1. The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed].
2. There is a failure to thoroughly review [any unexplained
discrepancy] [the failure of a batch or any of its components to meet any of
its specifications] whether or not the batch has been already distributed.
3. Your firm failed to establish [adequate] written
procedures for production and process controls designed to assure that the drug
products have the identity, strength, purity, and quality that they are
purported or represented to possess.
4. Laboratory controls do not include the establishment of
scientifically sound and appropriate [specifications] [standards] [sampling
plans] [test procedures] designed to assure that [components] [drug product
containers] [closures] [in-process materials] [labeling] [drug products]
conform to appropriate standards of identity, strength, quality and
purity.
5. Equipment used in the manufacture, processing, packing or
holding of drug products is not [of appropriate design] [of adequate size]
[suitably located] to facilitate operations for its [intended use] [cleaning
and maintenance].
6. Equipment and utensils are not [cleaned] [maintained]
[sanitized] at appropriate intervals to prevent [malfunctions] [contamination]
that would alter the safety, identity, strength, quality or purity of the drug
product.
7. Procedures designed to prevent microbiological
contamination of drug products purporting to be sterile are not [established]
[written] [followed].
8. Written procedures are not [established] [followed] for
the cleaning and maintenance of equipment, including utensils, used in the
manufacture, processing, packing or holding of a drug product.
9. Appropriate controls are not exercised over computers or
related systems to assure that changes in master production and control records
or other records are instituted only by authorized personnel.
10. There is no written testing program designed to assess
the stability characteristics of drug products.
11. Aseptic processing areas are deficient regarding the
system for monitoring environmental conditions.
12. Testing and release of drug product for distribution do
not include appropriate laboratory determination of satisfactory conformance to
the [final specifications] [identity and strength of each active ingredient]
prior to release.
13. Procedures designed to prevent microbiological
contamination of drug products purporting to be sterile did not include
[adequate] validation of the [aseptic] [sterilization] process.
14. Control procedures are not established which [monitor
the output] [validate the performance] of those manufacturing processes that
may be responsible for causing variability in the characteristics of in-process
material and the drug product.
15. Reports of analysis from component suppliers are
accepted in lieu of testing each component for conformity with all appropriate
written specifications, without [performing at least one specific identity test
on each component] [establishing the reliability of the supplier's analyses
through appropriate validation of the supplier's test results at appropriate
intervals].
16. Routine [calibration] [inspection] [checking] of
[automatic] [mechanical] [electronic] equipment is not performed according to a
written program designed to assure proper performance.
17. Batch production and control records [are not prepared
for each batch of drug product produced] [do not include complete information
relating to the production and control of each batch].
18. Employees are not given training in [the particular
operations they perform as part of their function] [current good manufacturing
practices] [written procedures required by current good manufacturing practice
regulations].
19. There is no quality control unit.
20. Aseptic processing areas are deficient regarding the
system for cleaning and disinfecting the [room] [equipment] to produce aseptic
conditions.
21. The identity of each component of a drug product is not
verified by conducting at least one test to verify the identity, using specific
identity tests if they exist.
22. Procedures describing the handling of written and oral
complaints related to drug products are [not written or followed] [deficiently
written or followed].
23. Buildings used in the [manufacturing] [processing]
[packing] [holding] of a drug product are not maintained in a good state of
repair.
24. Employees engaged in the [manufacture] [processing]
[packing] [holding] of a drug product lack the [education] [training]
[experience] required to perform their assigned functions.
25. Procedures designed to prevent objectionable
microorganisms in drug products not required to be sterile are not
[established] [written] [followed].
26. Established [specifications] [standards] [sampling
plans] [test procedures] [laboratory control mechanisms] are not [followed]
[documented at the time of performance].
27. The [accuracy] [sensitivity] [specificity]
[reproducibility] of test methods have not been [established]
[documented].
28. Drug products are not stored under appropriate
conditions of [temperature] [humidity] [light] so that their identity,
strength, quality, and purity are not affected.
29. Drug product component testing is deficient in that at
least one specific test to verify the identity of each component is not
performed.
30. Laboratory records do not include complete data derived
from all tests, examinations and assay necessary to assure compliance with
established specifications and standards.
31. Drug products do not bear an expiration date determined
by appropriate stability data to assure they meet applicable standards of
identity, strength, quality and purity at the time of use.
32. The quality control unit lacks the responsibility and
authority to [approve] [reject] all [components] [drug product containers]
[closures] [in process materials] [packaging material] [labeling] [drug
products].
33. Procedures for the cleaning and maintenance of equipment
are deficient regarding sufficient detail of the methods, equipment, and
materials used in the cleaning and maintenance operation, and the methods of
disassembly and reassembling equipment as necessary to assure proper cleaning
and maintenance.
34. The written stability testing program is not
followed.
