A solid dose of innovation

Published: 29-Apr-2016

Contract development and manufacturing organisations can help optimise time to market as well as bringing technical expertise and high quality manufacturing services to the development of innovative technologies for solid dose delivery, argues Recipharm

You need to be a subscriber to read this article.
Click here to find out more.

Solid dose formulations remain the preferred format for dosages and, as a result, the corresponding market looks healthy with strong prospects for continued growth. Nevertheless, the market faces multiple challenges – but it also offers opportunities for contract development and manufacturing organisations (CDMOs) that possess the advanced scientific and technological skills to provide customers with solutions that combine an extensive range of resources, facilities and service capabilities.

One of these challenges is the increasing demand for capabilities that support the formulation and development of fixed dose combination drugs. This need addresses increased patient adherence to the prescribed treatment and, in some cases, improved clinical benefits. Additionally, it extends differentiation of branded products in the marketplace.

The development of fixed dose combination products requires advanced formulation skills to address the specific pharmacokinetic profile requirements for each of the APIs incorporated into a single solid dose unit

Whether it is the virtual pharma companies out to establish a niche product with a strong differentiator, big pharma companies that want to add novel products to their pipelines, or established pharma companies that want to extend lines and diversify their brands, they are all behind the driving impetus to bring such products to market. In this respect, clinical trials aimed at the testing and monitoring of the interaction between various active pharmaceutical ingredients (APIs) are increasingly in play, leading to findings that it is safer and entirely feasible for certain active pharma ingredients to be successfully taken together as one fixed dose combination. As a result, CDMOs with highly advanced technical expertise and capabilities, with the advanced technologies and facilities that are required in this specialist market, are in demand.

The development of these novel and exciting fixed dose combination products requires advanced formulation skills to address the specific pharmacokinetic profile requirements for each of the APIs incorporated into a single solid dose unit. Such formulations are therefore usually covered by additional patents, and the corresponding clinical development often leads to regulatory protection providing full exclusivity that lasts a couple of years.

Those new products bring multiple advantages to healthcare, including increasing the stability, efficacy and safety of drugs, reducing side-effects and improving the therapeutic outcomes of drug treatments. They also improve patient compliance and convenience of administration due to a decrease in the number of doses that are required to be taken each day.

Beyond fixed dose combinations, other drugs require controlled release formulations. For the treatment to be effective, the API needs to be protected to avoid its degradation until it reaches a specific stage of the gastrointestinal tract where it should be released and resorbed.

It might also be that the release of the API needs to be prolonged so that it lasts for a long enough period of time to reduce dosage frequency compared with a drug presented as a conventional dosage form. In some cases, a controlled released formulation might reduce the variability of the pharmacological effect of the drug between patients or with the same patient along its fed state. Controlled released formulation also applies to drugs that are poorly soluble and require enhanced formulations to be actually resorbed using separately a spraying process in aqueous or solvent conditions to increase the loading of the API.

As a consequence, new developments are undertaken aimed at improving the pharmacological impact of the drug. This requires innovative formulations that allow the release of APIs at defined points in the gastrointestinal tract with the appropriate kinetic to optimise the resorption and avoid the peaks of concentration of the API concerned in the patient’s blood. Providing ways of achieving this is particularly important for ensuring that the drug has a much safer impact on the body – eliminating harmful and unwanted side-effects. Consequently, the drugs are able to work and the most effective patient treatment is enabled.

Opting for pellets

Advanced technical solutions are at hand that meet all of these solid dose challenges for both fixed dose combinations and controlled release formulations. A technical option is to develop and manufacture products in coated pellet form to be filled into hard gelatine capsules or compressed into tablets – providing an answer to a number of the key challenges that this article highlights.

The pellet technology represents a valid option both for controlled release and for fixed dose combination products. Pellets take the form of small, free-flowing, spherical or pseudo-spherical particulates; these are uniform in size with smooth surfaces that lend themselves well to complex, coated oral drug delivery systems and can also incorporate several APIs. Different pellets incorporating each different API can be blended together into a hard gelatine capsule.

Coated mini-tablets of 2.5mm diameter can reduce the volume of granulate compared with larger tablets

Coated mini-tablets of 2.5mm diameter can reduce the volume of granulate compared with larger tablets

Alternatives to pellets are mini-tablets. Such small tablets of about 2mm diameter are prepared along a process comparable to tablets of a larger size, although it requires much tighter parameters to avoid variability between such small units. Mini-tablets are used to reduce the required volume of granulate while securing an appropriate distribution of the API, with a much better control of the release profile compared with tablets.

When intended for gastrointestinal tract delivery, pellets or mini-tablets may be provided with pH-sensitive or time-controlled polymer coatings – enabling each of the APIs to be released at just the right point with the right speed. They are also highly cost effective and easy to scale up for commercial manufacturing supply. Furthermore, the products have the benefit of having a rapid development time, speeding their course to market.

