101 activities (e.g., higher volume of production for a drug product, sterile production, manual 102 manipulations) and lower risk compounding activities (e.g., lower volume of production, non- 103
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 .
Current Good Manufacturing Practice--Guidance for Human Drug Compounding Outsourcing
Facilities Under Section 503B of the FD&C Act
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact (CDER) Marci Kiester 301-796-0600.
U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) January 2020
Pharmaceutical Quality/Manufacturing Standards (CGMP) Revision 2
Current Good Manufacturing Practice--Guidance for Human Drug Compounding Outsourcing
Facilities Under Section 503B of the FD&C Act
Guidance for Industry
Additional copies are available from: Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) January 2020
Pharmaceutical Quality/Manufacturing Standards (CGMP) Revision 2
Contains Nonbinding Recommendations
Draft -- Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. CGMP FOR OUTSOURCING FACILITIES................................................................ 3
A. Quality Assurance Activities ......................................................................................................... 3 B. Facility Design ................................................................................................................................ 5 C. Control Systems and Procedures for Maintaining Suitable Facilities ...................................... 7 D. Environmental and Personnel Monitoring ................................................................................ 10 E. Equipment .................................................................................................................................... 12 F. Containers and Closures ............................................................................................................. 12 G. Components .................................................................................................................................. 14
1. Regulatory Policy Regarding Component Supplier Qualification Testing.................................... 17 2. Regulatory Policy Regarding Testing for Finished Product To Be Used as a Source Material for Processing .......................................................................................................................................... 17 H. Production and Process Controls ............................................................................................... 18 1. General Production and Process Controls .................................................................................... 19 2. Drug Product Sterilization............................................................................................................. 19 I. Release Testing ............................................................................................................................. 22 J. Laboratory Controls .................................................................................................................... 25 K. Stability/Expiration Dating for Compounded Drug Products................................................. 26 1. Stability Program and Beyond-Use Dating ................................................................................... 26 2. Establishing an In-Use Time for Sterile Drug Products................................................................ 29 3. In-Use Time and BUDs for Sterile Drug Products ........................................................................ 30 L. Packaging and Labels .................................................................................................................. 31 M. Reserve Samples........................................................................................................................... 31 N. Complaint Handling .................................................................................................................... 32 IV. REFERENCES................................................................................................................ 32 V. GLOSSARY..................................................................................................................... 34 APPENDIX A. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT INTEND TO TAKE REGULATORY ACTION REGARDING CERTAIN RELEASE TESTING REQUIREMENTS ................................................................................................... 37 APPENDIX B. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT INTEND TO TAKE REGULATORY ACTION REGARDING STABILITY TESTING AND EXPIRATION DATE REQUIREMENTS ..................................................................... 43
Contains Nonbinding Recommendations
Draft -- Not for Implementation
1 Current Good Manufacturing Practice--Guidance for Human Drug
2
Compounding Outsourcing Facilities
3
Under Section 503B of the FD&C Act
4
Guidance for Industry1
5
6 7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 11 for this guidance as listed on the title page. 12
13 14 15 16 I. INTRODUCTION 17 18 This guidance describes FDA's policies regarding compliance with current good manufacturing 19 practice (CGMP) requirements for facilities that compound human drugs and register with FDA 20 as outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act 21 (FD&C Act). Under section 501(a)(2)(B) of the FD&C Act, a drug is deemed to be adulterated if 22 it is not produced in accordance with CGMP. FDA's regulations regarding CGMP requirements 23 for the preparation of drug products have been established in 21 CFR parts 210 and 211.2 FDA 24 intends to promulgate more specific CGMP regulations for outsourcing facilities. Until these 25 final regulations are promulgated, outsourcing facilities are subject to the CGMP requirements in 26 parts 210 and 211. This guidance provides for conditions under which FDA generally does not 27 intend to take regulatory action against an outsourcing facility regarding certain CGMP 28 requirements in parts 210 and 211 during this interim period. This guidance applies to drugs 29 compounded in accordance with section 503B. In addition, this guidance generally applies to 30 drugs that outsourcing facilities repackage and biological products that outsourcing facilities 31 mix, dilute, or repackage in accordance with relevant guidance for outsourcing facilities.3 32 33 This guidance reflects FDA's intent to recognize the differences between outsourcing facilities 34 and conventional drug manufacturers, while maintaining the minimum standards necessary to
1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research and in cooperation with the Office of Regulatory Affairs at the Food and Drug Administration.
2 Positron emission tomography (PET) drug products are subject to CGMP regulations at 21 CFR part 212 and are not covered by this guidance.
3 See guidances for industry Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities and Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application (Biologics guidance). To the extent that the policies in the Biologics guidance differ from this guidance (e.g., conditions concerning assigning a beyond-use date to repackaged biological products based on stability testing), the policies described in the Biologics guidance apply. FDA updates guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents.
1
Contains Nonbinding Recommendations
Draft -- Not for Implementation
35 protect patients from the risks of contaminated or otherwise substandard compounded drug
36 products.
37
38 This guidance revises the draft guidance Current Good Manufacturing Practice--Interim
39 Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the
40 FD&C Act issued in July 2014. Revision 1 was developed to (1) include considerations for non-
41 sterile compounded drug products; (2) differentiate between requirements applicable to sterile
42 compounded drug products and non-sterile compounded drug products where appropriate; (3)
43 include changes regarding stability testing, including the assignment of a beyond-use date (BUD)
44 as an expiration date, and release testing requirements; and (4) address reserve samples and
45 provide guidance on "in-use times." Revision 2 refines a description of antimicrobial
46 effectiveness testing in section III.K. and clarifies that section C of appendix B does not apply to
47 non-sterile unpreserved aqueous drug products.
48
49 In general, FDA's guidance documents do not establish legally enforceable responsibilities.
50 Instead, guidances describe the Agency's current thinking on a topic and should be viewed only
51 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
52 the word should in Agency guidances means that something is suggested or recommended, but
53 not required.
54
55
56 II. BACKGROUND
57
58 The Drug Quality and Security Act added a new section 503B to the FD&C Act.4 Under section
59 503B(b), a compounder can register as an outsourcing facility with FDA. Drug products
60 compounded in an outsourcing facility can qualify for exemptions from the FDA approval
61 requirements in section 505 of the FD&C Act,5 the requirement to label drug products with
62 adequate directions for use under section 502(f)(1) of the FD&C Act,6 and the drug supply chain
63 security requirements in section 582 of the FD&C Act,7 if the conditions in section 503B are
64 met. Outsourcing facilities are inspected by FDA according to a risk-based schedule and must
65 comply with other provisions of the FD&C Act, including CGMP requirements under section
66 501(a)(2)(B) (see section 503B).
67
68 Under section 501(a)(2)(B), a drug is deemed to be adulterated if:
69
70
[T]he methods used in, or the facilities or controls used for, its manufacture, processing, packing,
71
or holding do not conform to or are not operated or administered in conformity with current good
72
manufacturing practice to assure that such drug meets the requirements of this [Act] as to safety
73
and has the identity and strength, and meets the quality and purity characteristics, which it
74
purports or is represented to possess . . . .
75
4 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587588 (2013). 5 21 U.S.C. 355. 6 21 U.S.C. 352(f)(1). 7 21 U.S.C. 360eee-1.
2
Contains Nonbinding Recommendations
Draft -- Not for Implementation
76 Further, section 501 of the FD&C Act, as amended by the Food and Drug Administration Safety
77 and Innovation Act,8 states:
78
79
For purposes of paragraph (a)(2)(B), the term "current good manufacturing practice" includes the
80
implementation of oversight and controls over the manufacture of drugs to ensure quality, including
81
managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of
82
drugs, and finished drug products.
83
84 CGMP requirements for finished drug products, except PET drug products, are established in 21
85 CFR parts 210 and 211. The primary focus of this guidance is on those aspects of part 211 that
86 relate to sterility assurance of sterile drug products and the safety of both sterile and non-sterile
87 compounded drug products more generally, including with respect to strength (e.g., subpotency,
88 superpotency), and labeling or drug product mix-ups, because these aspects of outsourcing
89 facility operations pose the highest risk to patient safety if not conducted properly.
90
91 The recommendations in this guidance are consistent with the principles of good manufacturing
92 practice, which hold that quality is best assured by implementing appropriate controls throughout
93 the manufacturing process, with end-product testing providing additional assurance. This
94 guidance also provides a risk-based approach to CGMP requirements. Accordingly, this
95 guidance focuses on control of raw materials, facility design and maintenance, production
96 techniques and controls, and personnel practices as the most critical aspects of ensuring quality
97 for all drug products. Other CGMP requirements, such as testing samples of the finished drug
98 product before batch release and the collection of reserve samples, provide additional assurance
99 of drug quality and are described with respect to higher risk outsourcing facility operations. For
100 example, the guidance distinguishes, where applicable, between higher risk compounding
101 activities (e.g., higher volume of production for a drug product, sterile production, manual
102 manipulations) and lower risk compounding activities (e.g., lower volume of production, non-
103 sterile production, use of automated equipment).
104
105 Depending on the level of risk, the guidance describes certain conditions under which FDA
106 generally does not intend to take regulatory action against an outsourcing facility regarding
107 specific CGMP requirements.
108
109
110 III. CGMP FOR OUTSOURCING FACILITIES
111
112
A. Quality Assurance Activities
113
114 Quality assurance activities are needed to ensure that procedures are followed and a quality drug
115 product is produced (see, e.g., §§ 211.22, 211.180, 211.192, 211.198). Part 211 (see, e.g.,
116 § 211.22) requires that drug producers establish a quality control unit to oversee various aspects
117 of production, including strength as well as sterility assurance activities for sterile products and
118 microbiological quality for non-sterile products.
119
8 Pub. L. No. 112-114, 126 Stat. 993 (2012). 3
Contains Nonbinding Recommendations
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120 The quality control unit should be independent; that is, the quality control unit should not take on
121 the responsibilities of other units of the outsourcing facility's organization, such as those handled
122 by production personnel, in order to preserve the integrity of the quality control unit's functions.
123 FDA has found that quality control units that are independent from other operations are more
124 likely to be able to fulfill their required functions.9 FDA recommends the staffing level be
125 adequate to perform all quality assurance functions at a level commensurate with the scale of the
126 compounding operation, including number and volume of drug products compounded.
127
128 Procedures describing the role and responsibilities of the quality control unit must be established
129 and followed (§ 211.22(d)). The following aspects of quality assurance and quality control are
130 critical to ensuring the quality of compounded sterile and non-sterile drug products at
131 outsourcing facilities.
132
133 The quality control unit is responsible for ensuring that each batch of finished drug product is
134 sampled and tested to ensure that it meets appropriate specifications for release (see
135 §§ 211.22(a), 211.165(d)). For sterile products, procedures should be established and followed to
136 ensure that for each batch intended to be released without completed sterility testing (see section
137 I and Appendix A), the results of the sterility testing, once available, are reviewed and added to
138 the batch record (see § 211.188).
139
140 The quality control unit must periodically (at least annually) review records of compounding
141 operations to evaluate the quality standards for each drug product to determine the need for
142 changes in specifications or control procedures (§ 211.180(e)). As part of this review, the quality
143 control unit should identify trends and evaluate quality indicators such as (where required by
144 part 211):
145
146
· Results of environmental monitoring.
147
148
· Results of personnel monitoring.
149
150
· Where water is used as a component in the drug product, results of water system testing
151
for water that is purified/processed on-site, or if water is purchased as an incoming
152
component, testing results from the supplier or results of testing conducted by the
153
outsourcing facility.
154
155
· Results of finished drug product testing.
156
157
· All media fills/process simulations performed since the last review.
158
159
· Periodic scrutiny of operations to ensure adherence to procedures and proper aseptic
160
technique.
9 FDA inspection information indicates that most outsourcing facilities maintain personnel in a quality control unit that is fully separate from compounding operations. However, FDA recognizes that there may be an extraordinary circumstance in which an individual in the quality control unit may need to participate in another operation. In such circumstances, that person is still accountable for implementing all of the controls and reviewing compounding operations to ensure that facility, process, and product quality standards have been met. See § 211.22.
4
Contains Nonbinding Recommendations
Draft -- Not for Implementation
161
162
· Complaints, discrepancies, failures, and yield variation.
163
164 The quality control unit is responsible for discrepancy and failure investigations and the
165 development and oversight of effective corrective actions, which also include changes necessary
166 to prevent recurrence, regarding the following (see, e.g., §§ 211.192, 211.180(e)):
167
168
· Results of tests and examinations, regardless of batch disposition, if applicable to
169
evaluate the quality of components, containers, closures, in-process materials, and
170
finished product. Examples of such tests and examinations include but are not limited to
171
sterility testing, endotoxin levels, content assay, impurity assay, particulate matter,
172
reconstitution time, content uniformity, preservative content testing, microbial
173
enumeration, tests for specified microorganisms, and, weight, volume, or counts.
174
175
· Unexpected results (e.g., potential defects) or trends.
