Regulatory Aspects On Pharmaceutical Excipients By Mr. Pankaj Dhapade


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This presentation covers latest understanding and regulatory scenario on pharmaceutical excipients.

1. What are Excipients?
2. Types of Excipients
3. Classification of Excipients
4. DP v/s Excipients
5. Composition profile of Excipients
6. Facts related to Excipients
7. Process Change
8. Information Disclosure
9. Difficulties and Challenges
10. Dossier Requirements
11. Development Pharmaceutics
12. Excipients Certification Scheme

Published in: Education, Business

Regulatory Aspects On Pharmaceutical Excipients By Mr. Pankaj Dhapade

  1. 1. Regulatory Aspects On Excipients Mr. Pankaj Dhapade B. Pharma, MBA (Pharmaceuticals), PGDPRA Wockhardt Ltd
  2. 2. Agenda 1. What are Excipients? 2. Types of Excipients 3. Classification of Excipients 4. DP v/s Excipients 5. Composition profile of Excipients 6. Facts related to Excipients 7. Process Change 8. Information Disclosure 9. Difficulties and Challenges 10. Dossier Requirements 11. Development Pharmaceutics 12. Excipients Certification Scheme
  3. 3. What are Excipients? Pharmaceutical excipients are substances other than the API, which have been appropriately evaluated for safety and are intentionally included in a drug delivery system. For example excipients can: 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, enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use.
  4. 4. Types of Excipients Standard Excipients Mixed Excipients Co-processed Excipients compendial or non-compendial substances a simple physical mixture of two or more compendial or non-compendial excipients a combination of two or more compendial or non-compendial excipients that are neither mixed excipients nor co-processed excipients produced by means of a low- to medium-shear process designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change They may contain other components including concomitant components, residual processing aids and/or additives where the individual components are mixed but remain as discrete chemical entities, i.e. the nature of the components is not chemically changed However in some instances, formation of necessary components may occur, such as in-situ salt formation.
  5. 5. Types of Excipients Standard Excipients Mixed Excipients Cont……. Co-processed Excipients Simple physical mixing is typically mixing is typically of extended of short duration duration Ex: Lactose as a diluent Magnesium Stearate as a lubricant etc Mixed excipients may be either solid or liquid Ex: Opadry (Grades) Eudragit (Grades) Many different co-processing methods may be used, including standard unit operations such as granulation, spray drying, melt extrusion, milling etc. The choice for a specific application will depend on the materials used, their form (e.g. whether dry powders or liquid) and the specific physical properties desired. Likewise the ratios of the components may vary depending on the desired performance.
  6. 6. Co-processed Excipients Examples… …
  7. 7. Classification of Excipients Why should we classify excipients? They have many diverse uses, functions, manufacturing processes and origins So the risks posed to the patient are also very variable Hence a one size fits all definition of GMP is not going to be enough
  8. 8. Classification of Excipients The classification of excipients in three classes is based on, 1. Class I: The IPEC-PQG GMP Guide will be the foundation for class I 2. Class II: An intermediate class II between these should be defined (Investment in the quality management system is high) 3. Class III: The highest class III should not exceed EU Part II / ICH Q7 GMP
  9. 9. DP v/s Excipients (Composition) Drug Products Excipients Active Pharmaceutical Ingredient(s): APIs are potent component which show desired actions Nominal Component(s): The component of an excipient being able to perform its function in the drug product(s) in which it is used Excipients: Inert materials which influence the performance of drug product Concomitant component, Additives and Processing aids: Other necessary components which helps excipients to perform their intended functions Impurities: Unreacted starting materials, by-products, degradants and residual solvents Impurities: Unreacted starting materials, by-products, degradants and residual solvents
  10. 10. Composition Profile of Excipients The composition profile of excipients includes following components Nominal component Concomitant components Additives Processing aid Degradants Residual solvents Other components Components having exposure concerns
  11. 11. Composition Profile of Excipients Nominal component: The main components of an excipient are those which in most cases contribute to the excipient being able to perform its function in the drug product(s) in which it is used Concomitant components: The substances in addition to the main components should be considered as part of the composition profile, and thus not be construed as being undesirable, nor confused with the presence of added substances Additives: Additives are chemical substances which are intentionally added to excipients to improve their physico-chemical properties, e.g. antioxidants, stabilizers, pH modifiers or flow aids.
