EPM Oral Solid Dosage Supplement 2017

O RA V L S OL O UM LID E DO 4: SA G E

SERIES

THE FORMULATION SOLUTION SPI Pharma looks at the challenges of patient experience in OSD and how these can be solved.

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Problem solving

EDITOR’S DESK

Oral solid dosage forms are still the preferred method of delivery for the pharma industry but what challenges are encountered and how does the industry solve these potential problems?

A

n overriding comment I have found when reading about oral solid dosage (OSD) forms is that they are the preferred method of delivery for the pharma industry. And, thinking about supermarket and pharmacy shelves, of course, in general what we buy is a tablet or capsule of some description. It’s easy to self-administer and widely accepted as an efficacious way to receive treatment.

However, as a sector there are certain challenges that pharma manufacturers need to overcome. One such challenge is the ever-shrinking drug discovery pipeline. In an effort to overcome this, we are seeing more combination therapies being considered and drugs that are already in existence being applied to different indications. Fixed-dose combinations, for example, are a popular way of managing the shrinking drug pipeline as they offer a useful way of protecting patents and enable quick development of a new chemical entity.

Specific patient groups, in particular paediatrics and geriatrics, also raise a set of challenges. Swallowability of an OSD form is a key consideration for both these groups so, in response the industry have developed orally

disintegrating formulations, effectively tastemasked medicines and smaller tablet sizes to help these patients.

Linking with the above is the issue of patient compliance. Pharma manufacturers have therefore, spent a substantial amount of time looking at the patient experience when consuming an OSD form. Mouth-feel, swallowability, number of tablets required, tablet size and taste all factor into this and can potentially mean a patient adheres to the treatment regimen or doesn’t.

I think along these lines, Michael Dell, CEO and founder of Dell Technologies probably said it best: “Real entrepreneurs have a ‘passion’ for what they’re doing, a ‘problem’ that needs to be solved, and a ‘purpose’ that drives them forward.” And, certainly when looking at the innovation, problemsolving and care for the patient considered in OSD forms, all three ‘Ps’ are there in abundance.

The last point I will touch on here is the rising tide of biologics. These macromolecules throw up their own set of challenges, size of molecule, protection of the biomolecule and bioavailability, for example. New formulation techniques and process, which are being developed, are set to help with these molecules and soon there should be biologics and biosimilars available in OSD forms.

Problem-solving, therefore, is a key aspect of OSD formulations — certain challenges must be overcome to ensure the safe and effective delivery of the medicine while also ensuring the patient experience is optimal.

Contents 5

PREFERRED ROUTE In this Q&A we speak to Patheon about the industry’s preferred route of drug delivery, OSD forms.

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ON THE COVER — THE FORMULATION SOLUTION SPI Pharma discusses the challenges of providing the best possible patient experience and how these can be solved.

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CHALLENGES OF CONTAINMENT Here, Bosch Packaging Technology goes into detail about containment in OSD.

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UNDERSTANDING THE CONTINUOUS PROCESS Considering the challenges of implementing continuous tablet production and how dynamic powder characterisation may help.

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THE RIGHT TOOLS This case study looks at how the right choice of tools can help in tablet compression

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THE SOLUBLE OPTION Catalent highlights the benefits of their orally disintegrating tablet technology and what is on the cards for the future.

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Q&A

Preferred route Oral solid dosage forms are the most common dosage forms and the preferred option for many pharmaceutical products. They are non-invasive, convenient and typically less expensive forms of medication that patients can self-administer. In this Q&A we speak with Sanjay Konagurthu — senior director, PDS Global Science and Technologies, Pharma Services, Patheon, part of Thermo Fisher Scientific — about this sector.

Q. What are the benefits of oral solid dosage forms over other delivery routes?

Q. What opportunities do you foresee in the sector for the near future?

A. Oral solid dosage (OSD) forms are manufactured using conventional manufacturing processes such as direct blending or granulation techniques. They are the preferred delivery type for pharmaceuticals, and offer several advantages including increased chemical and physical stability through the use of tablets or capsules, unique shapes and colours that can be easily associated with a brand, and controlled-release options.

A. Innovation in drug delivery technologies for oral solid dosage forms is expected in the future, with improvements in safety, quality and manufacturing costs. Targeted therapies and personalised medicine arising from innovations in computer technologies, imaging and sensors is expected to result in significantly enhanced patient treatment and monitoring.

Additionally, their cost-effective nature often makes them the preferred dosage form for clients. The popularity of OSD forms drives pharmaceutical formulation scientists and engineers to continually refine and improve their manufacturing processes.

Q. What challenges are you faced with when developing an OSD formulation?

A. Drug formulators need to be aware of a compound’s performance, stability and manufacturability throughout formulation and process development at all stages of product development. While development scientists commonly work on formulation and stability aspects in the early phases of a drug product, scale-up is not always easy. Therefore, it is necessary to develop the process knowledge at different scales of manufacturing. This knowledge should guide equipment selection, link the critical process parameters (CPPs) to critical quality attributes (CQAs) and establish the design space (DS).

