Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

	In highly regulated industries, such as pharma, compliance and adherence to good manufacturing practices (GMPs) are essential to ensure basic product safety, efficacy, and quality. To learn more about the changes in GMP and regulations in pharma over the past few decades, as well as how harmonizing approaches is beneficial to the industry, 

spoke with Afshin Hosseiny, chairman of the ECA Foundation.

Reviewing the past few decades, what have been the biggest changes in GMP and regulatory guidelines?

Pharmaceutical manufacturing and product testing have gone through major changes over the past 30 years due to the introduction of new products as well as technological advances in manufacturing and automation. These advances in product and technology have driven changes in the regulations, ensuring that adequate controls remain in place whilst maintaining the basic GMP expectations of product safety, efficacy, and quality. 

	The European Medicines Agency (EMA) was established in 1995 with the main objective of harmonizing the existing national medicines regulatory bodies across the European Union. The introduction of the EU GMP guidelines for human medicines was a major step forward in establishing common GMP requirements across the EU. Since then, we have seen changes in these requirements to allow regulation to remain in line with the technological advances introduced by the manufacturers. 

	Publication of the EU GMP Part II for APIs was a major challenge for the manufacturers of APIs, as historically, they were treated as chemicals with little or no GMP perspective during manufacturing and supply. The GMP for APIs, followed by clarification of the role of qualified persons (QPs) in relation to the GMP compliance of APIs for use in the manufacture of medicines, created additional challenges for QPs. 

	Other major changes in the regulations included approaches and controls required for sterile manufacturing processes, the application of GMP to computerized systems, and, most recently, the management of the pharmaceutical products’ supply chain, ensuring product integrity from manufacturer to the final customer. ECA, through its various working groups, has been involved in reviewing, commenting, and preparing implementation guidelines for the industry for the past 20 years, ensuring a harmonized approach to implementation of the new regulations.

What are the benefits of harmonizing approaches to GMP and regulatory guidance and what work is being done to progress regulatory harmonization? 

The EU has been developed to facilitate open borders with free movement of products and people. Medicinal products manufactured and released by a QP in one member state can be sold in any of the 28 member states across the EU. To facilitate this, we have to ensure everybody operates to the same standard; therefore, harmonization of the regulations and their application and controls are critical in achieving the EU objective. 

	Over the past 20 years, ECA has played a major role in this task by providing a bridge between the industry and the regulators, developing interpretation documents, participating in joint meetings to improve the industry personnel’s understanding of the regulations and the regulator’s understanding of the challenges manufacturers have to overcome when producing medicines for supply. The harmonization has also helped to reduce workload for manufacturers as well as regulators, allowing them to move the focus of their attention to the more critical areas of GMP. 

	A recent benefit of harmonization is the mutual recognition agreement between the EMA and the US Food and Drug Administration, creating a substantial benefit by reducing the number of inspections performed by both the regulators and industry, which will avoid duplicate inspections.  

Are there specific regulations the industry should expect to be introduced in the near future? 

Introduction of new and complex products will force the development of new regulations. Undoubtedly, there will be new regulations for the development and manufacture of advanced therapy medicinal products (ATMPs), further development of guidelines on data governance, and of course the finalization of the Annex 1 (manufacture of sterile products), all of which will pose major challenges to the pharma industry. We anticipate additional product development requirements for the application of quality management principles to product development through to final commercial supply becoming a major focus point for the regulators. 

	ECA will continue to progress through its working groups in influencing the development of these regulations, ensuring a harmonized approach across the industry. Our working groups are currently actively involved in providing input to the Annex 1 guidelines. In addition, our newly established groups, such as the ATMP group and the Cannabis Based Medicines group, will be working across the industry and the regulators to ensure adequate harmonized GMP regulations for these medicines which are to be developed in the near future. 

	When referring to this article, please cite it as F. Thomas, “Regulatory Harmony,” 

Articles

Harmonization of regulatory guidelines not only reduces workloads for manufacturers and regulators but can potentially help to accelerate patient access to vital therapies.

Regulatory Harmony

	Instrumentation and technology have been crucial in the pharma industry over the years, allowing for advancements in manufacturing speed and efficiency and improving analysis sensitivity. In a special interview, Bjoern-Thoralf Erxleben, senior manager-European Innovation Centre of Shimadzu Europa, spoke with 

about the past, present, and future of analytical instrumentation within the pharma industry.

