Proposals for revision and comments on EMEAHMPWP34403 Points to by rxb16942

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        Proposals for revision and comments on EMEA/HMPWP/344/03
     "Points to Consider on the Biopharmaceutical Characterisation of Herbal
                               Medicinal Products"

Preamble

The FIP (International Pharmaceutical Federation) Special Interest Group (SIG) "Quality of
Pharmaceuticals" elaborated a framework of points which should be considered for the
biopharmaceutical characterisation of herbal medicinal products. The document was published in a
revised form recently [1,2] considering some of the comments which had been submitted to the
authors in response to the first publication of the paper. Related to these activities the Working Party
on Herbal Medicinal Products of the EMEA published a draft guidance document
EMEA/HMPWP/344/03 "Points to consider on the biopharmaceutical characterisation of herbal
medicinal products“ which incorporates major points from the FIP recommendations.

The FIP recommendations and the EMEA/HMPWP draft guidance deal with biopharmaceutical
aspects related to quality and bioequivalence of herbal medicinal products. However both fields are
not stringent separated and not discussed distinctly. Both documents are based on the following
consumption stated in the FIP recommendations and is equivalent cited in the EMEA/HMPWP draft
guidance: „In most cases there is no doubt that a complete and rapid dissolution of the whole plant
extract is a prerequisite for the clinical efficacy of HMPs“ There is no evidence at all in the published
literature which supports this assumption. Contradictory, evaluating the available data in the literature
it becomes evident that the linkage between biopharmaceutical properties and efficacy of herbal
medicinal products is much more complex, involving e.g., intestinal metabolism and active transport
rather than simple dissolution and passive diffusion of active constituents beside effects of non-active
constituents on absorption [3-14]. Additionally the FIP recommendations [1,2] cross reference to the
BCS-system, in which solubility and permeability of APIs are addressed. However as for herbal
medicinal products only very limited data are available on permeability. All decision trees provided
are based solely on solubility, which is not compatible with the BCS concept. Therefore, the BCS-
system is in the present stage of knowledge about herbal APIs not applicable for HMPs. These are
major weak points in the argumentative basis for demands on extensive biopharmaceutical
characterisation of herbal medicinal products and concepts using such data for the proof of
bioequivalence. Consequently, it is questionable from a scientifically point of view, if the data
available today build a sound and valid basis for the regulatory requirements given in the
EMEA/HMPWP draft guidance. Nevertheless comments and proposals for revision are given.

The comments given with respect to the EMEA/HMPWP draft guidance apply also to the FIP
recommendations. The comments (in footnotes) and proposals for revision (in italics) given below
represent the opinion of the biopharmaceutical expert committee of the German Cooperative on
Phytopharmceuticals:

                    •   Prof. Dr. A. Nahrstedt (Chairman, University of Münster)
                    •   Dr. B. Frank (Kneipp-Werke)
                    •   Dr. J. Freudenstein (Schaper&Brümmer)
                    •   Dr. F. Gaedcke (Finzelberg)
                    •   Prof. Dr. M. Keusgen (University of Marburg)
                    •   Dr. R. März
                    •   PD. M. Veit (LAT GmbH)
                    •   Prof. Dr. H. Winterhoff (University of Münster)
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Points to Consider on the Biopharmaceutical Characterisation Justification of
Bioequivalence of Herbal Medicinal Products

1. Introduction

For herbal medicinal products the active substance is defined as the whole native herbal drug
preparation (e.g. the native extract) in its entirety, even though not all constituents contribute
to efficacy.

Biopharmaceutical parameters related to quality such as dissolution behaviour of the extract
in solid oral dosage forms are usually evaluated in the course of pharmaceutical
development. In case that biopharmaceutical parameters are critical and optimisation of
these parameters could not be achieved, they have to be considered for release and shelf live
specifications. However, most herbal medicinal products are based on well established
formulations which are regarded to be not critical regarding concerning biopharmaceutical
parameters.

Additionally to the biopharmaceutical characterisation related to the quality, comparative
biopharmaceutical characterisation may be used for the justification of bioequivalence.1 In
contrast to chemical defined products, the biopharmaceutical quality and behaviour of herbal
medicinal products (HMPs) in the context of bioequivalence studies are is not well
documented. In most cases an in-vitro / in-vivo correlation biopharmaceutical
characterisation is complicated by the complex composition of the herbal drug preparations,
the extensive metabolism of their constituents and the resulting analytical difficulties.

The following considerations apply to immediate release solid dosage forms with systemic
action containing preparations from the same from herbal drugs.

