Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices

1
2
3
4
5
6
Endotoxin Testing Recommendations
for Single-Use Intraocular Ophthalmic
Devices
Draft Guidance for Industry and Food
and Drug Administration Staff
7
DRAFT GUIDANCE
8
9
10
11
This guidance document is being distributed for comment purposes only.
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Document issued on: April 17, 2014.
You should submit comments and suggestions regarding this draft document within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft guidance.
Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic
comments to http://www.regulations.gov. Identify all comments with the docket number listed in
the notice of availability that publishes in the Federal Register.
For questions regarding this document, contact the Division of Ophthalmic and Ear, Nose, and
Throat Devices (DOED) at 301-796-5620.
26
27
28
29
30
31
32
33
34
35
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Office of Device Evaluation
Division of Ophthalmic and Ear, Nose, and Throat Devices
Contains Nonbinding Recommendations
Draft - Not for Implementation
Preface
36
37
38
39
40
41
42
43
44
Additional Copies
Additional copies are available from the Internet. You may also send an e-mail request to CDRHGuidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1836
to identify the guidance you are requesting.
2
Contains Nonbinding Recommendations
Draft - Not for Implementation
45
46
47
48
49
50
51
Endotoxin Testing Recommendations
for Single-Use Intraocular Ophthalmic
Devices
Draft Guidance for Industry and
Food and Drug Administration Staff
52
53
54
55
56
57
58
59
This draft guidance, when finalized, will represent the Food and Drug Administration's
(FDA's) current thinking on this topic. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. You can use an alternative approach
if the approach satisfies the requirements of the applicable statutes and regulations. If you
want to discuss an alternative approach, contact the FDA staff or Office responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
I. Introduction
This guidance document was developed to notify manufacturers of the recommended endotoxin
limit for the release of intraocular devices and single-use intraocular ophthalmic surgical
instruments/accessories in an effort to mitigate future Toxic Anterior Segment Syndrome
(TASS) outbreaks. TASS is a sterile inflammatory condition localized to the anterior segment of
the eye following intraocular surgery. It has been associated with significant decreases in vision
and has required additional surgical procedures, including corneal transplants and glaucoma
surgery, to resolve some of its sequelae.
National outbreaks of TASS have been associated with endotoxin. Devices used inside the eye,
including intraocular devices and single-use intraocular ophthalmic surgical
instruments/accessories, can potentially be contaminated with endotoxin as part of the
manufacturing, sterilization, or packaging processes. This guidance document provides
recommendations for endotoxin limits as well as endotoxin testing to manufacturers and other
entities involved in submitting premarket applications (PMAs) or premarket notification
submissions [510(k)s] for different categories of intraocular devices to aid in the prevention of
future outbreaks of TASS.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
3
Contains Nonbinding Recommendations
Draft - Not for Implementation
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. Definitions
A. Intraocular Fluids: A non-gaseous fluid intended to be introduced into the eye to aid
performance of surgery such as to maintain anterior chamber depth, preserve tissue
integrity, protect tissue from surgical trauma or function as a tamponade during retinal
reattachment.
1. Ophthalmic Viscosurgical Device (OVD): Both viscous and viscoelastic
intraocular fluids intended for use during surgery in the anterior chamber as a
surgical aid to maintain space in the eye and protect ocular tissue from surgical
trauma. They are usually intended for use in cataract surgery, corneal transplant
surgery, and glaucoma filtration surgery. These devices are typically prepackaged in a syringe and require PMA approval prior to being marketed. This
term includes viscoelastic surgical aids.
2. Liquid Endotamponades: Fluid implants such as silicone oil or perfluorocarbon
used to flatten and position a detached retina onto the choroid in the treatment of
retinal detachments or proliferative vitreoretinopathy. These devices require PMA
approval prior to being marketed.
B. Intraocular Lenses (IOLs): An artificial lens used to restore vision and replace the
natural lens of the eye after it is removed during cataract surgery. It can also be used in
eyes where the natural lens is not removed but that require correction of refractive error.
Examples of types of IOLs include monofocal, toric, multifocal, accommodative, iris
reconstruction and phakic. Unlike other IOLs, iris reconstruction lenses are used to
cosmetically correct defects in the appearance of the eye, usually caused by the absence
of an iris.