What advancements in analytical instrumentation do you believe have been the most integral to the pharma industry?

Analytical instruments have vastly improved over the past three decades. There has been digitalization, miniaturization, automation, as well as new technologies, methods, and features, and there have been improvements in robustness, routine capabilities, and specifications all the way up to design.

	Looking at liquid chromatography (LC) as an example, this technique has progressed from 200/300 bar pressure up to more than 1000 bar for routine systems. The most tremendous improvements, however, have occurred in mass spectrometry (MS). Over the years, MS instruments, and LC–MS systems in particular, went through a revolutionary development. In the pharma industry, the wide use of MS and MS–MS methods in analysis has enabled shorter development cycles and process changes. It must be noted as well, that major improvements in column technology, such as smaller particles, new chemical modifications, and new fused core columns, have made LC more suitable for a wider variety of pharma applications. 

	Currently, interest in supercritical fluid chromatography has risen, largely driven by ecological aspects. Other reasons behind the increased interest are that technological improvements allow for easier operation and routine stability compared with more traditional techniques. 

	Computer technology, volume of data, and processing speed are also drivers of market change as complex techniques can be performed routinely and conveniently. Last but not least, for analytical instrumentation in general, regulations for data handling, integrity, and compliance have been applied that improve and maintain safety of, and confidence in, final pharma products.

How have instrument developers overcome the challenge of slow adoption of technological advancements? 

When discussing pharma markets, it is important to differentiate between R&D on one side and production, quality control and quality assurance (QA/QC) on the other. Indubitably, new development and directions require advances in technologies, higher sensitivity, and constant improvements of existing systems. At the same time, however, samples still have to be measured routinely and quality of the results must be ensured; standard workflows and established procedures perhaps cannot or should not be changed often and/or immediately. 

	The challenges for the manufacturer are to ensure that workflows can be maintained without requiring big changes and re-certification. This not only covers the introduction of new instruments and software, but also new concepts for the education of users and ways to adapt analytical instrument operation easily. Modern teaching tools such as e-learning and interactive sessions are possible solutions; applying more artificial intelligence (AI) and machine-to-machine learning scenarios are others. This will change the role of the user in future to become more of an observer or supervisor who only intervenes in cases of error during the analytical process, based on standard procedures proposed by the system.

	Furthermore, compliance with regulations and the use of registered methods is a subject where both parties (vendor and user) have to maintain dialogue with the authorities to shorten processes and increase flexibility for adaptations without infringement of existing rules and guidelines. 

In the future, what technological/instrumentation advances do you see as potentially creating a paradigm shift within pharma? 

Today’s trends towards AI, automation, and big data are still just at the preliminary phase. Data handling and IT infrastructure will change in line with the implementation of AI in the pharma industry.  

	The number of small molecules in development is already declining, and biopharmaceuticals are becoming more prominent in the industry. Targeted medication based on genetic-profiling and specially designed therapy will change the classical pharma development direction over the coming years. Personalized medicine will take more effort from R&D groups, require a closer link to hospitals/patients than now, and will require less production capacity. 

	In general, new and optimized production procedures will be established to meet the needs of the therapies in development. These processes will be fully controlled and have automated analytical arrays, which will offer direct feedback on parameters. Further improvements in separation and MS technology may lead to advancements in analytics. 

	For the most part, traditional analytical arrays will be replaced by ‘targeted screening’ and only in the case of non-conformity will detailed analysis be performed. This does not mean that traditional analytics will stop; on the contrary, sensitivity and operability will be even more important than now. 

	New methods and instrumentations will emerge in the future, in addition to those that are currently established to reduce analysis time. The traditional or ‘classic’ analysis in pre-clinical and clinical trials will be more in-depth for deviations from ‘standard’ results. As long as metabolism pathways and structures are known, screening for molecules can be performed with less (or nearly no) separation, which saves time and enables automation using AI approaches. 

	Non-destructive methods will also be increasingly required and should be prioritized as fast scanning of products is necessary to identify fake products. 

	When referring to this article, please cite it as F. Thomas, “Tooling Up for Pharma,” 

Instrumentation advancements over the past 30 years have certainly enabled greater efficiency in pharma development and analysis despite slow adoption by the industry.


