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Susan Haigney is managing editor of BioPharm International, firstname.lastname@example.org.
Industry experts discuss the formulation and development issues that should be considered when addressing scale up from small-scale batches to commercial production.
An API’s physiochemical properties and its pharmacokinetic profile, as well as patient considerations, should dictate drug product formulation, according to experts at Catalent. Budget and timeline constraints, however, sometimes create difficulties. “The positive effects of formulation approaches on solubility, permeability, and ultimately bioavailability should be weighed against complexity, cost, and risk-to-launch of the chosen technology,” says experts at Catalent. “It is unrealistic to expect any formulation group to tackle all these considerations without the experience from many multiple product launches or the ability to leverage the expertise across a large and diverse formulation team.”
According to Joe Masi, Sr. Director MS&T, at Cambrex, pharmaceutical companies turn to contract development and manufacturing organizations (CDMOs) to “resolve capacity shortages, tighten development timelines, reduce processing costs, and/or lack of internal development capability, etc.” Pharmaceutical companies are requesting end-to-end services more and more, according to Masi. “This includes API, formulation development, analytical methods development, manufacturing, and packaging development. In addition, pediatric formulation and fixed-dose combination products (two or more active ingredients in one product), as well as modified-and controlled-release complex formulation, continue to gain popularity and are often outsourced.”
When it comes to outsourcing formulation development, however, challenges may arise when scaling up from small-scale batch to commercial production. Dr. Baerbel Hinneburg, director Technology and Process Transfer at Vetter Pharma-Fertigung GmbH & Co. KG, states that “concrete planning of execution with attention to detail is critical.”
BioPharm International spoke with Masi, Hinneburg, and experts at Catalent about the formulation and development issues that should be considered when addressing scale-up from small-scale batches to commercial production.
BioPharm: What formulation challenges occur when moving from clinical to commercial phases?
Hinneburg (Vetter): From a processing and technical point of view, one example is a change in material and equipment that may occur when moving from clinical to commercial manufacturing, such as the use of larger compounding equipment or a change from disposable to non-disposable material. One must be aware of the impact a change in material could have on the relevant attributes derived from the drug product profile. This awareness avoids further lab trials that need to be undertaken to determine the appropriate operational parameters that help maintain the quality and functionality of the drug product producedwith the new process.
Masi (Cambrex): Usually, batch size and equipment used throughout development phases are small due to API availability, manufacturing cost, and the scale needed to meet clinical and registration requirements. However, some manufacturing process parameters may need to be changed when scaling up or using large-sized equipment for commercial production.
Common challenges could occur during different manufacturing steps. A few examples are listed below.
Blending step: Material flow (i.e., the flowability of granules) is one common challenge during manufacturing. Funnel flow is non-uniform, and the materials adhere to the walls of the hopper, resulting in blend uniformity issues during the blend. To overcome the issue, change the geometry of mixers, blenders, and hoppers to improve flow of materials through the hopper. Another way is using vibratory mechanisms to ensure a mass flow or having a paddle stirrer in the hopper.
Compression step: Sticking and capping issues are commonly observed during compression. When different compression machines are used, they may not directly generate expected results. Modification of a tableting process can sometimes reduce or eliminate film formation or sticking during compression without making any drug formulation changes. Modifications include changes to pre-compression force, compression force, and tableting turret dwell time/speed. These modifications may be helpful in delaying the sticking behavior.
Coating step: When using a large-sized coater, some of the parameters from the small coater may not work and coating uniformity may suffer. Coating variability usually increases at a faster pace with higher pan speeds. Therefore, the first consideration is to reduce coating pace to obtain better coating uniformity. The spray distribution across the tablet bed may be another cause of the coating uniformity issue. However, with functional coatings it is important that each nozzle is spraying the same amount of coating suspension. Each nozzle must have an even spray and be calibrated to ensure it functions properly. In early formulation and clinical phases of development, there are options to modify the qualitative formulation to overcome these challenges. However, because it is often difficult to make major changes at later phase without regulatory involvement, engage with an experienced CDMO from the earlier clinical development phase. They can help to develop and manufacture quality products with minimal to no clinical or regulatory impact.
