Susan Schniepp, distinguished fellow at Regulatory Compliance Associates, discusses the regulatory requirements for improving manufacturing lines.
Q: I work for a contract manufacturing organization (CMO) and my management has dedicated capital funds to update some of our manufacturing lines. I need to work with my clients to get approval to make the necessary changes. Many of my clients feel any changes to the manufacturing line would require a prior approval supplement (PAS), which would be a challenge for our company. Do you have any advice regarding a regulatory strategy that I could propose to my clients that would satisfy them and minimize downtime?
A: This is a great question and a complicated issue. 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. In the past three years, FDA has issued three important guidelines to help facilitate the dialog between clients and CMOs (1) and expedite the regulatory post approval change (2, 3).
The first step in the process of upgrading your facility is to get the agreement, or at least, an acknowledgment from your clients that they are aware that you intend to upgrade the facility and that it may affect their regulatory filing. The first guideline that helps you facilitate the dialog with your 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 you have a quality agreement, then you need to check and see whether the contract organization or the client has the responsibility to maintain the facility. If you have relegated this responsibility to your clients and they are hesitant to implement the upgrade, remind them that the quality agreement guideline gives you the authority to maintain your 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 you and your client(s) may have responsibilities outlined in the quality agreement regarding maintaining and upgrading the facility but you, as the CMO, need to adhere to CGMPs and make sure your 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.”
CMC post-approval changes
The second guideline that helps in updating your facility in a timely manner is the chemistry, manufacturing, and controls (CMC) post-approval 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, you still need to do all the necessary work to ensure the change is appropriate and does not affect product quality.
There may still be some clients wary of the change even when you notify them of the change 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-effected-in-30-days supplement. By employing the use of a comparability protocol you are, in essence, making sure your client understands the change you will be implementing and the data you will be collecting and reviewing to assess that the upgrade was successful and did not affect product quality. The comparability protocol is a nice compromise when you have clients insisting on a PAS and others who are comfortable with the annual reportable strategy. It allows you 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 chose an alternative. The best way to convince a client of a filing strategy is to make sure you have a robust quality agreement in place that gives you the responsibility for maintaining your facility. Become familiar with the regulations and use them to justify your recommendation. 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 you implement a facility upgrade in a timely manner while reducing your downtime to make the improvement.