objectionable microorganisms within and beyond regulations
TRANSCRIPT
1For Business Use Only, Stephen McGrath PhD. 21st November 2013
Stephen McGrath, Ph.D.Site MicrobiologistTeva Pharmaceuticals Ireland
Objectionable microorganisms: within and beyond regulations
Pharmig 21st Annual Conference
Sterile, Respiratory and Specialty Quality Operations
November 21st 2013
2For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Microorganism?”
3For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Microorganism?”
Objectionable:Arousing distaste or opposition; unpleasant or offensive
Casu marzu
“Objectionable” is a subjective term open to interpretation and can mean different things to different people
4For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Microorganism?”
However you define what an objectionable microorganism is, the quality and safety of the pharmaceutical product provided to customers remains the responsibility of the manufacturer.
For non-sterile pharmaceutical products it is up to the manufacturer to demonstrate that microorganisms present in products are safe to release to market.
Any and all microorganisms present in non-sterile dosage forms may be considered objectionable unless demonstrated otherwise.
5For Business Use Only, Stephen McGrath PhD. 21st November 2013
The concept of Objectionable Microorganisms in Non-sterile Pharmaceutical products is not a recent development.
1982: The USP Microbiology Committee stated that the demonstration of “absence of objectionable microorganisms” was not the intent of the tests described in the Microbial Limit Tests <61>.
1993: FDA guide to inspections of Microbiological Pharmaceutical QC Labs: The USP Microbial Limits Chapter <61> provides methodology for selected indicator organisms, but not all objectionable organisms.
What is an “Objectionable Microorganism?”
6For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Organism” Scott Sutton October 2012 A pure interpretation in regards to patient health would lead to the following requirements:
Objectionable in view of the product’s intended use or to its shelf-life stability, and;
For products not required to be sterile
What is an “Objectionable Microorganism?”
7For Business Use Only, Stephen McGrath PhD. 21st November 2013
A microorganism can be considered objectionable if it represents a potential health hazard to the user who is using the product as directed, or if it is capable of growing in the product. Objectionable microorganisms are defined as contaminants, that depending on the microbial species, number of organisms, dosage form, intended use and patient population, would adversely affect product safety. Additionally, microorganisms may be deemed objectionable if they adversely affect product stability or if they damage the integrity of the container closure system.
USP <2022> Microbiological Procedures for absence of specified Microorganisms-Nutritional and dietary supplements.
What is an “Objectionable Microorganism?”
8For Business Use Only, Stephen McGrath PhD. 21st November 2013
• Is a known Pathogen• Is a Specified Microorganism (USP <61> & <62>)
Potential Health Hazard
• Can potentially exceed the TAMC spec• Has the potential to metabolise product constituents
Capable of growing in the product
• Has the potential to metabolise the API• Could produce metabolites that affect analytical testing• Has the potential to produce toxins/mycotoxins
Adversely affect product safety
• Has the potential to metabolise product constituentsAdversely affect product stability
• Has the potential to degrade or disrupt the containerDamage the container
closure system
• Is known to infect via the route of product administration• Is associated with infection in the target population
Dosage form & patient Population
What is an “Objectionable Microorganism?”
9For Business Use Only, Stephen McGrath PhD. 21st November 2013
Potential Health Hazard
Pathogen: A microorganism that causes or can cause disease
FDA Bad Bug Book
Campylobacter JejuniYersinia enterocoliticaShigella sppVibrio parahaemolyticusBacillus cereusListeria monocytogenes
What is an “Objectionable Microorganism?”
10For Business Use Only, Stephen McGrath PhD. 21st November 2013
Potential Health Hazard
Specified Microorganism (USP <62>/ PhEur 2.6.13)
Bile Tolerant Gram Negative Bacteria Escherichia coli Salmonella Pseudomonas aeruginosa Staphylococcus aureus Clostridia Candida albicans
What is an “Objectionable Microorganism?”
11For Business Use Only, Stephen McGrath PhD. 21st November 2013
Capable of growing in the product
Metabolic capabilities of the isolate versus product formulation
Water activity (aw) Osmolality/Osmolarity pH Antimicrobial properties of product constituents Presence of preservatives Presence of natural raw materials Synthetic product Storage temperature
What is an “Objectionable Microorganism?”
12For Business Use Only, Stephen McGrath PhD. 21st November 2013
Is the isolate known to be problematic for the dosage form?
