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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