Technology Transfer Plays an Increasingly Important Role in Pharmaceutical Quality Systems

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Technology Transfer Plays an Increasingly Important Role in Pharmaceutical Quality Systems A robust and secure manufactured product is the desired end result for pharmaceutical companies.

1 Technology Transfer Plays an Increasingly Important Role in Pharmaceutical Quality Systems A robust and secure manufactured product is the desired end result for pharmaceutical companies. Scale-up and technology transfers have gained increasing importance and relevance in the process of manufacturing such pharmaceutical goods. This paper explores the science of manufacturing products and how quality by design, technology transfers, and process validation play a factor in creating the desired robust product for commercialization. Technology Transfer in Pharmaceutical Quality Systems

Table of Contents The Importance of Processes in Manufacturing and Product Robustness 3 Technology Transfer 3 Quality by Design 3 Steps for Successful

2 Table of Contents The Importance of Processes in Manufacturing and Product Robustness 3 Technology Transfer 3 Quality by Design 3 Steps for Successful Technology Transfer 5 The 3 Models of Technology Transfer Process 6 Process Validation Then and Now 7 Advantages of Technology Transfers 7 Conclusion 8 2

The Importance of Processes in Manufacturing and Product Robustness Successful pharmaceutical products are created when effective processes in manufacturing are in place and a high-level of product

3 The Importance of Processes in Manufacturing and Product Robustness Successful pharmaceutical products are created when effective processes in manufacturing are in place and a high-level of product robustness exists. Manufacturing is the science of combining the knowledge of specific products and processes, the application of critical-to-quality product attributes and process parameters, process control technologies, and quality systems infrastructure together. Robustness is the ability of a process to maintain the acceptable level of quality and performance while simultaneously maintaining a tolerance for input variability. Technology transfer plays a huge part in increasing the effectiveness of manufacturing processes and commercialization of robust compounds. Technology Transfer Technology transfer is a critical step in the first stage of the development life cycle of pharmaceutical drugs. The first step is gathering all prior knowledge, data, and expertise as a basis for developing a manufacturing control strategy. The second step is to transfer the knowledge of production, analytics, and processes gathered from development to the manufacturing sites. Fluctuations and parameters are controlled for in the contained environment of commercial production. The transfer helps verify controls set during development and is adjusted accordingly when needed. Technology transfer is an approach that factors in qualification and on-going continuous improvement. Quality by Design A quality by design (QBD) approach helps ensure that a desired technology is successfully transferable. To properly engage a QBD approach, one should form a diversely skilled and collaborative team for development. Inputs and outputs that have the potential to impact quality should be reviewed. Information on sources of variability should be studied by undertaking uni and/or multivariant experiments. Knowing where and when quality could be affected and understanding measurements of capability such as repeatability and precision is a crucial characteristic of quality by design. Important parameters such as the design space should be defined by identifying a set of input ranges known as critical process parameters (CPPs). This will generate increased probability of critical quality attributes (CQAs), meeting the expected appropriate standards. The ICH Q10 highlights the importance of pharmaceutical quality systems as a common method for tech transfer. From ICH Q10 The change management system should provide management and documentation of adjustments made to the process during technology transfer activities. Aspects of management review should be performed to ensure the developed product and process can be manufactured at commercial scale. 3

Pharmaceutical Development Technology Transfer

Commercial Manufacturing Products Product GMP

Action (CAPA) System Change Management System

4 Pharmaceutical Development Technology Transfer Investigational products Investigational Commercial Manufacturing Products Product GMP Discontinuation GMP GMP PQS Elements Enablers Process Performance & Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Knowledge Management Quallity Risk Management 4

Steps for Successful Technology Transfer For successful technology transfer to take place, here are some of the key steps that should be followed: 1.

