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Change notification

 

Overview

Change notification is an important aspect of biopharmaceutical manufacture. It is part of ensuring that the drug manufacturers have control of their processes, are aware of, and can respond to, changes that may impact their product so as not to adversely effect product quality or supply. At the same time suppliers need to be aware of the impact necessary changes may bring, how they can support end users and manage necessary changes smoothly. Typically those suppliers working directly with end users (tier one suppliers) will also have an extended supply chain and it is also important to manage change notification consistently with these suppliers, and indeed throughout the extended supply chain

Current practices surrounding change notification in the biopharmaceutical industry are neither efficient nor conducive to accelerating the adoption of single-use systems.  

From a drug manufacturer’s perspective, it is common to observe that change data packages are lacking in technical content or detail, and that the time allowed for change implementation is too short.  Occasionally, changes are learned of after the fact, possibly even by happenstance. 

From a supplier’s perspective, it is difficult to understand the potential impact of a change on a customer: the end user’s regulatory environment is not always transparent to the supplier; how drug manufacturers use supplier data can also be unknown or misunderstood by the supplier, and; drug manufacturers do not have a uniform set of needs and expectations.

These observations may be attributed to industry-wide deficiencies in communication and process standardization. Communication requires that:

– End users explicitly inform suppliers of their regulatory, business, and technical drivers/expectations related to change notification, and the ways in which the supplier’s products are being used.  

– Suppliers likewise are required to document changes and communicate notifiable changes clearly, promptly, and with technical rigor. 

Aligning all parties to a change notification process, to definitions of terms, and to clarified roles and responsibilities would greatly facilitate communication and process standardization across the industry. This is the ongoing mission of the BioPhorum/BPSA change notification workstream and publication of this whitepaper is a key milestone. The workstream will now be focusing on how these principles can be effectively implemented and derive benefit against the backdrop of existing practices and systems.

FAQ

How to categorize changes?

Changes fall into one of five levels. Levels 1, 2, and 3 changes are expected to have a possible impact to a drug manufacturer; level 3 changes are anticipated to have highest impact and levels 2 and 1 progressively less (see figure 1). Level 0 changes are those for which it is highly unlikely that the change would have an impact on the drug manufacturer. To categorize a change (0, 1, 2, or 3), one should have a group of individuals who represent internal subject matter expertise and a strong understanding of bioprocessing (see page 11). This group should holistically assess the proposed change to estimate the complexity of drug manufacturer’s change qualification effort. Because “complexity” is not a quantifiable term, the team should then estimate the time needed by a typical drug manufacturer to qualify the change. This estimate of time is then used as the means by which a change level is derived (see table 2). When the supplier team is uncertain, it is recommended to discuss the proposed change with one or more drug manufacturers to gain help in understanding relative complexity and hence qualification time associated with a change. The fifth level of change, “emergency,” is a change that normally would be described as level 1, 2, or 3. However, due to unusual circumstances, the change must be managed in an expedited manner.

What do we mean by non-notifiable change?

‘Non-notifiable is a change that has no anticipated impact to either patient safety of drug product quality. This change has been reviewed by the supplier change management team and determined not to have an anticipated impact as defined. This review is documented and stored in a document control system’.

What is the role of the N2 supplier in change notification?

N2 suppliers are to notify their direct N1 customers at a minimum. The N2 suppliers should also notify the end user if it is known the end user uses the product or the end user requests notifications (even if they are not selling the products directly). The N2 suppliers should take into the account the same timelines listed in this guide. N2 suppliers may also need to interact directly with the end users in sharing the data package and supporting questions the end users may have when evaluating the change.

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