B/POR REVIEWS RISING TIDE OF FDA 483s AND WARNING LETTERS AT FIRMS TO INCLUDE BEN VENUE LABS, HOSPIRA AND FORMATECH
Policy changes and enforcement strategies implemented by the FDA have led to an increase in the number of inspection of sterile manufacturers — especially injectables. There is greater oversight and detailed review of all protocols and processes. Any issue or potential issue must have a corrective action with a demonstrated positive outcome. There no longer exists a prescribed sequence of events before a FDA 483 and subsequent Warning Letter are issued. Vendors must now have strategies to ensure GMP compliance at facilities and be prepared for more frequent and thorough audits.
FDA Increases Vigilance on Aseptic Processing Facilities
The FDA appears to be increasing its vigilance on the bio/pharmaceutical industry. In particular, there has been increased scrutiny by the agency on aseptic processing facilities. This is evident by the rising tide of 483s and warning letters at these facilities. Examples include:
- Ben Venue Labs (BVL -Bedford,Ohio,USA), which recently exited the contract manufacturing arena after regulatory inspections by the FDA and EMA resulted in several noncompliance observations. In fact, problems at BVL date back to a 2007 warning letter from the FDA, and the company just announced this week that it will temporarily suspend the manufacture and distribution of products produced in itsBedford facility.
- Hospira (Lake Forest,Ill.,USA), which received a warning letter from the FDA in August 2010 as a result of cGMP deficiencies cited at the company’s pharmaceutical and device manufacturing facilities in bothRocky Mount andClayton,N.C.,USA.
- Formatech (Andover,Mass.,USA), which received an FDA warning letter in February 2011 for cGMP violations at it clinical manufacturing facility.
- Genentech (San Francisco,Calif.,USA), which received a 483 from the FDA in September 2011 for problems at itsSan Francisco plant which produces Avastin.
- GlaxoSmithKline (London,UK), which received a FDA warning letter in October 2011 for failing to prevent microbiological contamination and to ensure laboratory control procedures were properly in place at itsUK site.
“There is no doubt that in the last few years’ policy changes and enforcement strategies implemented by FDA have led to an increase in the number of inspections of sterile manufactures, particularly manufacturers of sterile injectables,” explained Joachim del Boca, Vice President of Quality Assurance, Vetter Pharma International (Ravensburg,Germany). “We have noticed a distinctive change in both the frequency of inspections by the FDA and degree of vigilance by their inspectors to ensure all of our processes and protocols meet stringent quality controls.”
The FDA released new guidelines in 2004 for sterile drug products manufactured by aseptic processing. However, in the wake of congressional pressure following the heparin scandal in 2008, the agency began instituting several changes allowing it to improve enforcement.
“Several years ago, FDA hired a large number of new employees and put many of those employees in the field offices. As a result, there are more inspections today than a year ago, more inspectional observations, and more enforcement actions growing out of those inspections,” commented Meredith Manning, co-director for the pharmaceutical and biotechnology practice group at the law firm Hogan Lovells.
In fact, according to the FDA, while the number of inspections related to sterile products has increased 9% over the past year from 162 in 2010 to 176 in 2011, the number of 483s issued as a result of these inspections has increased by 27%.
In addition to having more boots on the ground to conduct inspections, the FDA is reacting much more rapidly and no longer allowing for long-term discussion surrounding issues at facilities. The other major change is that the 15-business day window for responses to 483s and warning letters is now being strictly enforced.
“We notice that today there is far greater oversight and detailed review of all protocols and processes. There is no room for deviation or error. Any issue or potential issue must have a corrective action with a demonstrated positive outcome, and this action must be put into place in a very short period of time,” said del Boca.
“Previously, a 483 was only written after an extended amount of conversation back and forth. There is no longer a sequence of events before a 483 and warning letter is written,” explained Barry Friedman, Ph.D., a consultant who specializes in FDA regulatory compliance for the pharmaceutical, biotechnology and medical device industries. “In other words, there used to be a ‘three strikes and you’re out’ rule, now it is a ‘one strike and you’re out’ rule.”
The Industry Under Fire
The observation has been made that the FDA’s response is a legitimate crack down on companies that have been cutting corners to lower costs. “What has been happening over the years is that accountants have been running these companies with cutting cost in mind which has lead to the slack off on GMP compliance,” expressed Michael Anisfeld, the president of Globepharm and a consultant on GMP/quality activities for the healthcare manufacturing industry.
Another contributing factor to the surge of GMP compliance issues is the changing dynamic of the employee pool which has resulted in a degradation of knowledge concerning compliance. “People have retired; companies have consolidated; and, there have been many layoffs. As a result, there are a number of people who are responsible who don’t have the education, training, or experience to work in or manage an aseptic processing facility,” Friedman added. “For example, more and more the FDA is reporting that QC is being managed by a chemist with no microbiological background.”
Unfortunately, the increase in regulatory actions against companies has been a contributing factor in the growing number of drug shortages in the industry, especially for oncology drugs.
“We go through cycles in the industry and we are in a cycle now,” explained Friedman. “What is making it more difficult, though, is that the FDA is not allowing any wiggle room as they once did.” Therefore, CMOs and clients must be prepared for the changes in the regulatory climate.
In response, several CMOs are putting strategies in place to ensure GMP compliance at facilities and to be prepared for more frequent and thorough audits. “If the FDA is going to be more vigilant and stringent in its review processes, then we as manufacturers of sterile products must be even more vigilant and stringent in our manufacturing,” explained del Boca.
In fact, Vetter has embraced the new regulatory approach and put several mechanisms in place to make certain their facilities are prepared. “We began by reviewing recently issued FDA warning letters sent to other sterile manufacturers and checking the issues highlighted against our own internal systems, making any changes and adjustments in our manufacturing processes as necessary,” continued del Boca. “We look for the root causes of issues and take corrective actions that are appropriate. This is true for our suppliers as well. Demanding tight quality control by suppliers helps ensure that any product used in manufacturing meets exacting standards. For the relationship with our clients, it means that the production processes they employ are carefully reviewed, risk assessment is quantified and controls put in place to ensure the API is of highest quality before it reaches the manufacturing stage.”
The concern, though, is that many companies will opt out of the business all together rather than make extensive changes at their facilities or pull drugs of the market instead of answering questions regarding quality assurance that may arise during an audit. Unfortunately, though, this could further exacerbate the drug shortage problem throughout the industry.
To avoid this scenario, Anisfeld concluded that companies have to be more diligent in following GMPs with the knowledge that the FDA is now going “to be more in their face.” This is especially true for CMOs, which are more vulnerable to the impact that a warning letter has on a company’s image.
“On the flip side, CMO clients must have a secondary place for production [in the wake of the added regulatory pressure],” added Friedman. “Clients can’t blame the CMO if they don’t have any product to distribute. The client, not the CMO, is ultimately responsible.”
From: Bio/Pharmaceutical Outsourcing Report, Vol 16; No. 11, November 2011