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Particles and new requirements: The importance of GMP Annex 1 for sterile primary packaging materials!

Close-up medical syringe with a vaccine.
Mar 19, 2024
8 minutes

The revised GMP Annex 1 came into force on August 25, 2023, significantly increasing the regulatory requirements for pharmaceutical companies and their suppliers, particularly in the area of sterile primary packaging production. This revised guideline focuses more strongly on safety and quality controls and requires the implementation and ongoing adaptation of comprehensive contamination control strategies. The aim is to reduce the risks of microbial and particulate contamination as far as possible.  This article discusses the key aspects of these changes and their direct impact on the manufacturing processes of sterile primary packaging. In addition, practice-oriented, strategic approaches are presented in order to meet the new, increased standards.

Sterile primary packaging plays a crucial role in the safety of medicines. These specialized packaging solutions come into direct contact with the medicines and undergo rigorous sterilization processes during their manufacture.
Their primary task is to protect the medicines from contamination during storage and up to the moment of administration. This is particularly important for parenteral medicines and ophthalmic products, as these are introduced directly into the human body and must therefore be sterile.

Sterile primary packaging materials can be divided into two main categories:

  • Protection-oriented primary packaging materials: these are designed exclusively to protect the medicine from external influences. A classic example of this is vials, which have no direct administration function but keep the contents safe and sterile.
  • Administration-oriented primary packaging materials: These not only fulfill the protective function, but are also actively involved in the application of the medication. Typical examples of this are syringes and other applicators that both ensure the safety of the medication and enable it to be administered.
    The distinction between these two types is of immense importance not only for the application, but also for the regulatory requirements.

While protection-oriented primary packaging materials must mainly follow the guidelines of Good Manufacturing Practice (GMP for short), administration-oriented packaging materials are subject to additional strict criteria of the European Medical Device Regulation (EU) 2017/745 (MDR).

Safety right from the start: New requirements for sterile packaging!

GMP Annex 1 "Manufacture of Sterile Medicinal Products" plays a special role in good manufacturing practice. This binding document sets out in detail the specific requirements that pharmaceutical companies must observe in the production of sterile medicinal products.

These requirements range from ensuring adequate human resources and the implementation of comprehensive quality controls to compliance with aseptic filling standards. With the update of August 22, 2022, the requirements of Annex 1 "Manufacture of Sterile Medicinal Products" were significantly tightened. This revision aims to further raise the standards for the sterile filling of medicinal products.

As a result, pharmaceutical companies are now obliged to meet these increased requirements and pass them on to their suppliers of primary packaging materials accordingly. For the manufacturers of these packaging materials, this results in particularly strict requirements for the purity of their products. In particular, this includes the control and minimization of bioburden, endotoxins, particle contamination - including pyrogenic substances of non-biological origin - as well as extractables and leachables.

From bioburden to leachables: key factors for pure medicines!

The following is a detailed analysis of the four key elements that are critical to drug purity: from microbiological contamination, known as bioburden, to endotoxins and particle contamination, to extractables and leachables.

Bioburden - microbiological contamination: In the context of manufacturing sterile medicinal products, microbiological contamination, also known as bioburden, is a decisive factor. The requirements for microbiological purity are particularly high for products that enter the bloodstream directly, such as intravenous drugs. In this context, sterility means that the probability of the presence of viable microorganisms after sterilization is at most 1 in a million (10^-6). Achieving sterility is primarily based on two pillars:

  1. the careful control and continuous monitoring of hygiene conditions throughout the manufacturing process.
  2. the use of a scientifically validated sterilization procedure.

Endotoxins: As far as endotoxins are concerned, the sterilization process itself poses certain risks. Endotoxins, which are decay products of bacteria, can lead to serious health complications if they remain in the drug. In order to minimize this risk, it is essential that both the validation phases of the sterilization process and the release process of the individual batches include specific tests for endotoxins. These tests serve to effectively detect and quantify the presence of these toxic substances to ensure safe use of the drug.

Extractables and leachables: Following on from the consideration of endotoxins, it is equally important to consider the potential hazard of extractables and leachables. Leachables are substances that can pass from the primary packaging materials into the medicinal product under normal conditions of use. Extractables, on the other hand, are substances that can be dissolved out of the packaging materials under extreme conditions, such as high temperatures. Careful selection of materials and their comprehensive analysis are essential as part of the risk management process in order to prevent the release of these substances.

Particle contamination: Another key requirement and significant challenge for sterile pharmaceuticals is the control of particle contamination, particularly non-biological pyrogens, which is directly dependent on the manufacturing processes. It is crucial to

  • Identify the potential risks and causes of particle contamination at each production step and under each environmental condition,
  • validate the manufacturing processes,
  • to produce under controlled conditions,
  • plan, implement and validate the cleaning of cleanrooms and, where applicable, products on a risk-based basis.

Finally, comprehensive quality control, including verification and confirmation of compliance with established limits for particulates, should be an integral part of the batch release process.

Comprehensive overview of implemented control strategies as a new standard!

One of the key new requirements of GMP Annex 1 is the implementation of an effective contamination control strategy. This is a risk-based approach with the support of which all relevant processes are to be designed (Contamination Control Strategy - CCS). Risk-based means looking at all processes, employees, materials, utensils and environmental conditions that have an impact on product quality, particularly with regard to the types of contamination mentioned above, in order to

  • Systematically identify risks to safety and quality
  • Evaluate the identified risks and
  • Derive, implement and monitor appropriate risk mitigation measures. Each measure taken (e.g. a specific control) aims to mitigate an existing or potential risk.

The CCS is therefore the leading document for the planning, implementation and verification of adequate contamination control, which is continuously being developed and summarizes all circumstances into a common thread. Pharmaceutical manufacturers must clearly state and take into account their own strategies and controls for primary packaging materials used.

Strong together: TentaConsult supports your quality goals

The adaptation to the revised requirements of GMP Annex 1 for manufacturers of sterile, protection-oriented primary packaging is groundbreaking, as the new requirements are increasingly being imposed on primary packaging manufacturers by pharmaceutical customers.

TentaConsult Pharma & Med GmbH is at your side to tackle specific challenges in the pharmaceutical industry, medical technology and the packaging sectors. We offer customized support in the development of your contamination control strategy and the implementation of the new requirements of Annex 1 to the EU GMP guidelines. Our team of medical device and sterile manufacturing experts are on hand to support you with any questions you may have.

Contact us today to optimize your processes and stay one step ahead of the new regulatory requirements.


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Ronja Loy
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