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Polpharma is a Polish CDMO of APIs and a significant European API producer, delivering products to companies worldwide. 
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Overview of process development & scale up services for APIs & intermediates as well as contract manufacturers (CMO, CDMO) offering such services.
Scale-up is the term used to refer to an increase in the batch size of pharmaceutical products such as intermediates and APIs, usually from the milligram to kilogram scale. Furthermore, if a drug is successful, it may scale-up multiple times throughout its life cycle to meet growing demands.
Synthetic organic chemists in the pharmaceutical and fine chemical industries continuously seek such advances to help improve yield, purity, and stereoselectivity of intermediates and APIs (active pharmaceutical ingredients).
The ultimate goal of custom API synthesis is to scale up or go from producing milligram quantities in a laboratory to producing commercial APIs from kilogram to ton quantities in a pilot or commercial scale plant, all while maintaining high quality and reproducibility at the lowest cost.
With scale up, the efficiency of the custom API synthesis process becomes increasingly important. In the end, the goal is to have viable process research that produces the same results day after day, creating a reliable, cost-effective supply chain for drug products.
For successful scale-up timing is everything. Scale-up is a balancing act, and requires judgment calls to know when a process is ready to move to the next level. Furthermore, it is essential that the drug substance manufacturing process is scalable from a technical and economic viewpoint.
Contract services offered by fully integrated CDMOs (contract development and manufacturing organizations) include API scale-up (drug scale up) processes from laboratory scales to pilot scales, and ultimately the commercial production scale.
Objectives of API Scale Up:
- Formulation Related: Identification and control of critical components and other variables.
- Equipment Related: Identification and control of critical parameters and operating ranges.
- Documentation: Records and reports according to cGMP.
- Production and Process Research Related: Evaluation, validation, optimization and finalization of process controls.
- Product Related: Development and validation of reprocessing procedures.
Efficiently scaling up an API involves various process development technology and API manufacturing processes. Some of the most important process development and scale-up steps for active pharmaceutical ingredients (APIs) are explored in detail below.
I. Process Development
Process development is the strategy via which an API manufacturing process is identified for a drug substance from an early stage through scale-up and tech transfer to commercial manufacturing.
It is carried out by process research developers who operate process development technology and work closely with process engineers and technology transfer teams to define suitable API manufacturing routes in order to ensure seamless production, from mgs to kgs.
- Synthetic Route Development
Synthetic route development or route scouting is an analytical development service carried out during the early stages of process development that offers significant benefits such as improving scalability. Synthetic route development further helps in identifying small to large scale custom API capabilities and custom synthesis technologies required to successfully carry out API production.
- Process Optimization & Process Validation
For delivering quality pharmaceutical products it is important to optimize and validate API development and manufacturing activities. Process optimization can aid process development by providing a framework for process improvement. Process optimization projects rely on the expertise of scientists and engineers.
Meanwhile, process validation establishes documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
II. cGMP Scale Up
In cGMP scale up, the formula created during the process development stage is transformed into a viable, robust product by the development of a reliable and practical method of manufacturing under cGMP conditions that affects the orderly transition from laboratory to routine processing in a full-scale CDMO facility. Furthermore, cGMP scale up activities are supported by technology transfer teams.
- Tech Transfer
Technology transfer (tech transfer) is a process development technology to transfer information necessary to manufacture quality APIs and drug products consistently. Alternatively, technology transfer is the process of taking an invention from its inception in a laboratory all the way up to a commercialized product.
A CDMO (contract development and manufacturing organization) that can optimize the custom API synthesis process early during technology transfer will reduce the risk of project delays or failures.
API Scale Up Stages:
- Early Scale Up / Laboratory Scale Batches
The early scale up development phase, generally 100-1000 times lesser in quantity (milligrams) as compared to the production-scale batches, takes place during the laboratory scale stage of API scale-up.
Laboratory scale batches (early scale up batches) are produced at the research and development stage. Furthermore, laboratory scale batches may be used to support early scale up during clinical and/or preclinical stages.
- Pilot-Scale Batches
Pilot-scale batches are used to test the behavior of a product during small scale custom API development and manufacturing, before proceeding with large scale production.This is the stage where a lab scale formula is transformed into a viable product by using practical custom synthesis services and manufacturing procedures.
Pilot scale labs often use cGMP kilo lab units to achieve low volume, test batches of active pharmaceutical ingredients (APIs). cGMP kilo lab units are normally used to carry out process research or simulation in the laboratory. cGMP kilo lab units can also be used for low volume production of active pharmaceutical ingredients (APIs).
- Production Scale / Large Scale Batches
The last stage of scale-up (kilogram stage) is the production scale. Production scale batches are referred to as the 100X batch and this is the scale at which fully integrated contract research organizations, and more importantly contract development and manufacturing organizations (CDMOs), run during routine marketing of products.
