The proposed Annex 1 to the EU Good Manufacturing Practice (GMP) represents a move towards establishing a recognised global standard in maintaining clean environments: it will be used by the Pharmaceutical Inspection Co-operation Scheme (PIC/S), the World Health Organisation (WHO) and the EU GMP.
Employing the highest standards used in ensuring patient safety to form the basis for the new stringent guidelines, it is clear that continuous EM within aseptic facilities will become increasingly important. Why? It is simply the best way to reduce risk.
The sectors most affected by the draft revision are the pharmaceutical industry and associated healthcare trades, but also the specialist food industry. In these particular fields, the requirements for sterile manufacture are extremely rigorous; for the obvious reason that these industries carry the most potential risk to the public should contamination occur.
The best line of defence
While a continuous monitoring programme is not a legal requirement in these industries, the latest revision of Annex 1 underlines the importance of risk reduction; continuous monitoring is the best way to achieve this.
Contamination can carry serious consequences for both the business and the public, as recent high-profile cases confirm. Even if a contamination is contained, it can still cause damage to the manufacturer in lost revenue and dented reputation. The more stringent standards on the horizon call for a stricter environmental monitoring protocol. This means rethinking your best line of defence in advance.
An EM programme will typically include monitoring of viable and non-viable particulates, and aseptic process simulations. It is now strongly suggested that airflow patterns and complex gas flow paths must also be considered
Currently, the degree to which you monitor your facility environment, or the frequency with which you monitor for microbiological particulates, is up to you with guidance regarding the areas grade A through to D. The alert and action levels implemented in a facility are based on the products and the intended use of the aseptic facility, making the spectrum for action very broad. However, it has already been robustly advised that a well-developed EM programme should be employed to ensure safety standards are met.
The draft revision gives far more insight into the best EM practice to apply across most, if not all, industries. An EM programme will typically include monitoring of viable and non-viable particulates, and aseptic process simulations. It is now strongly suggested that airflow patterns and complex gas flow paths must also be considered. Additional EM must be implemented when maintenance activities take place in the facility, with risk assessments re-evaluated to ensure absolutely nothing slips through the net.
The benefits of implementing a continuous EM programme will become more obvious as time goes by. You will immediately see more accurate readings across the facility, enabling any rising risk to be managed very quickly.
Longer-term, this ongoing monitoring should significantly reduce the risk of contamination, supporting your bottom-line growth targets and further strengthening business reputation. Essentially, the processes employed must showcase long-standing preventative results that indicate that a sterile environment is kept in a state of minimised risk.
The continuous EM process you implement in your operation must tackle both viable and non-viable microbiological entities within your aseptic environment.
To support your process, you will need to create detailed reports substantiating the type of EM to be included. Crucially, you must then actively use this data to make improvements, wherever possible, to further reduce any risk. It is important to track the adjustments made to your current system and to track the frequency of your monitoring.
Preparing for Annex 1 compliance
Every area of your business should be assessed in terms of environmental monitoring as the first stage in planning your new EM programme. Details of each activity should be taken, including all equipment and processes involved and current protocols for cleanroom staff in all aspects of production. For this, we would recommend breaking preparation down into four steps.
1. EM audit
Regardless of how your business operates and in which sector it falls, there are some general best practice notes that all organisations relying on aseptic processes should observe. Start with a full EM audit: What methods are you currently using? Why? What sort of data are you gathering? How are you using that data to inform your compliance protocol?
For total compliance under the new revision, your entire manufacturing facility, including equipment and process design, must qualify against, be optimised for, and validated according to Annex 11 and Annex 15 of EU GMP.
Technologies that prevent risk and contamination must be implemented so control measures are in place for the protection of the product. These measures must safeguard against potential risks of contamination from external sources of particulate and microbial contamination, such as outsourced materials, personnel and your surrounding environment.
2. Understand the utilities chapter
The draft EU GMP Annex 1 includes a chapter on ‘utilities’, which must be closely followed. It outlines the required equipment and other materials that will come into contact with your product that may directly or indirectly influence it. It looks into water systems, the steam used for sterilisation activities, compressed gas, vacuum and cooling systems. The revision makes a specific call for a better and more holistic contamination control strategy. It is expected that you document this strategy formally, so every effort made to minimise the risk of contamination is reflected and can be presented if necessary.
3. Analyse your current EM in-depth
Make a detailed report of all monitoring of the following factors, including method, frequency and the last time any changes were made:
- Non-viable particulates
- Airborne viable
- Pressure differentials
- Temperature and humidity
- Direction of airflow
- Surface microbial contaminants on personnel and equipment, work tables, floors and walls.
Data collected from this programme should be used to provide insight into the aseptic condition of critical areas. Check all documentation covering:
- The control of your manufacturing facility and operations
- Short-term and long-term evaluation processes
- How well your detection system works to alert you if microbial and particulate matter gain access into your operation
- Training and regular behaviour of your operators and employees
- Your standard operating procedures (SOP’s)
- Any differential pressure issues in your facility and the indicators of your HVAC and HEPA systems
- The organisms recovered in your facility
This insight must be used when evaluating possible changes in control mechanisms in your facility.
4. Active and passive EM options
An EM programme should be geared around your particular business needs, size and sector. For best results, you should create a programme with various active and passive elements. Consider all areas of your operations and how you will monitor: surfaces (contact plates and swabs); air (passive settle plates and active air samplers); operators gloves and garments (finger dabs, contact plates); and compressed gases.
You should also understand the full specifications and implications of any materials or equipment that could compromise the microbiological quality of your product.
Finally, fully document all disinfection and sanitisation processes implemented throughout your operation.
Tools for an effective continuous EM
Once you have established the vulnerabilities in your current programme, you can start to look at the best options for your business in terms of new equipment or protocols. The best continuous EM scheme combines environmental monitoring techniques and equipment. It is highly recommended that settle plates, air samplers and validated protocols are all used to minimise risk and see the maximum benefits.
If you are already using a combination of methods, but still suffering higher risk rates than you would like, it is worth checking how you could upgrade your air samplers or consider stock control of your settle plates. It might be that your active sampling equipment simply needs a service or that your protocols need to be adjusted. The point is, achieving better results does not necessarily mean a large investment in completely new equipment; it may be a case of some fine-tuning.
A final word to the wise
Most importantly in light of the new draft Annex 1, regulated businesses should not do nothing. Once the draft is approved, if you have not already ensured your environmental monitoring is up to scratch, you will be running to catch up. Particularly, when regular reviews of your new EM programme will be key to ensuring your processes are providing the information needed to direct and motivate appropriate measures to counter any risk. And, regulations are likely to only get tighter.
This article will appear in the November issue of Cleanroom Technology.
