The Evolution of Biological Medicines: From Blood Products to Advanced Therapies

Purpose and Scope

The history of biological medicines is not simply a chronology of increasingly sophisticated technologies. Each major transition changed what could be manufactured, what could be characterised, how medicines could be developed and, consequently, what pharmacovigilance needed to observe after clinical use began. The progression from biological materials obtained directly from humans or animals to recombinant proteins, monoclonal antibodies, biosimilars, gene therapies and cell therapies represents a succession of changes in the nature of the medicinal product itself.

For pharmacovigilance, this history matters because the safety profile of a biological medicine is interpreted in the context of its biological source, structure, mechanism, manufacturing process, clinical use and expected duration of exposure. The surveillance questions that arise for a plasma-derived product are not identical to those for a recombinant protein, and neither provides the complete framework needed for a gene or cell therapy. Understanding the sequence of technological transitions therefore helps explain why biological-product pharmacovigilance has developed into a set of product-specific considerations within the wider Good Pharmacovigilance Practices framework.

This article follows the major stages of that evolution. It begins with biological materials and blood-derived medicines, moves through vaccines and purified biological substances, then examines recombinant biotechnology, monoclonal antibodies and biosimilars before reaching gene, cell and tissue-engineered therapies. The purpose is not to provide a history of every biological medicine. Instead, it identifies the transitions that materially changed the biological-product landscape and establishes the historical framework for the type and subtype articles that follow.

The historical account should also be distinguished from the regulatory history of the European Union itself. Biological medicines existed long before the modern EU pharmaceutical framework. EU regulation progressively developed mechanisms for quality, authorisation, biological products, biosimilars and advanced therapies as the underlying science changed. The two histories therefore intersect but should not be treated as the same chronology.

Biological Medicines Before Modern Biotechnology

The earliest biological medicines were obtained from biological materials rather than manufactured through modern recombinant biotechnology. Human blood and plasma became important sources of therapeutic products, while animal-derived materials and extracts were used for a range of medical purposes. Vaccination also established a distinct tradition in which biological material was deliberately used to induce protection against infectious disease.

These products established several principles that remain relevant to modern pharmacovigilance. The source material could affect product quality and safety; biological activity could be more difficult to define solely through chemical analysis; and the process used to collect, prepare and purify the material was inseparable from the characteristics of the resulting medicine. For products derived from human plasma, control of collection, donor selection, pooling, testing, pathogen reduction or removal and manufacturing became central elements of product safety.

The scientific limitation of this early period was not simply a lack of manufacturing technology. Biological substances were often difficult to isolate in a sufficiently pure and consistent form, and their biological activity could not always be predicted from a complete chemical description. This encouraged the development of biological assays, improved purification methods and progressively stronger manufacturing controls.

From a pharmacovigilance perspective, the resulting products created an early need to distinguish adverse reactions caused by the pharmacological action of the active substance from risks associated with the biological source or manufacturing process. That distinction would become even more important as biological medicines became more complex.

Blood and Plasma-Derived Medicinal Products

Medicines derived from human blood and plasma form one of the most important historical branches of biological medicine. Plasma can be separated into therapeutically useful proteins, including albumin, immunoglobulins and coagulation factors, and these products subsequently became established treatments for immune deficiencies, bleeding disorders and other conditions.

The development of plasma fractionation transformed plasma from a biological starting material into a source of multiple defined medicinal products. However, the source remained biologically consequential. Large pools of donated plasma created a potential route for transmission of infectious agents, making donor screening, testing, validated manufacturing controls and pathogen-reduction or removal processes essential parts of the product-safety framework.

This history established a pharmacovigilance lesson that remains relevant to biological medicines: a product's safety cannot always be understood solely from its intended pharmacological action. Source material, manufacturing steps and product traceability can create additional safety dimensions. The later EU framework consequently developed specific requirements and guidance for biological medicinal products, including considerations for products derived from blood and plasma.

