New EMA Requirements for Excipient GMP's

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The European Commission Health and Consumers Directorate – General has published draft “GUIDELINES ON THE FORMALISED RISK ASSESSMENT FOR ASCERTAINING THE APPROPRIATE GOOD MANUFACTURING PRACTICE FOR EXCIPIENTS OF MEDICINAL PRODUCTS FOR HUMAN USE” for public consultation.

Following presentation has been prepared by " Drug regulations" a not for profit organization which provides free online resources for the Pharmaceutical Professional.

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New EMA Requirements for Excipient GMP's

  1. 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 9/17/2015 1
  2. 2.  This presentation is compiled from freely available resource like the website of EMA.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 9/17/2015 2 Drug Regulations : Online Resource for Latest Information
  3. 3.  Regulatory basis  Directive 2011/83/EC provides, in Article 46(f)  The holder of the manufacturing authorisation shall ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate good manufacturing practice is.  This shall be ascertained on the basis of a formalised risk assessment in accordance with the applicable guidelines referred to in the fifth paragraph of Article 47. Visit Drug Regulations for Latest Information. 3
  4. 4.  Regulatory basis  Such risk assessment shall take into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects.  The holder of the manufacturing authorisation shall ensure that the appropriate good manufacturing practice so ascertained, is applied.  The holder of the manufacturing authorisation shall document the measures taken under this paragraph Visit Drug Regulations for Latest Information. 4
  5. 5.  Regulatory basis  The fifth paragraph of Article 47 of Directive 2001/83/EC.  The Commission shall adopt guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients referred to in the second paragraph of point (f) of Article 46 Visit Drug Regulations for Latest Information. 5
  6. 6.  EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE- GENERAL has issued a draft “GUIDELINES ON THE FORMALISED RISK ASSESSMENT FOR ASCERTAINING THE APPROPRIATE GOOD MANUFACTURING PRACTICE FOR EXCIPIENTS OF MEDICINAL PRODUCTS FOR HUMAN USE”  Draft published on February 6th , 2013.  Open for comments till April 30th , 2013.  Final Guidance published in March 2015 6
  7. 7.  Manufacturing Authorisation Holder should incorporate excipient risk assessment/risk management procedure in the Quality Management System.  Risk assessment/management documentation for appropriate GMP for excipients should be available on site. Visit Drug Regulations for Latest Information. 7
  8. 8.  Use tools listed in ◦ EudraLex Volume 4, Guidelines for G M P , Medicinal Products for Human and Veterinary Use, Part III: GMP Documents ◦ Quality Risk Management guidelines (ICHQ9)  Assess the risks presented to the quality, safety and function  Classify the excipient as “low risk”, “medium risk” or “high risk.  Use tools like Hazard analysis and Critical point analysis  Refer following links for additional information ◦ Quality Risk Management ◦ Quality Risk Managment : Basic Concept ◦ Basic Risk Facilitaation Methods. ◦ FMEA 8
  9. 9.  Identify the risks presented to the quality, safety and function of each excipient from its source : ◦ Animal ◦ Mineral ◦ Vegetable ◦ Synthetic Visit Drug Regulations for Latest Information. 9
  10. 10.  Evaluate risk w r t ◦ Transmissible Spongiform Encephalopathy ◦ Potential for viral contamination ◦ Potential for microbiological or endotoxin/pyrogen contamination ◦ Potential, in general, for any impurity originating from the raw materials  Aflatoxins,  Pesticides  Generated as part of the process and carried over (e.g. residual solvents and catalysts 10
  11. 11.  Evaluate risk w r t ◦ Sterility assurance (for excipients claimed to be sterile) ◦ Potential for impurities in the absence of use of dedicated equipment and/or facilities ◦ Environmental controls ◦ Storage conditions / transportation conditions ◦ Cold storage management ◦ Supply chain complexity ◦ Stability of excipient ◦ Packaging integrity evidence Visit Drug Regulations for Latest Information.11
  12. 12.  Evaluate risk with respect to function of the excipient ◦ The pharmaceutical form and use of the medicinal product containing the excipient (e.g. ointment product, injection/infusion etc.) ◦ The function of the excipient in the formulation (e.g. lubricant in a tablet product or preservative material in a liquid formulation etc.) ◦ Proportion of excipient in the medicinal product Visit Drug Regulations for Latest Information. 12
