Featuring a Summary of Ben Venue Issues
Policy changes and enforcement strategies implemented by the FDA have led to an increase in the number of inspection of both Contract Manufacturing Operations (CMOs) and in-house sterile manufacturers — especially injectables. There has been a 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 after a Form FDA 483 is issued. Contract Manufacturing Operations, in particular, must now have strategies to ensure GMP compliance at their facilities involved in “arms length” activities with innovator and generic firms and be prepared for more frequent and thorough audits.
This has been particularly true of Ben Venue Laboratories (BVL), Bedford, OH, a subsidiary of Behringer-Ingelheim Corporation. On May 25, 2011 BVL was issued a Form FDA 483 which contained 48 Observations and was 33 pages in length. The Company subsequently was issued a second Form FDA 483 on December 2, 2011 that contained 10 Observations and was 12 pages in length. Although emphasis has been placed upon the FDA and their audits within this article, other regulatory agencies also visiting included the MHRA, the French Regulatory Authorities and Health Canada. The second regulatory audit was reported within a press release by the European Medicines Agency (EMA) on November 22, 2011 and indicated that the UK and French medicines regulatory agencies together with the US FDA audited the site on November 7-11, 2011 and highlighted several shortcomings in the Quality Management System, particularly in relation to the aseptic filling process in the North Complex of the BVL facility. The FDA released their separate findings in December. Please note that neither of these organizations, MHRA or the French Regulatory Authorities, usually release their Observations; however, they will issue both recalls and press releases regarding them.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) performed an analysis to decide on appropriate regulatory action. The CHMP conducted a product specific benefit/risk assessment for each medicine covering both released and quarantined batches and reviewed the need for urgent interim measures. As a precautionary measure, the CHMP concluded that the potential risk of batch contamination due to the shortcomings in Quality Management at the North Complex means that only medicines which are absolutely essential to meet patients’ needs can be used and which are currently not available from another source. Various alternative manufacturers supplying the EU market and which would not lead to product shortages were recommended for recall.
When an innovator or a generics product organization requests the manufacture of a product regardless of whether it is a small or large molecule, the ultimate responsibility for its manufacture, Quality Assurance and compliance to final product standards rests with the Company requesting the CMO to provide that product. The requirements that are placed upon the CMO are based upon both the contractual arrangement as well as a Quality Agreement. Having a contractual arrangement without a Quality Agreement is akin to committing “Quality Assurance” suicide.
In recent press releases, a number of firms have indicated that they can no longer provide product to the consuming public because of the inability of BVL to provide the fill/finish that was contracted. While some of the products have been generics, other have been innovator products which have found success in treating various diseases to include cancer. These drugs are also often involved with other products within clinical trials which also must be placed “on hold” because of this lack of product. Within these press releases, one is left with the opinion that everyone else is responsible for the lack of product, but the innovator firm.
The question that one must ask is “if the product is that critical, why does this firm not have a secondary vendor that can become available when issues arise?” Contingencies such as the “long arm of regulatory agencies” is not the only potential issue that may impact a successful innovator product. Often, one must consider natural disasters to include tornados, hurricanes, snow storms as well as fire and the floods from the breakage of pipes. Some of these obviously lead to more significant shutdowns than others; however, backup plans should be available for each. And, of course, component suppliers are another area which cannot be forgotten. How often are we asked to assure that we have a second supplier for critical components.
The following selections from several of BVL’s Form FDA 483 Observations demonstrate how the various CMO regulatory issues can be extrapolated from the FDA 2004 Guidance for Industry Sterile Drug Products and applied to those CMOs that perform contract Fill n’ Finish.
A review of these Observations suggests that many of them relate to either not following or following incorrectly the FDA’s Guidance for Industry Sterile Drug Products (September 2004). The Observations that follow include examples where the Company’s documentation either “falls short” or “exceeds” the requirement of the Guidance. Enclosed are comments from Observation 3.0 which discusses issues related to the “Media Fill Program Parameters and Specifications” document #030-SOP-029 which contains sections “a” through “h”. from May 2011 Form FDA 483.
e. The (b)(4) Product Specific media manufacturing batch record #1105-08-2125730, dated 9/19/10, document process simulations with manual interventions of the lyophilization pre-chilled vial steps, which is performed prior to the aseptic filling process. However, the media fill process failed to include the requisite manual interventions established by the ” Media Fill Validation Master Plan” (VMP), document #VMP22709M dated 8/30/10, “Media Fill Program Parameters and Specifications” document #030-SOP-D-29, effective date 01 Jun 2010, and the 9/19/2008 assessment document #RA31208M.
f. The media fill manufacturing batch records do not accurately account for the number of vials that are filled and there is no reconciliation to assure that all media filled vials are accounted for.
g. “Media Fill Program Parameters and Specifications” document #030-SOP-0-29, effective date 06 Apr 2011, establish “the test parameters and test specifications required for media fills” and “Each intervention should be documented such that growth positive test results may be appropriately correlated to a designated tray of media filled units. However, after performing the requisite manual interventions the media filled vials are discarded and not included with the incubated vials.
13. The firm has recovered at least 1,171 microbial contaminants between 01/01/10 and 03/30/11, including 1,047 actions of gram-positive organisms, 108 actions of gram negative organisms, and 16 actions of mold organisms from various locations within the firm’s classified areas, including the Class 100 and Class 10,000 manufacturing areas. However, the firm has not investigated these microbial contaminants to determine the root cause of the contamination, nor have they initiated any corrective action to address the contamination.
These four sets of Observations provide information regarding the shortcomings of the Quality Unit function and their lack of understanding of the FDA’s Guidance for Industry documents. Other Observations included one where BVL was not performing a media fill on each aseptic filling line at a six month interval. The FDA discovered during their investigations that they may have been occurring as infrequently as once each year. One could argue that again this was because of shortcomings of the Quality Unit. However, personal experiences from audits suggest that this is often not created by the Quality Unit, but by upper management’s desire to continue manufacturing because of Client requirements. Thus, SOPs and policies are violated and the Quality Unit receives a regulatory violation that was not created by them.
This represents an example of a violation that unfortunately is too often observed, i.e., where the Quality Unit is “zapped”, but the root cause is upper management who has suggested that production not be ceased, that the facility not be cleaned, that the water systems not be shut down for periodic maintenance.
In summary, the FDA has since August 2009 with the institution a 15 business day turnaround for both Form FDA 483 Observations and Warning Letters begun to enforce their regulations. Innovator and generic companies that are manufacturing at CMOs need to assure that these organizations are meeting the regulatory requirements. Auditing teams must be comprised of personnel that understand what requires auditing. A documentation review alone is not satisfactory. Individuals that understand the entire six elements of the Quality System should be present and provide the knowledge to assure that the CMO both understands and follows the GMP requirements.