Tooling Up for Pharma

	Borosilicate glass vials have been a mainstay for primary pharmaceutical packaging for many years and are set to maintain a strong position in the industry, particularly in light of the surging global market of generic parenteral drugs (1). To find out more about the evolution of glass vials, current exacting requirements for these primary packaging solutions, and future developments, 

spoke with Florence Buscke, global product manager Glass Vials at Schott.

Could you highlight how glass vials for the pharma industry have evolved during the past 30 years?

Pharmaceutical vials made of high-quality glass tubing have come a long way from initially being only a commodity product to an integral part of the final drug product. Here, it is important to understand that without such vials (or any other form of primary packaging for that matter), the drug can neither be transported, stored, nor administered. 

	When describing the development of primary packaging or glass vials in particular, three important aspects should be considered-chemical quality, dimensional quality, and cosmetic quality. The basis for all three is the purest possible borosilicate glass, which has been the gold standard for over a century. As it is very stable and chemically inert, these very properties make borosilicate glass an attractive material in which to package drugs. 

	It is also worth noting that leading vial manufacturers have made great progress when it comes to the converting process. For instance, automated inspection systems can be used to inspect all key surfaces of the vials and detect defects invisible to the human eye. 

	Cutting-edge forming technology paired with ever more intelligent machine vision systems has helped to constantly tighten specs in all quality dimensions, increasing the overall quality standard for the entire industry. The goal is to obtain a ‘zero defect’ vial (i.e., containers with accurate dimensions and a flawless surface without any chips or cracks, plus a homogeneous inner surface that withstands drug container interaction). 

Currently, what are the expectations of pharma companies when it comes to glass vials, and what technologies are available to meet the required specifications?

Many of the latest pharmaceuticals have exacting packaging requirements to protect against interactions between the drug and the container. At the same time, the extremely high costs of developing and producing highly potent drugs, such as biologics or vaccines, put pressure on the pharmaceutical filling process to increase yields and reduce waste. As a result, the focus of the pharma industry has shifted towards a holistic approach that includes individual requirements of the drug, the performance of the filling concept, and the primary packaging (e.g., the vial) being the link between the two. 

	This calls for an increasing variety of container options that include functional contact surface coatings, delaminationâcontrolled containers, but also the standardization of transport features like nests, tubs, or trays. Here, relying on industry standards, such as using the same tub sizes for ready-to-use vials, syringes, or cartridges, helps to reduce processing complexity and the respective costs. 

	The good news is that leading packaging providers have these solutions available. As an example, Schott recently introduced a modular vial concept called EVERIC that allows for the combination of the aforementioned attributes to package biologic drugs, even with low filling volumes.

Are there any future developments in pharmaceutical glass vials that you believe will be important to the industry?

When it comes to the requirements for future drugs, we believe that industry suppliers already have a lot in place. The challenge rather lies in intelligent combinations-as regards technologies and also cooperation within the industry. 

	One example is the usage of data to build intelligence into the vials. Enormous amounts of data are generated at each step of the value chain. This includes data on the wall thickness and diameter of each tube and later on, process data during conversion. Ideally, these data could be exchanged with the pharma company in a good manufacturing practice (GMP)-compliant way to facilitate incoming inspection and validation. In return, feedback on the quality level of the vials during filling and finishing would be very valuable information for converters. 

	Another example is the traceability of vials. Data matrix codes that would make each individual vial identifiable could be used to avoid mix-ups, support anti-counterfeiting, assist with targeted recalls, facilitate line clearance, or in general to gain process insights (e.g., on lyo edge effects). 

	In both examples, pharmaceutical companies and their suppliers must join forces to get a better understanding of what kinds of data are needed at each point. This all boils down to closer overall integration. Today, all major pharma companies have set up programmes to include packaging suppliers in the early stages of drug development. If the supplier knows what is in the drug pipeline, they can focus on packaging innovations that are most relevant to the market. In the future, it could be very beneficial to step up the dialogue between drug developers and packaging suppliers as well as fill and finish specialists. This new type of cooperation mindset would be a very positive development for patient and supply safety and even help to reduce healthcare costs.

	1. Grand View Research, “Pharmaceutical Glass Packaging Market Size, Share & Trends Analysis Report by Product, and Segment Forecasts, 2019–2025,” Market Research Report, June 2019. 

