Major USFDA warning Letters observation from 2000

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