Plasma-derived medicines also demonstrate why historical categories should not be confused with current manufacturing technologies. Some therapeutic proteins that were historically obtained from biological sources can later be produced through recombinant technology. The therapeutic function may remain similar while the biological source, manufacturing process and associated safety considerations change. Classification therefore needs to describe both the product and the technological context in which it is made.

Vaccination as a Parallel Biological-Medicine Tradition

Vaccines developed along a partly independent path from therapeutic proteins. Their purpose is to expose the immune system to an antigen or antigenic material in a manner intended to generate protective immunity rather than to replace or modify an endogenous protein directly. The history of vaccination therefore contributed a different set of biological-product concepts, including antigen selection, attenuation or inactivation, adjuvantation, immune response and population-level prevention.

Over time, vaccine technology expanded from early whole-organism approaches to purified antigens, conjugate vaccines, recombinant antigens, viral-vector platforms and, more recently, nucleic-acid-based approaches such as messenger RNA vaccines. These transitions changed both the composition of the product and the way its safety profile could be evaluated.

Vaccines also highlighted the importance of exposure context in pharmacovigilance. Unlike many medicines used to treat an existing illness, vaccines are frequently administered to healthy populations and may be delivered through structured immunisation programmes. Safety surveillance must therefore consider background event rates, age-specific risks, dose schedules, coadministration, population coverage and, where relevant, batch and product identification. The pharmacovigilance questions are consequently influenced by both the biological platform and the epidemiological context of use.

The European Commission's historical account of EU pharmaceutical regulation records major milestones including EU rules for vaccines and blood-derived medicines, the first recombinant vaccine for hepatitis B in 1986, and later development of advanced therapies. [1] These regulatory milestones followed technological developments rather than creating them, but they illustrate how the regulatory system progressively adapted to new biological-product categories.

From Extracts and Fractions to Defined Biological Substances

A major transition occurred as biochemistry and protein purification allowed biologically active substances to be isolated, characterised and manufactured with greater consistency. Hormones, enzymes, growth factors and coagulation proteins could increasingly be treated as defined therapeutic substances rather than relatively crude biological extracts.

This transition did not eliminate biological complexity. Instead, it changed the central scientific question from "what biological material produces the therapeutic effect?" toward "what defined biological substance is responsible for the effect, and how can it be produced and controlled consistently?" The resulting products created a foundation for modern protein therapeutics.

Insulin illustrates this transition particularly well. Insulin had initially been obtained from animal sources, but advances in recombinant DNA technology subsequently enabled production of human insulin using microorganisms. The European Commission identifies 1982 as a milestone for the first synthetic insulin and 1986 for the first recombinant vaccine. [1] In the broader history of biotechnology, recombinant insulin became an early demonstration that a therapeutic protein could be produced through genetic engineering rather than extracted from a biological source.

For pharmacovigilance, this shift introduced a more explicit relationship between molecular identity, manufacturing system and product quality. It also created new opportunities to investigate whether differences in production, purification, formulation or structural characteristics could influence safety or immunogenicity.

Why the Historical Sequence Matters for Pharmacovigilance

The early stages of biological-medicine development established the concepts that continue through the later history: source, structure, manufacturing process, biological activity, immune response and traceability. What changed over time was the relative importance and complexity of each element.

A useful way to view the evolution is therefore not as a simple list of technologies but as a series of expanding control questions:

The sequence shows why biological-product pharmacovigilance cannot be reduced to a single generic list of adverse-event categories. The technology determines what the product is capable of doing, what uncertainties remain after authorisation and which evidence sources may be most informative during post-authorisation surveillance.

The Recombinant Biotechnology Revolution

Recombinant DNA technology changed the biological-medicine landscape by allowing therapeutic proteins to be produced from engineered microorganisms or cell systems rather than extracted directly from tissues or fluids. The significance of this transition was broader than replacing one source with another. It created a manufacturing platform in which the genetic construct, host cell, culture conditions, purification process and formulation could all contribute to the characteristics of the final medicinal product.

