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Quality and safety - especially in times of change

The pharmaceutical industry is developing at an unusually rapid pace. Manufacturing companies are confronted with enormous challenges due to high market growth, new medicines and therapy forms, changing regulations and progressing digitization. Johannes Rauschnabel, PhD, Chief Pharma Expert at Bosch Packaging Technology, casts a glance at some important areas of growth and describes the changes drug producers as well as processing and packaging specialists are facing.

by Dr Johannes Rauschnabel
Chief Pharma Expert
Bosch Packaging Technology
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The market for pharmaceuticals is growing persistently. According to a current market report by the QuintilesIMS Institute1, expenses for drugs will amount to 1.5 trillion US dollars globally in 2021. This equals an average annual growth rate of between four and seven percent in medication expenses or three percent in doses. Despite political uncertainties regarding general healthcare, the U.S. will record the largest growth, while the so-called pharmerging markets will require about two thirds of the entire drug volume.
The reasons are obvious: global population is increasing (by 1.24 percent per year until 2030) and ageing at the same time. All in all, the proportion of people aged 65 to 80 will rise to 28 %, compared to 22 % in 2000. Increasing urbanization and a growing middle class are making drugs available and affordable for more people and also lead to a higher demand for medication.

Megatrend biologics
While the demand for common medication such as pain killers and prescription drugs like antibiotics is increasing in the pharmerging markets, completely new forms of treatment are emerging in industrialized countries thanks to the access to more complex substances. Accordingly, one of the most important pharmaceutical trends of the past years is extending to more and more people and regions. Groundbreaking changes are occurring in the area of biological agents, for instance regarding the treatment of cancer, autoimmune diseases, as well as rare illnesses which only affect a very small group of patients.
In the still relatively new cancer immunotherapy, for instance, the body’s own immune system is stimulated to fight against tumor cells. Monoclonal antibodies attach themselves to the characteristic structures on the tumor surface and mark the cells for macrophages or induce cell death. A further break-through in cancer therapy was achieved with checkpoint inhibitors. To protect the body against autoimmune reactions that would destroy its own tissue, the immune system is equipped with checkpoint molecules which prevent an overreaction of the immune system. By blocking the checkpoints, they open the way for the immune system to fight the tumor consisting of endogenous cells.
A highly promising research and application area deals with antibody-drug conjugates (ADCs). These high-quality biopharmaceuticals connect a certain substance to an antibody, which binds to a target structure such as an antigen on the surface of a tumor cell. This way, cytostatic agents - natural or synthetic substances, which inhibit either cell growth or cell division - can get to the center of the tumor cell like a Trojan horse, and can unfold their chemotherapeutical effect. Kinase inhibitors also range among the increasingly used targeted cancer therapies. They are able to slow down unrestrained cell growth, for example in chronic myeloid leukemia, by blocking the signal cascade that triggers cell growth. These molecules are set to become a new therapeutic standard. At the same time, they open up market opportunities for replica products.

Less expensive solutions for the masses
For several years, the pharmaceutical industry was awaiting the biopharma patent cliff with a certain concern. Now, the patents of some large biotechnical molecules have expired – and the production of biosimilars has begun. First biosimilars have already been approved during the past two years, for instance for the treatment of neutropenia or rheumatoid arthritis. Moreover, approximately 15 replicas of the monoclonal antibody Bevacizumab2 are currently being tested. Patent rights for the reference product will expire in 2019 in the U.S. and in 2022 in Europe. For patients, this development is a great progress, since many drugs are now produced in larger quantities and are sold at significantly lower prices. Authorities such as the U.S. Food and Drug Administration (FDA) promote the approval of biosimilars to make them available quickly for many people, while reconciling therapeutic advances with cost reductions.
As far as cancer treatment is concerned, the situation is similar in the pharmerging markets. Here, especially generic cytostatic drugs offer access to therapies that were so far very difficult to obtain or not available at all for the majority of the population. The cost-efficient manufacture of generic cytostatics now also enable these countries to make medicine available for a large amount of patients.