Highly technical processing equipment is required to produce such pellets or mini-tablets. Firstly, the pellets are manufactured by the agglomeration of granules of drug substances and excipients or by coating neutral core (sugar or cellulose) with drug substance (core layering). Once these pellets are created, the next step is the coating process. Coating will determine the stage of the gastrointestinal tract where the API is released. Coated pellets and/or mini-tablets containing different APIs can then be blended and incorporated into hard gelatine capsules. Granulation and coating steps require very specific equipment in different scales and a judicious selection of excipients and adjuvants. The process parameters and the definition of the formula itself constitute the core of the required expertise to provide superior pharmaceutical formulations.

Coated pellets with a modified release profile enable each of the APIs to be released at the right time and at the right speed

Coated pellets with a modified release profile enable each of the APIs to be released at the right time and at the right speed

Once all the formulation is determined, the next development stage is the carrying out of bioequivalence studies to establish that the pharmacokinetic profile of the new formulation is comparable to that of the original products taken in separate unit doses. Such studies might be co-ordinated by the CDMO that develops the product.

Fixed dose combination

With regard to fixed dose combinations, one example of the application of industry solutions in this highly technical field is to be found in the formulation, development and manufacturing of RHB-105. The product is a proprietary fixed dose oral combination therapy, owned by RedHill Biopharma. It comprises two antibiotics (amoxicillin and rifabutin) and a proton pump inhibitor (omeprazole), combined into an all-in-one oral capsule. It has a planned indication for treatment of H. pylori infection – and the product has successfully met its primary endpoint in its first Phase III study.

This shows the higher efficacy and safety of the three components when combined into this particular fixed dose drug, proving that the new combined product is more reliable than that which existed separately prior to its creation. Furthermore, this product will benefit from a fast track review status from the US Food and Drug Administration (FDA), as well as having strong regulatory protection in place as a stamp of approval that bears testament to its medical value to the patient.

RedHill has partnered with Recipharm on this product. Developing the formulation and meeting the highly complex production demands for such drugs requires sophisticated formulation skills and development and manufacturing expertise, combined with the implementation of a highly integrated solution across three FDA approved sites, each with its own specialist manufacturing capabilities. Recipharm’s Fontaine and Pessac sites manufacture the omeprazole mini-tablets, while in Strängnäs, further expertise in preparing tablets as well as in encapsulating and packaging the finished product ready for final release has been developed.

There is especially strong demand for CDMOs to work on controlled release and fixed dose products

There is especially strong demand from customers for CDMOs to work on controlled release and fixed dose products. The technical skills needed for this extend well beyond just what is required for product manufacturing.

With fixed dosage combination and variable release programmes, selective CDMOs offer the expertise and development capabilities to prepare the pharmaceutical part of the regulatory submissions in accordance with the expectations of various authorities – with the goal of getting the submissions to the regulatory authorities as early as possible.

Regulations stipulate that the files that need to be compiled and drawn up must be highly robust. The pharmaceutical component to them is especially technical as it requires specialist knowledge to address each and every aspect of the development and manufacturing processes involved in the production of these types of complex formulations. A great deal of technical data needs to be gathered about the profile of the drug, including its stability and dissolution profiles. The capability to carry out this task effectively is critical in meeting the expectations of the bioavailability of the API for the product concerned.

1.3mm coated spherical pellets: the coating determines at which stage of the gastrointestinal tract the API is released

1.3mm coated spherical pellets: the coating determines at which stage of the gastrointestinal tract the API is released

Producing fixed dose combination products also further heightens the growing market and customer demand for CDMOs to develop the capability to provide one-stop-shop solutions across the entire production life cycle – carrying out everything from formulation and development to clinical supply and then full commercial-scale product manufacturing. First, they need to redesign the formulation and then enact full redevelopment of the product before carrying out the manufacturing – both initially at a clinical batch scale and then full-scale commercial supply. Contained within the full suite of services, there is an imperative need for full product resource, project management and manufacturing capabilities.

Furthermore, highly experienced one-stop-shop CDMOs help their customers to accelerate time to market and bring additional value to the services they provide by removing redundancies and efficiently co-ordinating activities, from the early development stage right up to commercial production, including clinical studies and the preparation of the pharmaceutical part of the regulatory submission.

Significant time and resources are saved for customers who are freed from the burden of engaging multiple partners. Moreover, there is no loss of time due to tech transfers with the seamless transition from development through to clinical batch and then on through to commercial-scale manufacturing. The ultimate aim of such CDMOs is the development of innovative formulations, clinical and commercial-scale manufacturing and the supply chain, while bringing products to market in as a swift fashion as can be achieved.

The authors

Jean-François Hilaire is Executive VP, Head of Strategy and Global Integration, Recipharm

Dr Philippe Gorria is Director of Pharmaceutical Development, Recipharm Pessac, France

You may also like