	When referring to this article, please cite it as F. Thomas, “Raise a Glass to Pharma Vials,” 

Glass vials have come a long way from mere commodities and are now considered an integral part of final drug product.


Raise a Glass to Pharma Vials

	Driven by a multitude of factors, such as an ageing population, increases in prevalence of chronic diseases, and rising adoption rates of biopharmaceuticals worldwide, the biopharma market is projected to grow rapidly over the coming years (1). A market that has developed significantly during the past three decades, the biopharma industry is also a sector that is demanding a significant evolution and sophistication in terms of purification and analytical methods.

discussed the development trends, as well as the current and future analytical technology advancements in the market, with Christian Rohrer, director of Sales & Marketing of Tosoh Bioscience-a company that is also celebrating the 30th anniversary of the European subsidiary.

What major developments have you witnessed within the biopharmaceutical industry during the past three decades? 

During the past 30 years, the whole biopharmaceutical sector has been facing the same changes as the rest of the society-for example, the rise of digitalization and, even more critically, environmental and societal sustainability imperatives. To embrace these industry challenges, we believe the onus lies with ensuring people are put first, so, placing both customers and employees at the centre of every decision.

	From a biopharmaceutical industry viewpoint, the shift from small molecules to large biomolecules has been noticeable. In the early years, the main biopharmaceuticals in development included insulin, growth hormones, and blood factors. Monoclonal antibodies became more of an all-rounder for multiple applications. Later on, the focus within the biopharmaceutical field shifted from a ‘monoclonal antibody only’ view to a diversification of the molecules of interest. This shift has enabled for the targeting of more specific subtypes of diseases. 

	However, the development of new biological drugs has become more challenging, with clearly increasing cost, regulations, and time constraints from both a financial and societal stakeholder’s standpoint. As a consequence, the whole industry has been required to be innovative and forward-looking so that it can offer exacting solutions while also keeping productivity and efficiency in mind.

As analysis and purification are of critical importance in bio/pharma, could you elaborate on some of the analytical technological advancements that have given rise to a paradigm shift in this industry?

Due to the greater complexity of biopharmaceuticals in comparison to small-molecule drugs, the biopharmaceutical industry requires a sophisticated toolbox of purification and analytical methods. 

	One example for an analytical tool in biopharma is size-exclusion chromatography (SEC). In terms of advancement in SEC, which has become an industry standard in quality control for monoclonal antibodies, expansions in capabilities have come through the development of novel columns, allowing for highly efficient ultraâhigh-performance liquid chromatography (UHPLC) analysis of protein aggregation. For downstream processing, there have been advances in high capacity packing materials, improving economies and providing more environmentally-friendly platform solutions.

	Additionally, modern drug formats require stationary phases with unique selectivities for both purification and analysis, for which novel salt-tolerant ion exchange media for the purification of biomolecules, and innovative affinity media to efficiently capture antibody constructs have been introduced. Furthermore, new HPLC columns based on Fc receptors, such as FcγIIIa receptor, have been developed that allow for rapid evaluation of biologic activity and glycoform patterns of antibodies at stages when bioassays are cost-prohibitive or time-consuming.

In the future, what technological advancements do you see as being integral for biopharma and why? 

We foresee the need of many technological advancements-both in term of products and methods-to fulfil the requirements of customers for miniaturization, automation, product safety, or regulatory evolutions. 

	On the one hand, the diversification of the therapeutic targets is evolving into personalized medicine, and gene- and cell-based therapies, which will become more common as the cost of techniques to develop these forms of therapies is lowering. On the other hand, the pressure on development costs and time efficiencies will inevitably rise as quicker access and cheaper cost of medications is expected from governments and patient groups, on a global scale. The opportunities and challenges to develop ground-breaking therapies while meeting expectations should motivate companies to remain at the cutting-edge of scientific and technical developments while also maintaining consistently high quality and services. 

	However, some upcoming transformations have not yet been identified. Therefore, flexibility and an ability to be able to react to the unexpected is important for global companies to guarantee resilience in the future. For example, Tosoh Corporation has evolved into a global enterprise based on 

-a craftsman-like approach-to ensure it is prepared for new developments and challenges. 

	1. Allied Market Research, “Biopharmaceuticals Market by Type and Application-Global Opportunity Analysis and Industry Forecast, 2018–2025,” Market Research Report, July 2018. 