176
177
· Failures that occur during validation or revalidation. These could include process
178
validation, sterilization, or depyrogenation processes, including media fill/process
179
simulation failures, as applicable.
180
181
· Stability failures, including failures of quality that are determined to have causes other
182
than degradation of the drug product.
183
184
· Environmental and personnel monitoring results that exceed alert or action limits.
185
186
· Process deviations or equipment malfunctions that involve critical equipment, such as
187
sterilizers, lyophilizers, pellet machines, capsule machines, mixers, and homogenizers.
188
189
· Complaints that indicate possible drug product contamination or other potential risks to
190
patients (e.g., hazy or cloudy drug product, foreign matter/particulates in injectable drug
191
products, cracked or leaky containers, change in color or appearance, particles falling out
192
of oral solutions).
193
194
B. Facility Design
195
196 Part 211 sets out the requirements applicable to the design of facilities used in the manufacture,
197 processing, packing, or holding of a drug product (see, e.g., § 211.42). The design of a facility
198 should consider the products produced and must provide the necessary level of control to prevent
199 mix-ups and contamination (§ 211.42).
200
201 The production areas in which components, drug products, in-process materials, equipment, and
202 containers or closures are prepared, held, or transferred must be designed to minimize the level
203 of contaminants so as to prevent objectionable microorganisms in non-sterile drug products (see
204 § 211.113(a)) and prevent microbiological contamination of drug products purporting to be
205 sterile (see § 211.113(b)). Processing and controlled areas must be clean and sanitary (§ 211.56).
206
5
Contains Nonbinding Recommendations
Draft -- Not for Implementation
207 Additional Considerations for Sterile Drug Products
208
209 Outsourcing facilities should meet the following elements:
210
211
· Sterile drugs should be produced only in ISO 5 or better air quality as determined under
212
dynamic conditions (see Table 1 for International Organization for Standardization (ISO)
213
cleanroom classification standards).
214
215 Table 1. ISO Classification of Particulate Matter in Room Air*
ISO Class Name
Particles/m3
3
35.2
4
352
5
3,520
6
35,200
7
352,000
8
3,520,000
*Limits are in particles of 0.5 µm and larger per cubic meter (current ISO) measured under dynamic conditions. Adapted from ISO 14644-1:2015, Cleanrooms and associated controlled environments--Part 1: Classification of air cleanliness by particle concentration.
216
217
· The facility should be designed and operated with cascading air quality (e.g., by proper
218
air classification and air pressurization) to protect the ISO 5 zone (or critical area10). The
219
facility layout, room separation, and process flow must be designed to prevent the influx
220
of contamination from adjacent areas and rooms of lower air quality and to avoid any
221
disruption of HEPA unidirectional flow (§ 211.42).
222
223
· The air cleanliness classification of the area surrounding the ISO 5 zone immediately
224
adjacent to the aseptic processing line should, at a minimum, meet ISO 7 standards under
225
dynamic conditions.
226
227
· If an isolator11 is used, the surrounding area should, at a minimum, meet ISO 8 standards
228
under dynamic conditions.
229
230
· If a restricted access barrier12 is used (e.g., a glove box), the surrounding area should, at a
231
minimum, meet ISO 7 standards under dynamic conditions.
232
233
· Terminally sterilized drugs should be produced in ISO 8 or better air quality as
234
determined under dynamic conditions.
10 A critical area is an area designed to maintain sterility of sterile materials. See guidance for industry Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice.
11An isolator is a decontaminated unit supplied with ISO 5 or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment. For further information, see also guidance for industry Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice.
12 See guidance for industry Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice.
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Contains Nonbinding Recommendations
Draft -- Not for Implementation
235
236 The ISO 5 zone or critical area must be qualified (i.e., shown to meet the specifications; see
237 §§ 211.42, 211.113(b)). Qualification should include at least the following studies and tests,
238 which must be documented as having been conducted (see § 211.113(b)), including the particular 239 conditions under which the studies and tests were conducted:13
240
241
· Airflow studies (e.g., an in-situ smoke study) should be conducted under simulated
242
operational conditions to evaluate airflow patterns because of the risk for contamination
243
of exposed product in the critical area. These studies should be conducted at the critical
244
area to demonstrate unidirectional flow and sweeping action over and away from the
245
product under dynamic conditions and should be repeated when any changes are made to
246
the critical area that might affect airflow.14 Because proper control of airflow is necessary
247
to prevent contamination, any indication of poor air control (e.g., non-unidirectional,
248
turbulent) must be corrected before use (see §§ 211.42, 211.113(b)).
249
250
· HEPA periodic testing/recertification should be performed at least twice a year to ensure
251
that appropriate airflow and quality are maintained. These tests should include integrity
252
testing of the HEPA filters, particle counts, and air velocity checks.
253
254
· Velocities of unidirectional air should be measured 6 inches from the HEPA filter face
255
and at a defined distance close to the work surface in the ISO 5 area.
256
257
· If any portable ISO 5 units are moved from one location to another, requalification of the
258
unit should be performed before resuming sterile compounding.
259
260
C. Control Systems and Procedures for Maintaining Suitable Facilities
261
262 To prevent contamination or mix-ups during the course of operations, § 211.42 requires separate 263 or defined areas or other similar control systems for a facility's operations.15 Section 211.56
264 requires that procedures be established and followed that assign responsibility for sanitation and
265 describe in detail the cleaning schedules, methods, equipment, and materials to be used in
266 cleaning buildings and facilities.
267
268 For multiuse facilities and nondedicated equipment, changeover and cleaning procedures for
269 equipment and utensils must be established and followed to prevent contamination, including
270 cross-contamination between products (see §§ 211.42, 211.67).
271
272 Procedures for cleaning and disinfecting must also be established (see §§ 211.42, 211.56,
273 211.67). Equipment surfaces that come in contact with drug products, containers, or closures
274 must be cleaned at appropriate intervals to prevent contamination (see § 211.67). The suitability
13 In addition to documenting these tests and studies, the CGMP regulations generally require that other key activities be documented (see part 211, subpart J: Records and Reports).
14 Additional information may be found in NSF/ANSI 49--2014 Biosafety Cabinetry: Design, Construction, Performance, and Field Certification.
15 For example, this would be especially critical when using powders because powder particles can become airborne and contaminate other areas unless airflow is designed to contain such particles.
7
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275 and efficacy of the cleaning agents and cleaning methods should be evaluated, and the cleaning 276 agent's compatibility with applicable work surfaces should be assessed. Published literature and 277 supplier certificates of analysis (COAs) can be relied on when initially determining the 278 effectiveness of agents used to clean and disinfect, as necessary, the facility and equipment 279 surfaces, provided that the supplier's cleaning procedures are followed. The expiration dates of 280 cleaning and disinfection agents should be closely monitored and expired solutions should be 281 discarded. 282 283 For non-sterile drug production, water used as a final rinsing agent for any equipment or utensils 284 that come in direct contact with the drug product should meet the requirements for Purified 285 Water, USP, or higher quality standards.16 286 287 If powder drugs are handled, procedures must be established and followed to appropriately 288 manage cross-contamination risk (see § 211.100). This is particularly important if the powder is 289 cytotoxic or highly sensitizing. FDA recommends the physical segregation of areas in which 290 powder drugs are exposed to the environment. For penicillin products, a separate facility is 291 required (see § 211.42(d)). However, FDA has clarified that separate buildings may not be 292 necessary, provided that the manufacturing operation involving penicillin is isolated (i.e., 293 completely and comprehensively separated) from the areas in which non-penicillin products are 294 manufactured.17 For non-penicillin beta-lactam products, FDA recommends complete and 295 comprehensive separation from other products.18 Additionally, appropriate controls related to 296 movement of equipment, product, and personnel should be established to prevent cross297 contamination of non-beta-lactam products. 298 299 In general, processes and procedures at an outsourcing facility should minimize contamination 300 risks posed by, for example, the number and complexity of manipulations, number of 301 simultaneous operations and workstations, and staging of materials used in the process. 302 303 Additional Considerations for Sterile Drug Products 304 305 HEPA filters should be qualified to provide appropriate air quality and be periodically 306 maintained and tested to ensure intended air quality. Discolored, dirty, or damaged HEPA filters 307 should be repaired or replaced. 308 309 Temperature and humidity must be maintained in cleanroom areas; such controls are critical to 310 reduce microbiological growth (see § 211.46). A specification for humidity should be established 311 considering that higher humidity supports microbial growth, while too little humidity can cause 312 problems with static electricity (which may be particularly problematic when working with 313 powders) and may lead to increased particulates. Cleanroom temperature and humidity 314 specifications should be maintained solely through the facility's central heating, ventilation, and
16 See FDA's Guide to Inspections of High Purity Water Systems at https://www.fda.gov/inspections-complianceenforcement-and-criminal-investigations/inspection-guides/high-purity-water-system-793. 17 Preamble to the final rule, "Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding." 43 FR 45014, at 45038 (September 29, 1978). 18 See guidance for industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing CrossContamination.
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Contains Nonbinding Recommendations
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315 air conditioning (HVAC); peripheral devices such as stand-alone (de-)humidifiers and air 316 conditioners should not be used because they generate airborne particles, are water sources, and 317 may harbor microorganisms. As a scientific matter, a system for environmental monitoring must 318 include the establishment of pressure differential limits (see § 211.42), and control systems 319 should include built-in alarms to detect excursions. An adequate control system includes 320 monitoring for pressure differentials, humidity, and temperature during production and taking 321 prompt action to correct adverse conditions, which are necessary activities to prevent 322 contamination during aseptic processing (see §§ 211.42, 211.46, 211.58). If a problematic 323 condition cannot be immediately corrected, production should stop until it has been corrected. 324 Regardless of whether production is stopped or allowed to continue, the impact of any 325 excursions on product that is already in process should be evaluated. Among other requirements 326 in § 211.192, any unexplained discrepancy must be investigated, the results of which must be 327 documented. 328 329 Monitoring procedures should require documentation and investigation of any instances in which 330 there is a loss of positive pressure in the cleanroom during actual production and documentation 331 of the batches affected and the corrective action taken. These checks should be conducted 332 regularly on a schedule that considers the environment, such as use of an isolator versus a less 333 protected process, and the results should be recorded in logs and evaluated against prespecified 334 alert and action limits at each check. 335 336 In addition to the requirements in §§ 211.42 and 211.56, FDA recommends that outsourcing 337 facilities ensure that air vents and airflow are not obstructed--by large equipment, for example-- 338 in such a way that could potentially compromise aseptic operations. Equipment that is not 339 needed for the specific cleanroom operations conducted should not be stored in the cleanroom. 340 341 Procedures for cleaning and disinfecting ISO 5 areas/units should include detailed instructions 342 for consistently and properly cleaning and disinfecting surfaces that are difficult to access. A 343 system for cleaning and disinfecting all critical areas to produce aseptic conditions includes 344 sporicidal and other sterile disinfectants and lint-free sterile wipes (see § 211.42). Procedures 345 must describe the methods and schedule for cleaning (see §§ 211.42, 211.56, 211.67, 211.182) 346 and should include the use of sporicidal disinfectants in the ISO 5 area and other classified areas 347 on a regular basis. 348 349 Water used as a cleaning or rinsing agent for any equipment or utensils that will not be 350 subsequently disinfected or sterilized and depyrogenated must be sterile (see § 211.113(b)). 351 Purified Water, USP, is considered acceptable for use with equipment or utensils that will be 352 sterilized and depyrogenated. 353 354 Based on the results of environmental monitoring (see section D below), the disinfection 355 program must be revised if there are indications that the frequency of disinfection or the methods 356 or type of disinfectant(s) used are inadequate to ensure appropriately clean surfaces (see 357 §§ 211.42, 211.56, 211.67, 211.113). Conducting disinfectant effectiveness testing may be useful 358 in guiding revision of the disinfection program in such cases. 359
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360 Critical equipment surfaces that come in contact with sterile drug products, containers, and
361 closures must be sterilized at appropriate intervals (see § 211.67); disinfection alone is not
362 sufficient (see section E below). Single-use disposable equipment and supplies that are purchased
363 presterilized and depyrogenated and are discarded after one use need not be resterilized.
364
365
D. Environmental and Personnel Monitoring
366
367 The frequency and methods of environmental and personnel control and monitoring should be
368 commensurate with the risk to product quality. For example, for non-sterile drugs, aqueous-
369 based drugs present the highest microbiological risk to patients. Consequently, water system and
370 environmental monitoring for aqueous non-sterile drug production should be performed more
371 frequently than for non-aqueous non-sterile drugs. During aqueous non-sterile drug production,
372 temperature and humidity should be monitored daily and air (viable19 and nonviable particles)
373 and surfaces (viable particles) should be monitored periodically (e.g., at least quarterly). Aseptic
374 sterile drug production environments should be monitored at least daily during production. Also,
375 monitoring of product residue may be necessary to ensure that the cleaning program is effective
376 or containment is maintained, with an increased frequency of monitoring and sensitivity of
377 methods when contamination poses a higher risk, such as when producing cytotoxic or highly
378 sensitizing materials.
