presentations should afford robust 
108  protection for each unit produced to prevent the hazard of injury resulting from exposure to 
109  incidental contamination during multiple uses of the product.19 There are numerous ways in 
110  which such presentations might fail to prevent microbial contamination. Any ophthalmic drug 
111  product that lacks adequate preservative properties, when exposed to in-use contamination, is 
112  especially vulnerable to proliferation of microbes that can pose severe harm to consumers. CCSs 
113  must provide adequate protection against foreseeable external factors in storage and use that can 
114  cause deterioration or contamination.20 
115   
116  For information on delivery and dispensing characteristics of multidose containers, see section 
117  VII.B.2 of this guidance.  
118   
119   
120  III.  VISIBLE PARTICULATE MATTER 
121   
122  The use of a robust visual inspection program and the implementation of CGMP requirements 
123  are important to ensure products are not adulterated. For topical ophthalmic drug products 
124  packaged in opaque containers, appropriate technologies (e.g., X-ray spectroscopy) or 
125  destructive testing should be used to identify particulates within the accepted visible size range.21  
126   
127  Ophthalmic drug products with names recognized in the USP are generally required to also meet 
128  the particulate matter requirements in USP General Chapter <771> Ophthalmic Products
 
16 See USP General Chapter <51> Antimicrobial Effectiveness Testing. 
17 FDA also does not recommend using silver in CCSs for ophthalmic drug products because silver may continually 
leach into the drug product. 
18 Liquid ophthalmic preparations packed in multidose containers that do not contain one or more suitable and 
harmless substances that will inhibit the growth of microorganisms should be packaged and labeled with necessary 
warnings to minimize injury from contamination during use. See 21 CFR 200.50(b). 
19 Ibid. Furthermore, appropriate written procedures designed to prevent microbial contamination of sterile products 
must be established and followed, including validation of all aseptic and sterilization processes. See 21 CFR 
211.113(b). 
20 See 21 CFR 211.94(b). 
21 For topical ophthalmic drug products that include inherent visible particulates by design, such as suspensions and 
emulsions, stability testing can be used to evaluate any changes in the particle size over the shelf life of the product. 
See USP General Chapter <771> Ophthalmic ProductsQuality Tests. 
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129  Quality Tests.22 Noncompendial ophthalmic drug products should also follow the above USP 
130  General Chapter. Adherence to compendial standards can assist applicants and manufacturers in 
131  complying with CGMP regulations (e.g., 21 CFR 211.165(e), 211.167(b), and 211.194(a)(2)).  
132   
133   
134  IV.   EXTRACTABLES AND LEACHABLES 
135   
136  Ophthalmic drug products should be evaluated for extractables and leachables from the CCS. 
137  Leachables have the potential to interact with the formulated drug product, which could 
138  compromise product quality and therapeutic effect. The assessment of extractables and 
139  leachables should consider the primary, secondary, and tertiary packaging components of the 
140  CCS, including the labeling components.  
141   
142  Semipermeable CCSs can, over time, leach low molecular weight compounds (e.g., plasticizers, 
143  lubricants, pigments, stabilizers, antioxidants, binding agents) from CCS components or from 
144  labeling components (e.g., inks, adhesives, varnishes) into the drug product. However, this is less 
145  of a concern for products packaged in glass containers (e.g., biological products).  
146   
147  General tests for CCSs are described in USP General Chapters, such as <87> Biological 
148  Reactivity Tests, In Vitro; <88> Biological Reactivity Tests, In Vivo; <660> ContainersGlass; 
149  and <661> Plastic Packaging Systems and Their Materials of Construction. For more 
150  information about testing extractables and leachables, applicants and manufacturers should 
151  consult USP General Chapters <1663> Assessment of Extractables Associated With 
152  Pharmaceutical Packaging/Delivery Systems and <1664> Assessment of Drug Product 
153  Leachables Associated With Pharmaceutical Packaging/Delivery Systems. Applicants should 
154  also refer to the guidance for industry Container Closure Systems for Packaging Human Drugs 
155  and Biologics: Chemistry, Manufacturing, and Controls Documentation (May 1999). 
156   
157  A.  Extractables Studies 
158   
159  Where extractables testing is conducted to comply with CGMP requirements, manufacturers 
160  should document the following information about their extractables studies, and applicants 
161  should provide this information in their application (see 21 CFR 211.194(a)).  