	When referring to this article, please cite it as F. Thomas, “Analysis and Purification: Instrumental to BioPharma,” 

To deal with the complex requirements of biopharmaceuticals, companies need a sophisticated toolbox of analytical and purification techniques.


Analysis and Purification: Instrumental to BioPharma

	The pharmaceutical industry was an early adopter of machine vision, as these optical inspection systems aid in guaranteeing product safety and integrity. With the introduction of more stringent regulations throughout the industry, such as the European Union’s Falsified Medicines Directive (EU FMD), optical inspection is now, more than ever, an integral part of the industry.

	To find out more about these essential systems within pharma, the challenges of safety regulations, and the future of packaging technology, 

interviewed Dietmar Karepin, business development manager healthcare of Vitronic.

As a machine vision systems provider, what significant transformations have you seen in the pharma during the past three decades?

Thirty years ago, industrial machine vision was a new technology that became established over the years. Prior to the introduction of this technology, quality inspections in the pharma industry were performed using statistical process controls-basically with manual spot checks. The first machine vision systems were often elaborately produced even if the camera resolution and computing power were quite basic compared to today’s standards. 

	Vision systems have changed significantly over the past 20 years, however, not only in size, but also in components. Today, automated optical inspection systems are designed to meet the requirements of the pharma industry and also feature an optimized and compact design, which can be easily integrated in filling and sealing processes, making these systems an important and integral part of pharma manufacturing.

	Machine vision technologies have developed rapidly as production has increased, automation has expanded, and cyclic output has risen in the pharma industry. Nowadays, automated optical inspection systems perform extremely complex inspection tasks while also collecting high volumes of data. Take vials, for example, they are inspected at a high rate of 10 vials per second. To ensure that inspections meet demanding requirements in terms of reliability and speed, extremely powerful and intelligent inspection equipment is required. This inspection equipment must comprise hardware and software components that are tailored to the inspection requirements at hand. 

	One area that has grown in significance is documentation. Currently, the industry requires extensive documentation to ensure that the systems and machines are qualified to meet pharmaceutical industry standards. Great emphasis is also placed on system compliance to regulatory guidance such as the US Code of Federal Regulations (CFR) 21 Part 11-electronic records and electronic signatures. 

	Furthermore, the link between machine vision and data technology has changed significantly over the past five to six years. Automated inspection processes require systems to be increasingly flexible, with the ability to access much more data. 

With the introduction of stricter safety regulations, such as the EU FMD, what challenges do pharma companies face?

To be able to comply with the EU FMD regulation, the industry had to ensure that as of February 2019 drugs requiring a prescription were sold only in packaging with a serial number and with their original seal. The data must also be saved to a central IT database. For international pharma companies, current challenges include the number of regulations set forth by each individual market. These regulations can vary greatly and include the United States e-pedigree and Chinacoding, for example. 

	Medical safety is the number one priority. Not only the quality of the product but also other relevant data, including packaging information, must be protected from misuse and fraud and documented thoroughly. Furthermore, tamper evidence is required to ensure that unauthorized tampering and changes to the product are recognized immediately. In short, the product must arrive at the pharmacy in its original packaging completely intact. In this context, pharmaceutical packaging includes more and more information such as labels, codes, and special safety data, which is sometimes invisible to the human eye. All of this information must then be captured by the optical inspection.  

	In addition to typical optical quality inspections, supplementary solutions must be implemented in the pharmaceutical packaging process for traceability purposes. Customers are, therefore, seeking end-to-end solutions, preferably from a single source.

What are your future predictions for inspection technology improvements that may lead to a paradigm shift in pharmaceutical packaging?

Processing smaller batches is becoming more common in the pharma packaging industry. This requires that lines are more flexible and can be reconfigured quickly, and as such, inspection systems need to be more flexible too. On the one hand, they must be scalable to the different product types, and on the other hand, they must be easy to reconfigure even by the user if necessary. 

	Additionally, personalized healthcare is requiring new approaches to production and, in turn, to automated quality control. Intelligent and interconnected systems that can manufacture for batch size one are a clear trend, and not just in the pharma industry. 

	Data captured by automated inspection systems offer huge possibilities. One of the greatest challenges of the future is to use the data even more intelligently. One promising application is what is known as closed loop, which can be used to help us draw conclusions about machine parameter settings based on findings from the inspection process. In the automated application, data from the inspection [are] fed back directly to the machine control unit, which can automatically make corrections to machine parameters there. Furthermore, we are exploring applications for deep learning methods in specific inspection environments so that we can continue to improve processes and defect detection results.

