Case Study: Tablet reformulation Technology Transfer / Scale-up
GLOBAL PHARMACEUTICAL COMPANY
To reduce costs and increase market competitiveness, a global pharmaceutical company decided to modify the formulation and some manufacturing process stages for a drug in tablet administration form. Some main objectives were to meet the reference features such as adequate physical stability to humidity and palatability and same bioavailability compared to the actual product.
PTM Consulting applied Quality by Design (QbD) and Quality Risk Management (QRM) principles merged with Design of Experiments (DoE) statistical tool during the development and scale-up stages in order to transfer the process from the laboratory scale, to the pilot scale (designed for clinical batches production), and then to the industrial scale.
The project objectives concerned:
- Product Quality: Maximize the quality of the information during the scale-up stages and minimize failure risks related to the project;
- Regulatory Compliance: Meet Regulatory standards;
- Business Impact: Minimize costs, time and resources involved.
The process was developed following two principles:
|1||Risks related to the target previously identified have been minimized and controlled using the QRM application;|
|2||Process performances (e.g. cost of product quality, defect reduction) have been optimized using different statistical tools, such as the DoE tool.|
Quality Risk Management Application
The boundaries of the analysis, hazards and the risk acceptability criteria were defined.
We used our process mapping methodology to structure process activities, inputs, outputs, controls and mechanisms. From this stage, the following
information was obtained:
- 21 of the 58 total parameters were considered potentially critical and they could impact on process outputs;
- Information traceability related to each single stage and activity which would be fundamental for the following risk analysis execution;
- Requirements identification for machines and equipment from the perspective of the industrial scale-up;
- Check of the control systems implemented for the identified parameters.
We developed a model to maximize the amount of extractable information from process mapping. Then, starting from process mapping, a structured and functional risk analysis was developed.
FMEA technique, used to perform risk analysis, allowed to:
- Identify 30 hazards related to project targets (safety, regulatory and business);
- Identify the risk root causes which involved unacceptable risks;
- Develop corrective actions to convert unacceptable risks to acceptable.
Before starting optimization activities, the process was controlled. Our proprietary software allowed us to maintain traceability both in the process mapping and risk analysis. This approach managed each change such as process, product or controls because it is flexible and easy to maintain.
Design of Experiments Application
We extrapolated information during risk analysis to rationalize the number of critical parameters which were essential to test. We wanted to obtain the required quality product and minimize development times, number of resources involved and the related costs. DoE helped quantify the impact of the variables on outputs (dissolution profile, resilience etc.). Using the design space obtained and identified for each development process scale, all the
project targets and objectives were achieved.
Referring to the laboratory scale a feasible and scalable formulation was obtained and the customer gained the process know-how.
Regarding the pilot scale, the equipment laboratory results were confirmed and the tablet with features comparable to reference was obtained, hence clinical studies passed successfully.
At the industrial scale, the knowledge developed during the development process enabled the customer to optimize the process with a high degree of reproducibility.
Through this approach, the customer achieved all the project targets:
- Product specifications were consistently met when moving from the old to the new process configuration;
- Regulatory impacts were managed using specific risk analysis;
- Business impacts were minimized using a lower number of batches in respect to the number used in a traditional approach. Furthermore, the number of resources involved was not increased. Costs related to product development resulted in less than those which was estimated by the customer.