Recombinant technology enabled expansion of therapeutic proteins beyond products that could be obtained economically or consistently from natural sources. Human growth hormone, insulin, erythropoietin and several coagulation factors became examples of therapeutic proteins that could be manufactured using biotechnology. Other recombinant proteins followed, including cytokines, enzymes and replacement proteins.

The scientific advantage was accompanied by a new regulatory and pharmacovigilance challenge. A recombinant product may be structurally related to an endogenous human protein while still possessing product-specific characteristics resulting from expression and manufacturing. Differences in glycosylation, aggregation, impurities or other quality attributes can influence biological activity or immune recognition. Consequently, characterisation and process control became central to the regulatory assessment of biotechnology-derived medicines.

This development also changed the meaning of a manufacturing change. For a biological product, changing the production system, manufacturing site, raw material or purification process may alter relevant product attributes even when the intended active substance has not changed in name. Comparability principles therefore became an important part of the lifecycle management of biological medicines. Pharmacovigilance complements, but does not replace, the prospective quality and regulatory assessment of such changes.

Monoclonal Antibodies and Targeted Biological Therapy

The development of monoclonal antibody technology introduced another major transition. Monoclonal antibodies offered a means of recognising a defined molecular target with high specificity, opening a large new therapeutic field in oncology, immunology and other diseases. The emergence of therapeutic antibodies transformed biological medicines from predominantly replacement or supplementation therapies into highly targeted pharmacological interventions.

The clinical significance of monoclonal antibodies is reflected in the European regulatory timeline. The European Commission identifies rituximab in 1998 as the first molecularly targeted cancer medicine in its historical overview, followed by infliximab in 1999 and trastuzumab in 2000. [1] These milestones illustrate the transition from biological products primarily understood through their replacement or immune-stimulating functions toward products designed around defined molecular targets.

Monoclonal antibodies also demonstrated why molecular specificity does not imply a simple safety profile. The intended target may itself be responsible for important pharmacological effects, while immune activation, infusion reactions, immunogenicity, altered immune function and off-target or downstream consequences may contribute additional risks. The size and structural complexity of antibodies also create manufacturing and characterisation considerations that differ from those of smaller proteins.

As antibody engineering advanced, products could be modified through humanisation, Fc engineering, altered binding characteristics and other approaches. Antibody-drug conjugates and related formats subsequently combined antibody targeting with additional therapeutic components. These developments expanded the biological-product taxonomy and reinforced the need to distinguish molecular architecture from mechanism, therapeutic class and manufacturing platform.

From Class-Level Biology to Product-Specific Biologicals

The expansion of recombinant proteins and monoclonal antibodies changed the scale of the biological-medicine landscape. Increasing numbers of products could share a therapeutic target or biological mechanism while remaining distinct medicinal products with their own manufacturing histories and clinical evidence.

This created an important pharmacovigilance distinction between class effects and product-specific effects. A biological mechanism can make a safety outcome biologically plausible across several products, but the existence of a similar mechanism does not establish that every product has the same safety profile. Differences in molecular structure, target affinity, formulation, impurities, manufacturing process, dose, route of administration and clinical population may alter the observed risk.

The historical development of biological medicines therefore strengthened the need for product-level identification. The later European GVP framework specifically emphasises product and batch traceability for biological medicines. [2] The historical reason is clear: as biological products became more numerous and more closely related, pharmacovigilance needed to preserve the ability to distinguish the medicine actually administered from the broader class to which it belonged.

Biosimilars: A New Stage of Biological-Medicine Maturity

The development of biosimilars represented a different kind of technological transition. Rather than creating a new biological modality, biosimilar development established a regulatory pathway for medicines that are highly similar to an already authorised biological reference medicine. The concept recognised a fundamental property of biological medicines: because of their molecular complexity and manufacturing processes, an independently manufactured biological product cannot generally be treated as an exact molecular copy in the same way as a conventional generic.

