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24 Gerson et al. changes can be made in full understanding of listing of contents and a cross-referencing or why the process and product is in its current index system. The team leader’s database configuration, and the reasons for the selec- will be an important component of the docution of particular unit operations, equipment, ment. For example, sections of the technol- and conditions, can be clearly understood. Engineering and manufacturing personnel ogy transfer document could be as follows: are well equipped today to understand the • Executive summary of transfer package, scientific and technical reasoning behind • Product description, new processes, and a well-executed technol- • Product release specifications, ogy transfer document capitalizes on this re- • Process description/characterization, source. In addition, problems always occur, • Development batch records, and problem solving is significantly aided by • Process development, detailed knowledge of why each step was • Validation, and chosen and which approaches did not work during development. In this way, old experi- • Stability plan and data. ments are prevented from being repeated, and the root cause of a difficulty can more easily TRANSFER DOCUMENT PACKAGE be identified. In the vaccine and pharmaceutical industries, The assembly of this document is per- technology transfer projects typically take formed most efficiently in parallel with the several years to complete. As the technology transfer process. To wait until the document transfer document is written, each member is complete before proceeding with tangible of the technology transfer team is trained in aspects of the technology transfer would use of the technology transfer document. The greatly impede progress, defeating the objec- project transfer champion, or team leader, is tive of rapid licensure. In analogy to “design- responsible for document assembly, uniforbuild” construction, the transfer project mity of language and style and completeness. should begin to plan facilities, select up- Management of this aspect of the transfer is stream and long lead-time equipment, and itself complex, as parts of the package are begin detailed engineering while down- contributed by many functional areas over an stream aspects of the process are in final extended period of time. Clearly, discipline stages of development. Such an approach in- must be exercised to ensure the document is volves some defined risk, different for each completed by the end of the transfer process, project, that should be carefully managed by that it is internally consistent and technically the technology transfer team. Process knowledge is never complete, there is always some correct. risk in any scale-up project, but careful identification of the known and the required but unknown will allow progress and direct de- PRODUCTION SCALE QUALIFICATION velopment efforts. As with most key docu- Successful start-up of a new production fa- ments in the pharmaceutical industry, the cility is the objective of every new facilities technology transfer document will require project. All too often, mechanical completion sign-off to show that it has been read and of a new facility is met with a demand for approved by each function. immediate production of consistency lots. Most of the projects the authors examined TECHNOLOGY TRANSFER DOCUMENT CONTENTS experienced this demand, and most had not budgeted either the time or the funds for ‘practice’ runs following mechanical com- The technology transfer document will be pletion and validation. By formalizing procomprehensive in nature, more an encyclope- duction scale qualification as part of the vali- dia than a digest, and will require a detailed dation process, the startup of the new process
Transfer of Processes from Development to Manufacturing 25 in the new facility is included in the budget useful for stability or other technical studies. and the schedule. Financially, the PSQ lots are charged to Establishment of a formal process to gen- research, with lots chosen for sale charged erate higher quality consistency lots through back to manufacturing. Operating costs dur- the budgeting for and planning of production ing the PSQ runs can be used to determine scale qualification lots greatly enhances the standard costs for the new product. While opportunity for successful transfer from de- the costs of PSQ lots can be substantial, prevelopment to manufacturing. The production planning for these costs is preferable to re- scale qualification (PSQ) lots are not neces- covery from unplanned consistency lot fail- sarily intended to be consistency lots, thus increasing the flexibility for making necesures.sary improvements to SOPs and batch records. In this methodology, PSQ lots are performed for every new process introduction, or when there has been a major process TRAINING BETWEEN DEVELOPMENT AND MANUFACTURING change, immediately following the tradi- Effective training of all involved in the new tional installation qualification (IQ), opera- process, from production operators to regulational qualification (OQ), and process quali- tory personnel involved in preparing the fication (PQ) validation procedures. license submission, is essential to project The PSQ lots are done under full cGMP success. Training is required in both the unproduction conditions, with fully signed derstanding of the technology transfer pro- SOPs and batch records, in fully validated cess and in the technical transfer. Training (IQ, OQ, PQ) equipment and facilities, with in the technology transfer process provides fully released raw materials, and full QC a structure for subsequent training in the protesting with validated testing protocols. The cess technology. Generally, training is initi- PSQ runs are a team effort involving devel- ated during validation activities (IQ, OQ, PQ) opment, technical services, manufacturing, and completed during PSQ. Following stan- and quality control, and the process certifies dard cGMP requirements, all training is doc- the training of the operators. They are also umented, and involves identified members done in the full knowledge that after each of all relevant departments. Course material run, the process will be evaluated and that, is based on information in the technology if required, revised SOPs or batch records will be issued prior to the next run. Most transfer document. importantly, they are done in full knowledge that each run may not be a consistency run PROJECT TRANSFER CHAMPION suitable for inclusion in a license application Consistent leadership throughout the techor for ultimate sale. Such runs are rigorously nology transfer process is an important as- controlled practice runs that are necessary to pect of success. The product transfer cham- develop a final successful production propion is a person in manufacturing or cess. They take time, are expensive, and pay development with overall responsibility to for themselves by ensuring a workable, con- move the project forward and the personal sistent production process that can be used and managerial commitment to carry it with few changes to produce the new through to completion. As leader of the tech- product. nology transfer team, the project transfer In the authors’ experience, 6–8 PSQ runs champion is required to take a proactive role are sufficient to finalize the production pro- by directing the technology transfer team cess. Typically, the last three runs comprise through technical and managerial difficul- the consistency runs, in that there is full com- ties, and by presenting the progress and needs pliance to all cGMPs in replicate runs. Mate- of the project to the organization to ensure rial produced by problematic runs may be the availability of required resources. The
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