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Robert Westney, M.S., RAC, CMQ/OE
Director of Quality and OperationsCryologics, Inc.March 7, 2017
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About the PresenterAbout the PresenterAbout the PresenterAbout the Presenter
� Bob Westney, M.S. QA/RA, RAC, CMQ/OE◦ 30 years of industry experience◦ QC Microbiology, Quality Assurance, Regulatory Affairs◦ Pharmaceutical, Biologics, Dietary Supplements, Medical
Devices
� Founder and Owner of Cryologics, Inc.
� Cryologics’ Director of Quality and Operations
� LinkedIn Profile: https://www.linkedin.com/in/robert-westney-m-s-rac-cmq-oe-45669112
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https://store.pda.org/ProductCatalog/Default.aspx
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Please complete the survey at the end of this Please complete the survey at the end of this Please complete the survey at the end of this Please complete the survey at the end of this presentationpresentationpresentationpresentation◦ This will contribute to our Microbiology
community’s understanding of current thinking and practices
◦ We will provide the results of the survey to respondents
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PDA 10th Annual Global Conference on MicrobiologyOctober 2015
Do YOUYOUYOUYOU incorporate in-house isolates in compendial testing?
AgendaAgendaAgendaAgenda
� Industry Debate Over the Use of In-House Isolates in Compendial Testing
� Preparation of In-House isolates for Use in Testing
� Regulatory Enforcement Actions, and Compendial and Industry Guidance◦ Disinfectant Efficacy Testing◦ Media Growth Promotion Testing◦ Test Method Suitability/Qualification◦ Rapid Microbiological Methods
� Strategies for Selecting In-House Isolates for Use in Compendial Testing
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Industry Debate Over the Use of In-House Isolates in Compendial Testing
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"Good practice includes the periodic challenge of prepared media with low levels of organisms. This includes USP indicator organisms as well as normal flora."
U.S. Food and Drug Administration: “Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories” (1993)
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PMF List (2010-2016)
� “As soon as an environmental isolate is put onto growth media, it is no longer an ‘environmental isolate’.”
� “EM organisms will stop to behave as such after a few transfers.”
� “This is one of the problems with using 483 observations as ‘cGMP’. They are not. They are the observations of one inspector who may or may not be knowledgeable in microbiology.”
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Join: http://www.microbiologynetwork.com/pmflist_faqs.asp
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PMF List (2010-2016)
� “The use of house isolates/environmental isolates for incoming growth promotion testing on media is not an EP or USP regulatory requirement. Although, more and more investigators and inspectors do want to see that these house isolates are used on your growth promotion panel and might be erroneously interpreting them as a GMP requirement.”
� “Adding 1 or 2 EM organisms to compendial testing is arbitrary. What I recover today may not be what I recover tomorrow so why validate a method with such an unknown variable?”
� “The industry practice for EM media is to add one or two plant isolates.”
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PMF List (2010-2016)
� “Sharon Thoma during the ask the regulator panel discussion at the October PDA Micro Conference emphatically stated that she would give a company a 483 observation if they did not conduct GPT with both the compendial organisms and house isolates.”
� “Despite the FDA position the requirements of an official USP test is defined in the test chapter ... It has become a cGMP requirement although it is misguided.”
PMF List: 4/22/16
� “It is true that properly maintained and stored cultures will have minimal genetic drift, and genetically will be the strain that was originally isolated.
� It is also true that microorganisms adjust and adapt physiologically to their current situation. This is not a change in genes but in gene regulation.” [emphasis added]
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Julie Schwedock, PhDRapid Micro Biosystems
The arguments against the inclusion of in-house isolates fall into two categories:
1. An “environmental” isolate, once cultured in the Microbiology laboratory, loses its “wild-type” genetic traits.
2. The regulatory expectation that in-house isolates be included in compendial testing is represented by only a few “rogue” FDA inspectors, and is not an Agency-wide expectation.
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Does an “environmental” isolate lose its “wild-type” traits after being cultured?