Sound scientific/engineering principles and mechanistic models should be employed whenever possible for scale-up of pharmaceutical unit operations. In addition, a robust risk assessment programme invoking Quality by Design (QbD) principles at each stage of development is critical for successful scale-up.

Q. Are there specific patient groups that may benefit from OSD forms?

A. OSD forms are the preferred route of drug delivery due to broad patient acceptability. Strides are being made to formulate oral solid dosage products that are paediatric and geriatric-friendly by developing them such that they are easily swallowed and tastemasked, both of which lead to better patient compliance.

Furthermore, as oral delivery of biologics becomes more feasible, this will open up more avenues for drugs that can currently only be administered via an injectable route.

Patheon has a flexible business model to adapt to the changing demands of the industry. From a technology standpoint, as well as an integrated model for supporting client needs, there are many areas for growth within the market. For example nearly 90% of pharmaceutical industry pipelines are poorly water soluble (Biopharmaceutical Classification System Class II or IV) Patheon’s Quadrant 2 in-silico platform is a differentiated approach to solubility enhancement. This approach leverages in-depth knowledge of a molecule’s physico-chemical properties to select the appropriate solubility enhancement technology as well as guiding excipient selection thereby leading to a reduction or elimination in rework and improvement in advancement to the clinic.

Having an integrated CDMO for manufacturing of the active pharmaceutical ingredient (API) to the finished drug product and subsequent clinical packaging and distribution can result in a vastly simplified supply chain and reduces time to key milestones. This can result in significant time and cost savings by using a global network of fully integrated facilities that offer a comprehensive range of technologies and services. Patheon OneSource is designed to deliver the above strategy.

Continuous manufacturing holds great promise for the pharmaceutical industry, enabling faster pharmaceutical production and more reliable products using an uninterrupted process. The efficiencies of scale and manufacturing times compared to traditional batch processing can be significant. Continuous manufacturing is widespread in other process industries (e.g., chemical, food, automotive etc.) and significantly improves reliability, while reducing waste and costs compared with the batch method.

Q. And, what about potential pitfalls?

A. Development of an OSD form is a complex endeavour and has opportunities for continuous improvement and innovation.

We are making great progress to deliver the most challenging molecules orally along with improvements to the supply chain and manufacturing with the assurance of product quality.

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COVER STORY

The formulation solution Oral solid dosage is still the preferred method of drug delivery, however, the patient’s experience when taking medication can mean they adhere to the regimen or not.

Here, Dr Brian Wilson and Dr Graeme MacLeod from SPI Pharma look at the challenges of giving the patient the best experience possible and how these challenges can be solved.

O

ral solid dose forms are still the most preferred method of delivering drugs to patients within the global pharmaceutical market. Not only do they offer a convenient, stable and efficacious route for administration of medicines but they also have the potential to improve the patient experience in taking the medication over the treatment process.

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This latter point is key when considering patient adherence. If the patient has a good experience when taking the medication they are more likely to adhere to the treatment regimen. As a result of improved adherence it is possible to guarantee the efficacy of the treatment and reduce the total cost to healthcare providers.

The goal in a patient friendly dosage form is to reduce any unpleasant characteristic in taking the dosage regimen. Negative perception or failure of the formulated dosage can come from taste, mouthfeel, number of tablets needed, residence time in the mouth, and difficulty in swallowing. Some examples of dosage forms that have the patient experience in mind and are considered to be ‘patient friendly’ are chewable tablets, fast melt tablets, orally disintegrating tablets or orally dispersible powders.

Making convenient doses Both seniors and paediatric patients present challenges when it comes to making convenient and dosage forms. The task is to make the dosage form easy to take orally. Some dosage forms are required to be relatively large and often-above 1000 mg, while patients with dysphagia find tablets at 100–200 mg difficult.

Tablet size is less important in rapidly disintegrating dosages since they form an easily swallowed matrix. This can assist patients who display any degree of dysphagia. The fast disintegration time and positive organoleptics are key for patient acceptance. An alternative approach would be to formulate the drug as an orally dispersible powder that again disperses rapidly in the mouth.

We have also designed products that specifically target dosage forms with high drug loads. This provides the formulator with the ability to reduce the number of tablets that a patient requires. One aspect of patient-adherence is reducing the number of tablets taken and reducing the perception of dosing fatigue.

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The goal in a patient friendly dosage form is to reduce any unpleasant characteristic in taking the dosage regimen.

The right approach

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Reducing unpleasant dosage attributes starts with the excipients used and the manufacturing approach. Our excipients and preformulated systems offer a positive sensory perception in terms of taste, smell, mouth feel, number of tablets needed, and residence time in the mouth.

