Biopharmaceutical plant commissioning, that period between start-up and validation, is too often treated as an isolated part of the plants project life cycle, ignoring the impact that commissioning decisions can have on subsequent project phases.
A Commissioning Master Plan (CMP) is a practical way to define commissioning goals and align them with overall project goals. The alignment and integration of the plants commissioning teams objectives with those of the plant project team can improve quality and save both time and money.
During commissioning, the capabilities of the systems including process, utility, HVAC and electrical are tested to assure proper functioning and adherence to design criteria. Any discrepancies are identified and the necessary remedial actions are taken. During this phase, the manufacturing team can be trained in the operation of the plant systems. So, at the end of commissioning, direct-impact systems are turned over to qualification, and indirect- and no-impact systems are turned over to system owners.
The validation team will confirm that the equipment and systems perform in accordance with the Functional Requirements Specifications (FRS) and Detailed Design Specifications (DDS), reliably and with repeatability. In a successfully commissioned facility, it is expected that a minimum number of deviations will arise during the Installation and Operational Qualification (IQ/OQ) and Performance Qualification (PQ) execution phases of validation. By minimizing the number of validation-phase deviations, commissioning can help to reduce the overall validation duration, and consequently the overall project timeline and cost.
Trends in Commissioning Biopharmaceutical Plants
The process of commissioning biopharmaceutical plants is evolving in response to excessive deviations found during the IQ/OQ/PQ execution phases of validation. These deviations cause the repetition of some validation activities, resulting in unanticipated project schedule delays and costs. Commissioning has evolved to help reduce the time required for commissioning and validation by discovering and correcting discrepancies before the validation phase starts. Additionally, there is a trend towards integrating commissioning and validation to minimize the duplication of activities.
Even as late as the mid-1990s, commissioning was not well-defined. Some viewed it merely as mechanical startup after the plant utilities were connected or as repeating Factory Acceptance Tests (FAT) at the site and calling them Site Acceptance Tests (SAT). Still others viewed it as the phase that occurred between start-up and validation. It was treated much less formally, without the aid of a CMP to define the purpose, scope and expectations of commissioning. Too often, inadequate effort was put into defining the objectives of the commissioning phase and insufficient time was allowed for verifying how well the design requirements were met. These factors led to excessive deviations during the qualification phases of validation.
Planning for Commissioning
Having a formalized and documented commissioning strategy ensures that commissioning goals are met. The first step is the writing of the Commissioning Master Plan (CMP) by a designated commissioning leader. The CMP is written based on the agreements formed between different functional groups, such as Validation, Manufacturing (Owner), Engineering, Quality, Commissioning and Construction. The inclusion of the manufacturing team helps ensure that the plant will meet manufacturings needs. The validation team helps make certain that the turnedover systems are truly ready for validation, and that they meet agreed-upon acceptance criteria backed by system turnover documentation packages.
The CMP must define the boundaries of systems that will be commissioned, and must categorize each of the systems as having a direct, an indirect, or no impact; it must also specify the roles and responsibilities of project personnel and how to coordinate commissioning and related activities for a project.
The CMP needs to detail the steps of the commissioning process, such as:
- Commissioning Test Plan (CTP) development;
- System checkout prior to commissioning;
- CTP execution;
- Review of the executed CTP;
- Turnover of the executed CTP to Validation/Manufacturing.
Typically, only the CTPs for the direct-impact systems require QA/Validation before and after post-execution approval.Therefore, the direct-impact system CTPs often have the look of draft IQ/OQ protocols, having been modeled after the validation documents, which ensures a minimum number of deviations during the IQ/OQ and PQ execution phases of validation.
Determining the right makeup of the commissioning team is important to reduce post-validation changes and assure that input is obtained in a timely manner so any required changes have the least impact on schedule and cost. The commissioning engineers need to be familiar with the design intent, process requirements and validation expectations. Having process engineers knowledgeable in the plant design intent and experienced in troubleshooting will help resolve errors correctly and in a timely fashion. The manufacturing personnel bring their invaluable operating experience and are well qualified to determine the ease of operability and safety of the system design.
At the same time, the commissioning team must evaluate the suggestions made by plant operators to ensure that they are not based on personal preferences. The automation engineers are required to perform automation verifications of automated systems. For an automated system, three-quarters of the commissioning time is spent in automation verification or automation documentation upkeep, therefore it is important that automation engineers stay on schedule. Using experienced automation engineers who are wellversed in process control-loop tuning will save considerable time.
Simulating process conditions without using the product is another plant commissioning challenge. Sometimes process changes are required even after the systems have been validated. Some of these changes are improvements, or are due to recent process changes from process development groups. These types of changes are unavoidable.
