Co-Processed Excipients: Regulatory Challenges. Carl Mroz Colorcon Limited June 2009

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1 Co-Processed Excipients: Regulatory Challenges Carl Mroz Colorcon Limited June 2009

2 What is a Co-Processed excipient? Several types of excipient contain multiple components by design Use of processing aids Use of additives Blends Co-processed materials

3 Use of Processing Aids These are normally used to enhance the manufacturing process of the excipient, for example a filter aid can be used to increase yield or the induce manufacturing efficiencies In some cases residues of processing aids will remain in the final excipient

4 Use of additives Additives are sometimes used to enhance the storage or handling of the excipient, for example: The PhEur monograph for macrogol states that a suitable stabiliser may be added The USNF monograph for polyethylene oxide states that a suitable antioxidant may be added

5 Blends Blends of excipients are sometimes used for the convenience of using a fixed proportion of certain materials in combination. An EU guideline* gives guidance on mixed excipients and how to refer to them in regulatory dossiers. Example: ready-to-use preparations for film coating *EMEA/CHMP/QWP/396951/2006

6 Co-Processed Materials Co-processed materials have been developed to enhance the performance of the excipient in the manufacture or use in the dosage form.

7 Co-Processed Materials-A Definition A co-processed excipient is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical change

8 Solid State Characterisation Molecular Level Arrangement of individual molecules in the crystal lattice, will influence polymorphism, pseudo-polymorphism and the amorphous state Particle Level Concerns individual particle properties, such as shape, size, surface area and porosity Bulk Level Concerns multiple particles, influencing flowability and compressibilty Co-processing involves incorporating one excipient into the particle structure of other materials using various processes Coprocessed Excipients for Solid dosage Forms SK Nahaegari and AK Bansal Pharmaceutical Technology January 2004 p.52-64

9 Processes used for Co-Processing These include: Granulation Co-Spray Drying Melt extrusion

10 Co-Processed Excipients- Examples (1) Trade name Manufacturer Components % Claimed benefits Ludipress BASF Lactose PVP 93 7 Low hydroscopicity Good flowability Constant tablet weight Avicel CE- 15 FMC MCC Guar Less grittiness, improved tablet palatability Pharmatose DCL40 DMV ßlactose Lactitol 95 5 High Compressibility Low lubricant sensitivity StarLac Meggle Lactose Maize Starch Good flowability

11 Co-Processed Excipients- Examples (2) Trade name Manufacturer Components % Claimed benefits ProSolv JRS MCC Silicon Dioxide Di-Pac Domino Sucrose Maltodextrin Better flow, les sensitivity to wet granulation, better tablet hardness For direct compression StarCap1500 Colorcon Maize Starch Pregel Starch Xylitab 200 Danisco Xylitol Na CMC 98 2 Tablet disintegration and dissolution independent of ph Directly compressible

12 Co-Processed Excipients- Regulatory A very limited number of co-processed excipients are included in pharmacopoeial monographs Microcrystalline Cellulose and Carboxymethylcellulose Sodium (USNF) aka Dispersible Cellulose BP Compressible Sugar (USNF) (BP) Various acrylate dispersions (truely co-processed?) (USNF and PhEur)

13 Co-Processed Excipients- Regulatory However the majority of commercially available coprocessed excipients are not described in a major pharmacopoeia.

14 Co-Processed Excipients- Regulatory However the majority of commercially available coprocessed excipients are not described in a major pharmacopoeia. Should they be treated in the same way as novel excipients?

15 Co-Processed Excipients- Regulatory For any new excipient regulatory agencies should be looking for a safety assessment However in the case of co-processed excipients the components, the manufacturing process and component combination are not novel The only novel parameters are the physical form and the functionality

16 Co-Processed Excipients- Regulatory Therefore it should not be necessary to perform a full toxicological assessment It should be possible to provide data to bridge to the safety data of the components However the bridging assessment needs to be fully justified by demonstrating that the co-processing process does not create a change of regulatory significance

17 Co-Processed Excipients- Regulatory The absence of significant chemical change should be demonstrated using suitable techniques including: Scanning Electron Microscopy Pyncnometry FT-IR 13 C NMR X ray diffraction Viscosity measurements Differential Scanning Calorimetry etc etc

18 Co-Processed Excipients-Conclusion Co-Processed excipients certainly have a role in pharmaceutical innovation Can be custom designed to possess specific characteristics and functionality for specific applications Co-Processing does create a new entity But demonstration of the lack of significant chemical change should allow entry to market much faster (and more cost effectively) than with a truly novel chemical or biological excipient

19 Acknowledgements Professor Brian Carlin, FMC BioPolymer Dr Chris Moreton, FinnBrit Consulting