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Performance qualification

Published
Topics: Aseptic services

Performance qualification is the final step in the qualification process and ensures the pharmacy aseptic clean room suite functions correctly in routine use.

This article forms part of a series
  1. Designing and building pharmacy aseptic clean rooms
    1. Planning a new build project
    2. Assembling a clean room design and build team
    3. Writing a business case for a clean room build
    4. Writing the User Requirement Specification
    5. Understanding clean room qualification
    6. Design qualification
    7. Installation qualification
    8. Operational qualification
    9. Performance qualification

Contents

  1. Understanding performance qualification
    1. Phase 1
    2. Phase 2
    3. Phase 3
  3. Defining the PQ protocol
  4. Pre-requisites before starting PQ
    1. PQ team
    2. Operational qualification (OQ)
    3. Standard operating procedures (SOPs)
  6. Undertaking PQ 1
    1. Establishing the bioburden
    2. Demonstrating cleaning efficacy
    3. Demonstrating facility performance
    4. Validating transfer decontamination
    5. Validating operator activities
    6. Validating aseptic processes
  8. Closing out PQ 1
  9. Undertaking PQ2
  10. Closing out PQ2
  11. Progress to PQ3

Understanding performance qualification

Performance qualification (PQ) provides assurance that facility and process design consistently meet the objectives of the URS and can deliver products of suitable quality when working in normal operating parameters.

Data from PQ will inform ongoing monitoring programmes and will support understanding of the level of requalification needed in the event of future facility failure or planned shutdown.

PQ can be split into 3 phases.

Phase 1

This is the initial PQ, carried out before medicine preparation commences in the new facility. This phase includes process, cleaning, operator and transfer validations, and should seek to assess worst case conditions. This may include areas with poor airflow, high traffic during normal use, difficult to clean areas and critical points of the workflow.

Phase 2

This follows Phase 1 and is carried out during the early stages of use of the new facility to prepare medicines. It continues until sufficient data is gathered to provide meaningful understanding of the performance of the facility and equipment when in use. The results obtained from this phase inform the routine physical and microbiological monitoring programme and parameters.

This phase should continue long enough to assess facility and process effectiveness under worst-case conditions, such as the maximum interval between full cleans.

Phase 3

Phase 3 is the routine monitoring and requalification of the facility and equipment.

Defining the PQ protocol

Protocols may be developed by appropriate expert contractors, but the user is responsible for PQ and must approve all PQ documentation.

The PQ protocol sets out the objectives, scope, testing requirements and acceptance criteria for the process, and typically includes:

  • prerequisites
  • programme of cleaning, testing and validations
  • test methods (physical and microbiological)
  • sampling plans
  • deviations
  • acceptance criteria

Pre-requisites before starting PQ

In addition to the PQ protocol, the following pre-requisites must be met before commencing.

PQ team

Personnel involved in the execution of the PQ must be named in the PQ protocol. The team may include:

  • Production Manager
  • Head of QA
  • Accountable Person
  • Chief Pharmacist
  • RQA or third party GMP advisor, validation or testing personnel
  • Production team

Refer to the article about assembling a clean room design and build team (SPS page) for further guidance.

It is likely that the sampling, testing and cleaning will be undertaken by the unit’s operational team alongside running the existing service. This will put considerable strain on staffing resources, so capacity needs careful consideration and management to ensure realistic scheduling and timescales.

Operational qualification (OQ)

Operational qualification (OQ) must be completed and approved before PQ begins. For further details refer to the article about operational qualification (SPS page).

Standard operating procedures (SOPs)

All relevant standard operating procedures (SOPs) should be issued for use, and all staff trained and familiar with the new processes. This will include all preparation, cleaning and decontamination, equipment use, and monitoring processes.

Initial versions of SOPs should be used during PQ. These may require further refinement in response to findings identified during PQ.

Undertaking PQ 1

PQ is the responsibility of the user but can be supported by appropriate expert validation contractors. Even if some aspects are outsourced, it is essential for the user to gain full understanding of the unit’s performance, and for senior personnel to review results contemporaneously.

All qualification activities should be documented contemporaneously including the outcome (for example, pass, pass with comment, or fail) and related deviations.

All test reports, raw data, test instrument calibration certification, deviations and changes should be appended.

PQ1 activities are performed before any medicines are prepared in the facility. This includes, but is not limited to:

Establishing the bioburden

Bioburden is the baseline level of microbiological cleanliness. Surface sampling at defined locations establishes the baseline bioburden. This should be done with the facility at its ‘dirtiest’, usually immediately after the end of the OQ testing and before any cleaning has taken place.