C. Capsular Tension Rings: A prosthetic device designed to stabilize the crystalline lens
capsule in the presence of weak or partially absent zonules in patients undergoing
cataract extraction with an intraocular lens.
D. Glaucoma Devices: A device used to treat glaucoma, a condition in which the pressure
within the eye (i.e., intraocular pressure) is abnormally high, resulting in damage to the
optic nerve. These devices are often partially implanted in the anterior segment of the eye
with the other portion of the device residing on the eye. These devices include aqueous
shunts.
E. Phacofragmentation System: A phacofragmentation system is an AC-powered device
with a fragmenting needle intended for use in cataract surgery to disrupt a cataract with
ultrasound and extract the cataract. The hand piece is composed of a tip that delivers
ultrasound energy which emulsifies the lens and aspirates lens material from its open end.
a. Sleeves: Surrounding the tip of the phacofragmentation handpiece is the sleeve,
which is often of rubbery consistency and allows for irrigation around the tip as
well as a barrier to tip penetration into lens material.
b. Tubing: Any lumened device that transmits fluid into or out of the eye.
F. Retinal Prostheses: Devices implanted on or beneath the retina, or on the outer surface of
the globe, that use electrical stimulation to provide some level of visual stimulation for
persons suffering from degenerative retinal conditions.
4
Contains Nonbinding Recommendations
Draft - Not for Implementation
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
G. Endotoxin: High molecular weight complex associated with the cell wall of Gramnegative bacteria that is pyrogenic in humans and specifically interacts with Limulus
amebocyte lysate (LAL).1
H. Endotoxin unit (EU): Standard unit of measure for endotoxin activity initially
established relative to the activity contained in 0.2 ng of the U.S. Reference Standard
Endotoxin Lot EC-2 (USP standard reference material). Endotoxin is expressed in
International Units (IU) and one EU is equal to one IU.1
I. Anterior segment: The front third of the eye including all structures located between the
front surface of the cornea and vitreous.
J. Anterior chamber: The space in the eye that is behind the cornea and in front of the
iris. It contains aqueous humor.
K. Posterior segment: The rear two-thirds of the eye located behind the lens. It includes
the vitreous, retina, optic disc, choroid, pars plana, and most of the sclera.
L. Posterior chamber: The space between the back of the iris and the front face of the
vitreous. It is also filled with aqueous humor.
M. Aqueous humor: A transparent, watery fluid circulating in the anterior and posterior
chamber of the eye. It maintains the intraocular pressure of the eye, provides amino acids
and glucose to the avascular ocular tissues and plays a role in the immune response of the
eye.
N. Bacterial endotoxin test (BET): Assay for measuring active endotoxin by combining a
liquid test sample with Limulus amebocyte lysate (LAL) reagent and measuring the
resulting proportional reaction by visual, turbidimetric, chromogenic, or other validated
means of detection.1
III. Background
TASS has been increasing in frequency. Some cases of TASS are severe enough to require
secondary surgical interventions including glaucoma surgery and corneal transplantation.2 It is
estimated that clusters of three to twenty cases of TASS occur several times each year,
translating to an estimated incidence of more than 1 in 1,000.3 The use of inadequately or
improperly processed ophthalmic surgical instruments is one of many factors suggested as a
potential cause of TASS.4-7 In many TASS cases, bacterial endotoxin from medical devices is
believed to cause the inflammation.8, 9 Endotoxin was found to be an intrinsic contaminant of a
balanced salt solution used in cataract surgery that resulted in a massive TASS outbreak in 2005
involving 112 patients.10
Because bacteria thrive in any media containing water, medical devices that are aqueous in
nature, contain an aqueous component, or are otherwise exposed to water during the
manufacturing process are vulnerable to bacterial proliferation and subsequent endotoxin
contamination. Thus, ophthalmic viscosurgical devices (OVDs) that are commonly used in
ophthalmic surgery are prone to endotoxin contamination. Further, the raw materials used in
fabricating sodium hyaluronate (HA)-based OVDs, which are of biological origin, can also be a
