Danzas aristocráticas

In developing the process for a bulk drug, the need to gather and properly organize a process body of knowledge is compelling:

1. The dossier requires that the process foundation—

chemistry, engineering, scale-up, bulk drug chemical and physicochemical attributes, environmental impact, process controls, preparative and developmental history, and bulk=

dosage issues—be readily available and well organized for the assembly of the various individual submissions.

Increas-ingly, these submissions need to provide a level of bulk drug process validation; namely, a persuasive case that, on the basis of the actual performance during the preparative and developmental effort, the process is capable of disciplined manufacture and thus result in bulk drug output that is consistently safe and efficacious.

Additionally, the dossier should have the documentary basis for being able to include in the submissions a similarly persuasive case that the proposed manufacturing plans are generally sound. To wit, that the intended manufacturing milieu will do justice to the process needs as identified during its development. Such bridge documentation, while not reliev-ing the technology transfer team from the burdens of what-ever inspection the manufacturing plant may face, greatly facilitates the task of preparing for such inspection and for dealing with it if it occurs. Just as importantly, the said bridge documentation also provides the regulatory reviewer with sufficient background to answer a number of probable questions and thus avoid their being asked during the review cycle.

It is rather easy for practitioners, when faced with the above tasks, to get thoroughly lost in the detailed ‘‘how to’’ without fully grasping the scope and objectives of the dossier on the process, which have been defined above. As the literature on ‘‘how to’’ grows and seminars, workshops, and guidance documents proliferate, the practitioner should first seek a clear understanding of what it is that the submission review and the plant inspection basically seek to accomplish. The above para-graphs are an attempt to clearly define just that, and additional background material, still at the usefully gen-eral level, is suggested (18,19).

2. The technology transfer to manufacturing demands that the process be well documented. Most important, and as a coalescence of the process know-how, a comprehensive process document, written for the specific purpose of impart-ing knowledge, is a requisite for the tasks of:

a. process design;

b. project engineering design and construction;

c. procurement of materials;

d. preparation of start-up plans and operating proce-dures;

e. transfer of the in-process and QC analytical methods;

f. assessment of the process safety issues in the specific context of the plant: operational safety, industrial hygiene, thermochemical, and environmental safety;

g. assembly (and timely approval) of environmental and other regulatory permits;

h. definition of the process start-up targets of yield, capacity, waste loads, etc.;

i. dealing with assorted other matters, such as those arising from the plant’s insurance, etc.

It is, of course, unacceptable to bind together all manner of development reports and send them over with a cover memorandum (part of what is aptly known as ‘‘over the fence’’

technology transfer). Attachments are very important, but a well-edited document that is rich in content and aimed at guiding the downstream practitioners is the indispensable first vehicle for the transfer of the know-how. Not even the most thorough collaboration between development and manu-facturing can completely remedy the lack of the above com-prehensive process document intended for imparting knowledge.

There is no attempt here to gloss over the extraordinary effort and discipline required to turn out such documen-tation on a timely basis. The consolidation stage is intense, the gentle slope of the know-how curve notwith-standing. Yet, the quality of the technology transfer—on both the short and the long term—is very much enhanced if such a document is available soon enough.

Conversely, and as indicated in Figs. 11 and 13, the joint effort with the operating organization (planning and process design) unavoidably overlaps the actual develop-ment of the process, sometimes to a great extent; e.g., if an early decision is made to build a new plant or substan-tially alter an existing plant, the downstream work

can-not await a sufficient definition of the process, and infor-mation needs to flow as the process is developed. This is a very demanding task for all involved that benefits from considerable practice, significant skills of process design on both sides and from a spirit of collaboration, prefer-ably steeped in previous joint successes. Unlike other chemical processing activities, new bulk drugs are exceedingly driven by the ‘‘time to market’’ imperative and organizations that can significantly overlap process development with manufacturing readiness work have a strategic advantage. However, having such skills and practices do not relieve the development team from the duty of comprehensively documenting the process at the earliest reasonable time.

3. After successful technology transfer, which must, of course, be well documented also, the original process body of knowledge serves as the foundation for management of the change control system, for training of new manufacturing per-sonnel and as the basis for sound process improvement work.

Indeed, significant second-generation processes are most often based on approaches suggested and partially elaborated during the original development.

4. Although the interaction with suppliers and contract manufacturers will be discussed more amply under VII, it is often that process information needs to be transmitted to out-siders, including prospective licensees of the drug candidate.

Indeed, this happens most likely during the developmental phase as help is sought in the preparation of intermediates, the bulk drug itself or in further development of the process or an alternative route for which the outside collaborator may be better positioned.

It is in such instances that having a system for continu-ing process documentation pays off in the rapid satisfaction of needs that may arise unexpectedly. Ideally, the material should exist in organized form so as to permit knowledgeable technologists to assemble and edit a preliminary process doc-umentation package in a matter of a few days and a full pack-age in, say, 2 weeks. Of course, the transmittal of internal documents ‘‘as is’’ is fraught with the risk of undue disclosure

and it is best to transmit documents assembled and edited for the specific purpose at hand, a task hardly feasible if the material does not exists or exists disjointed or incomplete.