However, every drug or compound that our customers formulate may have its own unique challenges that require careful thought and consideration. Our technical experts have years of experience in the design and the manufacture of oral dosage forms. Our customers can leverage this expertise to ensure the final dosage form meets the correct requirements for the patient. We also offer services to address taste and sensory issues if the attributes of the API negatively influence the taste or organoleptics.

SPI Pharma has a number of global customers that formulate a variety of actives into a range of oral dosage forms. A common theme with these customers are the challenges that prevent them from getting to market fast. An easy to use, preformulated and coprocessed platform requires minimal development time. This enables our customers to accelerate product development and provide speed to market strategies. This also means that patients benefit by having convenient dose engineered to enhance their medicine taking experience. In addition to our formulation and technical support, we also have a dedicated team of regulatory professionals who can help our customers navigate the license application process, again increasing the speed to market.

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Products and selection We offer a number of products used to formulate the range of orodispersible patient friendly dosage forms. Our base excipients can be used to custom build a formulation. The preformulated products already contain the functionality desired for that dosage form, which significantly decreases development time. These systems only require dry blending in the active, flavours, colours and lubricant to obtain near optimal performance on standard tablet presses. See sidebar for more detailed information on the products offered.

Products offered for patient friendly dosage forms Mannogem product line — This product line contains powdered, granulated and spray dried mannitols that provide specific performance attributes used in chewable or fast melt tablets.

Advantol 300 — This coprocessed, preformulated system delivers speed in development for chewable and fast melt dosage forms. Advantol 300 offers exceptional compaction and disintegration times.

Pharmaburst 500 — This coprocessed, preformulated system provides an excellent carrying capacity for high drug loads. In addition, these tablets retain very short disintegration times, which is a requirement from patients and regulators regardless of the tablet size.

Pharmaburst 500 is engineered to significantly reduce development time, as it offers a complete formulation solution.

Pharmasperse 415 — This is a preformulated product for the creation of orally dispersible powders, packaged in stickpacks or sachets. The strength of this product is not only the shorter development time, but also that it is designed to be used without the need for a water or food vehicle.

Lubripharm SSF (sodium stearyl fumarate) — This is a lubricant system that offers a lower impact to disintegration time and tablet hardness. This is often essential for developing orally disintegrating tablet or fast melt tablets. In addition, Lubripharm gives fewer incompatibilities compared to standard direct compression lubricants.

Additionally, we have found that our customers look for information in various ways depending on how they are tackling the formulation and with what type of information they are given at the start of a project.

We have a table for Mannogem Mannitol,1 which differentiates the grades, notes the target applications, and lists the possible dosage forms. If the formulator already knows what application they need, this will help them to determine which grade is best suited for their requirements.

Advancing approaches One of the main advances we have seen in OSD formulation over the past decade is in the development and use of co-processed excipients and the use of full pre-formulated solution platforms that provide the requisite functional attributes for both compaction and disintegration.

These engineered solutions provide improved performance and also simplify formulation time; thus, leading to a decreased development time and products getting to market to help patients more quickly.

In the future, we believe that some advancement will come in the manufacturing approach, leading to unique process improvements in creating the dosage forms. As an example, the pharma industry is moving toward continuous processes that will require even more pre-engineered or co-processed excipient platforms to help with the upcoming unique challenges.

An increased emphasis will likely be put on the development of specific formulations for certain groups of patients, such as paediatrics and geriatrics where there are still minimal amounts of specifically designed products catering to the specific challenges of these patient groups. Flexible dosing, palatability and swallowability will be absolute key considerations for future oral dose forms. As a result, designing improved and novel, agile excipient platforms that meet these specific challenges will become a core requirement.

We also offer product selection guides for our Antacid Active and DC Calcium Carbonate products. These tools allow our customers to follow a thought process to determine what product grade would work best for their formulation and then steers them to further information about that product. The comparison guide is a quick reference to explain what the components are, how they work and why they are used in a formulation.2

References: 1. https://www.spipharma.com/products/mannogem-mannitol 2. https://www.spipharma.com/documents?document_type_id=1166

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SAFETY

Challenges of containment Containment in oral solid dosage is not just about product quality, regulatory adherence and patient safety. In fact, containment solutions for OSD are primarily concerned with the safety of those involved in producing life-saving medication — the operators. Marcus Behrens, vice president Sales Pharma Solid, Bosch Packaging Technology, goes into more detail…

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Containment prevents biological agents from escaping either both into the working surroundings and the external environment.

I

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solator technology has been an integral part of pharmaceutical liquid filling operations for decades.

Many of these parenteral drugs must comply with the highest possible standards and are therefore protected from contamination during production and filling. Consequently, the main task of isolator technology is to ensure absolute sterility, thus protecting the product and hence the patient from any kind of exterior influence. In oral solid dosage (OSD) production, it is of course equally important to protect drugs and patients from any harm. However, the focus is slightly different and more towards the operational part.

