Riesgo Microbiologico

Risk Assessment and Setting Microbial Limits Specifications for Non-Sterile Pharmaceutical and Over-The-Counter Drug Products
A3P Meeting Montreal, Canada November 22, 2005 Tony Cundell, Ph. D Consulting Microbiologist Scarsdale, New York, USA Microbiological Consulting
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Risk Assessment and Setting Microbial Limits Specifications

Presentation Overview: ! Risk Assessment for Microbial Contamination of Non-Sterile Pharmaceutical Products ! Setting Microbial Limits Specifications ! Establishing Objectionable Microorganisms Requirements for Different Dosage Forms ! Implementing Reduced Testing Programs
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Risk Assessment for Microbial Contamination

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Is there a hierarchy for risk of microbial contaminations based on dosage form, route of administration, formulation, manufacturing processes, product packaging, storage conditions, and drug recipient health status?
Risk Assessment
The descending order of risk for microbial infection of the drug product recipient based on route of administration is: ! Parenteral and intrathecal products (sterile products) ! Ophthalmic products (sterile products) ! Inhalation solutions (sterile products) ! Aerosol inhalants ! Nasal sprays ! Otics ! Vaginal suppositories, ointments, and creams ! Transdermal patches
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Risk Assessment
The descending order of risk for microbial infection (continued): ! Topical lotions, ointments and creams
! Rectal suppositories, ointments, and creams
! ! ! !
Oral liquids (aqueous) Oral liquids (non-aqueous) Liquid-filled capsules Oral tablets and powder-filled capsules
Factors Influencing Potential for Microbial Infection

! ! ! ! ! ! !
Pathogenicity of the organism Invasiveness of the organism Virulence of the organism Inoculum size Route of introduction into the body Frequency of administration Host resistance
Risk Assessment
Other major considerations in terms of susceptibility of a non-sterile pharmaceutical product to microbial contamination includes: ! Whether the active ingredient has inherent antimicrobial activity ! Whether the formulation supports microbial growth ! The water activity of the product ! The manufacturing process ! Whether it is a multiple or single-use product
The Water Activity, Use Profile, Potential for Microbial Growth, Invasiveness of the Route of Administration and Potential for Recipient Infection of the Major Pharmaceutical Dosage Forms
Dosage Form Water Activity (Aw) Single or multiple use Potential to support microbial growth Moderate to high Invasiveness of the route of administratio n Very high Potential for patient infection
Parenteral Products
0.99
Pre-filled syringe (single use) Vials (multiple use) Form-fill-seal (single use)
Low
Ophthalmic products
Liquids and creams (0.97) ointments (0.55) 0.99
Moderate to high
High
Low
Inhalation solutions
Multiple
High
High
High
The Water Activity, Use Profile, Potential for Microbial Growth, Invasiveness of the Route of Administration and Potential for Recipient Infection of the Major Pharmaceutical Dosage Forms
Dosage Form
Water Activity (Aw)
Single or multiple use
Potential to support microbial growth Low
Invasiveness of the route of administratio n High
Potential for patient infection Low
Aerosol Inhalant Nasal Spray Vaginal Suppositories Topicals Oral Liquids Liquid-filled Capsule Tablets and Capsules
0.25
Multiple
0.99 0.30 0.97(lotion) to 0.6 (0intment) 0.90 0.3 0.3
Multiple Single Multiple Multiple Single Single
High Low Moderate to High Moderate to High Low Low
Moderate Moderate Low to Moderate Low Low Low
Moderate Low to Moderate Low to Moderate Low to Moderate Low Low 9
Microbial Standard Setting

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The U.S. Pharmacopeial Convention Inc. is an independent standards organization, empowered by the U.S. Federal Food, Drug, and Cosmetic Act as the official drug standardsetting organization for drug products. The USP-NF contains legally recognized standards of identity, strength, quality, purity, packaging and labeling for more than 3,500 drugs. Individual drugs may have a USP/NF monograph which may or may not contain Microbial Limits requirements.

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The referee microbial testing methods for pharmaceutical ingredients are defined in USP Chapter <61> Microbial Limit Tests. The microbial enumeration tests are the Total Aerobic Microbial Count (TAMC) and the Total Combined Yeast and Mold Count (TCYMC). Also pharmaceutical products are screened using the USP Absence of Specified Microorganisms test appropriate for the dosage form.