5 Steps for Successful Technology Transfer For successful technology transfer to take place, here are some of the key steps that should be followed: 1. Documentation/Information: The first step includes taking clear documentation of all process/product knowledge, running consistent and controlled procedures for all processes, and utilizing prior knowledge derived from similar products. 2. Personnel: Establish a proper integrated cross-functional team of experts, including members from different departments such as operations, CMC, Analytical, Quality, Tech Operations, and R&D. Having a variety of professionals with different expertise is beneficial because they are able to widen the talent and skills of your team by contributing in their respective roles and responsibilities. 3. Technology Evaluation/Development: Technical components are important so one should ensure processes are robust, analytical methods correspond to each other, and the process as a whole is understood well by the parties involved. Excellent design and efficient operation of the equipment is also vital. Tools such as ICH Q8, Q9, Q10, uni and/or multivariant design of experiments, identification and verification of CPPs (critical process parameters) and CQAs (critical quality attributes) are helpful at this stage. 4. Execution: This is the exciting and final step where you can expect to successfully manufacture demonstration batches if the previous steps have been successful. Process validation includes on-site training with equipment until the receiving site has the ability to perform the process accurately. There must be continuous monitoring through several means of measurement. PAT (process analytical technology), software engineering tools, and proactive analysis of the staff are just a few examples of the devises used to control for the transfer. The pharmaceutical quality system is a strategy tool that is executed to help control for changes and continuously document the learning and knowledge acquired prior to and after the technology transfer. 5

6 Control Strategy Life Cycle: Insufficient process knowledge will result in a lot of unwanted results detrimental to the process. Some of which include sub-robust processes (decreased CpK), lower production rates, increased product defects, decreased reliability of processes, inefficient validation, and incapability of managing fluctuations in raw materials, API, process controls, and operators. The 3 Models of Technology Transfer Process The technology transfer process can be understood through multiple models: 1. The Empirical Model: This model based on understanding of processes from experimental relationships/correlations such as IVIVIC correlations, DOE s (regression models). The empirical model is used most frequently out of all models. 2. The Mechanistic Model: This model is built on predictive models that rely on principals derived from physics and chemistry. It is used to predict property responses without the need for experimentation although an empirical experiment can be conducted to confirm results. Examples of processes using the mechanistic model include lyophilization and liquid flow based on computational fluid dynamics. 3. The Semi-Empirical or Hybrid Model: This model is a combination of the empirical and mechanistic models. This hybrid approach is based on understanding derived from results of the mechanistic model but experimentation to verify is essential. Examples of processes using this model include population model for granule growth, and probability of granules colliding and adhering. 6

7 Process Validation Then and Now Process validation has changed a lot throughout the years. The traditional approach demanded that processes be based heavily on the empirical method with the usage of validation but less emphasis on material variability. Regulatory agencies are now emphasizing the need for better understanding of products and the processes before attempting validation. In the 21st century, the Process Validation Lifecycle approach has replaced traditional means. A robust validation is formed after using QBD life cycle approach in development, including the first principal of understanding and a more mechanistic approach. This approach uses uni and/or multi variants, model tools, prior knowledge, control strategies, process monitoring, PAT for trending, continuous verification, and is characterized as a proactive, continuously-engaging attitude. Process Validation Lifecycle Approach Advantages of Technology Transfers There are many advantages from using scale-up and technology transfer as part of your pharmaceutical quality system: Compliance and regulatory issues are resolved, 7

A well-developed process based on scientific principles The end-production of a robust product of superior quality Robustness also guarantees a positive identification of CPP S and CQA S, followed by

8 A well-developed process based on scientific principles The end-production of a robust product of superior quality Robustness also guarantees a positive identification of CPP S and CQA S, followed by other parameters and measurements that controlled for Knowledge is well documented in records, resulting in quicker resolution of errors, scientific support for investigating these errors, fewer deviations from desired results, and continuous improvement. Commercial capability from better manufacturing efficiencies, higher yields, and enhanced process control. Conclusion Using the principals of the quality by design approach will generate robust and safe products. There are rules and regulations that must be followed to enable a smooth and robust technology transfer for commercialization. A word of caution: never underestimate the complexities during scale-up and we recommend utilizing all tools available. A plan that includes research development, manufacturing technical operations, quality control, and manufacturing is highly recommended. A final manufactured product that is robust in nature is often a result of a well thought-out plan that is executed with diligence. 8

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Importance of ICH Guidance in Fulfilling Process Validation Requirements

Importance of ICH Guidance in Fulfilling Process Validation Requirements Presented by: Gamal Amer All rights reserved. Do not copy without permission. Principal 1 Premier Compliance Services, Inc. Process