Operator protection is paramount In OSD production, the main challenge lies in protecting the operating staff. Just imagine an operator who has been working with hypnotic agents for an entire day without the obligatory containment protection.

How is he supposed to perform his tasks for an entire shift, or even drive his car home?

The same — and worse — is true for extremely potent drugs such as oncology therapeutics or hormones, which are also rapidly advancing in OSD. The need for appropriate containment solutions has evolved with the toxicity of the drugs.

Containment prevents biological agents from escaping either both into the working surroundings and the external environment. During capsule filling and even more during tablet compression, operators risk exposure to extreme dust development. Containment protects them from the harmful effects of product contact and product residue during all steps of the manufacturing, pressing and filling process.

It is quite difficult and awkward to protect staff with personal protective equipment (PPE). Highly potent APIs require closed processing and the use of self-containing equipment. Moreover, containment solutions must also be implemented for sampling, cleaning and maintenance activities. Very strict boundary levels have been defined, which make sure that even an unforeseen leakage will have no negative impact on the operators’ health.

These levels are expressed in two different ways. The occupational exposure limit (OEL) is defined in microgram per cubic metre, and is related to the maximum permissible API concentration in the air at a workplace during an eight-hour shift. The occupational exposure band (OEB) relates to the toxicology of the API. OEB 5 is the highest level of toxicity, corresponding to a maximum OEL of just 1 µ/m3. If transferred to the Empire State Building in New York, the entire building would only be allowed to be exposed to one-twentieth of a teaspoon of this API. Depending on the pre-defined OEB or OEL, different containment technologies are required to ensure the best possible operator protection.

Containing all process steps Containment systems can be built around existing equipment. They require closed containers or biological cabinets, rooms with specially designed air handling and secure operating procedures, as well as containment interfaces, such as infeed, outfeed and de-dusting. What makes them so complex is the required sealing properties. Containment systems must be sealed as completely and as reliably as possible according to the defined OEB and OEL levels — not only during filling or pressing operations but also during sampling, maintenance and cleaning operations. All-round, inflatable seals make sure the contained equipment is optimally closed.

Moreover, pressure measurements in the sealing enable operators to react very quickly in case of an unexpected leak.

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As far as cleaning of contained capsule filling systems is concerned, we can distinguish two main technical options. The more cost-effective solution for products with a lower toxicity level such as orphan drugs or immunosuppressants includes dry, manual cleaning and an optional wetting function. The use of glove ports and handheld spray nozzles is probably the easiest way to clean the interior. The nozzles and the use of fine mist enable the operator to accomplish the task up to OEB 4 with as little water consumption as possible while binding airborne particles.

The most important prerequisite is that all corners and components are easily accessible.

Proven processes for new concepts At OEB 5, washing-in-place (WIP) is not only the safest but realistically the only option. At this level of toxicity, it is even more important to prevent operator faults and to ensure reproducible results. If the washing programme is able to store and recall cleaning protocols, WIP processes are reproducible at any time.

This is easiest to accomplish with proven technologies and equipment that have been in use for decades.

The inte rio filling m r of the GKF 70 2 achine, w hich is su ProTect capsule ited up t o OEB 4 .

Relying on established processes also enables an easier transfer of containment technologies to other equipment, such as tablet presses. While the main principles of containment remain the same, there is one significant difference: tablet pressing operations develop a much higher amount of dust. These large material agglomerations are difficult to bind with mist. However, the operator can still save large amounts of water resources — if the equipment is designed according to the criteria of accessibility and reproducibility.

Since you never know A compact exterior and interior design, a straightforward exactly how toxic a drug arrangement of all components and an intelligent electronic system largely facilitates manual washing is going to be until it operations and makes all parts of the machine easily has been thoroughly accessible.

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tested, R&D processes require especially flexible containment solutions

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From R&D to complete systems

With the emergence of more and more highly potent OSD, R&D activities are especially important — not only for the development of new drugs, but also of new containment solutions. Since you never know exactly how toxic a drug is going to be until it has been thoroughly tested, R&D processes require especially flexible containment solutions.

Before proven otherwise, a new drug will usually be classified as highly toxic during the first phases. Equipment that is able to handle both very small R&D batches and small to medium production batches is the safest option, both in terms of process stability and containment.

Some drug manufacturers have already constructed entire containment facilities, where building and equipment are optimally fine-tuned to one another. Involving the equipment supplier at an early planning stage can help save time, space and costs by integrating all required equipment to complete systems, including elements such as the air management system, a WIP centre to supply cleaning materials, or an automated remote monitoring system for lights out operation capabilities.

Thanks to the use of sensors and the increasing connectivity of machines and facilities, manufacturers can further increase production flexibility and efficiency — and are well equipped for future containment challenges.

