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Weekly UpdatesATHENS, GA -- The top three drug GMP violations in fiscal 2009 involved failings in manufacturers' quality control units, failure to adhere to production procedures and validation, but laboratory controls--a persistent problem in inspections for many years--came in fourth.
In fact, laboratory control violations were down from fiscal 2008, according to data released at the University of Georgia College of Pharmacy's 34th International Good Manufacturing Practices conference here March 17-19.
The top three 483 violations encompassed the following:
* 887 citations for QCU (Quality Control Unit) Responsibilities
* 709 for Adherence to Production Procedures
* 618 for Production Procedures (Validation)
Susan Turcovski, supervisory investigator in FDA's Florida District, reported on the overall Top 10 list and also offered the top three Quality System, Production System and Laboratory System deficiencies for 2008 and 2009 (through March 6).
An examination of these three areas indicated that in 2008 there were 110 citations for 211.22(d)--The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. Comparably, before the end of the first quarter in 2009, 45 of these citations had already been issued. If this trend continues throughout the year, FDA would record 180 occurrences of this deficiency in 2009, a 63% increase over the prior year, Turcovski said.
The second most observed Quality System citation in 2008 was for 21 CFR 211.192, issued to 66 manufacturers. Within the first week of March 2009 this citation had already been issued 36 times--more than 50% of the prior year total.
She said this section of CFR states: 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. 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.
The No. 3 Quality System GMP citation for 2008 refers to training and was seen 47 times by FDA investigators. Section 211.25(a) states: 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 manufacturing practice]. By early March 2009, there had been nine citations issued for this training violation. If this trend continues throughout the year, FDA will see a nearly 50% reduction from the prior year.
Fellow conference presenter Rebecca Rodriguez, FDA National Expert Investigator, also addressed the issue of training at length in her presentation, "Regulatory Expectations for Training." Rodriguez's presentation referred to 21 CFR 211.25(a): Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with GMP requirements applicable to them. She also remarked that, "GMP regulations are flexible about frequency for training; basically you decide what's appropriate ... Supervisors should have education, training and experience to perform their functions [since] what they do will impact the product's manufacturing."
Of more than 25 additional Quality System deficiencies discussed by Turcovski, seven were related to training. "We find employees are not aware of standard operating procedures or don't know where they are," said Turcovski after discussing deficiencies such as: Employees can't perform tasks according to SOP; No training when SOPs are revised; No annual GMP training; and Excessive number of operator errors in manufacturing or laboratory.
Human error was also a significant part of Rodriguez's discussion. "I often see human error as the cause of problems. I saw a company having problems with cleaning procedures. Sure enough, SOPs were not clear. We interviewed operators and discovered they were doing different things. It was not the operators' fault because the SOP was not clear in the first place." She then asked, "How do you train someone when SOPs aren't clear?.
Rodriguez noted the following types of human error:
* Organizational/systemic
* Procedural (SOPs)
* Careless work
* Voluntary/intentional
* Involuntary
Providing another example of human error, Rodriguez recalled, "I did an inspection when a company was having a high rate of human error. [According to the SOP] people that were giving maintenance services were not supposed to leave the door open."
She observed the facility throughout the day and did not find any problems but recalled, "As we were leaving at 5 p.m. Friday, after the employees and managers had gone, we saw a door open and this opened a can of worms [regarding other procedural violations] nobody from the firm was observing." Rodriquez also pointed out that periodic supervision and oversight are necessary to observe what employees are doing and if they apply what was learned in training.
She added that, "If you don't have enough people or the right equipment, training won't resolve the situation. I have seen companies that have a number of problems with process and they keep retraining. Well, maybe knowledge wasn't transferred properly when the process was developed." She continued, "Sometimes training is not the only solution or the solution. Maybe the job qualifications are not well defined and the person shouldn't have been chosen as an employee. It could also be an organization, maintenance or equipment issue."
Further discussion of Quality System deficiencies by Turcovski addressed investigations:
* Failure to conduct or inadequate/incomplete investigations for OOS results; Microbial contamination or media fill failures; All rejected batches; Environmental, water or product bio-burden excursions; Complaints; Temperature excursions during shipping
* Failure to extend investigations to other lots affected
* Undocumented and/or unsubstantiated investigation conclusions
* Lack of or inadequate corrective or preventive actions taken, including recalls
She also mentioned lack of authority as an issue in citing two additional deficiencies: Lack of authority to implement corrective actions and Lack of responsibility and authority to reject batches.
Moving on to Production System GMP citations for 2008, the No. 1 citation was Written production and process control procedures are not [followed in the execution of production and process control functions] [documented at the time of performance]. This Section 211.100(b) violation was given 58 times in 2008 and had been issued 20 times in 2009. The second leading citation involved Production Systems, 211.110(a), which was slapped on 71 companies in 2008, and occurred when 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. In 2009, 20 companies had been cited.
The No. 3 Production System citation, 211.100(a), was observed 52 times in 2008 and 16 times in 2009. The deficiency reads, There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess.
Continued discussion of Production System deficiencies included review of the following:
* Manufacturing processes are not specific, i.e., mixing times, speeds, temperature, etc.
* Validation records do not demonstrate consistent and reproducible processes
* A second-person check was not done for addition of materials and critical steps
* Reprocessing was not validated
Laboratory Controls violations also included a comparison of 2008 and 2009. In 2008, 69 citations for Section 211.160(b) were issued when it was observed that 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. By March 2009 this citation had been issued 30 times, equivalent to 43% of the 2008 total. Additional Laboratory Control System deficiencies reviewed by Turcovski included: Lack of raw material and finished product testing; Failure to follow test procedures; Inadequate OOS investigations; and Incomplete documentation in laboratory notebooks.
Rodriguez suggested that manufacturers wishing to revisit regulations and guidelines for training and quality control should review ICH Q7, "A Good Manufacturing Practices Guide for Active Pharmaceutical Ingredients," Q9, "Quality Risk Management. (FDA June 2006, ICH) and Guidance for Industry, "Quality Systems Approach to Pharmaceutical GMP Regulations. (FDA, September 2006).
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