	When referring to this article, please cite it as F. Thomas, “Farther Than the Eye Can See,” 

Machine vision systems have been an integral part of pharma manufacturing and packaging for many years and, with the introduction of stricter safety regulations, are set to become more vital.


Farther Than the Eye Can See

	Over the course of the past three decades, since 

was launched, much has changed within bio/pharma. Industry has witnessed periods of growth, followed by strategic divestiture in more recent years, a boom in biologics, regulatory harmonization, as well as significant technological advances, to name but a few. Added to these specific industry shifts, overarching societal and economical changes, such as government changes and Brexit, have also left a mark on bio/pharma and are set to continue to impact the industry for some time to come.

	In looking back over the 30 years that 

has been reporting on industry developments, several trends have clearly shaped the industry, while some other trends have perhaps done so a little less obviously. For this special anniversary issue feature, the editors take a trip down memory lane to cover some of the major happenings of the bio/pharma industry over the past three decades.

	Well, ‘begin at the beginning’ is a little misleading, as the ‘beginning’ for 

does not represent the beginning of the bio/pharma industry itself, but it does offer a nice starting point in terms of news and developments. 

	The first issue of the magazine was published in 1989-a big year in Europe, which saw the fall of the Iron Curtain and Berlin Wall. The year also gave rise to some interesting developments in bio/pharma. One such development was the introduction of the first ever proton pump inhibitor (PPI), omeprazole, by Astra (1)-which 10 years later would merge with Zeneca in one of the biggest European merger deals of its time. PPIs now represent one of the most frequently prescribed drugs in the world (2).

	Other introductions in 1989 included the addition of the conjugated 

influenza vaccine to routine national immunization programmes of certain European countries (3), and the initiation of supplementary rules for the authorization of vaccines and medicines derived from blood (4). Furthermore, measures to improve the quality of medicines throughout Europe were also taken in 1989 with the introduction of the first guidelines on good manufacturing practices (5).

The 1990s: Regulatory harmonization and intense M&A activity

	The start of the 1990s brought with it the inauguration of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), creating a platform for international cooperation (5). Since its inception, the ICH has evolved so that farther-reaching global harmonization of regulatory requirements-beyond that of the founding regions of Europe, United States, and Japan-may be attained.

	Moving into 1993, Europe began an exciting time as the Single Market was completed, comprising ‘four freedoms’ of movement of goods, services, people, and money; the Maastricht Treaty came into force, formally establishing the European Union (6). In 1995, the European Medicines Agency (EMA) became operational with the mission of promoting and protecting public and animal health throughout Europe (7).

	The then London-based regulatory body started work immediately, approving its first drug for human use, Gonal-F (follitropin-alfa) through the centralized procedure in October 1995. This approval marked an important milestone, as stated in the first general report of the European agency (8). In addition to Gonal-F, Taxotere (docetaxel), and Betaferon (interferon beta-1b) also gained marketing authorizations in November 1995 (8).

	A year later, 1996, a landmark achievement was attained in the treatment of HIV as lamivudine, ritonavir, and saquinavir were approved through the centralized EU-wide procedure under exceptional circumstances (9). These three HIV protease inhibitors, used in combination with nucleoside reverse transcriptase inhibitors, would set about a dramatic change of course of the HIV epidemic (10). 

	But, it wasn’t just regulatory achievements and market approvals making waves during the 1990s. M&As were intensifying with activity within the global pharmaceutical-biotechnology industry being valued as exceeding US $500 billion (€449 billion) in the period between 1988–2000 (11). 

Consolidation, specialization, and Brexit-noughties to now

	Roll on to the early-to-mid noughties and the M&A activity continues. ‘Bigger is better’ seemed to be the mantra for many bio/pharma companies, which looked to strategically operate with vast R&D hubs situated in multiple global locations. 

	The strategy of creating massive conglomerated operations has been attributed to the decline in R&D productivity that the industry was experiencing (12) and justified through economies of scale. Looming patent cliffs for many of the blockbuster drugs and the advent of personalized therapies has certainly led to a shift in momentum within the industry. Adoption of a leaner, more focused business model was inevitable and started being seen in the industry from the late 2000s (12).