379
380 Additional Considerations for Sterile Drug Products
381
382 21 CFR 211.42(c)(10)(iv) requires establishing a system for monitoring environmental
383 conditions in aseptic processing areas, and §§ 211.113(b) and 211.28(a) require personnel
384 sanitation practices and gowning to be both acceptable and qualified for the operations they
385 perform. For example, gowning procedures should ensure that there is no exposed skin on
386 personnel involved in any production activities in, or that can directly affect, the ISO 5 area.20
387 Procedures for monitoring the environment and personnel for the presence of viable particles and
388 nonviable particles should be established and followed as described here.
389
390 Operations and appropriate written procedures designed to prevent microbial contamination
391 include a well-defined and documented program for environmental monitoring that evaluates the
392 potential routes of microbial contamination of the human drug that could arise from the air,
393 surfaces, process, operation, and personnel practices (see §§ 211.42(c)(10)(iv), 211.100,
394 211.113(b)). The program should contain an appropriate detection component(s) to verify state
395 of control of the environment. However, environmental monitoring equipment should not
396 interfere with aseptic operations (e.g., instruments should not interfere with validated and
397 appropriate airflow patterns). In particular, the program should:
398
399
· Cover all production shifts and include monitoring during normal production conditions.
400
401
· Include at least daily monitoring of the ISO 5 zone during operations.
19 A viable particle consists of, or supports, one or more live microorganisms (see ISO 14644-6:2007, Cleanrooms and associated controlled environments--Part 6: Vocabulary).
20 See guidance for industry Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice for further recommendations regarding gowning.
10
Contains Nonbinding Recommendations
Draft -- Not for Implementation
402
403
· Establish alert and action limits and appropriate responses when excursions occur.
404
405
· Describe the use of sampling (e.g., contact plates, swabs, active air samplers), alert and
406
action limits and responses, and testing methods (e.g., media, plate exposure times,
407
incubation times and temperatures) that are designed to detect environmental
408
contaminants, including changes in microflora type and amount, and the scientific
409
justification for the testing methods selected.
410
411
· Be supported by a scientific justification for sampling locations, based on risk, and
412
sampling methods, which may be based on risk and peer-reviewed literature.
413
414
· Investigate results that exceed established limits or demonstrate adverse trends; determine
415
product impact; and execute appropriate actions.
416
417 Personnel monitoring should:
418
419
· Include a routine program for daily/shift monitoring of operators' gloves and an
420
appropriate schedule for monitoring other critical sites of the gown (e.g., gown sleeves
421
for hood work) during or immediately after completion of aseptic operations. Monitoring
422
should take place before planned disinfection so that actual operating conditions are
423
being assessed.
424
425
· Establish and justify limits that are based on the criticality of the operation relative to the
426
contamination risk to the product.
427
428
· Call for an investigation of results that exceed the established levels or demonstrate an
429
adverse trend, a determination of the impact on the sterility assurance of finished
430
products intended to be sterile, and the development and execution of appropriate
431
corrective actions.
432
433 If microbiological media used in performing tests, including environmental and personnel
434 monitoring, are not purchased from a qualified supplier,21 the outsourcing facility or contract
435 laboratory's procedures should establish the validity of each medium, including its growth
436 potential. The quality control unit of an outsourcing facility that opts to rely on a contract
437 laboratory for any of the duties described in this section of the guidance must ensure the
21 A supplier could be qualified by following the recommendations for component supplier qualification in section III.G.1. of this guidance. Specifically, the outsourcing facility should have a quality agreement with each supplier and make the quality agreement available for review upon request by FDA. Each quality agreement should include, at a minimum: a description of the testing performed before a lot is released and shipped to the outsourcing facility and the specific quantitative (or qualitative, if applicable) results of a representative lot that would be provided on each COA; examples of testing records (such as growth promotion) that the supplier generates in performing release testing before shipping each lot to the outsourcing facility; a description of packaging, labeling, tamper-evident seals, and other features used to ensure package integrity while the purchased media is in distribution; and a commitment that the supplier will notify the outsourcing facility if there is identification of a problem with the quality of the media already shipped to the outsourcing facility.
11
Contains Nonbinding Recommendations
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438 existence, appropriateness, and implementation of contract laboratory procedures (see §§ 200.10,
439 211.22, 211.160).
440
441
E. Equipment
442
443 Several provisions of part 211 address controls over the equipment used to compound (see
444 §§ 211.63, 211.65, 211.67, 211.68).
445
446 Equipment (mechanical, electronic, or automated) must be qualified as capable of performing its
447 intended functions or operations before first use, and procedures for routine calibration and
448 maintenance must be established and followed (see § 211.68). Equipment surfaces that come in
449 contact with components, in-process materials, or drugs must not be reactive, additive, or
450 absorptive so as to alter the quality of the drug (see § 211.65). Equipment needs to be designed
451 and located to facilitate operations, cleaning, and maintenance, and equipment may require
452 sanitization or sterilization to prevent contamination (see §§ 211.63, 211.67).
453
454 Outsourcing facilities may choose to use single-use disposable equipment (e.g., transfer tubing
455 and temporary holding vessels), which reduces the need for cleaning between different batches
456 and the potential for contamination (see § 211.67). Single-use disposable equipment should be
457 inspected for damage or contamination following use. The suitability of single-use disposable
458 equipment for its use in processing may be determined by the use of a valid COA from the
459 supplier in lieu of testing or examination by the outsourcing facility (see §§ 211.65, 211.113). In
460 addition, the integrity of the packaging of the single-use disposable equipment should be verified
461 upon receipt before use.
462
463 Additional Considerations for Sterile Drug Products
464
465 Equipment that comes into contact with the drug product must be evaluated to ensure adequacy
466 for intended use, including to ensure sterility and cleanliness at time of use (see §§ 211.65,
467 211.67(a)). For sterility and endotoxin limits, a valid COA may be used in lieu of testing by the
468 outsourcing facility for single-use disposable equipment (see §§ 211.65, 211.113).
469
470 If the outsourcing facility does not use presterilized and depyrogenated single-use disposable
471 equipment (e.g., filters, transfer tubing, temporary holding vessels), the equipment must be
472 sterilized and depyrogenated before use through processes that have been validated22 (see
473 §§ 211.65, 211.67(a) and (b), 211.100, 211.113).
474
475
F. Containers and Closures
476
477 Controls for the containers and closures in which the compounded drug product is packaged are
478 critical to ensuring the quality of compounded drug products and are expected to be implemented
479 by outsourcing facilities (see §§ 211.80, 211.82, 211.84, 211.87, 211.94, 211.113).
22 A process has been validated if it has been demonstrated and documented to consistently achieve the desired result when performed under defined conditions.
12
Contains Nonbinding Recommendations
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480 481 Scientifically sound and appropriate criteria23 for containers and closures must be established to 482 ensure that drug product containers and closures used for compounded drug products are suitable 483 for each particular drug product for which they will be used (see § 211.160(b)). As part of the 484 selection process, testing of the drug product container-closure system under the proposed 485 storage conditions for the finished product must be performed to verify its ability to meet 486 established quality specifications of the finished drug product over the expiry period (see §§ 487 211.94, 211.166). Testing must be performed again if the manufacturer's specification of the 488 container or closure is changed (see §§ 211.94, 211.166). Appropriate procedures must be 489 established for testing or verifying the testing, as applicable, of the containers and closures 490 before use to determine whether they meet the criteria for use; the tests and results must be 491 documented (see §§ 211.84(d)(3), 211.184). Each lot of containers and closures must be 492 examined to verify identity and tested to ensure conformity with appropriate specifications 493 before use (see § 211.84(d)). 494 495 Containers and closures must be handled and stored to protect them from risk of contamination 496 and must be examined and cleaned to prevent introduction of contamination (see §§ 211.80, 497 211.82, 211.84, 211.94). 498 499 If containers or closures are stored for long periods in the absence of a supplier's expiration date 500 or established in-use period, or if they are exposed to air, heat, or other conditions that might 501 adversely affect the drug product container or closure, the containers and closures must be 502 retested or re-examined for integrity and fitness for use before they are used (see § 211.87). 503 504 Additional Considerations for Sterile Drug Products 505 506 Containers and closures that come into contact with the drug product must be evaluated to ensure 507 adequacy for intended use, including to ensure sterility and cleanliness at time of use (see 508 §§ 211.80, 211.84(d)(6)). 509 510 FDA generally does not intend to take regulatory action against an outsourcing facility regarding 511 the identification or testing of each lot of containers and closures if (1) for a finished drug 512 product intended to be sterile, the supplier certifies and labels the material as ready-to-use, 513 sterile, and nonpyrogenic; (2) the supplier's packaging integrity is verified upon receipt before 514 use; and (3) the valid COA provided by the supplier is reviewed to verify that the product is 515 represented to meet the required specifications established by the outsourcing facility, including 516 sterility and depyrogenation. Any container or closure not meeting acceptance requirements must 517 be rejected or not used until rendered suitable for use (see §§ 211.84(d) and (e)). 518 519 If the outsourcing facility does not use presterilized and depyrogenated containers and closures 520 (e.g., vials, syringes), the containers and closures must be sterilized and depyrogenated before 521 first use through processes that have been validated (see § 211.94(c)). 522
23 For sterile drug products, see guidance for industry Sterile Drug Products Produced by Aseptic Processing-- Current Good Manufacturing Practice for recommended test methods and criteria.
13
Contains Nonbinding Recommendations
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523 Procedures for storage, if appropriate, of sterilized containers or closures must be established in a
524 manner to prevent contamination and to maintain sterility (see §§ 211.80(a) and (b)). For
525 example, safeguards must be in place to ensure that containers and closures are not contaminated
526 when held for use in areas where other materials are received, unpacked, and stored.
527
528 Containers or closures that are purchased as sterile must not be used after the supplier's
529 expiration date without testing or examination to verify that container or closure integrity has
530 been maintained (see § 211.87). Once the presterilized primary package has been breached, it
531 should remain under the hood or in the ISO 5 area until the containers or closures are used.
532 Where appropriate, any containers or closures removed from the ISO 5 area may be used for
533 sterile production after resterilization using a validated process (which must also establish that
534 the integrity of the container or closure is maintained) or used for drug products that do not
535 require a sterilized container or closure (§§ 211.84, 211.87, 211.94).
536
537
G. Components
538
539 Controls over the source and quality of components are required (§§ 211.82, 211.84, 211.87,
540 211.113). When producing sterile drug products, one aspect of such controls is the
541 consideration of whether the incoming components are non-sterile. The following controls are
542 considered critical to ensuring the quality of compounded drug products and are expected to
543 be implemented by outsourcing facilities.
544
545 Scientifically sound and appropriate specifications must be established for the components used
546 in each drug product (see § 211.160(b)). Scientifically sound and appropriate specifications
547 include those that address the attributes necessary to ensure the quality of the finished drug
548 product and are appropriate for the intended use of the drug product, including the route of
549 administration, as specified in the directions for use. A specification should generally conform to
550 the model described in the ICH guidance for industry Q6A Specifications: Test Procedures and
551 Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. A
552 specification should minimally include those tests described in ICH Q6A's section 3.2,
553 "Universal Tests/Criteria." Other dosage form-specific attributes may also be considered (see
554 ICH Q6A section 3.3, "Specific Tests/Criteria"). Attributes can include identity, strength, purity,
555 particle size, sterility, bacterial endotoxin level, content uniformity, microbial enumeration, tests
556 for specified microorganisms, or other characteristics that could affect the quality of the final
557 drug product.
558
559 To be eligible for the exemptions provided in section 503B of the FD&C Act, each bulk drug
560 substance used in compounding must be "accompanied by a valid certificate of analysis" (section
561 503B(a)(2)(D)). FDA interprets this provision to mean that each lot of a bulk drug substance is
562 accompanied by a valid COA.24 FDA recommends that the COA conform to the model described
563 in ICH Q6A.25 In addition, to be eligible for the exemptions provided in section 503B of the
24 Under certain conditions, a valid COA may be relied upon to minimize testing of incoming components (see § 211.84).
25 The COA should be in English or should be translated into English to facilitate use by the outsourcing facility and review by FDA on inspection if needed.
14
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564 FD&C Act, the bulk drug substance must be manufactured by an establishment that is registered
565 under section 510 of the FD&C Act (section 503B(a)(2)(C) of the FD&C Act).
566
567 Each shipment of each lot of components must be tested to verify identity and evaluated for
568 conformity with appropriate specifications before use (see § 211.84). Components should not be
569 used beyond the supplier's labeled expiration (or re-test) date. If the component does not have an
570 expiration date, the supplier should provide the date or testing should be conducted to establish
571 an expiration date.
