Many things have been delayed as a result of the COVID-19 pandemic; from holidays and weddings to construction projects and sporting events. In the pharmaceutical sector, conversely, we’ve largely seen the opposite effect, with pharmaceutical companies rising to the challenge of battling the virus and escalating development projects to aid resilience in the healthcare supply chain.

It is this mission critical, industry-wide focus on firefighting in a time of crisis that has prompted a hiatus in one area, however, which is now causing confusion and concerns about compliance for future capex projects. Following the last update to the Orange Guide in 2017, there has been a mooted update to EU GMP Annex 1 (manufacture of sterile medicinal products) for around five years, and the consultation on the proposed changes closed in December 2020. 

With fresh variants, renewed lockdowns and healthcare systems under continued intense pressure, it’s still impossible to predict when the contents of the EU GMP Annex 1 consultation document will transition to become regulatory requirements. One thing is certain, however, more stringent compliance criteria is on the horizon and it’s important to understand the implications of the proposed changes on projects currently at concept or design stage to avoid design changes during the build, or compliance issues on completion.

In this article, we will discuss the proposed EU GMP Annex 1 changes and how these are likely to affect compliance for both existing medicinal products manufacturing facilities and future developments.

What’s in the consultation document?
The proposed EU GMP Annex 1 requirements focus on eliminating the risk of product contamination during the manufacturing process and, critically, when the completed product leaves the cleanroom environment in which it has been manufactured. The proposals are all about driving high standards in sterile pharmaceutical manufacturing and protecting patients from any potential ill effects of contamination. These aims are already at the heart of the way pharmaceutical facilities are designed, constructed and operated, but there is nervousness in the sector because, if followed to the letter, the proposed new rules could lead to onerous, disruptive and expensive requirements to change manufacturing layouts. 

At the core of the proposed changes is a requirement to implement unidirectional flows for both people and materials. Under current regulations, the route into a clean-classified facility for people and materials is segregated, with people entering and exiting via a people air lock (PAL) and materials entering through a materials air lock (MAL), which is also used to remove finished product from the sterile manufacturing area. The new proposals require two PALs; one for people in and one for people out, along with two dedicated MALs; one for materials in and one for products out. This would not only impact on the design of the facility, but also on the footprint required for the additional air locks and unidirectional flow of people and materials.

EU GMP Annex 1 and existing facilities
In theory, the revised rules would mean upgrading existing facilities to comply. In practice, however, this would not only be challenging and expensive; in many scenarios there simply would not be the space available to achieve the changes. A more likely and pragmatic approach is that there will be increased reliance on contamination control systems (CCS) and risk assessment, effectively requiring a qualified person from the client’s quality assurance team to demonstrate the operational mitigations in place to avoid contamination risk.

How will this work in practice? There will need to be clearly defined operational controls that are proven to prevent contamination. Operators will be able to leverage data from QA testing, along with procedural best practice, to evidence a comparable level of risk reduction with existing single PAL and MAL layouts as they could achieve with unidirectional flows. For example, they will need to calculate full clean times for the PAL and MAL to ensure that cleaning can be completed between people and materials entering the facility and people and product leaving the controlled area. It sounds simple, but the timing calculations for cleaning regimes will also have to be coordinated with shift changes and gowning/de-gowning times. Moreover, each operator will need to consider how the arrival of visitors to the controlled area will affect cleaning regimes and contamination risk and what will happen if a member of the team needs to leave mid shift, due to illness for example.

It should also be noted that changes to cleaning regimes to evidence stricter contamination control will incur knock-on effects. Faster cleaning means more frequent air changes, and increased air changes means reduced maintenance intervals for filter changes. Fundamentally, there will need to be a collaborative approach across QA, operations, maintenance and HR to determine the best, risk free strategy for compliance, and BES can advise as part of that process.

EU GMP Annex 1 and new capex projects
While CCS mitigations may be the most practical and economical way to achieve compliance for existing facilities, the reality is that new facilities will need to be designed and constructed with unidirectional flows and dedicated PALs and MALs for ingress and egress if the proposed changes are brought into force. This will not only affect the level of detail in the design, but will also have an impact on spatial requirements for the building and the flow of the sterile manufacturing area in relation to adjacent facilities on site.

The consultation document also includes other proposals that will affect design parameters and the space requirements for sterile medicinal products manufacturing facilities. For example, where primary and secondary change areas have sometimes been combined in the past, the proposed EU GMP Annex 1 rules require a defined chain of classified change areas for ingress and egress, which again will affect layouts and spatial requirements. 

Collaborative design

The consultation is now closed, but we don’t know when the changes will be implemented or if they will remain unchanged from the proposals issued for comment. However, it is clear that there is a focus on reducing contamination risk through design best practice and this will have implications for both existing and new medicinal products sterile manufacturing facilities.

Ultimately, the most common source of contamination is humans and, alongside measures to rethink the flow of people and materials in clean environments, the proposed new rules lay the foundations for increased automation in the sector. For the team at BES, design is a collaborative process  -  across our multidisciplinary team and with the client - and understanding the most appropriate response to EU GMP Annex 1 changes for each project will, as always, involve understanding the client’s priorities and mission critical parameters to provide the right bespoke solution.