35. Specific identification tests are not conducted on
components that have been accepted based on the supplier's report of
analysis.
36. The quality control unit lacks responsibility to
[approve] [reject] all procedures or specifications impacting on the [identity]
[strength] [quality] [purity] of drug products.
37. Buildings used in the manufacture, processing, packing
or holding of drug products are not [maintained in a clean and sanitary
condition] [free of infestation by rodents, birds insects, and other
vermin].
38. Written records of investigations into [unexplained
discrepancies] [the failure of a batch or any of its components to meet
specifications] do not [always] include the conclusions and follow-up.
39. Written records are not [always] made of investigations
into [unexplained discrepancies] [the failure of a batch or any of its
components to meet specifications].
40. Written production and process control procedures are
not [followed in the execution of production and process control functions]
[documented at the time of performance].
41. Records are not maintained so that data therein can be
reviewed at least annually to evaluate the quality standards of each drug
product to determine the need for changes in specifications or manufacturing or
control procedures.
42. Written procedures are not [established] [followed] for
evaluations conducted at least annually to review records associated with a
representative number of batches, whether approved or rejected.
43. Written procedures have not been developed for the
[surveillance] [receipt] [evaluation] [reporting to FDA] of post marketing
adverse drug experiences.
44. Time limits are not established when appropriate for the
completion of each production phase to assure the quality of the drug
product.
45. GMP training is not conducted [on a continuing basis]
[with sufficient frequency] to assure that employees remain familiar with CGMP
requirements applicable to them.
46. Buildings used in the manufacture, processing, packing,
or holding of a drug product do not have the suitable [size] [construction]
[location] to facilitate cleaning, maintenance, and proper operations.
47. Drug products failing to meet established [standards]
[specifications] [quality control criteria] are not rejected.
48. The written stability program for drug products does not
include [reliable] [meaningful] [specific] test methods.
49. Laboratory records are deficient in that they do not
include a complete record of all data obtained during testing.
50. Procedures describing the calibration of instruments,
apparatus, gauges and recording devices are [not written or followed]
[deficiently written or followed].
51. Written procedures are not [established] [followed] for
evaluations done at least annually and including provisions for a review of
[complaints] [recalls] [returned or salvaged drug products] [investigations
conducted for each drug product].
52. Actual yield and percentages of theoretical yield are
not determined at the conclusion of each appropriate phase of [manufacturing]
[processing] [packaging] [holding] of the drug product.
53. Aseptic processing areas are deficient regarding air
supply that is filtered through high-efficiency particulate air filters under
positive pressure.
54. Strict control is not exercised over labeling issued for
use in drug product labeling operations.
55. Each batch of drug product required to be free of
objectionable microorganisms is not tested through appropriate laboratory
testing.
56. The batch production and control records are deficient
in that they do not include documentation of the accomplishment of each
significant step in [manufacturing] [processing] [packing] [holding].
57. Written procedures for cleaning and maintenance fail to
include [assignment of responsibility] [maintenance and cleaning schedules]
[description in sufficient detail of methods, equipment and materials used]
[description in sufficient detail of the methods of disassembling and
reassembling equipment as necessary to assure proper cleaning and maintenance]
[instructions for removal or obliteration of previous batch identification]
[instructions for protection of clean equipment from contamination prior to
use] [parameters relevant to the operation].
58. Input to and output from [the computer] [related systems
of formulas] [records or data] are not checked for accuracy.
59. Access to the storage area for labels and labeling
materials is not limited to authorized personnel.
60. Establishment of the reliability of the component
supplier's report of analyses is deficient in that the test results are not
appropriately validated at appropriate intervals.
61. Written records of major equipment [cleaning]
[maintenance] [use] are not included in individual equipment logs.
62. Deviations from written production and process control
procedures are not [recorded] [justified].
63. The labels of your outsourcing facility's drug products
do not include information required by section 503B(a)(10)(A) of the Federal
Food, Drug, and Cosmetic Act (FD&C Act).
64. The [separate or defined areas] [control systems]
necessary to prevent contamination or mix-ups are deficient.
65. The establishment of [specifications] [standards]
[sampling plans] [test procedures] [laboratory control mechanisms] including
any changes thereto, are not [drafted by the appropriate organizational unit]
[reviewed and approved by the quality control unit].
66. Records associated with drug product [components]
[containers] [closures] [labeling] [production] [control] [distribution] and
within the retention period for such records, were not made readily available
for authorized inspection.
67. An adequate number of batches of each drug product are
not tested [nor are records of such data maintained] to determine an
appropriate expiration date.
68. Equipment for adequate control over [air pressure]
[micro-organisms] [dust] [humidity] [temperature] is not provided when
appropriate for the manufacture, processing, packing or holding of a drug
product.
69. Determinations of conformance to appropriate written
specifications for acceptance are [not made] [deficient] for drug
products.