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CONTINUOUS MANUFACTURING

Understanding the continuous process In this article, Jamie Clayton, operations director, Freeman Technology, considers the challenge of implementing continuous tablet production and evaluates dynamic powder characterisation as a technique to support the development of a continuous wet granulation process.

R

ising development costs, the requirement for faster times to market and the growth of generics production, have contributed to the need to improve efficiency across the pharmaceutical life cycle. Quality by design (QbD) and the application of process analytical technology (PAT) are driving progress, and smarter approaches to process development and A successful process operation, such as continuous manufacturing, are gaining momentum. therefore requires

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a comprehensive understanding of how material properties and process parameters influence the output of each stage.

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Batch production still dominates as it is well established and has recognised benefits.

Manufacturing discrete batches makes it easier to isolate problems, and stringent regulations can also deter development of new practices.

However, even a well-optimised batch process can suffer inefficiencies; batch variability and products out of specification are not uncommon.

Continuous processes provide benefits such as reduced labour requirements, lower capital investment and simplified scale-up at the same time as addressing problems associated with batch variability to ensure consistent output. However, developing continuous processes that deliver these benefits is a challenge that requires a comprehensive understanding of both the process and the materials.

Many pharmaceutical manufacturing operations can already be considered semicontinuous; roller compaction, milling and tabletting, for example. However, the finished tablets are the product of several sequential operations which together combine active pharmaceutical ingredients (APIs) and excipients to deliver a tablet with the required critical quality attributes. Figure 1 illustrates the typical stages in tablet production, which in batch manufacturing are managed on a discrete basis.

The first step is often wet or dry granulation, to convert often dissimilar excipient and API particles into a homogeneous, granulated mass to avoid downstream segregation and improve processability. In wet granulation, the exiting mass is dried to remove excess moisture, and in both cases the granulate is typically milled prior to the addition of further additives to enhance performance in the tablet press. To ensure efficient processing, the output of each of these operations must be optimised for the next stage and in batch manufacturing, the approach is to apply well-defined procedures, assess the outcome, apply any remedial action, then move material to the next stage. This requires manual intervention and off-line analysis.

Continuous manufacturing involves integrating each of the process steps, making it essential to control each in real time to ensure a suitable output for the following stage, with minimal intervention between stages. However, the various processes employed in tabletting will subject powders to a range of stresses and flow regimes, such as forced flow through an extruder, unconstrained flow into an empty tablet die, and compression. A successful process therefore requires a comprehensive understanding of how material properties and process parameters influence the output of each stage.

In wet granulation, for example, screw speed, feed rate and water content all contribute to granulate properties so success relies on understanding how a powder responds to these variables and how to manipulate them to produce granules that are optimised for subsequent steps.

It’s increasingly acknowledged that traditional powder tests, such as angle of repose, flow through an orifice, and tapped density measurements, provide limited information. They may provide some insight into powder behaviour but are often compromised by poor repeatability and reproducibility, as well as a lack of sensitivity.

Furthermore, the test conditions don’t represent the conditions in process, limiting the ability of these methods to deliver relevant information.

In contrast, dynamic flow testing measures various properties of a powder in motion, and under conditions that simulate the process environment, providing relevant information that rationalises in-process behaviour.

Figure 1: Typical steps in oral solid dosage production

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Basic flowability energy (BFE) is determined by measuring the axial and rotational forces acting on a rotating blade as it descends through a powder (Figure 2) and reflects how a powder will flow under forced conditions, such as those in an extruder or feed frame. Measuring BFE in different states quantifies the impact of processing conditions such as consolidation and fluidisation. determines r Rheometer ting e FT4 Powde and force ac ue rq to e Figure 2: Th th n of tio r nc de fu w a h a po flowability as verses throug ade as it tra against a bl

Table 1: BFE data for granules manufactured under different conditions

Case study: Applying dynamic powder testing to define a wet granulation design space Studies were undertaken to quantify the quality of granules produced during wet granulation. The aim was to investigate relationships between dynamic flow properties of granules and critical quality attributes of the resulting tablets.

A GEA Pharma Systems ConsiGma 1 high shear wet granulation and drying system was used to produce granules and BFE was measured at four stages: on exit from the granulator; post-drying; post-milling; and following blending with a lubricant. Two different blends were evaluated: one based on paracetamol (APAP) the other on dicalcium phosphate (DCP).

The first investigation assessed the impact of varying water content, powder feed rate and screw speed on the BFE of the resulting granules.

Figure 3 shows how BFE of the APAP granules produced at different screw speeds varies as a function of water content.

