Registration and future development of excipients

inEurope

Dr. Jan OmelkaMeggle GmbH & Co. KG, Germany

Overview

• Registration of excipients in the EU• GMP status for excipients• Harmonization• Future development of excipients

Members of European Pharmacopoeia

European Pharmacopoeia - ObserversEuropean Countries NON-European Countries

Albania China

Georgia Canada

Ukraine Algeria

Bulgaria Senegal

Morocco

Tunasia

Syrai

Australia

Malaysia

Authorisation Procedure

Apart from

• the national authorisation procedures,

two new authorisation procedures have been created on the basis of regulations and directives of the European Commission:

• the centralisedand

• the decentralised

authorisation procedures.

Centralised authorisation procedure

Here authorisation of medicinal products is not granted by a national agency but by the European Commission in Brussels. The organisational procedure is handled by the EMEA in London.

Decentralised authorisation procedure

These are mutual recognition procedures. The marketing authorisation already granted by one EU Member State is to be recognised by the licensing agencies of other Member States within 90 days, unless there are major objections against doing so.

IA. ADMINISTRATIVE

IB. SUMMARY OF PRODUCTCHARACTERISTICS

IC. EXPERT REPORTS

II. CHEMICAL, PHARM.,AND BIOLOGICALDOCUMENTATION

III. PHARMACO.,TOXICOLOGICALDOCUMENTATION

IV. CLINICALDOCUMENTATION

V. SPECIALPARTICULARS

SUMMARYof theDOSSIER

COREDOSSIER

Standard Format: EU Dossier

StabilityControl Test onFinished Product

Control Test onIntermediates

Control of Starting Materials

Method of PreparationComposition

Composition of Proprietary Product

Container

Clinical Trial Formula(e)

Development Pharmaceutics

Pre-formulation studies

Explanation of choice of composition

Compatibility with container/closure

Summary in vivo BA/BE studies

EU Core Dossier (Part II): Development Pharmaceutics

Composition of the Medicinal Product

• Excipients must be listed, specifying their common name, their quantity and the use andreference to any relevant standard.

• When the common name is not sufficient to indicatefunctional specifications, the brand name with commercial grade should be specified.

• In the case of excipients presented as a mixture of compounds, details as to the composition shouldbe provided in qualitative and quantitative terms.

Pharmaceutical Excipients

Substances, other than the active ingredient, which have been appropriately evaluated for safety and are included in a drug delivery system to:

• aid in the processing of the drug delivery system during its manufacture;

• protect, support or enhance stability, bioavailability, or patient acceptability;

• assist in product identification; or

• enhance any other attribute of the overall safety and effectiveness of the drug during storage or use

Specifications and routine tests

Excipients described in the

• European Pharmacopoeia

or, failing this,

• in the pharmacopoeia of a Member State

Certificate of Suitability (COS)

By means of a certificate of suitability granted by the secretariat of the European Pharmacopoeia, the manufacturer of a drug substance can provide proof that the substance is suitably controlled by the monograph of the European Pharmacopoeia

Certificate of Suitability (COS)

The certificate of suitability does not guarantee in any way that the individual batches of the substance are of a sufficient quality. It certifies that by testing in accordance with the monograph of the European Pharmacopoeia it is possible to check whether or not the purity of the substance is suitable. In other words, it ensures that all possible impurities from this particular route of manufacture can be fully controlled by the tests of the monograph.

GMP for Excipients

There is no overall European requirement for GMPfor excipient manufacture, although article 33 in therecent directive 2004/27/EC10 does introduce GMP for “certain excipients”.

The definition of these has yet to be specified, although it is expected to be on the basis of the risk of application of the excipient.

ICH International Conference on Harmonization

The objective of the ICH exercise is to promote international harmonization of the requirements for registration of pharmaceuticals among the three regions EU, USA, and Japan so that medicines are developed and made available:

• in a timely and efficient manner, • preventing unnecessary duplication of clinical trials in

humans, and • minimizing the use of animal testing without

compromising safety and effectiveness.