Catalent: The main challenge of a formulation proven as safe and effective for the therapeutic action tested in patients is to ensure that as we move from the beginning of the quality-by-design (QbD) process to commercial process validation, there are no changes in correlated critical material attributes (CMAs) (APIs, excipients, synthesis route, suppliers, etc.) and that none of the critical process parameters (CPPs) (associated with scale up to commercial batches) will affect the critical quality attributes (CQA) of the product that ensured efficacy and safety in clinical-phase stages. If any change is necessary to apply as part of the process, a risk assessment and mitigation should be implemented to assure the desired quality, considering the safety and efficacy of the pharmaceutical form.
BioPharm: What steps should be taken for successful scale-up from small-scale batches to commercial production?
Hinneburg (Vetter): To prepare a robust and reproducible commercial production process, we perform a QbD approach. This approach involves a combination of gap and risk analysis to identify and evaluate any factors that could potentially impact CQA and any not obvious scale-up process steps that become CPPs. A comprehensive process design to accommodate both known and newly identified CPPs, combined with a process qualification to verify a constant product quality and define a control strategy, is essential.
Masi (Cambrex): First, define the target product profile (TPP), which describes the use, safety, and efficacy of the product. Prior knowledge and in-depth understanding of formulation, excipients, and process is advantageous when defining the TPP and will reduce the number of experiments and analytical testing required and, consequently, the manufacturing and testing costs.
The next step is to identify the CQAs of the final product. CQAs should be studied thoroughly and controlled to meet the TPP. To achieve the desirable CQAs, it is necessary to identify and control CPPs. CPPs identified throughout the development and scale-up process include raw material and API controls (particle size distribution, polymorphs, and impurities), process controls, and design spaces around individual or multiple unit operations (granulation, compression, coating, packaging). These CPPs are monitored throughout development and updated upon the collection of new information.
Successful scale up can be achieved by a QbD approach, which includes design of experiments (DoE), risk assessment, and process analytical technology (PAT).
Catalent: Most frequently, there will be changes between the equipment used in small-scale batches to ones in the commercial setting. With the difference in the equipment, the CQAs (e.g., dissolution) of the drug product could be affected, and this may depend on the complexity of the formulation. It is important to understand the correlations between the equipment scale, CPPs, and CQAs as this knowledge will help to fine tune the CPPs in the commercial-scale production that will produce drug product with the desired CQAs. These relationships can be studied by appropriate DoE at small-scale.
BioPharm: How can quality by design be used to ensure quality during formulation development?
Masi (Cambrex): The concept of QbD is to deliver a quality pharmaceutical product by designing a robust manufacturing process.
Quality cannot be tested into the product at the end; it should be built into the product from the beginning. The knowledge gained from development studies can be utilized to design the working space, specifications, and manufacturing controls. Changes in formulation and manufacturing processes during development can be used to gain knowledge and support design space.
Pharmaceutical QbD is a systematic approach with predefined objectives and emphasizes product- and process-understanding and control based on scientific knowledge and quality risk management.
Successful QbD involves defining the target product profile and then identifying critical quality attributes, followed by developing and controlling critical process parameters etc., which will eventually ensure quality products.
Solid QbD during formulation development can: reduce batch-to-batch variability and defects, improve product development and manufacturing efficiency, develop a robust manufacturing process that leads to greater regulatory confidence and increased product quality, improve yields, reduce investigations and testing, and lower manufacturing costs.
Catalent: Practicing QbD in formulation development emphasizes holistic and systematic investigation, understanding, and prediction of variances caused by the drug substance(s), functional excipients, formulation design, biopharmaceutics, and process development (instead of finding them out through normal means or through accidental variation). The key elements of QbD are risk assessment, conducted by cross functional teams; DoE; statistical analysis; and PAT. These elements help identify and measure risks and variabilities, correlate CMAs and CPPs to CQAs, establishing design space, control strategies, and relevant specifications, and ensuring right-first-time production at reduced costs, reduced time, and increased efficiency.
BioPharm: How do analytical methods change from clinical development to commercial production?
Catalent: Often, analytic methods do not change dramatically from clinical development to commercial production, but the understanding of the method and information changes. Early phase methods are developed for speed and to minimize cost, and the assay/purity methods are commonly adapted from the method developed by the API manufacturer (for ease of tracking API impurities).
Dissolution methods may simply be discriminating rather than profile generating, and things such as extraction procedures may need to be optimized. Once a drug has moved from clinical to commercial, a commercial quality control laboratory performs a method evaluation and transfer to confirm that the method can be performed, and the same results can be obtained using similar instrumentation. If there are any nuances to the method (understanding its variability, the level of validation performed, the experience on different equipment or by different analysts), then changes are usually minor adjustments and the method is updated. Changes in the analytical methods could support certain adjustments during a validated-state maintenance process if they merit it. Historical data generated by the method can be used to adjust or refine the acceptance criteria as the program progresses from clinical to commercial batch production.