� There has been no published empirical evidence that an in-house microbial isolate either does or does not lose its “wild-type” traits upon culturing.
� United States Pharmacopeia (USP <61>): “Seed-lot culture maintenance techniques (seed-lot systems) are used so that the viable microorganisms used for inoculation are not more than five passages removed from the original master seed-lot”.
� Although in most cases an in-house isolate likely becomes physiologically more “robust” upon culturing, it is reasonable to assume that a limited number of passages from the source culture allows the microorganism to retain its “wild-type” genetic traits.
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Are 483 observations and Warning Letters limited to just a few “rogue” inspectors?
� “Compliance versus science”
� The trend in citing firms for not meeting this requirement demonstrates that the Agency’s SMEs recognize the scientific merit of including in-house isolates in compendial testing.
� Defending against this expectation is a challenge!
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U.S. Food and Drug Administration: “Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories” (1993)
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Preparation of In-House isolates for Use in Testing
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Read Plates
“X” number of days
Concentration Changed?????
“X” number of days
• Yes, probably• Start over!• Management: “What did you do
wrong?!”
� Other Challenges◦ Advanced Planning! “Converging” all in-house
organisms so that they’re all ready to use on any given day at the necessary concentration� Bacillus spp: 18-24 hrs� Staphyloccocus spp: 2-3 days� Molds: 5-7 days◦ “Emergency” media orders (or, “Oh #$!@&, we’re out of
media! Order an overnight shipment!”)� ATCC organism GPT results are available in about a week,
but you have to wait another week for your in-house organisms are even ready to use (then add another week)
� Release “at risk”… QA (and FDA!) loves constant planned deviations
◦ You can send out your organisms to have them custom preserved in the concentration you need… BigBigBigBig expense… MONTHS!!!!
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Brief history of Cryologics….Brief history of Cryologics….Brief history of Cryologics….Brief history of Cryologics….
• YEARS of wrestling with previously described challenges… “There has to be another way!”
• Established laboratory facility, qualified equipment, qualified suppliers, SOPs, etc. in 2010
• Years of experience, and trial and error, extensive R&D… Achieved a successful, efficient and FAST “first pass” process for creating a stable product
• Launch of operations in Spring 2011
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� Low straightforward pricing published on website
◦ Competitors: “It depends…”
◦ No “developmental”, “setup”, “organism”, or other non-refundable fees; no “deposit”
◦ Fraction of competitors’
� Low turnaround time
◦ Weeks, not MONTHS!
� No combining components
◦ Thaw, mix, use
◦ Eliminates incidental contamination
� Minimal culturing from your passage
� Stable for several months
� We’re fellow microbiologists!
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Turnaround times…
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Turnaround times…
Disinfectant Efficacy Testing
Regulatory Enforcement Actions
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� “Disinfectant effectiveness studies against representative microorganisms and/or specific in-house isolates were not conducted for cleaning agents used in your facility to disinfect production areas, including aseptic areas.” [FDA Warning Letter, March 28, 2008]
� “No rationale was provided for the ATCC organisms used nor was [sic] actual EM isolates used for the study.” [FDA Memorandum, Biologics License Application, 2009]
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� “The firm was unable to provide scientific rationale for the use of the selected organisms used in the Disinfectant Efficacy study. These organisms were not representative of organisms isolated from the facility nor were they representative of the USP guidelines.” [FDA 483 Observation, May 25, 2011]
� “Your response states that a supplemental disinfectant efficacy study, using mold spores of in house isolates on various surfaces, will be performed and completed by [redacted]. We suggest that this proposed study be conducted as soon as possible.” [FDA Warning Letter, July 12, 2012]
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Disinfectant Efficacy Testing
Compendial and Industry Guidance
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� “Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility... If indicated, microorganisms associated with adverse trends can be investigated as to their sensitivity to the disinfectants employed in the cleanroom in which the organisms were isolated.” [FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing -Current Good Manufacturing Practice, September 2004]
� “Selection of organisms should be based on the type of environmental isolates recovered from the facility (environmental isolates are preferred); however, if facility isolates are not available ATCC cultures ... representing facility isolates are acceptable until facility isolates can be obtained.” [PDA Technical Report No. 70, “Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing Facilities”, 2015]
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United States Pharmacopeia, <1072> “Disinfectant and Antiseptics”
� “… the most frequently isolated microorganisms from an environmental monitoring program may be periodically subjected to use-dilution testing with the agents used in the disinfection program to confirm their susceptibility, as there are real differences among different species in resistance to the lethal effects of different sanitizers.”
