WP 3 Task 3.4 Pharmaceutical and other specialty products Task leader: Alice Grigore

Crops2Industry “Non-food Crops-to-Industry schemes in EU27” WP 3Task 3.4 Pharmaceutical and other specialty productsTask leader: Alice Grigore

Content • Objectives • Progress of work • Results • Status of deliverables & milestones • Problems encountered • Plans for the next 6 Months

1. Objectives • to explore the potential and feasibility of the European industry to make high-value biobased products • to identify bio-industry demands on pharmaceutical and other special products • to identify restricting factors that inhibit broader industrial use of the feedstocks

2. Progress of work • Medicinal plants value chain – Establishing of the pathway to develop herbal products with high added-value • Market research ● Choice of crop ● Site selection ● Crop establishment and management ● Harvest ● Processing ● Financial analysis • Screening on the European specialty products based on medicinal and aromatic plants. Focus on the selected 5 MAP Pharma industry ● Cosmetics ● Dyes, colorants● insecticides ● Selected crops and bio-based industry ● Economic aspects • Quality characteristics required for herbal substances, herbal preparations and herbal medicinal products • Regulatory environment concerning herbal medicine • Restricting factors Restricting factors in technology ● Restricting factors in economics ● Quality control • Research gaps • Recommendations

3. Results Medicinal plants value chain – Establishing of the pathway to develop herbal products with high added-value The strategy for sustainable use of MAP has two main components: • regulation of collection of medicinal plants from the wild → to protect biodiversity • promotion of cultivation → to achieve a more stable production base and greater control over quality →provide new income opportunities to farmers →to meet demand

Market research The product should meet market requirements • EU is the largest single commercial market for MAPs; the annual growth rate is estimated at 5 to 10%. • Most of the herb market is supplied predominantly with imported botanical raw materials • Germany is the largest importer, followed by France, Italy, Spain, UK • Germany is the largest exporter, followed by Poland, France, Belgium, Spain, Bulgaria, Italy • Germany is also Europe’s largest (re-) exporter of MAP, followed by France.

The global market for plant-derived drugs was worth an estimated $19,5 billion in 2008. BCC Research expects this figure to grow to more than $26 billion by 2011 and $32.9 billion by 2013. • Globally, cancer treatment is expected to become the largest application of plant-derived drugs by 2011, with 24% of the market. • Indications in self-medication for herbal drugs include, in order of sales volume: cough/cold, circulation, digestion, relaxation/sleep, pain including muscles/joints, tonics/geriatrics (BCC Research)‏

Recent Comtrade statistics (2008-2009) show that: As regards plants and parts of plants (including seeds and fruits), of a kind used primarily in perfumery, in pharmacy or for insecticidal, fungicidal or similar purposes, fresh or dried, whether or not cut, crushed or powdered • imports exceed exports in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Portugal, Romania, Slovakia, Slovenia, Spain, UK, • exports exceed imports in Bulgaria, Cyprus, Hungary, Poland, Sweden

As regards essential oils (other than those of citrus fruit): • exports exceed imports - Austria, Bulgaria, France, Hungary, Luxembourg • imports exceed exports - Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Ireland, Italy, Latvia, Lithuania, UK, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden

Market trends that will potentially increase the demand for MAP are: • increased costs of pharmaceutical-based health care • search for new drugs and treatments of serious diseases • consumers seeking an alternative to pharmaceutical drugs •large pharmaceutical and OTC companies placing botanical medicines more strongly on the mass • increased emphasis on safety, efficacy and quality to conform to international standards • increased requests for organically certified raw material • need for new and eco-friendly herbal-based products – insecticides, dyes, etc.

Quality characteristics required for herbal substances, herbal preparations and herbal medicinal products Pharmacopoeial tests and acceptance criteria The European Pharmacopoeia contains important requirements pertaining to certain analytical procedures and acceptance criteria that are relevant to: • Herbal drugs - all mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried form but sometimes fresh.

Herbal drug preparation - are obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates. • Herbal medicinal products (the term includes “traditional medicinal product”) - any medicinal product, exclusively containing as active substances: ►one or more herbal substances • ► one /more herbal preparations, • ► one/more herbal substances in combination with one/ more herbal preparations.