572
573 Components that are not approved finished drug products (both active pharmaceutical
574 ingredients (APIs) and inactive ingredients) must be tested to verify identity and evaluated for
575 conformity with appropriate specifications and, if necessary and depending on intended use,
576 tested for endotoxin level and bioburden before use in compounding (see § 211.84). As described
577 in § 211.84(d)(2), in lieu of testing each shipment of each ingredient, a supplier's COA can be
578 accepted and evaluated to determine whether the lot can be used, provided that the following
579 conditions are met (see also Figure 1 below):
580
581
· The reliability of the supplier's analyses has been established at appropriate intervals and
582
through appropriate steps to:
583
584
o Confirm the supplier's test results for those tests relevant to the specifications
585
established for the compounded drug product.
586
587
o Confirm that the ingredient meets the applicable United States Pharmacopeia (USP)
588
or National Formulary (NF) monograph, if one exists.26
589
590
Such steps may include, but are not limited to, confirmatory testing and remote audit of
591
the supplier's procedures.
592
593
FDA recommends that these steps be carried out no less frequently than annually for
594
APIs and every 2 years for other components.
595
596
· At least one specific identity test has been conducted before use to confirm that the
597
component is the one specified in the purchase order.
598
599 In addition, as required by § 211.82(a):
600
601
· Each container or grouping of containers of components must be examined to verify
602
appropriate labeling regarding contents.
603
604
· The shipment's package integrity must be verified upon receipt before use.
605
26 Components, both bulk drug substances and other ingredients, used in compounding must comply with the standards of the applicable USP or NF monograph, if such monograph exists, to qualify for the exemptions provided in section 503B of the FD&C Act (see sections 503B(a)(2)(B) and (a)(3)).
15
Contains Nonbinding Recommendations
Draft -- Not for Implementation
606
607
Figure 1. Using a Supplier's COA in Lieu of Testing*
608
At appropriate intervals (e.g., annually for API and every 2 years for other
components):
· Confirm the supplier's test results for tests relevant to the product
Verify supplier analyses
specifications. · Confirm that the component meets the applicable USP or NF
monograph, if one exists.
Examine shipments
· Examine each container or grouping of containers to verify appropriate labeling regarding contents.
· Verify the package integrity of each container or grouping of containers.
· Conduct at least one specific identity test before use to confirm that the component is the one specified in the purchase order.
Conduct identity test on shipment
609 610 * See §§ 211.84(d)(2) and 211.82(a). 611 612 Acceptance of incoming lots of non-sterile components (including water) for use in sterile drug 613 products must include microbial and endotoxin testing and meet limits appropriate for the drug 614 product's intended use (see § 211.84(d)(6)). FDA generally does not intend to take regulatory 615 action against an outsourcing facility regarding the absence of such testing for water if it is 616 purchased and certified as sterile and nonpyrogenic and if it is accompanied by a valid COA; 617 however, the type of water purchased must be appropriate for its intended use (e.g., Sterile Water 618 for Injection, USP) (§ 211.84). The quality of water produced on-site and used as an ingredient 619 or processing aid must be tested regularly, using validated methods, at point of use to verify 620 acceptable microbial quality, chemical quality, and endotoxin limits (§§ 211.84, 211.160). 621 Acceptance criteria should be in agreement with those specified in the respective USP 622 monograph and be appropriate for the intended use of the product. 623 624 Any component not meeting acceptance requirements must be rejected (see § 211.84(e)). 625 626 Components must be retested or re-examined for identity, strength, quality, and purity after 627 storage for long periods or after exposure to air, heat, or other conditions that might adversely 628 affect the component (see § 211.87). However, additional testing is unnecessary if each lot of 629 components is stored under the supplier's labeled storage conditions, used within the established 630 (i.e., as labeled, as provided by the supplier, or as determined by the outsourcing facility) retest 631 or expiration date, and protected from contamination when portions of the lot are removed (see § 632 211.187). 633
16
Contains Nonbinding Recommendations
Draft -- Not for Implementation
634
1. Regulatory Policy Regarding Component Supplier Qualification Testing
635
636 FDA generally does not intend to take regulatory action against an outsourcing facility regarding
637 additional testing to confirm the supplier's COA under § 211.84(d)(2) if the outsourcing facility
638 enters into a quality agreement with each supplier of each component, makes the quality
639 agreement available for review upon request by FDA, and each quality agreement includes, at a
640 minimum:
641
642
· A description of the testing performed before a component lot is released and shipped to
643
the outsourcing facility and the specific quantitative (or qualitative, if applicable) results
644
of a representative lot that would be provided on each COA.
645
646
· Examples of testing records, such as chromatograms and spectrograms, that the
647
component supplier generates in performing release testing before shipping each lot of
648
the component to the outsourcing facility.
649
650
· A description of packaging, labeling, tamper-evident seals, and other features used to
651
ensure package integrity while the purchased component is in distribution.
652
653
· A commitment that the component supplier will notify the outsourcing facility if any
654
testing performed to generate the release COA is significantly modified (e.g., change in
655
principle of operation for a test method).
656
657
· A commitment that the component supplier will notify the outsourcing facility under
658
specified circumstances, including but not limited to a change in specifications or
659
identification of a problem with the quality of a component already shipped to the
660
outsourcing facility.
661
662
· A commitment that the supplier, if not the original component manufacturer, ensures the
663
component's pedigree to the outsourcing facility, including:
664
665
o A description of the supplier's qualification and audit requirements for each
666
manufacturer from which the supplier purchases components.
667
668
o A description of the supply chain authentication controls that the supplier has
669
implemented to verify that before receipt, each component is transported through
670
known and pre-established channels.
671
672
2. Regulatory Policy Regarding Testing for Finished Product To Be Used as a
673
Source Material for Processing
674
675 FDA generally does not intend to take regulatory action against an outsourcing facility regarding
676 the identification or testing of each lot of a product under § 211.84 that is to be used as a source
17
Contains Nonbinding Recommendations
Draft -- Not for Implementation
677 material and is an approved human finished drug product if all of the following conditions are
678 met:
679
680
· The product was purchased directly from a manufacturer registered and listed with FDA
681
under section 510 of the FD&C Act and has not been repacked or otherwise altered since
682
initial manufacture, or the product was purchased from a distributor that certifies that it
683
has not been repacked or otherwise altered since initial manufacture.
684
685
· The label of each lot of the product has been examined to verify that the product meets
686
required specifications before use.
687
688
· No portion of the lot has been subject to a recall for reasons that would make it unsuitable
689
for use.
690
691
· The shipment's package integrity has been verified upon receipt before use.
692
693
H. Production and Process Controls
694
695 Production and process controls are required when producing any drug product (see, e.g.,
696 §§ 211.22, 211.25, 211.28, 211.100, 211.111, 211.113, 211.188, 211.192).
697
698 Written procedures for production and process controls must be designed and followed to ensure
699 the consistent production of a drug that meets the applicable standards of identity, strength,
700 quality, and purity (see § 211.100). These controls are intended to ensure consistent yields;
701 batches failing to meet the theoretical yield must be investigated (see §§ 211.186, 211.192). The
702 degree of batch-by-batch control over product attributes or process parameters should be
703 commensurate with the risk of those attributes and parameters to the process and product. These
704 procedures should ensure documentation that all key process parameters are controlled and that
705 any deviations from the procedures are justified.
706
707 Before use in production, equipment, components, containers, and closures should be visually
708 examined for indications of damage, degradation, or contamination.
709
710 Batch records must provide complete documentation of the production of each batch of a drug
711 product (see § 211.188).27 The actual batch output (yield) must be compared to the projected
712 (calculated) output for each drug product (see § 211.103). If the actual output is different than
713 expected after accounting for sampling and known process loss, this finding should be
714 considered an indicator of a potential problem with production and must be investigated
715 (§ 211.192). An acceptance level for actual output should be established that ensures batch-to-
716 batch consistency. Failure to meet the acceptance criteria and production standards must be
717 investigated before making the batch disposition decision and may require that the batch be
718 rejected (see §§ 211.165, 211.192).
719
27 For aseptic operations that occur in a hood, a contemporaneous recording to the batch record is one that occurs as soon as possible after completion of that unit operation.
18
Contains Nonbinding Recommendations
Draft -- Not for Implementation
720 Additional Considerations for Sterile Drug Products
721
722
1. General Production and Process Controls
723
724 If a drug product intended to be sterile is not terminally sterilized, there must be a validated
725 sterilization step such as sterile filtration (see § 211.113(b)), and it is critical that the sterilization
726 step occur as close to filling into the final product container as is feasible.
727
728 The microbiological content (bioburden) of articles and components that are subsequently
729 sterilized should be controlled. If materials are stored or held during processing (e.g., before
730 sterilization, after sterilization, before container fill), storage or holding times must be
731 established (see §§ 211.110(c), 211.111). Production phase hold times for a drug product should
732 be limited, verified by testing, and based on an understanding of the associated risk of increased
733 bioburden and endotoxin. Hold time assessments can be performed as part of the process for
734 validating sterility assurance (see §§ 211.111, 211.113(b), 211.160). In addition, in-process
735 materials such as bulk stock solutions must be stored in equipment that is protective and does not
736 affect the quality of the drug beyond its established specifications (see §§ 211.65, 211.113(b)).
737
738
2. Drug Product Sterilization
739
740
a. Terminal sterilization
741
742 For sterile drug products that are terminally sterilized, at least a 10-6 sterility assurance level
743 should be demonstrated in validation studies during process development using an appropriate
744 sterilization load monitor, such as biological indicators and thermocouples.28 Validation studies
745 should be performed for each load size (container closure and number of vials) intended for
746 sterilization. For terminally sterilized drug products that are not subjected to an overkill terminal
747 sterilization cycle, presterilization bioburden limits should be established (i.e., determining the
748 number of microorganisms that can be reliably killed) and measured before sterilization. The
749 selected sterilization method should both sterilize and maintain the strength, purity, quality, and
750 package integrity of the sterile product.29
751
752
b. Aseptic processing
753
754 If a drug product intended to be sterile is not terminally sterilized, the finished drug product
755 should be sterilized immediately before filling into the final product container. This is typically
756 done by filtration; however, other validated sterilization methods may be used. If a finished drug
28 See guidance for industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. For products such as pellets or powders, validation studies should be conducted using a biological indicator placed inside the product (i.e., inside the powder or pellets in their marketed containers) and spaced throughout the load to verify that the sterilization cycle results in sterility of the entire batch. Pellets should be placed in a defined and specified pattern in the sterilization chamber to demonstrate that appropriate lethality is delivered to each unit of the batch. Refer to ISO 11137-1:2006, Sterilization of health care products--Radiation--Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices; and ISO 11137-2:2013, Sterilization of health care products-- Radiation--Part 2: Establishing the sterilization dose. See PDA Technical Report No.1 (Parenteral Drug Association 2007).
29 See also USP General Chapters <1211> Sterility Assurance and <1229> Sterilization of Compendial Articles.
19
Contains Nonbinding Recommendations
Draft -- Not for Implementation
757 product cannot be filtered (e.g., certain suspensions), components should be sterilized (e.g.,
758 filter) at the last possible step (e.g., before forming the suspension). Manipulations following the
759 component sterilization step must use aseptic practices to maintain sterility (see § 211.113).
760
761 Introductory training on microbiology, aseptic technique, cleanroom behavior, gowning, and
762 procedures covering aseptic manufacturing area operations must be established and conducted
763 before an individual is permitted to enter the aseptic manufacturing area or conduct operations in
764 a laminar flow hood (see § 211.25(a)). Once introductory training outside of the aseptic
765 manufacturing area is completed, further training based on department-specific requirements and
766 individual job descriptions should be conducted. Individuals would be considered qualified to 767 conduct aseptic operations after passing at least three successful, successive media fill
768 simulations based on a scientifically sound protocol designed to verify the adequacy of their
769 technique and behavior. Production simulations should be conducted in the same area where
770 production occurs.
771
772 Techniques intended to maintain sterility of items and surfaces should include the following:
773
774
· Sterile materials should be handled only with sterile instruments.
775
776
· After initial gowning, sterile gloves should be regularly sanitized (e.g., using sterile 70
777
percent isopropyl alcohol) during production or, when needed, changed.
778
779
· Sterile and non-shedding gowning components should be used. Gowning components
780
should be stored such that their sterility is not compromised.
781
782
· Torn or defective gowns should be changed immediately.
783
784
· Sterile products, the product-contacting surfaces of containers or closures, or other
785
critical surfaces should not directly touch any part of the gown or gloves.
786
787
· Personnel should move slowly and deliberately within the cleanroom or hood.
788
789
· Personnel should keep their bodies and objects out of the path of unidirectional flow
790
above open containers and products being filled.
791
792 Procedures for aseptic processing should address the following considerations:
793
794
· The design of equipment used in aseptic processing should limit the number and
795
complexity of aseptic manipulations and should be suitable for its intended use.
796
797
· Personnel, material, and process flow should be optimized to prevent unnecessary
798
activities that could increase the potential for introducing contaminants to exposed
799
product, containers or closures, or the surrounding environment.
800
801
· In-process material, including intermediates such as stock solutions, should be placed in
802
containers or closures that protect the material from the cleanroom environment.
