There are three topics in today’s pharmaceutical landscape com-manding the attention of both the industry and the regulators: drug shortages, quality metrics and aging facilities. It is increasingly difficult to discuss one of these topics without discussing the others. Maintaining facilities that are capable of manufacturing quality products and being able to provide these products consistently and without delay has become a high priority for the industry and FDA.
The first piece of information linking these topics emerged in 2012 when Congress passed the Food Drug Administration Safety and Innovation Act (FDASIA) which enhanced FDA’s capability to proactively react to, prevent, and alleviate drug shortages. This directive is codified in the language contained in Title VII – Drug Supply Chain and Title X - Drug Shortages. Specifically, Title VII Section 705 of the Act states FDA “shall inspect establishments described in paragraph 1 that are engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs (referred to in this subsection as ‘drug establishments’) in accordance with a risk-based schedule established by the Secretary”.1 Additionally, this section also describes the risk factors to be considered in establishing the inspection schedule. The last risk factor listed in this section is “Any other criteria deemed necessary and appropriate by the Secretary for purposes of allocating inspection resources.” Section 706 of the same act allows FDA to request certain information from companies in advance of or in lieu of inspections by stating “Any records or other information that the Secretary may inspect under this section from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection…”
The next piece of information linking these topics is found in Title X section 506C-1 (Annual Reporting on Drug Shortages). Title X section 506C-1 requires FDA to annually provide Congress “a report on drug shortages…” This statement links the manufacturers of drug products to the drug shortage problem when taken in context with the above FDASIA requirements.
The third piece of information came in the form of a February 12, 2013 Federal Register Notice. FDA asked the industry to “assist the Food and Drug Administration in drafting a strategic plan on drug shortages as required by the Food and Drug Administration Safety and Innovation Act…” This notice asked a series of thought-provoking questions including “What metrics do manufacturers currently use to monitor production quality?” and “How frequently would such metrics need to be updated to be meaningful?”.2 The purpose of asking for metrics was to see if there was a way to proactively collect information that could predict if a drug shortage was on the horizon and stave it off before it became a reality. It is important to note that many of the drugs experiencing drug shortages are older formulations such as sodium chloride for injection. Many of these products listed in the drug shortage are manufactured on production lines that are 25 to 30 plus years old.
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The thought process behind the proposal of metrics was basically to determine if drug shortage events could be predicted through the collection and evaluation of metrics then the drug shortage problem could be potentially avoided. Companies currently use a variety of metrics to measure performance including, but not limited to, corrective action and preventive action (CAPA), out of specification (OOS), batch rejection rate, complaints, field alerts, recalls, batch yield, training effectiveness, and environmental monitoring excursions. The goal is to review and define which of these metrics can be used to measure performance based on product quality and suitability as opposed to performance based on compliance standards. The hard part is trying to define them so they are not subject to interpretation: they are simple but comprehensive and applicable to traditional, biotech, virtual, contract manufacturers, drug substance manufacturers, etc. The industry needs to ensure the metrics chosen provide meaningful data while avoiding unintended consequences. The metrics need to be simple so they do not divert or dilute a company’s resources from daily activities associated with producing and delivering high quality medicines.
The concern with older facilities and manufacturing lines is that it is hard to predict when they will cease to be capable of producing high quality products to the market. While the lines may run smoothly for a time there are hidden issues that will eventually emerge causing the line to malfunction potentially creating a drug shortage. The older the line the more likely it will experience frequent interruptions and breakdowns. Production interruptions will be more common and the costs to remediate these issues will continue to rise. In some cases, replacement parts may be needed but could be difficult to procure.
In addition to the maintenance of the lines there are other considerations that need to be taken into account when discussing aging facilities. Not all the problems associated with aging facilities are related to the manufacturing lines. Many of the lines have nonautomated processes requiring human intervention. The older the manufacturing line is the more human intervention is required. The quality mindset and training of the operator is critical in these situations because of this constant human/product interface. Even if the line is fixed and production resumed the issues will remain below the surface ready to emerge again. Quality issues will continue, unit operations will breakdown, supply chains will be disrupted and scrap rate will increase will yield will decrease.
Associated with old manufacturing equipment and processes are aging analytical methods and equipment. Some of the analytical procedures used to determine the suitability of the product are outdated and, as with the production equipment, replacement parts can be difficult to find. In some cases, the chromatographic columns needed for analysis are no longer available. Breakdowns and older equipment issues associated with laboratory operations can contribute to the inability of a company to release product in a timely manner which can result in a drug shortage.
Many of the products on the drug shortage list are produced through contractual arrangements. It is more cost effective for a company to contract out product manufacturing to a third party. The cost of maintaining a facility dedicated to producing a product can be deferred if the product is outsourced to a contract manufacturing organization (CMO). The CMO has multiple clients and needs to maintain the facility to meet the needs of these clients. CMO operations can run 24/7 depending on product demand. This is not to imply that these arrangements are undesirable or that CMOs are somehow lacking. The reality is that the CMO lines, in many cases, are older and in need of updating. Traditionally, putting in a new manufacturing line would be done under a Prior Approval Supplement filing which could potentially render the line being replaced inoperable for, at a minimum, one year. A recommended two year product reserve would need to manufactured for every product being manufactured on that line. If we assume the line manufactures product for 15 customers and each customer has two products being produced on the line the ability to create a two year supply for each product while the line is being replaced becomes daunting. The question the industry needs to ask is: Is there a way to put in a new manufacturing line without shutting down operations for a one to two year period. The answer is “Yes, there is a way”.
