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Double-blinding Capsules for Clinical Trials

How over-encapsulation can help tackle bias?

Steve Rode, Manager Business Development, Capsules and Health Ingredients, Lonza

Hideyasu Fujiwara, Business Development Manager, Lonza Capsules and Health Ingredients

During the preparation of clinical studies, the method for visually blinding dosage forms is a vital consideration. While many blinding options are available to sponsors, overencapsulation remains the most popular for many reasons, including better accessibility, efficacy, ease, shorter development time and cost. However, over-encapsulation involves a number of individual operations that can create a variety of complex situations if not managed effectively. From capsule colour and size selection to having a well-trained team dedicated to the manufacturing process, it is vital that companies take the time to make sure each part of the process is managed properly to curtail problems and provide an effective blind in the study..

Capsules are tried, tested and trusted, but that is not to say that the method is simple or without innovation. Formulation considerations and patient-centricity have driven significant innovation by some businesses in the market. With the development of Hydroxypropyl Methylcellulose (HPMC) polymers, sponsors and manufacturers now have access to a capsule that is vegetarian and vegan-friendly and has a broader range of applications across different disease indications.

Here, Stephen Rode, Manager Business Development in Lonza’s Capsules and Health Ingredients business division and Hideyasu Fujiwara, Ph.D., Business Development Manager, Lonza Capsules and Health Ingredients, Japan discusses the importance of capsule selection and process considerations for providing an effective blind as well as how HPMC-based capsules can further the use of capsules in clinical trials.

Factors for effective blinding

Clinical studies are performed to evaluate the efficacy and safety of a trial drug in relation to a marketed comparator product or a placebo. When blinding a drug product, the goal for investigators is relatively simple: to prevent patients’ ability to identify the blinded product.In a double-blinded trial, this goal is extended to include the trial staff. The design of the clinical study and characteristics of comparators, as well as advantages and disadvantages for each blinding approach, must be explored to determine the best blinding option.

For clinical conditions in which exposure to the drug at the right time is a critical determinant of efficacy, and encapsulation is being used as a blinding method, it is strongly suggested that both the investigational and the reference drug are encapsulated to provide an effective blind. This will negate any questioning of the validity of the study’s results relating to the blinding method and ensure that appropriate comparisons and conclusions can be drawn without reproach.

For sponsors and their manufacturing partners, this can be challenging as they need to ensure that:

  • The blinded product is no more challenging to dose the patient than comparators or placebos;
  • The blinded drug product is expected to show the equivalent efficacy to the investigational medicinal product (IMP) or the commercial dosage form;
  • There is no risk of additional side effects; and
  • Resources/cost required for manufacture, blinding, qualification, release and stability are tightly controlled.

Over-encapsulation remains the most widely used method of blinding as it can deliver on all these fronts and is invariably the simplest technique to implement. When done correctly, over-encapsulation has no impact on the trial drug product’s stability or efficacy– meaning it requires little additional process development and analytical work– while offering the flexibility to blind a wide range of oral dosage forms.

Once the decision has been taken to over-encapsulate, it is important to select the appropriate components that will be needed and to plan ahead to curtail problems that could occur once the patient receives the supplies. This includes common challenges such as managing the ‘shadowing’ effect, where the dosage form is visible through the shell of the capsule, providing a consistent weight and feel, as well as selecting an appropriate inactive backfill present in the dosage form that prevents ‘rattling’, or achieve a uniform rattle.

Size

The size of a capsule will be heavily influenced by two things – the size and shape of the IMP and comparators and the potential to impact patient compliance.

The first step is to determine what size capsule shell is needed to properly blind each unit – remembering that uniformity is key so the difference in size between comparators and IMPs will have to be effectively managed. Although it is not completely necessary, it is recommended that the unit that is being encapsulated does not protrude above the body of the capsule shell when inserted. If the unit does not “sit” properly inside the body shell it may become necessary to backfill the capsule in a manner that will produce a considerable amount of waste.

If tablets are to be broken, it is critical that all of the tablet fragments are collected and accurately placed into each associated capsule shell.If all the fragments are not collected, the final dose of the blinded tablet could be altered. In addition, in some markets, regulators do not recommend breaking tablets to fit them inside capsules for blinded clinical trials, as there are questions raised around the impact this could have on drug efficacy and safety. For example, in the late 1990s, under newly modified regulations, tablets could only be broken if they had been designed with a score and the developer had specifically conducted studies around the potential impact of the broken tablet.

Study populations are also a vital consideration, as child and geriatric populations may have difficulty swallowing larger capsules. Capsule size is also an important factor where dysphagia, which is usually associated with Central Nervous System (CNS) indications, is a symptom of the disease or the restricts the ability to apply pressure using the tongue.

Selection of backfill material

Backfilling may be required to eliminate the rattle of a unit inside the capsule shell so that the patient is not able to determine the dose inside the capsule. If the rattle is not eliminated, the patient could possibly identify what is in the capsule, which could affect the clinical outcome or break the blind. In some cases, backfill may not be required as both the placebo or comparator and the active doses contain over-encapsulated units with similar rattle.