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The draft USP Informational Chapter <1111> Microbiological Quality of Non-sterile Pharmaceutical Products in Pharmacopeial Forum 29 (5) 1733-1735 September-October 2003 and at Stage 5b in the international harmonization process, at the time of this presentation, contains the acceptance criteria for the microbial quality of non-sterile dosage forms and pharmaceutical excipients.
Microbial Limit requirements for pharmaceutical dosage forms

Dosage Form TAMC cfu/g or mL 1000 TCYMC cfu/g or mL 100 Absence of Specified Microorganism Requirement (1 g or mL) E. coli; Salmonella spp. (Containing unprocessed animal, plant or mineral ingredients)
Tablets and capsules
Oral Liquids Rectal products Vaginal products Transdermal patches (per patch) Inhalants
1000 1000 1000 100 100
10 E. coli 10 10 10 10
S. aureus; P. aeruginosa; C. albicans S. aureus; P. aeruginosa S. aureus; P. aeruginosa Bile-tolerant Gram-negative bacteria S. aureus; P. aeruginosa Bile-tolerant Gram-negative bacteria 13
Topical and nasal products
100
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Objectionable Organisms
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It is a cGMP requirement to exclude objectionable microorganisms from non-sterile pharmaceutical products. The pertinent sections are 21 CFR 211.113 Control of microbiological contamination (a) Appropriate written procedures designed to prevent objectionable microorganisms in drug products not required to be sterile shall be established and followed.
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21 CFR 211.165 Testing and release for distribution (b) There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms that may cause infection when given by the route of administration of the drug product and/or cause physicochemical deterioration to the product. The objectionable microorganisms will vary by dosage form.
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How should a firm establish the objectionable organisms for each drug products? These are limited to organisms that can be isolated using the compendial methods, cause infection in the recipients of the drug product when given by the route of administration of the dosage form or deteriorate the product by proliferating within the product. Also the medical status of the target patient population may be considered.
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The objectionable microorganisms will vary by dosage form. For example, objectionable organisms for a topical drug product may be the pathogens P. aeruginosa, S. aureus, and S. pyogenes. In addition, P. fluorescens, B. cepacia and S. marcescens that may overcome the preservative system may also be considered objectionable.
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Objectionable Organism Policies

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Companies should develop scientificallyjustified guidelines listing objectionable microorganisms for each pharmaceutical dosage form For example, if the TAMC exceeds the alert or action level then representative colonies would be identified and if an objectionable organisms is found then the lot would be rejected This approach would result in consistent decision making and shorten the release decision making
Patient Populations
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Should separate Microbial Limit specifications should be developed for drug products administrated to immuno-compromised individuals?
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Patient Populations
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In a few cases, the target population of a drug product is clearly known to be immunologically compromised. However, in the majority of cases medications can be taken by patients ranging in age from newborns to the elderly and from those in excellent health to those in poor health and seriously compromised. Given this situation, the author believes that a single specification for each drug dosage form is preferable to multiple specifications.
Patient Populations
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For example, what should be the Microbial Limits requirements of an immunosuppressant drug used for organ transplant? The USP-recommended requirements for an oral tablet are TAMC NMT 1000 cfu/g; TCYMC NMT 100 cfu/g; absence of E. coli in 10 g. Are these counts too high? What should be the designated objectionable microorganisms?
Organ Transplant Microbial Infections

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Conventional Noscomial Infection, 0 -1 months: Wound infections, catheter-related infection and pneumonia. Candida spp. Opportunistic Infections, 1 -6 months: As above plus Nocardia, Listeria and tuberculosis. Aspergillus and Cryptococcus Community-Acquired or Persistent Infections, >6 months: Listeria and tuberculosis. Cryptococcus spp.
Organ Transplant Microbial Infections

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In general, the presenter believes that transplant patients will be more likely to obtain infections through invasive procedures, their food , and the general environment than from pharmaceutical drug products.
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General Risk Assessment

