Wednesday, February 4, 2015

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: 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
Dr. Reddy's Laboratories Limited CTO VI
Ipca Laboratories LTd
Sandoz Private Limited
Aarti Drugs Limited
Ipca Laboratories, Ltd.
Apotex Research Private Limited
Akorn India PVT
Micro Lab Limited
Hospira Healthcare India Pvt Ltd
Sharp Global Limited
Reference sourced from: 

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.


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