	As discussed by Sylvia M. Findlay in the December 2006 issue of 

 (13): “The shift of focus towards manufacturing drugs catering to a niche market is critical in tackling the declining revenue in pharma. Personalized medicines are becoming attractive to drug manufacturers and are likely to be big hit among the diseased population. These drugs herald the burgeoning of specialty pharmaceuticals.”

	In the regulatory space, EMA started efforts to get more treatments on the market that targeted rare diseases by adopting a new legislation (14). Applications for orphan therapies submitted to EMA peaked between 2011 and 2015 when a total of 1151 applications were received (15). Also, EMA adopted legislations on medicinal products for paediatric patients (2006) and for advanced therapy medicinal products (2007), mirroring the emergence and development in the industry of more specialized areas of medicines (6). 

	Of course, it would not be possible to discuss key developments impacting the bio/pharma industry without touching on Brexit. After the United Kingdom made its decision to leave the EU in 2016, work has been ongoing to prepare for every eventuality while also ensuring patient safety does not suffer too much. Brexit has already hindered the European bio/pharma industry, with commotions resulting from the relocation of EMA and the uncertain future already leading to a collapse in confidence in the region as an attractive place to do business (16). 

	In tackling health equality across the region, the World Health Organization’s Regional Office for Europe regularly reports on the state of health and well-being throughout Europe, which is closely linked to its overarching policy-Health 2020. The most recent report (17) revealed positive developments across the region but also emphasized that effective communication of health information and use of data can help to bridge the research-policy gap.

	“The European Region’s member states have in many ways been trailblazers in supporting and defining a vision for a truly forwardâlooking principle of information systems for health, thus making data, information, research, and evidence count for all of us-ensuring the availability of ‘evidence for all’,” stated Zsuzanna Jakab, WHO regional director for Europe (17).

	1. D. Taylor, “The Pharmaceutical Industry and the Future of Drug Development” in 

, R.E. Hester and R.M. Harrison Eds., pp. 1–33 (The Royal Society of Chemistry, London, UK, 2016).
	2. H. Luo, et al., 

18 537 (2018).
	3. R. Whittaker, et al., 

, 23 (3) 369–404 (2017).
	4. European Council, 

Council Directive 89/342/EEC-Extending the Scope of Directives 65/65/EEC and 75/319/EEC and Laying Down Additional Provisions for Immunological Medicinal Products Consisting of Vaccines, Toxins or Serums and Allergens 

(Brussels, 3 May 1989).
	5. EC, “50 Years EU Pharmaceutical Regulation Milestones,” Public Health Infographic, ec.europa.eu [accessed 22 July 2019].
	6. EU, “The History of the European Union,” Infographic, 

[accessed 22 July 2019].
	7. EMA, “History of EMA,” 

[accessed 22 July 2019].
	8. EMA, “First General Report on the Activities of the European Agency for the Evaluation of Medicinal Products,” 

, 15 Jan. 1996.
	9. EMA, “20th Anniversary of EMA,” 

(Core Media Services UK & Service Point, 2015).
	10. A.K. Pau, et al., 

, 28 (3) 371–402 (2014).
	11. P.M. Danzon, A. Epstein, and S. Nicholson, 

, 28 (4–5) 307–328 (2007).
	12. A. Gautam and X. Pan, 

, 21 (3) 379–384 (2016).
	13. S.M. Findlay, 

, 18 (12) (2006).
	14. EC, Commission Regulation (EC) No 847/2000, 

Official Journal of the European Communities 

(Brussels, 28 April 2000).
	15. EMA, “Orphan Medicines Figures,” Presentation, 

www.ema.europa.eu/en/documents/other/orphan-medicines-figures-2000-2018_en.pdf

 [accessed 23 July 2019].
	16. PharmTech, “Public Health and Economical Risks Mounting as Brexit Uncertainty Continues,” 

, 18 Jan. 2019.
	17. WHO Regional Office for Europe, “European Health Report 2018: More than Numbers-Evidence for All,” Report, 


	Vol. 31, No. 8
	July 2019
	Pages: 12–14

	When referring to this article, please cite it as F. Thomas, “Standing the Test of Time,” 

Much has changed in the bio/pharma industry over three decades. In this special feature, the editors take a trip down memory lane, highlighting some of the major happenings of the past 30 years.