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Clearly, injectable products because of their invasiveness must be sterile while tablets and capsules, in the absence of food borne pathogens, may contain a moderate bioburden without impacting the recipient of the drug product. Contamination, with high numbers of microorganisms, will impact nasal sprays, vaginal products, topical products, and oral liquids more than aerosol inhalants, tablets and capsules because their high water activity will support microbial growth.
Product Recalls
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What does the product recall history tell us about the risk of microbial contamination? A good summary may be found annually in March issue of The Gold Sheet The number of recalls for non-sterile pharmaceutical products for microbial contamination has been stable at an average of 6 recalls annually for the past 10 years. What products are recalled and which microorganisms are implicated?
Product Recalls
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The emphasis on waterborne gramnegative bacteria of the species Burkholderia (Pseudomonas) cepacia (9 recalls), Pseudomonas putida (3 recalls), Pseudomonas aeruginosa (3 recalls), Pseudomonas spp. (2 recalls) Ralstonia (Pseudomonas) pickettii (1 recall) is notable (40% 0f all recalls) and reflects the concern for bacteria capable for growth in liquid oral dosage forms overwhelming the preservative system.
Product Recalls
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Analysis of the underlying probable cause by the presenter suggest that they are 1) microbial contamination of water for pharmaceutical purposes, 2) the use of pharmaceutical ingredients with higher microbial counts, 3) failures of preservative systems to protect liquid products, 4) microbial contamination during the manufacturing process, and 5) improper storage of the products during their shelf life.
Factors Influencing the Potential for Microbial Contamination

! ! ! ! ! ! ! ! !
Product formulation Pharmaceutical ingredients Preservative systems Manufacturing processes Equipment cleaning Environmental controls Packaging - multiple versus single use Water activity Potential for misuse by customer
Manufacturing Processes and Microbial Contamination

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Manufacturing steps with a potential to increase the product bioburden of a compressed tablet include equipment cleaning, milling, wet granulation, static air drying, and film coating. Steps will a potential to decrease the bioburden include fluid bed drying and compression.
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Microbial Limit Specifications

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Is it necessary to include Microbial Limit specifications in the regulatory filings for all non-sterile pharmaceutical dosage forms?
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Guidance for setting Microbial Limits specifications for non-sterile drug products may be found in: ! The ICH Harmonized Tripartite Guideline Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances Q6A Step 4 October 6 1999- Decision Tree #8: Microbiological Attributes of Non-Sterile Drug Products

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Draft Guidance for Industry Drug Product Chemistry, Manufacturing, and Controls (CMC) Information January 2003 references Decision Trees # 6 and #8 in ICH Q6a Specification for the rationale for not performing microbial limits testing for nonsterile drug substances and excipients, and non-sterile drug products
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The draft FDA guidance document states it is advisable to perform microbial limit testing of a non-sterile product unless its components are tested before manufacture and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination or proliferation. A proposal to exclude microbial limit testing from the specification should be scientifically justified.

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The guidance document specifically states that Periodic Quality Indicator Tests (PQIT) designated and justified in a regulatory filing can include microbiological testing of solid oral dosage forms. This can be the basis of a reduced testing program
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Applications may propose a Sunset Test Protocol with a commitment to drop a specification such as Microbial Limits after an agreed number of production batches, e.g. 10 to 20 lots, are tested and meet the test criteria. Also, a proposal to drop a test, based on historical data, may be submitted postapproval in a prior approval supplement.

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The proposal should include: 1) the reason why the sunset provision is proposed, 2) the number of consecutive batches that will be tested, 3) the criteria for dropping the test, and 4) the post-approval reporting mechanism for notifying CDER of the test results when the criteria have been met.
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Opportunities
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When justified by formulation, manufacturing processes and testing histories, lot-by-lot Microbial Limit testing of liquid- and powder-filled capsules, compressed tablets, rectal suppositories, topical ointments, aerosol inhalants and lip balms may be replaced by periodic testing or the elimination of all testing. The microbial resistance of other dosage forms may be increased by decreasing the water activity of the formulations.
Water Activity to Prevent Microbial Contamination

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Enigl & Sorrells (1997) Water Activity and Self-Preserving Formulas, In: PreservativeFree and Self-Preserving Cosmetics and Drugs: Principles and Practice, J.J. Kabara & D.S. Orth, 1997 There is no technical reason why self-preserving formulations, i.e. using low water activity, cannot be used for cosmetics, OTC drugs & pharmaceuticals
Water Activity to Prevent Microbial Contamination

USP draft chapter <1111> Microbiological Attributes of Non-sterile Pharmaceutical Products The microbial quality of non-aqueous or dry dosage forms that do not support microbial growth because of low water activity will primarily be a function of those microorganisms introduced through ingredients or during processing.
Water Activity and Microbial Limits Testing

Friedel and Cundell (1998) Since the water activity requirements for different gram-reactive bacteria, bacterial spores, yeast & molds are well described in the literature, the appropriate microbial testing program for products of differing water activities can established.
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Why is Aw Important for Microbial Growth?