  12. 12. Composition Profile of Excipients Processing aid: Processing aids are chemical substances which are used for a specific processing need or benefit in an excipients manufacturing process, e.g. filter aids Processing aids may be or may not be removed during the excipient manufacturing process Degradants: Some excipients may degrade with time due to a variety of factors. If the degradants have any toxic potential, they should also be quantified. Residual solvents: Residual solvents are either organic or inorganic liquids (regardless of the source) that remain in the excipient due to incomplete removal via the manufacturing process. No specific guideline exists for directly addressing residual solvents in excipients.
  13. 13. Composition Profile of Excipients Other components: In addition to the components listed above, other components that may be present are either organic or inorganic substances that are not the defined entity (main/concomitant components) of the excipient, but are present as a direct result of variables in the excipients manufacturing process. e.g. unreacted starting materials, residual catalyst or metal reagents, reaction byproduct and raw material components Components having exposure concerns: Where possible, excipient manufacturers should identify and set appropriate limits for any components having exposure concerns, e.g. endocrine disrupters, allergens, genotoxins, endotoxins in excipients for parenteral use, etc.
  14. 14. Facts related Excipients 1. The proprietary or trade secret information could be shared via DMF, CDA and CEP 2. No comparable excipients DMF system is available in Europe but the proprietary or trade secret information could be shared via CDA and CEP 3. Contaminants would not be regarded as part of the composition profile. however, they should be controlled through Good Manufacturing Practices (GMP) 4. Where feasible the generation of a composition profile should involve the identification, classification and quantification (expressed as a range) of each component or, if unidentified, an appropriate qualitative description such as peak retention time
  15. 15. Facts related Excipients 5. For excipients for which purity can be measured directly, any undesirable organic and inorganic components present at or above 0.1% should be identified and assessed to determine the need (if any) for quantitative limits 6. If quantitative limits are needed, appropriate analytical techniques should be used. If identification/quantification is not possible, a qualitative description, such as chromatographic retention time should be assigned 7. For excipients for which direct measurement of purity is not feasible, indirect techniques (such as assay minima, extractable maxima, LOD or ROI) should be used to provide an estimate of overall excipient purity 8. Levels of residual solvents, potentially toxic components and genotoxic components should be assessed and reported in line with the guidelines
  16. 16. Process Change If the excipient manufacturer decides to modify the process, they should use the IPEC Significant Change Guide to determine if the process changes will require customer notification. The composition profile may not be fully disclosed to the customer. However, it will be an important consideration in evaluating the effects of a change.
  17. 17. Information disclosure The IPEC Excipient Information Package should contain the standard information to be disclosed to the excipient user, including non-confidential composition profile information. Additional information relating to the composition profile may be available upon request, subject to a Confidential Disclosure Agreement if necessary.
  18. 18. Difficulties and Challenges The difficulties and challenges in regulation of excipients are No explicit requirement for GMP for excipients Different awareness of specific pharma requirements amongst excipients manufacturers Pharmaceutical manufacturers are struggling with comprehensive - Supplier qualification, supplier audits and testing on delivery Pharmaceutical user audits are important but infrequent/incomplete Lack of human resources with regulators to perform audit GDP (Good Distribution Practice) needs to be included Ways have to be found to engage the entire excipient industry despite its diversity Practically, QP has responsibility for the quality of excipients based on internal standards
  19. 19. Dossier requirements The dossier requirements of excipients are , 1. Specification 2. Analytical procedures 3. Validation of analytical procedures 4. COAs 5. TSE/BSE certificates/MSDS 6. Justification of specifications 7. The qualitative and quantitative composition of the mixed excipient should be submitted, the specifications of the mixture as a whole and of each component should be stated.
  20. 20. Development Pharmaceutics The development pharmaceutics requires following information on excipients, The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g. stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. The ability of excipients (e.g. antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated.
  21. 21. Excipients Certification Scheme Excipients are critical components of medicines and they have no therapeutic activity. Value of the global excipients market: approx. $5.8 bn Expected value of the global excipients market 2018: approx. $ 8.8 bn Excipients have a high influence on the potency and bioavailability of the active ingredient In practice, the innovator pharma companies have been qualifying their excipients suppliers to build quality in their products and they are achieving through physical audit. This kind of approach of innovator pharma companies is increasing the expectations of regulators to audit all excipients suppliers by drug products manufactures or third party