Burkholderia cepacia in topical products and nasal solutions
December 2012: Congestion relief nasal gel voluntarily recalled after isolation of “small amount of Burkholderia cepacia in a single sample of the product taken from the affected lot”
What is an “Objectionable Microorganism?”
Dosage form & patient Population
13For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Microorganism?”
Does the isolate have the metabolic capability to degrade the product quality over time?
Adversely affect product stability
14For Business Use Only, Stephen McGrath PhD. 21st November 2013
Has the isolate the metabolic capability to disrupt the integrity of the container closure system thus leaving the drug exposed to secondary contamination?
Influence on Extractable/leachable profile
What is an “Objectionable Microorganism?”
Damage the container closure system
15For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Microorganism?”
All of the previous information plus: Has the isolate the capability to produce toxins, metabolise the API or produce metabolites that may interfere with analytical QC testing?
Adversely affect product safety
16For Business Use Only, Stephen McGrath PhD. 21st November 2013
What is an “Objectionable Microorganism?”
“There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But there are also unknown unknowns. There are things we don't know we don't know.”
Known Knowns: Pathogens including Specified Microorganisms
Known unknowns: Objectionable Microorganisms
Unknown unknowns: Viable but non-culturable
17For Business Use Only, Stephen McGrath PhD. 21st November 2013
What regulators see as an Objectionable Microorganism
18For Business Use Only, Stephen McGrath PhD. 21st November 2013
FDA Code of Federal Regulations
21 CFR 211.84 (d)(6) “Each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.
21 CFR 211.113 (a) “Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
21 CFR 211.165 (b) “There shall be appropriate laboratory testing, as necessary of each batch of drug product required to be free of objectionable microorganisms.”
What regulators see as an Objectionable Microorganism
19For Business Use Only, Stephen McGrath PhD. 21st November 2013
USP <1111> Microbiological Examination of nonsterile products: Acceptance criteria for
pharmaceutical preparations and substances for pharmaceutical use.
....for a given preparation it may be necessary to test for other microorganisms depending on the nature of the starting materials and the manufacturing process.
In addition to the microorganisms listed, the significance of other microorganisms recovered should be evaluated in terms of the following:
– The use of the product– The nature of the product– The method of application– The intended recipient– Use of immunosuppressive agents– The presence of disease, wounds, organ damage
Risk based assessment
What regulators see as an Objectionable Microorganism
20For Business Use Only, Stephen McGrath PhD. 21st November 2013
What regulators see as an Objectionable Microorganism
• Any Microorganism present in numbers greater than the acceptable limit for the dosage form (USP<1111>)High numbers
• Microorganisms associated with diseasePathogens
• Listed in USP <62>, <1111>Specified
Microorganisms
• unless “a risk-based assessment of the relevant factors is conducted by personnel with specialized training in microbiology and in the interpretation of microbiological data.” demonstrates otherwise
Everything else
Is that all?
21For Business Use Only, Stephen McGrath PhD. 21st November 2013
What regulators see as an Objectionable Microorganism
Would you eat Casu Marzu if a risk assessment said it was safe to do so?
Regulatory inspectors may have strong beliefs/opinions on what constitutes an objectionable microorganism.
It is prudent to keep up to date with regulatory thinking through the literature, symposia presentations, recall notices, e-forums etc.
22For Business Use Only, Stephen McGrath PhD. 21st November 2013
How the regulatory view stands with USP <62<
23For Business Use Only, Stephen McGrath PhD. 21st November 2013
USP <62> ...Will allow determination of the absence of, or limited occurrence of Specified microorganisms that may be detected under the conditions described. The tests are designed primarily to determine whether a substance or preparation complies with an established specification for microbiological quality.
Absence of : Bile tolerant Gram negative bacteriaEscherichia coliSalmonellaPseudomonas aeruginosaStaphylococcus aureusClostridiaCandida albicans
How the regulatory view stands with USP <62<
24For Business Use Only, Stephen McGrath PhD. 21st November 2013
USP<62> is a set of instructions for performing tests to demonstrate the absence of particular (specified) microorganisms
It does not mention “Objectionable microorganisms”
It does not indicate the significance of the organisms with respect to particular product formulations, dosage forms, intended recipients
USP<1111>/PhEur 5.1.4 provides guidance for acceptance criteria for microbiological quality of nonsterile dosage forms
However... “In addition to the microorganisms listed in Table 1 the significance of other microorganisms recovered should be evaluated in terms of the following:.....”
