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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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: [email protected]
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Draft — Not for Implementation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
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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 products 2 (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 [email protected]
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, FDA’s guidance documents do not establish legally enforceable responsibilities.
57 Instead, guidances describe the Agency’s 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 Manufacturers 10 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 Processing—Current 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 FDA’s 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 FDA’s current thinking on this topic.

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97 should implement a well-designed and rigorous antimicrobial effectiveness testing program that
98 covers the product’s 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 Products—Quality 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> Containers—Glass;
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 chromatography–mass
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 chromatography–mass
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, FDA’s 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 FDA’s 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 (µg/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 Ophthalmology’s 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 Products—Quality 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 work 36 to evaluate storage conditions in two different orientations—an
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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