  22. 22. Excipients Certification Scheme The purpose of this qualification is to ensure that the safety of the drug product is not compromised by the excipient Both manufacturing (GMP) and distribution (GDP) aspects need to be covered Patient Safety = Excipient Specification + GMP + GDP
  23. 23. Excipients Certification Scheme There are issues to perform physical audit of excipient suppliers. A. MAH Perspective 1. Suppliers will not agree to an audit 2. Not enough days in the year for an audit to audit every supplier 3. Travel costs continue to rise and employees don’t want to travel 4. Language barriers 6. In house auditors are not familiar with chemical processing etc resulting in less effective audits B. Supplier Perspective 1. Not enough days in the year for an audit from every customer 2. Language barriers 3. Value of business with user does not justify audit time and cost
  24. 24. Excipients Certification Scheme Solution! The use of 3rd party audit organisations is ACCEPTABLE
  25. 25. Excipients Certification Scheme EXCiPACT is a new, voluntary, international scheme that provides for the high quality, independent certification of manufacturers and suppliers of pharmaceutical excipients to prescribed cGMP and cGDP standards, as a means of ensuring patient safety through supplier quality, while minimising the overall supply chain costs.
  26. 26. Excipients Certification Scheme The excipient certification scheme (EXCIPACT) was commenced in May 2008 with EFCG and IPEC Europe, now comprises 5 trade associations 1. FECC - European Association of Chemical Distributors 2. IPEC - Americas (International Pharmaceutical Excipients Council - Americas) 3. IPEC - Europe (International Pharmaceutical Excipients Council - Europe) 4. PQG - Pharmaceutical Quality Group (UK) 5. EFCG – European Fine Chemical Group
  27. 27. Excipients Certification Scheme Excipact Goals Acceptance by all stakeholders Acceptance of certificates globally Building on existing guides and new standards Guides easy to understand and apply for all stakeholders Guides should be applicable to as many excipients as possible Certification assessable for as many accredited 3rd party organizations as possible
  28. 28. Excipients Certification Scheme Excipact Benefits 1. More safety: through certified compliance to recognized GMP and GDP standard 2. Cost and time savings: only a single audit is needed to prove GMP/GDP compliance 3. Worldwide acceptance: building on existing ISO standards, and supported by major industry organizations
  29. 29. Excipients Certification Scheme Why Certification? Absence of regulations for GMP or GDP for excipients More formal an objective than self assessment Permits industry self regulation Ability for supplier to initiate process Applicability to manufacturers and distributors of excipients Well developed and accepted assessment model using 3rd party certification organisations
  30. 30. Excipients Certification Scheme Certification & 3rd Party Audits Provides information on Supplier’s GMP practices from experienced auditors with knowledge of excipient manufacturing & GMPs Allow companies to focus resources on excipients with highest risk Reduces audit load for suppliers and users Helps define a level playing field for all Helps small companies (both users and suppliers) and those with limited budgets Makes 100% audit verification of suppliers practical
  31. 31. Excipients Certification Scheme Quality of Auditors is Critical All authorities and others have expressly stated that 3rd party auditors can only be valuable if the auditors are competent. Competency like quality is something we all understand but is difficult to define – Excipact has included a section devoted to just this aspect. Competency: the ability to apply knowledge and skills to achieve intended results
  32. 32. Excipients Certification Scheme Quality of Auditors is Critical Competency framework defined using ISO 19011 standards Alternative starting routes to qualification possible i.e. experienced in ISO 9001, GMP or GDP Considered best practices e.g. Qualified Person assessment processes Training programme for auditors to be developed
  33. 33. Excipients Certification Scheme Auditor Competency & Qualification 1. Required knowledge & audit skills a. Tertiary scientific education b. Work and Audit experience c. ISO 9001 knowledge d. GMP/GDP knowledge e. Excipient Knowledge 2. Knowledge assessed orally or by exam 3. Supervised first audit
  34. 34. Excipients Certification Scheme Certification Scheme: Program Elements Excipact to be a Legal Entity representing partner organizations Certification Body: Accredited to ISO 9001, ISO/IEC Guide 65, ISO 17021 or equivalent and verified by Excipact Excipient suppliers to be certified on a 3 year cycle Annual site surveillance audit Triennial recertification audit
  35. 35. Excipients Certification Scheme Certification Scheme: Audit Documentation 1. Audit Report lists observations and rates findings as critical, major or minor 2. 3rd Party Technical Experts review audit report and findings, recommend certification if, No critical, no major without CAPA, no minors that indicate failure of quality system element 3. Audit Report available to pharmaceutical customer from excipient supplier
  36. 36. Thank You!!!