By Fran DeGrazio, executive editor
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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.
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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.