70. Reserve samples from representative sample lots or
batches of drug products selected by acceptable statistical procedures are not
examined visually at least once a year for evidence of deterioration.
71. Each component is not tested for conformity with all
appropriate written specifications for purity, strength, and quality.
72. Procedures describing the handling of all written and
oral complaints regarding a drug product are not [established] [written]
[followed].
73. Not all adverse drug experiences that are both serious
and unexpected have been reported to FDA within 15 calendar days of initial
receipt of the information.
74. The quality control unit lacks authority to [review
production records to assure that no errors have occurred] [fully investigate
errors that have occurred].
75. Aseptic processing areas are deficient regarding systems
for maintaining any equipment used to control the aseptic conditions.
76. All records of [production] [control] [distribution]
[components] [drug product containers] [closures] [labeling] associated with a
batch of drug product were not maintained at least one (1) year after the
expiration date.
77. Changes to written procedures are not [drafted, reviewed
and approved by the appropriate organizational unit] [reviewed and approved by
the quality control unit].
78. Deviations from written [specifications] [standards]
[sampling plans] [test procedures] [laboratory mechanisms] are not [recorded]
[justified].
79. Acceptance criteria for the sampling and testing
conducted by the quality control unit is not adequate to assure that batches of
drug products meet [each appropriate specification] [appropriate statistical
quality control criteria] as a condition for their approval and release.
80. Reserve drug product samples are not [appropriately
identified] [representative of each lot or batch of drug product] [retained and
stored under conditions consistent with product labeling].
81. The quality control unit lacks responsibility for
approving or rejecting drug products [manufactured] [processed] [packed] [held]
under contract by another company.
82. Aseptic processing areas are deficient in that [floors]
[walls] [ceilings] are not smooth and/or hard surfaces that are easily
cleanable.
83. Written procedures are lacking which describe in
sufficient detail the [receipt] [identification] [storage] [handling]
[sampling] [testing] [approval] [rejection] of [components] [drug product
containers] [closures].
84. There was a failure to handle and store [components]
[drug product containers] [closures] at all times in a manner to prevent
contamination.
85. Each lot of [components] [drug product containers]
[closures] is not withheld from use
until the lot has been sampled, tested, examined, and released by the quality
control unit.
86. The batch production and control records are deficient
in that they do not include [complete
labeling control records] [specimen] [copy] of labeling.
87. Distribution records do not contain the [name and
strength of the drug product] [description of dosage form] [name and address of
consignee] [date and quantity shipped] [lot or control number of drug
product].
88. Complaint records are deficient in that they do not
include the findings of the [investigation] [follow-up].
89. There is a lack of written procedures [assigning
responsibility] [providing cleaning schedules] [describing in sufficient detail
the methods, equipment and materials to be used] for sanitation.
90. Backup data is not assured as [exact] [complete] [secure
from alteration, erasure or loss] through keeping hard copy or alternate
systems.
91. The calibration of [instruments] [apparatus] [gauges]
[recording devices] is not done at suitable intervals [in accordance with an
established written program] [with provisions for remedial action in the event
accuracy and/or precision limits are not met].
92. Your outsourcing facility has not submitted a report to
FDA identifying a product compounded during the previous six months as required
by section 503B(b)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C
Act).
93. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding operations related to aseptic processing of
drug products.
94. The drug product is not identified with a lot or control
number that permits the determination of the history of the manufacture and
control of the batch.
95. Representative samples are not taken of each shipment of
each lot of [components] [drug product containers] [closures] for testing or
examination.
96. The [number of containers to be sampled] [amount of
material taken from each container] is not based upon appropriate
criteria.
97. Component testing is deficient in that each component is
not tested for conformity with all appropriate written specifications for
purity, strength, and quality.
98. The procedures for the annual quality standards record
evaluation are deficient in that they do not address a review of a
representative number of [approved] [rejected] batches.
99. Drug product production and control records, are not
[reviewed] [approved] by the quality control unit to determine compliance with
all established, approved written procedures before a batch is released or
distributed.
100. The master production and control records are deficient
in that they do not include complete [manufacturing] [control] [instructions]
[sampling] [testing] [procedures] [specifications] [special notations]
[precautions].
101. Laboratory records do not include the initials or
signature of a second person showing that the original records have been
reviewed for [accuracy] [completeness] [compliance with established
standards].
102. An NDA-Field Alert Report was not submitted within
three working days of receipt of information concerning [bacteriological
contamination] [significant chemical, physical, or other change or
deterioration] in a distributed drug product.
103. You did not [establish] [follow] written quality
assurance procedures.
104. The container of your outsourcing facility's drug
products does not include information required by section 503B(a)(10)(B) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act).
105. Procedures for the cleaning and maintenance of
equipment are deficient regarding the protection of clean equipment from
contamination prior to use.
106. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding the manufacturing and processing
operations.