162   
163    A risk assessment in support of their study approach. 
164   
165    Data from their extractables studies, which generally should be conducted following the 
166  framework provided in USP General Chapter <1663> and should take into account the 
167  primary, secondary, and tertiary packaging components. 
168   
169    Information on the use of extraction conditions (e.g., media, temperature, time, analytical 
170  techniques). 
171   
 
22 See section 501(b) of the FD&C Act.  
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172    Information on the use of analytical procedures (e.g., gas or liquid chromatographymass 
173  spectrometry), including method validation information. 
174   
175    An assessment of the resultant extractables profiles.  
176   
177  Where a CCS has been used in an approved ophthalmic drug product, an applicant can refer to 
178  previously submitted information to address the recommendations above, when feasible and with 
179  adequate justification. 
180   
181  B.  Leachables Studies 
182   
183  Because leachables can stem from different sources and be formulation dependent, applicants 
184  and manufacturers should have adequate data to identify and characterize the potential risks 
185  associated with the leachables from the CCS and describe how these risks are mitigated, such as 
186  by conducting leachables studies. 
187   
188  Where leachables testing is conducted to comply with CGMP requirements, manufacturers 
189  should document the following information about their leachables studies, and applicants should 
190  provide this information in their application (see 21 CFR 211.194(a)). 
191   
192    Data from three primary stability batches, each of which generally should be followed 
193  through expiry as described in USP General Chapter <1664>. 
194   
195    Information on the use of analytical procedures (e.g., gas or liquid chromatographymass 
196  spectrometry), including method validation information. 
197   
198    An assessment of the resultant leachables profiles.23 
199   
200    The acceptance criteria contained in drug product specifications.24 
201   
202  In addition to the leachables studies, a separate toxicological risk assessment of the leachables 
203  should be conducted.  
204   
205  C.   Safety Thresholds 
206   
207  Because of the variety of chemical species and the enormous capability of modern analytical 
208  techniques in detecting trace amounts of chemicals, it is neither practical nor necessary to 
209  identify all detected leachables for safety qualification. However, because ophthalmic drug 
210  products are applied directly to the eye, applicants and manufacturers should assess compatibility 
211  and safety concerns of any potential leachables exceeding the qualification threshold discussed 
212  below. The safety assessment should address the ocular toxicity and irritancy potential of such 
213  leachables, in addition to systemic safety, as appropriate. 
214   
 
23 See section IV.C of this guidance. 
24 Ibid.  
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215  Applicants and manufacturers can use a safety threshold approach to assess the potential of 
216  leachables and extractables to leach into and/or interact with the formulated drug product. The 
217  following recommended leachables thresholds are expressed in parts per million (ppm) (i.e., the 
218  parts of a leachable per unit mass of the ophthalmic drug product)25: 
219   
220    Reporting threshold: 1 ppm. 
221    Identification threshold: 10 ppm. 
222    Qualification threshold: 20 ppm. 
223   
224  Manufacturers should document information about their safety thresholds, and applicants should 
225  list leachable impurities above the reporting threshold along with other impurities in the drug 
226  product specification section of NDAs and ANDAs, but not in BLAs (see 21 CFR 211.194).26 
227   
228   
229  V.   IMPURITIES AND DEGRADATION PRODUCTS 
230   
231  A.   NDA, ANDA, and OTC Monograph Drugs 
232   
233  The establishment of scientifically sound and appropriate specifications to comply with 21 CFR 
234  211.160(b) includes identifying test methods and acceptance criteria for impurities and 
235  degradation products. NDA and ANDA applicants should generally follow the principles of 
236  reporting, identifying, and qualifying degradation products and impurities outlined in the 
237  International Council for Harmonisation (ICH) guidance for industry Q3B(R2) Impurities in New 
238  Drug Products (August 2006).27 Manufacturers should generally establish thresholds and 
239  acceptance criteria for impurities and degradation products according to USP General Chapter 
240  <1086> Impurities in Drug Substances and Drug Products. Manufacturers should document the 
241  following information and applicants should include it in the drug product specification section 
242  of NDAs or ANDAs (21 CFR 211.194(a)): 
243   
244    Each specified identified degradation product or impurity as a percentage of the active 
245  pharmaceutical ingredient (API). 