� “To demonstrate the efficacy of a disinfectant within a pharmaceutical manufacturing environment, it may be deemed necessary to conduct the following tests: (1) use-dilution tests (screening disinfectants for their efficacy at various concentrations and contact times against a wide range of standard test organisms and environmental isolates); (2) surface challenge tests (using standard test microorganisms and microorganisms that are typical environmental isolates, applying disinfectants to surfaces at the selected use concentration with a specified contact time, and determining the log reduction of the challenge microorganisms)...”
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� “It is recommended to periodically review challenge testing of the selected sanitizers, disinfectants, and sporicides if representative new isolates are routinely recovered in the environmental monitoring program. This supports the effectiveness of the sanitizer, disinfectant, or sporicide on new contaminants discovered in operations.” [Parenteral Drug Association Technical Report No. 13, “Fundamentals of an Environmental Monitoring Program”, 2014]
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Media Growth Promotion Testing
Regulatory Enforcement Actions
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� Not limited to aseptic manufacturers! Manufacturers of non-sterile products have been subject to regulatory enforcement.
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� “… the growth promotion tests for media used during environmental monitoring did not include the use of the normal microbial flora commonly recovered and isolated from the various production and support areas.” [FDA Warning Letter, February 24, 1997]
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� “Growth promotion testing performed on media fill vials does not include evidence the media is capable of detecting environmental isolates found in class 100 filling areas...” [FDA Warning Letter, January 11, 2001]
� “… your firm does not perform challenge testing to the sterility media with environmental isolates from the environmental monitoring program.” [FDA Warning Letter, October 29, 2010]
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� Growth promotion studies were deficient because there was “no inclusion of environmental isolates in the growth promotions that are conducted, including growth promotion studies for aseptic media simulations.” [FDA 483 Observation, May 2008]
� “… the firm does not test TSA … during growth promotion tests for microorganisms to include for example, molds, yeasts and other potential known environmental contaminants found in the manufacturing facility and/or raw materials.” [FDA 483 Observation, April 30, 2010]
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� The FDA expressed its satisfaction that the firm complied with its expectation: “Growth promotion studies were conducted successfully using indicator microorganisms per USP as well as local isolates.” [FDA Memorandum, BLA Recommendation, January 16, 2009]
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Media Growth Promotion Testing
Compendial and Industry Guidance
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� “The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates. Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge.” [FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004]
� “… for the Growth Promotion test, representative microflora isolated from the controlled environment or ATCC strain preparations of these isolates may also be used to test media.” [USP <1116>, “Microbiological Evaluation of Clean Rooms and Other Controlled Environments”]
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� “… microorganisms used in growth-promotion testing may be based on the manufacturer's recommendation for a particular medium, or may include representative environmental isolates.” [USP <1117>, “Microbiological Best Laboratory Practices”]
� USP clarifies parenthetically that “these latter are not to be construed as compendial requirements.”
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From PDA Technical Report No. 22, “Process Simulation for Aseptically Filled Products” (2011):
� “The growth promotion properties of the incubation media should be evaluated using pharmacopeialmethods. The inclusions of tests for environmental organisms or those isolated from sterility test positives are recommended.”
� “Growth promotion testing ... is performed using pharmacopeial methods. Consideration should be given to testing with other microorganisms found in the aseptic processing area environment, such as those isolated during environmental and personnel monitoring and sterility test contaminants.”