Where backfill is required, it is recommended to choose an excipient that is present in the dosage form being blinded.

Dissolution profiles and stability work may need to be conducted to verify that the material selected does not affect the pharmacokinetic profile.

The most commonly used excipients for backfilling are Microcrystalline Cellulose and Lactose Monohydrate. These materials are used both independently of one another, as well as combined in a blend. In some cases, research has shown that the combination of the two may improve the dissolution results, meaning excipients for backfilling can affect the dissolution of the product1.

Depending on the grade of the material chosen, a lubricant, usually Magnesium Stearate, present at less than 0.5 per cent, is added as part of the backfill formulation. Not all grades of these two materials require such lubrication and the choice of adding the Magnesium Stearate is usually based on its presence in the formulation of the unit being encapsulated.

Colour

The colour of the capsule is an extremely important detail that requires much consideration. It is not only critical to choose a colour and opacity that will completely hide the enclosed unit and prevent shadowing, but to consider colour-effect associations.

The ideal colour is one that does not show any shadowing or air pockets due to the backfill, or allow for the encapsulated tablet or capsule to be seen. Ideally capsules for over-encapsulation are generally opaque capsules in nature and are usually not the same colour or shade as the unit being blinded, but rather slightly darker or more opaque in colour.

It is vital that the colour dyes and pigments used in the colour formulation are accepted wherever the study is being conducted. Many countries have restrictions on particular colours which need to be researched prior to selection.As regulatory rulings of various countries are constantly open to review and change, it is recommended that decisions regarding daily intake limits be made with advice from relevant regulatory experts.

Colour psychology is also an important factor when it comes to customer preferences and should be considered. It can also play a significant role in patient adherence and there is evidence it can alter therapeutic effect in some indications2.

HPMC

HPMC-based capsules show great potential in becoming a viable alternative to gelatine-based formulations, where required. They are often preferred in clinical trials, and for many investigational New Drug Substances (NDSs)3, because they have the added flexibility to accommodate a vast array of drug products and formulations.

With potent NDSs under development, challenges deploying APIs in gelatine-based capsules are contributing to a shift towards the use of HPMCbased capsules. Issues with cross-linking reactions can lead to dissolution delay, difficulty containing hydroscopic APIs and mechanical stability.

Benefits of HPMC as a base material include the following:

  • Offers lower moisture content, which helps stabilise formulations and mitigates the challenges associated with APIs and excipients that are incompatible with gelatine.
  • Polymers can withstand a wider range of temperature variation and fluctuation in storage and transit, meaning there is less chance for brittleness or breakage when compared to traditional gelatinebased capsules.
  • HPMC is also non-ionic, enabling pH independent drug release, which can lead to more consistent bioavailability of the drug product. It has also been shown that advanced HPMC capsules without a gelling agent can provide improved and parallel dissolution performance compared to other HPMC capsules with a gelling agent4.

Customer preferences and perceptions

Provenance is becoming more important and there is increasing consumer demand for products free from any animal proteins and with colours and ingredients derived solely from natural sources.

Gelatine-based capsules offer traditional benefits and are supported with data to prove compatibility, but they do not meet clean-label requirements. Developers of therapeutics of all kinds are responding to emerging social and cultural trends, forging a path for innovative clean-label products in the form HPMC-based capsules compatible with vegetarian and vegan lifestyles.

In summary

Over-encapsulation is one of the simplest solutions for blinding oral solid dosages in clinical trials. Its simplicity combined with high efficacy means it will continue to be the de facto blinding technique of choice wherever it is appropriate.

To deliver an effective blind and successful study, consideration must be given to the size, colour and material choice of the capsule as well as its compatibility with the IMP and comparator products - dissolution, diffusion and stability studies may be an essential element of selection in some instances.

HPMC-based capsules offer a range of development benefits that complement traditional hard-gelatine capsules. The introduction of these polymers increases accessibility to capsules for sponsors and gives them greater flexibility and product compatibility when selecting their dosage format.

Sponsors and clinical supply, manufacturing and service partners that understand and control every step of overencapsulation—from material selection to manufacture—will gain an efficient means for the integrity of their study and avoid bias.

--Issue 40--

Author Bio

Steve Rode

Steve Rode is focused on supporting and growing the pipeline of new pharmaceutical and OTC products utilising Lonza’s diverse portfolio of capsule-based products and technologies. With more than 31 years of industry experience, Steve has had the privilege of working with many top pharmaceutical and consumer healthcare companies in the development and launch of pivotal products

Hideyasu Fujiwara

Hideyasu Fujiwara is supporting and growing the pipeline of new pharmaceutical and OTC products utilising Lonza’s diverse portfolio of capsule-based products and technologies. With more than 20 years of experience in the pharmaceutical industry, Hideyasu has had the privilege of working with many top Japanese pharmaceutical companies on a wide range of projects from early development stage to generic development.

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