246   
247    Each specified unidentified degradation product or impurity as a percentage of the API. 
248   
249    Any individual unspecified degradation product or impurity. 
250   
251    Total degradation products or impurities. 
252   
253  However, FDAs recommended thresholds for individual unspecified degradation products or 
254  impurities are different for ophthalmic drug products than the corresponding thresholds provided 
 
25 These thresholds are based on historical data from approved drug products. For topical ophthalmic drug products, 
ppm is used instead of a limit on concentration because of the risk of local toxicity to the eye.  
26 See section V.B of this guidance for an explanation of this recommendation for BLAs.  
27 Acceptance criteria for specified degradation products in generic drug products should be established according to 
the guidance for industry ANDAs: Impurities in Drug Products (November 2010). 
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255  in ICH Q3B(R2) for the same dose range (see table below for these different thresholds, which 
256  are based on historical data from FDA-approved drug products). There are two reasons for the 
257  differences in recommended thresholds compared to the ICH recommendations: First, 
258  ophthalmic drug products are directly administered to the eye, and direct, local application has 
259  the potential to produce high local concentrations in the eye. In contrast, the recommendations in 
260  ICH Q3B(R2) are generally used to support safety determinations for drug products that act 
261  systemically. Second, these differences also account for the fact that less is known about the 
262  potential effects of individual unspecified degradation products or impurities than specified 
263  degradation products or impurities. 
264   
265  FDAs Recommended Thresholds for Unspecified Degradation Products or Impurities 
266  in Ophthalmic Drug Products*  
Drug Product Strength (% w/v)  Recommended Identification and 
Qualification Threshold 
Greater than 0.1% to less than or equal to 1%**  0.1%  
(> 0.1% to  1%) 
Less than or equal to 0.1%  1% or 1 ppm*** 
( 0.1%) 
267  *These recommended thresholds apply to OTC monograph ophthalmic drug products and ophthalmic drug 
268  products submitted under NDAs and ANDAs. 
269  ** Limits above 1% will be evaluated on a case-by-case basis. 
270  *** Whichever is higher; ppm=parts per million (i.e., parts of a leachable per unit mass of the ophthalmic 
271  drug product). 
272   
273  For individual unspecified degradation product or impurity limits that exceed the recommended 
274  thresholds in the table above, manufacturers should document identification and safety 
275  information for the degradation product or impurity, and applicants should provide such 
276  information in their application. Safety information should address both local ocular toxicity as 
277  well as general systemic toxicity. 
278   
279  B.   BLAs 
280   
281  For ophthalmic biological products, degradation products or product impurities can be controlled 
282  by specific acceptance criteria at release and under storage based on historical ranges in pivotal 
283  clinical trials. However, some ophthalmic biological products include product-related substances 
284  (including some that form under storage) that retain biological activity. Moreover, individual 
285  quantitation of each of these individual species may not always be technically feasible. For this 
286  reason, impurity considerations for ophthalmic biological products should include product-
287  related substances in addition to degradation products and product-related impurities. Therefore, 
288  for ophthalmic biological products, specifications should be established for attributes (e.g., 
289  charge variant profile) that are known to be reflective of the mixture of product-related 
290  substances and product-related impurities. Other impurities, such as process impurities, can be 
291  controlled by using (1) drug product release criteria based on risk assessments for each impurity 
292  or impurity class (i.e., host cell proteins), and (2) historical process clearance. Applicants should 
293  establish acceptance criteria for impurities, including leachables and process impurities, as 
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294  required to control product quality, safety, and efficacy.28 Impurity amounts should be clearly 
295  defined as a percentage of the active ingredient or in current conventional units for ophthalmic 
296  biological products (e.g., milligram/milliliter (mg/mL), microgram/milliliter (g/mL), 
297  nanogram/milligram (ng/mg)). 
298   
299   
300  VI.  IN VITRO DRUG RELEASE/DISSOLUTION TESTING FOR QUALITY 
301  CONTROL 
302   
303  The rate and extent of drug release from ophthalmic drug products are quality criteria that may 
304  reflect aspects related to formulation and process variants that are important to control to ensure 
305  consistent quality. One approach that applicants can consider as part of the quality control 
306  strategy for certain ophthalmic dosage forms (e.g., suspensions, emulsions, semi-solids) is the 
307  use of in vitro drug release/dissolution testing. Other approaches are also acceptable, such as 
308  using one or more CQAs that are sensitive to the formulation and process variants. The applicant 
309  should provide scientific justification for how the control strategy will ensure consistent product 
310  quality. 
