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An Over view of Quality Considerations for Excipients

a report by

Steve Moss
Manager, New Product Supply and Business Development, GlaxoSmithKline


Although they do not have the therapeutic benefit of active pharmaceutical ingredients, excipients remain essential constituents of virtually every pharmaceutical product. Excipients fulfil an extensive and diverse range of functions. They may be used to facilitate processing during manufacturing of bulk product, for example to aid solubulisation, or during manufacture of the final dosage form, for example to prevent adherence to machinery. Excipients may be critical in the formulation to ensure the drug is acceptable to the patient, or be the actual mechanism for delivering or controlling the release of the active. Processing aids during packaging of the pharmaceutical product, such as stopper lubricants, or during the use of the final dosage form, such as syringe lubricants, could also be regarded as excipients and they demand similar quality considerations. Table 1 illustrates some of the wide variety of functions that excipients fulfil. Whereas active pharmaceutical ingredients are virtually always developed specifically for the pharmaceutical industry, the majority of excipients have primary uses in other industries. Commonly used excipients in oral pharmaceutical products include the colouring, flavouring, bulking and taste-masking agents, which are large-scale ingredients for the food industry. Topical pharmaceutical products utilise the basic constituents of many cosmetic creams and ointments. Many other excipients such as solvents, preservatives, buffers, and pH adjusters have applications in the bulk or speciality chemicals industries. Excipients manufacturers may therefore intend to primarily meet the requirements of a very different industry for their products. The detailed regulatory and patient requirements well understood by pharmaceutical manufacturers may need additional explanation and discussion with excipient suppliers when deciding to use their products. Comprehensive technical and safety considerations need to be taken into account for the use of excipients, and product registration processes demand that the pharmaceutical manufacturer include extensive detail. For novel excipients, the requirements for registration approach those for active pharmaceutical ingredients.

Pharmaceutical manufacturers also have a duty to ensure that materials are suitable for use in their products not only by specification, sampling and testing, for which there are detailed regulatory requirements1, but also by control of the excipient manufacturing process with appropriate use of Good Manufacturing Practice (GMP). The pharmaceutical manufacturer and their excipient suppliers must have open communications to ensure that each partys expectations are well understood. This is particularly important where there are specific requirements for the pharmaceutical industry. These may be tighter specified limits for functional parameters, or a particular focus on contamination such as microbial bioburden or absence of pyrogens. One of the key reasons pharmaceutical companies often audit their excipient suppliers is to assure the control of excipient manufacturing process is compatible with the use in particular pharmaceutical products.
Registration Detailed Technical Requirements

Dr Steve Moss has been Manager of New Product Supply and Business Development within a corporate quality department of GlaxoSmithKline for three years. Previously, he managed groups of auditors responsible for the quality of pharmaceutical suppliers and contractors. He also spent eight years in the chemical industry where he had roles in development, production and project management. Dr Moss led the development team for the GMP guide PS 9100:2002 Pharmaceutical excipients for the UK Pharmaceutical Quality Group (PQG). He is currently part of the joint team of the PQG and International Pharmaceutical Excipients Council of Europe and Americas preparing a common excipients GMP guide. He received his BSc and PhD from the University of Sheffield, an MBA from the Open University and is eligible to operate as a Qualified Person under EU directives for medicinal products.

Detailed requirements for excipients are defined in European directives and guidelines for pharmaceutical products2,2a,2b,2c,2d. Some of the key requirements are summarised in Table 2. For registration of a new pharmaceutical product all the excipients, including any constituents, must be identified. The rationale for inclusion of the excipients in the formulation must be provided, and the compatibility with the active substance established. Interaction between excipients and active substance can be due to many effects3 and there are many considerations for excipient compatibility, some of which are listed in Table 3. Where some of the excipient is lost during processing, the inclusion of additional quantities to allow for this should be explained. There are specific requirements for colouring matter, human or animal origin materials and for novel excipients. For colours, the requirement is to use only those allowed by directives covering food and medicines for permissibility4,4a and purity5. Perhaps suprisingly there is no similar requirement for flavours. The reason is that the legislation for flavours is not so well