In many cases it may be assumed that a complete and rapid dissolution of the herbal drug
preparation e.g. extract, from a solid oral formulation is a prerequisite for a non-problematical
bioavailability and clinical efficacy of HMPs. Some preparations such as lipid extracts and
essential oils however, are not easily soluble and do not dissolve completely from the
pharmaceutical formulation. Such preparations and formulations may be more indicative for
biopharmaceutical problems.1

The present points to consider document proposes some scientific aspects and strategies
concerning biopharmaceutical bioequivalence2 studies for HMPs. They should be read in                                  Formatiert
conjunction with other CPMP guidance related to the biopharmaceutical characterisation                                 Formatiert
bioequivalence3 of medicinal products, especially the CPMP „Note for guidance on
1
  There is no evidence in the published literature supporting the assumption on complete and rapid dissolution.
Evaluating the available data it becomes evident that the link between biopharmaceutical properties and efficacy
of herbal medicinal products is much more complex, involving e.g. intestinal metabolism and active transport
rather than simple dissolution and passive diffusion [3-14] (see preamble). There are no publications available
indicating problems in the bioavailability of lipophilic extracts [15]. However there are data available indicating
the opposite, e.g. thymole from thyme extract [16] or 1,8-cineole, menthole and alpha-pinene and [17,18].
2
 The scope of the Guideline is biopharmaceutical characterisation for bioequivalence rather than bioequivalence
in the context of quality of herbal medicinal products.


3
    All guidelines available and cited in the text refer to bioequivalence in their title (e.g. CPMP/EWP/1401/98)
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investigation of bioavailability and bioequivalence“ (CPMP/EWP/QWP/1401/98), as well as
in conjunction with the CPMP„Note for guidance on quality of herbal medicinal
products“(CPMP/QWP/2819/00) and the CPMP „Note for guidance on specifications: test
procedures and acceptance criteria for herbal drugs, herbal drug preparations and herbal
medicinal products“(CPMP/QWP/2820/00).



2. Classification of active substances in HMPs as a prerequisite for biopharmaceutical
   Characterisation


As the whole herbal drug preparation is regarded as the active substance, several types of
preparations, depending on the pharmaceutical-analytical, pharmacological-toxicological and
clinical findings, can be identified. In the case of extracts, the European Pharmacopoeia
defines the following types of extracts:

A: Standardised extracts containing constituents (single or groups) that are solely responsible
for the acknowledged and documented therapeutic activity. Standardisation (adjustment) to a
defined content is acceptable (e.g. standardised Senna leaf dry extract) using inert excipients
or preparations with a higher or lower content.

B1: Quantified extracts containing chemically defined constituents (single or groups)
possessing relevant pharmacological properties (active markers). These substances are likely
to contribute to the clinical efficacy; however, evidence that they are solely responsible for the
clinical efficacy is not yet available (e.g. extracts of Ginkgo, St. John`s Wort).The
characterisation of these extracts should take into consideration as far as possible the
particular state of knowledge concerning the documented efficacy, quality and safety of an
extract. Standardisation by blending lots of an herbal drug before extraction or by mixing
different     lots     of     herbal      drug    preparations     is     appropriate/acceptable.
Adjustment/standardisation using excipients is not acceptable.

CB2: Other extracts containing no constituents documented as being determinant or relevant
for efficacy, or as having pharmacological or clinical relevance. In these cases, chemically
defined constituents (markers) without known therapeutic activity, may be used for control
purposes (e.g. Valerian or Stinging nettle root extract). These markers may be used to monitor
good manufacturing practice or as an indicator for the assay of the herbal drug preparation.


The European Pharmacopoeia classification of extracts is useful to determine the scientific
level and the future efforts for the biopharmaceutical characterisation of HMPs. Similar
considerations should apply to other herbal drug preparations such as powders used in e.g.
tablets or capsules.
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3. Special aspects of HMPs in biopharmaceutical characterisation for justification of
bioequivalence2

HMPs are in many cases based on herbal drugs and preparations such as extracts used for a
long period of time. Their use is often described in literature but not in all cases it is based on
systematic pre-clinical and clinical studies. HMPs may show great differences in the extracts
used, the dosage forms and strengths. This raises the question of the clinical relevance of
existing differences and thus, the biopharmaceutical characterisation for justification of
bioequivalence2 of such HMPs.

In order to decide on the type and on the extent of tests related to the biopharmaceutical
characterisation for justification of bioequivalence and on the need of bioequivalence studies,
the differences of extracts described in literature and the type of extracts, in the sense of
„conventional extract“ described in Pharmacopoeias or monographs of ESCOP, WHO,
CORE-SPCs or „refined extract purified extract“, should be considered. A reduced set of
biopharmaceutical tests may be acceptable if a wide range of different conventional extracts
or preparations corresponding to type B or C have been widely used and are described in the
literature that supports safety and efficacy of a product.

