New Annex 1 GMP Sterile
The EU GMP Annex 1 on “Manufacture of Sterile Medicinal Products” has finally been revised and published after several years.
This new regulation states that its aim is: “provide general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.”
With that in mind, let’s look at the change that most impacts our day-to-day activity.
The Contamination Control Strategy (CCS): is a planned set of controls to reduce and control the concentration of micro-organisms, endotoxins/pyrogens and particulates.
For these we must define all critical control points and evaluate the effectiveness of all controls for our process and define or re-evaluate the monitoring measures used to manage the risks associated with contamination.
To meet the requirements of the standard and ensure control of particulate and microbiological contamination, we must make use of QRM in establishing our CCS.
What is CCS and how does it impact us?
This Contamination Control Strategy (CCS) is a living document, which we will need to include within our quality assurance system and must be periodically reviewed and evaluated according to the impact of changes made.
How do we develop this document?
Let’s take a closer look at what the steps would be to design our Control Contamination Strategy:
- Selection of a multidisciplinary team: it is necessary to assemble a group that has all the experience and knowledge required to carry out the elaboration and analysis of the document in order for the document to fulfil its objective. It should have the participation of experts in aseptic processing and microbiological contamination, experts in facilities, equipment or technologies associated with the process and experts in quality and regulatory compliance.
- Data collection: sufficient information on the process, product, facilities, personnel, etc. must be collected to efficiently identify possible sources of contamination.
- Select a formal tool: to perform the risk assessment: you can choose from the different risk analysis tools described in the ICH Q9 guideline. The chosen tool must allow an objective evaluation of the information collected. This will simplify the analysis and ensure that your conclusions are based on scientific evidence, not on the subjective opinion of the staff involved in the analysis.
- Hazard identification: for this purpose, it is essential to have carried out a mapping of the process in all its stages and components. The greater the amount of detail collected about the process, the easier it will be to detect possible sources of contamination.
- Identification of existing and needed controls: assess what controls you have already in place to control the contamination, and what additional controls you will need to be implemented, if necessary.
Which stages of my process should I assess?
When carrying out the RA, we should base our assessment on data from the following stages of our process:
- Plant and process design (monitoring system, preventive maintenance, etc.)
- Facilities and equipment (qualification, validation, design, working flows, etc.)
- Personnel (training, hygiene, gowning, quantity, etc.)
- Services (WFI, HVAC, Pure steam, etc.,)
- Raw material controls
- Packaging material and sealing systems
- Approved suppliers
- Process risk assessment.
- Process validation.
- Preventive maintenance
- Cleaning and disinfection
- Monitoring systems
- Prevention: Continuous improvement based on information derived from the above (CAPA).
We must not lose sight of the possible sources of contamination in our assessment of these stages, hence the importance of collecting all the information for each stage. For example:
Let’s see how we could determine the possible sources of contamination of a Production Process using the Ishikawa Diagram.
We will assess whether each of the points selected could be a source of contamination.
The other major change in Annex 1 is in the PQS (Pharmaceutical Quality System), based on ICHQ10. Specifically, this system must ensure the following:
- An effective risk management system is integrated in all areas of the product lifecycle.
- The manufacturer has sufficient knowledge and experience of the products manufactured and the equipment, engineering and manufacturing methods employed that have an impact on the quality of the product.
- A root cause analysis of procedure, process or equipment failures is performed so that the risk to the product is properly understood, and appropriate corrective and preventive actions (CAPA) are implemented.
- Risk management is applied in the development and maintenance of the CCS, to identify, assess, reduce/eliminate (where applicable), and control contamination risks.
- The outcome of risk management shall be periodically reviewed as part of the continuous quality management, during change control and during the periodic product quality review.
- Processes associated with the packaging and transport of sterile products should not compromise the sterile product. Consideration should be given to container integrity, contamination risks, and avoidance of degradation by ensuring that products are stored and maintained in accordance with recorded storage conditions.
- Persons responsible for the quality release of sterile products have appropriate access to manufacturing and quality information and possess adequate knowledge and experience in the manufacture of sterile products and their critical quality attributes. This is to enable such persons to ensure that the sterile products have been manufactured in accordance with the registered specifications and are of the required quality.
- All non-conformities, such as failures in sterility testing, deviations in environmental control, or deviations from established procedures, should be investigated. The investigation should determine the potential impact on process and product quality and whether other processes or batches may be affected. The reason for including or excluding a product or batch from the scope of the investigation must be clearly justified and recorded.