Media fills Periodic performance qualification (Re-Validation)

Transcription

1 Media fills Periodic performance qualification (Re-Validation) Minimum number of Simulations Number of units Contaminated Units Action a Two per Year (Retrospective & Prospective Validation) < to Investigation, revalidation 1 Investigation, consideration of repeat to media fill > 1 Investigation, corrective measures, revalidation 1 Investigation > a The simulations shall cover all line configurations and all shifts. > 1 Investigation, corrective measures, revalidation

2 Media Fill Requirements Representative interventions Bracketing of containers Media filled containers obtained during the validation must be filled with enough medium to contact the inner container closure surfaces when the unit is inverted or swirled. Growth promoting media Media fill vials must be incubated for not less than fourteen (14) days. Containers will be initially incubated from 20 C 25 C for seven days followed by incubation at 30 C - 35 C for an additional seven days. Incubation must be held in this temperature sequence. Growth promotion performed after 14 days of incubation. Media fill units must be read at the 14 th day. Personnel must be qualified (including mechanics and Quality personnel)

3 New Technology in Aseptic Processing

4 Medium Enabling Media Fill Reads Growth

5 AMO Qualification Results End point Titration Trial Growth Medium 10^1 10^2 10^3 10^4 10^5 Color change of positive wells neg 2 3P TSB filtered neg neg red to yellow neg neg Staphylococcus aureus ATCC neg Inoculum level = cfu/ml 2 3P TSB autoclaved neg red to yellow neg neg neg neg 2 TSB autoclaved neg neg bronze to off white neg End point Titration Trial Growth Medium 10^1 10^2 10^3 10^4 10^5 Color change of positive wells neg 2 3P TSB filtered neg red to green/blue neg Pseudomonas aeruginosa ATCC neg neg Inoculum level = cfu/ml 2 3P TSB autoclaved neg red to green/blue neg neg neg 2 TSB autoclaved neg neg bronze to yellow neg

6 Qualification Results End point Titration Trial Growth Medium 10^1 10^2 10^3 10^4 10^5 Color change of positive wells neg neg 2 3P TSB filtered neg red to yellow neg E. coli ATCC neg Inoculum level = cfu/ml 2 3P TSB autoclaved neg neg red to yellow neg neg 2 TSB autoclaved neg bronze to off white neg End point Titration Trial Growth Medium 10^1 10^2 10^3 10^4 10^5 Color change of positive wells neg neg neg 2 3P TSB filtered neg neg red to yellow/pink neg neg Serratia marcescens ATCC neg neg Inoculum level = cfu/ml 2 3P TSB autoclaved neg neg red to yellow neg neg neg neg 2 TSB autoclaved neg neg bronze to yellow neg neg

7 Qualification Results End point Titration Trial Growth Medium 10^1 10^2 10^3 10^4 10^5 Color change of positive wells neg 2 3P TSB filtered neg neg red to cloudy pink neg neg Candida albicans ATCC neg neg neg Inoculum level = cfu/ml 2 3P TSB autoclaved neg neg red to cloudy pink neg neg neg neg 2 TSB autoclaved neg neg bronze to cloudy yellow neg neg

8 Azbil BioVigilant s Instantaneous Microbial Detection Systems

9 Investigation of Microbial Excursions

10 Investigation Tools PAT - Product Assessment Team FTA: Fault Tree Analysis - A top-down analysis technique, which logically and graphically illustrates the various combinations of possible events, both faulty and normal, that can occur in a system leading to an undesired event (i.e., a system failure). PFMEA: Process Failure Modes and Effects Analysis A bottom-up analysis technique which examines potential failures in a product s manufacturing process and the effects of these failures on the product as well as the system around it (i.e., users, patients, environment, etc.). RPN: Risk Priority Number - A numerical index in a PFMEA that provides an indication of the level of risk associated with a specific cause of failure and is used as a means of prioritizing corrective action efforts. The index is calculated by multiplying the Severity, Occurrence, and Detectability ratings for a specific failure mode cause.

