Who is Who in Dosage Form
The Who is Who in Dosage Form section, provides the point of view of some of the companies that deal with dosage form technologies on what is going on in this specific area of the pharmaceutical industry.
Companies interviewed by Pharma Horizon have given their opinion on the following three topics: the lights and the shadows of the dosage form marketplace; main market novelties in the upcoming future; actions undertaken by companies in order to propose cutting edge solutions.
Dose form technologies and expertise to enhance bioavailability
The movement toward personalized medicine, which is a highlight in our sector, is having the effect of smaller patient populations resulting in reduced manufacturing volumes of these high value solid oral dosage forms, particularly in the oncolytics area. Oncology is one of the top therapeutic areas of interest in pharma today. A shadow is that today’s highly specific, novel compounds may be difficult to formulate to achieve optimal bioavailability. Manufacturers must employ unique dosage form technologies, and possess a high level of expertise to handle the nuances in sophisticated formulation development in order to be successful in this area.
Unique delivery systems and profiles will become more apparent in oncolytics, as we have already seen in pain management. This includes dual APIs in a single dose, coating API on a core, or modified release formulations – extended or controlled release profiles, for example.
AbbVie Contract Manufacturing utilizes hot melt extrusion (HME) – a technology pioneered nearly two decade ago – as a key formulation development and dosage form technology to enhance bioavailability of solid oral doses, including potent. HME is an environmentally friendly, robust and reliable enabling technology recognized globally by regulators.
Scaling up to commercial manufacture levels require a high level of expertise and experience to ensure the formulation delivers the correct dosage and associated therapeutic effect.
Ensuring the safe handling of hi-value therapeutics
Aseptic fill and finish dosage form manufacturing is on the rise as very few biopharmaceutical companies have the expertise or resources to execute in-house. Fill and finish manufacturing is a complex and highly specialized process involving a substantial number of manipulations. Executing it well requires special facilities, equipment, and a tremendous amount of operator training.
In addition, biotech companies who develop and manufacture biologic drug product must have the ability to successfully preserve the native state of a biologically active protein in order to deliver effective therapies. For complex biotherapeutic drug product manufacturing, not only does the bulk drug substance require special handling procedures, but the formulation, sterile filtering, and filling of the final drug product does as well. Biologic drug developers and the contract manufacturing organizations they partner with must consider a broad range of factors critical to the success of their manufacturing.
A controlled environment equipped with the expertise and experience needed to ensure the safe handling of high-value therapeutics becomes incredibly important.
Althea is focused on aseptic fill and finish and has invested significant resources to build manufacturing platforms that specifically protect the integrity of large molecule biologics. With respect to current drug delivery challenges, Althea has developed a cutting-edge solution, Crystalomics® Formulation technology that enables crystallization complexes of therapeutic proteins allowing drug developers the ability to design highly concentrated formulations with low viscosity and increased stability. This approach transforms daily injections into weekly and intra-venous into sub-cutaneous injections while retaining integrity, structure, and activity.
Better process understanding key to advancing dosage form manufacture
Physical processing of the multiple components that go into modern dosage forms creates considerable complexity in process understanding. The linkages between critical quality attributes and the constituent material properties and process parameters of the multiple unit operations involved (granulation, compaction and coating) grow exponentially as the number of materials increase.
With a regulatory drive moving manufacturers away from low sigma, conventional batch processing towards high sigma, flexible continuous manufacture, there is an increased need to improve our understanding of the processes that produce dosage forms, the influence of technology options, and the upside and downside consequences across the value-chain, of choices made in product, in process design, and in manufacture.
Owned by our member organisations, and operating through a unique collaborative ethos, Britest has been active in the field of process understanding and whole process design for over fifteen years. Britest is currently driving projects that will help pharmaceutical companies better understand, select, and optimise different and competing dosage form technologies. Digital Design, for example, offers the exciting prospect of more sophisticated definition, design and control of optimized pharmaceutical manufacturing processes using data analysis and first principle models to deliver new, higher quality medicines to patients, faster and more cost effectively. The ADDoPT project (www.addopt.org) is working across the pharma value chain making Digital Design more widely usable within the pharmaceutical industry, increasing efficiency and effectiveness of drug development and manufacture.
The future of suppository medication in the pharmaceutical marketplace
Suppository medication has been utilized for thousands of years as a safe and effective delivery mechanism allowing medication to quickly enter the bloodstream, bypassing both the liver and the kidneys. Rectal suppository medication allows fast systemic absorption with less toxicity to the body.
Although cost efficient and trusted, the technology hasn’t been modernized in over one hundred years. It is not currently thought of as a leading edge technology, yet offers pragmatic therapeutic benefits.
Improved suppository drug formulations are currently being created to enhance the drug release profile. In addition, novel technologies that can reduce administration times from 45 minutes to less than one minute are available on the market today. These new delivery improvements make suppository usage more conducive to lifestyles of people in the 21st century.
