The Pharmaceutical Industry currently embraces advanced digital technologies and automation but is moving towards the combined strengths of human creativity and machine efficiency to continue to drive technological innovation while prioritizing individual patient needs.
Approximately eighty percent of molecules in development face solubility and bioavailability issues that require the complex challenge of experimentation, data collection and analysis. Appropriate communications along with knowledge and technology transfers are key to a successful development program.
Developability is an assessment of the properties of a candidate molecule that predict the ease and likelihood with which it can be developed into a safe, effective, manufacturable, and marketable drug product. Such an assessment may include pH stress studies, thermal and oxidative stress studies and physical form evaluation.
Formulation of a drug substance into an elegant pharmaceutical drug product is a process involving multiple steps. Formulations may be simple or complex, sterile or non-sterile, solid, liquid, or semi-solid. The use of artificial intelligence and machine learning predictive modeling and simulation tools may be utilized to speed up the development, de-risk and troubleshoot. Considerations include safety, efficacy, manufacturability and stability.
Manufacturing Science is the body of knowledge available for a specific product and process, including critical-to-quality product attributes and process parameters, process capability, manufacturing and process control technologies and quality systems infrastructure.
Robustness is a function of formulation and process design. It Is the ability of a process to demonstrate acceptable quality and performance while tolerating variability in inputs.
While experimentation in manufacturing is limited versus research and development, the state of robustness can be determined via proactive process monitoring. Control capability when processing at pilot versus manufacturing scale should be understood.
Knowledge transfer is the practical problem of transferring knowledge from one part of the organization to another. It seeks to organize, create, capture or distribute knowledge and ensure its availability for future users.
Technology transfer is closely related to (and may arguably be considered a subset of) knowledge transfer. It is the process of transferring skills, knowledge, technologies, and methods of manufacture among individuals or groups to ensure that scientific and technological developments are accessible to a wider range of users who can then further develop this information and technology into new products, processes, applications, materials or services.
From a pharmaceutical perspective, technology transfer involves the transfer of a drug substance and/or drug product manufacture, and/or testing from one suitable facility/location to another suitable facility/location. Ideally, the drug substance and/or drug product quality should be the same or better at the new location.
Scale-up and technology transfer can be complicated. Per ICH Q10, “the goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement.”
Technology Transfer Is a valuable step in the drug developmental lifecycle leading to successful commercial manufacturing. It is the transition of the product, its process and its analytical methods knowledge between development and manufacturing sites. Ideally, all gathered formulation and manufacturing development knowledge are used as the basis for the manufacturing control strategy, the approach to process qualification and on-going continuous improvement. The intent is to ensure that the variability of the process and its parameters are controlled and sufficient in the face of the rigors of a commercial production environment. Further, it is desired to verify that the parameters established during development are still within the determined design space and/or adjusted at scale-up.
Keys to effective Technology Transfer
Technical transfer should be a science-led approach, e.g., DOE, QbD based on risk assessment and available data, while leveraging statistical tools and modeling for decision making, i.e., quality is built in from the beginning.
Important considerations are efficiency and resource leverage across the organization via a scientific network that is adept at transitioning information with a clearly defined handover process and which minimizes delays with time and cost savings.
Experience, which involves a strong track record of performing transfers between sites, includes an understanding how to rapidly scale-up and validate processes with a focus on product quality.
Comprehensive support is required to ensure that the technical transfer process is smooth and seamless. This support includes all aspects of the transfer from consideration of the available equipment at the new site, to the understanding of the critical process parameters, and to the handover of the manufacturing process and its quality control.
Transparency in communications, collaborations, and process management – All process documentation, including all successful runs and any failures or issues must be fully documented to ensure complete information transfer. Complete and frequent communications are a necessity to mitigate risks and compliance with regulatory requirement.
Key Elements of Technology Transfer
Documentation and Information
- Consistent and controlled procedures for technology transfer and for running the process
- Assurance of clear documentation for all process/product knowledge
- Understanding of prior knowledge from similar products
Personnel
- The integrated interdisciplinary team of cross functional experts, for example, Operations, Technical Operations, CMC, Supply Chain, Analytical, Quality and R&D.