Design and development considerations The experience and data accumulated during the development of a herbal medicinal product should form the basis for the setting of specifications. Specifications = a list of analytical or biological procedures which provide assurance that the appropriate quality of the product will be maintained. The setting of specifications is part of an overall control strategy which includes control of raw materials and excipients, in-process testing, process evaluation/validation, stability testing and testing for consistency of batches, intended to ensure safety and efficacy.

A key issue in manufacturing herbal products and medicines is standardization. Standardization is the process of producing herbal extracts or phytochemicals in which product potency is guaranteed through consistency in specific active compound content level. This process requires high knowledge in phytochemical analysis and process technology to ensure the quality assurance required. Product value increases in the following order: fresh material < dried powder < non-standardized extract < freeze/spray dried extract < standardized extract < phytomedicine.

Regulatory environment concerning herbal medicine The herbal medicinal market in Europe is currently affected by substantial changes of the regulatory environment. General intention is to harmonize the regulation of medicinal products, food and other consumer goods at centralized European level. Difficulties come from: -the heterogeneity of the starting material itself (chemical composition, natural variability, diverse sources), -the heterogeneity of plant preparations (plant part used, type of preparation, manufacturing process), and the lack of accurate quality/safety data for often non-standardized low price products.

There are great differences between Member States in the definition and categorization of herbal medicines. A single medicinal plant may be defined as a food, a functional food, a dietary supplement or a herbal medicine in different countries, depending on the regulations applying to foods and medicines in each country. →This makes it difficult to define the concept of herbal medicines for the purposes of national drug regulation and also confuses patients and consumers.

Besides EMEA, other key players are involved in the regulation of herbal market: -European Directorate for the Quality of Medicines (EDQM) with the Commission of the European Pharmacopoeia (Ph Eur) and the European Scientific Cooperative on Phytotherapy (ESCOP, founded 1989). The EDQM includes 36 European Member States and 20 observers such as the American FDA and the WHO. Its role is to harmonise the quality standards for use by healthcare professionals.

Screening on the European specialty products based on MAP Focus on the selected 5 medicinal plants Pharmaceutical and other specialty crops are the starting point for a wide range of products: ● essential oils ● human and veterinary drugs ● herbal health products ● inks ● colorants and dyes ● perfumes ● beauty products ● novel plant protection products ● a range of intermediate products from which the above are manufactured

Pharma industry • In the past 20 years, 28% of new drug entities were either natural products or derived from them as semi-synthetic derivatives → importance of plants as a source of new drug molecules • developing new therapeutic strategies for cardiovascular and infectious diseases, diabetes, obesity, cancer and allergy. • a wide range of medicinal preparations: tea, tinctures, medicinal oils, essential oils, compresses or plasters, eye washes, balsams, cataplasms, as well as a great number of pharmaceutical forms: tablets, capsules, syrups, ointments, hydrophilic gels, eye-drops, nasal sprays and drops.

Cosmetics • In the last years a new concept has developed – cosmeceutics -cosmetic products that include ingredients designed not only to enhance the appearance but to also have a positive physiological effect at the cellular level. • The use of new products is increasing: men’s grooming products, anti-aging products, spa-at-home, detoxification products.

Dyes, colourants • There is an increasing development of new natural compounds able to substitute chemical additives for food and beverage industry (as antioxidants or colorants) • Natural dyes are rarely used in modern dyeing, except by specialist companies and craft dyers. Only a limited number of plant species exhibit the potential for large-scale production and some of them can be used as dyestuffs only for food, but not for textiles. Method for obtain and purify compouds and stability studies must be developed.

Insecticides • Alternative insecticides normally mean the insecticides are less toxic to humans and breakdown more rapidly in the environment than conventional insecticides. → “environmentally friendly”. • The most known natural insecticides are pyrethrins, limonene and linalool which are volatile molecules. This sector needs to be developed.