20
Contains Nonbinding Recommendations
Draft -- Not for Implementation
803
Containers or closures holding sterile in-process material should not be breached in an
804
environment less than ISO 5.
805
806
· Products should be transferred under appropriate cleanroom conditions. For example,
807
transfer, loading, and unloading of aseptically filled product to and from the lyophilizer
808
should occur only in classified areas that provide ISO 5 or better protection to the
809
partially sealed containers.
810
811
· All aseptic manipulations, including processing of sterile materials, filling, and closing
812
(e.g., placement and sealing of stoppers on vials), should be performed under
813
unidirectional flow that is ISO 5 or better.
814
815
· Appropriate steps to prepare equipment for sterilization should be established, such as
816
cleaning and use of wrapping that ensures protection while still allowing penetration of
817
the sterilizing agent.
818
819
· The validation of sterilization operations for equipment associated with aseptic
820
processing (e.g., holding vessels, filling equipment, lyophilizer) and periodic verification
821
activities and results must be documented (see § 211.113(b)).
822
823
· For sterile drug products that are filter-sterilized, prefiltration bioburden limits should be
824
established and measured before sterile filtration, unless all components consist of FDA-
825
approved sterile drug products and/or components purchased and certified to be sterile
826
and nonpyrogenic. A sterile pharmaceutical sterilizing-grade filter appropriate for the
827
drug product (e.g., chemically compatible) should be used. The filter must be compliant
828
with § 211.72 and filter integrity testing should be conducted after each filtration or
829
production run.
830
831 For aseptic processing of sterile drug products (i.e., not subjected to terminal sterilization), the
832 process for ensuring sterility must be validated (§ 211.113(b)), for example by conducting media
833 fills simulating the production process. Validation should be performed semi-annually. Media fill
834 studies should closely simulate aseptic manufacturing operations incorporating, as appropriate,
835 worst-case activities and conditions that are challenging to aseptic operations. The media fill
836 program should address applicable issues such as the following:
837
838
· Factors associated with the longest permitted run of the aseptic processing operation that
839
can pose contamination risk (e.g., operator fatigue, quality of processing environment).
840
841
· Representative number, type, and complexity of normal interventions that occur with
842
each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages,
843
equipment adjustments). (The maximum number of expected interventions should be
844
included to simulate worst-case conditions.30)
30 When the possibility of contamination is higher based on the process design (e.g., manually intensive filling lines), a larger number of units, generally at or approaching the full production batch size, should be used. In contrast, a process conducted in an isolator can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation.
21
Contains Nonbinding Recommendations
Draft -- Not for Implementation
845
846
· Lyophilization, when applicable.
847
848
· Aseptic assembly of equipment (e.g., at start-up, during processing).
849
850
· Number of personnel and their activities. (The maximum expected number of personnel
851
should be included to simulate worst-case conditions.)
852
853
· Representative number of aseptic additions (e.g., filling containers and closures as well as
854
sterile ingredients) or transfers.
855
856
· Shift changes, breaks, and gown changes (when applicable).
857
858
· Type of aseptic equipment disconnections/connections.
859
860
· Aseptic sample collections.
861
862
· Operational configurations in the ISO 5 zone and line speeds (when applicable).
863
864
· Weight checks.
865
866
· Container-closure systems (e.g., size, type, compatibility with equipment).
867
868
· Specific provisions in written procedures related to aseptic processing (e.g., conditions
869
beyond which discarding of exposed materials in the ISO 5 area or line clearance is
870
mandated).
871
872
I. Release Testing
873
874 Sections 211.165 and 211.167 require that finished drug products be tested to determine whether
875 they meet final product specifications before their release for distribution. Section 211.22
876 establishes that the quality control unit is responsible for ensuring that the finished drug product
877 is not released until this testing is conducted and the results confirm that the finished drug
878 product meets specifications. Procedures for final release testing should be established and
879 followed as outlined here.
880
881 Appropriate specifications must be established for each drug product (see § 211.160(b)).
882 Specifications must address those attributes necessary to ensure the quality of the finished drug
883 product and must include, at a minimum (§§ 211.160(b), 211.165, 211.167):
884
885
· Identity and strength of the API.31
31 If the API is known (from literature or other scientific information) to have the potential to form genotoxic degradants as discussed in ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk, the presence of the impurity or impurities should be evaluated as part of the assay or, if the assay method is not sufficiently sensitive, using a different test.
22
Contains Nonbinding Recommendations
Draft -- Not for Implementation
886
887
· Purity of the drug product.
888
889
· For drug products purporting to be sterile and/or nonpyrogenic, sterility32 and a limit for
890
bacterial endotoxins.
891
892
· Antimicrobial effectiveness for sterile drug products labeled as multiple dose and for
893
aqueous non-sterile drug products labeled as multiple dose.33 If antimicrobial
894
effectiveness testing was previously performed using the subject formulation and
895
container-closure system, preservative content testing may be used in lieu of a full
896
antimicrobial effectiveness study. Appropriate specifications for aqueous drug products
897
labeled as multiple dose include assurances that the product is adequately self-preserving
898
or contains appropriate preservative content to limit microbial proliferation of
899
microorganisms and assure that the product maintains its quality and purity for each
900
dose.34
901
902 The product must also meet any other specifications included in an applicable USP monograph
903 (see, e.g., section 501(b) of the FD&C Act). In addition, FDA recommends consideration of the
904 following specifications:
905
906
· Color, clarity.
907
908
· pH, if applicable (e.g., for aqueous formulations).
909
910
· For drug products that are not solutions, content uniformity.35
911
912
· For drug products that are non-sterile, microbial testing (i.e., microbial enumeration, tests
913
for specified microorganisms).
914
32 Sterility testing should be conducted using USP General Chapter <71> Sterility Tests. Any other method used for sterility testing should be validated. See, for example, USP General Chapter <1223> Validation of Alternative Microbiological Methods or PDA Technical Report No. 33 (see Parenteral Drug Association 2013) for recommended validation methods. 33 See USP General Chapter <51> Antimicrobial Effectiveness Testing for more information. 34 Unsafe injection practices, including the improper use of needles, syringes, and vials for more than one patient, threaten patient safety and have resulted in multiple blood borne bacterial and viral infection outbreaks. Bacterial infections have been transmitted to patients when single-dose containers were used improperly, the contents became contaminated, and these contents were then administered to multiple patients. Therefore it is critical that drug products that are not adequately self-preserving and do not contain appropriate preservative content be labeled as single-dose to prevent such risks to health. 35 For oral solid dosage forms (e.g., tablets and capsules), content should be assessed between dosage units. For nonsolid oral products (e.g., suspensions), the content should be assessed within the container (e.g., from the top and bottom of the container).
23
Contains Nonbinding Recommendations
Draft -- Not for Implementation
915
· For drug products that are solutions purporting to be sterile, a limit for visible particles36
916
and subvisible particles (10µm-100µm).37
917
918 Other appropriate specifications for generally recognized attributes for the dosage form, such as
919 those described in ICH Q6A, should also be considered. For example, the specification for
920 immediate release solid oral dosage forms typically includes disintegration testing, while non-
921 immediate release dosage forms include dissolution testing as a measure of the release rate of
922 drug substance from the drug product (see § 211.167).
923
924 Procedures for release must be established that ensure that each batch of a drug product is not
925 released until the following have been completed (see §§ 211.22, 211.165, 211.167, 211.192):
926
927
· An appropriate laboratory determination has been conducted to ensure that each batch of
928
a drug product conforms to specifications.
929
930
· A review of environmental and personnel monitoring data, if applicable, has been
931
conducted to ensure that manufacturing conditions were acceptable during production of
932
the batch.
933
934
· Associated laboratory data and documentation have been reviewed by the quality control
935
unit, and they demonstrate that the drug product meets specifications.
936
937
· A designated qualified individual from the quality control unit has authorized final
938
release.
939
940 Under certain conditions described in Appendix A, FDA generally does not intend to take action
941 against an outsourcing facility regarding the release testing requirements described immediately
942 above and in the appendix.
943
944 Additional Considerations for Sterile Drug Products
945
946 Finished product sterility testing provides additional verification of sterility, even for those
947 products compounded from sterile starting materials, because an unexpected event posing a risk
948 to sterility may have occurred but may not have been detected. Appendix A describes the
949 conditions under which FDA generally does not intend to take regulatory action against an
950 outsourcing facility regarding finished product sterility testing based on mitigating factors, such
951 as the use of a validated terminal sterilization method and the use of other approaches to evaluate
952 sterility of the finished product before release.
953
36 Such a limit may be established for any solution by following USP General Chapter <790> Visible Particulates in Injections.
37 Applicable only to parenteral preparations. See USP General Chapters <788> Particulate Matter in Injections and <789> Particulate Matter in Ophthalmic Solutions for additional information.
24
Contains Nonbinding Recommendations
Draft -- Not for Implementation
954 For finished products purporting to be nonpyrogenic, the product must meet endotoxin limits38
955 before release (§ 211.167). For finished products compounded from starting materials that are
956 sterile and nonpyrogenic, endotoxin testing can be conducted on all starting materials (through
957 testing of the starting materials, or reliance on a statement of the limit met on a valid COA, or
958 where specified in an applicable USP monograph) or through testing of samples of the finished
959 product. The fact that a starting material is labeled nonpyrogenic does not necessarily ensure that
960 the finished product will meet the appropriate endotoxin limit because starting materials,
961 including FDA-approved products, may have been tested against different endotoxin limits,
962 depending on the intended dose and the route of administration.39
963
964
J. Laboratory Controls
965
966 When testing components, in-process materials, and finished drug products, laboratories must
967 use controls to ensure the reliability of the tests (§ 211.160). Each laboratory used to test
968 components, in-process materials, or finished drug products--whether in-house or external to the
969 outsourcing facility--must employ the following critical aspects of laboratory controls to ensure
970 the quality of non-sterile and sterile drug products compounded by the outsourcing facility (see
971 §§ 211.160, 211.194):
972
973
· Follow appropriate written procedures for the conduct of each test and document the
974
results.
975
976
· Design sampling and testing procedures to ensure that components, in-process materials,
977
and drug products conform to the specifications set for the drug product.
978
979
· Use analytical methods and equipment that are suitable for their intended use and are
980
capable of producing valid results. If using a validated or an established compendial test
981
procedure in a specification, the test has been verified and documented to work under the
982
conditions of actual use.
983
984
· Keep complete records of all tests performed to ensure compliance with established
985
specifications and standards, including examinations and assays.
986
987 When an outsourcing facility seeks the services of a contract facility to perform all or part of the
988 testing of a drug, the outsourcing facility's quality control unit is responsible for approving and
989 rejecting drugs tested by the contractor. See §§ 200.10(b) and 211.22(a) and guidance for
990 industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. In addition,
991 FDA recommends that contract facilities performing testing of a drug be ISO 17025 accredited.
992
38 Typically, endotoxin testing is not required for topically administered ophthalmic products. See USP General Chapter <771> Ophthalmic Products--Quality Tests. 39 See also guidance for industry Pyrogens and Endotoxins Testing: Questions and Answers.
25
993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034
Contains Nonbinding Recommendations
Draft -- Not for Implementation
K. Stability/Expiration Dating for Compounded Drug Products
1. Stability Program and Beyond-Use Dating
A stability program must be established to assess the stability characteristics of finished drug products, and the results of stability testing must be used to determine appropriate storage conditions and expiration dates (§ 211.166). Stability testing is used to ensure that a drug product will retain its quality (e.g., strength) and remain sterile, if applicable, through the labeled expiration date. A stability program for compounded drug products should use past experiences, available literature, and fundamental scientific principles to establish the parameters for the program. An expiration date is established through the conduct of a stability program that includes testing to assess the product's performance against specifications after aging to the desired expiration date (§ 211.137); the conditions outlined in ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products are recommended.
FDA understands that a compounded drug's batch size may be small and the frequency of batch production may vary considerably. The policies regarding stability testing and expiration dating in this guidance recognize these potential aspects of compounded drug production while addressing concerns regarding the quality of these products using a risk-based approach.
FDA generally does not intend to take regulatory action against an outsourcing facility regarding stability testing requirements if all of the following apply:
· The drug product is compounded solely by combining two or more drug products approved under section 505 of the FD&C Act.
· The approved drug product labeling of at least one of the components specifies how to assign an in-use time.
· The compounded drug product has been prepared and labeled with an in-use time in accordance with the approved product labeling.
· The in-use time is used as the expiration date, provided the in-use time does not exceed the expiration date of any of the approved drug products used to compound the drug. If two or more approved drug products with in-use times are used in the compounded drug product, the shortest in-use time is used as the expiration date for the compounded drug product.
In addition, taking into account the unique aspects of compounding, FDA generally does not intend to take regulatory action against an outsourcing facility under the conditions described in the remainder of this section and in Appendix B, such as using a BUD established through limited stability testing or, for certain lower risk situations, using a default BUD as the expiration
26
1035 1036 1037
1038 1039 1040
1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072
Contains Nonbinding Recommendations
Draft -- Not for Implementation
date, in lieu of establishing an expiration date through the conduct of a full stability program required under part 211,40 if all of the following apply:
· The compounded drug's BUD does not exceed appropriately established expiration or retest-by dates for any of the components used to compound the drug.
