Understanding Annex 1 For Sterile Medicinal Products

By Fran DeGrazio, executive editor, Drug Delivery Leader

One of the most common topics regarding product development for drug delivery that I still get questions about is the Annex 1 guidance document for sterile medicinal products. Because there remains a high level of interest in this document from the EU, I thought I would use this article to revisit it.

Background On Annex 1

For those of you who may not be familiar with it, the Annex 1 document offers technical guidance on Good Manufacturing Practices (GMP) for sterile medicinal products, as defined by European Commission Directive 2017/1572. This updated version became effective in August 2023.

The GMP/GDP inspectors working group and the PIC/S (Pharmaceutical Inspection Co-operation Scheme) committee jointly recommended this updated version of Annex 1 since it was revised to reflect a more up-to-date regulatory and manufacturing approach. Why this is important is that some people are under the impression that this document only applies to Europe. The fact that this has been sanctioned by PIC/S indicates that it serves as a de facto global guidance. PIC/S is a global co-operative in the field of Good Manufacturing Practices. It currently comprises 56 participating authorities coming from Europe, Africa, America, Asia and Australasia. The FDA actively participated in Annex 1 through this forum. One additional important activity of PIC/S is that it is commonly used to train regulatory inspectors from around the world.

Scope Of Annex 1 And Focus Of Inspections

The Annex 1 document covers a wide range of sterile products such as active ingredients, excipients, primary packaging materials, and finished dosage forms. It provides guidance that should be considered in the design and control of facilities, equipment, systems, and procedures. In particular, it points to principles of Quality Risk Management related to the prevention of microbial, particulate, and endotoxin/pyrogen contamination of the final product. So, what will inspectors likely look for when they come into a manufacturing site relating to Annex 1?

Inspectors will examine your Contamination Control Strategy (CCS) to verify that risks to product quality have been assessed and controlled. The CCS should address the entire manufacturing site, all critical control points and their effectiveness, and offer reliable assurance of contamination prevention. It is important to understand the overall process rather than focusing on isolated parts.

The CCS requires detailed technical knowledge and periodic evaluations. For that reason, people who have hands-on knowledge of the process should be included in generating the CCS. This includes shop floor personnel. The use of the CCS should be part of the site’s continuous improvement process.

Key Points to Consider

While I will summarize key points made in the document, this summary article cannot take the place of reading the  59-page document.  If you are in the pharma and biopharmaceutical manufacturing industry, I suggest increasing your familiarity by reading the actual guideline.

There are 4 specific topics to highlight:

Key Consideration #1: Updating Facilities And Equipment

The Annex 1 guidance encourages moving to more modern sterile manufacturing processes such as those using Restricted Access Barrier Systems (RABS), barrier isolators, robotics, and continuous monitoring systems. There is a recently released technical report from the PDA entitled: Points to Consider No 12: Restricted Access Barrier Systems. This document can only be accessed via the PDA website and does a helpful job of going into fundamental details around the subject of RABS systems. Consider it complementary to Annex 1.

One key aspect of transitioning to new technologies in the fill/finish process is removing personnel  from the facility’s filling environment. It is well-known within industry that human presence poses a significant risk of introducing biological and particulate contamination into sterile manufacturing processes. Reducing human contact can enhance the quality of drug products.

Key Consideration #2: Training And Deploying Personnel

There will always be people involved in the process, even while, as noted above, the risk of their physical presence can be minimized by the addition of newer equipment. The key issue is that they must have adequate qualifications and experience. They need to understand it is their responsibility to protect sterile products from contamination of any kind. This is about assuring that people are not just following procedures but also understanding the “Why” behind what they are being asked to do. It is essential that they understand cleanroom behaviors and have an awareness of aseptic processes.

Innovative ways of training should be utilized such as the use of virtual reality or having personnel swap roles for a time.

Ultimately, senior management must own the responsibility of ensuring that effective quality systems are in place and that they are incorporated as part of the culture across all functions.

Key Consideration #3: Monitoring Processes

It is critical that the people designing and commissioning your control systems, such as process monitoring, have the appropriate knowledge to do so. Remember that you are not just gathering data for the sake of gathering data. It needs to be reviewed, understood, and reacted to when needed.

Big data analytics will be crucial for evaluating the CCS. It allows for analysis, visualization, and sharing of information. Understanding relevant data is essential for assessing CCS effectiveness, which may vary across processes, drugs, and packaging systems

Key Consideration #4: Testing And Controlling Raw Materials And Packaging

There need to be adequate controls and testing of incoming raw materials to ensure that levels of bioburden, endotoxin/pyrogens, and particulate are suitable for use.

Obviously, if you are moving from traditional filling equipment to a barrier type system, the primary packaging components and the package they are delivered in will also need to be adjusted. The use of Ready to Use (already washed and sterilized) packaging components delivered in port-bags is definitely the trend.

There is also a reinforcement made in the Annex 1 document of concerns relating to the CCI (Container Closure Integrity) of primary packaging. The reason for this is that lack of CCI is an open invitation for microbial or particulate ingress.

Active engagement with suppliers of these products will be important, as their understanding and controls become inputs into your CCS and final product.

Key Takeaways From Annex 1

There are several key takeaways:

• Invest in updating older manufacturing facilities and the people involved in the manufacturing process.
• The package used to hold the drug is critical to product quality not only as individual components but as a total system to assure container closure integrity.
• Annex 1 will be globally adopted over time and reinforced via regulatory inspections.
• A comprehensive and living Contamination Control Strategy that drives continuous improvement is critical to anyone manufacturing aseptic drug product.