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Table 1: Examples of excipient function by stage or application




Bulk processing

Facilitate manufacture of bulk product

Dosage form processing

Facilitate manufacture of dosage form

Dosage form Packaging processing Dosage form acceptability

Facilitate manufacture of finished product Patient tolerance Appearance

Solvent Co-solvent Gelling agent pH adjuster Anti-foam Lubricant Glidant Binder Diluent Solvent coating Capsules Stopper lubricant Tonicity adjuster pH adjuster Colour Flavour Fragrance Sweetener Colour Printing ink Penetration enhancer Disintegrant Propellant Inhalation powder carrier Polymeric coatings for API particles, tablets, or patches Antioxidant Sequester Buffer Preservative Vial wetting agent Syringe lubricant

for the Quality of Medicines (EDQM) for a European Certificate of Suitability (CEP) for the material.9 The certificate can then be used by manufacturers of medicinal products in their marketing authorisations. The registration requirements for novel excipients, being used for the first time in a medicinal product or by a new route of administration, approach those for active pharmaceutical ingredients. Full details of manufacture, characterisation and controls, with clinical and non-clinical safety data and stability data are all part of the submission. This is both very costly and very time-consuming to the pharmaceutical company and excipient manufacturer involved, and tends to discourage the innovation of new materials. However, there are examples where development of novel excipients has been successful. These tend to be for direct action of active pharmaceutical ingredient (API) availability, for example in solubilisation or controlled release mechanisms. The prior use of commercial materials for food can support use in oral products, and use for cosmetics can support use in topical products.
GMP for Excipient Manufacture Guidelines and Potential for Inspection

Identification Dosage form activity/delivery Aid activity

Control release of active Retain activity

Product use

Prevent spoilage Ensure patient receives dosage

developed as there is no list of approved materials, although commission regulations for food use indicate that this should be developed soon.6,7 Following the intense focus on risk of Transmissible Spongiform Encephalopathies (TSEs), there are detailed additional controls for use of materials or animal origin. The best policy is to avoid use of these materials where suitable materials of vegetable or synthetic origin are available, and many pharmaceutical manufacturers in Europe have substituted materials of animal origin with these alternatives. Where materials of human or animal origin must be used, the requirements are to minimise the risk of TSE agents, by control of the source and type of tissue used, the manufacturing process and audit and traceability. Directive 2003/63/EC requires demonstration of compliance with the Note for Guidance.8 One way of demonstrating compliance with the requirements is for the supplier to apply to the European Directorate

There is no overall European requirement for GMP for excipient manufacture, although article 33 in the recent 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. The same directive requires GMP for active pharmaceutical ingredients and the entitlement to inspect manufacturers of active substances used as starting materials (article 77). There is no specific mention of regulatory inspections for excipient manufacturers, although these are described in support of European Certificates of Suitability. Inspections of manufacturers of animal origin materials were carried out by many regulators at the height of the interest in TSE risk. It is also likely that inspections would be carried out for manufacturers of particularly novel excipients or those with specialist applications. There also remains the possibility to request voluntary inspections. Directive 2004/27/EC infers that the GMP requirements for the certain excipients will be the same as the principles of good manufacturing practice for active substances used as starting materials, which will be Annex 18 of the EU GMP guide.1 The World Health Organization (WHO) published GMP guidelines specifically for excipients manufacturers in 199911. The French