Targeting illnesses more precisely
Medicine is also advancing rapidly in the area of vaccines, where targeted campaigns are promoted strongly for instance by the WHO or UNICEF. Pharmaceutical companies are also committed to providing cost-efficient solutions for the development of new vaccines to fight malaria, HIV, Zika or Ebola - diseases which have now also made their way to the industrialized nations. Two aspects are at the center of attention: making these vaccines available for a large population, and simplifying their administration. Untrained staff or patients themselves should be enabled to administer their medicines as effectively and painlessly as possible.
The next step towards an even more targeted treatment consists in the use of stratified medicine. As opposed to cytostatic drugs, which kill both abnormal and healthy cells with a high division speed and can stop hair growth or lead to hair loss, stratified medicine follows a different approach by addressing patient groups with the same genetic preconditions. Molecular diagnostics serve to identify the genotype of a patient, thus predicting the efficacy and compatibility of each drug. This not only raises effectiveness; it also leads to less side-effects following the adaptation of the dose to a specific genotype.

Changing role concepts
All these pharmaceutical innovations require intensive research and development as well as adequate production environments to ensure a fast time-to-market. Pharmaceutical manufacturers must adhere strictly to legal requirements, and always be aware of potential changes to existing guidance. They must adapt their production environments to the demands of highly potent substances, while keeping new processes and increasing digitization in mind. Most importantly, they must be able to rely on high-quality equipment.
In the course of these changes, the roles of drug producers and equipment manufacturers have also changed – from a mere business relationship of purchaser and vendor to a partner-like collaboration, where equipment suppliers assume more responsibility. New projects hardly ever focus on a single machine. In contrast, the trend is towards complete solutions that go far beyond technical or mechanical know-how. Suppliers have advanced to partners, who accompany the entire process with profound market knowledge and technological expertise before, during and after project implementation, thus ensuring a fast time-to-market of new pharmaceuticals.

From laboratory to production
Before new pharmaceutical products can be introduced to the market, they undergo long and expensive research and development processes. At the same time, producers depend upon a fast market entry to make full use of their exclusivity during the limited patent protection timeframe. The keyword for a fast market launch is “scale-up”, meaning the transfer from laboratory to production scale. Parameters and recipes must be precisely conveyed from laboratory equipment to larger machines, always in line with Good Manufacturing Practice (GMP). Here, new simulation tools help to calculate the required process conditions and save a significant amount of time. Besides scale-up, another trend towards “scale-out” is currently to be seen, especially with small batches of targeted medicine. Manufacturing capacity is increased by copying existing manufacturing equipment and transferring it to other sites or even contract manufacturing organizations. This requires well defined processes, as well as affordable and robust equipment with a high degree of automation.
Speed is especially important for the production of generics in both pharmerging and industrialized nations. The latter are facing constantly rising cost pressure, while the pharmerging markets require affordable medication for a large population. Prerequisites are sophisticated, robust technologies with easy handling as well as short cleaning and changeover times. Biosimilars are produced in both small and large volumes. Whenever frequent product changeovers are on the agenda, pre-sterilized single-use systems offer a solution with hardly any preparation time. They combine high filling accuracy with maximum safety – and omit the need for time-consuming cleaning, sterilization and validation of product contact parts.

Continuous processing
The production of complex pharmaceuticals also focuses on cost-efficiency. A concept that favors this approach is “continuous processing”, and has already been applied in the food or chemical industry for some years. In contrast to batch production, continuous processing implies the production and processing of materials in a continuous, uninterrupted process. In spring 2015, Dr Janet Woodcock, director of the FDA’s Center of Drug Evaluation and Research, repeatedly raised the question why this method was not yet more widely used in the pharmaceutical industry3. Despite a slow development pace, the climate has changed over the past years: leading technology companies are currently working on new continuous technologies for solid pharmaceuticals, which above all aim at reducing costs and enhancing efficiency.

