Objectionable microorganisms within and beyond regulations

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


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



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.


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 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



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.



• 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




Pathogen: A microorganism that causes or can cause disease

FDA Bad Bug Book

Campylobacter JejuniYersinia enterocoliticaShigella sppVibrio parahaemolyticusBacillus cereusListeria monocytogenes




Specified Microorganism (USP <62>/ PhEur 2.6.13)

Bile Tolerant Gram Negative Bacteria Escherichia coli Salmonella Pseudomonas aeruginosa Staphylococcus aureus Clostridia Candida albicans



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



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”


Dosage form & patient Population



Does the isolate have the metabolic capability to degrade the product quality over time?

Adversely affect product stability


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


Damage the container closure system



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



“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


What regulators see as an Objectionable Microorganism


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.”



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




• 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?



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.


How the regulatory view stands with USP <62<


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



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:.....”



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



New emerging objectionable microorganisms


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



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”



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



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



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.



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......



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



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.



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



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)



• 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:


What will help and what will constrict?



Eliminate lab error

Accurate Identification

Eliminate mix-up

Does the data stack up?



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”



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



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



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


Reactive


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



Proactive Risk

Assessment

Microorganisms in Product

Reactive Risk Assessment

Product Disposition

Continuous Improvement Loop for Non-Sterile Pharmaceutical Manufacture



Raw materials Manufacture Distribution

Traditional Microbiology focus

Proactive Microbiology RA Focus


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


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.

Health & Medicine

Objectionable microorganisms within and beyond regulations