The United States Food and Drug Administration (FDA) defines a Warning Letter as
“…a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act (the Act), its implementing regulations and other federal statutes. Warning Letters should only be issued for violations of regulatory significance, i.e., those that may actually lead to an enforcement action if the documented violations are not promptly and adequately corrected. A Warning Letter is one of the Agency’s principal means of achieving prompt voluntary compliance with the Act.
While violations are generally determined through the FDA’s own inspections, they can also be issued based upon evidence obtained by state personnel. A Warning Letter is considered by the agency to be informal and advisory. While it communicates the agency’s position on a matter it does not commit the FDA to taking enforcement action. For these reasons the FDA does not consider Warning Letters to be final actions on which it can be sued.
The FDA expects that most individuals, firms, and government establishments will voluntarily comply with the law. When departures are observed the FDA gives an organization an opportunity to take voluntary and prompt corrective action before it initiates an enforcement action. A step in this process, depending on the nature of the violation, is to issue a Warning Letter, which also serves to establish “prior notice.”
The agency has a computer application called the Compliance Management System (CMS, or MARC-CMS).) that is used for electronically submitting Warning Letter recommendations from district offices to FDA Centers. All recommendations by the district offices must use the CMS for submitting the proposed Warning Letter, the Form FDA 483 that supports the alleged violations, the Establishment Inspection Report (EIR), and any written response by the firm.
Observations in brief:
1 | Procedures not in writing, fully followed |
2 | Investigations of discrepancies, failures |
3 | Absence of Written Procedures |
4 | Scientifically sound laboratory controls |
5 | Control procedures to monitor and validate performance |
6 | Written procedures not established/followed |
7 | Calibration/Inspection/Checking not done |
8 | Training–operations, GMPs, written procedures |
9 | Cleaning / Sanitizing / Maintenance |
10 | SOPs not followed / documented |
11 | Testing and release for distribution |
12 | Prepared for each batch, include complete information |
13 | GMP Training Frequency |
14 | Equipment Design, Size and Location |
15 | Procedures for sterile drug products |
16 | Test methods |
17 | Lack of written stability program |
18 | Procedures to be written and followed |
19 | Training , Education , Experience overall |
20 | Complaint Handling Procedure |
21 | Calibration – at intervals, written program, remedial action |
22 | Reports of Analysis (Components) |
23 | Lack of quality control unit |
24 | Quality control unit review of records |
25 | Items to cover on annual reviews |
26 | Complete test data included in records |
27 | Written warehousing procedures established/followed |
28 | Following/documenting laboratory controls |
29 | Written program not followed |
30 | Written procedures fail to include |
31 | Buildings not maintained in good state of repair |
32 | Procedure Deviations Recorded and Justified |
33 | Review of representative number of batches |
34 | Procedures To Be in Writing |
35 | Written record of investigation incomplete |
36 | Lab controls established, including changes |
37 | Written records kept in individual logs |
38 | Storage under appropriate conditions |
39 | Procedures for non-sterile drug products |
40 | Identity Testing of Each Component |
41 | No written record of investigation |
42 | Expiration date lacking |
43 | Changes to Procedures Not Reviewed, Approved |
44 | Strict control not exercised over labeling issued |
45 | Microbiological testing |
46 | Components withheld from use pending release |
47 | Valid stability test methods |
48 | Written in-process control procedures |
49 | Records reviewed annually |
50 | Approve or reject procedures or specs |
51 | Cleaning/maintenance records not kept |
52 | Computer control of master formula records |
53 | Extent of discrepancy, failure investigations |
54 | Approval and review of procedures |
55 | Second person sign off |
56 | Deviations from laboratory control requirements |
57 | Actual vs. theoretical yields not determined |
58 | Sanitation–buildings not clean, free of infestation |
59 | Annual visual exams of drug products |
60 | Written Procedures Not Followed |
61 | Complete instructions, procedures, specifications et. al. |
62 | Defined areas of adequate size for operations |
63 | Establishment of time limitations |
64 | Procedures are written, and followed |
65 | Adequate number of batches on stability |
66 | Written sanitation procedures lacking |
67 | Returned drug procedures in writing and followed |
68 | Suitability of testing methods verified |
69 | Validation lacking for sterile drug products |
70 | Procedures Written and Followed |
71 | Establish reliability of supplier’s C of A |
72 | Equipment for Environmental Control |
73 | Testing Each Component for Conformity with Specs |
74 | Written distribution procedure |