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Microorganisms need available water within a product to proliferate. Water activity and not water content is a better measure of the free water, in contrast to bound water, that microbial cells require for metabolic activity and osmotic regulation.
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Effects of Reduced Aw on Microbial Growth

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Longer lag phase, slower growth rate, and lower numbers of organisms in the stationary phase Reduced microbial toxin production Below a specified Aw for an organism, microbial growth will not occur and vegetative microorganism will die-off However, the resistance of microorganisms to heat increases with decreasing Aw
Microbial Growth Limits and Water Activity

Aw 0.91 0.88 0.86 0.80 0.70 0.60 Microbial Growth Limit Bacterial pathogens with the exception of S. aureus Yeast (Practical Limit) S. aureus Production of Mycotoxins Molds (Practical Limit) Absolute limit for all microbial growth
Role of Water Activity in Drug Formulation

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Formulations can be developed to lower water activity to make products especially inhalants, nasal sprays, topical products and oral liquids less susceptible to microbial contamination and to optimize preservative systems.
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Water Activity of Dosage Forms

High Risk ! Aw >0.95: Nasal sprays, inhalant solutions, rectal creams, liquid antacids, and eye drops. ! Aw >0.90: Oral liquids, and topical lotions ! Aw >0.85: Cough syrups, oral canker sore gels, and oral analgesic suspensions
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Water Activity of Dosage Forms

Low Risk ! Aw >0.55: Ophthalmic ointments, and topical ointments ! Aw > 0.45: Liquid-filled capsules ! Aw >0.40: Liquid-centered cough drops ! Aw >0.30: Lip balm, powder-filled capsules, compressed tablets, vaginal suppositories, rectal suppositories, and multiple vitamin tablets ! Aw < 0. 20 Metered dose aerosol and powder inhalants
Conclusions
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The risk of microbial contamination varies widely amongst non-sterile pharmaceutical dosage forms. With low risk dosage forms the elimination routine microbial limit testing may be justified A knowledge of the risk can be used to reduce the incidence of microbial contamination
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Risk Assessment and Setting Microbial Limits Specifications for Non-Sterile Pharmaceutical and Over-The-Counter Drug Products

Risk Assessment and Setting Microbial Limits Specifications

Risk Assessment for Microbial Contamination

Factors Influencing Potential for Microbial Infection

Liquids and creams (0.97) ointments (0.55) 0.99

Water Activity (Aw)

Single or multiple use

Potential to support microbial growth Low

Invasiveness of the route of administratio n High

Potential for patient infection Low

0.99 0.30 0.97(lotion) to 0.6 (0intment) 0.90 0.3 0.3

Multiple Single Multiple Multiple Single Single

High Low Moderate to High Moderate to High Low Low

Moderate Moderate Low to Moderate Low Low Low

Moderate Low to Moderate Low to Moderate Low to Moderate Low Low 9

Microbial Standard Setting

Microbial Standard Setting

Microbial Standard Setting

Microbial Limit requirements for pharmaceutical dosage forms

Tablets and capsules

1000 1000 1000 100 100

Topical and nasal products

Objectionable Organism Policies

Organ Transplant Microbial Infections

Organ Transplant Microbial Infections

General Risk Assessment

Factors Influencing the Potential for Microbial Contamination

Manufacturing Processes and Microbial Contamination

Microbial Limit Specifications

Microbial Limit Specifications

Microbial Limit Specifications

Microbial Limit Specifications

Microbial Limit Specifications

Microbial Limit Specifications

Microbial Limit Specifications

Water Activity to Prevent Microbial Contamination

Water Activity to Prevent Microbial Contamination

Water Activity and Microbial Limits Testing

Why is Aw Important for Microbial Growth?

Effects of Reduced Aw on Microbial Growth

Microbial Growth Limits and Water Activity

Role of Water Activity in Drug Formulation

Water Activity of Dosage Forms

Water Activity of Dosage Forms

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