Biopharmaceuticals and biosimilars: manufacturing challenges

Biosimilars/Research | Posted 23/10/2020 post-comment0 Post your comment

Biopharmaceuticals include a complex active pharmaceutical ingredient (API). This is manufactured using living systems such as microbial and mammalian cells which makes manufacture a complicated process. A recent paper by Sia et al. published in GaBI Journal [1] has explored current biopharmaceutical processes and the challenges posed by manufacturer.

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The article highlights that, with the expiration of patents of biopharmaceutical products, there will be a rise in the production of biosimilar products. These products have a complex molecular structure and high molecular mass and are far more difficult to characterize than smaller, conventional chemical pharmaceuticals. They are also sensitive to various conditions such as temperature, pH and mechanical stress, and these must be monitored in manufacturing and processing to ensure the product’s quality, safety and efficacy.

The manufacturing processes
Details of the manufacturing processes are highlighted in [2]. In summary, they include upstream processing (obtaining and categorizing starting materials, creating cell banks and seed lots, and cell culturing), downstream processing (Isolation, concentration and purification of API) and formulation and filling.

The manufacturing challenges
Process and product understanding
The quality of biopharmaceuticals is influenced by the processing steps. As such, processing must be designed to ensure the critical quality attributes (CQAs) of biopharmaceuticals remain within specifications. These are analytical measures associated with the quality, safety and efficacy of a product. Inappropriate processing steps can affect quality, and changes to processes or formulation must be validated to assure product quality.

Variability of host cells
Host cells have an inherent variability that can have unpredictable effects on biopharmaceutical quality. A number of factors related to this can cause issues that make it difficult to ensure consistent product quality.

Downstream processing bottleneck
Chromatography used in downstream processing is commonly considered to be a key bottleneck in biopharmaceutical manufacturing. Designing chromatographic purification has proved challenging due to lack of standardization. As such, the designing process is non-trivial and is often wasteful in terms of time, materials and money.

Recommendations and insights into good manufacturing practice (GMP)
Sia et al. advise manufacturers to demonstrate extensive product and process understanding as there may be methods that are not suitable or relevant for their products. In addition, due to their inherent complexity, biopharmaceuticals present challenges in assuring product quality. This can be addressed with real-time monitoring and better predictive modelling.

The article also highlighted that robust GMP guidelines are needed to safeguard public health by assuring the quality, safety and efficacy of biopharmaceuticals. As such, the article investigated the need for global harmonization of GMP standards for biopharmaceutical production [3]. It has also outlined the challenges that must be overcome to achieve acceptable GMP harmonization [4].

Related article
Biopharmaceuticals and biosimilars: challenges in manufacture, regulation and international harmonization of GMP

1. Sia CH, Sia MK, Chan LW. Global challenges in the manufacture, regulation and international harmonization of GMP and quality standards for biopharmaceuticals. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(2):52-63. doi:10.5639/gabij.2020.0902.010
2. GaBI Online - Generics and Biosimilars Initiative. Biopharmaceuticals and biosimilars: manufacturing processes []. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 23]. Available from:
3. GaBI Online - Generics and Biosimilars Initiative. Global harmonization of GMP standards for biologicals []. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 23]. Available from: 
4. GaBI Online - Generics and Biosimilars Initiative. Biopharmaceuticals and biosimilars: regulatory challenges for global harmonization GMP standards []. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 23]. Available from: 

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