75 | Labeling control records including specimens or copies |
76 | Buildings of Suitable Size, Construction, Location |
77 | Handling and Storage to Prevent Contamination |
78 | Written procedures followed |
79 | Manufacturing Instructions and Specifications |
80 | Complaint Investigation/Follow-Up Findings |
81 | Establishment of calibration procedures |
82 | Failing drug products not rejected |
83 | Distribution Record Requirements |
84 | Recall facilitation |
85 | Results not used for expiration dates, storage cond. |
86 | Late submission of 15-day report |
87 | Contamination, chemical or physical change, deterioration |
88 | Approve or reject components, products |
89 | Identity of major equipment and lines used |
90 | Failure to develop written procedures |
91 | Distinctive ID or code not recorded in batch record |
92 | Authority lacking to review records, investigate errors |
93 | Protective Apparel Not Worn |
94 | Distribution Recall System |
95 | Acceptance criteria for sampling & testing |
96 | Written procedures not followed |
97 | Supervisor Training/Education/Experience |
98 | Written calibration / inspection records not kept |
99 | Written procedures describing in detail |
100 | Quarantine – actual practice |
101 | Instruments, apparatus, et. al. not meeting specs |
102 | Clothing appropriate for duties performed |
103 | Representative Samples |
104 | Sampling and testing plans not described |
105 | Signature and checking of records — 2 persons |
106 | Adequate lighting not provided |
107 | Washing and toilet facilities are deficient |
108 | In-process materials specifications |
109 | Reserve samples identified, representative, stored |
110 | Status of Each Lot Identified |
111 | Drug products – samples representative, identified properly |
112 | Identification of persons involved, each significant step |
113 | Complaints reviewed by Quality Control Unit |
114 | Description of containers, labels, et. al. |
115 | Written QA procedures established, followed |
116 | Laboratory equipment calibration records |
117 | Written sanitation procedures not followed |
118 | Control procedures fail to include the following |
119 | Sampling and testing plans not followed |
120 | Theoretical yield statement including percentages |
121 | input/output verification |
122 | Environmental Monitoring System |
123 | Testing in same container – closure system |
124 | Test method modification records not maintained |
125 | Identification of containers, lines, equipment |
126 | Certificates of Testing (Containers, Closures) |
127 | Late submission of annual safety reports |
128 | Timely submission |
129 | Equipment not clean |
130 | Determination need for investigation |
131 | Adequate controls (general) |
132 | Contract drug products–lack of responsibility |
133 | Adequate lab facilities not available |
134 | Inadequate number of personnel |
135 | Reprocessing procedures not written or followed |
136 | Label storage access limited to authorized personnel |
137 | Lot or control number assigned |
138 | Disposition recorded by lot identification |
139 | Examination on receipt, before acceptance |
140 | Quarantine Storage of Components |
141 | Representative Samples Criteria |
142 | Specific information required in individual logs |
143 | Personnel dating/signing equipment log |
144 | Testing and standardization of standards et. al. |
145 | Maintenance of Complaint File |
146 | Washing and toilet facilities not provided and accessible |
147 | Written procedures lacking for use of pesticides etc. |
148 | Quarantine of Rejected Components et. al. |
149 | In-process materials characteristics testing |
150 | Investigations made into any unexplained discrepancy |
151 | In-process and laboratory control results |
152 | Written complaint record to be maintained at facility |
153 | Late submission of quarterly safety reports |
154 | Failure to meet specifications |
155 | Suitable for intended use |
156 | Analytical methods |
157 | Mfg / Processing Operations Area |
158 | Label reconciliation discrepancies evaluation/investigation |
159 | Prevention of cross contamination, mix-ups |
160 | Unlabeled filled containers controls |
161 | Examination of packaging and labeling |
162 | Retest of approved components/containers/closures |
163 | Rejecting When Specifications Not Met |
164 | Records not made readily available to FDA |
165 | Stability sample storage conditions described |
166 | Homeopathic drugs, assessment of stability |
167 | Responsible firm officials notified in writing |
168 | Laboratory Test Method Verification |
169 | Complete Test Data |
170 | Complaint Record required information |
171 | Equipment construction – reactive surfaces |
172 | Plumbing System Defects |
173 | Active ingredient retained sample kept |
174 | Backup data not assured as exact and complete |
175 | Containers sampled so as to prevent contamination |
176 | Microbiological Contamination Exam |
177 | Reprocessing procedures lack steps to be taken |
178 | In-process materials specifications testing |
179 | Drug products-sampling procedures/specifications |
180 | Weights and measures of components used |
181 | Identification of each component or in-process material |