However, some changes are due to deficiencies in process simulation without product. Commissioning teams should keep these deficiencies in mind. For instance, using water or even buffers has its limitations and may deceive the instrumentation used to test the control-loop response. As a result, the final code may not provide the range of operating parameters that would be seen with actual product. The commissioning team should decide ahead of time which buffers will be used to simulate product for example, it should verify UV control and conductivity adjustment control and for which operations.
The good news is that errors found during commissioning will be less costly to fix than validation errors. In part, this is due to less stringent documentation requirements that are followed during commissioning. It may also be easier for the plant commissioners to resolve the discrepancies than the validators because of the commissioners familiarity with the equipment or system and the plant design intent. Finally, it is common for trade contractors, such as piping installers and electricians, to still be on site during commissioning, which reduces the cost of making corrections to the installed systems.
Commissioning may also be viewed as the ideal time to optimize operating parameters to decrease processing time and reduce utility usage. Although workable operating parameters are determined during the design phase and confirmed during commissioning, the processes may have changed or process steps may have been optimized since the design phase.
Any changes that have occurred since the end of the design phase need to be considered and updated in the FRS and DDS before validation. Validation confirms that a system operates with repeatability and reliability and according to the design documents. The validation period is not the time to optimize operating parameters, except for some limited time variables such as lengthening the Clean-In-Place (CIP) rinse period during Performance Qualification (PQ). During commissioning, CIP flow rates corresponding to varying flow paths, recirculation volume in the tank, or even valve sequencing can be readily optimized. Thus, it is recommended that commissioning periods be used for optimizing operational parameters.
Determining the acceptance criteria for the commissioned systems up front will facilitate turnover of the executed CTPs. It is important to determine what acceptance criteria the validation team and the manufacturing team will use. For example, with regard to a Steam-In- Place (SIP) OQ, the team might want to ascertain the acceptable heat-up and dwell profile from the validation team. Often, its not enough that the temperature stays above 121.5° C during the SIP dwell period at the clean-steam pressure setting dictated by the validation team. Validation may require that after the heat-up, the dwell temperatures need to remain steady.
Another example is for a CIP OQ. The team should ascertain the maximum acceptable sprayball rinse periods (or the maximum number of one-minute bursts) from the manufacturing team. The manufacturing team may require that the rinse periods not exceed specified times to prevent excessive water usage or delays in plant operations.
A third important example is the drainability of process vessels. It is not enough to say that ISPE Bioprocessing Equipment Guidelines will be followed. How much time will be given to drain? Will beading of water droplets be allowed? How about a thin sheath of liquid adhering to the metal surfaces? Acceptance criteria for each operation or recipe must be clearly communicated between the commissioning team and the validation team.
Ready?
So, when should a system be considered fully commissioned, and thus ready for validation? Both commissioning and validation teams must agree on the number of times a system needs to run through all of its recipes successfully from start to finish and what types of errors would require recipes to be re-run in their entirety. Resolution of these issues prevents the under- or over-commissioning of a system. Both teams should also discuss circumstances under which systems should be returned to the commissioning team for further commissioning work.
Without sacrificing quality, the time required for commissioning and validation can be reduced. This can be accomplished by leveraging certain activities performed only during commissioning and not repeating them during validation, avoiding unnecessary duplication of tasks. The leveraged activities would be commissioned under stricter guidelines with more reviews and controls in place.
The following are examples of testing that could be performed only during commissioning and then leveraged for validation:
Mechanical Installation & Operation Verification
- P&ID walkdown
- Utilities verification
- Specification & data sheets
- Instrument identification & calibration
- Pressure vessel documentation
- Engineering turnover package
- Agitator rotation and operation
- Sprayball coverage testing
- Tank drainage testing
Automation Installation & Operation Verification
- Electrical drawings
- Control system hardware installation
- Control system hardware configuration
- Software installation
- Alarm and interlock testing
- I/O loop testing
Rewards
Giving more time to run and aggressively challenge systems during commissioning facilitates a shorter and more predictable validation period. Well-commissioned systems allow Installation and Operation Qualifications to be confirmatory activities, not long and drawn-out troubleshooting exercises. With this approach, it is common to find hundreds of errors for an automated process system during commissioning. However, during IQ/OQ, that same system should not incur more than a small fraction of the errors uncovered during commissioning.
A well-commissioned plant is ready to transition to an easy validation effort, and will allow the overall project goal to be achieved on time. With careful planning, the overall commissioning/ validation duration can be reduced while maintaining quality.
About the Author
Ms. Heinbockel has 14 years of biopharmaceutical experience in design and start-up of biopharmaceutical plants. She has been leading Alfa Laval Biokinetics process design teams on projects for the last six years, and has extensive experience in downstream processing, clean utilities and CIP systems. She has also spent five years in field commissioning and performing operational and performance qualification of the systems that she designed.