At constant screw speed, increasing water content, results in a higher BFE. Decreasing screw speed, at a given water content, produces granules with a lower BFE. This is consistent with the observation that higher water content and lower screw speeds tend to produce larger, denser and more cohesive granules that present substantial resistance to blade movements. Furthermore, granules produced at a water content of 11% and screw speed of 600 rpm have similar BFE values to those generated using a screw speed of 450 rpm and a water content of 8%. This introduces the possibility of producing granules with similar properties using different process conditions, an important factor in defining the operating scope.

Figure 3: Increasing granulator screw speed and decreasing water content produces APAP granules with a lower BFE

Figure 4: Increase feed rate to the granulator produces DCP granules with a lower BFE

Table 1 shows BFE measurements for two pairs of granules, each pair having similar BFE values but produced using different conditions.

Conditions 1 and 2 result in granules with a BFE ≈ 2,200 mJ, while 3 and 4 have a BFE ≈ 3,200. The BFE of these granules was also measured at the four stages detailed above.

Figure 4 shows the impact of dry powder feed rate.

The BFE of DCP granules, produced with a fixed water content of 15% and constant screw speed of 600 rpm, was found to be indirectly proportional to feed rate. Reinforcing previous findings, granules produced at a feed rate of 18 kg/hr with 15% water had similar properties to granules containing 25% water made at a feed rate of 25 kg/hr.

Figure 5 shows how the BFE changes following each stage of the process. Granules made using conditions 3 and 4 show an increase in BFE after drying while those produced using conditions 1 and 2 remain relatively consistent. This increase can be attributed to the granule’s relatively large size which, in combination with increased density Figure 5: As the granules are dried, milled, and blended BFE and hardness, results in changes significantly, but a distinct difference remains between the increased mechanical two sets interlocking when dried, and greater resistance to forced flow.

The granules produced using conditions 1 and 2 have a weaker structure, lower density and relatively small size, and are therefore less prone to mechanical interlocking. The BFE of these samples therefore only changes slightly following drying. After milling, particle sizes are more similar and flowability for the four batches converge, although differences in granule density, shape and stiffness still exist, rationalising the differences in BFE which are retained following lubrication.

These results demonstrate the flexibility to produce granules with specific flow properties. The next stage was to determine whether such properties could be targeted to ensure tablet quality.

Tablets were produced from the four sets of lubricated granulates and Figure 6 shows the strong correlations between the BFE of the granules at each stage and the hardness of the resulting tablets. This demonstrates how operators can ensure a critical quality attribute of the finished product by adjusting critical process parameters to Figure 6: BFE of the granules correlates strongly with tablet hardness target properties of an intermediate. This has the potential to accelerate development and scale-up and facilitate efficient process control during routine operation.

The need for increased efficiency throughout the pharmaceutical lifecycle is encouraging the industry to innovate new manufacturing practices. The economic gains of continuous manufacturing are a considerable attraction but the challenge of developing successful processes is not inconsiderable. This case study highlights the relationship between the flow properties of a formulation and the critical quality attributes of the resulting tablets, demonstrating the potential role of dynamic powder characterisation in advancing manufacturing processes and the implementation of continuous manufacturing.

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CASE STUDY: TABLET PRODUCTION IMPROVEMENT

The right tools Who:

Novartis and I Holland

What:

Improvement of tablet production

How:

Application of coating solution

The companies Novartis, is a company that provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines, over-the-counter and animal health products.

I Holland has origins that date as far back as 1910 when it was established as a general engineering and machining company by Mr Israel Holland. It is now a global manufacturer and supplier of tablet compression tooling.

The problem The Italian division of Novartis approached I Holland with a variety of challenges they encountered when producing a stimulant laxative in the form of a 5 mm round tablet.

Novartis reported a number of key issues when using tools from their existing supplier, including wear, alignment and interchangeability problems. There were also difficulties with tip breakage under high compression force and consistency of the working-length of the punch.

Monoblock mult i-tip tooling he lps to increase prod uctivity.

The key issues Technical issue – wear to the tooling Novartis Italy’s tooling from their existing supplier, was seen to wear very quickly with an average of 300 million tablets produced per tooling set and dies having to be turned after just 150 million tablets.

Technical issue – breakage Breakage was another major issue during production. With a maximum force of just 15–17 KN, breakage was still occurring. The lower tip was fracturing regularly, with lateral forces and excessive clearance contributing to the problem.

The tooling used was wearing very quickly.

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Technical issues – alignment It was found that some of the long-standing presses being used had wear on the turret guides and die bores. This is a challenge that many manufacturers face. These presses had many years of working life to come, but the problem needed a creative engineering solution.

Alignment issues were found on the press, with wear of the die pockets

The results Due to the proactive approach taken by the tablet compression specialists at Novartis and an excellent working partnership with I Holland’s technical support staff and local agent Vis Viva, tooling was integrated which incorporated the coating solutions and the superior monoblock multi-tip; this resulted in much improved productivity.

Alongside the change to the dies and the coating used, modifications were made to the clearance and radius on the lower tips. With these adjustments the problems previously encountered were solved completely.

