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Looking for pharma scale-up services? Find CDMOs, CMOs offering drug product scale up manufacturing & formulation development on PharmaCompass.
Q1. What is formulation scale-up?
Scale up is defined as the increase of a product in size, number or extent, according to a fixed ratio. For organizations scale-up may also refer to an increase in production or capacity. In the pharmaceutical industry formulation scale-up is the term used to refer to the increase in the batch size of pharmaceutical drug products.
If a pharmaceutical drug product is successful, then it may scale-up multiple times throughout its life cycle to meet growing demand. Eventually, scaling down may also happen in response to shrinking demand for drug products.
On the way from laboratory to market, scale-up is a part of product research and development (R&D) and optimization. Commercial batch manufacturing should be considered as a possibility when new formulations are in the R&D phase. Producing materials at a larger scale without performing small-scale experimentation is unreasonable as an overall tactic for modern pharmaceutical product development.
Years ago, scaling up pharmaceutical production of a new therapy was a linear, iterative process that demanded patience and deep pockets. Best practices, and more than a little trial and error, moved processes from the bench to the manufacturing floor.
Over the past decade, as manufacturing operations have become more complex, engineering advances in modeling, digitalization, single-use process equipment, and process intensification have made scale-up manufacturing more systematic, for drug products.
Scale-up manufacturing can be challenging and involves risk. However, small-scale process development, using appropriate equipment and applying well established guiding principles, mitigates risk using a material-sparing and resource efficient approach.
Contract services offered by fully integrated contract development and manufacturing organizations (CDMOs) include formulation scale up contract services from laboratory scales to pilot scales, and ultimately the commercial production scale.
Q2. What are the different -approaches that a CDMO can consider for process optimization and scale up?
Approaches to process optimization and scale-up should include, at a minimum, defining the target product profile as it relates to various factors, identifying CQAs of the complex drug products containing Active Pharmaceutical Ingredients (APIs), determining the quality attributes of the drug substance and excipients prior to selection, selecting an appropriate manufacturing process, and if possible identifying a control strategy.
Approaches to Process Optimization and Scale-Up:
Approach 1 - Full Design of Experiments
The US FDA defines QbD as “Systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management”.
Quality by Design is the modern approach for producing quality pharmaceuticals. In the QbD approach, process parameters and quality attributes are identified for each unit operation. Therefore Quality by Design (QbD) is a multifunctional exercise for managing a product’s lifecycle intended to increase the understanding of products and processes thereby decreasing risk to patients.
Approach 2 - End Product Testing
End product testing can be applied by pharmaceutical organizations to document that complex drug products meet legal or internal quality standards. Finished product testing is performed as per FDA guidelines. All finished dosage forms (FDFs) must be tested prior to distribution.
The tests that are performed ensure that the pharmaceutical drug products or finished dosage forms (FDFs) meet established specifications and that these specifications account for their purity, integrity, efficacy, and concentration. The tests can include titrations, Spectrophotometer, pH, conductivity, HPLC, GC, AA, and others.
Approach 3 - Hybrid Method
A third method combining elements from approaches 1 and 2 optimizes the balance between development time and cost and maintains a good understanding of the manufacturing process. This hybrid approach can be achieved by breaking the manufacturing process into defined sections.
Q3. What are the different steps involved in scale up of pharmaceutical formulations?
As noted above, the possibility of pharmaceutical manufacturing for commercial drug products (commercial batch manufacturing) should be considered as a possibility when new formulations are in the R&D phase. Any processes involved in fabricating the drug must be scalable in terms of safety and efficacy, and economic factors must also be considered.
Some Steps Involved in the Scale Up of Pharmaceutical Formulations:
- Process Development & Process Optimization
Process development is a part of drug formulation development services. It is used to establish, implement, or improve a pre-existing manufacturing process. It ensures a product can be routinely made aseptically and meet specifications before manufacturing at scale.
