Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Principle, pharmaceutical quality system

On this page

• Scope
• Principle
• Pharmaceutical quality system (PQS)

Scope

The manufacture of sterile drugs covers a wide range of:

• sterile product types, such as:
  • active substance
  • excipient
  • primary packaging material
  • finished dosage form
• packed sizes, from single unit to multiple units
• processes from highly automated systems to manual processes
• technologies, such as:
  • biotechnology
  • classical small molecule manufacturing systems
  • closed systems

This annex gives general guidance on applying the principles of quality risk management (QRM) in the design and control of facilities, equipment, systems and procedures used to manufacture all sterile drugs. Applying QRM ensures that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.

This annex provides guidance for the manufacture of sterile drugs. However, some of the principles and guidance may be followed when manufacturing other products that are not intended to be sterile, but where it's considered important to control and reduce microbial, particulate and endotoxin/pyrogen contamination. The principles and guidance include contamination control strategy, design of premises, cleanroom classification, qualification, validation, monitoring and gowning of personnel. These other products include, for example, certain liquids, creams, ointments and low bioburden biological intermediates.

If you as a manufacturer choose to apply this guidance to non-sterile drugs, you should clearly document which principles you have followed and how you have demonstrated the compliance with those principles.

Principle

The manufacture of sterile drugs is subject to special requirements in order to minimize the risk of microbial, particulate and endotoxin/pyrogen contamination.

The following key areas should be considered.

• Facility, equipment and process should be appropriately designed, qualified and/or validated and, where applicable, subjected to ongoing verification according to the relevant sections of the Good manufacturing practices guide for drug products (GUI-0001).
  • Consider using appropriate technologies (for example, restricted access barriers systems (RABS), isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) to help:
    • protect the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination such as personnel, materials and surrounding environment
    • detect potential contaminants in the environment and the product quickly
• Personnel should have adequate qualifications, experience, behaviour and training, with specific knowledge of the principles related to contamination control during the manufacturing, packaging and distribution processes.
• Processes and monitoring systems should be designed, commissioned, qualified, monitored and regularly reviewed by personnel with appropriate process, engineering and microbiological knowledge.
• Raw materials and packaging materials should be adequately controlled and tested to ensure that level of bioburden and endotoxin/pyrogen are suitable for use.

Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Alternative approaches should be supported by appropriate rationale, risk assessment and mitigation, and meet the intent of this annex.

QRM priorities should include appropriate design of the facility, equipment and processes, followed by the implementation of well-designed procedures, and finally application of monitoring systems. These monitoring systems demonstrate that the design and procedures have been correctly implemented and continue to perform in line with expectations. Monitoring or testing alone does not give assurance of sterility.

A contamination control strategy (CCS) should be implemented across the facility. A CCS defines critical control points and assesses the effectiveness of all controls (design, procedural, technical and organizational) and monitoring measures used to manage risks to drug quality and safety. The CCS should establish robust assurance of contamination prevention.

The CCS should be actively reviewed and updated, where appropriate. The CCS should drive the continual improvement of manufacturing and control methods. Its effectiveness should form part of the periodic management review. Existing control systems that are in place and appropriately managed may not need to be replaced but should be referenced in the CCS. As well, the associated interactions between systems should be understood.

Contamination control and steps taken to minimize the risk of contamination from microbial, endotoxin/pyrogen and particle sources include a series of interrelated events and measures. These are typically assessed, controlled and monitored individually, but their collective effectiveness should be considered.

The development of the CCS requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (for example, pyrogen, endotoxin) as well as particulate (for example, glass and other visible and sub-visible particles).

Elements to be considered within a CCS should include:

• design of the plant and processes, including associated documentation
• premises and equipment
• personnel
• utilities
• raw material controls, including in-process controls
• product containers and closures
• vendor approval for key component suppliers, sterilization of components and single use systems (SUS), and critical service providers
• management of outsourced activities and availability/transfer of critical information between parties (for example, contract sterilization services)
• process risk management
• process validation
• validation of sterilization processes
• preventative maintenance to bring equipment, utilities and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination
• cleaning and disinfection
• monitoring systems, including an assessment of the feasibility of scientifically sound, alternative methods that optimize the detection of environmental contamination
• prevention mechanisms, such as trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA), and comprehensive investigational tools
• continuous improvement based on all of this information

The CCS should consider all aspects of contamination control. Ongoing and periodic review should take place, with updates to the pharmaceutical quality system as appropriate. Changes to systems in place should be assessed for any impact on the CCS before and after implementation.

The manufacturer should take the necessary steps and precautions to assure the sterility of the products manufactured within its facilities. Sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test.

Pharmaceutical quality system (PQS)

The manufacture of sterile drugs is a complex activity that requires specific controls and measures to ensure the quality of products manufactured.

The manufacturer's pharmaceutical quality system (PQS) should outline the specific requirements of sterile drug manufacturing. The PQS should also ensure that all activities are effectively controlled, to minimize the risk of microbial, particulate and endotoxin/pyrogen contamination in sterile drugs.

For details on the PQS requirements, consult section 4 of:

• Good manufacturing practices guide for drug products (GUI-0001)

The PQS for sterile drug manufacturing should also ensure that:

• an effective risk management system is integrated into all areas of the product lifecycle with the aim to minimize microbial contamination and ensure the quality of sterile drugs manufactured
• the manufacturer has sufficient knowledge and expertise of the products as well as the equipment, engineering and manufacturing methods that have an impact on product quality
• root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly identified and understood, and that suitable CAPA are implemented
• risk management is applied when developing and maintaining the CCS, to identify, assess, reduce/eliminate (where applicable) and control contamination risks
  • risk management should be documented and include the rationale for decisions taken related to risk reduction and acceptance of residual risk
• senior management oversee the state of control throughout the facility and product lifecycle
  • includes a regular review of risk management outcome as part of the ongoing quality management, during change, for a significant emerging problem and during periodic product quality review
• processes for the finishing, storage and transport of sterile drugs do not compromise the products
  • consider container integrity, risks of contamination and avoidance of degradation
• ensure that products are stored and maintained according to authorized storage conditions
• persons responsible for certifying/releasing sterile drugs have appropriate access to manufacturing and quality information, and have adequate knowledge and experience in the manufacture of sterile drugs and the associated critical quality attributes
  • able to determine if sterile drugs have been manufactured according to authorized specifications and approved process and are of the required quality

All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures, should be adequately investigated before a batch is certified/released. This investigation should determine the potential impact on process and product quality and if other processes or batches are potentially impacted.

The manufacturer should justify and record the reason for including or excluding a product or batch from the scope of the investigation.