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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2020 43 environmental/physical controls protecting the sterile materials should only be permitted when production is not underway. The firm must consider the potential impact that any new intervention could have on exposed materials and make a release decision based upon the data obtained during its execution. A decision should then be made whether the 'new' interven- tion should be approved. If it is to be allowed in the future, then it should be included in the firm's procedures and a detailed sequence for execution should be established, and appropriate training and demonstration provided. Audit preparation Media fills are often a major focus for regulators, and for both external and internal auditors. Poli- cies, protocols, procedures, and summary reports should be available for inspection. Staff members should also be prepared to answer questions such as the following: • Do you have a list of interventions that opera- tors are allowed to perform? • Do your intervention procedures/training pro- vide details on how the various interventions are to be performed? • How are the operators trained in the execution of the interventions in this list, and may I see an example of training materials used? • How do you confirm that the operators will perform the interventions as described? • How do you document the actual interventions performed for a particular lot? In short, FDA regulators' belief that media fills somehow 'validate' aseptic processing is incorrect. As with so many other aspects of quality, sterility can- not be tested in (28). Media fills are just another peri- odic test with a limit of detection that cannot detect a single cell. In microbiology, zero only means nothing grew, it doesn't equate to the attribute of sterility. References 1. FDA, Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987. 2. PDA TR# No. 22, PDA Journal of Pharmaceutical Science and Technology, Volume 50, Supplement S1 (1996). 3. J. Agalloco and B. Gordon, Journal of Parenteral Science and Technology, 41(4), p.128-141 (1987). 4. J. Agalloco, and J.Akers, Journal of Parenteral Science and Tech- nology, Vol. 47, No. 2, Supplement (1993). 5. J. Agalloco, and J. Akers, PDA Journal of Pharmaceutical Sci- ence and Technology, Vol. 51, No. 2, supplement, 1997. 6. PDA TR# 36, PDA Journal of Pharmaceutical Science and Tech- nology, 56 (3) (2002). 7. Federal Register, 68113–68116, December 4, 2007. 8. Federal Register, 51919–51933, September 8, 2008. 9. PDA TR# No. 22, PDA Journal of Pharmaceutical Science and Technology, 2011. 10. PDA, Points to Consider for Aseptic Processing–Part 1, PDA, Bethesda, MD, 2015. 11. PDA, Points to Consider for Aseptic Processing–Part 2, PDA, Bethesda, MD, 2016. 12. PDA, 2017 PDA Aseptic Processing Survey, 2017. 13. J. Akers and J. Agalloco, Pharmaceutical Technology, 39 (4), pp 48-60 (2015). 14. J. Akers, J. Agalloco, R. Madsen, Bioprocessing and Sterile Man- ufacturing, a Pharmaceutical Technology eBook, pp 24-30, 2016. 15. EMA, European Commission, EudraLex, Volume 4, Annex 1, Manufacture of Sterile Medicinal Products, December 2017. 16. EMA, European Commission, EudraLex, Volume 4, Annex 1, Manufacture of Sterile Medicinal Products, March 2020. 17. R. Madsen, J. Agalloco, and J. Akers, "Annex 1 Misses the Mark," PharmTech.com, March 2018. 18. FDA, Guideline on Sterile Drug Products Produced by Aseptic Processing, 2004 19. A. Cundell, et al., PDA J. Pharma. Sci. Technology 52 (66), pp 326–330 (1998). 20. PQRI, Aseptic Processing Working Group – Final Report, PQRI, Washington, DC, 2003. 21. J. Agalloco, Pharmaceutical Technology, 29 (3), p. 56-66 (2005). 22. J. Agalloco, and J. Akers, Pharmaceutical Technology, 29 (11), p. 74-88 (2005). 23. J. Agalloco, and J. Akers, Pharmaceutical Technology, 30 (7) , p. 60-76, (2006). 24. J. Akers and J. Agalloco, Pharmaceutical Technology, 41(11), pp. 32-39 (2017). 25. J. Agalloco, J. Akers, Pharmaceutical Technology, 31 (5), p. S8-11 (2007). 26. J. Agalloco, J. and J. Akers, Pharmaceutical Technology, 35 (4), pp 69-72 (2011). 27. J. Agalloco, Pharmaceutical Manufacturing, 10 (3), pp 28-32 (2013). 28. J. Agalloco and J. Akers, Pharmaceutical Technology, 34 ( 3), Supplement, pp. S44-45 (2010). PT Manufacturing — Contin. from page 14