182 | Failure to report non-alert ADEs |
183 | Supplies adequately controlled |
184 | Unauthorized Personnel in Limited Access Areas |
185 | Consultant Records |
186 | Cleaning SOP/inspection |
187 | Aseptic Processing Area |
188 | Air Supply |
189 | Sampling/testing of labeling/packaging materials |
190 | Examination of issued labels |
191 | Packaging line inspection before use |
192 | Examinations documented |
193 | Storage conditions |
194 | Identification of Each Lot in Each Shipment |
195 | Top/Middle/Bottom container sampling |
196 | Reactive/Additive/Absorptive Containers/Closures |
197 | Sample size – test intervals |
198 | Sterility/pyrogen-free testing |
199 | Sterility/pyrogens – test methods written, followed |
200 | Dedicated equipment: records part of batch record |
201 | Individual inventory record |
202 | Stability testing records not included |
203 | Quality Control Review |
204 | Adverse Drug Experience |
205 | Mixing adequacy |
206 | Returned drug products identified and held |
207 | Quarantine – written procedures |
208 | Retention time of reserve samples, in general |
209 | Actual yield, % of theoretical yield |
210 | Test method modification records do not include |
211 | Statement of methods and data |
212 | Data secured in course of each test |
213 | Signatures and dates–person who performs test |
214 | Adequate space lacking to prevent mix-ups and contamination |
215 | Failure to investigate serious, unexpected events |
216 | Failure by applicant to report ADE |
217 | Mix-up |
218 | Not capable of repeatable valid results |
219 | Review of records for errors |
220 | Written control procedures |
221 | Lab sampling and test procedures |
222 | Equipment |
223 | Record of all test data |
224 | Testing Procedures- Conformance to Standards |
225 | Cleaning SOPs/instructions |
226 | Component addition checked by 2nd person |
227 | Yield calculations not verified by 2nd person |
228 | Floors, walls, ceiling surfaces |
229 | Deviations of production time limits |
230 | Labels and labeling stored separately |
231 | Component identity verification |
232 | Component written specification |
233 | Record information required |
234 | Labeling: documentation of exam and review |
235 | Accurate reproduction |
236 | Batch production and Batch Control Record Requirements |
237 | Identification of Components and In-Process Materials |
238 | In-Process and Laboratory Control Results |
239 | Documentation of Actual Yield and Theoretical Yield |
240 | Documentation of Sampling Performed |
241 | Documentation of Batch Investigations |
242 | Variation in the Amount of Components Used |
243 | Identification of Person Performing Review of Lab Records |
244 | Complaint File Location |
245 | Reason for Not Conducting Complaint Investigation |
246 | Sewage and refuse disposal in safe manner |
247 | In-process sample representation/identification |
248 | Acceptance of drug products |
249 | Written calibration procedures |
250 | Drug product reserve containers |
251 | Record information inclusions |
252 | Written record not kept of program and validation data |
253 | Testing Containers & Closures Conformity with Specs |
254 | Records fail to include |
255 | Sampling and testing procedures described |
256 | Samples (various types) representative, identified properly |
257 | In process materials – conformance to written specs |
258 | Acceptance/Rejection Levels |
259 | Tentative expiration date |
260 | Accurate reproduction included |
261 | Records of any sampling performed |
262 | Inspection of packaging and labeling area |
263 | Dates not included for each significant step |
264 | Determination not to conduct investigation of complaint |
265 | Written record of complaint to include findings, follow-up |
266 | Written complaint record must include |
267 | Reporting of adverse drug experience to FDA |
268 | Sample identification and other information |
269 | Calculations performed are in the records |
270 | Record information maintained |
271 | Failure to report |
272 | Failure to review ADE information |
273 | Mfg and control changes not requiring a supplemental app. |
274 | (Flag to indicate ANDA applicant) |
275 | Lack Adequate Resources, Facilities, Equipment. |
276 | Prevention of contamination |
277 | Records to document all steps |
278 | Complete instructions, procedures, specs |
279 | Investigation of nonconforming product |
280 | Written complaint procedures |
281 | Product flow through building is inadequate |
282 | Cleaning SOPs/equipment protection |
283 | Penicillin processing area not kept separate |
284 | Batches Formulated to less than 100% |
285 | Weighing/measuring/subdividing operations |
286 | Quarantined Drug Products Area |
287 | Control / Lab Operations Area |
288 | Cleaning System |
289 | Labeling and packaging improperly approved/released |
290 | Destruction of obsolete labeling |
291 | Printing devices |
292 | Destruction of excess labels with lot numbers |
293 | Packaging line inspection after use |
294 | Correct labels during finishing operations |
295 | Representative samples after completion |
296 | Distribution of oldest approved drugs |
297 | Storage off Floor, Spaced Suitably |
298 | Container/Closure Written Test Procedure |