The main novelties coming to market in the near future will include unique formulations with controlled release of the API over a sustained period of time. Modernization will also make suppository drug delivery more patient/consumer friendly allowing faster and easier administration.
The continuing growth of highly potent formulations
The growth of the emerging bio/pharma market is fueled by healthy funding from venture capital, public equity and partnering deals. This provides a significant source of opportunities for CDMOs.
Choosing the right delivery of the Active Pharmaceutical Ingredient (API) is critical to a successful development program. In addition to physiochemical characteristics, there are business opportunities with the application of new sophisticated drug delivery systems.
Opportunities include intellectual property development, life-cycle management and the introduction of new products through 505(b)(2) filings.
With innovation in oncology expected to continue to be high, demand for the formulation of highly potent compounds will continue to grow. At CordenPharma we have assembled a service offering which targets both parenteral and oral solid dose delivery systems for oncological products.
Expanding parenteral capacity, such as CordenPharma has done with its new pre-filled syringe (60,000 units per day) line and vial filling line (50,000 units per day) with lyophilization capabilities, serves the needs for small molecules and the growing demand for oligonucleotides and biologics.
Investments in Drug Product technology are additionally aligned with a broader corporate strategy of offering integrated services (APIs, Drug Product, Packaging & Logistics) to clients.
This results in a simpler and faster development path.
Working to meet regulatory and anticounterfeiting measures
The lack of FDA approved capacities in sterile (PFS, lyophilisation and ophthalmic) and high potent (API and Drug Products) technologies are driving demand.
Additionally, packaging innovations that help to improve patients benefits or to reduce costs for the health insurances generate opportunities like:
- the ophthalmic Novelia system (preservative free multi-dose) from Nemera to reduce the side effects of preservatives on the eye. It is strongly supported by the European authorities and now growing in the USA;
- the pre-filled syringes (PFS) to make easier and safer the injections. It significantly reduces treatment costs for governments or insurance companies.
One of the major challenges of the industry is the anti-counterfeiting measures. To be on time in USA (November 2017) and in Europe in February 2019, it will significantly increase production costs.
Some CMOs might not invest and exit the prescription business to focus on the OTC, some products might be withdrawn from the market for this reason.
Generally speaking, the increasing regulatory expectations (Data integrity, Elemental Impurities, EU GMP: chapter 3&5, Annex 16, risk excipient, etc…) are generating additional fixed costs, especially in Manufacturing and Quality. Consequently, the critical mass of factories becomes essential to absorb those new costs and keep competitiveness.
Concerning the OTC/Medical Devices business in Europe, the switch from OTC to Medical Devices (EU /93/42) is still progressing.
In the USA as well as in Europe, the demand for natural products continues growing. More and more players are also adding food supplements to their offer. We also foresee an increase demand for monodose packaging such as solid and liquid stick packs.
Fareva invested more than 60 mEUR over the last 2 years to answer the high demand in technical products like PFS, BFS, and sterile ophthalmic ointment. We are also offering more and more ready to use products to customers looking for ready to sell generic drugs, medical devices and food supplements.
Present and future of premixed solutions
Demand for premixed solutions is increasing at a healthy rate, mainly due to the fact that premixed IV solutions are the preferred mode of delivery for antibiotics, pain management and cardiac medications globally.
By eliminating the need for admixtures, premixed bags manufactured in a cGMP compliant facility provide the highest level of safety available. In addition to reducing the risk of medical error, premixed bag greatly decrease the threat of microbial contamination.
Quality issues have plagued the injectable drug market in recent years. Numerous recalls due to product quality issues have contributed to shortages of many injectable products in the United States.
A key indicator of the quality of injectable drug products is the extent of foreign particulate matter.
Various Pharmacopeias include standards for the production of injectable products, but meeting requirements for the manufacture of products that are “essentially free” of particles is very challenging.
Overall design of the premixed fill, package material, and the functional attributes of the IV bag are integral to patient-centric product strategies.
With a vertical integration approach Grifols has control of the entire process from start to finish, ensuring that all parts of the manufacturing process are performed following the same high-quality standards.
The use of Form-Fill-Seal technology at Grifols Partnership for premixed bags provides a good example of how vertical integration results in the highest quality performance.
Safety should be more than just a regulatory requirement; should be a philosophy that goes hand- in-hand with quality, and both apply not only to the products, but manufacturing, communication and operational processes.
Addressing patient-centric drug specialization
The pharmaceutical industry is witnessing several upward trends. One is an increase in 505(b)(2) new drug application (NDA) pathway projects to help avoid unnecessary duplication of studies, most of which involve API held by virtual or small pharma organizations. Another is an increase in extended- or modified-release formulation projects with durations of two to six hours, rather than the typical 12 to 24 hours.
A third is an increase in potent and cytotoxic projects requiring Occupational Exposure Limit (OEL) Category 3-related handling, and a fourth is increased demand for roller compaction services that offer greater flexibility in batch sizes and inherent containment during processing.