107. Procedures designed to assure that correct [labels]
[labeling] [packaging materials] are used for drug products are not [written]
[followed].
108. Establishment of the reliability of the [container]
[closure] supplier's report of analyses is deficient in that the test results
are not appropriately validated at appropriate intervals.
109. Investigations of [an unexplained discrepancy] [a
failure of a batch or any of its components to meet any of its specifications]
did not extend to [other batches of the same drug product] [other drug products
that may have been associated with the specific failure or discrepancy].
110. Laboratory records do not include complete records of
the periodic calibration of laboratory [instruments] [apparatus] [gauges]
[recording devices].
111. Written procedures are not [established] [followed]
that describe the [in-process controls] [tests] [examinations] to be conducted
on appropriate samples of in-process materials of each batch.
112. Batch production and control records do not include the
results of any investigation made into any unexplained discrepancy, whether or
not the batch of drug product had already been distributed.
113. When errors occurred or a production batch or any
component of the batch, failed to meet specifications, you did not [determine
the need for an investigation] [conduct an investigation] [take appropriate
corrective actions] when necessary.
114. Your firm failed to have systems in place to enable
compliance with the verification requirements of the DSCSA.
115. Clothing of personnel engaged in the [manufacturing]
[processing] [packing] [holding] of drug products is not appropriate for the
duties they perform.
116. Protective apparel is not worn as necessary to protect
drug products from contamination.
117. Procedures for the cleaning and maintenance of
equipment are deficient regarding inspection of the equipment for cleanliness
immediately before use.
118. Records are not kept for the [maintenance] [cleaning]
[sanitizing] [inspection] of equipment.
119. Failure to maintain a backup file of data entered into
the computer or related system.
120. The batch records do not record the distinctive
[identification number] [code] [name of equipment] to identify major equipment
to show the specific equipment used in the manufacture of a batch of a drug
product.
121. Drug product [containers] [closures] were not [clean]
[sterilized and processed to remove pyrogenic properties] to assure that they
are suitable for their intended use.
122. There is no written assessment of stability of
homeopathic drug products based at least on [testing or examination of the drug
product for compatibility of the ingredients] [marketing experience with the
drug product to indicate that there is no degradation of the product for the
normal or expected period of use].
123. The plumbing system contains defects that could
contribute to the contamination of drug products.
124. Washing and toilet facilities lack [hot and cold water]
[soap or detergent] [air driers or single-service towels] [cleanliness].
125. In-process materials are not tested for [identity]
[strength] [quality] [purity] and approved or rejected by the quality control
unit [during the production process] [after storage for long periods].
126. A sample which is representative of each lot in each
shipment of each active ingredient is not [appropriately identified]
[retained].
127. Written procedures are not followed for the [receipt]
[identification] [storage] [handling] [sampling] [testing] [approval]
[rejection] of [components] [drug product containers] [closures].
128. Written distribution procedures are not [established]
[followed].
129. Procedures describing the warehousing of drug products
are not [established] [followed].
130. Laboratory controls do not include a determination of
conformance to [written descriptions of sampling procedures] [appropriate
specifications] for drug products.
131. The use of [instruments] [apparatus] [gauges]
[recording devices] not meeting established specifications was observed.
132. Results of stability testing are not used in
determining [appropriate storage conditions] [expiration dates].
133. Written procedures describing the handling of
complaints do not include provisions for [review by the quality control unit of
any complaint involving the possible failure of a drug product to meet any of
its specifications] [a determination as to the need for an investigation of any
unexplained discrepancy] [explaining the reasons for the failure of the batch
or any of its components to meet specifications].
134. Master production and control records lack [a
description of the drug product containers, closures and packaging materials]
[a specimen or copy of each label and all other labeling] [the signatures and
dates entered by the person or persons responsible for the approval of
labeling].
135. Master production and control records lack [complete
manufacturing and control instructions] [sampling and testing procedures]
[specifications] [special notations] [precautions to be followed].
136. The suitability of all testing methods is not verified
under actual conditions of use.
137. An annual report was not submitted [each year] [within
60 days of the anniversary date of U.S. approval of the application] to the FDA
division responsible for reviewing the application.
138. Your examination and testing of samples did not assure
that the drug product and in-process material conformed to specifications.
139. Your facilities are not adequate to ensure [the orderly
handling of materials and equipment] [the prevention of mix-ups] [the
prevention of contamination of equipment or product by substances, personnel,
or environmental conditions] that could reasonably be expected to have an
adverse effect on product quality.
140. Your outsourcing facility did not submit a report to
FDA identifying the drugs compounded during the previous six month period.
141. The number of qualified personnel is inadequate to
[perform] [supervise] the [manufacture] [processing] [packing] [holding] of
each drug product.
142. Procedures for the cleaning and maintenance of
equipment are deficient regarding maintenance and cleaning schedules,
including, where appropriate, sanitizing schedules.