Process development is therefore required for smooth scale-up manufacturing and technology transfer through to process optimization and characterization. Process optimization encompasses widely varying activities whose principal goal is to reduce costs by eliminating process steps, improving yields, shortening cycle times and producing higher-quality products.
- Laboratory Scale Batches
Laboratory scale batches or clinical batches are produced at the research and early development stage and are usually of very small size. They are used to support formulation and packaging development, preclinical to clinical development stages under clinical trials, and for the evaluation and definition of critical quality attributes (CQAs).
- Pilot Scale Batches
Next come pilot scale batches which may be used in the process-development or optimization stage. Pilot scale batches help researchers develop techniques that will be required to create much larger batches needed for manufacturing approved products. Pilot-scale is usually about 10% of the pharmaceutical production scale, which is also known as commercial scale.
- Commercial Scale Batches
Ultimately commercial or production scale batches are produced at a large scale. These batches are of the size that will be produced during the routine full manufacturing (pharmaceutical manufacturing for commercial drug products) and marketing of the product.
Commercial scale batches may also be referred to as validation batches that are manufactured consecutively in order to validate a process according to a validation and scale up protocol that was developed and authorized. Data on production-scale batches may not always be available prior to granting marketing authorization.
- Technology Transfer
In the pharmaceutical industry, technology transfer refers to a process of successful progress from drug discovery to product development, clinical trials and finally to full scale drug product commercialization.
Technology transfer is essential for scaling up Active Pharmaceutical Ingredients (APIs) and Finished Dosage Forms (FDFs), as it is the process of taking an invention from its inception in a laboratory all the way up to a commercialized pharmaceutical product.
Q4. What are the common challenges involved in formulation scale up and technology transfer?
Some Common Scale-Up Challenges:
- Four principal non-chemistry scale-up challenges that CDMOs and CMOs usually face when offering formulation scale up contract services include scaling to meet requirements, ensuring regulatory compliance of pharmaceutical products, securing adequate funding for drug product development and manufacturing, and protecting intellectual property.
- A substantial amount of expertise is required to seamlessly take products from preclinical to clinical and then to commercial scale. As such, it is important to ensure that the necessary steps and evaluations are carried out in order to manage complexities and reduce timelines.
- During plot plant scale-up projects various issues may arise including challenges associated with non-linear scale up, reaction kinetics, chemical equilibrium, material properties, fluid dynamics , thermodynamics, equipment selection, and agitation issues. Several in-depth engineering studies are required to overcome these scale-up challenges.
- Even for specialized contract development and manufacturing organizations (CDMOs), the journey from preclinical to clinical operations to pharmaceutical manufacturing for commercial drug products or drug product commercialization possesses its own slew of challenges such as capacity issues, general growth complications, internal culture, management maintenance, and standardizing a complicated operation for the mass market.
- One of the biggest concerns pharmaceutical manufacturers have when transitioning from small-scale to large-scale operations during the scale-up process is that they face a higher risk of pharmaceutical product contamination as they get to grips with new processes.
Some Common Challenges Associated with Pharmaceutical Technology Transfer:
- There are many barriers to successful technology transfer. All along the transfer path, from the supply side of technology to demand side, impediments occur at every node and, due to restrictions on movement of information and materials, for every linkage in the technology transfer chain.
- Technology transfer barriers comprise of issues relating to technical, organisational-economic, and system barriers. The three principal problems to be considered are asymmetric information, market power, and externalities. In addition, uncertainty regarding the qualities of the innovation as well as future prices of inputs complicate the technology transfer process.
- Technology transfer is a complex process involving several disciplines and with many associated risks that need to be managed. These risks can be more evident within any organization when transferring full manufacturing from one culture to another. In such cases, managing technology transfer and supporting the new drug product manufacturing site can become more complicated due to cultural and organizational differences between the involved sites.
Q5. Which are the different pharmaceutical companies offering formulation scale up contract services?
Various contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) have formulation development capabilities and offer technology transfer, process development and optimization, multi kilogram production, pharmaceutical formulation development and manufacturing services, etc. Some of the leading CDMOs and CMOs offering formulation