source of endotoxins. It has been shown that endotoxin in viscous materials such as OVDs incite
more inflammation intraocularly than endotoxin in aqueous solution due to the prolonged contact
with sensitive ocular tissue.11
5
Contains Nonbinding Recommendations
Draft - Not for Implementation
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
The general principles of endotoxin testing apply, as described in United States Pharmacopeia
(USP) <85> Bacterial Endotoxin Test12 and the most recent, FDA-recognized version 1 of
American National Standards Institute (ANSI)/Association for the Advancement of Medical
Instrumentation (AAMI) ST72 Bacterial Endotoxins-Test Methodologies, Routine Monitoring
and Alternatives to Batch Testing1. The endotoxin limit for OVDs specified in International
Organization for Standardization (ISO) 15798 (Ophthalmic implants-Ophthalmic viscosurgical
devices) is 0.5 endotoxin units (EU) per milliliter (mL). During cataract surgery, the anterior
segment of the eye can accommodate more than 0.3 ml of OVD after lens extraction and as much
as 0.1 mL OVD may remain in the eye at the end of the procedure. Hence, it is possible for 0.05
EU endotoxin to be left in the eye at the conclusion of the surgery, and this amount has been
shown to cause inflammation.12 This same study showed that inflammation can be elicited by as
little as 0.02 EU endotoxin in an OVD. Therefore, the FDA does not recognize the endotoxin
levels in the ISO 15798 (Ophthalmic implants-Ophthalmic viscosurgical devices) standard.
In ISO 11979-8 (Ophthalmic implants-Intraocular lenses-part 8: Fundamental requirements
Amendment 1), the endotoxin limit for IOLs is 0.5 EU per device or less. Any endotoxin present
on an IOL or other solid ophthalmic devices goes into solution when placed in an aqueous
medium such as the aqueous humor. Studies have shown that 0.08 EU endotoxin in a balanced
salt solution can elicit inflammation in the eye, albeit for a short period of time.11 For this reason,
FDA does not recognize the endotoxin limit in ISO 11979-8 (Ophthalmic implants-Intraocular
lenses-part 8: Fundamental requirements Amendment 1) or the limit in the ANSI series of
standards for intraocular lenses.
For solid, single-use posterior segment intraocular devices such as retinal prostheses, endotoxin
on the intraocular portion also goes into solution when placed in the eye. However, the
intraocular portion of retinal prostheses has limited exposure to sensitive ocular tissue when
compared to that of solid anterior segment devices. Hence, FDA agrees with using the ISO
16672 standard as a guide to establish endotoxin limits for solid posterior segment devices and
posterior segment intraocular fluids also called liquid endotamponades.
IV. Scope
The recommendations made in this guidance are applicable to devices used within the eye, either
as permanent implants or as single-use devices used in intraocular surgery. These include:
A. Intraocular Fluids (21 CFR 886.4275, Class III), including
1. Intraocular fluid (LWL)
2. Viscoelastic surgical aid (LZP)
B. Anterior Segment Solid Devices
1. Intraocular lenses (21 CFR 886.3600, Class III), including
a. Intraocular lenses (HQL)
b. Multifocal intraocular lenses (MFK)
c. Phakic intraocular lenses (MTA)
1
A searchable database of FDA-recognized consensus standards is available at:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.
6
Contains Nonbinding Recommendations
Draft - Not for Implementation
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
d. Toric intraocular lenses (MJP)
e. Accommodative intraocular lenses (NAA)
f. Implantable miniature telescope (NCJ)
g. Iris reconstruction lenses (NIZ)
2. Capsular tension ring devices (Class III), including
a. Endocapsular rings (MRJ)
3. Glaucoma devices
a. Aqueous shunts (21 CFR 886.3920, Class II), including
i. Eye valve implant (KYF)
b. Other glaucoma devices (Class III)
i. Intraocular pressure lowering implants (OGO)
4. Phacofragmentation systems (21 CFR 886.4670, Class II), specifically the accessories
of irrigation/aspiration sleeves and tubing (HQC)
C. Posterior Segment Solid Devices (Class III)
1. Retinal prostheses (NBF)
Endotoxin contamination of reusable manual ophthalmic surgical instruments is outside the
scope of this guidance. For more information on this topic, see FDA’s draft guidance
“Processing/Reprocessing Medical Devices in Health Care Settings: Validation Methods and
Labeling”
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm2
52999.htm) FDA’s draft guidance represents FDA’s proposed approach on this topic.