The obvious need to avoid undue disclosure of internal issues and business methods, names, distribution lists and the like, as well as to avoid transmitting information extraneous or strictly tangential to the technical matter at hand, must not be confused with undue reticence. If others are expected to properly implement in-house pro-cess know-how or to use it as the basis for an activity to be done on our behalf or as part of an agreement or license, the disclosure of the technical information must be no less than sufficient: what works and what does not work, the technical rationale for the prior decisions, our best under-standing of the process issues and sufficient detail of meth-ods, process design calculations, and data. In particular, data on thermochemical safety, industrial hygiene, and environmental profile need to be fully disclosed.

5. Developing the appropriate intellectual property is also greatly facilitated by the continuing process documentation sys-tem being advocated herein. Laboratory notebooks and pilot plant log or batch sheets, while useful for assigning dates of reduction to practice, compositions of matter, procedural details and for the identification of inventors, are generally inadequate sources of cohesive process information and history.

6. Finally, there is the organizational objective of fos-tering a professional climate for the process technologists to thrive. The rigors and satisfactions of authorship of scientific and technical documents arising from one’s own work are not to be underestimated; they contribute greatly to the indivi-duals and to the organization as a whole, even if intended for internal publication only.

The ready access to powerful computers has created an environment in which databases and templates or excessively formatted documents are quite seductive as a seemingly easier substitute to a system based on docu-ments composed in clear, informative, and persuasive prose. Thus, in such tempting systems, the process know-how can be thinly dispersed over an alphabet soup

of spreadsheets and form-like documents that, inevitably, lack the full benefits of reflection and perspective from an author (or authors) with a process story to tell or a point of view to present as to how to implement a process. Such temptation should be resisted, as extracting useful and applicable process knowledge from the former environ-ment is not possible without a substantial effort of retro-spective composition that would have been better applied to the creation of true process documents.

Scientists and engineers, usually handicapped as writers by the focus of their academic training and by misconcep-tion as to the scope of technical writing, are destined to further disadvantage if nudged by managerial conveni-ence or by conformity into documenting their work as if filling blanks in a form, or seeing the process body of knowledge as an array of suitably filled pigeonholes.

The effort in setting down and organizing the process body of knowledge should not trail the acquisition of the raw inputs, as tardy heroic efforts to properly document accumulated knowledge are invariably not as good as the task deserves. Figure 18 outlines the body of knowledge task on the applied effort vs. know-how plane.

Figure 18 The process body of knowledge in the know-how vs.

applied effort plane.

Finally, Table 4 offers an annotated template that, if followed with sufficient discipline, carries out the various missions of the bulk drug process body of knowledge. Of par-ticular value are the milestone reports and the specific issues reports, as they permit achieving depth and focus, while nurturing vigorous authorship by the process technol-ogists. Such documents are invaluable as part of the compre-hensive process documentation, as well as excellent raw material for the bridge documentation of the dossier. Their elaboration into external publications is usually a much les-ser effort than starting from raw data and status reports.

The following examples illustrate the proposed reports on milestone events and specific processing issues. Note that the titles of these reports have been composed by this author as fictitious from literature sources or approximate from his own experience with actual bulk drug process projects:

Table 4 The Scope of the Process Body of Knowledge and Its Applications

ICI 194008. The benzaldehyde imine route to the amine tosylate precursor. Bench development and readiness for scale-up (5, page 22)

MK-787 via the ADC-6 chiral route. Results and experi-ence from the first large-scale pilot campaign (C. B.

Rosas, personal communication, 2003).

Efrotomycin. Whole broth extraction in the mixer settler and in the centrifugally aided extractor. Results and recommendations for process design at the Stonewall plant (C. B. Rosas, personal communication, 2003).

MK-401. Early environmental assessment of alternatives for the trichloro precursor (C. B. Rosas, personal commu-nication, 2003).

MK-421. Large-scale synthesis of AlaPro in a continuous flow system. Process design and results obtained at the large pilot scale (20).

Diazomethane. Pilot scale generation by continuous reac-tion and scale-up criteria for the commercial scale (21).

LY228729. Kornfeld ketone route as the selection for scaled-up development (22).

These two kinds of reports, when added to well-designed status reports that issue regularly and not too frequently, pro-vide the basis for a repository of a well-organized body of knowledge that can be used for the various objectives pre-viously defined. Indeed, such reports are the core of the body of knowledge, as they gather, coalesce, and make cohesive for application the great deal of data and experience gathered during all aspects of process development.

Other aspects of the system in Table 4 are:

1. All the reports and documents listed originate in the bulk drug process development area, which embraces the disciplines and function shown in Fig. 12, and is part of R&D at large.

2. All process documents intended for the process design effort originate from the engineering disci-pline (chemical and biochemical), which embraces

the thermochemical and environmental safety func-tions within R&D. Material from the other disci-plines is attached as required.

3. All process documents intended for the dossier assembly are generated specifically for that purpose, usually through a CMC function (as per the chemis-try, manufacturing, and control component of the NDA). Such function is within the bulk drug process development area and not within regulatory affairs.

This latter function should not use other process documents for its purpose of assembling the dossier or attempt to edit regular process documents on its own.

4. The biobatch, although an event taking place in the dosage form development area (and documented accordingly), will usually generate the need to docu-ment the process and related history of the bulk drug inputs used.

5. The process document is generated upon completion of the technology transfer to first manufacture and is coauthored jointly by the bulk drug development area and the recipient manufacturing organizations.

Chapter 3 discusses this and all other aspects of the technology transfer in some detail.

VI. PROCESSING RESPONSIBILITY IN BULK