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COMBINING SAFETY AND EFFICIENCY IN RECONSTITUTED DRUGS IN THE FAR EAST MARKETS

Can advanced dual-chamber solutions help?

Valiant Chen, China Sales Manager, Bormioli Pharma

The article focuses on the peculiarities of the Chinese pharmaceutical market, characterized by high growth rates. In particular, reconstituted drugs are one of the highest growth market segments, with the increasingly growing need of dedicated solutions to protect drugs from moisture, which Bormioli Pharma has addressed presenting cutting-edge, advanced solutions.

Latest figures show that China is the second pharmaceutical market in the world after the United States, with an overall value amounting to about 103 billion dollars in 2020. A further leap forward is expected for 2021, with estimates forecasting Chinese pharmaceutical market to outperform the global market both in the short term (+13 per cent) and in the long term with a +5.6 per cent compound annual growth rate compared to the global value of +5 per cent. Latest estimates also show that China is likely to become the first pharmaceutical market in the world in 10 years, even though the figures show that the market has still a lot of consolidation to do before surpassing the United States, that now accounts for 40.4 per cent of the total revenues worldwide, compared to 11 per cent of China.

Indeed, demand for healthcare services and products in China continues to grow, alongside the government’s effort to advance the sector’s development with increased investments – up to 8 per cent of the domestic GDP in 2026, compared to 6.5 per cent registered in 2020 - in related infrastructure, pharmaceutical research, medical diagnostics as well as preventive treatment. Moreover, growing demand is coming from the national middle class, increasingly asking for quality medical services and products.

Besides the rapid growth, China has distinguished itself in the global pharmaceutical market as a country where more and more high value-added drugs and medications are produced. For example, in 2020 disease-wise Oncology has been the leading segment both by size and growth rate. Moreover, in order to save more lives, for urgent clinical cases, the government grants exemption from duties on drugs produced outside of China.

The production and consumption of such precious, high value-added APIs requires increasingly strong protection against atmospheric agents, such as light, oxygen and especially from moisture.

One of the answers that the pharma supply chain has developed is to increase APIs’ protection against atmospheric agents is drug reconstitution, meaning with it the freeze-drying process of the APIs that subsequently needs to be properly mixed with a solvent before being administered or consumed by the end user.

Reconstitution segment showed a growth of +4,6 per cent in the 2018-2019 period globally, but its growth rate is definitely more significant in the Far East and in particular in China.

In China, parenteral applications retain the largest share of the national market (more than 50 per cent), driven by the growth of pre-fillable syringe, in line with the global market trend, followed by the oral applications: in this segment, oral solid still account for the largest share but, it is outperformed in terms of value growth by the reconstitution segment, that grew +24 per cent year on year in 2019.

Globally, more than 900 million units of drugs are sold every year to be reconstituted, for an overall value of about US$3 billion. Among these, orally administered drugs are the most common.

But what does reconstitution mean in terms of steps to be undertaken by the end user and in terms of main risks that are related to this process? With standard reconstitution, a powdered drug is packaged in a glass or plastic bottle and the patient must add the solvent – which could be water, but also other liquids – by themselves. This represents a considerable risk, both for the safety of the drug to be administered and for the therapy adherence, since the patient could be untrained or not capable of administering it properly.

Secondly, after receiving the medicine, the patient goes home and opens the drug package. At this stage, our patient runs into two different kinds of packaging configurations: we could have a bottle with a level mark, accompanied by an instruction leaflet. This is the case of a glass or plastic bottle containing the powder, where the patient has to add water up to the level mark by following the instructions, properly mix and consume.

In this case, the patient has to check the correct quantity of solvent in the instruction leaflet, autonomously dose it using external and not controllable measuring devices and add it to the bottle.

In both cases, but especially in the latter, the risk of a human error is very significant. Indeed, an untrained patient often undervalues the importance of some critical elements for drug reconstitution, such as the quality and the correct dosage of the water used during the procedure.

A patient could use too little water, causing the powder to be mixed incorrectly or even overdose, while others could dilute the API in a larger amount of water, causing the drug to be not efficient in terms of therapy adherence. These mistakes could be both accidental or voluntary and might have a negative impact on the drug’s safety and efficacy.

Involuntary mistakes are primarily caused by incorrect assumptions or fundamental misunderstandings of the product. For example, some people add more water than required because they believe this would help in making the drug last for longer, allowing them to save money.

Needless to say, it is fundamentally important to fully comply with the indications stated on the leaflet in order to reconstitute a drug properly and safely, also ensuring its efficiency. On one hand, the direct consequence of adding too much water is a disproportionate dilution of the active ingredients, resulting in a loss of effectiveness. On the other hand, not using enough water can lead to serious problems of toxicity, as the active ingredients would show a higher level of concentration than required.