143. Records of the [calibration checks] [inspections]
of automatic, mechanical or electronic
equipment, including computers or related systems are not maintained.
144. Written production and control procedures include batches formulated with the intent to
provide less than 100 percent of the
labeled or established amount of active ingredient.
145. Each component is not added to a batch by one person
and verified by a second person.
146. Approved [components] [drug product containers]
[closures] are not retested or reexamined as appropriate for identity,
strength, quality and purity after [storage for long periods] [exposure to
conditions that might have an adverse effect]
with subsequent approval or rejection by the quality control unit.
147. Failure to reject any lot of [components] [drug product
containers] [closures] that did not meet the appropriate written specifications
for identity, strength, quality, and purity.
148. The written stability program for drug products does
not include [sample size] [test intervals] based on statistical criteria for
each attribute examined to assure valid estimates of stability.
149. The written stability program does not assure testing
of the drug product in the same container-closure system as that in which the
drug product is marketed.
150. Accelerated stability studies, combined with basic
stability information, used to support tentative expiration dates are not supported with ongoing full shelf life
studies.
151. The persons [performing] [double-checking] the cleaning
and maintenance are not [dating] [signing or initialing] the equipment cleaning
and use log.
152. Records fail to include an individual inventory record
of each [component] [reconciliation of the use of each component] [drug product
container] [drug product closure] with sufficient information to allow
determination of any associated batch or
lot of drug product.
153. Records do not include the disposition of rejected
[components] [drug product containers] [closures] [labeling].
154. The batch production and control records are deficient
in that they are not [an accurate reproduction of the appropriate master
production or control record] [checked for accuracy, dated, and signed].
155. The master production and control records are deficient
in that they do not include a statement of theoretical yield and [minimum]
[maximum] [yield percentages].
156. Laboratory records are deficient in that they do not
include a [description and identification of the sample received] [quantity]
[lot number] [date sample taken] [date sample received for testing].
157. Laboratory records are deficient in that they do not
include a statement of the results of tests and how they compare to the
established [specifications] [standards].
158. Components for drug product manufacturing are not
[weighed] [measured] [subdivided as appropriate].
159. In-process specifications are not [consistent with drug
product final specifications] [derived from previous acceptable process average
and process variability estimates where possible] [determined by the
application of suitable statistical procedures where appropriate].
160. Drug product samples are not [representative of the
entire batch] [properly identified].
161. A written record of the program along with appropriate
validation data has not been maintained in situations where backup data is
eliminated by computerization or other automated processes.
162. Each lot of [components] [drug product containers]
[closures] was not appropriately identified as to its status in terms of being
quarantined, approved or rejected.
163. A system by which the distribution of each lot of drug
product can be readily determined to facilitate its recall if necessary, has
not been established.
164. Samples taken of drug products for determination of
conformance to written specifications are not [representative] [properly
identified].
165. The reserve sample of drug product does not consist of
at least twice the quantity necessary to perform all the required tests of drug
product.
166. Batch production and control records do not include
complete labeling control records, including specimens or copies of all
labeling used for each batch of drug product produced.
167. Batch production and control records do not include the
specific identification of each batch of [component] [in-process material] used
for each batch of drug product produced.
168. Laboratory records do not include a complete record of
all data secured in the course of each test, including all [graphs] [charts]
[spectra] from laboratory instrumentation, properly identified to show the
[specific component] [drug product container] [closure] [in-process material]
[lot tested] [drug product tested].
169. Periodic reports of non-alert adverse drug experiences
have not been submitted [quarterly for an application which was approved less
than three years ago] [yearly for an application which was approved three or
more years ago].
170. Not all annual periodic adverse drug experience reports
have been submitted within 60 days of the anniversary date of the approval of
the application.
171. A post marketing 15-day Alert report based upon
scientific literature was not accompanied by a copy of the published
article.
172. An NDA-Field Alert Report was not submitted within
three working days of receipt of information concerning a failure of one or
more distributed batches of a drug to meet the specifications established for
it in the application.
173. You lack [a sufficient number of] personnel with the
necessary [education] [background] [training] [experience] to perform their
assigned functions.
174. You did not oversee production operations in a manner
to ensure that each PET drug [meets the requirements of the FD&C Act as to
safety] [has the identity and strength that it is supposed to have] [meets the
quality and purity characteristics that it is supposed to have].
175. Your firm lacks adequate production and process
controls to ensure the consistent production of a PET drug that meets the
applicable standards of identity, strength, quality and purity.
176. The RDRC did not keep minutes for each of its
meetings.
177. Your master production and control records for each
drug product were not [prepared, dated, and signed by one person]
[independently checked, dated, and signed by a second person].
178. The preparation of your master production and control
records was not [described in a written procedure] [followed in accordance with
your written procedure].