The European Union was the first region to establish a dedicated legal and scientific framework for biosimilars. The European Commission records the introduction of EU rules for copies of biological products in 2004, while EMA identifies 2006 as the year in which the first biosimilar was approved in the EU. [1,3] The framework subsequently expanded from relatively well-characterised recombinant proteins to increasingly complex products, including monoclonal antibodies.

The first monoclonal-antibody biosimilars marked an important further transition. In 2013, EMA recommended approval of biosimilar infliximab products, describing this as an extension of the biosimilar concept to a new and structurally complex product class. [4] The development demonstrated that the principles of analytical, functional, non-clinical and clinical comparability could be applied to increasingly complex biological medicines.

From a pharmacovigilance perspective, biosimilars introduced a need to integrate reference-product knowledge with product-specific surveillance. The safety history of the reference medicine provides an important scientific context, but each authorised biosimilar remains an identifiable medicinal product with its own manufacturing process, clinical exposure and post-authorisation safety information. The historical emergence of biosimilars therefore reinforced rather than removed the importance of product-specific pharmacovigilance.

The Move Toward Advanced Therapies

The next major transition moved beyond proteins as the primary therapeutic substance. Gene therapies introduced genetic material intended to produce a therapeutic effect, while cell therapies used living cells whose biological properties could contribute directly to treatment. Tissue-engineered products introduced another category in which cells or tissues are manipulated to repair, regenerate or replace human tissue.

These products changed the temporal dimension of pharmacovigilance. A conventional small molecule or many therapeutic proteins may be administered repeatedly and then cleared from the body, whereas a gene or cell therapy may produce effects that persist long after administration. The relevant safety question can therefore extend beyond the immediate post-treatment period.

The EU established a dedicated legal framework for advanced therapy medicinal products through Regulation (EC) No 1394/2007. EMA describes three principal ATMP categories—gene therapy medicinal products, somatic-cell therapy medicinal products and tissue-engineered medicinal products—with some products also classified as combined ATMPs when a medical device is an integral part of the medicine. [5]

The creation of the ATMP framework was not merely a new regulatory label. It reflected the emergence of medicinal products whose biological characteristics could not be adequately described using the traditional framework developed primarily for conventional chemical medicines or even conventional protein therapeutics. Manufacturing, biological activity, persistence, cellular behaviour and long-term effects could all become central to the benefit–risk assessment.

Gene Therapy and the Emergence of Long-Term Safety Questions

Gene therapy introduced a particularly important change in the relationship between administration and biological effect. Instead of supplying a conventional pharmacologically active molecule, gene therapy medicinal products can deliver genetic material intended to produce a therapeutic effect in the patient. Depending on the product, vector and target tissue, the consequences may persist for an extended period.

The first EU-authorised gene therapy medicinal product, alipogene tiparvovec, was authorised in 2012 for a rare inherited disorder of lipid metabolism. [1] Its authorisation represented a landmark in the transition from biological medicines based primarily on proteins or immune stimulation to therapies in which genetic material itself forms part of the therapeutic intervention.

For pharmacovigilance, this transition raises questions that are different in emphasis from those associated with conventional biological proteins. Surveillance may need to consider delayed adverse effects, persistence, immune responses to the vector or transgene, durability of effect and product-specific long-term risks. The relevant follow-up period and evidence sources depend on the product and its biological behaviour; they should not be assumed to be identical across all gene therapies.

The history of gene therapy therefore demonstrates a broader principle of the biological-product series: when the underlying technology changes, the pharmacovigilance framework must preserve the general GVP system while adapting the scientific questions to the characteristics of the product.

Cell Therapy and the Return of Living Biological Material as the Medicine

Cell therapy represents another fundamental change because the medicinal product may consist of living cells rather than a purified molecular substance. The cells may be autologous or allogeneic, may be genetically modified or otherwise manipulated, and may be intended to replace, modulate or destroy target cells.

