"Understanding USP 71 Sterility Tests and Extending BUD"

Transcription

1 "Understanding USP 71 Sterility Tests and Extending BUD" ERIC S. KASTANGO, M BA, RPH, FASHP CLINICAL IQ, LLC JULY 10, 2013

2 Disclaimer Although I am an Expert Consultant to the USP, I am speaking today in my individual capacity and not as a member of the Committee or as a USP representative. The views and opinions presented are entirely my own. They do not necessarily reflect the views of USP or any other organization I may be associated with, nor should they be construed as an official explanation or interpretation of <797>. ClinicalIQ content 2013, ClinicalIQ, LLC 2

3 Understanding BUD Recognizes the probability of contamination even under best conditions: Optimal employee performance 0.1% (1 contaminated dose out of 1,000) Contamination rates published in the literature 0.3% 16% Patient Safety: Protect patients from dangerous or even fatal overgrowths of microorganisms that may have been accidentally introduced Storage time: needs to be greater than zero but less than positive infinity* (> 0 and < + ) * Personal conversation with Dr. David W. Newton, September 30, 2009 ClinicalIQ content 2013, ClinicalIQ, LLC

4 Understanding BUD For patient safety, BUD must be based on two factors: Drug s chemical stability in conjunction with Microbiological limits BUD will always be whichever is shorter Must factor in chemical stability Concern that microbial over-colonization of solutions would occur over time. ph of solution is a consideration Neutral (ph 6-8) favorable for microbial colonization ClinicalIQ content 2013, ClinicalIQ, LLC

5 Microbiological Beyond-Use Dating Risk Category Room Temp Refrigerator Freezer ( -10 C) Immediate Use 1 hour 1 hour N/A Low 48 hours 14 days 45 days Low w/12-hr BUD 12 hours or less 12 hours or less N/A Medium 30 hours 9 days 45 days High 24 hours 3 days 45 days ClinicalIQ content 2013, ClinicalIQ, LLC

6 Sterility Testing Only required when USP <797> BUD limits are exceeded or when more than 25 units of HR CSPs are prepared. NO testing is required for any risk-level CSP prepared if handled within the limits, terms and conditions described in USP Chapter <797> ClinicalIQ content 2013, ClinicalIQ, LLC

7 Process Simulation Testing (PST) It is only a point-in-time representation of: The environment The equipment The procedure The personnel involved Test Media for Suitability Sterility Growth Promotion After the incubation period is complete USP FAQs Does not recognize PST as a means of extending BUD ClinicalIQ content 2013, ClinicalIQ, LLC

8 Non-Visibility of Microbial Contamination Numbers of Bacteria per ml in 1L bottles Millipore Corp. Hospital Pharmacy Filtration Guide (Cat. No. MP801) Bedford, MA; 1980:3 ClinicalIQ content 2013, ClinicalIQ, LLC

9 What is Sterility? Free from bacteria or other microorganisms American Heritage's Definition of Sterility Within the strictest definition of sterility, a specimen would be deemed sterile only when there is complete absence of viable microorganisms from it. <1211> Sterilization and Sterility Assurance of Compendial Articles Is it possible to demonstrate complete absence of microorganisms from a CSP? Absolute sterility can t be demonstrated without the complete destruction of every article from the lot of CSPs. ClinicalIQ content 2013, ClinicalIQ, LLC 9

10 Critical Concepts of Sterilization Sterility Assurance Level (SAL) is the probability of a nonsterile item making it through the validated sterilization process. Items terminally sterilized by moist or dry heat, irradiation, or chemical sterilants have a SAL of nonsterile item per 1 million items sterilized Items prepared aseptically with a 0.22 micron filter have a SAL of nonsterile item per 1 thousand items sterilized ClinicalIQ content 2013, ClinicalIQ, LLC

11 Standard of Sterility <1> Injections Parenteral articles are prepared.to ensure they meet pharmacopeial requirements for sterility, pyrogens,... Sterility Tests Preparations for injection meet the requirements under Sterility Tests <71> ClinicalIQ content 2013, ClinicalIQ, LLC

12 Standard of Sterility Aseptic Processing from USP Chapter <1211>: While there is general agreement that sterilization of the final filled container as a dosage form or final packaged device is the preferred process for assuring the minimal risk of microbial contamination in a lot, there is a substantial class of products that are not terminally sterilized but are prepared by a series of aseptic steps. ClinicalIQ content 2013, ClinicalIQ, LLC

13 Probability The sterility of a lot purported to be sterile is therefore defined in probabilistic terms, where the likelihood of a contaminated unit or article is acceptably remote. ClinicalIQ content 2013, ClinicalIQ, LLC

14 Sterility Testing USP <71> Sterility Tests states: These Pharmacopeial procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by method suitability of the sterilization process or of the aseptic processing procedure. ClinicalIQ content 2013, ClinicalIQ, LLC

15 Understanding all of the elements Risk Level Beyond-Use Dating (point in time) Chemical Stability Microbial Stability Aseptic technique ASSUMPTION! CSP is stored at its optimal temperature at all times. Due to the inherent low probability that a Sterility Test can detect low levels of contamination in a batch, sterility assurance must always be based on process design and control. ClinicalIQ content 2013, ClinicalIQ, LLC