· If the drug is compounded from an approved drug product, and the approved product labeling recommends one type of storage (e.g., refrigeration through the expiry date, such as 18 months), but also provides for storage at another condition (e.g., stable at room temperature for a time frame shorter than the expiry date, such as up to 14 days), the compounded drug product is not labeled with a BUD that is longer than the relevant storage time frame in the approved product labeling (e.g., the BUD of the compounded drug does not exceed 14 days for room temperature).
In addition, for repackaged products, FDA generally does not intend to take regulatory action against an outsourcing facility under the conditions described in the remainder of this section and in Appendix B, in lieu of establishing an expiration date through the conduct of a full stability program, if (1) the BUD does not exceed the expiration date of the drug product that is being repackaged; and (2) if the approved product labeling for the drug product being repackaged recommends one type of storage (e.g., refrigeration through the expiry date, such as 18 months) but also provides for storage at another condition (e.g., stable at room temperature for a time frame shorter than the expiry date, such as up to 14 days), the repackaged product is not labeled with a BUD that is longer than the relevant storage time frame in the approved product labeling (e.g., the BUD does not exceed 14 days for room temperature). For more information on repackaging, see the guidance for industry Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities.
Whether you use an expiration date or BUD to be used as an expiration date according to the provisions outlined below and in Appendix B, the two studies below are required to be completed before a batch is released (see §§ 211.166, 211.167). Each study only needs to be conducted once for each formulation and container-closure system, and a bracketing or matrixing approach can be considered to minimize the amount of testing. See Appendix B for more information regarding bracketing approaches.
· Container-closure integrity testing is conducted on samples aged to or beyond the desired BUD or expiration date to ensure that sterility is maintained over that time period.41
40 To meet the conditions under section 503B of the FD&C Act, the compounded drug product must be labeled with an expiration date (see section 503B(a)(10)(A)(iii)(VI)). 41 See USP General Chapter <1207> Package Integrity Evaluation--Sterile Products for more information on container-closure integrity testing.
27
1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095
1096
Contains Nonbinding Recommendations
Draft -- Not for Implementation
· Antimicrobial effectiveness testing for drug products labeled or intended to be multiple dose is conducted on samples aged to the proposed BUD or expiration date. (Note that antimicrobial effectiveness testing is container-closure specific.)42
Tables 2 and 3 highlight the conditions under which FDA generally does not intend to take regulatory action against an outsourcing facility for assigning a BUD to be used as an expiration date in lieu of conducting full stability studies required under part 211.
a. Non-sterile limited stability testing
For small batches (5,000 units43 in an aggregate batch44), FDA generally does not intend to take regulatory action if the relevant default BUDs provided in Appendix B are used for the expiration date and the conditions set forth in Appendix B are met. Alternatively, for small batches, FDA generally does not intend to take regulatory action if limited stability testing is conducted to support a BUD longer than the relevant default BUDs in accordance with Appendix B, and that BUD is used as an expiration date in lieu of conducting full stability studies required under part 211. For larger batches (>5,000 units in an aggregate batch), FDA generally does not intend to take regulatory action regarding stability testing if the relevant conditions for the limited stability testing outlined in Appendix B are met. If, at any time during a 6-month reporting period, the total number of units compounded exceeds the 5,000-unit limit, the conditions applicable to small batches (i.e., 5,000 units) do not apply.
Table 2. BUDs for Non-Sterile Compounded Drug Products, by Aggregate Batch Size
Aggregate Batch Size (over 6-month reporting period)
5,000 units
>5,000 units
Default BUD (no testing)
Default BUD, which may be further limited by literature or other scientific information.
See Appendix B for the conditions that must be met.
N/A. Default BUDs are not applicable to large aggregate
batch sizes.
BUD Based on Limited Stability Testing
Data-driven stability program. See Appendix B for the
conditions that must be met.
Data-driven stability program. See Appendix B for the
conditions that must be met.
42 See USP General Chapter <51> Antimicrobial Effectiveness Testing for more information. 43 Units are individual tablets or capsules for solid oral dosage forms and suppositories, inserts, or immediate containers (e.g., vial, syringe, IV bag, tube) for other dosage forms. 44 For the purposes of this guidance, batch size has been considered by defining aggregate batch as the sum of all units produced from any number of batches over the 6-month period for which a drug product report is submitted. For more information about product reports, see the guidance for industry Electronic Drug Product Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act.
28
1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111
1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127
Contains Nonbinding Recommendations
Draft -- Not for Implementation
b. Sterile limited stability testing
For small batches (1,000 units in an aggregate batch), FDA generally does not intend to take regulatory action if the relevant default BUDs provided in Appendix B are used for the expiration date and the conditions set forth in Appendix B are met. Alternatively, for small batches, FDA generally does not intend to take regulatory action if limited stability testing is conducted to support a BUD longer than the relevant default BUDs in accordance with Appendix B, and that BUD is used as an expiration date in lieu of conducting full stability studies required under part 211. For larger batches (>1,000 units in an aggregate batch), FDA generally does not intend to take regulatory action regarding stability testing if the relevant conditions for the limited stability testing outlined in Appendix B are met. If, at any time during a 6-month reporting period, the total number of units compounded exceeds the 1,000-unit limit, the conditions applicable to small batches (i.e., 1,000 units) do not apply.
Table 3. BUDs for Sterile Compounded Drug Products, by Aggregate Batch Size
Aggregate Batch Size (over 6-month reporting period)
1,000 units
>1,000 units
Default BUD (no testing)
Default BUD, which may be further limited by literature or other scientific information.
See Appendix B for the conditions that must be met.
N/A. Default BUDs are not applicable to large aggregate
batch sizes.
BUD Based on Limited Stability Testing
Data-driven stability program. See Appendix B for the
conditions that must be met.
Data-driven stability program. See Appendix B for the
conditions that must be met.
2. Establishing an In-Use Time for Sterile Drug Products
To be eligible for the exemptions under section 503B of the FD&C Act, the container for the compounded drug product must include directions for use, including, as appropriate, dosage and administration (section 503B(a)(10)(B) of the FD&C Act). If the compounded drug product requires additional manipulation before administration (e.g., reconstitution and/or dilution), FDA interprets the directions for use requirement to include an in-use time because the health care practitioner who manipulates or administers the drug would need to know how long it is expected to retain its quality after being manipulated. Furthermore, stability studies (as required by § 211.166) would be needed to support the stated in-use time. However, FDA generally does not intend to take regulatory action regarding the requirement to have data to support the stated in-use time, such as microbial challenge and stability studies, if the sterile product has directions for use that include an in-use time less than 4 hours at room temperature or less than 24 hours refrigerated.45
45 For a description of methods and acceptance criteria for microbial challenge studies, see Metcalfe 2009.
29
1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167
Contains Nonbinding Recommendations
Draft -- Not for Implementation
Under §§ 211.160 and 211.165(b), appropriate laboratory testing of products required to be free of objectionable microorganisms are required, and laboratory controls must include scientifically sound and appropriate specifications and test procedures designed to provide assurance that the product conforms to appropriate standards of identity, strength, quality, and purity. For multiple dose products, appropriate laboratory tests and specifications include ones for antimicrobial effectiveness, whether the product contains a preservative or antimicrobial activity is inherent in the formulation. See USP General Chapter <51> for antimicrobial effectiveness test methods and acceptance criteria. If the acceptance criteria described in USP General Chapter <51> are met, labeling up to a 28-day in-use period is considered to be appropriate for multiple-dose products, subject to the conditions regarding stability testing discussed below.
In addition to microbial challenge studies, the stability of the manipulated product must be assessed (see § 211.166). FDA generally does not intend to take regulatory action regarding the requirement to conduct full stability studies to assess the stability of the manipulated product if the tests conducted as part of the limited stability testing described in Appendix A are conducted on samples aged to at least 2/3 of the labeled BUD (if longer than the default BUDs outlined in Appendix B), manipulated (e.g., reconstituted or diluted) as described in labeling, and then held for the desired in-use time (up to 28 days).
The labeled directions for use46 should include instructions to the health care provider or patient that the time in storage plus the administration phase should not exceed the BUD. Consider, for example, a sterile powder formulation in a vial that must be reconstituted with Sterile Water for Injection, USP, before patient administration with a label that includes an in-use-time of within 4 hours at room temperature or within 24 hours if refrigerated. The in-use time begins when the sterile powder vial is entered and reconstituted with Sterile Water for Injection, USP. The reconstituted solution should be administered to the patient within 4 hours if the solution is held at room temperature or within 24 hours if it is stored in the refrigerator.
3. In-Use Time and BUDs for Sterile Drug Products
The outsourcing facility should establish the BUD placed on a compounded drug product's label, taking into consideration that the BUD is the date/time after which the product is to be discarded. The labeled directions for use should include instructions to the health care provider or patient accordingly. If the product does not require any manipulation (e.g., dilution or reconstitution) before administration, the directions for use should advise that administration to the patient should be completed before reaching the BUD. For example, if an IV bag containing a compounded drug product with a BUD of 24 hours is to be infused to the patient over a period of 4 hours, the infusion should begin by 20 hours to ensure that administration will be complete before reaching the BUD, at which point the compounded drug product should be discarded.
46 Section 503B(a)(10)(B) of the FD&C Act provides the following: "The container from which the individual units of the drug are removed for dispensing or for administration . . . shall include . . . directions for use, including, as appropriate, dosage and administration."
30
1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207
1208 1209 1210 1211 1212 1213
Contains Nonbinding Recommendations
Draft -- Not for Implementation
L. Packaging and Labels
Packaging of non-sterile and sterile drugs must be appropriate to the product and capable of ensuring the sterility, if applicable, and integrity of the product until it is administered to a patient (see §§ 211.94, 211.122). Labels must contain required information, and labeling operations must include controls to prevent mix-ups; furthermore, procedures must be developed to ensure these requirements are met (§§ 211.122, 211.125, 211.130, 211.134).
The following aspects of packaging and labeling are critical to ensure the quality of compounded drug products and must be implemented by outsourcing facilities:
· The container, closure, and packaging systems provide adequate protection against foreseeable external factors in storage, shipment, and use that could cause contamination or deterioration of the finished drug product (e.g., cracked vials, leaks in bags) (§ 211.94).
· Adequate controls have been established for issuing labels, examining issued labels, and reconciliation of used labels to prevent mix-ups (§ 211.125).
· There is adequate separation between the labeling and packaging operations of different products, including ones with different strengths or containers or closures, to prevent mix-ups (§ 211.130).
· Adequate controls have been established to ensure proper identification of any filled containers of non-sterile or sterile drug products that will be stored unlabeled for any period of time (§ 211.130).
· Packaging records include results of examinations of labels used (§ 211.134) and specimens or copies of all labeling used (§ 211.188).
· The labeled finished drug product has been examined for accuracy before release (§ 211.134).
M. Reserve Samples
An appropriately identified reserve sample that is representative of each lot or batch of drug product must be retained and stored under conditions consistent with product labeling (§ 211.170). FDA generally does not intend to take regulatory action against an outsourcing facility regarding reserve sample requirements if all of the following apply:
· Once >10,000 units are produced of a given drug product formulation and containerclosure system in a 6-month reporting period, an appropriately identified and representative reserve sample is collected each time 1,000 units of that specific formulation and container-closure system is produced for the remainder of the current reporting period and for the entire subsequent 6-month reporting period.
31
1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238
1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259
Contains Nonbinding Recommendations
Draft -- Not for Implementation
· The reserve sample is retained and stored under the labeled storage conditions and in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics (e.g., same material, same headspace for liquids).
· The reserve sample is held for at least 30 days following the expiration date.
· The reserve sample consists of at least the quantity of drug product necessary for all tests required at release, except for sterility and pyrogen testing.
N. Complaint Handling
Outsourcing facilities must have procedures for handling complaints that they receive about their compounded drug products (§ 211.198). Written and oral complaints concerning the quality or purity of a drug product must be reviewed by the quality control unit, which must determine the need to investigate the complaint in accordance with § 211.192 (§ 211.198). If an investigation is needed, in addition to the quality control unit, personnel appropriate to evaluate the complaint should be involved. Complaint handling procedures must include provisions for review to determine whether the complaint represents an adverse event that must be reported to FDA (see § 211.198, section 301(ccc)(3) of the FD&C Act, and the guidance for industry Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act).
IV. REFERENCES
Literature
FDA, 1993, Guide to Inspections of High Purity Water Systems, Silver Spring, MD.
Metcalfe, JW, 2009, Microbiological Quality of Drug Products After Penetration of the Container System for Dose Preparation Prior to Patient Administration, American Pharmaceutical Review.
Parenteral Drug Association, 2007, Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control, PDA Technical Report No. 1 (TR1), Bethesda, MD.
