UPDATES TO THE ISO
BIOBURDEN STANDARD
P.S. WHAT HAPPENED TO THE MICROBIOLOGISTS?
Martell Winters
Senior Scientist
Nelson L...
ADDITIONS TO ISO 11737-1
2
• ISO WG2 (Radiation) provided a list of
guidance to add to 11737-1
• Primarily information to ...
P.S. WHAT HAPPENED TO THE
MICROBIOLOGISTS?
• Obvious trend to not have in-house
microbiologist/sterilization person
• Hand...
• Have you ever heard this:
– “We can’t find the justification for…”
• How often do you ask RA to also be the
product engi...
• Having fewer manufacturing/sterilization
microbiologists in companies is reducing
knowledge base in the industry
• Stand...
WHAT AM I SAYING?
• Include knowledgeable people in your
company decisions
– Product design
– Manufacturing process design...
• Attend seminars (plural) – they are a good
starting point
• Common discussion in standards meetings
– How much guidance ...
LOW BIOBURDEN
• Seeing a lot of this with newer products
– Tissue/biologics
– Combination products with strict manufacturi...
LOW BIOBURDEN
• Is this a problem?
– Often requires different bioburden test methods
• Pooling of products for testing
• M...
• Sample pooling
– Facilitates low limit of detection
– Can usually resolve down to 0.1 CFU per sample
– Will mask individ...
POOLING IS A VIABLE OPTION
SAMPLE AEROBIC
BACTERIA
FUNGI TOTAL
BIOBURDEN
1 <4 <4 <8
2 4 <4 <8
3 <4 <4 <8
4 <4 4 <8
5 8 <4 ...
CONSIDER TESTING SEPARATELY
SAMPLE AEROBIC
BACTERIA
FUNGI TOTAL
BIOBURDEN
1 <4 <4 <8
2 4 <4 <8
3 24 16 40
4 <4 4 <8
5 56 8...
INCREASED SENSITIVITY
13
• Results in more accurate bioburden count
– Reduces the “less than” values (e.g. <4 CFU)
• Volum...
LOW BIOBURDEN
• How low is low?
– Varies per sterilization method
– Likely less of an issue with traditional overkill
meth...
BIOBURDEN TEST METHODS
• Most common:
– Immersion in peptone tween solution
– Extraction using mechanical shaking
– Membra...
BIOBURDEN TEST METHODS
• Is this always the right decision?
– No!
– How often is bioburden testing repeated due to
issues ...
BIOBURDEN TEST METHODS
• Keep in mind:
– Potential microorganisms on materials/components
• Understand their manufacturing...
EVALUATING BIOBURDEN DATA
• Guidance will be provided on:
– Dealing with TNTC results
– Bioburden spikes
• Options for cou...
BIOBURDEN SPIKE
SAMPLE
AEROBIC
BACTERIA
FUNGI TOTAL SAMPLE
AEROBIC
BACTERIA
FUNGI TOTAL
1 21 3 24 1 68 3 71
2 33 3 36 2 95...
BIOBURDEN SPIKE
20
• Definition?
– Single value more than twice the average
• Similar option used in radiation validations...
BIOBURDEN SPREADER
Throw it out?
Assign a value?
Additional testing?
Identify?
Investigate?
TOO NUMEROUS TO COUNT
TNTC
Throw it out?
Assign a value?
Additional testing?
Identify?
Investigate?
THANK YOU
23
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Updates to the Bioburden Standard ISO 11737-1; significant additional guidance. P.S. What happened to the microbiologists?

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Martell Winters, Senior Scientist, Nelson Laboratories

  • Important Presentation. This shortcoming of appropriately educated and experience Microbiologists will continue to increase risk in the gamma and EtO sterilization of Single Use and RTU primary containers - both seeing double digit gains in biopharma use
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Updates to the Bioburden Standard ISO 11737-1; significant additional guidance. P.S. What happened to the microbiologists?