An Over view of Quality Considerations for Excipients

regulator (AFSAPSS) has recently reconsidered insisting on their own specific GMP standards for excipients produced or distributed in France. This has been welcomed by industry as the proposed standards were inappropriate for excipients, being based on the WHO GMPs for active pharmaceutical ingredients. In the absence of specific regulatory guidance for excipient manufacturers, industry bodies have evolved GMP guidelines over several years. In the UK, the Pharmaceutical Quality Group (PQG) developed PS 9100:2002 Pharmaceutical excipients,12 which includes both a GMP guide and an audit standard, based on International Organization for Standardization (ISO) 9001:2000, which is commonly applied in the excipient manufacturing industry. This also includes a risk assessment process to define an appropriate level of GMP based on application of the excipient12a, which is consistent with the recent focus on risk-based approaches.13 The International Pharmaceutical Excipients Councils of Americas and Europe (IPEC) have published a Bulk Pharmaceuticals GMP guide14. The PQG and IPEC are now working together to amalgamate these two documents to produce a common excipients baseline GMP guide during 2005.15
GMP for Excipient Use Specifications, Rules and Guidance

Table 2: Some registration requirements for excipients2 Description & composition The constituents of the excipients... including colouring matter, preservatives ....etc The constituents of the outer covering of the medicinal products (intended to be ingested or otherwise administered to the patient) e.g. capsules, coated tablets... etc Pharmaceutical development Compatibility of the active substance with excipients Choice of excipients... relative to their respective functions and concentrations Any overages in the formulation shall be warranted Control of excipients Information of the quality & control of materials Demonstrate materials meet standards appropriate for their intended use Specifications justified, validated analytical procedures Specific requirements for: Colouring matter Human or animal origin materials Novel excipients

Key elements in the registration of a new pharmaceutical product are the quality and control of the excipients (see Table 1). This invariably involves specifications for the materials, by reference to a pharmacopoeial monograph or with detailed definition of the testing. Typical requirements include specific tests for the identity of the material, an assay and impurities determination, together with some physical properties such as density, colour or particle size. There is a trend to include functionality tests in the monographs for some materials, where functionality can be assessed by physical tests such as viscosity or particle size.15a These are included without limits, as the user must determine the acceptable ranges for their processes. Guidelines for control of residual solvents have been defined by the International Conference on Harmonisation (ICH) and these have been implemented in the EC.16 Control of residual heavy metals from use of catalysts in manufacturing processes is also proposed.17 Pharmaceutical product GMPs also define requirements for control of the use of excipients. Regulatory inspectors continue to report serious GMP deficiencies for suppliers, and sampling and testing of starting materials.18 In Chapter 5 (Production, Starting Materials) of the EC GMPs,1 pharmaceutical manufacturers are required to have a knowledge of

Table 3: Compatibility considerations for excipients

solubility lipophilicity pH isomerisation reduction/oxidation metal chelation complexation of API precipitation temperature stability absorption by processing contact materials absorption by packaging contact materials

their suppliers and to receive materials from approved suppliers, ideally direct from the producer. This is to minimise the risks from re-labelling or re-packaging by brokers or distributors. Pharmaceutical manufacturers must also check the containers on receipt for integrity and assure the identity of the contents of each container before release by QC. Annex 8 of the EC GMPs provides more detail on the sampling of starting materials, and requires the sampling of all containers for identity unless there is a validated procedure to ensure that no single container of starting material has been

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incorrectly labelled. The validation should take account of the knowledge of the manufacturer and the types of product the material will be used in. It effectively excludes less than the identity testing of every container of excipients for parenteral products or where the supply chain is not known or not audited. There is also particular UK guidance on certificates of analysis.19 This specifies conditions for use of a certificate of analysis from a third party as part of an overall system to assure quality. Quality control should assure that the issuing organisation is competent to do so, and there are specific requirements for the content of the certificate of analysis.


There are many quality considerations that must be taken into account for manufacture of the excipient, through to registration and use by the pharmaceutical manufacturer. Recent EC legislation has introduced the potential for an increased emphasis on GMP and inspection for certain excipients. Pharmaceutical manufacturers should work in co-operation with their excipient suppliers to ensure that they have a detailed understanding of the excipient and its application, and to demonstrate control in the manufacture and use of the material.

