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By Agnes Shanley, Editor in Chief
In this brief overview, observers and experts share insights into some of the industry’s most chronic recurring cGMP noncompliance areas, citing lessons that manufacturers might learn for the future. Some consultants refused to be interviewed, while others asked to remain anonymous because they work with some of these manufacturers to help them resolve these issues. However, the companies and the problems involved are in the public record.
What’s notable, one consultant says, is the fact that many of Big Pharma’s recent cGMP failures have involved fundamental quality principles and are coming from companies that know better. “Many of these companies were the shining example of compliance in their day,” he says.
Among the most glaring recurrent problem areas that FDA inspectors have noted (sidebar) is a failure to validate processes. In addition, many drug manufacturers today are inconsistent in documenting or systematizing QC operations, says Ken Reid, publisher of “Validation Times and Food and Drug Inspection Monitor,” both of which track FDA enforcement activities very closely. There is also frequently a failure to establish adequate laboratory controls or to get to the root “out of specification” (OOS) problems, he says.
Former FDA inspector Dennis Moore, now managing partner of AUK Technical Services, has seen this misunderstanding of Quality Systems first hand. During a recent visit to a company with a good compliance record and sophisticated approach to quality, Moore asked for a copy of the company’s Quality Policy, and, at one site, was presented with 20 different versions.
Pharma is still at a relatively early evolutionary stage in its quality and risk management systems, said Mike Long, Director of Consulting at Concordia Valsource, during a November webcast. In addition, Moore says, many companies are using HAZOP for risk management, but driving processes to their critical control points. This can lead to turf battles over which process is more critical. He suggests that drug manufacturers embrace the modern spirit of medical device quality management systems guidance. In fact, he says, ICH Q9 refers directly to this guidance and FDA inspectors are being trained in its principles.
|Top 10 Reasons Why Drug Manufacturing Plants Fail FDA Inspections
1. Failure to document, in writing, and/or follow QC responsibilities and procedures
2. Lack of process validation to assure proper identity, strength, purity and quality of drug
3. Insufficient laboratory controls
4. Lack of investigation into Out-Of-Spec batches, and complaints, or batch-to-batch variation
5. Insufficient GMP training and written procedures
6. Written SOPs and production procedures aren’t being documented and/or followed
7. Lack of written procedures for equipment cleaning and maintenance
8. Insufficient cleaning and maintenance
9. Lack of testing to assure the specs of API
10. Lack of in-process monitoring of critical process parameters that validate the performance of manufacturing processes that might cause variability.
Source: Sharon Toma, FDA Inspector, ORA from a presentation at the International cGMP Conference, March, 2012, summarized in Validation Times, March 2012
Corrective and Preventive Action (CAPA) programs, and failure to trace patient complaints in the field continue to dog manufacturers, based on a cursory look at FDA enforcement records. As Rick Friedman, Associate Director of FDA’s CDER’s Office of Manufacturing and Product Quality has said, manufacturers still emphasize the C in CAPA, when they need to focus on the P. It was just this failure to investigate serious adverse effects in patients that led to the inspection and closure of Teva’s Irvine facility.
CAPA is never directly spelled out in the cGMP code, says Moore. He suggests that drug manufacturers refer to the QSIT guidance on FDA’s website, as well as ISO 14971, both of which are medical device-oriented, for best practices.
Winners and Sinners?
When asked for examples of proactive corporate quality systems, consultants cited biopharmaceutical manufacturers as the best examples. Biopharma has had its problems with contamination, which led to one recent consent decree at Genzyme’s Allston facility. However, one consultant says biopharmaceutical manufacturers are generally more proactive about compliance and quality. He cites Genentech’s use of intermediate modeling and design of experiments to ensure process understanding when compounds reach commercial stage. He also mentions Amgen, which is currently studying how to use ASTM 2500 in qualification and validation efforts.
Another consultant praises Abbott’s approach to CAPA. At least before the restructuring, he says, the company used one standard CAPA system for its multiple product lines. In most cases, he notes, pharma companies are using different systems, or developing their own homegrown approaches, which can lead to confusion.
There are no real “winners” and “sinners” in this story. Today’s sinners are often the compliance models of the future. But here are some case studies in compliance from FDA’s recent inspection and enforcement records:
The company’s recent GMP problems showed a failure to investigate consumer complaints of foreign products in its oral solid dosage forms. There were more than 160 such complaints since 2009, but a root cause was never found. The company also failed to extend investigation into all potentially affected product batches. In addition, FDA noted that complaint investigations took up to 100 days, and there was no attempt to retrieve suspect material from the marketplace.
There was a mixup in packaging so that the wrong product was placed in the wrong package. “Line clearance is a core quality element of any manufacturing organization,” says an anonymous consultant. There were also failures to address root causes of contamination and repeated analytical and procedural failures.
• Johnson and Johnson
Three sites move toward remediation since being cited by FDA. All three were cited for failing to investigate complaints and establish root cause of quality problems.
The company’s Austin and Rocky Mount facilities received warning letters for problems with injectables, CAPA and sampling.
• Ben Venue
The company’s Bedford plant recalled 10 products due to sterility assurance problems, particulate contamination and low-fill volume. In addition, the company was sited for poor maintenance, staff training and building problems such as mold.
• Sandoz Canada
Crystalline material was found in sterile injectables; foreign matter and broken tablets were found in opiate products produced in Nebraska.
As one consultant points out, these failures aren’t intentional, but may reflect corporate cultures where greater value is placed on the creation and dissemination of systems and processes, rather than the content of these systems. “CEOs can talk the talk, but if they do not reinforce the concept that high quality will ultimately equate to bigger and better profits, it is just lip service,” he says.
Editor’s Note - Pharmaceutical Manufacturing will be increasing its coverage of compliance in 2013, and will also be launching a new e-newsletter focused exclusively on this area.
PharmaManufacturing.com is the site for knowledge, news and analysis for manufacturing and other professionals working in the pharmaceutical, biopharmaceutical and biotech industries.