Selected crops and their applications

An internet survey regarding species selected – Calendula officinalis, Lavandula angustifolia, Mentha piperita, Echinacea angustifolia and Plantago lanceolata – and their various uses in different European countries showed that these herbs are used for various purposes and are presented in various forms most of the raw material used by these manufacturers comes from own plantations Selected crops in EU 27 countries

COSMETICS

EXTRACTS

Data received from few important Romanian manufacturers show that: Small and medium companies prefer to develop their own network starting from raw material to final product. The products are designed mainly for medicinal and cosmetic use High income in the last year were obtained mainly from tea, tablets, capsules, volatile oil, solution for spa use and syrup sales The products are impossible to substitute with one synthetic drug (herbal products are usually mixture of active principles). Herbal products are adjuvant in classical medicine or have a preventive action. In pharmacological testing, the activity is compared to synthetic drugs. Selected crops in Romania

Restricting factorsRestricting factors in technology: Processing methods (primary and specific) conduct to herbal products of higher yield, lower operating costs, and faster production times. Products diversity- new products come from new technologies and new equipment . • Adequate processing methods The obtainment of a selective extract mostly leads to the high price of the product. • Herbal products can be sold in a variety of forms; packaging also plays an important role to attract consumers. →Need for appropriate equipment for extraction, processing, conditioning and packing herbal products

Restricting factors in economics - the product price (and not the product quality) is the most important factor that affects buying decision for many market segments. Local production have to compete with the import of cheap products and raw materials (especially from China and India)

Quality control • In the case of medicinal plants which are used directly as pharmaceuticals, the quality and thus the concentration of active compounds is much more relevant than the total yield (for example, increasing the plant product concentration by applying deliberately drought stress would be compensated by decreasing yields in biomass)‏ • ‏Inspite of the widespread usage of herbal pharmaceuticals there is a lack of proper standardization and quality control of the drugs. The problem is often due to the special characters associated with plant origin medicines (for example, Echinacea phytomedicines with multiple activities, species, and formulations)‏

Some producers choose to use encapsulated dried and milled plants instead of selective extracts or some choose to sell adulterated essential oils. For example, as regards -Roots of Parthenium integrifolium L., have been found to be adulterants/substitutes for Echinacea root; -Lavender oil is often adulterated by acetylated lavandin, aspic, synthetic linalool, linalyl acetate, -Mentha oil is the most adulterated oil, usually with Mentha arvensis -difficult to detect even at 85% or with synthetic compounds)

Research gaps There are several ways in which plant science can address future demand in this area. -optimising the profile and possibly increasing the content of active components of the raw material itself. -better preservation of these phytochemicals during crop maturation, post-harvest treatment and storage. -the factors that play a major role in bioactivity during processing should be at least maintained and possibly enhanced.

- improvement of plant performance and quality in different environments by revealing genetic and epigenetic mechanisms controlling plant plasticity in response to environmental stimuli ex. Cold or drought tolerant M. x piperitasuitable for Finnish climate conditions; Lavandula for dry areas - hybrids are generally less susceptible to environmental fluctuations than their parents. -Herbicide-resistant crops his means less spraying, less traffic on the field, and lower operating costs.

-As regards innovative products, the areas that could be developed are -pesticide and insecticide based natural compounds. -organic products -environmentally friendly methods for crop protection (allelopathic plants) -Phytotherapy in veterinary medicine is a domain which needs further study.

Focus on quality - the consumers must understand that the quality is more important than price. - development of stable molecular markers which assure without doubt the quality of herbal medicines. - conducting clinical trials in Europe in order to comply with regulatory requirements for product registration, especially in Germany and France which regulate botanical products mainly as drugs. In the past 20 years, completely new markets were created for botanicals based upon scientific support.

Results mentioned above were delivered on time to coordinator 4. Status of deliverables & milestones

Information on the specialty crops and crop products sector is difficult to analyze, because of its extreme diversity and variability and is limited by the reluctance of certain parts of the industry to document for commercial reasons. 5. Problems encountered

Update report with relevant data 6. Plans for the next 6 months

THANK YOU !

WP 3 Task 3.4 Pharmaceutical and other specialty products Task leader: Alice Grigore