The highest safety for humans and products
Biologic processes are becoming more complex and guidelines stricter. The highly potent ADCs, which consist of a biologic part (the antibody), a linker and a small active molecule, are toxic to the operator. At the same time, humans also pose the greatest contamination risk to these products. The effective protection of humans and products from each other requires suitable containment technology. In the manufacture of liquid pharmaceuticals, isolators are the enclosure of choice. Vials remain the containers most frequently processed in isolators, while the use of pre-filled syringes has especially risen in Europe. The development of new pre-filled, sterile primary packaging solutions such as pre-sterilized syringes, vials or cartridges has paved the way for the development of new line concepts.
In order to protect ADCs from external influences such as oxygen, moisture or sunlight, they are mostly freeze-dried in vials after filling. During the lyophilization process, water is removed from the product after it is frozen and placed under vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The substances are preserved until usage and have a much longer shelf life than their liquid counterpart. This requires a very exact integrity test of the packaging material.

New regulations are changing the pharma industry
Container Closure Integrity (CCI) is extremely important to ensure the sterility and stability – and thus quality and safety - also of lyophilized products. It requires the inspection of a large number of parameters. The United States Pharmacopeia (USP) has therefore revised its general chapter 12074, demanding more quantitative, non-destructive CCI test methods. Examples are high-voltage leak detection (HVLD) or headspace analysis (HSA). CCI inspection of sterile products will also be one of many topics during the revision of the “EU GMP Guideline for Manufacture of Sterile Medical Products Annex 1“ (Annex 1). This revision will certainly introduce the most significant changes to Annex 1 since its first publication in 1972.
A familiar, high-priority regulatory subject refers to the safety of patients and their protection against counterfeits. The unambiguous serialization of pharmaceutical packaging not only requires a data matrix code to be printed on folding cartons. A holistic serialization solution should be able to mass-serialize the packaged product, verify the codes and provide the packaging with tamper-evident labels or security seals. Moreover, the entire process should be consistently controllable and the data accessible at any time. Only this way do manufacturers - and later issuing authorities - have an exact overview of all process steps. A flexible and scalable machine and software concept is the obvious solution.

Pharma en route towards Industry 4.0?
Pharmaceutical serialization is a first step towards an increasing connectivity of production processes. State-of-the-art software solutions should not only be able to manage the allocation of serial numbers through to the last aggregation step. They should also connect single components and third-party equipment, packaging lines, own or third-party IT systems and entire production facilities. Compared to other industries, pharmaceutical production is still in a quite early stage - just as it is with continuous processing. However, digitization developments are advancing here, too.
Amongst others, software modules help to control and monitor production and quality data as well as logistic processes flexibly according to customer requirements. Easy-to-handle user interfaces not only facilitate the operator’s work. The current machine and production status can be clearly visualized from the global level down to a single machine. Drug producers can also obtain fast recipe and count values of a machine. Apps ensure that a transparent overview of machine data is delivered to mobile devices - no matter where the operator or line manager is within the production facility. These new possibilities help to reduce costs. But most importantly, they also enhance product quality and make it possible to provide patients all over the world with safe medication.

True line competence
The supplier in his role as partner of pharmaceutical companies, plays a very important part in all these areas. Which regulations must be implemented until when? Which laws will be changed in the coming years, which effects will they have on the production process? Which technologies are needed to instantly fulfill these requirements – and how can they be seamlessly integrated into the overall process? Whoever is able to answer all these questions and at the same time provide the corresponding technical solutions is ready to take on exactly this partner-like role.
For this reason, Bosch Packaging Technology has already been concentrating on more than single technologies and machines for quite some time. The focus in all projects is on pharmaceutical line competence and system integration, providing technology, services, consultancy and profound market knowledge from a single source. This also includes analyzing the market carefully, identifying future demands and implementing customer experience in new developments. The key to highest patient safety, process and product quality lies in the effective combination of all these requirements.

1. QuintilesIMS Institute, “Outlook for Global Medicines through 2021”, www.imshealth.com, December 2016.
2. Bevacizumab is an angiogenesis inhibitor for the treatment of six different malignant tumors. It is used in combination with chemotherapy.
3. Brennan, Zachary: FDA calls on manufacturers to begin switch from batch to continuous production; www.in-pharmatechnologist.com/Processing/FDA-calls-on-manufacturers-to-begin-switch-from-batch-to-continuous-production, 01.05.2015.
4. www.pharmacopeia.cn/v29240/usp29nf24s0_c1207.html
5. ec.europa.eu/health//sites/health/files/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf


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