If bioburden sampling is done too late in the process, for example when a deep clean has been undertaken, a representative sample of microorganisms may not be recovered.

Demonstrating cleaning efficacy

Surface samples are usually taken after each stage of the clean-down process. A progressive reduction in bioburden demonstrates the effectiveness of each stage and each cleaning agent.

When performing post-clean sampling, precautions should be taken to avoid re-contamination of the cleaned surfaces, for example:

  • fully gowning to the required level for the rooms of greatest control
  • sample from the lowest classification of rooms through to the highest, i.e. support rooms to isolator rooms
  • minimise the number of team members involved in each sampling session
  • undertake sampling as a single activity and minimise time spent in the rooms on other tasks

Access to the facility should be restricted until the results of the testing are reviewed and accepted, and access is authorised.

Demonstrating facility performance

Once authorised, sampling begins to demonstrate that the facility performs as intended.

Sampling is performed initially with the facility ‘at rest’ with no additional personnel present, then ‘in operation’, with the maximum occupation during process simulation activities.

Any out-of-specification results should be reported immediately and handled as a deviation.

At rest

During this stage sampling and recording will include:

  • active and passive (settle plates) air sampling
  • differential pressure readings
  • isolator reading
  • temperature readings

When enough data is gathered to provide assurance that the facility meets the acceptance criteria testing, qualification activities can progress to ‘in operation’.

In operation

The ‘at rest’ sampling and recording will continue and will also include:

  • contact plates before and after cleaning
  • particle counting including recovery rate testing

Validating transfer decontamination

Validation confirms that the procedures for decontamination are effective and reproducible.

The development of a spray and wipe transfer validation process is needed.

For gas sanitisation with vaporised hydrogen peroxide, a programme of cycle development and validation is needed. Seek specialist advice for further guidance.

Validating operator activities

Operator validation provides assurance that personnel can perform aseptic tasks within the cleanroom without compromising environmental control or contaminating products. This may include broth transfer, handwashing, and gowning.

Validation uses a combination of direct observation and microbiological monitoring.

Validating aseptic processes

Process validation is undertaken using aseptic process simulation (APS) with microbiological media. It provides assurance that the processes, when performed to the defined procedures, can consistently produce products that are free from microbial contamination.

APS tests should be based on the processes with the most aseptic manipulations or the most complex techniques. It may not be possible to mimic all processes with a single simulation and therefore a matrix approach is acceptable. The rationale for this approach must be documented.

APS should be based on the facility design, clean air devices, defined process flow, intended product range, and the contamination control strategy.

Particle counting may be performed during APS to assess the particle generation intrinsic to the aseptic processes, for example when opening component wrappers and piercing vial bungs, without handling real product.

Closing out PQ 1

Once PQ1 is complete all reports and results must be reviewed and approved by the user.

Personnel who may approve PQ1 must be defined in the VMP.

Closing out PQ1 will include review of:

  • test results
  • test equipment calibration certificates
  • changes, deviations and corrective actions

The PQ1 file containing the approved documents should be retained in the unit for reference during all subsequent validation stages and throughout the operational life of the clean room suite.

All deviations should be resolved before final approval and proceeding to PQ2. It may be possible to give interim approval and proceed when outstanding deviations are low risk. This should be risk assessed and the criteria defined as part of the VMP.

Undertaking PQ2

PQ2 involves repeating sampling that was undertaken at PQ1 to confirm that the facility continues to perform as expected while medicines are prepared. The frequency of sampling and number of sampling locations may be greater than during routine monitoring to help identify the worst-case sampling locations that will continue in use through PQ3.

Closing out PQ2

Once PQ2 is complete all reports and results must be reviewed and approved by the user.

Personnel who may approve PQ2 must be defined in the VMP.

Closing out PQ2 will include review of:

  • test results
  • test equipment calibration certificates
  • changes, deviations and corrective actions

The PQ2 file containing all approved documents should be retained in the unit for reference during all subsequent validation stages and throughout the operational life of the clean room suite.

All deviations should be resolved before final approval and proceeding to PQ3. It may be possible to give interim approval and proceed when outstanding deviations are low risk. This should be risk assessed and the criteria defined as part of the VMP.

Progress to PQ3

Once PQ1 and 2 are complete, the final phase of PQ begins. This is the routine monitoring and validation that will continue for the life of the unit or until a significant change that requires requalification.