The fact is that drug products are becoming increasingly complex while also moving toward greater patient-centric tailoring or specialization. This trend means contract development and manufacturing organizations like ours must remain flexible and keep things simple when it comes to formulating and manufacturing CTM batches. Flexibility and simplicity allow for accelerated timelines needed to supply materials to clinics quickly, especially when it involves GMP batches at very small scale — useful when API availability is limited, which is common in early stages of a project.
Currently, Metrics and its parent, Mayne Pharma, are completing an $80-million oral-solid dose site expansion to be fully operational in early 2018. When the building opens, Metrics will offer a more comprehensive “concept to commercialization” solution in one contiguous location for clients — providing larger scale and increased capabilities for seamless scale-up, and eliminating the need for site transfers. A highlight of the expansion includes commercial-scale manufacturing capability with solvent-based, fluid-bed processing and film coating — a first for our operations in the United States.
Inhalation dosage forms: managing complexities and overcoming hurdles
As incidences of respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma rise rapidly, so too is the global demand for inhaled drugs to treat these conditions. Such products create an opportunity to improve the effectiveness of treatments, allowing active pharmaceutical ingredients (APIs) to be delivered directly to the lungs in smaller doses, reducing the risk of side effects and drug-to-drug interaction.
However, inhalation drug products represent some of the most complex dosage forms on the market. For example, selecting the best formulation and device, ranging from metered dose inhalers (MDIs) to dry powder inhalers (DPIs) and nebulised forms, is critical during the development stages. There is also a need for more rapid and precise methods for analytical characterisation of inhalation aerosols, a challenge that is currently limiting the development of pharmaceutical products for inhalation.
With expertise in the development and manufacture of inhalation products, Recipharm is focused on overcoming these challenges and managing the complexities of developing inhalation dosage forms. The company expects to see more precise analytical characterisation techniques being used in the future, enabling rapid decision making and expediting drugs to market. Alongside this, Recipharm also provides development and manufacturing expertise for solids, semi-solids, liquids, APIs and ophthalmics.
Advancing to meet patient’s needs
The positive aspect of the pharmaceutical market is the great innovation impulse to meet the patient’s needs and to offer solutions for technology issues, combined with the more recently debated, cost reduction of innovative drugs. However, regulatory aspects will continue to challenge real innovations as they may be problematic, which could slow implementation.
New novelties such as the first 3D print tablet have been FDA approved recently; others are anticipated to hit the market using this same revolutionary technology which will redesign pharmaceutical facilities. Siegfried, like other CDMOs, will assist to an increase launch of new injector devices, coupled with cartridge systems to deliver more accurate doses of drugs, which ultimately prevents waste of expensive Drug Substances, especially for Biologics.
As a leading CDMO, we gauge often client incite to anticipate their future needs. Siegfried has decided to focus more in biologics fill and finish with an eye on personalized medicine, adding advanced equipment and new lines to our Sterile Drug Product units so we can offer customized solutions to meet customer needs. We feel it is important for Customers to minimize waste of expensive Drug Substance during filling operations in the clinical phase; we have installed and qualified a new filling line for vials dedicated to biologics and designed with this scope. Siegfried utilizes ‘Ready to Use’ vials which prevents expensive machine change parts and further qualifications. Additionally, we invested and qualified another filling machine to meet increasing demand of ‘pre-fill syringes’ and cartridges for the aforesaid devices.
These specific dosage forms allow patients to receive accurate doses of medicines without expensive overfills. These site enhancements combined with existing technologies to develop and manufacture vials, ampoules, ophthalmic bottles and tubes, tablets and capsules, we strongly believe will support both current and future market demand.
Developing patient-friendly dosage forms
Global consumer demand currently focuses on ease of use, better taste, and faster acting medications. Patient friendly drug delivery systems will open new doors to pharmaceutical companies looking to fulfill these needs.
As companies wrestle with pipeline and product life cycle management, patient friendly dosage forms have become an increasingly popular option. They are designed to appeal to the specific needs of various patient groups. Around 30 to 40% of the general population experiences dysphagia or has difficulty swallowing traditional pills. Even higher rates of dysphagia are seen in elderly patients, especially those in acute care facilities who are bedridden or suffer from conditions that affect swallowing.
APIs addressing indications such as cough/cold, pain management, fever reducers, CNS disorders, and many others, can be adapted to orally dispersible delivery systems when partnered with the right taste masking technology. Patient friendly dosage forms include, but are not limited to, Orally Disintegrating Tablets (ODT), Orally Dispersible Powders (ODP), and Chewable/Meltable tablets. These dosage forms meet specific performance requirements and help to reduce non-compliance by addressing specific customer needs of improved taste and greater convenience.
As a pharma company, we specialize in excipients and drug delivery systems, offering the first, and still gold standard, ODT on the market. We are also committed to continuing to expand the offering of products that work with many applications including sachets, taste masked actives, effervescents, and other novel dosage forms.