  13. 13.  Evaluate risk with respect to function of the excipient ◦ Any known quality defects/fraudulent adulterations, both globally and at a local company level related to the excipient; ◦ Whether the excipient is a composite; ◦ Known or potential impact on the critical quality attributes of the medicinal product; ◦ Other factors as identified or known to be relevant to assuring patient safety. Visit Drug Regulations for Latest Information. 13
  14. 14.  Document the risk profile of the excipient  Establish the elements of EU-GMP needed to be in place in order to control and maintain the quality of the excipient. ◦ EU-GMP, Part I, Annex 1 and Annex 2, Part II etc  GMP needed will vary depending on the source, the supply chain and the subsequent use of the excipient Visit Drug Regulations for Latest Information. 14
  15. 15.  As a minimum the following high level GMP principles should be considered: ◦ Establishment and implementation of an effective Pharmaceutical Quality system ◦ Sufficiently competent and appropriately qualified personnel ◦ Defined job descriptions for managerial and supervisory staff responsible for manufacturing and quality activities Visit Drug Regulations for Latest Information. 15
  16. 16.  As a minimum the following high level GMP principles should be considered: ◦ Training programmes for all staff involved in manufacturing and quality Activities ◦ Training programmes related to health, hygiene and clothing ◦ Provision and maintenance of premises and equipment appropriate to the intended operations Visit Drug Regulations for Latest Information.16
  17. 17.  As a minimum the following high level GMP principles should be considered: ◦ Documentation system(s) covering all processes ◦ Specifications for the various manufacturing and quality operations ◦ Qualification programme for suppliers ◦ System for quality control of the excipient and a responsible person independent from production to release the batches; Visit Drug Regulations for Latest Information. 17
  18. 18.  As a minimum the following high level GMP principles should be considered: ◦ Retention of records for incoming materials and excipients and retention of samples of excipients for the periods required by EudraLex Volume 4, Part II; ◦ Systems to ensure that any activity contracted out is subject to a written contract; ◦ Maintenance of an effective system whereby complaints are reviewed and excipients may be recalled; Visit Drug Regulations for Latest Information. 18
  19. 19.  As a minimum the following high level GMP principles should be considered: ◦ Change management and deviation management system; ◦ Self-inspection program; ◦ Environmental control and storage conditions. Visit Drug Regulations for Latest Information. 19
  20. 20.  Preform a gap analysis of the required GMP against the activities and capabilities of the excipient manufacturer  Obtain data / evidence for above through audit or from information received from the excipient manufacturer  Consider Quality system certification or accreditation of the excipient manufacturer 20
  21. 21.  Document the identified gaps between the required GMP and the activities and capabilities of the excipient manufacturer  Perform a further risk assessment to determine the risk profile for that excipient manufacturer as ◦ Low risk, ◦ Medium risk or ◦ High risk Visit Drug Regulations for Latest Information.21
  22. 22.  Use the Quality Risk Management guidelines (ICHQ9) – EU GMP to classify the risk profile of the excipient manufacturer.  Quality risk management tools such as those listed in there (HACCP etc.) should be used for this.  Implement a series of risk mitigation strategies ranging for the different risk profiles from acceptance through control to unacceptable Visit Drug Regulations for Latest Information. 22
  23. 23.  Establish a control strategy based on ◦ Audit ◦ Document retrieval ◦ Testing 23
  24. 24.  Perform on-going risk review based on ◦ Number of defects on received batches of excipients ◦ Type/severity of defects on excipients ◦ Monitoring and trend analysis of excipient quality; ◦ Loss of relevant quality system accreditation by excipient manufacturer ◦ Observation of trends in drug product quality attributes (this will depend on the nature and role of excipient) Visit Drug Regulations for Latest Information. 24
  25. 25.  Perform on-going risk review based on ◦ Observed organisational, procedural or technical/process changes at the excipient manufacturer; ◦ Audit (re-audit) of excipient manufacturer ◦ Questioners. ◦ 25
  26. 26.  Perform on-going risk review based on ◦ Based on the outcome of the risk review, the established control strategy should be reviewed and revised if needed. Visit Drug Regulations for Latest Information. 26
  27. 27.  This presentation is compiled from freely available resource like the website of EMA.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 9/17/2015 27 Drug Regulations : Online Resource for Latest Information

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