Trends in GMP Violations

It is essential that pharmaceutical manufacturers follow current good manufacturing practices (CGMPs) to ensure product quality and patient safety. FDA regularly inspects the manufacturing facilities of pharmaceutical companies to determine if GMPs are being followed. Pharmaceutical Technology spoke with Brian Hasselbalch, Acting Associate Director for Policy and Communication, Office of Manufacturing & Product Quality, Office of Compliance at FDA’s Center for Drug Evaluation and Research, to find out what trends in GMP violations and quality issues the agency has discovered in the past year.

Top GMP deficiencies

PharmTech: What were some of the top GMP deficiencies in pharmaceutical manufacturing that FDA documented in 2012?

Hasselbalch (FDA): FDA inspections of drug manufacturers are designed to always evaluate the facility’s quality system. The quality system includes evaluation of manufacturing problems-complaints, recalls, deviations, defects, and failures-so it may not be surprising that we tend to find CGMP deficiencies in this area. Inspection findings from 2012 show CGMP deficiencies in the following major areas:

• The quality unit does not function as the CGMP regulations require: Approving or rejecting procedures, major decisions about quality including batch release (21 CFR 211.22).

• Production and process controls are not proven valid and/or are not in writing sufficient to assure consistent performance (21 CFR 211.100).

• Complaints, defects, and failures are not fully investigated to determine cause and/or full scope of impact (21 CFR 211.192).

• Facility and equipment are not designed or maintained to assure cleanliness (sanitary surfaces and/or free of residual drug contamination) (21 CFR 211.67).

Major trends

PharmTech: What were the major trends in quality control violations in pharmaceutical manufacturing?

Hasselbalch (FDA): There is a problem of oversight: the quality unit is not governing operations as required; management is not providing sufficient resources to quality assurance activities. In some cases, we see evidence that the quality unit is not being allowed to govern operations bearing on quality assurance, and batch release decisions are made contrary to the CGMP regulations.

One area of change from past years to the more recent full year is that facility cleaning and equipment maintenance deficiencies have increased. FDA Warning Letters over the same period reveal problems particularly in sterile manufacturing operations, where the consequence of poor maintenance and cleaning often leads to more severe consequences for patient safety, such as production of a non-sterile injectable.

Improvements in quality control

PharmTech: What areas of quality control could pharmaceutical manufacturers improve upon?

Hasselbalch (FDA): First, manufacturers should prevent problems from happening by providing sufficient resources toward the creation of a well-designed, optimized manufacturing and control operation. This may not be a novel concept, but is still worth saying. Second, manufacturers should react more aggressively on information bearing on product quality. All too often, we see potentially negative quality information-such as consumer complaints, aberrant stability results, abnormal yield variations, adverse-event reports-being evaluated too slowly and incompletely. We understand the need for a response to such information to be thoughtful, but we often see manufacturers summarily disregard such data.

PharmTech: What areas have pharmaceutical companies improved upon in the past two years?

Hasselbalch (FDA): Inspection deficiencies appear to have decreased in quality-unit responsibilities (while still being higher than other types of deficiencies) and employee training.

Domestic versus offshore

PharmTech: What domestic manufacturing GMP deficiencies have FDA documented compared with offshore manufacturers?

Hasselbalch (FDA): Domestic and offshore manufacturers tend to have similar problems; usually, given the greater number of APIs being made offshore than here in the US, the differences are often explained by the nature of the processing and standards expected.

In fiscal year (FY) 2012, FDA performed approximately 500 preapproval-type inspections (specific to a site and application), which includes all types of application-listed facilities (API, finished product, processing, testing, and packaging). This is about the same number as in FY 2011.

In FY 2012, FDA performed about 1900 CGMP-type inspections (i.e., routine coverage) of facilities connected with human drug manufacturing (except medical gas; including all other drug types and APIs as well as finished product) here in the US and offshore. This is about the same amount as in FY 2011, but with one big difference: routine CGMP inspections of offshore facilities increased by about 20% in FY 2012 over FY 2011. We have planned for this increase to continue in FY 2013. Other FY 2013 changes over previous years include increased inspections of positron emission tomography facilities, which are primarily domestic sites.