Eudralex Volume 4 Annex 1 – Room for Improvement?

Eudralex Volume 4 Annex 1 is a crucial document that outlines the guidelines for good manufacturing practices (GMP) in the pharmaceutical industry. It is now live, apart from the section on Lyophilisation, which is still awaiting final approval, so I won’t be discussing that section directly.

Also, this critique of Annex 1 will only be an overview discussion rather than a fully detailed brief, as that would be a significantly longer document, perhaps even book-length, so this is very much an overview of my thoughts, comments and ideas on how you can help your business deal with some of the challenges that Annex 1 presents to the pharmaceutical industry and potentially some crucial omissions and improvements that could be made as we advance.

Remember, Annex 1 is not new in terms of concept, so you should not be surprised by its content. It has been a long time coming and was previously partially revised in 1996, 2003, 2007, 2017, and 2020, with the final revision published in August 2022. It now includes requirements from ICH (The International Council for Harmonisation), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) PIC/s and WHO. All of which should be familiar to Quality Specialists in most pharmaceutical businesses.

So, as we delve into the 2023 version of Annex 1 in its current form, it is essential to understand its significance and how it impacts pharmaceutical manufacturing.

For me, the most critical point of Annex 1 is the switch from a strategy of just “following the guidelines” to a “Risk-Based Approach” using Quality Risk Management (QRM)Techniques.

That is a significant change and is now formalised. Why is that so important, and why does it run through the document?

In essence, it will mean that from now on, you will have to understand your processes, how your business operates and demonstrate your understanding with facts and sound data.

That may sound obvious, but having been in the industry all my life and worked with many businesses globally, I have often asked, “Why do you produce your products in this way?” the response often is because it is in the guidance. So often, there is not always a detailed understanding of how they produce their products, but instead, just unthinkingly follow the guidance. However, with Annex 1, you must follow the guidance BUT critically demonstrate your understanding of what you do and why.

So what happens if your production techniques deviate from the guidance to remain in the specification due to how a particular product behaves? With the new guidance, I don’t believe there will be an issue during formal inspection and approvals because with the latest guidance, if you have the data, the risk assessments completed using sound QRM methodologies and robustly challenged and have done your “homework”, to prove what you are doing is valid, correct and maintains the quality of the product and improves patient safety, I am confident it will be approved or pass an inspection.

It reminds me of the early days of containment of processes, which I was involved with way back in the late 1980s and early 1990s. During that period, the technology was pushed to its limits, however, projects that I installed and developed challenged the thinking then, but in all cases, we had the risk assessments and the data to back up what we had developed and validated and all the regulatory bodies approved every process I ever worked on.

Now, containment technology is embedded into Annex 1 and one of the critical areas the guidance addresses, which I will discuss later.

One of the significant sections in the Annex is the requirement, though in reality, it has always been a requirement, which is the Contamination and Control strategy you will now be required to demonstrate. It is perhaps the most challenging area of the new guidance. This section (2.3 in the guidance) emphasises the importance of implementing robust measures to prevent cross-contamination and maintain product integrity. This critical change also migrates to a risk-based approach strategy, which, as I stated previously, is something Annex 1 stresses throughout the document. In this instance, manufacturers must identify critical areas where contamination risks can occur, implement appropriate controls to mitigate them and demonstrate a continuous improvement quality strategy to prevent them from happening again.

That will not be just in production areas but throughout the entire production cycle, including facilities, utilities, delivery, personnel and logistics, which, if you have not done so previously, is a herculean task.

In my view, it has been built on these six pillars, which are:

1.  People

2.  Facilities, Equipment, Utilities, Design and Qualification and Control

3.  Process Design, Validation and Control Measures.

4.  Product and Containment Closure Design, Validation and Control Measures

5.  Sterility Assurance, Performance Metrics and Monitoring Programmes

6.  On-going Quality Oversight and Continuous Improvement

Indeed, it will affect how you design your facilities, plan your logistics, and thoroughly map your processes. You should also look at any high potents you are processing, even though the guidance does not explicitly call this out, in my view, a significant omission.

A good Contamination and Control Strategy gets even more challenging as it is not something you do once and forget about. It is something that you will be expected to complete on a continuous improvement basis. This means that it will generate more CAPAs and more deviations with the aim that you will get better at reducing contamination and production errors while improving your quality.