V.
Recommendations
A. Intraocular Fluids
1. OVDs
a. The recommended endotoxin limit for release testing is ≤0.2 EU/mL regardless of
whether the intended site of use is the anterior or posterior segment.
b. Endotoxin test method validation:
The viscosity of OVDs can interfere with the BET. In addition to the general
validation requirements described in USP <85> and ANSI/AAMI ST72, the
validation of the BET should include recovery of known amounts of endotoxin
added/spiked to the OVD. For each OVD that is to be marketed, random samples
from 3 lots of the OVD should each be spiked with endotoxin to final
concentrations of 0.1, 0.2 and 0.5 EU/mL. Each test should be conducted in
triplicate (i.e., each lot should be spiked and sampled three times for testing). The
OVDs should then be tested for endotoxin using the BET and the percent
endotoxin recovery should be calculated. The detection limit may vary with the
method used for testing (e.g., gel clot, turbidimetric and chromogenic) and, as
such, it may be necessary to experiment with different methods to ensure maximal
recovery of endotoxin. For OVDs fabricated from HA of a high molecular weight,
it may be necessary to use an enzyme containing non-detectable levels of
endotoxin to break down large molecules and make endotoxin more accessible for
testing. The use of enzyme digestion will avoid the use of a high dilution factor to
7
Contains Nonbinding Recommendations
Draft - Not for Implementation
overcome interference, which may be necessary for the OVD to meet the
endotoxin limit.11
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
c. If performed, animal testing for quality control and acceptance criteria with
associated labeling claim:
The phrase “non-inflammatory” in the labeling of an OVD should not be used
since the OVD could elicit some inflammation but it may not be clinically
significant. OVDs may be labeled as having “low inflammatory potential” if
animal testing or another validated method for detecting inflammation is
performed as a product release test.
Although endotoxin in an OVD can be detected and quantified using a BET, the
amount detected is only an approximation of the actual value due to the inherent
limitations of the test. Furthermore, the amount of endotoxin detected can be
affected by the unique properties of the individual OVD (e.g., the molecular
weight), which could alter how the OVD binds to the ocular tissue and
consequently the efficiency of enzyme digestion. Thus, the only established
method to assure that an OVD has low inflammatory potential is to test the
product in the anterior segment of the eye with subsequent assessment of
inflammation.
Testing of an OVD in an animal model should be performed by injecting the
OVD intracamerally.13 The eyes should then be monitored for clinical signs of
inflammation using a slit lamp for at least three days. The test method should be
validated by quantifying the inflammation elicited by the OVD that has been
spiked with 0.01, 0.02 and 0.05 EU endotoxin, at a minimum.
We recommend that sponsors who intend to perform this testing submit a PreSubmission to obtain feedback from DOED on the animal testing validation
recommendations and the acceptance criteria for release testing as well as for any
other methods of detecting inflammation. 2
2. Liquid Endotamponades
a. Similar to ISO 16672 (Ophthalmic implants — Ocular endotamponades), the
recommended endotoxin limit for liquid endotamponades is ≤0.5 EU/mL.
B.
Anterior Segment Solid Devices
1. The recommended endotoxin limit for all anterior segment solid intraocular
devices is ≤0.2 EU/device. This limit applies to implants that are placed entirely
in the anterior segment such as IOLs, iris reconstruction lenses, and capsular
tension rings. For glaucoma devices, this limit applies to the segment of the
device placed in the anterior chamber and the segment(s) contacting the aqueous
2
For more information on Pre-Submissions, please see “Requests for Feedback on Medical Device Submissions:
The Pre-Submission Program and Meetings with Food and Drug Administration Staff”
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM311176.
pdf).
8
Contains Nonbinding Recommendations
Draft - Not for Implementation
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
humor even though the main portion of the device may reside outside the eye. For
single-use cannulated or lumened devices (e.g., irrigation/aspiration sleeves and
tubing), this limit applies to the fluid path and the portion of the device with
aqueous humor contact.
