Comment from Arvilla Trag

I have 34 years in Regulatory CMC, multiple IND and BLA submissions under my belt, and I give a RAPS workshop on “Module 3 Preparation with the Reviewer in Mind” once a year. Writing Module 3 is what I do. After reviewing the ICH M4Q(R2) draft, I am appalled that ICH had the nerve to release such a disaster of a document. There is no logic involved in the organization of this draft document. The process of raw / starting materials, intermediates and drug substance is listed completely backwards. Working Cell Bank generation is described before Master Cell Bank generation. How is one expected to understand the manufacture of a drug substance if the description starts at the end of the process and works backwards? Additionally, some explanation of how the very differently identified sections related to the R1 version would be beneficial. Not only is the sequence of the sections in this revision devoid of logic, the sheer number of sections – one for every noun, it appears – is absurd, especially in the way it separates closely related information. Line 101: "This overview serves as a high-level introduction to how the CQAs were used to guide drug substance, product, and process development,..." CQAs are not yet identified in development, so expecting them to guide development is very much putting the cart before the horse. Unless something else has changed drastically, CQAs are not definitively identified until PPQ is completed. Line 120: "The OCS should cover the control strategies only for the material(s) (e.g., drug substance) included in the application or submission." Pointless statement. What else would it cover? Line 165: Section 2.3.3.DS.M is not included in the TOC. Line 269: Working Cell Bank generation is described before Master Cell Banks generation, and testing of the cell banks is described in the next section (Line 278), instead of concurrently with the development of the cell line. Where is the logic? Control of adventitious agents is scattered throughout (Lines 282, 304, 309, 310, 342, 668, 1331, 1354), instead of concisely being located in a single section. Rather than describe something repeatedly (repeating information in a submission leads to conflicting information), simply cross-reference a section specifically for adventitious agent control. Line 293: “Information on multiple raw materials may be presented in a single tabular format, as appropriate.” Yet the sections regarding duplicative information on biological raw materials goes on in 2.3.3.RM.D Description, 2.3.3.RM.M Manufacture, 2.3.3.RM.C Control, and 2.3.3.RM.S Storage. All of the information delineated in the last four sections can be included very efficiently into a single section, with appropriate tables, eliminating the need to hop back and forth from one section to the next. Simply reword 2.3.3.RM.D to read “This section should include information on the raw materials (e.g., name, where in the process it is used, function, material specifications, and for biologics storage information, and reference to descriptions of adventitious agent control). Sections 2.3.3.RM.D, 2.3.3.RM.M, 2.3.3.RM.C and 2.3.3.RM.S are utterly superfluous. The same is true of the Reference Standard sections under 2.3.3.RS. I could continue, but it would take too long and (I hope) my point has been made. Why not have a separate M4Q(B) for biologics and one for combination products (M4Q[C])? That approach could not possibly screw things up as badly as this nightmare does. I am deeply grateful that I will be retired before mandatory implementation of this pathetic document. It has proven beyond any question that preparation of such a document by committee does not yield a useful product, only a collection of 28 different opinions jammed into a document that is utterly nonfunctional.