Parenteral Drug Association, 2013, Evaluation, Validation and Implementation of Alternative and Rapid Microbiological Methods, PDA Technical Report No. 33 (TR33), Bethesda, MD.
Guidances for Industry
Guidance for industry Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act
32
1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305
Contains Nonbinding Recommendations
Draft -- Not for Implementation
Guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements
Guidance for industry Electronic Drug Product Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act
Guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production
Guidance for industry Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application
Guidance for industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination
Guidance for industry Pyrogens and Endotoxins Testing: Questions and Answers
Guidance for industry Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities
Guidance for industry Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice
Guidance for industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products
Guidance for industry Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes
ICH Guidances for Industry
ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk
ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products
ICH guidance for industry Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
ICH guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
ISO Standards
ISO 11137-1:2006, Sterilization of health care products--Radiation--Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices
33
1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351
Contains Nonbinding Recommendations
Draft -- Not for Implementation
ISO 11137-2:2013, Sterilization of health care products--Radiation--Part 2: Establishing the sterilization dose
ISO 14644-1:2015, Cleanrooms and associated controlled environments--Part 1: Classification of air cleanliness by particle concentration
ISO 14644-6:2007, Cleanrooms and associated controlled environments--Part 6: Vocabulary
V. GLOSSARY
Action Limit: An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.
Active Pharmaceutical Ingredient (API): Any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body. API does not include intermediates used in the synthesis of the substance.
Aggregate Batch: The sum of all units produced from any number of batches over the 6-month period for which a drug product report is submitted.
Alert Limit: An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggering appropriate scrutiny and follow-up to address the potential problem. Alert limits are always lower than action limits.
Aseptic: Free from germs that cause disease; sterile.
Aseptic Manufacturing Area: The classified part of a facility that includes the aseptic processing room and ancillary cleanrooms.
Aseptic Process: The process by which a sterile product is packaged in a sterile container in a manner that maintains sterility.
Batch: A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single compounding order during the same cycle of production.
Beyond-Use Date (BUD): A date beyond which a compounded drug product should not be used. A BUD notifies the user of the period during which a compounded drug product's required quality characteristics (e.g., sterility, strength, purity, freedom from particulate matter) can be ensured.
Bioburden: The total number of microorganisms associated with a specific item before sterilization.
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Biological Indicator (BI): A population of microorganisms inoculated onto a suitable medium (e.g., solution, container or closure) and placed within appropriate sterilizer load locations to determine the sterilization cycle efficacy of a physical or chemical process. The challenge microorganism is selected based on its resistance to the given process. Incoming lot D-value and microbiological count define the quality of the BI.
Bulk Drug Substance: See definition for active pharmaceutical ingredient.
Cleanroom: A room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned a classification based on reproducibly meeting appropriate air cleanliness limits.
Component: Any ingredient intended for use in the manufacture of a drug product, including ingredients that may not appear in the final drug product.
Critical Area: An area designed to maintain sterility of sterile materials.
Critical Surface: Surfaces that may come into contact with or directly affect a sterilized product or its containers or closures.
Depyrogenation: A process used to destroy or remove pyrogens (e.g., endotoxins).
Disinfection: A process by which surface bioburden is reduced to a safe level or eliminated.
Endotoxin: A pyrogenic product (e.g., lipopolysaccharide) present in the bacterial cell wall. Endotoxins can lead to reactions ranging from fever to death in patients receiving injections.
Expiration Date: A date on the drug product label that indicates how long the drug can meet applicable standards of identity, strength, quality, and purity under labeled storage conditions before it is used. Expiration dates are determined based on product-specific stability studies evaluating the specific formulation of a drug product, in the specific container in which it is to be stored, and under the conditions to which it may be exposed. Temperature, humidity, and light are some of the factors that can affect whether and how much a drug product degrades over time.
HEPA Filter: A high-efficiency particulate air filter with minimum 0.3 m particle retaining efficiency of 99.97 percent.
In-Use Time: The maximum amount of time that can be allowed to elapse between penetration of a container-closure system once the drug product has been sterilized, or after a lyophilized drug product has been reconstituted, and before patient administration.
Intervention: An aseptic manipulation or activity that occurs in the critical area.
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Isolator: A decontaminated unit supplied with ISO 5 or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding cleanroom air and personnel).47
Lot: A batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, a specific identified amount produced in a unit of time or quantity in a manner that provides assurance of its having uniform character and quality within specified limits.
Operator: Any individual participating in the aseptic processing operation, including line set-up, filler, or maintenance, or any other personnel associated with aseptic line activities.
Pyrogen: A substance that induces a febrile reaction in a patient.
Terminal Sterilization: The application of a lethal agent (e.g., heat) to sealed, finished drug products for the purpose of achieving a predetermined sterility assurance level (SAL) of usually less than 10-6 (i.e., a probability of a non-sterile unit of greater than one in a million).
Unidirectional Flow: An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.
Viable Particle: A particle that consists of, or supports, one or more live microorganisms.
47 See Appendix 1 in guidance for industry Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice.
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APPENDIX A. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT INTEND TO TAKE REGULATORY ACTION REGARDING CERTAIN RELEASE TESTING REQUIREMENTS
Procedures for release must be established that ensure that each batch of a drug product is not released until the following have been completed (see §§ 211.22, 211.165, 211.167(a), 211.192):
· An appropriate laboratory determination has been conducted to ensure that each batch of a drug product conforms to specifications.
· A review of environmental and personnel monitoring data, if applicable, has been conducted to ensure that manufacturing conditions were acceptable during production of the batch.
· Associated laboratory data and documentation have been reviewed by the quality control unit, and they demonstrate that the drug product meets specifications.
· A designated qualified individual from the quality control unit has authorized final release.
A. Non-Sterile Drug Products
FDA generally does not intend to take regulatory action against an outsourcing facility regarding these release requirements under the conditions described in Table A, which is at the end of Appendix A. For any given product, consider which conditions in Table A apply. If multiple conditions apply, choosing the least stringent option for each individual batch release test among the applicable conditions would be consistent with the enforcement policy set forth in this appendix.
Example 1: All of the following conditions apply:
· The batch size is >60 units.
· The water activity is 0.6 (it is not a solid dosage form).
· The product is tested for strength by a method that is highly specific (e.g., high performance liquid chromatography (HPLC)) and uses a reference standard.
From Table A, conditions 2b and 3 apply; under those conditions, FDA generally does not intend to take regulatory action against an outsourcing facility regarding batch release tests for identity, AET/preservative content, microbial enumeration, or tests for specified microorganisms if the outsourcing facility assessed strength, content uniformity, pH, appearance, and the other appropriate specifications for that product.
Example 2: All of the following conditions apply:
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· The batch size is 30 units each month.
· The starting material is a bulk drug substance.
· The product is a solid dosage form.
· The product is tested for strength by a method that is highly specific (e.g., HPLC) and uses a reference standard.
From Table A, conditions 1b and 3 apply for the first batch of 30 units; conditions 2c and 3 apply for the second batch of 30 units (i.e., when a total of 60 units has been produced); conditions 1b and 3 apply for the third batch of 30 units; and so on. Under those conditions, FDA generally does not intend to take regulatory action against an outsourcing facility regarding batch release testing for identity, content uniformity, pH, AET/preservative content, microbial enumeration, tests for specified microorganisms, or the other appropriate specifications if the outsourcing facility assessed strength and appearance for every batch and also assessed content uniformity and the other appropriate specifications for that product for every other batch.
B. Sterile Drug Products
FDA generally does not intend to take regulatory action against an outsourcing facility regarding these release requirements as they apply to sterility testing if sterility testing is initiated before batch release (see also Table D in Appendix B for BUDs for products released without a completed sterility test) and established procedures specify that if the drug product fails to meet a criterion for sterility:
· All facilities that received the drug product are notified immediately of the test results and provided with any appropriate information and recommendations to aid in the treatment of patients.
· The notification is documented.
· FDA is notified in writing within 5 working days.48
In addition, FDA generally does not intend to take regulatory action against an outsourcing facility regarding the release requirements for sterility testing under the conditions described in Table B, which is at the end of Appendix A. For any given product, consider which conditions in Table B apply. If multiple conditions apply, choosing the least stringent option for each individual batch release test among the applicable conditions would be consistent with the enforcement policy set forth in this appendix.
Example 1: All of the following conditions apply:
· The batch size is 30 units each month.
48 Reports should be emailed to FDA at OFAlertReport@fda.hhs.gov.
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· The product is a solution or total parenteral nutrition (TPN) and the bulk solution but not the finished drug product is tested for identity and strength immediately before filling into the final and prelabeled drug product containers.
· The product is terminally sterilized using a validated sterilization cycle that uses physical, chemical, or biological indicators.
From Table B, conditions 2, 5, and 6 apply to the first batch of 30 units; conditions 1, 5, and 6 apply to the second batch of 30 units (i.e., when a total of 60 units has been produced); and so on. Under those conditions, FDA generally does not intend to take regulatory action against an outsourcing facility regarding batch release testing for identity, strength, sterility, pH, visible particulates, subvisible particulates (where applicable), or other appropriate specifications, including USP monograph specifications, if the outsourcing facility conducted testing for endotoxin, color, and clarity on that product for each batch and also conducted testing on pH, visible particulates, subvisible particulates (where applicable), and other appropriate specifications, including USP monograph specifications on every other batch.
Example 2: Both of the following conditions apply:
· The batch size is >60 units.
· Drug product is a multicomponent injectable drug product (e.g., total parenteral nutrition product, cardioplegia solution) compounded from APIs produced only by FDA-registered manufacturers, the finished product is compounded using automated equipment with validated software, and the equipment is calibrated immediately before and after each personnel shift.
From Table B, conditions 1 and 5 apply; under those conditions, FDA generally does not intend to take regulatory action against an outsourcing facility regarding batch release testing for identity and strength if the outsourcing facility conducted testing for sterility, endotoxin, pH, color, clarity, visible particulates, subvisible particulates (where applicable), and other appropriate specifications, including USP monograph specifications.
C. Additional Considerations
FDA generally does not intend to take regulatory action against an outsourcing facility regarding the requirement to test the finished product before release (see § 211.165, 211.167) if the drug product is aseptically filled into secured, sterile cartridges or cassettes that are designed to prevent misuse through a locking mechanism that prevents the outsourcing facility from testing the finished product, and all testing/examinations are conducted on a sample from the container that holds the pooled, compounded drug product (e.g., pump reservoir) after all final containers are filled.49
49 See Table 2 in USP General Chapter <71> Sterility Tests for more information regarding the volume to be sampled.
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To reduce the need for the manufacturing of additional units to meet the sterility testing requirement (see § 211.167) by following the procedures in USP General Chapter <71> Sterility Tests, FDA generally does not intend to take action against an outsourcing facility regarding the number of units tested if:
· For batch sizes up to and including 10 units that do not also meet conditions 3 or 6 in Table B, at least 1 unit is tested; and
· For batch sizes of greater than 10 units and fewer than 40 units, the sterility test is conducted using a number of containers that equals 10 percent rounded up to the next whole number.
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Table A. Conditions Regarding Batch Release Tests for Non-Sterile Drug Products
Batch Release Test
Test for which FDA generally does not intend to take regulatory action under the
conditions listed
Test expected to be performed, if applicable
Conditions
Identity Strength Content Uniformityc
p H Appearance AET/Preservative Contentd Microbial Enumeration (bacteria and fungi)e Tests for Specified Microorganismse Other Appropriate Specificationsf
Tests are conducted according to these conditions ...
1. Batch size <60 units,a if omitted tests are performed once 60 units are producedb
1a. Starting from FDA-approved product
1b. Starting from bulk drug substance
2. Batch size 60 units or once 60 units are producedb and considering the following characterizations of water activity:
2a. Water activity >0.6
2b. Water activity 0.6 (other than solid dosage forms)
2c. Solid dosage forms
... unless conditions 3 or 4 also apply. If so, choosing the least stringent option for each test among applicable conditions would be consistent with the enforcement policy set forth in this appendix.
3. Product tested for strength by method that is highly specific (e.g., HPLC) and uses a reference standard
4. Compounded drug product is single dilution of
FDA-approved drug product, or is made from one or
more dilutions of FDA-approved drug product performed per labeling dilution instructions and using
automated equipment calibrated immediately before
and after production
a Individual tablets or capsules for solid oral dosage forms and suppositories, inserts, or containers (e.g., vial, syringe, IV bag, tube) for other dosage forms.
b Omitted tests under these conditions need only be performed one time after a single batch of 60 or more units has been produced or once 60 or more units have been produced in more than 1 batch within a year of the time the first batch is produced, and resets once testing has been performed or at 1 year from the time the first batch is produced if a minimum of 60 units was not produced. For example, if the batch size is consistently 30 units (e.g., tubes) of a particular volume of drug, the omitted tests are conducted on every second batch produced. Or, if the first, second, and third batches in the year include 25, 30, and 10 units respectively, the omitted tests are performed on the third batch because the minimum of 60 units has been met.
c FDA generally does not intend to take regulatory action if content uniformity testing is not performed on solutions.
d If the drug product is self-preserving, then either test for the API/excipient that is providing the preserving effect or conduct antimicrobial effectiveness testing (AET). For products with a preservative, conduct preservative content testing. Nonetheless, AET should be performed at least one time on a formulation using the lowest preservative concentration for the subject formulation and container-closure system.
e See, for example, USP General Chapter <1111>.
f These include generally recognized attributes for each dosage form such as those described in ICH Q6A or USP monographs or general chapters.
