Annex 1: the real Novelty

Recommendation

11/12 February 2025
Heidelberg, Germany

Combination Products
Medicinal Products/Drugs meet Medical Devices

The long-awaited draft of the new Annex 1 to the EU-GMP Guidelines was published in December 2017. Many changes and amendments of course concern sterile production operations. Besides updated requirements taking into account new technologies and giving the Annex a clear structure one big goal was to include more Quality Risk Management (QRM) principles. In the current draft, the term "risk management" can be found 4 times and the term "risk assessment" 25 times in the new Annex 1.

Annex 1 clearly defines the requirements for cleanroom classes, air quality, sterilisation or minimum requalification intervals to address the critical risks of sterile manufacturing. But for almost all other processes, the application of QRM is enforced. This also concerns trend analysis, thorough investigations, root cause determination and corrective and preventive actions (CAPA) which support continuous improvement. QRM can also be used for the design of equipment, processes and the contamination control strategy.

Here is an overview and a comparison to the present Annex 1:

Topic	Where to use QRM principles	QRM principle already covered in the present Annex 1?
General principles: deviations from requirements in Annex 1	Justification of alternative approaches to those specified in Annex 1.
Pharmaceutical Quality System (PQS)	Risk management system integrated into the product life cycle. Identification, assessment, elimination (where applicable) and control of contamination. Prevention, monitoring and detection of any contamination. Establishment of process requirements and acceptance criteria for all elements of a sterile manufacturing process.
Contamination Control Strategy (CCS)	Process risk assessment as element within a documented CCS.
Premises	Evaluation of the need to demonstrate air flow patterns in non-A/B grade areas.
Clean room and clean air device qualification	Sampling locations for later stages of qualification and classification activities, such as performance qualification. For grade D, no "in operation" limits are defined in Annex 1. Companies should establish in operation limits based on a risk assessment and on historical data.	Sampling locations for "in operation" monitoring. Selection of the monitoring system The monitoring of grade C and D areas in operation.
Utilities	Nature and amount of controls.
Water Systems	Any breach of an action limit.
Aseptic preparation	Determination of the necessary background environment grade if isolators are used.
Terminally sterilised products	Decision in which grade operation is done (but with defined minimum requirements).	Decision in which grade operation is done (but with defined minimum requirements).
Filtration	Justification for the use of an alternative approach for the verification of the integrity of a sterilized filter assembly (for small batch sizes).
Blow-Fill-Seal technology	Justification of the machine's design and operational controls and determination of the monitoring of the background environment.
Single use systems	Evaluation of the applicability of the extractable profile data for each component.
Environmental monitoring	Establishment of a robust environmental monitoring program to determine for example locations, frequency of monitoring, number of samples and incubation conditions. Re-evaluation of the program in order to confirm the effectiveness.
Non-viable monitoring	Establishment of monitoring conditions such as frequency, sampling volume or duration, alert and action limits and corrective actions. Definition of limits for airborne particle concentration for Grade D.
Aseptic process simulation (APS)	Development of the process simulation test plan. In the case of a failed process simulation: Evaluation of aseptic production since the last successful process simulation and the justification of respective decision.	The number of containers used for media fills should be sufficient to enable a valid evaluation.
Quality Control	Samples taken for sterility testing (examples given for contamination risks).	Samples taken for sterility testing (some examples are given for contamination risks).
Clean Non Classified (CNC) area	Level, type and frequency of both the cleaning program and the environmental monitoring program.

Overall, risk assessments performed should be "documented and should include the rationale for decisions taken in relation to mitigating risks, discounting of potential risks and residual risk. The risk assessment should be reviewed regularly as part of on-going quality management, during change control and during the periodic product quality review."

So what could this look like in practice? Let's have a look on environmental monitoring for example: As said above, the basis for the environmental monitoring program is a risk assessment. This risk assessment is taking into account facility and equipment layout, the respective processes and other information like for example the typical flora and smoke studies performed. The outcome then is not only limited to the definition of the sampling locations. The information gained can be also used to define incubation processes, the frequency of future monitoring activities, alert levels and trending programs.