Blog #5 – November 2022
Welcome to the fifth of my memo’s on Technology Transfer.
This month I am looking at the last section of a typical technology transfer project workflow. Depending on the exact circumstances these steps can be different or be performed in a different order. Usually, these steps are not performed in isolation and often in parallel.
The “GMP batch execution” and “Post Validation” phases of the transfer process which follows on from last month’s blog on project initiation are shown below. Next month I will start to consider specific aspects of Technology Transfer.
GMP run / Pre-PPQ run
This can refer to both non-GMP engineering batches and to GMP-compliant product runs.
Often a company will perform a “test” pre-PPQ run under full GMP conditions prior to the PPQ runs. This can be looked upon as a dress rehearsal. The batch (or batches) will be treated as full commercial runs and tested in exactly the same way as the PPQ batches will be run. Such runs can provide product for stability samples with the aim of shortening the time between PPQ batches and the first stability results, or for initial comparability trials.
Provided that there are no (or acceptable & QA approved) deviations, this pre-PPQ batch can be commercialised, but only once all PPQ batches have been satisfactorily completed and a product licence obtained.
Such a batch can be used for the provision of stability batches.
Details for a pre-PPQ run will probably need to be included within any product licence submission.
PPQ protocol
This isa written protocol that, according to the FDA [Process Validation – General Principles and Practices – Jan 2011] “specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation”.
Recommendations for its content include as a minimum:
- Manufacturing conditions including operating parameters, limits & component / raw material inputs.
- Data collection and evaluation
- Tests and acceptance criteria
- Sample plan
- Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products.
- Status of the validation of analytical methods used in measuring the process, in-process materials, and the product.
- Deviation handling.
As this is a GMP document, it will have to be approved prior to use by the QA department.
PPQ execution
These are the GMP runs used to demonstrate that a drug is produced that is fit for its intended use. In terms of the validation lifecycle concept, this would be “Stage 2 – Process Qualification” as defined in the FDA Process Validation: General Principles and Practices document https://www.fda.gov/files/drugs/published/Process-Validation–General-Principles-and-Practices.pdf These batches are manufactured and the testing evaluated to determine if the process is capable of reproducible commercial manufacturing.
How many PPQ batches should be run is a common question. Industry has typically used three batches during the process performance qualification (PPQ) phase to demonstrate that a process is capable of consistently delivering quality product. The “rule of three” batches is no longer appropriate for process validation activities, the number of batches to manufacture now has to be “risk assessed” based on current knowledge and past history of the product. Even with my somewhat limited knowledge of statistics it is clear that a run of three batches cannot be statistically significant – although there are some statistically based methods available, and this is a topic I am going to cover in later blogs.
PPQ report
This report should document the performance of the PPQ runs and demonstrate that the acceptance criteria have either been met, or document the deviations concerned and the conclusions of any deviation investigations and any corrective actions to be taken.
A summary of all data collected should be included and this should be assessed and analysed as described in the PPQ protocol.
Very specifically, it must state a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a state of control, and if not, what actions will be required to be able to do so.
Deviations / CAPA
A deviation can be defined as any unwanted event that differs from the approved processes, procedures, instructions, specifications, or established standards.
Deviations can occur at any point in the manufacturing or associated operations of a drug product.
For a deviation to have occurred implies that either the process or its implementation has not “gone to plan”. All deviations need to be promptly investigated, a root cause found and corrective actions taken to prevent such deviations occurring again (referred to as Corrective Actions Preventive Actions – CAPA). Usually, these investigations should be conducted in a formal manner in line with ICH Q9. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk.
If the deviations have occurred during the performance of a PPQ batch, this might lead to the need to repeat the PPQ stage of the technology transfer.
Data Acquisition
Performance and analytical data – from both the PPQ batches and the subsequent commercial batches should be collected, preferable in a single location that can be accessed by all, including manufacturing, regulatory, QA, engineering etc. This data will be necessary for licence applications, manufacturing reviews and subsequent statistical analysis.
Once sufficient data has been collected to demonstrate statistically significant control of the process (say 30 batches), the number and frequency of the data points can be reduced.
The data points collected should be double-checked / confirmed by a second checker if possible.