Stability Testing of Herbal Medicinal Products - IPT …

1 BiopharmaUp until recently, Herbal Medicinal Products (HMPs)were mostly marketed in the UK as functional foodproducts under section of the Medicines Act. Inline with the harmonisation of legislation on herbalmedicines across the EU, Directive 2004/24 EC onTraditional Herbal Medicinal Products (THMPD) wasimplemented in the UK on 30 October 2005 (1) . Afterthis, companies were not allowed to introduce new(T)HMPs onto the market without complying withthis minimum registration. Observers believe that onlyvery few Products are likely to go the whole course of afull marketing authorisation, as the high requirementsthat a product has to meet to get an HMP-licence for well established ( Medicinal ) use (WEU) make this anextremely difficult venture.

2 Existing Products can stillbe sold until the end of the transitional period, April2011. Those companies that want to keep theirproducts on the market will need a new registrationbefore that there has been some leniency compared with theWEU full application concerning proof of efficacy, therequirements for proof of pharmaceutical quality havenot been eased. This includes state-of-the-art methodsfor quality control (QC) and Stability data according tothe current guidelines (2,3). Since creation of therequired documents and data for submission takesalmost one year to prepare, it is high time for companiesto start the analytical is appreciated that the Medicines and Healthcareproducts Regulatory Agency (MHRA) in the UK hasbeen open-minded to goal-oriented discussions rightfrom the start.

3 In Germany, there is already a longtradition of manufacturing, QC and use of HMPs on alicence (WEU) or registration (traditional) basis. Agroup of members of the German MedicinesManufacturers Association (4) founded a working groupto discuss special items about quality control andespecially Stability studies of (T)HMPs (5). Some aspectsof the paper prepared by this working group arepresented in this article; the aim is to introducepragmatic solutions to meet the legal requirements, whileat the same time limiting efforts to those that areabsolutely essential.

4 The cost of analytical testingrepresents a major part of the investment for aregistration not only initially on a one-off basis, but forcontinuing QC as well. This has special implications dueto the fact that most Herbal companies in the UK aresmall and medium-sized enterprises (SMEs), or theproducts are of minor importance within the portfoliosof Big Pharma companies. On the other hand, theTHMPD registration presents a number of advantagescompared with a licensed WEU Herbal medicinalproduct.

5 These include saving on the costs of expensiveclinical trials, facilitating the placing on the market ofcombination Products (for example, combinations ofherbal substances with vitamins and minerals), acomparatively faster access to the market (for newproducts in particular) and interesting claims for herbalOTC CHARACTERISTICS OF Herbal Medicinal PRODUCTSH erbal drugs and preparations are classified in theirentirety like the active pharmaceutical ingredient (API)in the HMP. From the chemical and analytical point ofview, Herbal drugs, Herbal preparations and HMPs arecomplex in nature due to the high number ofconstituents belonging to different chemical classes andhaving different analytical behaviours (for example,flavonoids versus essential oils).

6 In many cases, theseconstituents have only very low concentrations,especially in the finished regard to the constituents that are responsible forthe pharmacological activity of a Herbal preparation, the European Pharmacopoeia (6) and the QualityGuideline (2) subdivide them into: Standardised extracts Quantified extracts Other extractsParticular legal requirements for quality control and Stability studies of Herbal Medicinal Products (HMPs) focus on those aspects that areabsolutely in Pharmaceutical TechnologyBy Sven Oliver Kruse and Karim Sultan at DiapharmStability Testing of Herbal Medicinal ProductsIPT 33 2010 3/6/10 15:00 Page 64 Standardised extracts have a declared content ofconstituents with known therapeutic activity forexample, silymarines in Silybum marianum.

7 Therefore,standardised extracts are generally treated in the sameway as chemically defined APIs, including for exampledissolution Testing for solid oral extracts are limited to a defined range ofconstituents that are known to contribute to therapeuticactivity for example, hypericines in extracts without known effective constituents are essentially defined by their production process and their specifications that is, the ratio of herbalsubstance to genuine Herbal preparation ( drug -extract-ratio , DER, genuine).

8 CHOICE OF MARKERSAs described earlier, Herbal drugs/preparations arecomplex mixtures and, to calculate the quantity of a Herbal substance or preparation in an HMP (2), single chemically-defined constituents or groups ofconstituents are used as markers ; these are also called active markers for quantified extracts and analyticalmarkers for other extracts. The choice of marker(s)should be justified by its ability to identify and assay in aselective and robust manner (7). It is generallyrecommended to take account of the following: Literature research about known constituents EP Monograph or other pharmacopoeias and monograph drafts (Pharmeuropa) Analytical feasibility of the marker in the drugsubstance and drug product The marker s suitability for Stability studies Reference standards: availability, quality and costsMonographs may be a helpful tool to define a markerand can give helpful information about a suitablemethod.

9 But it should be taken into consideration thatthese monograph methods can only be used for thepurpose mentioned in the pharmacopoeia. Often, thesemethods are not applicable for a finished productcontaining this drug substance/preparation because theresulting concentration is too low, or matrix effects leadto a lack of selectivity. Methods and markers mentionedin pharmacopoeias are intended for batch releasepurposes only not for Stability studies and they are,therefore, not often considered for this kind of use.

10 Forthis reason, the authorities should not bind the applicantto the markers mentioned in the monographs, andshould allow alternative approaches in the sense of whereapplicable and if justified .CHOICE OF METHODSA gain, due to the complex composition of herbalpreparations, an analysis for QS is mostly done byrunning high performance liquid chromatography(HPLC) or gas chromatography (GC) and thin layerchromatography (TLC) methods, quantitativedeterminations by UV-visible spectroscopy orcombinations of these.