  1. 1. UPDATES TO THE ISO BIOBURDEN STANDARD P.S. WHAT HAPPENED TO THE MICROBIOLOGISTS? Martell Winters Senior Scientist Nelson Laboratories mwinters@nelsonlabs.com
  2. 2. ADDITIONS TO ISO 11737-1 2 • ISO WG2 (Radiation) provided a list of guidance to add to 11737-1 • Primarily information to help those involved in sterilization • Include main concepts here
  3. 3. P.S. WHAT HAPPENED TO THE MICROBIOLOGISTS? • Obvious trend to not have in-house microbiologist/sterilization person • Handed to QA, RA or manufacturing: – “While you’re at it, do sterilization too…” • Result: Relying on contract labs and sterilization facilities for decisions • NOT always the right decisions • Often rationales are not documented properly 3
  4. 4. • Have you ever heard this: – “We can’t find the justification for…” • How often do you ask RA to also be the product engineers? • …the finance person to also be the QA manager? • Is sterilization any less important than engineering or QA? 4 P.S. WHAT HAPPENED TO THE MICROBIOLOGISTS?
  5. 5. • Having fewer manufacturing/sterilization microbiologists in companies is reducing knowledge base in the industry • Standards bodies considering writing more guidance – Result is more information to be misunderstood • Quandary… 5 P.S. WHAT HAPPENED TO THE MICROBIOLOGISTS?
  6. 6. WHAT AM I SAYING? • Include knowledgeable people in your company decisions – Product design – Manufacturing process design – Sterilization process validation – Routine monitoring of product and process • If not hired people, contracted people – As your people interact with true experts, they learn and your company is better off 6
  7. 7. • Attend seminars (plural) – they are a good starting point • Common discussion in standards meetings – How much guidance can we give? – Why do we have to provide this guidance? This should be obvious! • Don’t wait until you have a problem to involve experts 7 WHAT AM I SAYING?
  8. 8. LOW BIOBURDEN • Seeing a lot of this with newer products – Tissue/biologics – Combination products with strict manufacturing processes – Automated processes – Short cycles/low doses of sterilization are needed 8
  9. 9. LOW BIOBURDEN • Is this a problem? – Often requires different bioburden test methods • Pooling of products for testing • Most probable number (MPN) testing • Increased sensitivity in test (lower limit of detection) – Often requires different approach to evaluation of bioburden data – Larger swings in bioburden counts can be seen with low-bioburden products • Larger implications for sterilized products 9
  10. 10. • Sample pooling – Facilitates low limit of detection – Can usually resolve down to 0.1 CFU per sample – Will mask individual product bioburden spikes – Example: • 5 samples pooled • Result (5 pooled): 4 CFU • Result (per sample): 4 / 5 = 0.8 CFU • Not always a good option – be careful! SAMPLE POOLING
  11. 11. POOLING IS A VIABLE OPTION SAMPLE AEROBIC BACTERIA FUNGI TOTAL BIOBURDEN 1 <4 <4 <8 2 4 <4 <8 3 <4 <4 <8 4 <4 4 <8 5 8 <4 <12 6 <4 <4 <8 7 4 <4 <8 8 <4 4 <8 9 <4 4 <8 10 <4 <4 <8 AVERAGE <4.4 <4.0 <8.4
  12. 12. CONSIDER TESTING SEPARATELY SAMPLE AEROBIC BACTERIA FUNGI TOTAL BIOBURDEN 1 <4 <4 <8 2 4 <4 <8 3 24 16 40 4 <4 4 <8 5 56 8 64 6 <4 <4 <8 7 4 <4 <8 8 <4 4 <8 9 120 32 152 10 <4 <4 <8 AVERAGE <22.8 <8.4 <31.2
  13. 13. INCREASED SENSITIVITY 13 • Results in more accurate bioburden count – Reduces the “less than” values (e.g. <4 CFU) • Volume factor – change <4 to something less • <1 – Filter all and re-incubate plates • <2 – Filter ½ for bacteria and ½ for fungi – If using an SIP, test larger portion of product – Pool samples together • Other options depending on product/situation
  14. 14. LOW BIOBURDEN • How low is low? – Varies per sterilization method – Likely less of an issue with traditional overkill methods (EO, steam, dry heat) – Radiation (possibly in new bioburden standard) • Low: Less than 10 CFU • Ultra-low: Less than 1 CFU – Repercussions for radiation • Test more often - initially • Test more samples – initially 14
  15. 15. BIOBURDEN TEST METHODS • Most common: – Immersion in peptone tween solution – Extraction using mechanical shaking – Membrane filtration – 0.45µ cellulose filter – TSA (SCDA) and SDA/PDA – 30-35°C and 20-25°C 15
  16. 16. BIOBURDEN TEST METHODS • Is this always the right decision? – No! – How often is bioburden testing repeated due to issues the first time around? – Are all your microorganisms accounted for? 16
  17. 17. BIOBURDEN TEST METHODS • Keep in mind: – Potential microorganisms on materials/components • Understand their manufacturing process and origin • Where are your microorganisms? – Potential microorganisms in assembly • Personnel/process involved • Water? • Material/component storage? • Cleaning processes – Which microorganisms are of greatest concern for sterilization process? 17
  18. 18. EVALUATING BIOBURDEN DATA • Guidance will be provided on: – Dealing with TNTC results – Bioburden spikes • Options for counting very high CFUs • What can cause them • Definition? – Spreading microorganisms – Zero CFU results on plates (less-than numbers) 18
  19. 19. BIOBURDEN SPIKE SAMPLE AEROBIC BACTERIA FUNGI TOTAL SAMPLE AEROBIC BACTERIA FUNGI TOTAL 1 21 3 24 1 68 3 71 2 33 3 36 2 95 6 101 3 39 3 42 3 50 3 53 4 694 3 697 4 56 3 59 5 15 6 21 5 55 3 58 6 82 3 85 6 17 3 20 7 33 3 36 7 27 3 30 8 27 3 30 8 26 3 29 9 12 3 15 9 95 3 98 10 36 3 39 10 151 3 154 Mean 99.2 3.3 102.5 Mean 64 3.3 67.3 Bioburden estimate 174.6 Bioburden estimate 114.7 Standard deviation 209.8 Standard deviation 40.9 Recovery efficiency 0.587 Recovery efficiency 0.587 What do you do with a spike? Throw it out (outlier)?
  20. 20. BIOBURDEN SPIKE 20 • Definition? – Single value more than twice the average • Similar option used in radiation validations – Single value which is over 2 SD above the mean • Mean + 2 SD….any value above that could be a spike – Based on internal alert and action levels • Perhaps best option – individualized for your product
  21. 21. BIOBURDEN SPREADER Throw it out? Assign a value? Additional testing? Identify? Investigate?
  22. 22. TOO NUMEROUS TO COUNT TNTC Throw it out? Assign a value? Additional testing? Identify? Investigate?
  23. 23. THANK YOU 23

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