179. An application holder did not [ensure wholesalers /
distributors who distribute the drug are authorized to distribute the drug]
[comply with the audit plan and schedule described in the REMS] [identify and
address non-compliant authorized wholesalers / distributors] [maintain a
Support / Call Center or a REMS Program website] [maintain the drug
distribution and dispensing records to ensure restricted distribution], as
required by your approved REMS Implementation System.
180. You did not [implement procedures] [document your
activities in accordance with your procedures] to ensure that all equipment is
[cleaned] [suitable for its intended purposes] [properly installed, maintained,
and capable of repeatedly producing valid results] that could reasonably be
expected to adversely affect the identity, strength, quality, or purity of a
PET drug, or give erroneous or invalid test results when improperly used or
maintained.
181. Personnel were observed conducting aseptic
manipulations where the movement of "first air" in the ISO 5 area is
blocked or disrupted.
182. [Lack of] [Inadequate] routine environmental monitoring
in the [ISO 5 area] [classified areas].
183. Failure to conduct media fills that closely simulate
aseptic production operations under the worst-case, most-challenging, and
stressful conditions.
184. Individuals responsible for supervising the
[manufacture] [processing] [packing] [holding] of a drug product lack the
[education] [training] [experience] to perform their assigned functions in such
a manner as to assure the drug product has the safety, identity, strength,
quality and purity that it purports or is represented to possess.
185. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding operations related to the receipt,
identification, storage, and withholding from use of [components] [drug product
containers] [closures] [labeling] pending sampling, testing, or examination by
the quality control unit before release for manufacturing or packaging.
186. Component [weighing] [measuring] [subdividing]
operations are not adequately supervised.
187. Yield calculations are not performed by one person and
independently verified by a second person.
188. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding operations related to the holding of rejected
[components] [drug product containers] [closures] [labeling] before
disposition.
189. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding operations related to the storage of released
[components] [drug product containers] [closures] [labeling].
190. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding operations related to the quarantine storage of
drug products prior to release.
191. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding operations related to the storage of drug
products after release.
192. Separate or defined areas to prevent contamination or
mix-ups are deficient regarding laboratory controls and operations.
193. Aseptic processing areas are deficient regarding
[temperature] [humidity] controls.
194. Procedures prescribing a system for reprocessing
batches to insure that the reprocessed batches will conform with all
established standards, specifications, and characteristics are not [written] [followed].
195. There is a lack of written procedures describing in sufficient detail
the [receipt] [identification] [storage] [handling] [sampling] [examination]
[testing] of labeling and packaging materials.
196. Labeling and packaging materials are not [representatively sampled] [examined]
[tested] upon receipt and before use in packaging and labeling of a drug
product.
197. Procedures describing in sufficient detail the controls
employed for the issuance of labeling are not [written] [followed].
198. Inspection of the [packaging] [labeling] facilities
immediately before use is not done to assure that all drug products have been
removed from previous operations.
199. Packaged and labeled products are not examined during
finishing operations to provide assurance that containers and packages in the
lot have the correct label.
200. Each lot in each shipment received was not identified
with a distinctive code for each container or grouping of containers for
[components] [drug product containers] [closures].
201. The containers of components, or drug product
containers or closures which are sampled are not opened in a manner to prevent
[contamination of their contents] [contamination of other components]
[contamination of other drug product containers] [contamination of other
closures].
202. Each lot of a [component] [drug product containers]
[closures] liable to objectionable
microbiological contamination is deficiently subjected to
microbiological tests before use.
203. Drug product containers or closures are [reactive]
[additive] [absorptive] so as to alter the safety, identity, strength, quality,
and purity of the drug beyond the official or established requirements.
204. Sampling and testing plans for drug products are not
described in written procedures which include the [method of sampling] [number
of units per batch to be tested].
205. The written stability program for drug products does
not describe the storage conditions for samples retained for testing.
206. Each batch of drug product purporting to be [sterile]
[pyrogen-free] is not laboratory tested to determine conformance to such
requirements.
207. Each batch of controlled-release dosage form drug
product is not laboratory tested to determine conformance to the specifications
for the rate of release for each active ingredient.
208. Test procedures describing the testing of controlled
release dosage form drug product are not [written] [followed].
209. Individual equipment logs do not show [time] [date]
[product] [lot number of each batch processed].
210. The entries in the equipment cleaning and use logs are
not in chronological order.
211. The batch production and control records are deficient
in that they do not include the identity
of major [equipment] [lines] used.
212. The batch production and control records are deficient
in that they do not include [weights]
[measures] of components used in the process.
213. The batch production and control records are deficient
in that they do not include identification of persons [performing]
[supervising] [checking] each significant step in the operation.
214. The batch production and control records are deficient
in that they do not include
documentation of batch investigations performed.