How the regulatory view stands with USP <62<
25For Business Use Only, Stephen McGrath PhD. 21st November 2013
Is the application of USP <61> and <62> in accordance with USP <1111> robust enough to ensure patient safety?
Raw materialsManufacturing
process
Product formulation Target population
Isolate identification
scheme
Risk Assessment
How the regulatory view stands with USP <62<
26For Business Use Only, Stephen McGrath PhD. 21st November 2013
New emerging objectionable microorganisms
27For Business Use Only, Stephen McGrath PhD. 21st November 2013
A review of reported recalls involving Microbiological control 2004-2011 with emphasis on FDA considerations of Objectionable Organisms.
Scott Sutton and Luis Jimenez Jan/Feb 2012
642 microbiologically-related recalls over the years 2004-2011 142 relating to non-sterile products 70% cited the presence of “objectionable microorganisms” 34% of these referred to the presence of Burkholderia cepacia
New emerging objectionable microorganisms
28For Business Use Only, Stephen McGrath PhD. 21st November 2013
Burkholderia cepacia: This Decision is Overdue
Torbeck, Raccasi, Guilfoyle, Friedman & Hussong. 2011
“Bcc organisms pose a clear and present danger to patient health and safety. The challenge is undeniable; now is the time to remove Bcc from our pharmaceutical manufacturing areas and products”
New emerging objectionable microorganisms
29For Business Use Only, Stephen McGrath PhD. 21st November 2013
Bacillus cereus: associated with foodborne illness from enterotoxin production
50 product recalls from 2004-2012. All associated with alcohol wipes
“Increasing recognition of Bacillus cereus pathogenicity and routes of infection”
What is an “Objectionable Organism” Scott Sutton October 2012
New emerging objectionable microorganisms
30For Business Use Only, Stephen McGrath PhD. 21st November 2013
The Human Microbiome Project
• Initiated in 2008 by US NIH
• Objective is to identify and characterise microorganisms associated with both healthy and diseased humans
• Complex interactions between People, Pharmaceuticals and Microorganisms
• Risk that members of the HMB could be transferred to Pharma products during manufacturing
• Onus on manufacturers to determine risk level and take action
New emerging objectionable microorganisms
31For Business Use Only, Stephen McGrath PhD. 21st November 2013
Unknown Unknowns
Viable but Non Culturable microorganisms
The significance and detection of VBNC Microorganisms
Dr. Paul Newby June 2007
Overall, the risk in terms of patient safety from organisms in the VBNC state is low
Detection and understanding of their occurrence in Pharmaceutical manufacturing environments/materials/products will lead to better process control.
New emerging objectionable microorganisms
32For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
33For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
GMP• Manufacturer’s responsibility that products are safe, pure and
effective
FDA• Free from objectionable microorganisms
USP • Significance of microorganisms recovered should be evaluated....
USP
• ....Where warranted, a risk based assessment of the relevant factors is conducted by personnel in specialized training in microbiology and in the interpretation of microbiological data......
34For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
Regulated
Microbial Risk in Pharmaceutical Manufacturing and ICH Q9
Guilfoyle, Friedman, Hughes, Hussong, Rosenberg and Brorson. 2013
“A risk-based assessment incorporating the five recommendations above should be conducted by appropriate technical staff, including microbiology personnel with specialized training in the interpretation of microbiological data”
USP<1111>: Risk based assessment to determine the significance of microorganisms recovered from nonsteriles.
USP <1115>: Risk-based approach to the control of potential contamination in nonsterile product manufacturing
35For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
Self Control
Engagement of Microbiology expertise across the product life-cycle for the purposes of identifying risks and implementing control measures will impart a competitive business advantage.
36For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
USP<1115> Bioburden Control of Nonsterile substances and Products (Draft)
A pragmatic scientific approach to management of microbial bioburden in nonsterile products requires consideration of patient risk and contamination control objectives to achieve a practical and appropriate level of risk management.
Outlines a risk-based approach to the control of potential contamination in nonsterile product manufacturing
37For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
The risk of infection resulting from nonsterile drug product generally is low, regardless of the route of administration, provided appropriate precautions and procedures are followed.....
....It is not possible to provide a comprehensive product-by-product list of objectionable microorganisms.....
....Manufacturers are responsible for determining whether microorganisms recovered from drug products are objectionable...
....Microbiological risk should be assessed on a case-by-case basis....
