Jeanne Moldenhauer (c) Jeanne Moldenhauer

Transcription

1 Jeanne Moldenhauer (c) Jeanne Moldenhauer

2 Presentation Overview Conflicts between regulatory and compendial guidance Understanding the requirements for non sterile and terminally sterilized products for EM Making sense of USP <797> for aseptic processes Risk based sampling in ISO 5 Areas (c) Jeanne Moldenhauer

3 Presentation Overview What is an Adverse Trend? What constitutes an objectionable organism and how would I know it s present? Using scientifically sound and appropriate methods or alternative methods Questions (c) Jeanne Moldenhauer

4 CONFLICTS BETWEEN REGULATORY AND COMPENDIAL GUIDANCE (c) Jeanne Moldenhauer

5 USP <1116> Microbiological Control and Monitoring of Aseptic Processes This was the old cleanroom chapter Now applicable only to aseptic Change in philosophy on monitoring contamination (c) Jeanne Moldenhauer

6 USP <1116> Number of sampling methods can be used nearly all of these methods rely on the growth and recovery of microorganisms, many of which can be in a damaged state caused by environmental stress and therefore may be difficult to recover. Numerical values presented are informational Not scientifically reasonable to suggest that the attainment of these values guarantees microbial control or that excursions beyond values in this chapter indicate a loss of control. (differences in equipment) Risk Assessment should be made over a significant period (c) Jeanne Moldenhauer

7 USP <1116> Number of sampling methods can be used Contamination recovery rate metric should be established on the basis of a review of actual findings within the facility. Each user should be to use contamination recovery rates to track ongoing performance and to refine the microbiological control program to lead to improvements. Under optimum operational conditions contamination recovery rate levels typically become relatively stable within a normal range of variability. (c) Jeanne Moldenhauer

8 USP <1116> No standard methods for air sampling Air sampling methods are highly variable. Do not assume.. that similar sample volumes taken by different methods will produce similar rates of recovery. Factors affecting microbial recovery and survival, e.g., media, incubation, environment, degree of stress (c) Jeanne Moldenhauer

9 USP <1116> Sample to sample variation in microbial sampling can be extensive. Not much data to define the accuracy, precision, sensitivity, and limits of detection of monitoring methods used in the aseptic processing of healthcare products. (c) Jeanne Moldenhauer

10 USP <1116> When contamination recovery rates increase from an established norm, process and operational investigation should take place. Differ depending on the type and processing of the product manufactured in the clean room, RABS, or isolator. (c) Jeanne Moldenhauer

11 USP <1116> Environmental monitoring program should be for a specific facilities and conditions. A single uncorrelated result on a given day may not be significant in the context of the technical limitations associated with aseptic sampling methods. (c) Jeanne Moldenhauer

12 USP <1116> Contamination Rates Table 3. Suggested Initial Contamination Recovery Rates in Aseptic Environments' Active Air Sample (%) Settle Plate (9 cm) 4 h Exposure (%) Contact Plate or Swab (%) Glove or Garment (%) Room Classification Isolator/Closed RABS (ISO 5 or better) <0.1 <0.1 <0.1 <0.1 ISO 5 <1 <1 <1 <1 ISO 6 <3 <3 <3 <3 ISO 7 <5 <5 <5 <5 ISO 8 <10 <10 <10 <10 A All operators are aseptically gowned in these environments (with the exception of background environments for isolators). These recommendations do not apply to production areas for nonsterile products or other classified environments in which fully aseptic gowns are not donned. (c) Jeanne Moldenhauer

13 USP <1116> Exceed Contamination Rates: corrective actions should be taken. Corrective actions may include following: Update the sanitization program, including selection of antimicrobial agents, application methods, and frequencies Increased review personnel practices, possibly including written critiques of aseptic methods and techniques Review of microbiological sampling methods and techniques When higher than typical recovery levels for glove and garment contamination are observed, additional training for gowning practices may be indicated. (c) Jeanne Moldenhauer

14 USP <1116> Significant Excursions >15 cfu recovered from a single ISO 5 sample, (airborne, surface, or personnel), should occur very infrequently. If it does: May be indicative of a significant loss of control when they occur Should prompt a careful and thorough investigation. (c) Jeanne Moldenhauer

15 USP <1116> Significant Excursions Abnormally high number of recovered colonies Is incident isolated or can be correlated with other recoveries. Review recovery rates for at least two weeks before the incident Carefully consider all recoveries, including those that are in the more typical range of 1 5 cfu. Identity of the organisms recovered is important in the conduct of this investigation. (c) Jeanne Moldenhauer

16 USP <1116> Significant Excursions Isolated single excursion Definitive root cause probably will not be possible Only general corrective measures can be considered Never wise to suggest a root cause for which there is no solid scientific evidence. Keep in mind: an awareness of the variability of microbial analysis. There is no scientific reason to treat a recovery of 25 cfu as statistically different from a recovery of 15 cfu. (logarithmic growth) (c) Jeanne Moldenhauer

17 USP <1116> Majority of samples will yield a recovery of zero contamination. Critical areas within an aseptic processing operation, it is expected that less than 1% of the samples will yield any recoverable contamination. Most advanced of modern aseptic operations that use separative technologies such as isolators or closed RABS, the recovery rate will approach zero at all times. (c) Jeanne Moldenhauer

18 FDA s Aseptic Processing Guidance Clean Area Classification (0.5 um particles/ft 3 )` ISO Designation (b ) > 0.5 μm particles/m 3 Microbiological Active Air Action Levels (c) (cfu/m 3 ) Microbiological Settling Plates Action Levels (c,d) (diam. 90mm; cfu/4 hours) ,520 1(e) 1 (e) 1, , , , , ,520, (c) Jeanne Moldenhauer

