June 13, 2023

Navigating GMP Annex 1: How Single-Use Assemblies will Comply

What is Annex 1?

Annex 1 of EU GMP is a widely recognized guideline that sets forth the requirements for manufacturing sterile medicinal products, particularly those used in the biopharmaceutical industry. It plays a crucial role in ensuring product quality, patient safety, and regulatory compliance. One significant aspect influenced by Annex 1 is the use of single-use assemblies in fluid management processes. Annex 1 emphasizes the need for a risk-based approach to ensure the integrity and sterility of single-use systems used in fluid management processes. This article aims to provide an overview of GMP Annex 1, its applicability, and the necessary actions that biopharma industry stakeholders must take to comply with its requirements, particularly in relation to single-use assemblies.

Scope, Applicability and Impact on Single-Use Assemblies

GMP Annex 1, also known as the "Manufacture of Sterile Medicinal Products," is a guideline published by regulatory authorities, such as the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). It outlines the principles and practices for the manufacture of sterile medicinal products to ensure their safety, efficacy, and quality as laid down in Commission Directive (EU) 2017/1572 for medical products for human use and veterinary use. 

GMP Annex 1 applies to pharmaceutical manufacturers, contract manufacturing organizations (CMOs), and other entities involved in the production of sterile medicinal products. It is applicable to a wide range of biopharmaceutical processes, including fluid management, where single-use assemblies are commonly employed. Manufacturers and industry professionals must assess the quality, performance, and suitability of single-use systems to meet the specified requirements. The deadline for coming into operation will be August 25, 2023.

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Equipped to comply with Annex 1 with Single Use Support

To comply with GMP Annex 1, biopharma industry stakeholders must proactively evaluate their fluid management processes and single-use assemblies. This involves conducting thorough risk assessments, implementing robust quality management systems, validating and qualifying single-use systems, and establishing appropriate monitoring and control strategies. Regular training and documentation of procedures are also essential to ensure compliance with GMP Annex 1.

Fermentation automated filling

PUPSIT: Pre-Use Post Sterilization Integrity Test

According to the Annex 1, the integrity of the sterilized filter assembly should be verified by integrity testing before use to check for damage and loss of integrity caused by the filter preparation prior to use. The filter integrity testing procedure is called pre-use post sterilization integrity test or PUPSIT (8.87 in Annex 1).

PUPSIT is an important step in ensuring the sterility of the final product and is commonly used in the pharmaceutical, biotech, and medical device industries. Whenever sterile filtration is part of the filling process, pre-use post sterilization integrity must be implemented.

Read more: Annex 1 and the PUPSIT requirement

Single Use Support does supply biomanufacturers with a fully automated and modular system for filling and filtration, named RoSS.FILL. Its modularity results in process flexibility and scalability from few mL to hundreds of liters. It is possible to aliquot liquids into bottles and both 2D and 3D single-use bags of 10mL up to 1000L. A PUPSIT rack can be attached to automated aseptic filling platforms if sterile filtration is part of the manufacturer’s process. All of the required single-use assemblies to perform the filtration integrity test PUPSIT, can be supplied by Single Use Support.*

PUPSIT - pre-use post sterilization integrity testing

PUPSIT - An Introduction to Pre-use Post Sterilization Integrity Testing

PUPSIT will contribute to simplifying not only integrity testing and validation but manufacturing processes in general, while keeping in line with current good manufacturing processes and any standards and guidelines defined by major authorities such as FDA and EMA. Read all about it!

Annex 1 and beyond

Annex 1 sets minimum requirements for reducing contamination. However, it does not limit automated systems and further approaches to overperform. It primary goal is to best possible reduce operational errors due to human intervention and any other possible occurrences leading to product loss, bioburden, and leakages.

Single Use Support emphasizes on the stated importance of the use of closed systems. In the annex 1 it says that closed fluid management systems “can reduce the risk of microbial, particle and chemical contamination from the adjacent environment. Closed systems should always be designed to reduce the need for manual manipulations and the associated risks” (8.127 of Annex 1). 

RoSS shell protecting single-use bags liquid transfer

Single-use technologies are increasingly used on production lines and could help to ensure compliance. For example, single-use bioprocess containers make it easier to maintain sterility across powder and liquid transfers or open handling by manual filling.  Single use systems should be designed to reduce the need for manipulations and complexity of manual interventions. (8.132 of Annex 1). In detail this includes

  • the interaction between the product and product contact surface (such as adsorption, or leachables and extractables)
  • the fragile nature of the system compared with fixed reusable systems
  • the performance of the pre- and post-use integrity testing for sterilizing grade filters
  • the risk of holes and leakage
  • the potential for compromising the system at the point of opening the outer packaging and
  • the risk of particle contamination

 Single Use Support can provide customers with documentation, risk assessments and product specified information, such as data for extractables and leachables of single-use systems, proving how the company fulfills the criteria with its solutions.

Extractables and leachables - what is the difference?

Extractables and leachables: definitions, differences & facts

Extractables and leachables are contaminants that are causing biopharmaceutical manufacturers headaches, as they can lead to impurities of highly valuable drug products. While extractables and leachables both describe foreign matter that can lead to contamination of highly valuable drug products, it is important to understand their characterization but also the difference between the two.

Conclusion

GMP Annex 1 significantly impacts the use of single-use assemblies in fluid management processes within the biopharmaceutical industry. It requires manufacturers and stakeholders to adopt a risk-based approach, implement proper controls, and ensure the integrity and sterility of single-use systems. Compliance with GMP Annex 1 is essential to maintain product quality, meet regulatory requirements, and safeguard patient safety.

Single Use Support is pioneering the biopharmaceutical industry and is at the forefront of advancing fluid and cold chain solutions. The process solutions provider takes the same approach as Annex 1, that automated single-use technologies and closed and protected systems help reduce the risk of contamination. As a trusted partner to multiple biopharmaceutical manufacturers and contract development and manufacturing organizations, Single Use Support is here to offer guidance in achieving maximum product quality, patient safety and navigating GMP Annex 1.

* IRIS Single Use systems are developed product-specifically. All filter capsules available on the market can be installed. Filter types are selected depending on product and quantity. SUS takes the recommended redundancy into account. The use of high-pressure resistant material, such as braided silicone (platinum cured) tubing and the interconnection protection with Oetiker clamps enables leakage-free testing of the filter components prior to filtration at high pressures and filtration after testing. The recommended working pressure is determined during development of the assmenly and the feasibility of testing is ensured. The venting and flushing of the system is taken into account in the configuration. Each assemly is a custom solution for the manufacturers process

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cgmp

cGMP - everything you need to know

The current Good Manufacturing Practice (cGMP) regulations - originated and checked by the FDA - apply to companies operating in pharmaceutical, biotech, or med tech industries. They require the latest standards in terms of production, manufacturing, and packaging and thereby ensure pharmaceutical quality meaning quality in manufacturing processes and patient safety as the ultimate goal. The detailed requirements, importance of cGMP, and how companies can best meet the cGMP regulations, are discussed in the following.

cgmp compliant single-use technology

Meeting cGMP regulations with innovative single-use technologies

Manufacturers in the pharmaceutical industry are required to comply with cGMP (Current Good Manufacturing Practice). End-to-end solutions based on automated single-use technologies are an auspicious choice for drug substance manufacturers, given their many advantages. Their implementation in the manufacturing process promises efficiency, high product quality, cost reduction, and energy savings.

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Microbial cGMP production: complete guide & manufacturer's overview

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David Seifert

Head of Sales Application Engineering – Sterile Consumables

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