New Challenges to the Cleanroom Paradigm for Multi-Product Facilities - Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a cont

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New Challenges to the Cleanroom Paradigm for Multi-Product Facilities
Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a controlled non-classified (CNC) ballroom environment.


BioPharm International
pp. 38-47

ADDITIONAL COMPLEXITY OF PROCEDURAL CONTROLS AND FLOW-PATH MANAGEMENT WITHOUT PHYSICAL SEGREGATION

Concurrent multi-product manufacturing in a ballroom environment without physical separation by walls or rooms to maintain order, where operators may be expected to perform operations anywhere in the manufacturing suite, requires the highest-level of procedural discipline. Moreover, the effectiveness of systems for management of people, material, equipment, and waste flows becomes absolutely crucial. Logistical approaches and use of spatial and temporal concepts effectively replace physical segregation approaches.

Because many process unit operations require manual manipulations in one form or another, personnel from the manufacturing teams can be the greatest source of production risk. This is particularly true if there is a strong dependence on manual additions, connections, and manipulations. Despite these challenges, concurrent multi-product operation is successfully practiced in other types of manufacturing facilities, including synthetic API manufacture. Many mitigation approaches exist for adaptation into this situation.

Effective written procedures and operator education are a necessity in any pharmaceutical manufacture. Training should be enhanced beyond this to improve understanding, including "the why" and to communicate the consequences of operational mix-ups. Regulatory agencies now expect this training. A stronger mitigation approach may be adopted from the increasingly well-understood philosophies described by human performance improvement or human error reduction. Color-coding and physical keying, for example, can be used to avoid making incorrect connections or additions. Demarcations on the floor (i.e., different colored, cleanable floors) can be used to show where particular unit operations should be performed or where certain materials should be staged. Additional measures such as bar coding parts and materials, cross checking of set ups before processing, and material additions/transfers, as well as introducing procedural and time segregation into the operational philosophy are some of the ways to manage flow paths.

5S techniques should play an increasing role to establish the disciplined and standardized ways of working required to achieve controlled and orderly execution. 5S is the name of a workplace organization method that uses a list of five Japanese words: seiri, seiton, seiso, seiketsu, and shitsuke. The list describes how to organize a workspace for efficiency and effectiveness by identifying and storing the items used, maintaining the area and items, and sustaining the new order. The decision-making process usually comes from a dialogue about standardization, which builds understanding among employees of how they should do the work. Engineering mistake proofing offers elegant solutions to the risk of error and mixups. Unique connectors, for example, that can only be used for the intended purpose can eliminate risk of wrong connectors being used.

It is also likely that manufacturing execution system (MES) controls would be employed to mitigate potential procedural errors while maintaining a highly flexible and lean operational environment. The following are example requirements for an MES system that could be employed in a multi-product, ballroom environment. The MES system will be used to:

  • Select and initiate process recipes
  • Ensure that the correct materials are added during a compounding procedure
  • Track the status and expiration dates for materials, media, and solutions used in the process
  • Ensure that the correct connections are made (e.g., through bar-coding, radio frequency identification [RFID], or near-field communications)
  • Ensure that the correct filters and consumables are used in the process
  • Ensure that clean equipment is used and that process-dedicated equipment is not mistakenly used in the wrong process
  • Confirm that samples and sample sources are correlated
  • Confirm operator qualifications prior to performing a task
  • Track operator activities and prompt the operator to make glove changes or gowning changes when moving from upstream to downstream processes or from one process to another
  • Document intervention events for evaluation and review.

Thoughtful integration of these powerful MES controls with a distributed control system (DCS) or other automation platforms will contribute to a successful multi-product manufacturing operation in which risks are well mitigated.

Highly automated plants based on stainless steel and hard-piped equipment that are cleaned with clean-in-place (CIP)/steam-in-place (SIP) systems offer well known, robust, and proven approaches to removing the human element. Closed system/ballroom concepts can be applied effectively in this situation. However, the increasing trend to support the production of niche, smaller volumes in a flexible way suggests that the opportunities automation offers will need to be applied in a different way and there are likely to be single-use elements and manual manipulations that cannot be easily automated. In this case, the procedural controls remain crucial.


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