So, it may become resource-heavy, both technically and in terms of the multi-disciplinary teams deployed to undertake the work, until the new AI systems and better analytical software is available that can analyse all the data captured.

This will also eventually remove all paperwork systems, such as paper batch sheets, as, increasingly, it will become impossible to review the large quantities of data collected and understand what that means to a business manually.

However, this switch to a Risk-Based Model or QRM model and the development of accurate data around your products is only a good thing. Nevertheless, if you struggle with this or are new to it, get some outside help and expertise. This will allow you to continue with Business as Usual while flexing these support services as and when needed.

As we move through the document, the Control and Management of Personnel (Section 7) is also highlighted as vital in ensuring GMP compliance. Annex 1 emphasises the need for adequate training and qualifications for all personnel involved in pharmaceutical manufacturing processes. It highlights the importance of continuous training programs to enhance knowledge and skills, enabling employees to perform their tasks precisely.

Including personal hygiene, who can enter an area, if you have suitable washing and changing areas, how you deal with laundry, and even how you move inside sterile areas.

Again, this is something that, in some instances, has yet to be given the importance it should have in the past.

Using newer technology in this area would help significantly, such as using video SOPs in areas where you must explain various dress codes. How to move in a sterile area, etc. or even embedding video technology into electronic batch sheets and SWIs on equipment monitors and even using gesture control rather than touching monitors in production areas.

Indeed, online training can play a significant role, which obviously must be competency-based. I would also consider augmented reality around process/packaging equipment and maintenance. Even using virtual reality, though this is not new technology, we should employ it in early-stage training as we prepare operators and technicians.

I expect this area to get even more disruptive with AI technology. This is something that Annex 1 needs to address, but without a doubt, in the coming months/years, it will have to be explored and reviewed as all businesses will deploy this technology very quickly.

Experts and expert businesses can help you deploy these new technologies and training online, etc., so make sure you ask reputable and experienced businesses like us or others who have done this before.

Sterilisation methods are another critical aspect covered in Annex 1 (section 8 – specifically 8.34 onwards). Annex 1 guides on selecting suitable sterilisation techniques based on product characteristics and, again, the common thread, appropriate risk assessments. By following these guidelines, manufacturers can ensure products are free from microbial contamination, safeguarding patient safety.

The document also guides other sterilisation techniques such as moist heat sterilisation, dry heat sterilisation, filtration sterilisation, and radiation sterilisation. These methods are crucial in ensuring the sterility of medicinal products throughout their lifecycle.

Also note the validation and re-validation implication of these aspects, including the areas of Media Fills – Aseptic Process Simulation (Section 9.32 onwards), which should generally be six months, depending on your process or what you have validated. This means re-validation will also need to be considered, which will be part of the QRM model, so you must do your homework. That is one of the benefits of working with a Risk-Based Model using QRM techniques; you can challenge the guidance if you have evidence that following the guidance harms your products.

Environmental monitoring (Section 9) is integral to GMP compliance, as highlighted in Annex 1. It stresses the need for regular monitoring of cleanrooms, processes, and controlled environments to detect any potential sources of contamination promptly. By implementing effective environmental monitoring programs, manufacturers can maintain optimal conditions for quality production.

There is also a move to slowly begin to allow businesses to determine what particulate level is allowable. This is currently at the lower and less challenging end of the scale. Still, I see a point whereby each business must justify the particulate control and viable level for each product manufactured and why.

If you think about that, it makes more sense to “shoehorn” each product into bandings and categories. In reality, it does not make much sense as every product is different, but until now, offering this simplistic guidance was considered the best way to go. However, moving to a Risk-Based model and perhaps in the future using AI and Machine Learning to do a lot of the data analysis, we may be able to have specific limits for each product rather than just bracketing them into a particular banding.

Annex 1 includes a section on cleaning and decontamination, which covers the following topics:

• General principles of cleaning and decontamination

• Cleaning and decontamination methods

• Validation of cleaning and decontamination methods

• Monitoring of cleaning and decontamination

It provides clear and concise guidance on these topics. However, there are a few areas where the Annex could be improved.