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From the Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme (PIC/S):
� “The medium selected should be capable of supporting a wide range of microorganisms, which might reasonably be encountered and be based also on the in house flora (e.g. isolates from monitoring etc.).” [Recommendation on the Validation of Aseptic Processes. PI-007-6, 1 January 2011]
� “Environmental or fastidious organisms may be used if alternative non-selective enrichment media have been selected for the sterility test.” [Recommendation on Sterility Testing. PI-012-3, 25 September 2007]
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Test Method Suitability/Qualification
Regulatory Enforcement Actions
Compendial and Industry Guidance
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� There has been no documented evidence that the FDA has cited a manufacturer for lack of inclusion of in-house isolates in microbiological test method suitability/qualification.
� “The test organisms selected should reflect organisms that could be found in the product, process, or manufacturing environment.” [FDA Final Rule on “Amendments to Sterility Test Requirements for Biological Products”, June 4, 2012]
� More regulatory scrutiny in the near future?!
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Rapid Microbiological Methods
Regulatory Enforcement Actions
Compendial and Industry Guidance
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� Rapid microbiological methods (RMMs) have become a growing area of advancement over the past several years.
� There has been no documented evidence that the FDA has cited a manufacturer for lack of inclusion of in-house isolates in rapid microbiological methods.
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� “You should develop a panel of microorganisms relevant to the product and process to challenge the performance of your RMM. We recommend that you include in your panel microorganisms which represent the following categories: … ◦ isolates detected in starting materials,
◦ isolates detected by in-process testing or during preliminary product testing,
◦ isolates detected by environmental monitoring of your manufacturing facility,
◦ isolates from your production areas which represent low nutrient and high stress environments …”
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FDA Guidance for Industry: Validation of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular and Gene Therapy Products (Draft), February 2008 [withdrawn][withdrawn][withdrawn][withdrawn]
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Conclusions…Conclusions…Conclusions…Conclusions…
� Do in-house microbial isolates lose their “wild type” characteristics upon culturing in the lab?
◦ NO, the prevailing evidence shows that they retain their NO, the prevailing evidence shows that they retain their NO, the prevailing evidence shows that they retain their NO, the prevailing evidence shows that they retain their genotypticgenotypticgenotypticgenotyptic characteristicscharacteristicscharacteristicscharacteristics
� Is the requirement to incorporate in-house microbial isolates into compendial testing confined to just a few “rogue” inspectors who don’t understand the science and GMPs?
◦ NO, the regulatory enforcement history shows that this NO, the regulatory enforcement history shows that this NO, the regulatory enforcement history shows that this NO, the regulatory enforcement history shows that this is an Agencyis an Agencyis an Agencyis an Agency----wide requirementwide requirementwide requirementwide requirement
Bibliography:http://cryologics.com/resources/bibliography/
Additional Enforcement Actions
Trade Journal Articles
Hyperlinks to Source Documents
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Selection of In-House Isolates for Use in Compendial Testing
Risk
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� Depends upon the test itself (growth promotion, disinfectant efficacy, etc.), and upon the nature of the manufacturing process and final product (aseptic/sterile vs. non-sterile).
� Risk
◦ Detection
◦ Assessment
◦ Management
◦ Mitigation
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� 21 CFR 211.113(a)
� 21 CFR 211.113(b)
� ICH Q9, “Quality Risk Management”, 2005
� USP <1111> “Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use”
� ICH Q7A, “Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients”, 2000
� PDA Technical Report No. 13, “Fundamentals of an Environmental Monitoring Program”, 2014
� Trade Journals
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Selection of In-House Isolates for Use in Compendial Testing
Strategies
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To re-cap…
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Risk???Risk???Risk???Risk???
