Key changes: The focus is on quality and safety in a rapidly growing industry

Quality and safety are in focus as industry advancements force a change, writes chief pharma expert at Bosch Packaging Technology, Johannes Rauschnable, PhD.

The market for pharmaceuticals is growing at an astonishingly rapid pace. According to a market report by the QuintilesIMS Institute, expenses for drugs will amount to $1.5 trillion globally in 2021. The reasons are obvious: global population is increasing (by 1.24% per year until 2030) and ageing at the same time. Increasing urbanization and a growing middle class are making drugs available and affordable for more people, while leading to a higher demand for medication.

Megatrend biologics

While the demand for common medication is increasing in the ‘pharmerging’ markets, completely new forms of treatment are emerging in industrialized countries.

Groundbreaking changes are occurring in the area of biological agents, for instance regarding the treatment of cancer, autoimmune diseases, as well as rare illnesses. In the still relatively new cancer immunotherapy, for instance, the body’s own immune system is stimulated to fight against tumour cells. Monoclonal antibodies attach themselves to the characteristic structures on the tumour surface and mark the cells for macrophages or induce cell death. A further breakthrough in cancer therapy was achieved with checkpoint inhibitors.

A highly promising research and application area deals with antibody-drug conjugates (ADCs). These biopharmaceuticals connect a certain substance to an antibody, which binds to a target structure, such as an antigen, on the surface of a tumour cell. This way, cytostatic agents can get to the centre of the tumour 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 leukaemia, by blocking the signal cascade that triggers cell growth.

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. The first biosimilars have already been approved, for instance for the treatment of neutropaenia or rheumatoid arthritis.

Moreover, approximately 15 replicas of the monoclonal antibody bevacizumab are currently being tested. Patent rights for the reference product will expire in 2019 in the US and in 2022 in Europe. For patients, this development is a great progress, as many drugs are now produced in larger quantities and are sold at significantly lower prices.

Targeting illnesses more precisely

Medicine is also advancing rapidly in the area of vaccines, where targeted campaigns are promoted strongly for instance by WHO or UNICEF. Pharmaceutical companies are 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 centre of attention — making these vaccines available for a large population, and simplifying their administration.

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.

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 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.

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 favours 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 an uninterrupted process.

In spring 2015, Dr Janet Woodcock, director of the FDA’s Center of Drug Evaluation and Research, raised the question why this method was not yet more widely used in the pharmaceutical industry. 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 surrounding them 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. The development of new pre-fi lled, sterile primary packaging solutions such as pre-sterilized syringes, vials or cartridges has paved the way for the development of new line concepts. To protect ADCs from external influences, they are mostly freeze-dried in vials after filling. 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 lyophilised products. It requires the inspection of a large number of parameters. The US Pharmacopeia has therefore revised its general chapter 1207, 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’. This revision will certainly introduce the most significant changes to Annex 1 since its fi rst publication in 1972.

Pharma en route towards industry 4.0?

Further regulatory changes have already occurred or must be implemented in the near future. For instance, the unambiguous serialization of pharmaceutical packaging requires a data matrix code to be printed on folding cartons. Software solutions should 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.

This calls for increasing connectivity and digitization — or what is nowadays called ‘industry 4.0’. In fact, the holistic pharmaceutical serialization is a first step towards an increasing connectivity of production processes. Compared to other industries, pharmaceutical production is still in quite an early stage — just as it is with continuous processing. However, digitisation 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 but also allow current machine and production status to be clearly visualized from the global level down to a single 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.

Changing role concepts

In the course of all these advances, the role of equipment manufacturers has also changed. Suppliers have become 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. This also includes analysing the market carefully, identifying future demands and implementing customer experience in new developments.

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 fulfil 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.