The application of the improved use of coating PharmaCote CN+ was trialed and the wear on the tooling was much reduced, this was after increasing compression by 20%. Results also saw no breakage during production. The increased tooling life saw output increase from 300,000 tablets to 400,000 tablets per set.

Use of PharmaCote HPG-TC saw a three-fold reduction on die wear. By changing to the recommended improvements, I Holland helped to increase the working life of the dies by three times, producing one billion tablets.

The new monoblock multi-tip, with the suggested coating, helped to reduce the overall cost, increase productivity and ensure the consistency of the punch length.

Lower tips were breaking easily

The trial With many issues being encountered during production of the tablet, it was important to find a comprehensive solution. I Holland started their analysis by investigating the tablet design being used and suggested a new design, which would help improve downstream manufacturing problems such as tablet sticking, picking, lamination, capping and premature tooling failures. Due to restrictions on the design; acceptance of the proposed design could not be accepted.

With this in mind, I Holland made new proposals on the die’s outer diameter. Due to the wear in the die pockets, an increase in the outer diameter was used to improve the fit, together with an increase in the upper die clearance to allow inter-changeability with the guides being used.

In addition to the above measures, I Holland’s R&D department conducted an in-depth steel analysis. This concentrated on the tool steel and coating being used by the existing supplier to see why it was failing. Trials took place using a variety of coating solutions to observe the effect on the end-product. I Holland advised the use of it’s premium ESR grade steel with PharmaCote CN+ (Chromium Nitride Plus) and HPG-TC (Tungsten Carbide) dies.

PharmaCote CN+ has impressive anti-stick properties combined with excellent wear and corrosion resistance. It was found to be the best coating solution to combat the challenges being encountered. Together with HPG-TC dies, a material with extremely high wear resistance and compressive strength, the results were outstanding.

Finally, a monoblock multi-tip tooling was also introduced. This is a punch incorporating multiple tips from a single piece of steel.

The conclusion Compressing these tablets brought with it many issues, but with a thorough investigation from I Holland, the key problems of wear, alignment, interchangeability and tip breakage were all overcome with a sophisticated solution.

The correct choice of punch and die treatment had a huge impact on productivity. When coatings are developed correctly, and their beneficial characteristics are matched to those of the formulation, they can help to increase corrosion resistance, wear resistance and prevent other problematic factors like formulations adhering to the punch tip faces.

In this instance a resilient coating solution was found that worked with the correct high-quality steel tooling choice to effectively and efficiently optimise the production process.

With a monoblock multi tip tool chosen as the best solution to help increase productivity, it was important to use a die alignment tool to check the wear of the die pockets and the alignment of the turret.

If setting of the die is not performed correctly, then both the upper and lower punch can be misaligned when entering the guide causing punch tightness. This will result in contact between punch tips and the die wall causing friction and heating resulting in premature wear.

The size of the die pockets is also important. Dependent on condition, the die table may have to be replaced, or a revised tolerance to the die specification would need to be applied. Die pockets must also be clear of any foreign objects or burrs and the die fixing bullets should be in good condition to ensure the multi tips work to their full capacity.

With the combination of well manufactured multi tip tooling, using the correct raw material and coatings, the use of multi tips help to see greater productivity, and a reduction in run-time per output of tablets, leading to less maintenance per batch and reduced press set-up time.

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16.10.17 13:44

PATIENT FOCUS

The soluble option Do you encounter difficulties when swallowing tablets?

Head of product development at Catalent Pharma Solutions, Ralph Gosden, reveals why the Zydis platform is still a game changer, and what is on the cards for the near future.

A

round 35% of the general population have difficulty swallowing!

Initially, I found this statistic hard to believe but actually having met people who do struggle, not just with the larger tablets but the smaller ones like paracetamol and even the contraceptive pill, I came to the realisation that there are many healthy, middle-aged people — as well as the usual sensitive patient groups — who cannot easily take pills.

Why Zydis?

Digging deeper, there are other factors that must be considered from a patient perspective when looking at swallowability. For example, in certain diseases, such as cancer, the treatment can cause a patient to suffer from a dry mouth, which makes taking tablets extremely uncomfortable.

Now, for patients who struggle to swallow or perhaps need a product that has a pleasant ‘mouth-feel’ to ensure adherence to a medication regime, this disintegrating technology offers great benefits and this is probably why we have seen growth in the full R&D pipeline of Zydis ODT.

Furthermore, for some patients who have mental health disorders, such as schizophrenia and bipolar disorder, side effects of these disorders (e.g., paranoia) can be a barrier to them adhering to their treatment schedules. If a pill tastes bad or sticks in the throat, for example, they may feel like someone is trying to poison them and will stop taking the drug.

How do we make it?

