Definition and Scope of the Technology Transfer

Technology transfer has become the term that more appropriately describes all the events associated with the first manufacture of a new bulk drug (or for that matter, of any new product with its own distinct process for manufacture,

Figure 7 A model for the flow of the process body of knowledge: Successful first manufacture (timely, sufficient, and reliable) depends not only on the assembly of the requisite process body of knowledge, but also on its timely flow to the various downstream activities. The model shown above has worked well in each of numerous instances that the author has seen it applied.

Figure 7 A model for the flow of the process body of knowledge: Successful first manufacture (timely, sufficient, and reliable) depends not only on the assembly of the requisite process body of knowledge, but also on its timely flow to the various downstream activities. The model shown above has worked well in each of numerous instances that the author has seen it applied.

which will usually come from without the manufacturing environment). Older and not-so-old practitioners are probably more comfortable with less comprehensive, but very descriptive terms, such as "process start-up'' or "process demonstration.''

In its broadest definition, so as to capture all the activities for its execution, the scope of bulk drug technology transfer encompasses the tasks listed below. (Here the reader is encouraged to place bookmarks on Figs. 11 and 13 of Chapter 2 for perusal, as well as review the approximate Gantt chart for the overall technology transfer in Fig. 8 below.)

Early stage (around the time the new drug candidate enters development):

(a) The operations area acknowledges the task of a probable first manufacture tied to an expectation of regulatory approvals to market a new drug.

(b) At the same time, the process development function acknowledges its share of the above task—providing the technology for the safe, dependable and timely execution of the first manufacture.

Process development/scale-up Joint manufacturing planning Process design and feedback

Biobatch_

Start-up planning/preparations Process documents issued Dossier filings and approvals Plant design & construction Transfer analytical methods Bulk drug process start-up

Pre-Approval Inspections_

Bulk drug inventory build-up Dosage form inventory build-up Product launch Tech transfer documentation

Figure 8 Gantt chart for the technology transfer of the chemical process for a new bulk drug: The chart shows all of the key components of the overall task, with an approximate indication of their relative positions on the time-to-market cycle and, to a less precise extent, of the relative widths of their timelines; the latter can vary considerably as a function of the process scope, new plant vs. retrofit into existing plant and in-house vs. extent of outsourcing.

(c) The need for probable capital approvals and subsequent expenditures is forecast, presumably within the parameters of an established longer-range plan that includes the launch of the new drug product as a probable event.

Next stage:

(d) The process development function begins its collaboration with the operations area in addressing the broad brush definitions of the project (as set out in II.A.1 above).

Next stage:

(e) Overlapping process development, design and manufacturing planning takes place.

(f) Capital approvals are sought, in portions and from a range forecasted for the total project.

(g) Starting material sources are developed and business terms negotiated (this may include extensive outsourcing of, say, intermediates manufacture).

Next stage (some time after the biobatch milestone, but before filings from the dossier take place):

(h) The process body of knowledge is documented.

(i) The final process design is completed.

(j) The plant design is completed and installation work proceeds.

(k) Starting materials and auxiliaries are purchased. (l) Start-up plans and operating procedures are developed.

(m) In-process, QC, and regulatory methods (stability) are transferred.

(n) Process safety issues in the specific context of the plant are settled: operational safety, industrial hygiene, ther-mochemical, and environmental safety.

(o) Environmental and other regulatory permits are assembled, filed, and approvals obtained.

(p) Definition of the process start-up targets of yield, product quality, capacity, waste loads, etc.

(q) The process validation plan is defined.

(r) The process start-up team is assembled.

(s) The plant installation is tested and readied for the process.

(t) The process is started up and validated.

(u) Preapproval inspections take place. (v) Process consolidation—the start-up continues to demonstrate all targets under (p).

(w) Results are documented, including updates operating procedures, in-process controls, etc. Heads of the startup team sign off.

(x) Mechanical/instrumentation items punch-list and the "To Do'' list are prepared.

(y) The start-up team is disbanded, but liaison persons are designated for matters arising. Manufacturing takes over.

The reader should beware that hidden within the above reassuring list are all the necessary actions to solve unexpected problems, particularly those arising during process start-up, validation, and consolidation, or those in response to significant observations from preapproval inspections. Difficulties in technology transfer are inevitable; no such large number of activities that must dovetail precisely can go without some adversity or something being overlooked. Yet, well-executed projects for complex chemical processes generally meet their targets of bulk drug deliveries and the existing process body of knowledge and assembled resources permit the swift resolution of arising difficulties.

An approximate sequence of events following the designated validation work (and its follow-up) that is useful for planning purposes is (assumes a multistep process of significant scope):

During validation—25% of design capacity is reached.

Month 2—60% of design capacity is reached.

Month 3—80% of design capacity is reached. All lots are without quality issues.

Month 4—100% of design capacity is reached. All lots are without quality issues.

Month 5—procedures updated. Summary memorandum on results is signed off and issued.

Month 6—Operating personnel training confirmed (but meant to continue). Comprehensive process start-up document issued.

Obviously, the above timetable will vary with the scope of the process start-up: number of steps, number of plant sites, intrinsic process complexity, time cycle (e.g., long fermentation cycles plus downstream processing plus any semisynthesis to follow). Sensible allowances to the above figures should be made.

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  • miia kokkonen
    What are scope of technology transfer?
    9 months ago

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