Quality by design (QbD) is a concept introduced into the pharmaceutical regulatory lexicon in 2005. It aims to ensure the quality of medicines by employing statistical, analytical, and risk-management methodology in the design, development, and manufacturing processes of medicines. Part of this is ensuring that all sources of variability affecting a process are identified, explained and managed by appropriate measures so that the finished medicine consistently meets its predefined characteristics from the start of development.

According to Dr Mansoor Amiji of Northeastern University: “Instead of relying on product quality as a readout after the product is made, you start to implement these procedures into the product production processes. This means that in each step along the continuum, you are optimising for quality.”

QbD principles are woven into regulatory guidance documents, primarily guidances Q8 to Q11 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Dr Amiji says that these harmonisation guidelines help industry understand the necessary requirements for developing pharmaceutical products. “They inform industrial scientists what is necessary to ensure that their product meets the safety and efficacy requirements to get a product approved in humans. These guidelines are continuously evolving and are common practice across many regions of the world.”

Practising QbD in biosimilar product development

One area in which QbD should be practised is that of biosimilars, also known as follow-on biologics or subsequent entry biologics. Biosimilars are biologic medical products that almost exactly replicate products already being manufactured by other companies. They are approved by regulatory bodies and can be manufactured when the original product’s patent expires.

To demonstrate bioequivalence for a generic small molecule drug, a company must carry out a Phase I clinical trial in healthy individuals to ensure that the area under the curve and maximum plasma concentration for their drug is equivalent to that of the brand name drug. They will need to conduct crossover studies in healthy individuals who will receive the brand name and the generic drug; the plasma concentration-time profile results will then be compared to see if the two are bioequivalent. For companies in the US, if the results show bioequivalence, an abbreviated new drug application (ANDA) containing the results is sent to the FDA to review and potentially approve.

For biosimilars, however, this process is slightly more complex. Dr Amiji states: “You have to consider factors such as the method of manufacturing, the technology, or the cell line. There are many variabilities with biosimilars and the brand name protein drug.” Because of this, biosimilarity is often considered on a case-by-case basis: “There is no general guidance for biosimilars, at least not in the US. Some countries are starting to implement general guidances, but this is mainly due to cost pressures. Protein-based drugs are extremely expensive and so if you can create a biosimilar and potentially lower the cost, then this is an incentive for many companies to try to get into that marketplace, but also for regulators to encourage development.”

In addition to this, there often needs to be additional scrutiny when assessing biosimilarity, especially as it concerns toxicity. “Even minor amounts of biological contaminants in your sample could cause unwanted biological effects,” Dr Amiji says. “This is especially the case if they derive from cell-based systems or microorganisms like E. coli, where small amounts of contaminants could cause significant toxicity. They may be therapeutically as effective, but the safety aspect is a key concern in approving biosimilarity.”

Since most biologics and biosimilars are large molecules, they may prove challenging to develop and manufacture on the large scale. However, the adoption of automation in the lab setting can set the stage for a pilot phase to drive optimisation and efficiency into a new era of drug development and manufacturing. Automation and digitisation allow vast amounts of quality assurance data to be collected, which can enable a robust audit trail and contribute to predictive modelling efforts. Enhanced data collection assists in monitoring quality measures in real-time and increases the likelihood that a product will remain on schedule throughout the drug development process by ensuring critical quality attributes (CQA) and QbD targets are met. This presents an obvious financial benefit in the form of cost savings and helps guarantee the safety and reliability of the final product.

To find out more about automation solutions to drive productivity in biologics drug development, please visit the PerkinElmer website.

QbD as an aspect of process and analytical methods

Process and analytical methods are another area of biosimilar production where QbD should be considered. Dr Amiji explains: “In a lot of small molecule drugs, you rely on sophisticated analytical methods to ensure the quality of your active ingredient and excipients. In the case of biosimilars, parameters such as specificity and limits of detection also need to be analytically validated and continuously improved upon.”

For example, when using a mass spectrometer that can detect impurities, it may be that the level of detection needed is very low, causing certain impurities in your sample to be missed. This could be a cause for concern when the product is being approved – the contaminant may still be present in the sample, but the spectrometer cannot detect it. To avoid situations like these, creating various protocols that allow for greater sensitivity and specificity is critical.

There have been continued efforts in the US, most European countries and some parts of Asia to harmonise and create similar types of requirements for biosimilars. Dr Amiji believes, however, that the US has been more cautious than other countries in this, and continues to approve biosimilars on a case-by-case basis.

Several of PerkinElmer’s technologies are being used to test biosimilars. For example, the Covid-19 pandemic brought messenger ribonucleic acid (mRNA) vaccines into international prominence. Because mRNA is highly unstable, these vaccines have had to be stored and/or transported at -80°C to avoid degradation.

There are ongoing attempts to improve the storage stability of mRNA vaccines by converting them to solid forms using various drying methods. Lyophilisation is one such method and has the potential to stabilise mRNA, but there are few reports that describe the interactions of lyophilised mRNA with excipients such as sugars, salts and lipids in the solid state. Capillary electrophoresis, mass spectrometry and reversed-phase high-performance liquid chromatography (HPLC) are some methods currently being used to analyse mRNA.

The PerkinElmer Spectrum Two™ FTIR Spectrometer with attenuated total reflectance accessory (ATR-FTIR) was used to probe the interactions of RNA with various excipients in lyophilised solid samples. For more information, please download this free white paper.

Following QbD to guarantee a drug product’s safety

All pharmaceutical products must ensure product quality assurance using QbD measures, whether brand names, generics or biosimilar drugs. “QbD is a universal principal when it comes to the quality of pharmaceuticals,” says Dr Amiji. “Once you start manufacturing a drug for the masses, you must follow the same QbD principles that you would if you were producing it for the first time.”

Given the high levels of scrutiny and quality control in the approval of generics and biologics, it is not surprising that consumers have few concerns relating to their safety. “In the case of generics, the only concerns you might see is where the brand name and generic drug contain different excipients,” explained Dr Amiji. “A patient may have a hypersensitivity to one of those excipients and will then be prescribed the brand name because of the reaction to the generic.”

Regardless of whether a drug product is intended for mass populations or certain prescriptions, QbD should always be followed in its development. “In terms of personalization of medicine, some of the attributes would need to be refined appropriately for the product, because each of product will dictate specific quality criterion,” Dr Amiji says. “Ultimately, the tests that are necessary will differ depending on the product, but quality assurance will always have to be in place to ensure that any product developed is safe and effective.”