It is key to use these data to assess critical method parameters that must be controlled carefully as part of the overall analytical control strategy-as the molecule moves to commercial testing and release.
Statistical tools are valuable to set acceptance appropriately for commercial products-while also considering practicality, so as to not fail a batch unnecessarily.
BioPharm: When moving from clinical-scale production to commercial production, what validation steps must be performed?
Masi (Cambrex): The successful transfer of a product from clinical- to commercial-scale production is based on a thorough understanding of the manufacturing process, the inherent variability in the process, and strategies to mitigate or control these sources of variability.
This knowledge is gained through scientifically based process development work and documented in reports that are used as the source documentation to create the commercial validation plan.
The validation plan and process risk assessments are used to justify and implement the validation strategy, number of validations batches to be executed, sampling plans, and testing criteria.
The validation batches are executed under protocol by trained personnel using qualified equipment. Enhanced physical and analytical testing may be done to assure process robustness and control. A validation summary report including physical and analytical batch data, statistical data treatment, and summary of batch outcomes is approved by discipline subject matter experts and the quality unit prior to commercial batch release to distribution.
Catalent: A total of three consecutive, successful (commercial-scale) batches need to be manufactured within 10 times the size of the registered batch size. Validation demonstrates that a specific process will produce batches that meet specification and that normal variation would not predict an out-of-specification result. Emphasis is given to those elements that have been established, through QbD, as having a significant impact upon product quality, accompanied by increased testing of samples from throughout the process. It is not good practice to use validation batches for experimentation beyond that which has already been demonstrated, as the costs of validation batches are typically very high.
BioPharm: What are some best practices for successful tech transfer?
Hinneburg (Vetter): In our experience, a dedicated transfer team that includes a wide breadth of experts is crucial. This team is responsible for the process design required to perform a QbD-driven tech transfer. Roles and responsibilities must be agreed upon, and a system that enables adequate communication and feedback should be established. Open communication and exchange of all information gained during development is a key element. The license holder should also check early in the process that all partners and suppliers can provide adequate quality and documentation systems that help ascertain regulatory requirements are being met.
Masi (Cambrex): The main goal of tech transfer is to transfer the product and process with minimal or no changes, which will minimize regulatory challenges and smooth the path to regulatory approval.
The success of a technology transfer depends on several things: the quality of the finished product, open communication between two parties, feasibility of scale-up to desired levels, and compatibility of equipment at the transferred site. Therefore, it is advisable to consult with the technical and regulatory experts from the transferred site regarding the feasibility of the process with minimal impact on finished product.
Important actions to take for a successful tech transfer include:
• Obtain detailed technology transfer documents such as product development reports, batch records, protocols, and documents containing CPPs, CQAs, and TPPs from the transferring site. Better communication between transferring and transferred site is a key for successful tech transfer.
• Understand formulation, manufacturing process, key equipment, function of each and every excipient, specifications, and critical manufacturing process parameters etc. for the tech transfer product.
• Perform a gap analysis between sites (transferring and transferred site) by evaluating the equipment and supporting the information by comparing differences in the make, model, type, and capabilities of equipment available between transferring and transferred site.
• Identify the regulatory strategy; SUPAC guidelines describe equipment in detail and classifies changes in three levels: Level I, Level II, and Level III changes. CBE30, PAS, and annual reportable are common strategies for tech transfer, which can save companies significant time and money.
• Perform feasibility batches and capture the critical process parameters and optimize the process before registration/validation batches.
• Gather stability data including bulk hold data on finished product to gain more confidence on the quality of the product from transferred site.
• Generate a comparison report to compare equipment and manufacturing process parameters between transferring and transferred site and to perform a risk assessment.
Catalent: First, understand and capture the historical technical details or lessons learned from previous manufacturer (s) via discussions or detailed development reports.
Second, understand customers’ timelines for milestones and plan critical activities (e.g., raw materials, specifications, analytical method transfer/validation, and ancillary equipment parts) accordingly.
Vol. 31, No. 10
When referring to this article, please cite it as S. Haigney, “Outsourcing Development: Small-Scale to Commercial," BioPharm International 31 (10) 2018.