So, Catalent’s commitment to putting the ‘patient-first’ is important when manufacturing an oral solid dosage form, as these popular delivery methods must also ensure a satisfactory level of patient adherence.

Zydis technology is an orally disintegrating tablet (ODT) form that has been around for about 30 years now. It allows us to load an API onto a disintegrating tablet, effectively taste-masked, that disperses within the mouth in as little as three seconds.

We start off with a suspension or solution, we dissolve polymer in water, add the active ingredient — at this stage with Zydis ODTs we are limited to 25% loading for a suspension, for a solution product it’s much lower because that can have impact on downstream processes. This gives us our batch, which can then be dispensed directly into the primary packaging pockets via metered dosing pumps.

But, the true magic of Zydis technology is in how we freeze it. It is flash frozen using nitrogen. Through this freezing process we actually drive off the water leaving the API adhered to the polymer matrix. It’s those gelatine strands that are left behind with the active material impregnated on it that gives us the fast dissolve.

What about the taste?

This is a commonly asked question, can a Zydis ODT be effectively tastemasked? When you pop the tablet onto your tongue and it dissolves, without taste-masking essentially all of that bitter tasting API would drop straight onto the taste buds, which is not going to give a great patient experience!

In fact, there is a lot we can do to help in this area. So, the first port of call is flavours — which, for many drugs, is effective. Sweeteners can also be used to mask bitter taste but more and more we are finding that there is a need to modify the pH.

pH modification

uct mix. d o r p h it lling w Blister fi

Through this type of modification, we can adjust the form of the drug — so, we can make it less soluble in the mouth and the tablet simply dissolves in the stomach instead and is absorbed in the usual way. Equally, we can employ more advanced approaches, such as ionexchange resins and cyclodextrins — binding the drug so that it is not available to the taste receptors, which again prevents dissolution in the mouth and the drug is absorbed in the usual way.

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“

I would also like to point out that pH modification can be effective for areas where we need buccal absorption as well. The pH in the mouth is naturally around about seven, if you want a lower pH to aid buccal …advantages of Zydis absorption, we can add additional pH modifiers into the formulation to technology include rapid the saliva pH and help the disintegration, bioavailability change drug get absorbed.

enhancement, smooth mouth feel and, a key thing, improved compliance…

”

Advantages and challenges

The advantages of Zydis technology include rapid disintegration, bioavailability enhancement, smooth mouth feel and, a key thing, improved compliance — which is a result of quality of the product and the ease of administration.

This is a well-known product now, but we have encountered some challenges, including masking the taste of very bitter APIs and restrictions of drug loading.

These challenges are associated with the big sellers too such as paracetamol, and let’s take ibuprofen as our example here. With ibuprofen the usual dose in a tablet is 200 mg so trying to put that into a Zydis ODT, we would end up with a tablet that is about 20 mm across and that doesn’t even take into consideration the extra weight we would need for taste-masking! Let’s face it, even if the tablet dissolves in the mouth that will be a daunting prospect, let alone the size of the blister packs that we would need on the supermarket shelves.

The solution?

So, we were faced with the challenge to effectively taste-mask ibuprofen and I can say that we’ve done it with Zydis Ultra. So, we’ve proactively developed this, we’ve got it to a great phase and are currently working towards commercial manufacture with customers.

We’ve achieved this by investing in some technology from the New Jersey Institute of Technology — acoustic coating. Essentially what we’ve been able to do with this technology is to take a polymer, which we then place in with the powder (completely dry), we subject the mix to intense vibrations and that coats each individual API particle. The polymer is transferred into a coating and it is seamless — so no cracks or deficiencies.

Something that we have been faced with in the past with the Zydis platform is that the coating can be knocked off. Basically, when we have put the coated particle into a tank full of suspension or solution and stirred it the coating has been disrupted.

To overcome this, we looked at a continuous manufacturing process where instead of making a tank and drawing off the individual doses and over the next 24–48 hours we’re filling off pockets from the batch, now what we’re doing is we’re taking our powder blend and mixing it with the liquid part of the Zydis formulation and literally at the point of dose they get mixed and go into the pocket and that allows us to overcome this issue with the coating being knocked off. So, the tastemasking is not affected.

An added benefit of mixing at the source too is that the drug loading restriction has also disappeared, and we found that we can go up to about 50%, so it brings the size of the tablets down by about half.

Future prospects?

When asking ourselves what would be great for the industry to achieve in the next five to ten years, we would all say a cure for cancer probably as our number one. That really would be great but for the foreseeable future a major area I can definitely envisage Catalent having some sway is in oral vaccines and the Zydis platform has the potential to remove the need for end-to-end coldchain storage of vaccines.

With Zydis technology, being able to process the product cold, just plays into the hands of being able to develop oral vaccines. We’ve currently got more than one development programme going on at the moment on oral vaccines and we’re building up a body of data on what we need to do to get these things to work, so watch this space!

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