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In the world of pharmaceutical manufacturing, maintaining the highest standards of quality, safety, and efficacy is paramount. To achieve this, regulatory guidelines play a pivotal role in guiding industry practices. One such critical guideline is Annex 1 of the Good Manufacturing Practices (GMP) for Medicinal Products, which provides guidelines for the manufacture of sterile products. Recently, Annex 1 underwent a significant revision, ushering in changes that have a profound impact on pharmaceutical manufacturers. In this blog, we will delve into the key revisions of Annex 1 and explore how they affect pharmaceutical manufacturers.

The European Commission's Directorate for Health and Food Safety issued the final version of the Annex 1 Manufacture of sterile medicinal products of the EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary use.

The EU GMP Annex 1 "Manufacture of Sterile Medicinal Products" was amended in 2022 with the goal of resolving ambiguities and inconsistencies and taking technical improvements into account. Annex 1 of the EU GMP specifies the manufacturing of sterile medical goods. These standards are aimed at reducing the potential of product contamination throughout production procedures and, more importantly, when the product exits the Cleanroom. Prior to the most recent regulatory amendment, EU GMP Annex 1 was last reviewed in 2008. Without a doubt, manufacturing technology for sterile items have progressed greatly over the last 15 years, hence a review of the standards is necessary.

• Requires validated test methods (precludes probabilistic methods)
• Statistically valid testing plan required based on scientifically justified QRM assessment.
• Physical measurement of integrity.
• Automatic inspection methods should be validated to LOD equal to or better than manual inspection methods.
• A sterility test is only regarded as the last in a series of control measures to assure sterility.
• Coordinated effort by Pharmaceutical Inspection Cooperation Scheme (PIC/S) and the World Health Organization (WHO).

Containers closed using methods like Blow-fill-seal (BFS), Form-Fill-Seal (FFS), SVP & LVP bags, ampoules, etc., require 100% integrity testing using validated methods. Other closure methods need sample testing based on validated techniques. Frequency hinges on system familiarity, with a scientifically sound sampling plan. Size depends on supplier approval, specs, and process knowledge. Visual inspection alone is inadequate for integrity testing.

Containers sealed under vacuum (where the vacuum is necessary for the product stability) should be tested for maintenance of vacuum after an appropriate pre-determined period and during shelf life.

The container closure integrity validation should take into consideration any transportation or shipping requirements that may negatively impact the integrity of the container (e.g. by decompression or temperature extremes).

• The Annex 1 Summary for IV Bags outlines a strategy to ensure the quality and integrity of intravenous (IV) bags throughout their lifecycle. This involves validated methods for Container Closure Integrity Testing (CCIT) that are quantitative and deterministic, preventing contamination or leaks.
• The document emphasizes a comprehensive quality risk management strategy, identifying and mitigating risks from manufacturing to distribution and use.
• Inspection methods vary based on risk. Physical measurements detect defects, leaks, or compromised seals.
• A sampling plan ensures product quality. IV bags under 100mL require 100% inspection.

A Contamination Control Strategy (CCS) should be implemented throughout the facility to define all critical control points and assess the effectiveness of all controls (design, procedural, technical, and organizational) and monitoring measures used to manage risks to the quality and safety of medicinal products. The CCS's integrated strategy should provide solid guarantee of contamination prevention. The CCS should be actively reviewed and modified as needed, and it should encourage continuous development of manufacturing and control procedures. Its effectiveness should be evaluated on a regular basis. Existing control systems that are properly managed may not need to be replaced, but they should be referenced in the CCS and the accompanying interconnections between systems should be understood.

The revised version states that the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacturing and ensure that all activities are effectively controlled so that microbial, particulate and pyrogen contamination is minimized in sterile products. In addition to the PQS requirements detailed in Chapter 1 of the GMPs, the PQS for sterile product manufacture should also ensure that:

• The integrated risk management system covers the product life cycle to minimize contamination and ensure sterile product quality
• The manufacturer possesses expertise in products, equipment, engineering, and manufacturing affecting product quality.
• Root cause analysis of failures identifies risks, leading to informed CAPA implementation for product protection.
• The risk management outcome should be periodically reviewed within ongoing quality management, change control, and product quality assessments.

Here is a quick rundown of quality management and regulatory expectations in the pharmaceutical industry, specifically related to package quality and container closure integrity:

• QRM: A method to identify, analyze, and manage risks to drug quality
• Holistic Approach: Considers the entire drug lifecycle for consistent quality.
• CQA's: Essential attributes controlled to ensure drug quality.
• CCI: Packaging's ability to protect product integrity.
• Scientific Methodology: Reliable, accurate testing methods.
• Sampling Plans: Testing procedures for batch release and monitoring.
• Validated Methods: Established, trustworthy testing procedures.

These practices collectively uphold drug safety, efficacy, and regulatory standards.

The systematic approach and examination of threats to the drug's quality throughout the product lifecycle is known as quality risk management (QRM). QRM principles provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. The evaluation of risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.

It is clear that using QRM methods in the pharmaceutical industry has become much more difficult thanks to the updated Annex 1 document. The only mention of risk in the previous iteration (2008) is found in Section 8: Cleanroom and Clean Air Device Monitoring. Contrarily, the updated draft Annex 1 contains references to risk in a number of sections, including Sections 2, 3, 4, 5, 7, 8, and 9. Given that manufacturing sterile medications is a complicated process, it needs special controls and precautions to guarantee the caliber of the finished goods. Risk-based quality control will be widely used to make sure that pharmaceutical products are of the highest quality.

There have been substantial improvements in sterile manufacturing technology since the 2008 version of Annex 1 was last visited, particularly with Restricted Access Barrier Systems (RABS) and isolators. Such improvements are evidently acknowledged in the current draft. For example, previous Annex 1 guidelines required all connections for aseptic processing to be performed under highly classified Grade A environments.

Annex 1 applies to pharmaceutical firms that manufacture products within the European Union as well as those that import into the European Union.

Section 3 of the paper discusses the production of sterile medicinal commodities and pharmaceuticals, while Section 4 discusses the maintenance and quality requirements of Cleanrooms, change rooms, and other sterile settings utilized during the manufacturing process.

Those working in the pharmaceutical, cleanroom, or sterile manufacturing industries are likely already aware of the new requirements that will go into effect in August 2023.

In conclusion, the revised Annex 1 of the EU GMP guidelines represents a significant milestone in the realm of pharmaceutical manufacturing. By addressing the evolving landscape of sterile product production and emphasizing key concepts, this revision brings about transformative changes that ultimately enhance product quality, safety, and efficacy.

• All regulatory guidance moving towards deeper scientific quality assurance
• Holistic life cycle approach to pharmaceutical packaging quality
• Deterministic methods must take priority; validation and control strategy.
• Thorough QRM strategy establishes the critical risks on IV bags.
• Risks mitigated with appropriate physical test method and scientifically justified sampling plans.
• 100% inspection not a requirement for most IV applications.
• Different methods may apply for different stages of development life-cycle.
• CGMP guidelines calling for deterministic physical testing of Container Closure Integrity (CCI)

For assistance in implementing the Annex 1 revision, PTI can support you. Reach out to one of our application experts for assistance with the right CCI quality risk management strategy.