THE MOST FREQUENT GMP VIOLATIONS IN THE MIRROR OF THE FDA WARNING LETTERS
The analysis of the warning letters of the last fiscal year offers no surprise at first glance: as in the recent years the FDA identified in their inspections an insufficient research into causes for deviations from defined standards and specifications. The corresponding paragraph 21 CFR 211.192 requires medicinal product manufacturers to clarify the reason for the deviation, to take corrective actions and also to create a complete documentation. The fact that in the last 5-year period on average annually about 22 companies received a warning letter in which this GMP deficiency was listed, shows that in many places the understanding of quality assurance departments in dealing with deviations, research into causes and corrective actions is still fragmentary.
Another, more detailed analysis of the warning letters is quite revealing. This analysis also takes into account the dosage form of the medicinal product which GMP violations according to 211.192 refer to. As the listing on the following pages suggests, addressees of complaints with regard to 211.192 were mainly manufacturers of oral dosage forms. They were followed by parenteral drugs manufacturers, companies in the area of blood/blood products and manufacturers of topical remedies. The respective scenarios are quite different. Main shortcoming is always the inadequate clarification and documentation of respective incidents.
A rather unexpected finding in the listing of the most common GMP deficiencies is the high number of citations with regard to 21 CFR 211.84 "Testing and approval or rejection of components, drug product containers, and closures". This citation can be found more often than ever before: 16 out of 32 companies receiving a warning letter for violations of part 211 in the fiscal year 2013 had not implemented the provisions of paragraph 211.84 as expected by FDA investigators. Interestingly, most of these companies (12 of 16) are manufacturers of topical products (ointments, creams, etc.).
The formulations in the warning letters with regard to this issue are very similar (in some cases identical) and are mostly limited to the following standard wording: "Your firm has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals" or "Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit." The citations are also summarised on the following pages.
Recommendation
7/8 May 2024
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Among the recipients of warning letters with quotes relative to Quality Control - 211.166 "Stability Testing" and 211.160 "General Requirements" - there are also many of the companies that have already been blamed for noncompliance of 211.84. This is not surprising, since the thematic context of all three sections is related to the function of quality control. These two paragraphs 211.166 and 211.160, as well as 211.192, have been among the top ten most cited GMP deficiencies for many fiscal years. Main deficiency associated with 211.166 is the lack of a defined stability testing programme (see the following pages) in writing; Therefore, the following sentence can be read in almost any warning letter: "Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates."
The information on violations 211.160 are more differentiated. Partly interesting scenarios are described, as, for example, "Inappropriate visual particle testing" or "disconnected audit trail function in the chromatography system". Here again mainly topical agents manufacturers are the addressees, though not as clear as in the previous paragraphs of Part 211. The main deficiency in the implementation of the requirements of 211.160 is the lack of scientifically sound and appropriate specifications, standards, protocols and test methods for products, intermediates, components, etc. A detailed list is shown following.
The analysis of warning letters of the past fiscal year has shown that the FDA increasingly focuses on issues like "Supplier Qualification" and, in this context, the critical questioning of the suppliers' analytical results and certifications. A closer examination of the warning letters of the current fiscal year will show whether this trend will continue.
For 12 years, the ECA has been collecting and systematically evaluating the FDA warning letters to pharmaceutical manufacturers, manufacturers of blood products and blood-processing companies and to API manufacturers. These complete analyses are available as "FDA Navigator with Warning Letters Report".
Violation of 21 CFR 211.192 "Production Record Review"
Main Failure: Inadequate root cause analysis
Oral Dosage Forms (solid and liquid) (11 Warning Letters)
- Incorrect labeling of final drug product; no documented investigation was performed; no preventive actions have been implemented.
- Failure of content uniformity and low yield of final product; no investigation was performed.
- Specifications have not been met (pH, specific weight, melting point, weight of capsules) ; batch release without root cause analysis
- Tablets with coloured specks and broken tablets were found; no failure investigation was performed
- Delayed recall of batches despite test specifications of uniformity of delivered dose were not met.