215. Laboratory records do not include complete records of
any testing and standardization of laboratory [reference standards] [reagents]
[standard solutions].
216. Laboratory records are deficient in that they do not
include [a statement of the method used in testing the sample] [the location of
the data that assures the accuracy and reliability of the test method].
217. Verification of the suitability of the testing methods
is deficient in that they are not [performed under actual conditions of use]
[documented on the laboratory records].
218. Laboratory records are deficient in that they do not
include all calculations performed during testing.
219. Laboratory records are deficient in that they do not
include the [initials] [signature] of the second person reviewing the record
for accuracy.
220. Complaint procedures are deficient in that they do not
include provisions that allow for the review and determination of an
investigation by the quality control unit.
221. Complaint records are deficient in that they do not
document the reason and the individual
making the decision not to conduct a complaint investigation.
222. Equipment surfaces that contact [components]
[in-process materials] [drug products] are reactive, additive or absorptive so
as to alter the safety, identity, strength, quality, or purity of the drug
product beyond the official or other established requirements.
223. Written procedures are lacking for the use of [rodenticides] [insecticides] [fungicides]
[fumigating agents] [cleaning and sanitizing agents] designed to prevent the
contamination of [equipment] [components] [drug product containers] [closures]
[packaging, labeling materials] [drug products].
224. Rejected [components] [drug product containers]
[closures] are not controlled under a quarantine system designed to prevent
their use in manufacturing or processing operations for which they are
unsuitable.
225. Written procedures are not [drafted, reviewed and
approved by the appropriate organizational units] [reviewed and approved by the
quality control unit].
226. Each component is not added to the batch by one person
and verified by a second person..
Determinations of conformance to appropriate written
specifications for acceptance are [not made] [deficient] for in-process
materials.
227. The reserve sample of active ingredient does not
consist of at least twice the quantity necessary for all tests required to
determine whether the active ingredient meets its established
specifications.
228. Drug product reserve samples are not stored in [the
same immediate container-closure system as the marketed product] [an immediate
container-closure system that has essentially the same characteristics as the
marketed product].
229. Evidence of reserve drug product sample deterioration
was not [investigated] [recorded and
maintained with other stability data].
230. The retention period for drug product reserve samples
(except those described in 211.170(b)(2) and (3)) is deficient in that they are
not retained for one year after the expiration date of the drug product.
231. Procedures describing the [holding] [testing]
[reprocessing] of returned drug products are not [in writing] [followed].
232. Containers are not [opened] [sampled] [resealed] in a
manner designed to prevent contamination of [their contents] [other components]
[other drug product containers or closures].
233. Components are not microscopically examined when
appropriate.
234. Control procedures fail to include [tablet or capsule
weight variation] [disintegration time] [adequacy of mixing to assure
uniformity and homogeneity] [dissolution time and rate] [clarity, completeness
or pH of solutions].
235. Written procedures for the [receipt] [identification]
[storage] [handling] [sampling] [examination] [testing] of packaging and
labeling materials are not followed.
236. Laboratory controls do not include determination of
conformance to appropriate written specifications for the acceptance of each
lot within each shipment of [components] [drug product containers] [closures]
[in-process materials] [labeling] [drug products] used in the manufacture,
processing, packing, or holding of drug products.
237. Samples taken to determine conformance to appropriate
written specifications for the acceptance of each lot within each shipment of
[components] [drug product containers] [closures] [labeling] are not
[representative] [adequately identified].
238. Written procedures for sampling and testing plans are
not followed for each drug product.
239. Where data from accelerated studies was used to project
a tentative expiration date beyond a date supported by actual shelf life
studies, there were no [stability studies] [drug product testing at appropriate
intervals] conducted until the tentative expiration date was verified or the
appropriate expiration date determined.
240. Batch production and control records do not include
results of the inspection of the packaging and labeling area [before] [after]
use for each batch of drug product produced.
241. Batch production and control records do not include
[in-process] [laboratory control] results for each batch of drug product
produced.
242. Batch production and control records do not include the
identity of individual major [equipment] [lines] used for each batch of drug
product produced.
243. Laboratory records do not include a record of all
calculations performed in connection with the test.
244. Laboratory records do not include a statement of the
results of tests and how the results compare with established standards of
identity, strength, quality, and purity for the [component] [drug product
container] [closure] [in-process material] [drug product] tested.
245. Adverse drug experiences that were the subject of post
marketing 15-day reports were not [promptly] investigated.
246. Follow-up reports were not submitted [within 15
calendar days of receipt of new information] [as requested by FDA] concerning
post marketing 15-day reports.
247. Individual ADEs which were not reported to FDA in a
post marketing 15-day alert have not been included in a periodic safety
report.
248. Not all quarterly periodic adverse drug experience
reports have been submitted within 30 days of the close of the quarter.
