Biopharmaceuticals and biosimilars: regulatory challenges for global harmonization of GMP standards

Biosimilars/Research | Posted 27/11/2020 post-comment0 Post your comment

A recent GaBI Journal [1] article by Sia et al. has explored biopharmaceutical good manufacturing practice (GMP) standards around the globe. The authors uncovered the challenges faced in attempting to achieve global harmonization of biopharmaceutical GMP standards.

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Sia et al. noted that to safeguard public health, it is vital to adopt appropriate GMP guidelines when manufacturing biopharmaceuticals. As such, the author highlighted the need for global GMP harmonization for biopharmaceutical products [2]. Through investigation of current GMP (cGMP) practices of various global regulatory authorities (RAs) and international organisations (IOs), the author uncovered several regulatory challenges that need to be overcome to assure the quality and safety of biopharmaceuticals globally.

Regulatory challenges
Evaluating biosimilarity
The article highlighted that the inherent variability of biopharmaceuticals makes it impossible for biosimilars to exactly replicate the reference product. Biosimilars are highly similar to the reference product and a ‘totality-of-the-evidence’ approach is used to evaluate biosimilarity. Therefore, biosimilar evaluation is more complex than that for generics. Additionally, there are doubts about the suitability of guidances when assessing some more complex biopharmaceuticals. Here, more harmonization between different regulatory perspectives will be of help.

There are differences between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) perspectives on interchangeability. Such differences can lead to confusion when manufacturers want their products approved for use in different countries.

Data integrity lapses
In recent years, FDA has recorded an increasing number of GMP violations related to data integrity. When data integrity is compromised this can lead to missing and inaccurate information needed for product approval and can jeopardize product quality assurance. This can occur unintentionally or deliberately through processes such as data manipulation. It has been revealed that data manipulation can occur despite the implementation of legislative guidelines, standard operating procedures (SOPs) and controls.

How to reduce the challenges posed by biopharmaceuticals
Industry 4.0
The role the Fourth Industrial Revolution - Industry 4.0 - could play in making biopharmaceutical manufacture and processing. The Industry 4.0 concept involves the amalgamation of physical and digital technologies to generate a constant flow of information, allowing real-time data access. Overall, Industry 4.0 allows greater interconnectivity and provides worldwide access to data. For example, by sharing knowledge of a specific cell genome, manufacturers can manipulate the gene more effectively and improve host-cell stability, leading to more consistent product quality.

Harmonizing guidelines
With the expected influx of biosimilars, Sia et al. emphasizes that RAs need to develop guidelines that facilitate the clinical decisions related to product choice and switching. In the EU, individual Member States make their own substitution policies and many countries have endorsed the interchangeability of biosimilars. In general, these countries recommend that there should be shared decision-making between the patient and prescriber, along with appropriate monitoring for early detection of adverse event. The authors advise that these countries share their regulatory experience so that other RAs can make informed choices when developing guidelines and this will promote harmonization.

Creating a culture of quality
Without a culture of quality, even the simplest and preventable data integrity-related violations can occur. Here, a critical element of quality culture is the ‘transparent and open reporting’ of data integrity-related violations at all organizational levels. There are many measures that can be adopted to facilitate a culture of quality, for example, by incorporating the ‘Leader 5Vs’ that correlate with a positive influence on quality culture – vision, visibility, voice, values, vigilance. Essentially, these emphasize that senior management has a key role in creating a vision, leading by example, and empowering their employees towards quality excellence.

Assuring the quality biopharmaceuticals
To achieve greater assurance of quality and safety of biopharmaceuticals, Sia et al. initially carried out an in-depth exploration of current biopharmaceutical manufacturing processes [3] and the challenges it faces [4]. This highlighted that the inherent variation in quality of product means there is a demand for extensive process and product understanding. This can be facilitated with globally harmonized GMP standards for biopharmaceuticals.

Through investigation of cGMP standards and harmonization for biopharmaceuticals, the authors stress that more effort is needed in providing guidelines on the interchangeability of biosimilars so as to encourage their use. Greater collaboration between RAs and IOs can facilitate improvement of existing guidelines and, together with technological advances, the challenges presented by biopharmaceuticals can be overcome.

Related articles
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. Global harmonization of GMP standards for biologicals []. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 27]. Available from: 
3. GaBI Online - Generics and Biosimilars Initiative. Biopharmaceuticals and biosimilars: manufacturing processes []. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 27]. Available from: 
4. GaBI Online - Generics and Biosimilars Initiative. Biopharmaceuticals and biosimilars: manufacturing challenges []. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 27]. Available from:

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