19 EU Annex 1 Requirements for Environmental Monitoring Recommended limits for microbial contamination (a) Grade air sample cfu/m3 settle plates (diameter 90 mm) cfu/4 hours (b) contact plates (diameter 55 mm) cfu/plate glove print 5 fingers cfu/glove A < 1 <1 <1 <1 B C D (a) These are average values. (b) Individual settle plates may be exposed for less than 4 hours. (c) Jeanne Moldenhauer

20 Regulatory Requirements for Environmental Monitoring Grade PIC/S Annex 1 Maximum permitted number of particles/m³ equal to or greater than the tabulated size At rest In operation 0.5µm 5.0µm 0.5µm 5.0µm A 3, , B 3, ,000 2,900 C 352,000 2,900 3,520,000 29,000 D 3,520,000 29,000 Not Defined Not Defined (c) Jeanne Moldenhauer

21 Issues Regulatory documents are cgmp and the counts do not match the USP. No clear regulatory guidance on how this should be resolved Therefore: DUPLICATE WORK to maintain both (or more) sets of acceptance criteria. Significant excursions: new terminology and may lead to other regulatory issues. States counts of 1 5 cfu s are typical does this mean 6 or higher are out of trend? (c) Jeanne Moldenhauer

22 Issues No information on non aseptic processes the consequence is that many investigators and auditors use aseptic requirements for all types of processes. (c) Jeanne Moldenhauer

23 UNDERSTANDING THE REQUIREMENTS FOR NON- STERILE AND TERMINALLY STERILIZED PRODUCTS FOR ENVIRONMENTAL MONITORING (c) Jeanne Moldenhauer

24 FDA s Aseptic Guidance Clean Area Classification (0.5 um particles/ft 3 )` ISO Designation (b ) > 0.5 μm particles/m 3 Microbiological Active Air Action Levels (c) (cfu/m 3 ) Microbiological Settling Plates Action Levels (c,d) (diam. 90mm; cfu/4 hours) ,520 1(e) 1 (e) 1, , , , , ,520, (c) Jeanne Moldenhauer

25 ISO Requirements for Environmental Monitoring ( ) Table 1: Selected airborne particulate cleanliness classes for cleanrooms and clean zones ISO Class ISO Maximum concentration limits (particles/m 3 of air) for particles >the sizes below 0.1µm 0.2µm 0.3µm 0.5µm 1µm 5µm (c) Jeanne Moldenhauer

26 General Misconception For many processes use of ISO classifications or the corresponding Grade A D classifications mean that the requirements in EU Annex 1 and/or the Aseptic Guidance for microbiological counts need to be met for non aseptic processes (c) Jeanne Moldenhauer

27 Use of Barriers for Safety Purposes Isolators and barriers can be used for reasons other than aseptic filling. These systems do not intrinsically mean that you have to meet the aseptic requirements. Microbiological limits for aseptic may not necessarily apply (c) Jeanne Moldenhauer

28 MAKING SENSE OF USP <797> FOR STERILE COMPOUNDING PHARMACY PROCESSES (c) Jeanne Moldenhauer

29 Environmental Monitoring Lists ISO requirements for particulates Needs to be at least ISO 8 Hoods should be ISO 5 Active Air Samplers: Follow instructions for verifications Passive Air Sampling: Exposed for 1 hr or longer, incubate usu. 30 o C 35 o C, for at least 48 hrs. (c) Jeanne Moldenhauer

30 Environmental Monitoring Determine counts over a period of time Trend data May be an issue if trend is 50% above baseline Evaluate at least weekly (c) Jeanne Moldenhauer

31 BUT Many are aseptic processes Some drugs regulated as DRUGs Expectation is to follow Aseptic Guidance (c) Jeanne Moldenhauer

32 RISK BASED SAMPLING IN ISO 5 AREAS (CAN I REALLY ELIMINATE SITES????) (c) Jeanne Moldenhauer

33 Common Question If I get zero s for a long period of time (say years) and I am working in a risk based environment, why can t I quit sampling? (c) Jeanne Moldenhauer

34 WHAT IS AN ADVERSE TREND? (c) Jeanne Moldenhauer

35 FDA Guidance It s Not just repetitive counts BUT What is it?????? (c) Jeanne Moldenhauer

36 WHAT CONSTITUTES AN OBJECTIONABLE ORGANISM AND HOW WOULD I KNOW IT S PRESENT? (c) Jeanne Moldenhauer

37 Common Concerns How would I know I have them, if I don t ID everything? C. pauculans Not usual human pathogen, BUT.. Mold and Gram negatives should they always be objectionable Microaerophilics/ P acnes false claims/misconceptions (c) Jeanne Moldenhauer

38 USING SCIENTIFICALLY SOUND AND APPROPRIATE METHODS OR ALTERNATIVE / NEW METHODS (c) Jeanne Moldenhauer

39 Change Our Thinking! Need to go to prevention not reaction Prevent contaminants in processes Prevent bacterial and mold contamination Re educate for prevention not reaction (c) Jeanne Moldenhauer

40 Use of Alternative Methods If you need to react, react sooner with rapid methods to have a minimal problem! (c) Jeanne Moldenhauer

41 QUESTIONS? (c) Jeanne Moldenhauer

42 Contact Information Jeanne Moldenhauer Excellent PharmaConsulting Office: Mobile: (c) Jeanne Moldenhauer