249. You failed to submit a periodic report containing [a
narrative summary and analysis of the ADE information for the reporting
interval in the report] [an analysis of the post marketing 15-day Alert reports
submitted during the reporting interval] [a history of actions taken since the
last report because of adverse drug experiences] [an index with a line listing
of your patient identification code and adverse reaction term(s) for all ICSRs
you submitted for the reporting interval].
250. An ICSR failed to include [patient information code]
[patient age at the time of the adverse drug experience or date of birth]
[patient gender] [patient weight].
251. You failed to maintain for a period of 10 years records
of all adverse drug experiences known to you, including raw data and any
correspondence.
252. Your equipment is not [constructed] [maintained] so
that surfaces that contact [components] [in-process materials] [PET drugs] are
not reactive, additive, or absorptive so as to alter the quality of the PET
drugs.
253. You did not examine and approve or reject [components]
[containers] [closures] [in-process materials] [packaging materials]
[labeling] [finished dosage forms] to
ensure compliance with procedures and specifications affecting the identity,
strength, quality, or purity of a PET drug.
254. Your written procedures are not adequate to ensure that
the [components] [containers] [closures] are suitable for their intended use.
255. You did not establish appropriate written
specifications for the [identity] [quality] [purity] of components.
256. You did not handle and store [components] [containers]
[closures] in a manner that prevents [contamination] [mix-ups] [deterioration]
and ensures that they are and remain suitable for their intended use.
257. You did not have written production and process control
procedures to [ensure] [document] that [all key process parameters are
controlled] [any deviations from the procedures are justified].
258. Your master production and control records did not
include complete [production and control instructions] [sampling and testing
procedures] [specifications] [special notations] [precautions to be followed].
259. Your batch production record does not include each
major production step (obtained from the approved appropriate master production
and control record).
260. You did not [establish] [follow] [maintain] a written
testing program to assess the stability characteristics of your PET drug
products.
261. You did not [establish] [follow] procedures to ensure
that each batch or sub-batch of a PET drug was not given final release until a
designated qualified individual authorized the final release by dated
signature.
262. The RDRC Chairman did not sign all [applications]
[minutes] [reports] of the committee.
263. The RDRC met without having more than 50% of its
membership present.
264. The RDRC met without having the appropriate
representation of the required fields of expertise.
265. The minutes of an RDRC meeting did not include the
numerical results of votes on protocols involving use in human subjects.
266. The RDRC did not submit annual reports to FDA as
required by regulations.
267. The RDRC did not [immediately] report to FDA a research
proposal that involves exposure of more than thirty (30) subjects.
268. The RDRC did not assure that the responsible
investigator obtained the informed consent of human subjects or their legally
authorized representative in the research study.
269. The RDRC did not assure that research was approved by
an Institutional Review Board (IRB).
270. You failed to submit an ICSR for the reporting period
[within 30 days of the close of the quarter] [within 60 days of the anniversary
date of the approval of the application].
271. You submitted an ICSR reporting initial reporter
information that failed to include the [name] [address] [telephone number]
[whether initial reporter is health care professional] [occupation of health
care professional].
272. Not all safety report submissions were made in an
electronic format.
273. Personnel were observed performing aseptic processing
outside of an ISO 5 area.
274. Your outsourcing facility did not submit a report to
FDA upon initial registration as an outsourcing facility identifying the drugs
compounded during the previous six month period.
275. Vermin or other animals or evidence of their presence
was observed in the [production area] [areas adjacent to production areas].
276. Use of [ingredients] [processing aides] not intended
for pharmaceutical use in non-sterile drug production.
277. Use of [ingredients] [processing aides] not intended
for pharmaceutical use in sterile drug production.
278. Personnel infrequently [changed] [sanitized] gloves to
prevent contamination.
279. Use of non-sterile [disinfecting agents] [cleaning
pads] [cleaning wipes] in the [ISO 5 area] [classified areas].
280. Failure to appropriately and regularly clean and
disinfect or sterilize equipment located in the ISO 5 area.
281. Smoke studies [were not] [were inadequately] performed
under dynamic conditions.
282. [Failure to conduct] [Inadequate] post-use
filter-integrity testing on filters used to sterilize drug products.
283. Biological indicators were not used to verify the
adequacy of the sterilization cycle.
284. Compounding with components, containers or other
materials that have not been verified to assure that they do not contribute
endotoxin contamination that may be objectionable given the product's intended
use.
285. Your outsourcing facility compounds drug products using
bulk drug substances that cannot be used in compounding under section 503B of
the Federal Food, Drug, and Cosmetic Act (FD&C Act) because they (a) are
not used to compound drug products that appear on the drug shortage list in
effect under section 506E of the Act and (b) do not appear on a list developed
by FDA of bulk drug substances for which there is a clinical need.
286. Your firm failed to notify [FDA] [immediate trading partners] within 24 hours after determining that product in your possession or control is an illegitimate product.
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