The use of living cells creates a different relationship between manufacturing and clinical performance. Product identity, viability, potency, composition and handling can become critical characteristics, while the biological behaviour of the cells after administration may influence both efficacy and safety. For some products, the manufacturing process is also tightly linked to an individual patient and therefore forms part of a complex chain extending from collection through manufacture to administration.

The pharmacovigilance consequences include the potential need to evaluate acute immune-mediated effects, infections, prolonged cytopenias, cellular persistence, delayed events and other product-specific outcomes. These risks are not universal across cell therapies; the appropriate surveillance questions depend on the cell type, engineering, target, manufacturing process and clinical context.

CAR-T therapy provides a particularly important example of this transition. These products use genetically modified T cells to recognise and attack target cells. Their development brought distinctive safety syndromes into routine clinical and regulatory attention, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The appearance of such risks illustrates how new modalities can create entirely new pharmacovigilance vocabularies and require integration of specialised clinical knowledge into safety surveillance.

From Technological Transitions to the Modern Biological Landscape

The history described above can now be understood as a sequence of changes in what constitutes the medicinal product. Early biological medicines depended on biological sources and extraction. Protein purification made specific biological substances more accessible. Recombinant biotechnology moved production into engineered biological systems. Monoclonal antibodies added highly targeted molecular recognition. Biosimilars established a framework for independent development of highly similar biological products. Advanced therapies then extended the concept of a medicinal product to genes, living cells and engineered tissues.

Each transition increased the range of biological characteristics that may be relevant to pharmacovigilance. The evolution is therefore cumulative rather than substitutive. Modern biological-product surveillance still needs the principles developed for earlier products—source control, manufacturing quality, product identification, traceability and immunological safety—while adding new questions appropriate to newer modalities.

A useful historical map is:

The dates in such a timeline should be understood as representative milestones rather than claims that a particular technology began in a single year. Scientific development is usually gradual, and technologies may have existed experimentally long before a landmark authorisation or regulatory milestone. The purpose of the timeline is to show the sequence of transitions that changed the biological-product landscape.

How the Evolution Changed Pharmacovigilance

The history of biological medicines explains why modern pharmacovigilance requires both a common system and product-specific scientific interpretation. The common system provides the processes for case management, signal management, risk management, aggregate reporting, safety communication, quality management and regulatory oversight. Product-specific knowledge determines which evidence should be considered and how the safety profile should be interpreted.

For early biological and plasma-derived medicines, the key questions included source safety, contamination and manufacturing controls. With recombinant proteins, the focus expanded toward molecular characterisation, immunogenicity and manufacturing comparability. Monoclonal antibodies introduced increasingly sophisticated questions about target biology, immune modulation and class versus product effects. Biosimilars required pharmacovigilance to integrate the reference-product evidence with product-specific identification. Gene and cell therapies introduced longer-duration biological effects and, for some products, complex manufacturing and administration pathways.

This does not mean that each new modality replaces the safety concerns of earlier modalities. A gene therapy can still raise immunogenicity questions; a monoclonal antibody can still be affected by manufacturing changes; a plasma-derived product still requires rigorous traceability; and a vaccine still requires careful population-level surveillance. The historical transition adds layers of scientific complexity rather than removing earlier principles.

Relationship Between Historical Development and the QPPV.com Taxonomy

The history provides the rationale for the taxonomy established in the preceding biological-medicinal-products article. The taxonomy should not be based solely on chronology, because a historical sequence is not itself a regulatory classification. Instead, historical development explains why the major categories exist and why some categories require their own pharmacovigilance framework.

The QPPV.com series will therefore use history as a bridge between classification and practice:

historical technology → biological characteristics → product family → distinctive safety questions → pharmacovigilance approach

For example, the emergence of recombinant biotechnology explains why recombinant therapeutic proteins form a meaningful family. The rise of monoclonal antibodies explains why antibody structure, target biology and immunogenicity require dedicated treatment. The development of biosimilars explains why similarity to a reference product needs to be distinguished from product identity. The development of gene and cell therapies explains why ATMPs require dedicated consideration of persistence, delayed effects, manufacturing and long-term surveillance.

