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Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of Pharmaceutical Technology's Editorial Advisory Board.
What to do when your CMO changes the manufacturing equipment line.
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. However, changes to manufacturing equipment do affect submissions.
Susan J. Schniepp
Consider the following scenario. A contract manufacturing organization (CMO) making aseptic injectable products is planning to update one of its manufacturing lines where multiple products from various clients are made. The equipment involved includes a vial washer, a depyrogenation tunnel, and a filling machine. In addition, a restricted access barrier system (RABS) will be added around the new filling machine and the automatic tray-off area to increase protection against human intervention.
These equipment updates will impact the regulatory filings of the CMO's clients. The affected clients are notified approximately six months prior to when the replacement is scheduled. Clients also are informed of the necessary downtime needed to complete the activities required to ensure that the new line is capable of producing the same quality of product as the previous line equipment.
In this scenario, the question most often posed to the CMO from the client is, "What is the recommended filing strategy for the proposed changes?" To address this question, several points must be considered. One consideration is that the CMO must adjust its production schedule to ensure that the product reamins available in the market during the scheduled downtime. Avoiding a drug shortage is particularly important in situations where the CMO is the sole source of the product.
Another item to consider is how well the CMO understands the client's filing with respect to equipment details. The goal of the CMO in this situation is to be out of commission for the shortest length of time and to propose the most reasonable and acceptable filing strategy to their clients and the appropriate regulatory agency.
In the most conservative case, these changes might be filed as a prior approval supplement (PAS). However, this approach requires regulatory agency approval before work can begin and, as a result, could lead to the manufacturing line being down for several months to a year.
Consider also that the project could take four to six months after approval, including performing the appropriate installation, operational, and performance qualifications and the process validation requirements needed to requalify the new line. In the least conservative case, these changes could be reported to the regulator in the client's annual report filing.
The most realistic filing strategy is to use the CBE-30 category to notify the agency of changes to the CMC section of the regulatory filing. With this approach, the replacement of the vial washer and the filler should be considered like-for-like replacements. In the 2004 FDA guidance for industry, Changes to an Approved NDA or ANDA for drug products, FDA considers, "changes to equipment of the same design and operating principle and/or changes in scale..." as annual reportable material (see Section VII.D.1 of the guidance) (1).
It is recommended that the use of a comparability protocol be employed to help prove this correlation. The more recent draft FDA guidance on this subject, the 2010 CMC Post approval Manufacturing Changes Reportable in Annual Reports, suggests the addition of the RABS to a Class A area be considered as annual reportable as indicated in Appendix A under Manufacturing Sites, section 2.1, which respectively states, "Addition of barriers to prevent routine in-process human intervention in a filling or compounding area that is qualified and validated by established procedures" (2).
Although many of the changes being made could be considered as annual reportable material, the replacement of the depyrogenation tunnel likely could be filed as either part of an annual report or a CBE-30. Submitting this change as a CBE-30 is supported by the following language taken from the 2004 guidance, "For sterile drug products, drug substances, and components, as appropriate ... Changes in dry-heat depyrogenation process for glass container systems for drug substances and drug products that are produced by terminal sterilization processes or aseptic processing" are considered as CBE-30 (see Section VII.C.1.d of the guidance) (1). The changes being made to the manufacturing line will not change the process or parameters for dehydrogenation, but they do replace the tunnel. Although this change could be considered an annual reportable, it is recommended it be a CBE-30 because of the critical nature of the tunnels function.
Because the replacement of the depyrogenation tunnel is considered a CBE-30 all the changes being made should be considered a CBE-30 per Section XII of the 2003 Guidance which states, "For multiple related changes where the recommended reporting categories for the individual changes differ, CDER recommends that the submission be in accordance with the most restrictive of the categories recommended for the individual changes" (3).
There are no easy answers when recommending filing strategies to a client. Regardless of what the CMO says, the client can always chose an alternative. The best way to convince a client of a filing strategy is to become familiar with the regulations, use them to justify the recommendation, use a comparability protocol for proving like-to-like equivalency, and present the recommendation to the client in a documented manner.
Susan J. Schniepp is vice-president of quality at OSO Biopharmaceuticals and a member of Pharmaceutical Technology's editorial advisory board, email@example.com.
1. FDA, Guidance for Industry: Changes to an Approved NDA or ANDA, Rev. 1 (Rockville, MD, April 2004).
2. FDA, Draft Guidance for Industry: CMC Postapproval Manufacturing Changes Reportable in Annual Reports (Rockville, MD, June 2010).
3. FDA, Guidance for Industry: Comparability Protocols—Chemistry, Manufacturing and Controls Information (Rockville, MD, February 2003).