2. Test sample preparation:
The standard 40 mL/device extraction ratio can be adjusted to accommodate the
small size of solid intraocular devices in accordance with the recommendation in
the “FDA Guidance for Industry Pyrogen and Endotoxin Testing: Questions and
Answers”
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/ucm314718.htm). The volume of the extraction solution chosen for use should
also take into consideration the endotoxin limit for the device and the sensitivity
of the LAL lysate used in the testing. ANSI/AAMI ST72 specifies the minimum
extraction time as 15 minutes at 37°-40°C or one hour at controlled room
temperature (typically 18-25°C), or other demonstrated equivalent conditions.1
Because of the extreme sensitivity of the eye to endotoxin, the FDA recommends
that the extraction be performed at 37°-40°C with agitation for a minimum of 60
minutes to maximize the extraction efficiency. For cannulated or lumened
devices, sample preparation should consist of filling the fluid pathway with the
extracting medium that has been pre-warmed to 37°± 1°C and then held at 37°±
1°C for at least 60 minutes.
C.
Posterior Segment Solid Devices
1. The recommended endotoxin limit for all posterior segment solid intraocular
devices is ≤0.5 EU/device. This limit applies to the segment of the device placed
in the posterior segment and any segment(s) contacting the vitreous even though
part of the device may reside outside the eye. For devices that have a segment that
contacts the aqueous humor and the vitreous or posterior segment, please contact
the Division for recommended limits.
2. Test sample preparation:
The test sample preparation is identical to that described for anterior segment
solid devices.
VI. References
1.
American National Standards Institute, Instrumentation AftAoM. Bacterial endotoxinsTest methodologies, routine monitoring, and alternatives to batch testing, ST72: 2011.
2.
Mamalis N, Edelhauser HF, Dawson DG, Chew J, LeBoyer RM, Werner L. Toxic
anterior segment syndrome. J Cataract Refract Surg 2006;32:324-33.
3.
Ronge LJ. Toxic Anterior Segment Syndrome: Why sterile isn't clean enough. EyeNet.
San Francisco: American Academy of Ophthalmology, 2002.
4.
Cutler CM, Brubaker J, Clouser S, Danford C, Edelhauser HE, Mamalis N. Toxic
anterior segment syndrome: common causes. J Cataract Refract Surg 2010;36:1073-80.
5.
Mamalis N. Toxic anterior segment syndrome. J Cataract Refract Surg 2006;32:181-2.
9
Contains Nonbinding Recommendations
Draft - Not for Implementation
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
6.
Holland SP, Morck DW, Lee TL. Update on toxic anterior segment syndrome. Current
Opinion in Ophthalmology 2007;18:4-8.
7.
Maier P, Birnbaum F, Bohringer D, Reinhard T. Toxic anterior segment syndrome
following penetrating keratoplasty. Arch Ophthalmol 2008;126:1677-81.
8.
Kreisler KR, Martin SS, Young CW, Anderson CW, Mamalis N. Postoperative
inflammation following cataract extraction caused by bacterial contamination of the cleaning
bath detergent. J Cataract Refract Surg 1992;18:106-10.
9.
Richburg FA, Reidy JJ, Apple DJ, Olson RJ. Sterile hypopyon secondary to ultrasonic
cleaning solution. J Cataract Refract Surg 1986;12:248-51.
10.
Kutty PK, Forster TS, Wood-Koob C, et al. Multistate outbreak of toxic anterior segment
syndrome, 2005. J Cataract Refract Surg 2008;34:585-90.
11.
Buchen SY, Calogero D, Hilmantel G, Eydelman MB. Rabbit ocular reactivity to
bacterial endotoxin contained in aqueous solution and ophthalmic viscosurgical devices.
Ophthalmology 2012;119:e4-e10.
12.
The United States Pharmacopeial Convention. Bacterial Endotoxins Test <85>. United
States Pharmacopeia, 2011.
13.
Buchen SY, Calogero D, Hilmantel G, Eydelman MB. Detecting endotoxin
contamination of ophthalmic viscosurgical devices: intracameral versus intravitreal assays in
rabbits. Ophthalmology 2012;119:e11-8.
10