Moreover, when discussing reconstitution, water quality is a critical factor, especially when access to safe drinking water is difficult. A contribution from the American University of Sharjah, in the United Arab Emirates, underlines all the possible concerns about the use of the wrong type of water while reconstituting.

First of all, it is uncommon for patients to be aware that, depending on the particular pharmaceutical process at play, different type of water is required (e.g. purified or highly purified, mineral, spring, drinking, distilled) and that the wrong type of water can negatively impact on the drug’s effectiveness. Secondly, patients often reconstitute drugs with tap water, which might be not safe to consume, due to contaminants over specific limits and as a result may lead to several types of health problems.

This consideration is all the more true for those countries dealing with water pollution issues. A study conducted by the World Health Organization (WHO) shows that deaths due to unsafe water are a daily concern in many countries.

Beyond these complexities, reconstitution also creates an issue in terms of drug protection. Powder, by its very nature, is highly sensitive to moisture, and a failure to protect the powder can result in a loss of drug efficacy, particularly when it comes to particularly sensitive APIs. In particular, moisture can interact with the stability of the drug causing changes in the chemical structure of the formulation (e.g., oxidation, hydrolysis) or in the physical structure (e.g., polymorphism), or causing microbial growth.

That’s why pharma packaging manufacturers are developing dedicated solutions to understand, address, and tackle the challenges presented by reconstitution, namely, complexity, dosage errors, poor safety features, and APIs protection, by designing brand new, innovative packaging solutions. Specifically, this refers to the design of dual chamber systems that allow for the reconstitution of the oral drug directly in the container, simply following a guided procedure and providing the right choice and the right amount of solvent.

A dual-chamber system is normally composed of a plastic or glass bottle pre-storing the solvent and a cap prestoring the powder. When the packaging is closed, both the solvent and the powder are unavailable to the patient, who has no possibility of tampering with the prestored doses. The integrity of the packaging is ensured by a tamper-evident ring, which has to be removed to make the reconstitution possible. After removing the ring, the patient can reconstitute the drug activating the mechanism, consuming it afterwards.

At this point, the advantages resulting from such a system should be self-evident. Firstly, a dual-chamber system leaves no dosing choice to the patient, as both the powder and the solvent are pre-dosed, ensuring a precise and accurate reconstitution and avoiding any occurrence of human error. Secondly, the solvent is chosen and provided directly by the pharmaceutical company. According to research conducted by the American University of Sharjah, providing pre-packaged water with all oral formulations that require water for reconstitution is the best way to avoid any confusion and health issues. Furthermore, the pharmaceutical company is free to choose what solvent to provide inside the packaging, allowing greater flexibility in drug formulation, since it will not be tied to water as a solvent anymore.

Chamber systems also offer other remarkable benefits in terms of drug protection: unlike the process required for standard drug reconstitution, dualchamber systems eliminate the possibility for powder loss, unless the packaging is completely destroyed. This is because the powder is safely stored and sealed inside the packaging and thus well protected from

That said, even though dual chamber systems offer a higher level of protection from external agents than standard packaging solutions, there are still particular cases in which the sensitivity of the drug or particularly extreme weather conditions require higher performance solutions. This is true in all the markets worldwide, but particularly for far east countries, given the specific climate conditions of the area, with a higher mean level of moisture when compared to other global areas. That’s why further solutions have been developed to properly address this issue, ensuring enhanced moisture protection to safeguard the efficiency of APIs.

These solutions usually feature an active barrier technology, able to maximise moisture performances on a multiple scale compared to standard dual-chamber
solutions available on the market.

Enhanced moisture solutions are identical to standard dual-chamber systems, featuring an active material layer in the chamber containing the API, regulating the level of moisture in the container below safety levels, enhancing performances and the product’s shelf life. These products are not just concepts, they’re already available for industrial production in different formats featuring different moisture absorption performances.

Oral drugs, such as antibiotics, syrups or other high-value treatments, represent an important segment of the global pharma industry. However, the standard reconstitution process still seems to be too complex, potentially unsafe or not completely safe, being subject to accidental or voluntary human errors. Packaging manufacturers and pharmaceutical companies can work together in order to develop effective solutions to make reconstitution more precise, safer and easier. Amongst the potential solutions, innovative dual-chamber systems appear to be a strong alternative to standard packaging methods. In particular, this has been demonstrated in our outreach to the Far East and Chinese market, collecting very positive feedback and in-depth technical requests that represent a good parameter of the market interest in such solutions.

--Issue 44--

Author Bio

Valiant Chen

With more than a decade experience in pharma packaging in China, Valiant built his career path in global pharmaceutical packaging companies, covering roles of increasing responsibilities, and leading relevant business development projects. He is now in charge of Bormioli Pharma’s business development in China.

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