New Product Introduction (NPI) phase
During the NPI phase, the process is operated at the CMO prior to the formal validation campaign. Some CMOs have developed
scaled-down laboratory and pilot models that allow them to gain familiarity with the process without tying up valuable commercial
manufacturing facilities, which would add to project duration and cost to the sponsor. This allows the consistency and robustness
of the process to be evaluated by the CMO at an early stage in the transfer. Process changes for facility fit purposes may
be evaluated during this phase. Additionally, the availability of qualified scale-down models is vital for effective troubleshooting
in manufacturing. Typically, if the sponsor company is leading process characterization, it would be responsible for evaluating
and performing supplemental process characterization studies to confirm the impact of any required process changes to the
product and process. However, this should be discussed, and the tech-transfer team should distribute workload between sending
and receiving teams to best use technical expertise and effectively maintain project timelines. The laboratory and pilot
runs allow an opportunity for testing the raw materials to be used in the process. Risk assessments based on historical knowledge
may help classify raw materials as crucial, where sponsor and CMO must agree on the supplier, and non-crucial where the CMO
may use an alternative vendor with similar specifications. However, it is important to stress that this should be tested at
laboratory and pilot scales to confirm that the final raw materials selected do not have any impact on the process and product
quality. Experiences from the laboratory- and pilot-scale studies as well as supplemental process characterization help to
drive the scope for the next stage of the NPI at the commercial scale.
At the commercial manufacturing scale, automation-, wet-testing, and engineering runs should be executed prior to the validation
campaign. These are performed under development protocols so there is clarity on the goals and success criteria as well as
the methodology to be used. At this stage of the program a balance needs to be reached between desired engineering run rate
that provides time for data analysis and adjustment between runs, available facility time, and campaign cost. The engineering
runs (sometimes referred to as shake-down or test runs) are product runs performed as a means to ensure that the process performs
as expected before commencing the process validation campaign. Key considerations for this stage are as follows:
- Should the engineering runs be done to GMP or non-GMP standards? The latter offers greater flexibility in making modifications
to the process under the guidance of technical experts without being constrained by the GMP requirements for change control
and batch-record approval. However, the material from this non-GMP engineering batch cannot be released for clinical or commercial
use. Another consideration is with respect to use of raw materials, such as chromatography resins from the engineering to
validation campaign. The high cost of the resin makes reuse attractive between campaigns. The requirements for allowing resin
reuse should be outlined in a protocol. Following execution, the data should be summarized in a report confirming that the
resin is fit for use in validation runs.
- The number and stagger between runs to allow evaluation of process data and any process or equipment modifications to be made.
Conducting runs back to back leaves little time to identify a problem, investigate its root cause, and develop potential corrective
action, so that the problem may affect multiple runs. This requires careful balancing of technical risks and the cost of
running at a slower pace to allow for such process trouble-shooting.
- Availability of scale-down models to run the process concurrently and aid with potential trouble-shooting work.
- Ensuring that contingency plans are developed for high or medium risk issues identified during the information transfer and
pilot-scale studies. This allows one to react quickly to potential technical problems that may arise during the execution
of the engineering runs. Contingency plans should consider additional runs to confirm that corrective actions remediate any
- On-site presence of technical experts from the sponsor company to ensure that the process is operated as originally designed
and to aid in process troubleshooting. This also helps to ensure fast communication back to the sponsor company so there is
transparency in operations.
The engineering campaign tends to be the most intensive phase of the TT. A readiness assessment is a key output from the engineering
campaign to ensure that the process is operating as expected and that all issues identified during the campaign have been
adequately addressed such that the team is ready to move forward to perform process validation.
The culmination of the TT work is the execution of the process validation campaign. There may be differences in validation
strategy between the sponsor and CMO, so early initiation of discussions between validation experts at both companies is recommended.
The output of these discussions is documented in the Process Validation Master Plan (PVMP), and process validation study protocols.
In addition to these, it is recommended that a process validation support plan is defined. The support plan details roles
and responsibilities during the validation campaign, ensures that data are actively being monitored and verified so that issues
can be identified and resolved rapidly without affecting the overall validation campaign. Both parties should agree at the
beginning about how frequently they will meet to review performance parameter (process outputs) and operating parameter (process
inputs) data. On-site presence from the sponsor company especially for critical steps in the process is recommended during
the validation campaign. This also facilitates discussion to identify any parameters excursions to understand impact on the
integrity of the validation study and if any additional runs are required.