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Best (current) advice…
� Include predominant in-house microbial isolates into your growth promotion, disinfectant efficacy and method suitability testing◦ Satisfies most inspectors’ and customers’
requirements
� Include isolates that represent risk
� “Burkholderia cepacia: This Decision Is Overdue”Lynn Torbeck, Diane Raccasi, Dennis E. Guilfoyle, et al. PDA J Pharm Sci and Tech 2011
� “The Risk of Bacillus cereus to Pharmaceutical Manufacturing”Sandle, T. American Pharmaceutical Review. November 2014
� FDA (fda.gov)◦ News Feeds (sign up)◦ Warning Letters◦ 483s◦ Recalls◦ Guidance documents (even drafts)
� Trade publications and groups� Industry conferences� PMF List� LinkedIn groups
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Keep your “finger on the pulse”…
� Two bases for selection of isolates
◦ Demonstrating adequate reduction of a high-level presence of an organism
� Disinfectant efficacy testing (“challenge”)
◦ Demonstrating adequate recovery of a low-level presence of an organism
� Media growth promotion testing
� Test method suitability/qualification
� Disinfectant efficacy testing (“recovery”)
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� Disinfectant efficacy testing
◦ Microflora of the manufacturing environment
◦ Typically evaluated in EM trend reports
◦ Undesirable trends (e.g., seasonal)
◦ Recovery of organisms considered “objectionable” or “of concern”
� Higher classification areas
� Controlled/Non-Classified areas
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Example …
� EM trend reports describe historical and consistent seasonal “blooms” of filamentous fungi (mold) during the autumn season.
� Corrective action = frequent sanitization with a sporicidalagent
� Characterize (ID) the species of the mold(s).
� Include the mold(s) in disinfectant efficacy testing and EM media growth promotion.
� Importantly, the early recovery of the species (detected through EM) signals the need to proactively implement frequent sanitization with a sporicidal agent.
� Don’t react to the “bloom” … Risk mitigation!Risk mitigation!Risk mitigation!Risk mitigation!
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Example …
� Introduction of an “objectionable” organism into the facility
◦ Non-sterile manufacturers… USP <62> organisms
◦ Recurring incident?
◦ Ingress into more stringently classified/controlled areas (material, personnel or equipment flow)?
� Conclusion
◦ Adverse trend?
◦ Shift in the facility’s normal microflora?
� Include the organism in disinfectant efficacy and growth promotion testing
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� Inclusion of in-house isolates in media growth promotion testing
◦ Media used for EM and water systems monitoring
◦ Media used for raw material, component, in-process product and finished product testing
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� Media used for raw material and component testing
◦ Previously recovered “objectionable” or fastidious organisms from non-sterile materials/components
◦ Previously recovered contaminants from sterile materials/components
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� Media used for in-process product testing
◦ Review of historical data (Annual Product Reviews)
◦ Critical control points – objectionable organisms
� Media used for finished product testing
◦ For non-sterile products, the approach is similar to that of selecting isolates from non-sterile raw materials and components
◦ For sterile products, include isolates recovered from previous sterility test positives or media fill failures
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� Test method suitability/qualification
◦ Employ the same strategy as that used for selection of isolates for growth promotion of media used for raw material, component, in-process product and finished product testing
� “Objectionable” and fastidious organisms
� Sterility test failures
� Media fill failures
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� Sources of information useful for selecting in-house isolates
◦ Annual product reviews
◦ EM and clean utility trend reports
◦ Process validation
◦ Cleaning validation
◦ Media fills
� Organisms representing riskriskriskrisk
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Review…Review…Review…Review…
� Industry Debate Over the Use of In-House Isolates in Compendial Testing
� Preparation of In-House isolates for Use in Testing
� Regulatory Enforcement Actions, and Compendial and Industry Guidance◦ Disinfectant Efficacy Testing◦ Media Growth Promotion Testing◦ Test Method Suitability/Qualification◦ Rapid Microbiological Methods
� Strategies for Selecting In-House Isolates for Use in Compendial Testing
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Robert Westney
Director of Quality and Operations
Cryologics, Inc.
Main: (610) 847-8781
Cell: (267) 377-7126
www.Cryologics.com
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PMF Fall ForumPMF Fall ForumPMF Fall ForumPMF Fall Forum
Early September 2017
Baltimore Inner Harbor (tentative)
http://microbiologynetwork.com/PMF_Events.asp
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