- Roles and responsibilities are clearly defined
Technology Evaluation and Development
- Well understood, robust process, and corresponding analytical methods
- Well designed and well understood equipment train
- Utilizes the principles in ICH Q8, Q9, QRM, and Q10
- Uni/Multivariant Design of Experiments
- Identification/verification of CPPs and CQAs and other important parameters.
Execution
- Successful manufacture of demonstration batches aids in site training and demonstrates that the receiving site has the ability to perform the process adequately and is the basis for Process Validation
Understand validation requirements and strategy
- Continuous monitoring , i.e. PAT, Proactive Process Analysis, etc.
Pharmaceutical Quality System
- Executable control strategy under site Quality System
- Utilize Pharmaceutical Quality System to help drive/control any changes, document learnings during and post transfer
Complexities of the New Product Introduction Process
Communication among teams is critical. Teams need to be organized and attend regular meetings to ensure projects remain on track, and any risks are quickly identified and mitigated.
Without effective collaboration between teams, siloed working can result in misunderstandings, errors, and delays potentially impacting product quality and project success
There should be a comprehensive knowledge transfer plan which Includes a detailed technical transfer plan, comprehensive manufacturing descriptions and technical gap analysis documents.
A robust regulatory strategy is necessary to ensure compliance with relevant regulations, guidelines and standards. Also, this strategy guides the compilation of necessary data, documentation and validation information required for submission of regulatory documents, such as DMFs, NDAs, and ANDAs.
Equipment should be like-to-like. Appropriate planning and process modeling are essential to make sure that even when changing equipment, the process can be run within a defined ‘design space’ ensuring accurate and reliable manufacturing. This is particularly true of new production processes as pilot stage equipment may not always be compatible with clinical or commercial manufacturing capacity.
Project management should follow a standard process to ensure timelines are maintained. Having a stage gate means there can be stops during certain technical transfer or developmental stages to ensure the necessary objectives, activities, and deliverables are met before moving forward. This helps to manage risk, ensure quality and streamline the transition from one phase to the next.
Role of Contract Development and Manufacturing Organizations (CDMOs) in the Technology Transfer Process
CDMOs have become integral part of the pharmaceutical industry involved in the intricacies of the drug development lifecycle. They offer specialized services and technologies to address complex development and manufacturing topics from early development through scale-up to commercial manufacture. They can provide advanced delivery systems and state-of-the-art engineering techniques that would require specialized knowledge, equipment and technologies that otherwise would require large Sponsor investments of time and money.
Use of Artificial Intelligence/Machine Learning in Technology Transfer
Machine learning algorithms and predictive analytics can optimize process parameters in real time ensuring optimal conditions for scale-up and manufacture. They can simulate manufacturing processes, identify potential issues and optimize them without the need for physical trials. Artificial intelligence technologies can enhance analytical validation by providing an integrated framework for data management, data flow, and storage requirements. These systems have the ability to integrate predictive modeling as well as accelerated stability testing by simulating extended storage conditions enabling rapid identification of degradation pathways.
Artificial intelligence can help streamline the preparation of submission ready documents, monitor real-time regulatory updates, and evaluate compliance impact of process modifications. Additionally, it can assist in analyzing development and production data to identify patterns and predict outcomes which allows for informed decisions on resource allocations to process adjustments.
Utilization of a QBD Approach Ensures a Robust Technology Transfer
Review of the manufacturing process to identify key inputs and outputs that could impact quality should be conducted. A Quality Risk Management evaluation to identify and understand the sources of variability should be part of this analysis.
Critical Process Parameters (CPPs), Critical Quality Attributes (CQAs) and other important parameters should be identified. Uni- and multi-variant experiments should be conducted to study the relationships and gain information on potential sources of variability. The understand of measurement capability, i.e., repeatability, precision, is an important consideration.
A Design Space should be defined and understood. It should consist of a set of input ranges (CPPs) that provide a high probability that the CQAs will meet the specifications. A control strategy should also be put in place.
Process and Scale-Up Understanding Through Models
There are several models that can be employed. One approach that is frequently used is the empirical approach based on experimental relationships or correlations. Examples include IV-IVC corrélations and design of experiments régression models.
Semi-empirical mechanistic models are based on a mechanistic understanding and requires some experimentation to fit parameters to verify. An example includes the population model for granule growth which uses probability of granules colliding and adhering.