The next stage of the series should consequently move from this historical landscape into type-level articles. Those articles will no longer need to repeat the complete chronology. Instead, each will examine the defining characteristics, development principles, mechanisms, clinical uses, important safety issues and pharmacovigilance implications of one biological family or subtype.

Pharmacovigilance Across the Biological-Product Lifecycle

Historical development also shows why pharmacovigilance cannot be separated from the product lifecycle. A biological medicine is characterised during development, assessed for quality, safety and efficacy at authorisation, monitored after introduction into clinical practice and potentially modified through manufacturing, formulation, indication or other lifecycle changes.

The scientific evidence available at each stage differs. Development studies establish the initial understanding of biological activity, toxicology, immunogenicity and clinical safety. Post-authorisation experience expands the evidence base and may identify rare, delayed or population-specific risks. Manufacturing changes may require comparability assessment and continued monitoring. New indications may change the exposed population and therefore the observed safety profile. For advanced therapies, long-term follow-up may remain important because the biological effect can extend well beyond administration.

The evolution of biological medicines therefore reinforces a central pharmacovigilance principle: surveillance should be capable of detecting changes in the safety profile while retaining enough product-specific information to explain what has changed, in whom, under what exposure conditions and with what biological plausibility.

Regulatory Evolution in the European Union

The European regulatory framework developed alongside these scientific changes. The European Commission's historical timeline records major milestones including rules for vaccines and blood-derived medicines in 1989, the establishment of the European Medicines Agency in 1995, the introduction of EU rules for biosimilars in 2004, the Advanced Therapy Medicinal Products Regulation in 2007, the first EU-authorised gene therapy in 2012 and strengthened EU pharmacovigilance legislation in 2010. [1]

These milestones should not be interpreted as a complete history of biological-medicine regulation. They illustrate a broader pattern: regulatory categories and procedures were progressively adapted as biological technologies created new types of medicinal products and new questions about quality, safety, efficacy and long-term monitoring.

The modern framework consequently combines general medicinal-product legislation with product-specific provisions and guidance. Directive 2001/83/EC provides the core legal framework and includes the definition of a biological medicinal product in Annex I. Regulation (EC) No 726/2004 establishes the centralised EU authorisation framework and includes important biotechnology-derived categories. Regulation (EC) No 1394/2007 establishes the dedicated framework for advanced therapy medicinal products. Good Pharmacovigilance Practices then provide the overarching pharmacovigilance system, with product-specific guidance addressing particular biological and population contexts. [5–8]

The regulatory framework remains dynamic. New technologies can create products that do not fit neatly into historical categories, and existing categories may require interpretation as scientific understanding develops. The biological-product taxonomy should therefore remain extensible rather than treating the current landscape as permanently closed.

Practical Implications for Pharmacovigilance Professionals

The historical perspective has several practical consequences for pharmacovigilance work. First, product identity should be preserved at a level that permits meaningful scientific and regulatory interpretation. A broad label such as "biologic" is insufficient when the safety question depends on the individual product, formulation, manufacturing process or batch.

Second, the assessor should understand the biological technology sufficiently to recognise which safety mechanisms are plausible. This does not require every PV professional to become a specialist in molecular biology, but it does require access to appropriate product, clinical, quality and regulatory expertise when a signal depends on specialised biological characteristics.

Third, historical knowledge can prevent inappropriate transfer of assumptions between modalities. A surveillance approach developed for a conventional recombinant protein may not be sufficient for a persistent gene therapy. Conversely, the existence of a new technology does not make established pharmacovigilance principles obsolete. The task is to preserve the general system while adapting the scientific assessment to the product.