16 USP <71> Sterility Tests Scott Sutton, Ph.D. 41

17 Disclaimer I am making this presentation as an independent agent I am not making this presentation as a representative of USP, PDA, PMF or any other organization with which I am currently associated. The views expressed in this presentation are offered as mine alone. 2

18 Overview of Presentation Who Cares? What are the compendial Sterility Tests? Product Requirements Method Suitability 3

19 FDA Apothecure - 03/18/2013 The Compounding Shop - 03/18/2013 Central Admixture Pharmacy Services, Livonia, Wallingford, Woburn 483 Issue Green Valley Drugs - 03/11/2013 Olympia Pharmacy - 03/04/2013 Medasus 3/18/13 Sterility Failures & Investigation Sterility Test non-compliant No sterility testing performed Sterility testing not performed on all batches Investigation of Sterility Test failures Sterility testing not performed on all batches Sample size for Sterility testing No sterility testing on finished product Bulk product released for dispensing before sterility test complete MedPREP Consulting, Inc - 3/15/13 Sterility testing not performed on all batches Investigation of Sterility Test failures Nora Apothecary and Alternative Therapies, Inc. 3/19/13 Sterility testing not performed on all batches 4 Investigation of Sterility Test failures

20 FDA Sutton, S GMP and Compounding Pharmacies. Amer Pharm Rev. 16(3): Articles/ GMP-and-Compounding-Pharmacies/ 5

21 The Press 6

22 Overview of Presentation Who Cares? What are the compendial Sterility Tests? Product Requirements Method Suitability 7

23 Sterility Testing Two separate tests Membrane Filtration Direct Transfer 20 Units, 2 media & temperatures Requires Growth Incubation period - 14 days Moldenhauer, J and S. Sutton Towards an Improved Sterility Test. PDA J of Science and Technology 58(6):

24 Membrane Filtration Filter required amount of product through two filters Neutralize/Rinse ml volumes suggested Formulations for dilution fluids suggested One filter into Soybean Casein Digest Broth (SCDB or TSB) incubate at o C for 14 days One filter into Fluid Thioglycollate Medium (FTM) incubate at o C for 14 days 9

25 Direct Inoculation Place required amount of product into sufficient recovery medium (with neutralizers?) Soybean Casein Digest Broth (SCDB or TSB) incubate at o C for 14 days Fluid Thioglycollate Medium (FTM) incubate at o C for 14 days 10

26 Product Requirements Minimum Quantity per Unit for Each Medium Liquids Minimum Quantity < 1 ml The whole contents of each container 1-40 ml Half the contents of each container, but not less than 1 ml >40 - <100 ml 20 ml per container >100 ml 10% of the contents of the container, but not less than 20 ml Antibiotic Liquids 1 ml 11

27 Product Requirements Minimum Quantity per Unit for Each Medium Solids Minimum Quantity < 50 mg The whole contents of each container 50 - <300 mg Half the contents of each container, but not less than 50 mg 300 mg 5 g 150 mg per container >5 g 500 mg per container Insoluble preparations, creams, and ointments to be suspended or emulsified - Use the contents of each container to provide not less than 200 mg 12

28 Number of Units to be Tested 13

29 Example 1-84 units of 10 ml 10 ml is between 1 and 40 ml Table 2 tells us to use ½ volume or 5 ml per unit 84 units is less than 100 Table 3 tells us to use the greater of 4 units or 10% of the batch = 8 units per medium We therefore must test at least 5 ml from each of 8 units for each medium 14

30 Example 2 6 units of 1.5 ml 1.5 ml is between 1 and 40 ml Table 2 tells us to use ½ volume but not less than 1 ml therefore we test 1 ml ml per unit 6 units is less than 100 Table 3 tells us to use the greater of 4 units or 10% of the batch = 4 units per medium We therefore must test at least 1 ml from each of 4 units for each medium. 15

31 Overview of Presentation Who Cares? What are the compendial Sterility Tests? Product Requirements Method Suitability 16

32 Method Suitability Test Can we neutralize any antimicrobial properties of the medication? Use specified challenge organisms Use specified total amounts of products 17

33 Method Suitability Test for Each Challenge Organism Filter maximal amount of medication to be tested Filter 2 volumes (100 ml?) of diluting fluid Add third volume, inoculate with <100 CFU challenge organism Filter Show microbial growth from filter in relevant medium at relevant temperature in 5 days 18

34 Method Suitability Test 6 challenge organisms FTM C. sporogenes P. aeruginosa S. aureus SCDB A. brasiliensis B. subtilis C. albicans 19

35 Method Suitability Examples Example 1-84 units of 10 ml 5 ml from 8 units = 40 ml for each organism; there are 6 6 x 40 ml = 240 ml total for Method Suitability Example 2 6 units of 1.5 ml 1 ml from 4 units = 4 ml for each organism 6 x 4 ml = 24 ml total for Method Suitability 20

36 Review of Presentation Who Cares? What are the compendial Sterility Tests? Product Requirements Method Suitability 21

37 Thank you for your attention Scott Sutton, Ph.D (cell)