4.       Implementation of the definitions of CPMP-Guideline 1401/98 for HMPs

4.1 Considerations related to the active substance(s)

The definitions of the EMEA CPMP Note for Guidance on BA/BE
CPMP/EWP/QWP/1401/98 address primarily chemically defined active substances and
finished products.
In contrast to synthetic active substances the composition of an herbal drug preparation is
determined by the manufacturing process (product by process) and the quality of the herbal
drug.
In the present state of technical development, biopharmaceutical tests are mainly based on
analytical parameters. However, having in mind the complex composition of herbal drug
preparations, biological testing systems may add valuable information on the comparability of
herbal drug preparations and HMPs.

For herbal drug preparations corresponding to type class A, it is accepted that defined
constituents are responsible for the therapeutic activity. Herbal drug preparations, originating
from the same herbal drug, but prepared with different extraction solvents, or by different
manufacturers, or by different methods of extraction may be considered to be "pharmaceutical
alternatives" if the quantity of constituents with known therapeutic activity is identical and the
drug to extract ratio is comparable 4 to the reference preparation.

For herbal drug preparations corresponding to class type B B1, a preparation may be classified
as a "pharmaceutical alternative" if the specifications related to the "pharmacologically active
markers", the extraction solvent the solvent strength of the extraction solvent5 and the native

4
  If – as stated in the text just in the sentence before – herbal drug preparations could be prepared with different
extraction solvents, or by different manufactureres and/or by different processes the drug to extract ratio in most
cases could not be comparable.
5
 Two solvents need to possess the same solvent strength in order to have the same potency to eluate equal
qualitative and quantitative patterns of constituents from the plant material [19,20,21].
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drug : extract ratio are the same equivalent and if no differences in solubility exist6, as
compared to the reference preparation/product. In addition, different comparative fingerprints
in considering the variability of the reference product should be documented6.
In case of “non conventional extracts” the primary extraction solvent and the drug : extract
ratio should be the same.

For herbal drug preparations corresponding to type class B2 C, a preparation may be
classified as "pharmaceutical alternative" if the solvent strength of the extraction solvent5 and
the native drug : extract ratio are the same equivalent. In addition, different comparative
fingerprints in considering the variability of the reference product should be documented 6.

4.2. Considerations related to the HMP for justification of bioequivalence.

Different formulations (e.g. coated tablets or soft gelatine capsules) using the active
constituents pharmaceutical alternatives as active substances (native extracts) at the same
dosis may not be regarded as pharmaceutical equivalent without considering their dissolution
of the extract

4.3     Solubility

For immediate release herbal medicinal products the solubility of the whole extract 7(Type C),
"active markers" (Type B1) or constituents with known therapeutic activity (Type A) may be
regarded as crucial characteristics for a biopharmaceutical comparison for with the reference
product. 7

4.3.1 In vitro dissolution tests with HMPs

For HMPs corresponding to type A, the in vitro release of the constituents with known
therapeutic activity should be compared with those of the reference product. Pharmaceutical
equivalence may be accepted if in both products in the test and reference product the in vitro
release dissolution profiles of constituents with known therapeutic activities exceeds 90% are
similar with respect to APPENDIX II of CPMP/EWP/QWP1401/98. In case of a low in-vitro
release or if the constituents have a low solubility significant differences, bioequivalence
studies may be necessary.

For HMPs corresponding to type B1 B, the in vitro release of "active markers" and solubility
of the extract should be compared with those of the reference product. Pharmaceutical
equivalence may be accepted if both parameters in both products exceed 90% in the test and
reference product the dissolution profiles of the "active markers" are comparable. In case of a
low in-vitro release or if the constituents have a low solubility significant differences,
additional clinical safety or bioequivalence studies may be necessary.

For HMPs corresponding to type C the solubility of the extract should be compared with the
reference product equivalence should be justified by dissolution testing using fingerprints.
6
  As the native extract is usually not available in contrast to chemically defined substances no comparative
studies on solubility could be performed. Comparative fingerprint analysis replaces comparative studies on
solubility.
7
 The "solubility" of the extract instead of dissolution could not be assessed easily as in the herbal drug
preparation and also the herbal medicinal product excipients which may be insoluble or partly soluble are present
and solubility of markers may not be representative for the whole extract. The guideline should only focus on
dissolution testing.
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If the solubility of the extract cannot be tested7 Alternatively the release of (an) appropriate
marker(s) should may be compared. The appropriateness of the marker for the
biopharmaceutical characterisation justification of bioequivalence must be justified.
If no appropriate marker can be found, a comparison of disintegration profiles may be
acceptable. The applicant has to justify why marker substances could not be identified and
why additional studies on clinical safety or bioequivalence are not necessary.


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