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Table B. Conditions Regarding Batch Release Tests for Sterile Drug Products
Batch Release Test
Test for which FDA generally does not intend to take regulatory action
under the conditions listed
Test expected to be performed
Conditions
Identity Strength Sterility Endotoxinc
p H Color Clarity Visible Particulates Subvisible Particulates Other Appropriate Specificationsd
Tests are conducted according to these conditions ... 1. Batch size 60 unitsa or once 60 units are producedb
········ · ·
2. Batch size <60 units, if omitted tests are performed once 60 units are producedb
····
3. Batch <10 units compounded pursuant to prescription for
single patient and label bears BUD per Table D in Appendix B, if
omitted tests are performed once 60 units are producedb
· · ·
... unless conditions 4, 5, or 6 also apply. If so, choosing the least stringent option for each test among applicable conditions would be consistent with the enforcement policy set forth in this appendix.
· · · · · · · · 4. Product tested for strength (potency) by method that is highly
specific (e.g., HPLC) and uses a reference standard
·
5. For solutions or total parenteral nutrition (TPN) only:
- Compounded drug product is single dilution of FDA-approved drug product, or is made from one or more dilutions of FDAapproved drug product performed per labeling dilution instructions and using automated equipment calibrated immediately before and after production
- OR -
- Bulk solution but not finished drug product is tested for identity
and strength immediately before filling into final and prelabeled
· · ·
·
·
·
·
·
drug product containers
- OR
- Drug product is multicomponent injectable drug product (e.g., TPN product, cardioplegia solution) compounded from APIs produced only by FDA-registered manufacturers, finished product is compounded using automated equipment with validated software, and equipment is calibrated immediately before and after each personnel shift
6. Product is terminally sterilized using validated sterilization cycle that uses physical, chemical, or biological indicators
······· · ·
a Individual tablets or capsules for solid oral dosage forms and suppositories, inserts, or containers (e.g., vial, syringe, IV bag, tube) for other dosage forms.
b Omitted tests under this condition need only be performed one time after a single batch of 60 or more units has been produced or once 60 or more units have been produced in more than 1 batch within a year from the time the first batch is produced, and resets once testing has been performed or at 1 year from the time the first batch is produced if a minimum of 60 units was not produced. For example, if the batch size is consistently 35 units (e.g., vials) of a particular volume of drug, testing is conducted on every second batch produced. Or, if the first, second, and third batches in the year include 25, 20, and 30 units respectively, testing is performed on the third batch because the minimum of 60 units has been met.
c For finished products compounded from starting materials that are sterile and nonpyrogenic, see section I, Release Testing, for more information on endotoxin testing.
d These include generally recognized attributes for each dosage form such as those described in ICH Q6A or USP monographs or general chapters.
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APPENDIX B. CONDITIONS UNDER WHICH FDA GENERALLY DOES NOT INTEND TO TAKE REGULATORY ACTION REGARDING STABILITY TESTING AND EXPIRATION DATE REQUIREMENTS
A. Default BUD (No Testing) for Non-Sterile Drug Products: Aggregate Batch Size 5,000 Units
FDA generally does not intend to take regulatory action against an outsourcing facility regarding the requirements for stability studies and expiration dates for non-sterile drug products under §§ 211.166 and 211.137 if (1) a BUD has been assigned according to Table C; (2) water activity testing is conducted as described below, if applicable, to determine the type of product for assigning the BUD; (3) literature or other scientific information, including relevant commercially available product labeling for a similar drug (e.g., components, dosage form, route of administration, primary container-closure type), does not indicate that the drug product may not be physicochemically stable over the time period listed; and (4) the BUD is used as the expiration date.50
The default BUDs in Table C are based on the likelihood of microbial proliferation as determined by water activity testing. Products with a water activity >0.6 are of greater concern microbiologically because there is potential for proliferation of microorganisms in the product. Use of a validated preservative strategy51 can greatly reduce the likelihood of microbial proliferation in finished drug products.
Water activity testing is conducted as follows to determine the type of product for assigning the default BUD:
· Solid dosage forms (i.e., tablets and capsules): No water activity testing is necessary.
· Products with water activity >0.6: No water activity testing is necessary if the product is known or assumed to have a high water activity (e.g., liquid oral solution) and the applicable default BUD for products with water activity >0.6 is used.
· Products with suspected low water activity (other than solid dosage forms) (e.g., suppository): Water activity testing is conducted once for each non-sterile drug product formulation according to validated test procedures such as those described in USP General Chapter <1112>. Depending on the results of the water activity test, the BUD should be set according to Table C.
50 To be eligible for the exemptions provided under section 503B of the FD&C Act, the compounded drug product must be labeled with an expiration date (see section 503B(a)(10)(A)(iii)(VI)). 51 See USP General Chapter <51>.
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Table C: Default BUDs for Non-Sterile Drug Products With Aggregate Batch Size 5,000 Units
Type of Product Solid dosage forms Water activity >0.6
Storage Conditions
Controlled Room Temperature (20° to 25°C)
Refrigerator (2° to 8°C)
180 days
N/A
Preserved: 30 days Unpreserved: Not applicable
Preserved: 30 days Unpreserved: 14 days
Water activity 0.6
90 days
N/A
B. Default BUD (No Testing) for Sterile Drug Products: Aggregate Batch Size 1,000 Units
FDA generally does not intend to take regulatory action against an outsourcing facility regarding the requirements for stability studies and expiration dates under §§ 211.166 and 211.137 if (1) a BUD has been assigned according to the criteria based on processing conditions in Table D; (2) literature or other scientific information, including relevant commercially available product labeling for a similar drug (e.g., components, dosage form, route of administration, primary container-closure type), does not indicate that the drug product may not be physicochemically stable over the time period listed; and (3) the BUD is used as the expiration date.52
Table D. Default BUDs for Aggregate Batch Size 1,000 Units With Given Processing and Storage Conditions
Storage Conditions
Processing Conditions
Contains a Preservative?
Controlled Room
Temperature
(20° to 25°C)
Refrigerator
Freezer
(2° to 8°C) (-25° to -10°C)
· Finished drug product is
aseptically processed; and
No
· A sterility test has not been completed before release Yes
6 days 28 days
9 days 42 days
45 days 45 days
· Finished drug product is
terminally sterilized;
No
14 days
28 days
45 days
· A validated sterilization
cycle that uses physical,
52 To be eligible for the exemptions provided under section 503B of the FD&C Act, the compounded drug product must be labeled with an expiration date (see section 503B(a)(10)(A)(iii)(VI)).
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chemical, or biological
indicators is employed; and
· A sterility test has not been
Yes
completed before release
28 days
42 days
· Finished drug product is aseptically processed or
No
terminally sterilized and has
a completed, passing sterility
Yes
test before release
28 days 42 days
42 days 42 days
45 days 45 days 45 days
C. Enforcement Policy Regarding the Use of Limited Stability Testing To Assign a BUD
Stability testing is intended to confirm the stability performance of a non-sterile or sterile compounded drug product held under the labeled storage conditions for the duration of the BUD. Procedures established for assessing the stability of drug products compounded by outsourcing facilities must achieve the following (§§ 211.122, 211.160, 211.166):
· Incorporate stability-indicating test methods that are reliable, meaningful, and specific.
· Evaluate samples of the drug product in the same container-closure system and with the same or representative label and adhesive that will be affixed to the container in which the drug product is marketed.
· Evaluate samples for stability that are representative of the batch from which they were obtained and are stored under suitable conditions.
· Incorporate testing to evaluate antimicrobial effectiveness for drug products labeled or intended to be multiple dose. If antimicrobial effectiveness has been previously established for the formulation and container-closure system, a test for preservative content may be used in lieu of a full antimicrobial effectiveness study.
FDA generally does not intend to take regulatory action against an outsourcing facility regarding stability testing and expiration date requirements if the outsourcing facility uses the approach outlined below describing a number of lots and a set of tests--which should be conducted at lot release as part of normal operations--to be performed at the time of the desired BUD. This section C does not apply to non-sterile unpreserved aqueous drug products because of the higher risk of microbiological proliferation.
The following conditions apply:
· Samples are evaluated following aging under the long-term storage conditions (i.e., temperature and humidity) in ICH Q1A(R2).
· The data from each time point are evaluated against the established specifications for the compounded drug product.
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· The BUD is not longer than 12 months.
· If the data for any test fall outside of the established specifications, the BUD is restricted to the last time point at which the data remained within specifications, or the default BUD (described above) is used.
Because of the possibility that a sample may not meet specifications at the final time point, FDA strongly recommends the inclusion of testing at at least one interim time point. If the data at the final time point do not confirm the stability of the product at the desired BUD (e.g., some measurements fall outside of the established specifications), but the data at the interim time point are acceptable (i.e., measurements meet the established specifications), a BUD equal to the interim time point meets the second condition above.
Under this policy, samples from one lot are tested. Each unit subjected to one or more tests that compromise the integrity of the primary container-closure is only tested at a single time point (i.e., not at additional time points). If a single unit is to be used for multiple discrete tests to minimize destructive testing, the unit dosage is subdivided into multiple aliquots that are not held longer than the time to complete the testing (typically not longer than 48-72 hours) and the aliquots are placed into appropriate testing containers (e.g., high performance liquid chromatography vials or sample tubes) that protect the sample from being compromised (e.g., from exposure to air, light, evaporation).
1. Non-sterile
a. Nondestructive tests
The following test is conducted:
· Appearance.
b. Destructive chemical tests
The tests to be conducted include:
· pH, if applicable (e.g., for aqueous formulations). · Assay.53 · Appropriate specifications.
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c. Microbiological tests, if water activity >0.6
The tests to be conducted include:
· Antimicrobial effectiveness testing/preservative content testing at expiry. · Microbial enumeration54 (USP General Chapter <61>). · Test for specified organisms55 (USP General Chapter <62>).
2. Sterile
a. Nondestructive tests
The following tests are conducted:
· Appearance. · Color and clarity. · Visible particulates.
b. Destructive chemical tests
The tests to be conducted include:
· pH, if applicable (e.g., for aqueous formulations). · Assay.56 · Subvisible particles (10µm100µm).57
c. Sterility or container-closure integrity tests
To confirm that sterility is maintained over the proposed BUD, container-closure integrity testing (such as described in USP General Chapter <1207>) or a sterility test (see USP General Chapter <71>) is conducted. When performed, container-closure integrity testing is conducted on a number of units that is suitable for the chosen test method.
D. Bracketing
Use of bracketing in stability studies allows for more streamlined evaluation of drug products for which there are multiple strengths or volume presentations produced. Bracketing assumes that the stability of intermediate strengths (or intermediate fill volumes) is adequately represented by
54 See, for example, USP General Chapter <1111>. 55 Ibid. 56 See note 31. 57 Applicable only to intrathecal, intravenous, intra-arterial, ophthalmic, intramuscular, sterile otic, and subcutaneous preparations.
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the extremes tested.58 For multiple drug products to be eligible for bracketing stability studies, the candidate formulations should vary only in strength (or concentration) or fill volume. Although individual excipient amounts may vary, all excipients (in worst-case amounts) should be in all bracketed formulations. Proportional formulations are not required. The same containerclosure system must be used (§ 211.166). If three or more strengths, concentrations, or volume presentations exist, intermediate cases for stability studies as follows may reflect an appropriate use of bracketing:
· If 3 or 4 drug product strengths, concentrations, or volume presentations are produced, test the high and low extremes (e.g., if available strengths include 2.0 mg/mL, 3.5 mg/mL, 5.0 mg/mL, and 10.0 mg/mL, test 2.0 mg/mL and 10.0 mg/mL).
· If 5-10 drug product strengths, concentrations, or volume presentations are produced, test the high and low extremes and 1 intermediate case.
· If more than 10 drug product strengths, concentrations, or volume presentations are produced, test the high and low extremes and 2 intermediate cases.
It is critical that determination of the extremes be done with care. For example, with respect to volume fill, the appropriate extremes are not necessarily always the highest and lowest fluid volume fills. Rather, the head space-to-fluid volume ratio may better represent the appropriate extreme depending on the container volume used in the various presentations.
Bracketing as described in this section does not apply to microbial testing of sterility, endotoxins, or bioburden. Bracketing may be appropriate for water activity testing and antimicrobial effectiveness testing when used in conjunction with a preservative content testing strategy.
58 See ICH guidance for industry Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products for more information on bracketing and matrixing.
48
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