USP<1115> Bioburden Control of Nonsterile substances and Products (Draft)
38For Business Use Only, Stephen McGrath PhD. 21st November 2013
The need for Risk Assessment
• Defines what an Objectionable Microorganism isUSP <2022>
• Provides standardised test methods for dosage formsUSP <61>,<62>
• Provides information on how to characterise/ identify isolatesUSP <1113>
• List specified microorganisms for dosage forms• Provides checklist for assessment of isolatesUSP <1111>
• Provides a tool (aw) for assessing the potential for isolates to impact dosage formsUSP <1112>
• Provides a risk-based strategy for controlling microbial contaminationUSP <1115>
• Provides information on how to control and monitor bioburden in controlled environments
USP <1116> (aseptic)
The tools are already there:
39For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
40For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
Eliminate lab error
Accurate Identification
Eliminate mix-up
Does the data stack up?
41For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
A strategy for Developing Robust Pharmaceutical Microbiological ControlDonald C. Singer August 2012
“The mission of a microbiologist is to develop in the pharmaceutical organization a foundation for understanding of microbial origin, and parameters for proliferation and survival; to continuously improve/embed the concepts for protection, exclusion, reduction, removal or destruction of contaminating microbiological entities”
42For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
Risk Assessment
ReactiveProactive
Proactive RA:Determine key risksAssess existing and implement new controls
Reactive RA:Pre-formatted checklist for assessment of isolates
Patient/Product Safety
43For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
USP <1115> Bioburden control of nonsterile drug substances and products
Top 5 Manufacturing risk factors
1) Ingredient Water2) Pharmaceutical ingredients3) Process equipment4) Manufacturing personnel5) Manufacturing environment
44For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
Assess the product and the process
Identify risks and control measures
Generate list of Objectionables
Assess robustness of product, process & controls
Identify potential threat microorganisms
Assess suitability of routine test methods
Consider developing specific tests
Proactive
45For Business Use Only, Stephen McGrath PhD. 21st November 2013
Reactive
What will help and what will constrict?
The use of the product
The nature of the product
The method of application
The intended recipient
Use of immunosuppressive agents
The presence of disease, wounds or organ damage
46For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
Proactive Risk
Assessment
Microorganisms in Product
Reactive Risk Assessment
Product Disposition
Continuous Improvement Loop for Non-Sterile Pharmaceutical Manufacture
47For Business Use Only, Stephen McGrath PhD. 21st November 2013
What will help and what will constrict?
Raw materials Manufacture Distribution
Traditional Microbiology focus
Proactive Microbiology RA Focus
48For Business Use Only, Stephen McGrath PhD. 21st November 2013
Conclusion
Microorganisms are expected to be present in nonsterile pharmaceutical products
It is the manufacturers responsibility to ensure that products are free from objectionable microorganisms
Every and any microorganism present may be considered objectionable unless demonstrated to be otherwise
Integration of microbiology expertise across all aspects of the product lifecycle will supply a competitive advantage
The application of a patient-focussed risk control strategy (proactive & reactive) in a CI loop will maintain that advantage
The tools are already there
49For Business Use Only, Stephen McGrath PhD. 21st November 2013
References1. Burkholderia cepacia: This decision is overdue. Torbeck, L. et al, 2011 PDA Journal of Pharm Sci & Tech.
2. Letter to the editor. Sutton,S. 2012 PDA Journal of Pharm Sci & Tech.
3. A review of reported recalls involving microbiological control 2004-2011 with emphasis on FDA considerations of objectionable organisms. Sutton, S. & Jimenez, L. 2012 American Pharm Review.
4. What is an “objectionable organism”?. Sutton, S. 2012. American Pharm Review.
5. Implications of the human microbiome on pharmaceutical microbiology. Wilder, N., Sandle, T., & Sutton, S. 2013 American Pharm Review.
6. Microbial risk in pharmaceutical manufacturing and ICH Q9. Guilfoyle, D.E., et al. 2013 PDA Journal of Pharm Sci & Tech.
7. Microbial diversity in pharmaceutical product recalls and environments. Jimenez, L., 2007 PDA Journal of Pharm Sci & Tech.
8. A review of cleanroom microflora: types, trends, and patterns. 2011 Sandle, T. PDA Journal of Pharm Sci & Tech.
9. A strategy for developing robust pharmaceutical microbiological control. 2012 Singer, D.C. American Pharm Review.
10. Microbial limit tests: the difference between “absence of objectionable microorganisms and absence of specified microorganisms. 2006 Sutton, S. PMF Newsletter June.
11. The significance and detection of VBNC Microorganisms. Newby, P. 2007. American Pharm Review.