Finally, the history reinforces the importance of cross-functional interfaces. Biological-product safety can require information from pharmacovigilance, clinical development, medical safety, quality, manufacturing, regulatory affairs, epidemiology and, for advanced therapies, specialised manufacturing and clinical teams. Effective governance allows these disciplines to contribute their respective evidence without collapsing distinct regulatory processes into one another.

Inspection Perspective

An inspection of pharmacovigilance for a biological medicinal product would not be expected to test historical knowledge for its own sake. The practical question is whether the organisation's understanding of the product is sufficient to operate an effective safety system.

An inspector could reasonably examine whether the pharmacovigilance system can identify the actual biological product involved in a case; whether relevant product and batch information is captured where required; whether safety surveillance reflects the known biological characteristics of the product; whether interfaces with quality and manufacturing functions are defined; and whether product-specific risks are incorporated appropriately into signal management and risk-management activities.

These are illustrative inspection questions rather than claims about specific inspection findings. They follow from the operational consequences of biological-product complexity: the organisation needs evidence that its pharmacovigilance system can connect product identity, biological characteristics, exposure, safety information and regulatory action.

Key Takeaways

Biological medicines evolved through a series of technological transitions rather than through a single invention. Blood and plasma-derived products established the importance of biological source and manufacturing control; vaccines developed a distinct tradition of immune-mediated prevention; purification and recombinant biotechnology enabled increasingly defined therapeutic proteins; monoclonal antibodies introduced highly targeted biological therapy; biosimilars established a framework for independently manufactured highly similar biological medicines; and advanced therapies extended the concept of a medicinal product to genes, living cells and engineered tissues.

The pharmacovigilance implications accumulated with these developments. Source, manufacturing, biological activity, immunogenicity, traceability and product identity remain important, while newer modalities add questions concerning persistence, cellular behaviour, delayed effects and complex manufacturing pathways. The appropriate approach is therefore not to replace general GVP principles for each new technology, but to apply those principles with scientific controls and evidence appropriate to the product.

This historical framework provides the bridge to the next stage of the QPPV.com series: dedicated type and subtype articles that explain the defining characteristics and pharmacovigilance implications of the major biological-product families.

References

1. European Commission. 50 years of EU pharmaceutical regulation milestones. Historical timeline covering major EU legislative and therapeutic milestones, including biological products, biosimilars, advanced therapies and pharmacovigilance. Available from the European Commission.
2. European Medicines Agency. Good pharmacovigilance practices (GVP): Product- or Population-Specific Considerations IV — Biological medicinal products. Current EMA GVP guidance on pharmacovigilance considerations for biological medicinal products.
3. European Medicines Agency. Biosimilar medicines: overview. EMA overview of biological medicines, biosimilarity and the EU biosimilar framework, including the first EU biosimilar in 2006.
4. European Medicines Agency. European Medicines Agency recommends approval of first two monoclonal-antibody biosimilars. EMA, 2013; describes the first recommended approvals of biosimilar infliximab products and the extension of the biosimilar framework to monoclonal antibodies.
5. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, as amended. In particular Annex I, Part I, provisions concerning biological medicinal products.
6. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Union procedures for the authorisation, supervision and pharmacovigilance of medicinal products for human and veterinary use and establishing a European Medicines Agency, as amended.
7. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004.
8. European Medicines Agency. Advanced therapy medicinal products: overview. EMA overview of gene therapy, somatic-cell therapy, tissue-engineered and combined ATMPs.

Regulatory Note

This article is a historical and educational overview. Dates and milestones are presented to explain the development of biological medicinal products and the evolution of the European regulatory context; they are not intended to constitute a complete legal history or to imply that a technology originated in the year of a particular regulatory milestone. Legal requirements should be determined from the applicable current EU legislation and current EMA guidance. EMA GVP guidance represents regulatory guidance within the EU pharmacovigilance framework; statements describing good operational practice or pharmacovigilance interpretation in this article should not be read as additional legal requirements unless expressly identified as such. Current product-specific regulatory status and requirements should be verified against the applicable current legislation, EMA materials and product documentation before operational use.