Annex 1 of the EU guidelines on good manufacturing practice (GMP) for medicinal products outlines the requirements for the manufacture of sterile medicinal products in the EU.¹ This article explores how the latest update to GMP Annex 1 impacts the sterile medicine production supply chain and how ready-to-use (RTU) containers, such as vials and cartridges, offer a time-efficient and cost-effective solution for compliance.

Introduction and Key Trends in Sterile Manufacturing

Sterile manufacturing plays a critical role in the global pharmaceutical supply chain. The market for sterile-manufactured drug products is expected to grow at a CAGR of 15% from 2022 to 2027,² driven by biologics, biosimilars, and personalized medicines. This growth necessitates increased production capacity, efficiency, and quality while reducing complexity and waste.

However, expanding sterile capacity involves significant investment, long lead times, and regulatory compliance challenges. New regulations often require costly equipment upgrades, such as Restricted Access Barrier Systems (RABS) and isolators, which could increase the level of difficulty for smaller companies to implement.

The sterile manufacturing sector is evolving rapidly, driven by several key trends³ including:

1. Reduced Total Cost of Ownership (TCO): Streamlined processes and improved yields reduce costs and increase efficiency.
2. Innovation In Products and Processes: New technologies and processes enhance manufacturing and distribution.
3. Industry Convergence: Collaboration among stakeholders in drug development and manufacturing.
4. Competitive Intensity: Small and medium-sized injectable personalized products require flexibility in production lines and workforce skills to optimize processes and reduce waste.

Adapting to these trends is crucial for success in sterile manufacturing, with a focus on reducing lifecycle duration and demonstrating ROI. Growth in sterile manufacturing is driven by underserved regions. Currently, over 80% of global capacity is in North America and Western Europe. However, drug shortages and patent expirations are pushing companies to expand in emerging markets, leveraging cost-effective technologies and capital investments. Local production is supported by rising living standards and government initiatives to strengthen internal supply chains.

Emerging economies in Asia, Eastern Europe, South America, and Africa present significant growth opportunities. However, this requires substantial investment in new equipment and the revamping of existing lines, along with sufficient time for qualification and validation. Overcoming these barriers with innovative approaches is vital for market success. To balance the demand for flexible sterile capacity with cost and time constraints, companies may need to partner with other stakeholders in the drug supply chain.

GMP Annex 1 Overview and Impact on Manufacturers

The updated GMP Annex 1, effective from August 25, 2023, introduces significant changes to sterile manufacturing, emphasizing Pharmaceutical Quality Systems (PQS), Quality Risk Management (QRM), and Contamination Control Strategy (CCS). It also expands coverage for new technologies such as isolators and RABS and updates requirements for monitoring, disinfection, and training.

Manufacturers must establish a comprehensive CCS to ensure sterile products are produced under compliant conditions. This involves implementing modern PQS elements and extensive use of QRM principles, as outlined in ICH Q9 and Q10 guidelines.⁴ Ensuring compliance reduces the risk of contamination and ensures patient safety.

How Design Can Help Manufacturers Ensure Compliance

The new Quality Risk Management (QRM) updates require manufacturers to identify measures to mitigate potential risks in their processes. This involves a comprehensive evaluation of a facility’s infrastructure, production processes, equipment design, and primary packaging materials. The updated GMP Annex 1 covers a wide range of sterile product types, including active substances, excipients, primary packaging materials, and finished dosage forms. This reduces the need for extensive qualification and validation activities for primary containers, as contamination and sterility are managed by packaging producers with robust quality systems.

Key drivers for adopting new technologies include increased sterility assurance, reduced manufacturing costs, and improved efficiency. However, these changes require significant economic investment and may lead to production interruptions. A practical solution to reduce execution times and costs is the use of sterile and ready-to-use (RTU) packaging. RTU packaging simplifies the filling process by eliminating steps such as washing, depyrogenation, drying, and sterilization, which are typically required for preparing primary containers before filling. This approach enhances sterility assurance and operational efficiency while minimizing contamination risks.

Comparison of Traditional and RTU Processes

Comparing traditional and RTU processes highlights the efficiency of RTU components. RTU containers reduce complexity, cost, and time while supporting quality and regulatory compliance. Key aspects include:

• Manual with Traditional Containers: Involves multiple steps and higher risk of contamination.
• Semi-Automatic with Traditional Containers: Reduces some manual handling but still complex.
• Automatic with RTU Containers: Streamlines processes, reduces handling, and improves efficiency.

RTU containers demonstrate superior efficiency by avoiding several production steps, thereby reducing complexity and costs while enhancing process control and product quality in line with market and regulatory expectations. By analyzing each step we can highlight the following key aspects:

• Incoming Stage

Traditional containers require extensive quality control (QC) testing and documentation review before release for filling, necessitating appropriate warehouse storage. In contrast, RTU containers arrive pre-washed and pre-sterilized in a nest-and-tub or tray packaging, with containers well separated. This packaging prevents frictive sliding during transportation, reducing particle generation and the risk of scratches, which can lead to contamination and defects.

