The Relationship between Commissioning, Classification and Qualification in GMP Cleanrooms

When setting up a new cleanroom for pharmaceutical/GMP production, three terms are often confused: commissioning, classification and qualification. In practice, these steps are closely interlinked. However, they have different functions from a regulatory and technical perspective.

Commissioning initially demonstrates that the system is technically operational. Classification verifies the air cleanliness class based on defined particle measurements. Finally, qualification - particularly PQ - assesses whether the cleanroom and HVAC system are suitable for the GMP manufacturing process under the intended operating conditions.

1. Commissioning: technical functionality prior to GMP certification

Commissioning is primarily a technical step. It typically involves the testing, adjustment and documentation of the HVAC system, such as filters, airflows, pressure cascades, sensors, building automation, alarms, doors and airlocks. The aim is to bring the systems into a stable operating state to the extent that they can be qualified.

2. Classification: standardised verification of air cleanliness

Cleanroom classification is not a complete GMP certification, but rather proof of a specific level of air purity based on particle concentration. ISO 14644-1 defines the classification of air purity in cleanrooms and cleanroom areas based on airborne particles, whereby in the GMP context only particle sizes >=0.5 µm and >=5 µm are considered. The standard expressly makes no mention of the biological, chemical or other nature of the measured particles.

According to Annex 1, for the initial classification, particles must be measured both in the 'at rest' state and under simulated operating conditions (for repeat classifications, 'in operation'). For the minimum number and positioning of measurement points, Annex 1 refers to ISO 14644-1. For aseptic areas and their background, it is required that risk-based measurements be taken at all critical points. This may result in additional measurement points. Naturally, the individual selection must be justified in the documentation.

3. Qualification: from installation through function to process

EU GMP Annex 15 describes qualification as a lifecycle approach. Qualification activities should be considered from the URS through design, installation, operation and performance to the end of use. The User Requirement Specification (URS) serves as a reference point throughout the entire validation lifecycle; the DQ demonstrates that the design is GMP-compliant and meets the URS requirements.

4. What measurements does Annex 1 require for cleanrooms?

Annex 1 lists the following tests in particular for the qualification of cleanrooms and cleanroom equipment - insofar as relevant to design and operation: Classification in accordance with ISO 14644-1, leakage and integrity testing of installed filter systems, air volume and air velocity measurements, pressure differential testing, air flow direction and visualisation of flow conditions, microbiological air and surface contamination, temperature, relative humidity, recovery testing and, where applicable, containment leakage testing.

This makes it clear: classification is only one part of qualification. It primarily considers particulate air cleanliness. Qualification additionally assesses the technical and microbiological requirements necessary to ensure that the room is suitable for the intended GMP manufacturing process. In particular, all critical parameters and critical locations must be identified and qualified.

ISO 14644-3 provides the technical test methods for this. The standard describes test methods to support classification and to evaluate further controlled conditions in cleanrooms; in doing so, it distinguishes between different airflow concepts and operating conditions.

5. Same measurement - different purpose

Many measurements are carried out multiple times. This often raises the question in projects as to whether the same measurement can be used for commissioning, classification and qualification. The answer is: methodologically, often yes; but from a regulatory perspective, only if the conditions, acceptance criteria, documentation and data integrity are appropriate.

6. Why PQ is more than a repetition of classification

PQ answers a different question to classification. Classification asks: What air cleanliness class does the room achieve under defined conditions? PQ asks: Does the cleanroom function as part of the specific manufacturing process?

Therefore, PQ must reflect the intended use case. For a sterile or aseptic process, this typically means: maximum staffing levels, installed and operational production equipment, real or simulated material flows, routine interventions, door and airlock operation, and various operating modes of the HVAC system. Annex 1 defines the 'in operation' state as a fully installed system with a fully functional HVAC system, equipment installed and running in the defined operating mode, and a maximum number of personnel carrying out or simulating routine work.

This is precisely where the difference lies compared to a purely technical acceptance test: a room may be technically well-calibrated and classified as being in a static state, but may reveal weaknesses under real-world use involving personnel, material transport, machine movement or interventions. The PQ is intended to highlight such weaknesses before the room is approved for GMP production.