311   
312   
313  VII.  CCS DESIGN AND DELIVERY AND DISPENSING CHARACTERISTICS 
314   
315  This section describes recommendations regarding design elements and delivery and dispensing 
316  characteristics that applicants and manufacturers should consider for ophthalmic drug product 
317  CCSs. When the CCS that holds or contains an ophthalmic drug also delivers it, it may also be a 
318  device constituent part and, together with the drug contained within, a combination product (see 
319  21 CFR 3.2(e)). Combination products are subject to the CGMP requirements under 21 CFR part 
320  4, subpart A.29 
321   
322  A.  CCS Design  
323   
324  1.  Tamper-Evident Packaging  
325   
326  All containers of ophthalmic drug products must be sterile at the time of filling and closing and 
327  sealed to prevent product use without destruction of the seal.30 Additionally, ophthalmic drug 
328  products that are OTC drugs must comply with the tamper-evident packaging requirements of 21 
329  CFR 211.132. If the CCS has a nonretaining tamper-evident ring (e.g., collar or band) to seal the 
330  bottle and cap, special care should be taken so that the ring does not detach from the bottle 
331  during use, which could cause an eye injury. OTC drugs with tamper-evident rings should also 
 
28 See ICH guidance for industry Q6B Specifications: Test Procedures and Acceptance Criteria for 
Biotechnological/Biological Products (August 1999). 
29 For further information, see the guidance for industry and FDA staff Current Good Manufacturing Practice 
Requirements for Combination Products (January 2017). See also the guidance for industry Certain Ophthalmic 
Products: Policy Regarding Compliance With 21 CFR Part 4 (March 2022) for more information regarding 
ophthalmic drugs and biological products packaged with eye cups, eye droppers, or other dispensers. 
30 See 21 CFR 200.50(a)(3). 
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332  include a positive-retention mechanism similar to those on disposable plastic beverage bottles to 
333  prevent the rings from coming off during use. 
334   
335  2.  Tips 
336   
337  For CCS designs in which the tip is sealed until opening, multistep procedures are discouraged 
338  because a patient may touch and contaminate the tip with their hands while attempting to unseal 
339  it. FDA recommends use of single-step procedures that involve simple directions and twisting 
340  the cap without removing it. 
341   
342  3.   Torque Specifications  
343   
344  Applicants and manufacturers should consider the torque specifications for drug product CCSs 
345  because some patients may have difficulties twisting off CCS caps that require extra effort to 
346  open. FDA recommends that torque be low enough so that special populations, including the 
347  elderly, can open caps without undue difficulty but high enough so that caps remain in place 
348  during manufacturing, storage, shipping, and handling. 
349   
350  4.  Color Coding  
351   
352  Color coding the caps of ophthalmic drug products is an effective tool in characterizing their 
353  therapeutic class.31 FDA recommends that applicants and manufacturers use a uniform color-
354  coding system as described in the American Academy of Ophthalmologys Color Codes for 
355  Topical Ocular Medications policy statement.32  
356   
357  B.   Delivery and Dispensing Characteristics  
358   
359  1.   Unit Dose Containers 
360   
361  For all topical ophthalmic drug products,33 FDA recommends that the maximum fill volume of a 
362  unit dose (nonpreserved) container be no more than 0.5 mL for solutions, emulsions, and 
363  suspensions. FDA also recommends that the maximum fill for a unit dose ointment or gel be no 
364  more than 1 gram. Unit dose containers should not be able to be recapped.  
365   
366  2.   Multidose Containers  
367   
368  a.  Drop size 
369   
370  For all topical ophthalmic drug products,34 FDA recommends that the drop size in a multidose 
371  CCS be between 20 and 70 microliters.  
 
31 See guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to Minimize 
Medication Errors (May 2022).  
32 See https://www.aao.org/about/policies/color-codes-topical-ocular-medications. 
33 See footnote 2. 
34 Ibid. 
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372   
373  For ophthalmic drug products submitted for approval under an ANDA, applicants should 
374  conduct a one-time drop volume/drop weight study to determine drop size during delivery or 
375  dispensing. The drop size of the generic product should be within 10% of the drop size for the 
376  reference listed drug (RLD) and within the recommended drop size of 20 to 70 microliters. For 
377  any deviations from the RLD, the ANDA applicant should provide a justification to demonstrate 
378  that there will be a similar number of delivered doses as the RLD. ANDA submissions should 
379  include information on the measurement of drop volume/drop weight and testing conditions, 
380  such as the number of drops in the container and its holding angle during dosing.  