11 FTA Top Event or Potential Hazard OR Gate: Any input causes output AND Gate: All inputs together cause output Intermediate Event Basic Event Symbol Event not Further Developed Alternate Basic Event Symbol Intermediate Event Transferred to Another Page A Transfer symbol: locate as an input on another page

12 Calculation of Probability - FTA Symbol Definition Equation P1 P2 P3 P4 AND Gate All input events must occur together for the output event to occur. P4 = P1 * P2 * P3 P1 P2 P3 P4 OR Gate Output event will occur if any or all of the input events occur. P4 = (P1 + P2 + P3) (P1 * P2 + P1 * P3 + P2 * P3) + (P1 * P2 * P3)

13 Fish Bone Analysis - FMEA

14 5M-8D Man Machine Root Cause Method Milieu Material

15 Probability/Occurrence - FMEA Range Scale Title X=1/10 5 Very High Occurrence 1/100 x < 1/10 4 Likely Occurrence 1/1000 x < 1/100 3 Possibly Occurrence 1/10000 x <1/ Unlikely Occurrence x > Remote Occurrence

16 Severity - FMEA Range Scale Title Physical Harm 5 Catastrophic Major Impact to Intended Use 4 Critical Reduced Recoverable Impact to Intended Use 3 Significant Minor Impact to Intended Use 2 Marginal No Adverse Impact to Intended Use 1 Negligible

17 Detectebility - FMEA Range Scale Title No Process control available. Occurs while product is in use. Process is unable to mitigate the problem. Detected prior to customer use Process has single point of detection. 5 No Detection 4 Customer Detection 3 Single Pass Detection Process has likely multiple points of detection. Process has multiple detection points to ensure detection of failure prior to final delivery 2 Multiple Pass Detection 1 Process Detection

18 RPN - FMEA Range Title 46 or greater High Impact Medium Impact 1 to 10 Low Impact RPN is obtained by multiplying the Severity, Occurrence, and Detectability

19 Workshop Group I Media fill of 15,000 units Shift one First 4999 units are clear followed by 1 unit contaminated. Shift two has 4000 units clear and 1000 contaminated units. Shift three All units are contaminated. Group II Biannual HEPA certification fails on 60% of your HEPA filter grid. What is the immediate action? How many media fills will be required? What does 60% failure rate does and says about the environmental controls?

20 Workshop Group III Media fill of 25,000 units Shift one First 8,334 units are clear. Shift two 7000 units clear and 1300 intervention units are contaminated. Shift three 8,333 units are clear. What actions must be taken? Group IV A new product is introduced to the manufacturing site which happens to have antimicrobial activity. The existing bracket is 2-10mL. The new product will be filled at 9.5mL. What process simulation activities will have to be modified to accommodate the new product?

21 Rope Model Each Unit operation of Aseptic Processing is like a thread of a rope. Identify the basic threads of the ROPE. Understand HOW each thread functions. Learn WHY each thread is important. The more unit operations that have issues or fail, the higher risk to the product.

22 References PDA J. Pharmaceutical Science and Technology. Technical Report No 29 Points to Consider for Cleaning Validation, 1998 V. 52 No 6 Supplement includes advantages and disadvantages of sampling techniques and analytical methods Cleaning and Cleaning Validation: A Biotechnology Perspective, PDA, FDA, Guide to Inspections Validation of Cleaning Processes, Division of Investigations, Office of Regional Operations, Office of Regulatory Affairs, July

23 References Continued AOAC Germicidal Spray Products Testing European Committee for Standardisation: EN Chemical Disinfectants and Antiseptics - Quantitative Non-Porous Surface Test for the Evaluation of Bactericidal and/or Fungicidal Activity of Chemical Disinfectants Used in Food, Industrial, Domestic and Institutional Areas Biotechnology Inspection Guide, CFR 211 and proposed revisions to 21 CFR 211 FDA warning letters

24 References Continued 21 CFR 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packaging or Holding of Drugs; General 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals 21 CFR 820 Quality System Regulation USP <1072> Disinfectants and Antiseptics ISO Aseptic Processing of Health Care Products ISO Clean rooms and Associated Controlled Environments ISO Medical Devices Quality Management Systems

25 References Continued FDA, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice September 2004 EU Guidelines to GMP Annex 1 Manufacture of sterile medicinal products PDA Technical Report 22 (TR22) Process Simulation Testing for Aseptically Filled Products PDA Journal of Pharmaceutical Science and Technology Point to Consider For Aseptic Processing, Supplement Volume 57, Number 2, 2003 PIC/S PI Recommendation on the validation of aseptic processes (1 st July 2009)