Annex 1 and Ensuring Filling Technologies Fit the Need

Most of us have learned the importance of ensuring that the technology utilized fits the intended need. This rings especially true in the world of pharma given the criticality of activities performed and potential impact to the patient. Often, we consider people, processes, and systems to be the trifecta of considerations in quality system design. When it comes to manufacturing, one could argue that equipment, facility, and process (which includes people) should be paramount in design considerations. 

The manufacturing process, people/process/equipment flows, microbial testing locations, and several other topics must be understood prior to locking down a general process. They are linked and must all work together to make a functional platform for reliably producing quality product. One cannot be forced upon another as some organizations have learned. It is a rare opportunity to start from scratch with a greenfield or brownfield opportunity vs. implementation within a current, pre-defined structure. In all situations, having the relevant stakeholders will minimize errors and the potential need to remodel or make modifications in the future, and will build a pride in ownership among those involved. And by the way, always include the lead quality professional in your organization as a key stakeholder!  

Eudralex and Annex 1

This common challenge is likely a reason why there is a focus, specifically within the Eudralex and Annex 1, to ensure there is a proper evaluation of both filling and manufacturing technologies to ensure that they are appropriate for a given process.

One particular emphasis in this latest version of Annex 1 is specific to configurations with fusion closures and restricted access barrier systems (RABS) technologies. Instructions are clear in Annex 1, Manufacture of Sterile Medicinal Products, Section 6.2.1, regarding the location of heating, cooling, and hydraulic systems and their proximity to the product.  It is important to physically locate these systems outside of the filling room to minimize impact to the product. These systems can prove to be difficult to clean, and the air and/or heat generated from the heating and cooling devices could either harbor microorganisms or create an environment supportive of their growth.

Further down in Annex 1, Sections 8.21, 8.22 and 8.98 provide additional clarity on the expectations for execution of Form Fill Seal (FFS) and other fusion related technologies.  Given this type of closure method, all units should be subjected to 100% integrity testing and the methods used to perform this testing should be validated. Additionally, the closure methods themselves should be validated. It is important in the development of the validation strategy and approach that: (1) consideration is given to the sample volume, sampling strategy for true representation of the batch throughout various phases of the process (e.g., filling, sealing/fusing, cutting, etc.); and (2) the validation approach covers the various configurations as defined by a robust risk assessment and approved validation protocol. Additionally, critical process parameters (CPPs) should be understood, validated, controlled, and monitored as a part of developing an appropriately designed process.  This approach can only be performed by having a comprehensive understanding of the product, its relationship with the equipment, and the development of the overall process. 

Partnering to Ensure Compliance

Partnering with your environmental monitoring colleagues is important, as building a robust monitoring program based on the design and process is imperative, especially due to the closure type.  The environmental monitoring plan must be aligned with the area classification requirements discussed in Annex 1, Sections 8.103 and 8.104, based on the type of equipment utilized specifically for Blow Fill Seal (BFS) technologies, which is a type of FFS technology.  

Understanding how these items come together and are interrelated gives the greatest chance of success. There is nothing more frustrating than being asked to “Make it work” when the technology does not fit the use. These pressures can provide an opportunity to cut corners or compromise on the most effective and compliant approach to manufacturing sterile product. Annex 1, as well as other regulations, provide guidance and expectations on how to get this done in a compliant manner. Circling back to the original trifecta (people, processes, and systems) minimizes the chance of ending up with a square peg in a round hole. You can shave the sides, reshaping the square peg, exert a lot of force to push it through, try adjusting the round hole, etc.; and at the end of the day, it could just not be the right fit. The technology must fit the need.        


Natasha Howard is an Independent Consultant with Quality Executive Partners, Inc. (QxP). Natasha has 22 years of experience in the pharma industry, with a focus on managing personnel and complex projects, coordination of operational activities, and design and qualification of equipment and facilities.

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