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,
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).