The pharmaceutical industry has been trying to become more efficient from both manufacturing and regulatory perspectives. The challenge is to improve processes, quality systems, and manufacturing capabilities while operating efficiently and in a manner that ensures safe, effective, and cost-efficient medicines to patients. Many updates to processes and quality systems can be easily and readily implemented with little or no impact on regulatory filings. When a change impacts regulatory filings, it has the potential to disrupt the supply chain if it is not handled appropriately and as efficiently as possible. FDA seems to recognize these situations and has been working to help lessen the regulatory filing burden to companies while not affecting the quality of the products. The FDA has issued three important guidelines to help facilitate the dialog between clients and CMOs3 and expedite the regulatory post approval change.4,5
The first step in the process of upgrading a facility is to get the agreement, or at least, an acknowledgment from clients that they are aware of the intended upgrade to the facility and that it may affect their regulatory filing. The first guideline that helps facilitate the dialog with the client is the quality agreements guidance issued in May 2013.1 This guideline states “… FDA recommends that owners and contracted facilities implement written quality agreements as a tool to define communications, delineate responsibilities, and assure the quality, safety, and effectiveness of drug products.” If there is a quality agreement in place it should clearly state who has the responsibility to maintain the facility. If this responsibility has been relegated to clients and they are hesitant to implement the upgrade, the CMO needs to remind the client that the quality agreement guideline gives the CMO authority to maintain the facility (including necessary equipment upgrades) by stating “A quality agreement does not exempt contracted facilities from CGMP requirements related to the operations they perform, regardless of whether such CGMP requirements are specifically discussed in the quality agreement.” Bottom line, both the CMO and their client(s) may have responsibilities outlined in the quality agreement regarding maintaining and upgrading the facility but the CMO needs to adhere to CGMPs and make sure their facility is maintained per 21 Code of Federal Regulations (CFR) 211.58 requirements that “any building used in the manufacture, processing, packaging, or holding of a drug product shall be maintained in a good state of repair.”
The second guideline that helps in updating the facility in a timely manner is the chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that can be documented in an annual report that was issued in March 2014.2 This new revision reiterates the concept of like-for-like replacement while expanding some of the facility changes that can be made as an annual report. For instance, the new guidance states, “For equipment used in aseptic manufacturing processes (e.g., new filling line, new lyophilizer), replacement of equipment with that of the same design and operating principle, when there is no change in the approved process methodology or in-process control limits” … and … “In the manufacturing of sterile products, the addition of barriers within a conventional fill area to prevent routine in-process human intervention in an existing filling or compounding area that is qualified and validated by established procedures” are acceptable changes to include in an annual report. Many pharmaceutical professionals would have considered these changes as needing prior approval before being implemented. Be cautious, though; just because these improvements can be managed through the annual report process, all the necessary work to ensure the change is appropriate and does not affect product quality still needs to be conducted and documented.
There may still be some clients wary of the change even when notified of the proposed upgrade and the guidelines that support making the change without going through the PAS process. This is where the third guidance comes into play, and it is the updated guidance on comparability protocols for human drugs and biologics.3 A comparability protocol has the potential to decrease the filing category. For instance, items that would normally be handled as a PAS have the potential to be considered as a changes-being-effectedin- 30-days supplement. By employing the use of a comparability protocol, the CMO is, in essence, making sure the client understands the change being implementing and the data being collected and reviewed to assess the upgrade was successful and did not affect product quality. The comparability protocol is a nice compromise for clients insisting on a PAS and as well as for those clients comfortable with the annual reportable strategy. It allows the CMO to file the protocol as a PAS and build the inventory needed in preparation for the anticipated shutdown period.
There are no right or wrong answers when recommending filing strategies to a client. Regardless of what the contract manufacturing organization says, the client can always choose an alternative. The best way to convince a client of a filing strategy is to make sure there is a robust quality agreement in place that gives the CMO responsibility for maintaining their facility. Become familiar with the regulations and use them to justify the recommendations for upgrading. Finally, use a comparability protocol for proving like-to-like equivalency, and present the recommendation to the client in a documented manner. These steps should help in implementing a facility upgrade in a timely manner and reduce downtime while making necessary upgrades to the facility that will only improve efficiencies and great reduce the potential for drug shortages that are a direct result of aging manufacturing lines.
References
- FDASIA.
- FDA, Federal Register, Vol. 78, No. 29 (Feb. 12, 2013) 9928-9929.
- FDA, Guidance for Industry: Contract Manufacturing Arrangements for Drugs: Quality Agreements (CDER, CBER, CVM, May 2013).
- FDA, Guidance for Industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (CDER, March 2014).
- FDA, Guidance for Industry: Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information (CDER, CBER, April 2016).