One area of concern is the lack of specific guidance on using QRM in cleaning and decontamination, something I have had experience with while discussing this with a client. While Annex 1 mentions the importance of risk management in several places, it does not provide detailed guidance on implementing it in this context.

Another area of concern is the lack of specific guidance on using new technologies in cleaning and decontamination. It mentions new technologies in a few places but does not provide detailed guidance on validating and implementing them. Again, this is something I have touched on previously in this document.

In my view and based on my experience, the Annex could be improved by perhaps providing more specific guidance on some of the more complex aspects of cleaning and decontamination, such as the removal of recalcitrant residues, residues embedded in surfaces and the cleaning of complex equipment.

The Barrier Technologies sections of the Annex have been significantly expanded, reflecting the growing importance of barrier or containment technologies in the manufacture of sterile products, which should also include high-potency drugs and other hazardous products.

Nevertheless, the overall containment sections of the Annex are well-written and comprehensive. They provide clear guidance on the design, operation, and qualification of barrier/containment systems. Although, there are a few areas where the guidance could be improved.

One area for improvement is in the guidance on selecting containment technologies. The Annex provides a good overview of the available containment systems but does not provide specific guidance on choosing the right system for a particular application. This can be challenging for those new to this technology and its application.

Another area for improvement is in the guidance on the qualification of containment systems. The Annex provides a good overview of the general principles of containment qualification; however, it does not provide specific guidance on the types of tests that should be performed or the acceptance criteria that should be applied. This can lead to variability in how containment systems are qualified, which can impact the effectiveness of containment as a sterile barrier or, a containment system for high potents or both.

But any business supplying and qualifying containment systems for several years can offer sound advice on what is acceptable.

For instance, Annex 1 does not guide on using containment in conjunction with other risk mitigation measures. For example, Annex 1 does not discuss the role of occupational exposure monitoring in containment programs, which is equally critical. This is a significant omission, as occupational exposure monitoring is a valuable tool for assessing the effectiveness of containment and identifying any potential problems early on, even in a sterile process.

The one good point is that the guidance now states that you can have a Grade A isolator in a Grade C/D environment with an appropriate Risk Assessment, leading to significant operating cost reductions. Unfortunately, not so for RABS, where you can only operate one log down. The guide states a Grade A RABS can only operate in a Grade B environment, and I would suggest those with ORABS may want to consider keeping the entire area Grade A inside and outside of the RABS as these systems are more susceptible to contamination risk in my view.

Overall, the Barrier Technology sections of Annex 1 are a valuable resource for companies manufacturing sterile medicinal products. However, notwithstanding the comments made previously, the guidance could be improved upon, with help around the selection and qualification of containment systems and the use of containment in conjunction with other risk mitigation measures, such as occupational exposure monitoring.

Giving more specific guidance on the qualification of containment systems, including the types of tests that should be performed and the acceptance criteria that should be applied. However, there are references to air flows, first air principals, smoke testing and keeping visual records.

The Barrier Technology sections of Annex 1 are a good step forward regarding guidance in using barrier technology while manufacturing sterile medicinal products. It now formalises the use of the technology and embeds it into sterile production, which should have been done formally many years ago.

In conclusion, Eudralex Volume 4 Annex 1 is a comprehensive guide covering various aspects critical to maintaining GMP compliance within the pharmaceutical industry. From containment strategies to sterilisation methods and personnel qualifications, this document provides valuable insights into best practices for ensuring product quality and patient safety. By adhering to the guidelines outlined in Annex 1, manufacturers can enhance their manufacturing processes and contribute to the overall improvement of pharmaceutical manufacturing standards.

Annex 1 will play a pivotal role in the pharmaceutical industry, providing guidelines for good manufacturing practices (GMP) concerning the manufacture of sterile medicinal products.

It will help manufacturers develop and embed barrier technologies into their processes, have a robust contamination and control strategy in an environment of continuous improvement, have the highest personnel requirements, develop a risk-based QRM approach, have challenged and validated sterilisation methods, robust environmental monitoring, and training and qualifications.

This document is a valuable resource for pharmaceutical manufacturers striving to uphold the highest quality and safety standards.If you need any help or support with any of your Annex 1 challenges or if you want more information visit our website at www.austarunion.com.

Written by

Ewart Richardson     AUSTAR Consultant