- Humidity and temperature excursions in the packaging room; written procedure for failure investigation is inadequate, therefore no investigation was conducted.
- Assay OOS results were first ignored; the subsequent retrospective investigation is insufficient and does not support the assumed root cause.
- Two different products were mixed up; filling and packaging areas were not included in the investigation
- Recall of batches, OOS reports, problems with product stability; no investigation including conclusion and tracking.
Parenterals (7 Warning Letters)
- Impurity peak (HPLC) appeared during stability testing; insufficient root cause analysis
- pH was OOS and visible particles were detected; lots were rejected but no investigation has been conducted.
- Sterility test failed and lots were rejected; root cause was determined but other batches manufactured in the same line and already distributed have not been recalled from the market.
- Endotoxin values out of specification; no root cause analysis; batches partly distributed
- Visible discoloration and stains on the clean side of the HEPA filter; no samples of the discoloration or stains were tested at the time to determine if mold was in fact present.
- Potential microbial growth due to a defective closure component; an investigation was performed but already distributed batches were not included. Complaints were received but product recall was delayed.
- Nozzles of the filling line became clogged and 2 media fills failed; no investigation was conducted
- Defective gloves were used in sterile manufacturing; no investigation was initiated. Manufacture was continued using the same defective gloves
Blood/Blood Products (2 Warning Letters)
- A Red Blood Cell unit was returned with a complaint that it contained visible clots. No documented investigation was conducted.
- Multiple consumer complaints related to mislabeled bags, mix-ups etc. were received; the investigations have failed to identify the deficiencies.
Recommendation
7/8 May 2024
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Topicals (2 Warning Letters)
- Batch release by Quality Assurance without prior batch record review and approval.
Violation of 21 CFR 211.84
"Testing and Approval or Rejection of Components, Drug Product Containers, and Closures"
Main Failure: No specific identity test has been conducted; the suppliers' Certificates of Analysis have been accepted without having established its reliability through appropriate validation of the supplier's test results at appropriate intervals; no supplier qualification
Topicals (12 Warning Letters)
Oral Dosage Forms (solid und liquid)
(3 Warning Letters)
Blood/Blood Products (1 Warning Letter)
- Failure to withhold from use each lot of drug product containers, closures and components until the lot had been sampled, tested, and released for use by the quality control unit. Failure to conduct at least one specific identity test on a component. The reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals had not been established (e.g. failure to subject the water to routine microbiological testing; failure to compare the identity tests to a known standard).
- Failure to test and release drug product components prior to use in manufacturing processes,
Violation of 21 CFR 211.166 "Stability Testing"
Topicals (9 Warning Letters)
Parenterals (4 Warning Letters)
Oral Dosage Forms (solid und liquid)
(2 Warning Letters)
Blood/Blood Products (1 Warning Letter)
- No written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates.
- The stability testing program is not followed.
Violation of 21 CFR 211.160
"General Requirements"
Main Failure: Failure to establish scientifically sound and appropriate specifications, standards, sampling plans and test procedures for drug products, drug product components, container closure systems, in-process materials, and labeling.
Topicals (5 Warning Letters)
No final drug product specification; failure to establish identity test procedures and assays; no written program for calibration of laboratory instruments or equipment; no microbiological testing of the water used to manufacture drug products.
Parenterals (4 Warning Letters)
No scientific justification of the sampling plan for environmental monitoring; visual inspection procedure of the ampoule is inappropriate, as operators have repeatedly failed to detect visible particles. Failure to establish adequate controls during stability testing (samples got lost); failure to follow lab control procedures, deviating procedures were not documented and justified. Audittrail function in several HPLC systems were disabled.
Oral Dosage Forms (solid und liquid)
(4 Warning Letters)
Blood/Blood Products (1 Warning Letter)
- Lab control procedures were not followed and deviating procedures were not documented and justified; procedures for handling OOS results were circumvented; no validation of analytical test procedures (HPLC); samples for in-process testing are not representative.
Author:
Dr. Gerhard Becker
CONCEPT HEIDELBERG