299 | Establish reliability of supplier’s C of A |
300 | Protection from external factors |
301 | Record maintenance 1 year (except exempt OTC) |
302 | Testing of reconstituted drugs |
303 | Accelerated stability studies |
304 | Review of problem drugs |
305 | Identification of Equipment and Lines |
306 | Labeling Control Records and Label Copies |
307 | Animal housing |
308 | Theoretical Weight and Measure |
309 | Theoretical Yield and Percentages |
310 | Comparison of Test Results to Specifications |
311 | Adequate ventilation not provided |
312 | Exhaust systems inadequate to control air contamination |
313 | Rodenticides et. al. registration and usage |
314 | Measured components for manufacturing |
315 | Verification of component addition |
316 | Specification description of sample/testing |
317 | Sampling/testing of in-process materials |
318 | Drug product sample |
319 | Test devices not meeting specifications |
320 | Compositing of Sub Samples |
321 | Containers Marked to Show Samples Taken |
322 | Packaging line inspection documentation |
323 | Distribution of oldest stock first |
324 | Incoming lots – conformance to written specs- |
325 | In-process samples representative, identified properly |
326 | Reserve drug product sample quantity – all tests |
327 | Failing to test for penicillin cross-contamination |
328 | Description of containers and closures |
329 | Photocopying of records not allowed |
330 | Components complete listing |
331 | Weight or measure of each component |
332 | Test results, comparison with standards not included |
333 | Returned drug products with doubt cast as to safety et. al. |
334 | Late submission |
335 | Domestic adverse drug experience reporting form |
336 | Submission of report follow-up |
337 | Interval |
338 | Incomplete periodic safety report |
339 | Wrong form – domestic ADE |
340 | Failure to maintain records |
341 | Distribution data |
342 | Failure of responsible person to report AE (non-RX Drug) |
343 | Records inspection denied (non-Rx drugs) |
344 | Non-applicant reports directly to FDA |
345 | Failure to develop written procedures |
346 | Equipment not suitable |
347 | Equipment not properly maintained |
348 | Oversight of production operations |
349 | Examine, approve or reject |
350 | Proposed changes to existing specs/methods |
351 | Content of written procedures |
352 | Written specs – components |
353 | Weights and ID codes |
354 | Production area & equipment checks |
355 | Lab written procedures |
356 | 30 hours after completion |
357 | Appropriate Recommendations to Facilities Re: Sterility Fail |
Click Here For Details (details will be upload very soon)
Flash Back:
Facts reported by few news sites and channels:
On a cold Sunday afternoon in January, Peter E. Baker (Since 2008, Peter has audited 110 facilities with 36 other inspectors. mail: peter.e.baker@fda.hhs.gov) is in Toansa village, Punjab. He is at the gates of the showcase plant of Ranbaxy, Indias leading pharmaceutical company, some 160 km from Chandigarh airport. This plant makes the active ingredients that go into tablets. The security guard seems unaware not only about who Baker is, but also about the organisation he represents – the US Food and Drug Administration (FDA). He contacts the plant supervisor.
Drug industry executives know Baker only too well. A senior executive at a Mumbai-based pharma major says of Baker, a veteran investigator with the FDA: “Not only does he catch you when you least expect him to, but his style of functioning is unique. He will look at the most unexpected places in the plant… If he finds anything wrong, he will doubt everything, and youve had it.”
Last 10 Firms Inspected
Date of Last Inspection
|
Firm Inspected
|
2014-11-21
|
Dr. Reddy’s Laboratories Limited CTO VI
|
2014-10-17
|
Ipca Laboratories LTd
|
2014-08-29
|
Sandoz Private Limited
|
2014-08-09
|
Aarti Drugs Limited
|
2014-07-18
|
Ipca Laboratories, Ltd.
|
2014-07-01
|
Apotex Research Private Limited
|
2014-06-12
|
Akorn India PVT
|
2014-05-13
|
Micro Lab Limited
|
2014-03-22
|
Hospira Healthcare India Pvt Ltd
|
2014-03-10
|
Sharp Global Limited
|
Reference sourced from: http://fdazilla.com/
Stories doing the rounds in pharma circles tell of dustbins being checked at one company, and urinals in another. The executive adds: “We look into every minute detail now, but still just hope and pray that nothing ever goes wrong.”
A pharma company CEO, who does not want to be named, says: “After I learnt that the Mohali facility of Ranbaxy did not have water heaters in the bathrooms, I checked all our bathrooms in the plant, and to my surprise, we did not have them either. The thought that it could become a point for closure… I immediately had them installed.”
Another pharma company head personally took his team of experts to check urinals and drains in the plant after reading the FDAs observations on Wockhardts factory.
References:
1. http://businesstoday.intoday.in/story/indian-pharmaceutical-companies-under-immense-us-scrutiny/1/203528.html
2. http://www.financialexpress.com/article/pharma/cover-story/forecast-2015/27085/
3. https://www.fdanews.com/
4. http://fdazilla.com/
5. http://en.wikipedia.org/wiki/Form_FDA_483
5. http://en.wikipedia.org/wiki/Form_FDA_483