Fully integrated contract manufacturers, for API development and manufacturing, have the custom synthesis expertise to provide cGMP scale up services from the laboratory scale to the large scale, commercial manufacturing of production-scale batches.
With API scale-up (drug scale up), come a number of challenges - from making sure the chemistry works in larger equipment, to eliminating new impurities. Furthermore, problems that arise at the production scale can be quite costly when compared to the smaller quantities produced in earlier stages.
Some other common challenges involved in scaling up an API:
- In unit processes, reactions may poorly impact product selectivity during scale up if they are not properly understood at the lab scale. This can result in an increase in commercial APIs with impurities - impacting both yield and quality.
- Non-linear scale-up is the number one challenge to pilot plant API scale-up and is the cause behind several other challenges. It basically means you cannot take a chemical process in the lab and drop it into a pilot plant by simply increasing the chemicals and equipment involved in a proportionate manner.
- Creating multiple batches in the kilo lab during API manufacturing. You can't create one batch in the kilo lab and expect it to be ready for production-scale batch manufacturing. It's important to run the substance in the kilo lab through three batches to make sure the chemistry works according to GMP guidelines.
- Active substances are often micronized to increase the surface area of the drug substance. A micronized API often exhibits static charges and adheres to the walls of the processing equipment. Cohesion or adhesion to surface parts can result in inconsistent funnel flow, rat holing, and content uniformity issues.
- Drying commercial APIs at production scales can be complicated. Residual solvents are a frequently-encountered problem during drying, and they are mainly the result of the crystallization process.
However, many formulation process or engineering solutions can be applied to overcome these challenges related to scaling up an API in order to successfully manufacture quality products at the development and commercial scale with minimum to no clinical or regulatory impact. Some of these solutions are explored in detail in the subsequent question.
There are several challenges involved in the scale-up process of a drug substance. Scaling up an API in full production mode is the final stop on the road to commercialization. Being overly diligent in earlier stages can go a long way to making it an easier and less costly one.
Some ways to minimize the challenges of moving from lab scale to large scale manufacturing:
- It is important to ensure that the necessary steps and evaluations are carried out in order to manage complexities and reduce timelines of moving from lab scale to large scale manufacturing.
- A thorough working knowledge of the chemical reactions including the effects of scale-dependent factors (such as mixing, mass transfer and heat transfer) is necessary for efficient scale-up. Using simulation software, the effects of mass, heat transfer and mixing changes can be predicted at larger scales.
- It is important for R&D (research and development) chemists to identify potential plant issues and to attempt to address these concerns suitably at the R&D (research and development) stage. Laboratory studies can help address many issues to avoid surprises that might occur in the plant scale-up batches.
- Generating safety data at lab scale can potentially help in designing the hardware for pilot-scale batches or commercial scale batches - leading to inherently safer process technology.
- After each stage of scaling up is complete, it is essential for the receiving team to study the batch record reports, to better understand the issues experienced in the development phase. It is also imperative that teams engage in cross-departmental communication, to ensure lessons learned are carried forward to maximise the chance of scale-up success.
- Another way to eliminate potential scale-up problems is to develop formulations that are very robust with respect to processing conditions.
- Taking an integrated approach to drug substance development can help overcome issues and speed up timelines. As such, the popularity of working with CDMOs that offer end-to-end solutions and that can develop drug substances with the end goal in mind is increasing.
Fully integrated CDMOs (contract development and manufacturing organizations) are flexible, good at problem solving and may have widespread experience in scaling up fine chemicals, chiral compounds, intermediates and APIs.
Some of the leading CDMOs for API scale-up include:
Solara Active Pharma Sciences
Solara offers contract research and manufacturing services that support API scale up at production scale quantities from 500 grams to 10-kilograms, or higher quantities of multiple batches.
Minakem
Minakem provides fully integrated & technology-oriented contract manufacturing services ranging from process development, kilo lab & pilot API scale-up (drug scale up) to full industrial scale manufacturing of complex molecules including chiral compounds, intermediates & highly potent APIs (HPAPIs).
ZCL Chemicals Ltd
ZCL's highly qualified professionals work in product development, analytical development & IP rights. Their activities include route scouting, organic chemistry synthesis, process development, drying, scale up, tech transfer, synthesizing impurities (from organic chemistry), contract research for chiral compounds, fine chemicals, intermediates and APIs, etc.
Medichem S.A
Medichem's pilot plant is an independent building used for process validation, process scale-up and also for small scale pilot production for lots of 15 to 50 kg.
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Scale up of the Med. Chem. Route to get quantities as fast as possible.
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Anthem Biosciences offers API GMP and non-GMP manufacturing from mg to ton scale.
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