Guest Column | June 11, 2019

What To Do When Your CDMO Receives A Warning Letter

By Barbara Berglund, COO, CMC Turnkey Solutions

Warning Letter

You have just completed a full technical transfer to a CDMO for your commercial drug product. You selected this CDMO because it provides a wide range of support services and has a fully functional chemistry and microbiological laboratory, a manufacturing science and technology team, a production team that includes manufacturing and packaging, and a quality assurance team. This has been a two-year program and you are gearing up to launch the opening campaign.

The regulatory team from the CDMO alerts you that it has been issued a warning letter by the FDA. A warning letter is issued if an organization has significant violations or if the organization has not adequately addressed concerns stated by the FDA during routine or nonroutine inspections. The warning letter makes it clear that the CDMO must correct the problem or problems on a specified timeline, and the FDA will return to verify that actions taken by the organization will adequately address the issues. If the CDMO is unable to address the issues, an enforcement action, including forced shutdown, can result.

Initial Concerns And Considerations

This situation is the cause of tremendous anxiety for you. Your first concern is whether manufacturing the drug product or products at this site is safe for patients. If you have already distributed some of your drug product, you will need to determine whether the issues stated in the warning letter have a quality impact on your product (presumably, the regulatory and quality departments at the CDMO have also performed this risk analysis) and, depending on the scope of the issues, you may need to consider taking actions as serious as recalling the product or as minor as reviewing documentation and paperwork.

Your next concern may be resources. If you have already manufactured batches, you have committed active ingredient or drug substance as well as other ingredients. You may not have a supply to make more batches, or there may be a prohibitive cost associated with additional procurement of the drug substance or other ingredients. There are also manufacturing costs, the cost of testing and putting batches onto stability, the cost of lost time, and perhaps even the cost of having a drug shortage situation.

Perhaps you have a unique process that cannot be performed at many CMOs. Perhaps you have expensive or specialized equipment that has been qualified in place; even if you have a backup CMO, you may not be able to transfer equipment to the other organization. Perhaps you changed to the current CDMO due to quality issues at the previous site, or perhaps the supply needs were greater than the capabilities at another site.

You will have many other concerns, including logistics, distribution, storage, and project and program management. Also, there is the need to communicate clear messages up to executive management and/or investors. This includes fact reporting and risk management. All of this is due to the vigilance of the regulatory body that found issues with the CDMO. Presumably, the CDMO had passed the quality audit performed by your organization; this is not surprising, as the CDMO had been operating with the scrutiny of not only the FDA but also of other quality auditors, and possibly of regulatory agencies outside the U.S.

How To Respond

So, now you need to do determine next steps. Those steps are driven by the nature of the issues identified by the FDA and the severity and potential impact on your product. For example, if the issues are limited in scope to a filling line that is not used for your product, your risk assessment would determine whether the same situation(s) could potentially occur on the line you are using. This would include looking at overall practices at the organization to see if the same issue is possible. As an example, if there is an issue with cleaning and cross-contamination on one line, it is possible that the same practices are conducted on another. In either case, you would need to determine whether previously manufactured product is impacted or whether delays to future production need to be considered.

The issue may be facility-wide. Perhaps the environmental program has not adequately considered a potential introduction of contamination or, in a parenteral facility, perhaps smoke studies had not previously been performed, and when the organization performed the smoke studies in response to an FDA observation, a previously undetected airflow that reduces sterility assurance has come to light. In this case, the facility needs to be redesigned in some way to prevent contamination. You would need to carefully examine the process for your own product to determine if it was affected. For example, even if this is a facility concern, but you are taking other extra-protective measures within your own process, you may not be impacted.

Another facility issue may be the inspection process. Perhaps the CDMO’s visual inspection practices or automated inspection validation could be called into question, in which case rejected materials may not be detected and could reach the end user. If your product uses the impacted system, you may be able to take your product, either already manufactured or not yet manufactured, to another organization for inspection or re-inspection. This could be expensive, and performing due diligence will take some time, but it is a solution for this kind of issue. Similarly, issues with final product kitting, packaging, or labeling could result in further production at another facility.

Part of finding the right solution for your product(s) involves the CDMO itself. Maintaining a collaborative relationship is key; if possible, you would want to at least be a spectator in its resolution to the FDA, and perhaps even a collaborator. If your product is on a different line or in a different key functional area, it may not be easy to get the attention on your product. Part of this lies in the question of whether you and your own organization want to stick with this CDMO or move on. Moving on is always expensive, frustrating, and filled with unknown risks. After all, your organization had previously approved the current CDMO, and it took two years for it to be ready. There are regulatory submissions, updates, more stability batches, possible process changes based on facility, engineering batches, validation studies, test procedure validation, quality assurance documents, specifications, cold chain concerns, and other logistics.

Prevention Is The Best Medicine

You may wonder if this could have been prevented. As stated above, the assumption is that not only did your quality group approve the facility, but the facility was already approved by the FDA and perhaps other agencies. In addition, it had passed other client audits, and many organizations also have ISO 9001, ISO 13485, OSHA, and other certifying bodies auditing them.

You could look at trends in agency findings. When you see that a finding is repeated in multiple facilities in the last year or more, you could take a proactive approach prior to your quality audit to target potential issues in the CMO/CDMO, looking at whether there is an issue that had been previously undetected simply due to less focus in quality and regulatory audits. Also, examining the exact nature of previous 483 observations on the facility will clarify whether the CMO has repeat occurrences or common errors and whether the organization is addressing FDA concerns. In a typical audit, the CMO will provide a regulatory inspection history, but typically simply indicates an outcome such as “voluntary action indicated.” This does not tell you the nature of the observations. So, up-front preparation for the quality audit is a good approach, with continued vigilance during the year to see if regulatory audits are successful. A typical supplier quality program would have requalification audits occurring every two to three years, so staying vigilant between audits may not prevent issues from occurring, but it might allow you to do contingency planning for your product.

Having an alternate site for production is an excellent approach, although it will not solve a problem that occurred during the manufacture of your existing batches. That would allow, however, for contingency planning and prevention of drug product shortages that may occur during enforcement actions.

Ideally, you should do as much planning and preparation as is possible for the potential that your CDMO may enter a warning letter situation. But further, understanding the risk to your own product line is essential, and reacting appropriately is even more important. The safety of the end user is the primary focus of the risk assessment, with economic considerations to mitigate or prevent risk being secondary.

About The Author:

Barbara Berglund is COO of CMC Turnkey Solutions, where she applies over 20 years of experience in finished pharmaceutical, API, and medical device manufacturing. She has direct experience with quality assurance and manufacturing of commercial and clinical-trial sterile liquid and lyophilized parenterals, microencapsulated products, intravitreal products, suspensions, and solid dosage forms. Beglund has held strategic leadership positions in quality assurance, quality control, sterile manufacturing, and project management and has a particular interest in technical transfers both of processes and analytical procedures. She is a certified Project Management Institute (PMI) Project Management Professional (PMP), ASQ (American Society for Quality) CQA (Certified Quality Auditor), and ASQ CMQ/OE (Certified Manager of Quality/Organizational Excellence).