Mechanistic models are predictive models based on underlying physics and chemistry principles. They can predict property response without experimentation. Empirical experiments can be performed to confirm.
Insufficient Process Knowledge Results in a Poorly Scaled-up Process
Incomplete and improperly performed technical transfer events will result in sub-robust manufacturing processes with decreased reliability. Manufacturing processes will not be capable of handling variations of raw materials, drug substances, process controls, operators, etc. This will cause an increased number of atypical results, i.e., product defects, elegance issues, etc. This causes insufficient process validation and ultimately, reduced production rates.
Process Validation
Regulatory agencies are emphasizing the need for a more thorough understanding of the product and its process prior to process validation. The traditional validation approach involves three lots and is largely a univariant and empirical approach with minimal emphasis on material variability.
A 21st Century Process Validation Lifecycle approach involves a more inclusive QbD holistic approach which understands that scale-up is a critical link in this process and utilizes prior knowledge, understanding of fundamental first principles, and the use of modeling tools, along with leveraging a control strategy to ensure a robust process validation.
A control strategy implementation plan which involves process monitoring/process analytical Technology (PAT) for trending/continuous verification is important to ensure continuous proactive improvement. (We are always learning.)
The Payoff
A robust, well-developed validated process which is based on scientific principles. This involves positive identification of CPP’s, CQA’s and other important parameters, and assurance that they are monitored and controlled. Working within established design space results in global regulatory flexibility.
Compliance with relevant regulations, guidelines and standards results in the necessary data, documentation and validation information required for submission of regulatory documents such as Drug Master Files (DMFs), Marketing Authorization Applications (MAAs), Supplemental New Drug Applications (sNDAs), etc.
A superior quality product that is knowledge built and that is well documented via CAPA and change management processes. There is scientific support for identifying the true root cause for atypical results. This results in fewer and quicker resolution of deviation events.
A proactive approach to improvement results in commercial capabilities of better manufacturing efficiencies, higher yields, and enhanced process control.
The Technology Transfer Report should contain the following information.
- Qualitative and Quantitative Formulation
- Information on Drug Substance and Excipients
- Manufacturers/Suppliers
- Special Handling Requirements – Light, Moisture, Heat
- Specifications
- Explanation as to why a specific grade or particle size is required
- Manufacturing Process Flow Chart
- Manufacturing Process Description
- In-process Controls
- Hold Time(s)
- Typical Yields
- Special Handling Concerns
- Special Concerns – Problem areas during development, etc.
- Manufacturing Process Control Strategy – CPPs, CQAs, and Critical Material Attributes (CMAs), etc.
- Special Handling Requirements for Drug Product
- Proposed Specifications
- Summary of Available Stability Data
- Summary of Scale-up Activities to Date
- Packaging Considerations
Conclusions
The approach taken to development should include a certain degree of rigor that enables a robust technology transfer to commercialization. Using a sound QbD principles-based approach to development supports the manufacture of a quality product. Developing a continually improved process in conjunction with Pharmaceutical Quality Systems assures meeting or exceeding GMP requirements.
Do not underestimate the complexities during scale-up and utilize all tools available to you. It is a collaborative effort with Research and Development, Manufacturing Technical Operations, Quality, Manufacturing etc. that is needed to assure a successful technology transfer and a robust final manufactured product.
References
ICH Q8(R2): Pharmaceutical Development, August 2009
ICH Q9(R1) – Quality Risk Management, November 2021
ICH Q10 – Pharmaceutical Quality System, April 2009
IR Holgate, “Drug Development: What is Formulation Development and Why is it Important?” Drug Development & Delivery, January/February 2025, Vol 24 No 1, pp 36-40
R Kumar, “Outsourcing Pharma Development: Harnessing CDMOs for Innovation and Efficiency,” January/February 2025, Vol 24 No 1, pp 55-59
U Hanenberg, et al., “New Product Introduction: Addressing the Pitfalls of Progressing from Pilot to Product Through Effective New Product Introduction,” January/February 2025, Vol 24 No 1, pp 60-63
B Chatterjee, “How CDMOs are Creating Strategic Advantages with Emerging Technologies,” Tablets and Capsules, March/April 2025, pp29-31
S Konagurthu, “Combining the Power of Human and Technological Innovation to Combat Drug Formulation Challenges,” American Pharmaceutical Review, March 2025, pp 46-48