1. The rules governing medicinal product in the European Union, Volume 4. Medicinal product for human and veterinary use: Good manufacturing practice. http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm 2. Commission directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. 2a. Excipients in the dossier for application for marketing authorisation of a medicinal product. 3AQ9a London: European Agency for the Evaluation of Medicinal Products. (1994). 2b. Note for guidance on inclusion of antioxidants and antimicrobial preservatives in medicinal products. CPMP/CVPM/QWP/115/95, 8 July 1997. 2c. Note for guidance on development pharmaceutics. CPMP/QWP/155/96, 28 January 1997. 2d. Note for guidance on quality of water for pharmaceutical use. CPMP/QWP/158/01, May 2002. 3. P Cowley and L Martini. Pharm. Technol. Eur. 26-34, March 2001. 4. Council Directive 78/25/EEC of 12 December 1977 on the approximation of the laws of Member States relating to the colouring matters which may be added to the medicinal products (As modified by Directive 81/464/EC of 24 June 1981). 4a. European Parliament and Council Directive 94/36/EC of 30 June 1994 on colours for use in foodstuffs. 5. Commission Directive 95/45/EC of 26 July 1995 laying down specific purity criteria concerning colours for use in foodstuffs. 6. Commission Regulation (EC) No 1565/200 of 18 July 2000 laying down the measures for the adoption of an evaluation programme in application of Regulation (EC) No 2232/96 of the European Parliament and of the Council. 7. Commission Regulation (EC) No 622/2002 of 11 April 2002 establishing deadlines for the submission of information for the evaluation of chemically defined flavouring substances used in or on foodstuffs. 8. Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 Rev. 2 October 2003) adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for Veterinary Medicinal Products (CVMP). 9. Council of Europe Public Health Committee (Partial Agreement) Resolution AP-CSP (99) 4 (adopted by the Public Health Committee (Partial Agreement) (CD-P-SP) on 22 December 1999) Certification of suitability to the monographs of the European Pharmacopoeia (revised version). http://www.pheur.org/medias/download/APCSP9904E.pdf 10. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the community code relating to medicinal products for human use. 11. Good Manufacturing Practices: supplementary guidelines for the manufacture of pharmaceutical excipients, WHO Expert Committee on Specifications for Pharmaceutical Preparations, 35th report, Geneva, WHO, 1999, Annex 5 (WHO Technical Report Series, No 885). 12. PS 9100:2002 Pharmaceutical excipients, The application of ISO 9001:2000 and GMP guide for pharmaceutical excipients, June 2002, Pharmaceutical Quality Group of the Institute of Quality Assurance, ISBN 0 906810 83 3. http://www.iqa.org/information/d2-11.shtml See also www.pqg.org 12a. A McCraight, and S Moss. PS 9100:2002 Pharmaceutical Excipients an updated GMP standard for excipient suppliers. Pharm. Technol. Eur. 15(1), 31-36, (2003). 13. Pharmaceutical cGMPS for the 21st Century A Risk-Based Approach: Second Progress Report and Implementation Plan, http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm 14. IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients, revised 2001. See also www.IPEC.org 15. Please contact the author for further information: sm45336@gsk.com 15a. The purpose and content of pharmacopoeial excipient monographs: TRI-PEC position paper. Pharmeuropa 15(2), 236238, (2003).


An Over view of Quality Considerations for Excipients

16. Topic Q3C (M) Maintenance of Note for Guidance on Impurities: Residual Solvents (CPMP/ICH/283/95), CPMP/ICH/1507/02, 25 April 2002. 17. Note for Guidance on specification limits for residues of metal catalysts, CPMP/SWP/QWP/4446/00, 17 December 2002. 18. J Taylor, G Munro, G Lee, and A McKendrick. Good Manufacturing Practice and Good Distribution Practice: an analysis of regulatory inspection findings for 2001-02. Pharm J 2003; 270: 127-129. 19. Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002 ISBN 011 322559 8, Page 32.