The four steps for registering innovative and complex raw materials

A best practice approach that provides license holders with a pragmatic, simple and regulatory-acceptable solution to mitigate the regulatory challenges associated with a second source of supply for non-compendial materials.

The Covid-19 pandemic has put extra strain on an already stretched biopharmaceutical supply chain. As industry has grown exponentially over the last couple of years, there has been an increased demand for materials and many existing products share these with the new Covid-19 vaccines, testing kits and therapies. As a result, these materials have been diverted to this high-priority use. 

The pandemic has therefore demonstrated that reliance on sole sources of supplies is not a commercially valid strategy. 

When a raw material has a compendial status, changing to a second source of supply does not lead to a regulatory change – the material from the second source will comply with the same registered specification. 

However, when a raw material is not compendial, defined and registered through its name, supplier, and part number, the registered details change – leading to a post-approval regulatory notification and review before implementation. Depending on the regulatory authority, the review period and implementation can vary from 6–14 months and more (for a major change). 

This situation has led to the publication of the BioPhorum approach to the registration of innovative raw materials using quality by design principles, which contains a best practice approach to registering innovative and complex raw materials. This allows future changes to be notified as minor and can be documented in the license holder’s pharmaceutical quality system or notified to the agency in the product annual report for immediate implementation (with no review required). 

The approach provides license holders with a pragmatic, simple and regulatory-acceptable solution to mitigate the regulatory challenges associated with a second source of supply for non-compendial materials. 

Quality by design 

The BioPhorum approach is based on ‘quality by design’ (QbD) principles and consists of four steps: 

  1. Defining the target material profile 
  1. Describing the material attributes 
  1. Reviewing the product summary control strategy 
  1. Identifying the critical material attributes (CMAs).  

The proposal allows the systematic identification of CMAs, defined as those impacting product quality and process performance. These CMAs are then used to register the raw materials as part of the product control strategy.  

It then allows flexibility of supply – if the same CMAs are met for the two materials (current and second source), the change is considered minor as it will have no impact on product quality. 

It is important to note that the BioPhorum approach only allows regulatory relief, not relief from the qualifying work required to assess that the change has no impact on product quality. The scientific approach to reach that conclusion is unchanged – it is just notified to the regulatory agencies differently.  

The proposal is aligned with the QbD principles defined in ICH Q8, Q9, and Q10. It is also aligned with Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management as CMAs are likely to be defined as Established Conditions. 

The approach can be applied to different families of non-compendial raw materials used when manufacturing biologics – such as ancillary raw materials, CGT starting materials, and excipients – making it very powerful for the industry. BioPhorum member organizations have already used it.  

In this first version of the approach, a virus-retentive filter used to manufacture monoclonal antibodies is shown as an example. 

This paper is intended to be the start of a transformational change in the registration of raw materials for the biologics industry. Implementing the recommendations will bring a different approach to registering product control strategies – through well-defined critical attributes of the raw materials. 

The approach has many benefits for the biomanufacturing industry. These include increased flexibility of supply, enhanced quality of regulatory submissions, and potentially improved product and process robustness through the definition and control of the CMAs. 

There are also benefits for the agencies when reviewing and approving manufacturing authorizations. These include fewer notifications/supplements if the post-approval change can be documented in the biomanufacturer’s pharmaceutical quality system or the product annual report. 

Ultimately, a continuity of the supply chain will mean patients have better access to medicines that, in the case of biologics, are often a matter of life and death. 

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