ICH Members

The six members of ICH:

Regulatory bodies– FDA, USA – EU (European Commission—EMEA)– MHLW, Japan

Research based industry

– PhRMA Ph. Research and Manufacturers of America – EFPIA European Federation of Pharmaceutical Industry– JPMA Japanese Pharmaceuticals Manufacturers

Association

ICH Quality Topics

• Q2 Analytical Procedures• Q3 Impurities• Q4 [Pharmacopeia]• Q5 Biotechnological/Biological products• Q6 Specifications• Q7 GMPs• M4 Common Technical Document • Q1 Stability

Q7A- GMP Concept

• GMP controls apply to all steps in the manufacturing process beginning with the use of starting materials

• Only critical manufacturing steps are subject to process validation

GMP Standard for Excipients

Developed by a team of excipients manufacturers and pharmaceutical companies.

“Three levels of GMP”,(written in the ICH Q7A style)

Designed as an aid to users, one of the key practical elements in this document is

“How to assign an appropriate level of GMP for excipients using a risk assessment approach based on patient safety.”

Current Situation

“ Since this standard (Q7) titled only applies for API´s the FDA is not using the Q7A guideline to audit excipientproducers.”

Irwin SilversteinInternational Pharmaceutical Excipients Auditing (IPEA)

What is IPEC?

IPEC is a federation of three independent regional industry associations:

• Europe (IPEC Europe)• Japan (JPEC)• US IPEC-Americas

.

Focus of IPEC

• law• regulations • science • business practices of its region

Cooperation of IPEC´s

The three associations work together on:

• excipient safety and

• public health issues

• harmonization of regulatory standards and pharmacopoeial monographs

Future development of excipients

New excipients

For new excipients and for excipients presented as a mixture of compounds the following should be taken into consideration:

Any bibliographical data • on the chemistry and • on the toxicology and • the field in which the product is already used.

Scientific data

This documentation is justifying the choice and use of an excipient which is used for a particular purpose:

“it will determine the properties which must be checked during the routine tests and which will be the subject of certain specifications in connection with the bioavailability of the product”

(see note for guidance: Specifications andControl Tests on the Finished Product).

Scientific data

Nevertheless, scientific data are not systematicallyrequired for well-known excipients.

For example, they are not required for excipients which have been used in similar medicinal products for a long period of time and when their characteristics and properties have not changed significantly

Need for new excipients

• the growing popularity of the direct-compression process and a demand for an ideal filler-binder that can substitute two or more excipients

• tableting machinery's increasing speed capabilities, which require excipients to maintain good compressibility and low weight variation even at short dwell times

• shortcomings of existing excipients such as loss of compaction of microcrystalline cellulose (MCC) upon wet granulation, high moisture sensitivity, and poor die filling as a result of agglomeration

Need for new excipients (continued)

• the lack of excipients that address the needs of a specific patients such as those with diabetes, hypertension, and lactose and sorbitol sensitivity

• the ability to modulate the solubility, permeability, or stability of drug molecules

• the growing performance expectations of excipients to address issues such as disintegration, dissolution, and bioavailability

Compounds

Coprocessing is based on the novel concept of two or more excipients interacting at the subparticle level, the objective of which is

• to achieve synergy fuctionality improvements

and

• to mask the undesirable properties of individual excipients

DC-CompoundsCo-processed multi-purpose excipients mainly used for Direct-Tabletting

Ludipress Lactose + PVP BASF

DCL 40 Lactose anh. + Lactitol DMV

Xylitab Xylitol + Na CMC Danisco

ProSolv MCC + Silicon Dioxide Mendell

ForMaxx Ca carbonate + Sorbitol Merck

DC-Compounds

Co-processed multi-purpose excipients made by Meggle:

Cellactose 80 (1990) lactose + powder cellulose

MicroceLac 100 (1995) lactose + MCC

StarLac (2000) lactose + corn starch