381   
382  b.  Dose uniformity of suspension drug products 
383   
384  As recommended in USP General Chapter <771> Ophthalmic ProductsQuality Tests, a 
385  resuspendability/redispersibility test should be performed for all ophthalmic suspension drug 
386  products. For multidose containers, data for a one-time dose-uniformity study (from top, middle, 
387  and bottom of the container) should be provided from at least three pilot or exhibit batches to 
388  demonstrate that the drug substance is uniformly dispersed and the labeled dose can be 
389  consistently delivered throughout the shelf life. Alternatively, applicants may consider providing 
390  data from development batches (such as investigational new drug batches) that represent the to-
391  be-marketed formulation to demonstrate dose uniformity. 
392   
393   
394  VIII.   STABILITY 
395   
396  Manufacturers of drug products must establish a program to evaluate the stability of drug 
397  products and to use the results of the stability testing to determine appropriate storage conditions 
398  and expiration dates (21 CFR 211.166). The following stability recommendations should be 
399  considered when developing a stability testing program.35  
400   
401  A.  Container Orientation During Storage 
402   
403  The stability of ophthalmic drug products can be affected when they are stored under different 
404  orientations. Before conducting primary stability studies, NDA applicants should conduct 
405  preliminary development work36 to evaluate storage conditions in two different orientationsan 
406  upright position and either an inverted or horizontal position. Data from this preliminary work 
407  should be used to capture and characterize differences in quality attributes, if any, and determine 
408  the worst-case orientation. NDA applicants should use this worst-case orientation when 
409  conducting stability tests using batches that represent the commercial manufacturing process.  
410   
 
35 For detailed information on the stability protocol, annual stability testing, and data reporting, refer to the FDA 
guidances for industry Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003); ANDAs: 
Stability Testing of Drug Substances and Products (June 2013) and ANDAs: Stability Testing of Drug Substances 
and Products, Questions and Answers (May 2014). For BLA products, refer to the ICH guidance for industry Q5C 
Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (July 1996). 
36 See guidance for industry INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls 
Information (May 2003). 
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411  Products submitted under a BLA do not rely on preliminary development work to establish 
412  storage conditions during stability. Rather, these products rely on primary stability studies, 
413  frequently including process validation batches, to determine storage under real-time conditions. 
414  Where interactions between a formulated liquid biological product and the CCS (other than 
415  sealed ampules) cannot be excluded, applicants should place stability samples in an upright 
416  position and in either an inverted or horizontal position (i.e., in contact with all CCS surfaces) to 
417  determine the effect of all product-contact CCS components on product quality.37  
418   
419  For products submitted for approval under an ANDA, applicants should place primary stability 
420  batches in an upright position and either an inverted or horizontal position, and data from both 
421  orientations should be provided in the original submission. The determination of worst-case 
422  orientation from this comparison should be used to justify use of that orientation for routine 
423  stability batches following approval.38 
424   
425  Manufacturers must have a written stability testing program that includes the storage conditions 
426  for samples retained for testing (see 21 CFR 211.166(a)(2)), and should generally follow similar 
427  principles to determine the worst-case orientation for stability studies. 
428   
429  B.  Water Loss  
430   
431  For ophthalmic drug products packaged in semipermeable CCSs, applicants and manufacturers 
432  should conduct a water loss test to assess the moisture transmission properties of the CCS and the 
433  protective properties of any secondary packaging used. Where water loss testing is conducted to 
434  comply with CGMP requirements, manufacturers should document information on the test 
435  methods and acceptance criteria used, and applicants should include such information in their 
436  application (see 21 CFR 211.194(a)). 
437   
438  C.  Freeze/Thaw Study for Emulsions and Suspensions 
439   
440  For ophthalmic drug products that are emulsions or suspensions, applicants and manufacturers 
441  should perform a one-time freeze/thaw thermal cycling study to evaluate the effects of any high 
442  and low temperature variations that may be encountered during shipping and handling, which 
443  could affect the quality and performance of the drug product.39 FDA recommends this study 
444  consist of three cycles, with temperatures cycling between freezing (-20 C to 0 C) and ambient 
445  (25 C to 35 C) temperatures for a cumulative minimum of 3 days. Periodically throughout the 
446  study, and at the end of a predetermined number of cycles, the samples should be analyzed for all 
447  quality attributes and compared with the control drug product. Applicants that use alternative 
448  conditions and durations for their tests should provide a justification for the test conditions used. 