• Washing and Depyrogenation

Standard containers need washing and depyrogenation before filling, involving significant handling and processing. This increases the risk of contamination and defects. Washing uses purified water, Water For Injection (WFI), and pharma gases, with manual de-wrapping and feeding. Depyrogenation requires high temperatures, which can damage containers. RTU containers eliminate these steps, reducing handling and associated risks.

Operational and Quality Advantages of Using RTU Containers

RTU (Ready-to-Use) containers offer several operational advantages over traditional containers, particularly by eliminating manual processes involved in washing and depyrogenation, which can introduce inconsistencies, quality deviations, and potential yield reductions. Stevanato Group’s RTU production process includes washing, depyrogenation, and 100% visual inspection, reducing risks associated with these steps while minimizing waste.

Key Benefits of Pharmaceutical Companies choosing RTU Containers are listed below and quantified in  Table 1.

• Reduction in production time

• Reduction in equipment involved

• Reduction in employees’ resource

• Reduction in maintenance activities

• Reduction in validation and re-validation activities

• Reduction in inventory/stock of spare parts

• Reduction in environmental and process controls

• Reduction in risk of product defects generated RTU containers help mitigate contamination risks, a key goal under updated GMP Annex 1 requirements. They require less preparation in contamination control strategies (CCS) due to fewer risky activities. RTU packaging suppliers must meet strict quality standards and provide documentation to ensure sterility.

 The use of RTU containers offers several quality advantages to pharmaceutical companies. These are listed below and quantified in Table 1.

• Less documentation and effort for qualification
• Minimal human intervention, reducing the risk of contamination
• Fewer activities needed for IQ, OQ, PQ, and PV protocols
• Reduced risk of container contamination due to better packaging and handling
• Less aseptic manipulation and fewer process controls in Grade A areas

Overall, RTU containers improve efficiency, reduce contamination risks, and enhance product quality by eliminating several manual, high-risk steps in the production process.⁵

Conclusion Summary

Our market analysis highlights several key points:

1. Rapid Growth and Challenges: The sterile pharma market is expanding quickly which presents significant challenges.
2. Need for Simplification: Reducing complexity is essential to enhance service levels while preserving quality.
3. Importance of Innovation: Innovation will be a crucial differentiator.
4. Collaboration is Key: Cooperation among supply chain stakeholders is vital to overcome challenges and seize market opportunities.

The pharmaceutical market operates under strict regulations, requiring suppliers to be resilient and adaptable to new guidelines. The revised Annex I introduces key rules for sterile applications including:

1. Knowledge and Awareness: Understand your end-to-end processes thoroughly.
2. Risk Management: Be aware of risks throughout the manufacturing process, including materials and suppliers.
3. Mitigation Strategies: Implement and document risk mitigation measures.
4. Partner Involvement: Collaborate with partners to adopt the best solutions.
5. Focus on Innovation: Use barrier technologies to minimize risks from human intervention.

Implementing RTU primary packaging, like Stevanato Group’s EZ-fill® platform, offers significant benefits, preserving quality, enhancing sterility assurance, reducing operational risks, and minimizing recalls.

Under the updated Annex 1, a Contamination Control Strategy (CCS) is crucial for demonstrating compliance and mitigating risks to patient safety. RTU packaging is an effective solution for controlling contamination and reducing human intervention.

RTU materials also support manufacturers by reducing capital expenditure (CAPEX) through subcontracting washing and depyrogenation, allowing a focus on aseptic filling in restricted equipment (RABS or Isolator).

In summary, RTU primary packaging materials provide a robust solution to meet regulatory expectations and capitalize on market growth opportunities.

We can summarize and quantify those advantages in two main categories as listed in Table 1 below.

** Results of Table 1 refer to the findings and conclusions derived from investigations or studies conducted by Giovanni Cosmi and Mirko Gabriele.

References

1. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en#annexes

2. IQVIA, Alira Health; Data communicated during the Capital Markets Day, Sep. 27, 2023

3. Growth Opportunities in Sterile Injectable Outsourcing – Frost & Sullivan – June 2022

4. https://www.ich.org/page/quality-guidelines

5. Advances in Vial Processing in Pharmaceutical Primary Packaging to Reduce Risk of Vial Damage and Particle Contamination – Pharmaceutical Processing World

White Paper:  EZ-fill platform: ready to use vials, syringes and cartridges platform – Stevanato Group

Technical report PDA n 43

Pharma glass defects Article – Matthew Hall – Sept 8, 2023 – LinkedIn