449   
 
37 See ICH guidance for industry Q5C Quality of Biotechnological Products: Stability Testing of 
Biotechnological/Biological Products (July 1996). 
38 See guidance for industry ANDAs: Stability Testing of Drug Substances and Products Questions and Answers 
(May 2014). 
39 See guidance for industry Drug Stability Guidelines (December 2008). This guidance was published by the Center 
for Veterinary Medicine, but FDA recommends that its thermal cycling study recommendations also be applied to 
drugs intended for human use. 
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450  D.   In-Use Stability Studies 
451   
452  In-use stability studies are used to determine expiration dates and support labeling claims for 
453  appropriate storage conditions that may change after opening, such as a change in temperature or 
454  light exposure (see 21 CFR 211.166, 21 CFR 211.137(b)). Manufacturers should document 
455  information on in-use stability studies, and applicants should submit such information in their 
456  application.  
457   
458  Under 21 CFR 211.137(h), OTC drugs that do not bear dosage limitations in their labeling and 
459  are stable for at least 3 years, as supported by appropriate stability data, are exempt from the 
460  expiration date labeling requirement. Accelerated testing programs can be appropriate to 
461  establish stability for the purposes of meeting this requirement. 
462   
463   
464  IX.  GLOSSARY 
465   
466  Container closure system (CCS): For the purpose of this guidance, the CCS includes primary 
467  packaging components (e.g., bottles, drug-dispensing tips, tubes with liner, caps), secondary 
468  packaging components (e.g., overwrap), and tertiary packaging components (e.g., shipping 
469  boxes). 
470   
471  Critical quality attribute: Physical, chemical, biological, or microbiological property or 
472  characteristic that should be within an appropriate limit, range, or distribution to ensure the 
473  desired product quality.40  
474   
475  Degradation product: An impurity resulting from a chemical change in the drug substance 
476  brought about during manufacture and/or storage of the new drug product by the effect of, for 
477  example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate 
478  container closure system.41  
479   
480  Extractables: Organic and inorganic chemical entities that are released from a pharmaceutical 
481  packaging/delivery system, packaging component, or packaging material of construction and into 
482  an extraction solvent under laboratory conditions.42 
483   
484  Impurity: Any component of the new drug product that is not the drug substance or an 
485  excipient in the drug product.43 
486   
487  Leachables: Foreign organic and inorganic chemical entities that are present in a packaged 
488  drug product because they have leached into the packaged drug product from a 
489  packaging/delivery system, packaging component, or packaging material of construction under 
 
40 ICH guidance for industry Q8(R2) Pharmaceutical Development (November 2009). 
41 ICH Q3B(R2). 
42 USP General Chapter <1663>. 
43 ICH Q3B(R2). 
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490  normal conditions of storage and use or during accelerated drug product stability studies.44 
491   
492  Preservative: A substance added to a drug product to protect it from the growth of 
493  microorganisms.  
494   
495  Semipermeable CCS: CCSs that permit the passage of solvent or foreign volatile materials 
496  through the CCS wall. 
497   
498  Specified degradation product: A degradation product that is individually listed and limited 
499  with a specific acceptance criterion in the new drug product specification. A specified 
500  degradation product can either be identified or unidentified.45  
501   
502  Specified impurity: An impurity that is individually listed and limited with a specific 
503  acceptance criterion in the new drug substance specification. A specified impurity can be either 
504  identified or unidentified.  
505   
506  Unidentified degradation product: A degradation product for which a structural 
507  characterization has not been achieved and that is defined solely by qualitative analytical 
508  properties (e.g., chromatographic retention time).46  
509   
510  Unidentified impurity: An impurity for which a structural characterization has not been 
511  achieved and is defined solely by qualitative analytical properties (e.g., chromatographic 
512  retention time).  
513   
514  Unspecified degradation product: A degradation product that is limited by a general 
515  acceptance criterion, but not individually listed with its own specific acceptance criterion, in the 
516  new drug product specification.47 
517   
518  Unspecified impurity: An impurity that is limited by a general acceptance criterion but not 
519  listed with its own specific acceptance criterion in the new drug substance specification. 
 
44 USP General Chapter <1664>. 
45 ICH Q3B(R2). 
46 Ibid. 
47 Ibid. 
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