„Objectionable Organisms“ Dr Robert Johnson. Objectionable Organisms Agenda: –Pharmacopieas versus regulators Regulators concerns Pharmacopieas concerns

„Objectionable Organisms“

Dr Robert Johnson

Objectionable Organisms

• Agenda:– Pharmacopieas versus regulators

• Regulators concerns• Pharmacopieas concerns

– Determining whether an organism is „objectionable“

– An approach by one company

– Future considerations for microbiological testing

Pharmacopieas versus regulators

• Pharmacopieas need to have a referee test for:– Sterility– Preservative efficacy– Antibiotic / vitamin potency– Endotoxins– Microbial limits etc....

• These are not driven by concerns over GMP but for „named“ materials to meet compliance with pharmacopeial requirements i.e.– if a material monograph requires a test for microbial limits then

Ph.Eur 2.6.12 or USP <61> is applied


• Regulators agree with the pharmacopieas where the needs are identical

• However there are situations where the regulators requirements are not covered by the pharmacopieas referee test methods

• An example of this is the CFR requirement for the „absence of objectionable organisms“........

The USA code of federal regulations (CFR 211.113 and 211.165) state..........

FDA - No Objectionable Organisms

21CFR 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

Testing for Objectionable Organisms

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

BUT….


• The original USP chapter <1111> „Microbiological attributes of non sterile pharmaceutical products“ discusses:

– The need for adherence to cGMPs to minimise product contamination during manufacture

• Control of equipment, environment, people, raw materials (natural v synthetic), storage etc

– The frequency and type (total count and / or specified Objectionables) of microbiological monitoring depending on material type and stage of production e.g. early / intermendiate stages .. Raw materials !!


• The original USP chapter <1111> „Microbiological attributes of non sterile pharmaceutical products“ discusses:

– The evaluation of the significance of the numbers and type (specified indicator and objectionable) of micro-organisms in raw materials and non sterile pharmaceutical product in terms of:

• Product use• Nature of the product• Potential hazard to the user• Further production processing

So the USP recognises the potential need to minimise, recover and evaluate objectionable organisms......

In Fact….


• The harmonised compendial methods for the microbiological quality of non sterile pharmaceutical preparations (Ph.Eur 2.6.12, 2.6.13, USP<61>, <62>) is linked , for example, to Ph.Eur chapter 5.1.4 and the new USP<1111> Chapter „Microbiological quality of pharmaceutical preparations“

• Ph.Eur 5.1.4 / USP<1111> provide guidance on the number and type of micro-organisms for non sterile dosage forms.

• It also discusses the need to evaluate the significance of other organisms recovered from the material........

Ph. Eur. 5.1.4(USP <1111>)

Ph. Eur. 5.1.4(USP <1111>)

Testing for Objectionable Organisms• So are regulators and phamacopieas

harmonised ??

– The pharmacopieal monographs may require e.g. the absence of Pseudomonas aeruginosa and provide a test !!

– However it does not meet the regulators requirements that any organism in the final product be acceptable to the product and the target patient !!!

So What are the Regulators and Pharmacopieas concerns !!!!!!

Regulators Concerns

• The Regulators will enforce the purely GMP requirement to test to e.g. Micro limits test if that is stated in the product licence / pharmacopieal monograph.

• They will also state that performing e.g.– the Micro limits test may be necessary, but.. – is not sufficient to assure the microbiological quality of

the product i.e......

• You must test for „Objectionable microorganisms“

Because…

Regulators Concerns

• The Regulators have seen a number of microbiological contamination problems with topical, nasal and inhalation drug products

• FDA state that topical preparations contaminated with Gram negative microorganisms pose a moderate to serious health threat.

• Classic example was the contamination of Povidone Iodine with Pseudomonas (Burkholderia) cepacia

Regulators Concerns

• Each company should therefore develop a microbial specification for their non sterile products, and include „objectionable microorganisms“ e.g. Burkholderia cepacia. BUT......

• Compendial methods (USP<62>, Ph.Eur 2.6.13) do not provide a method to identify Burkholderia cepacia

• Example:...................

Regulators Concerns

• Recall of Metaproterenol sulphate inhalation solution contaminated with Ps. Gladioli and Ps cepacia.

• USP product monograph did not require microbial testing and even if it had these organisms would NOT have been identified.

• The potential pulmonary infection could have been fatal particularly for:– Patients with cystic fibrosis, chronic obstructive airway disease etc

Regulators Concerns• Regulators may expect to see microbial identification

performed on microorganisms recovered on total count plates and not just restricted to the pharmacopiea „indicator organisms“

• The importance of identifying recovered microorganisms (total or specific) depends upon the product and its intended use e.g.

• Organisms recovered from a tablet may only be identified if found in large numbers whereas....

• Topicals, inhalants etc may require identification of organisms from both plate counts and enrichment tests

WHY....

Regulators Concerns• In the 1960‘s several outbreaks of disease were traced

back to contamination of non sterile pharmaceutical products primarily with Burkholderia cepacia

• Literature reports also highlighted the ability of Burkholderia cepacia to survive in various preservatives and disinfectants e.g. Benzylkonium chloride, Chlorhexidine, Povidone Iodine etc

• This led to:– 21 CFRs requiring product not to be release to the market

containing „Objectionable microorganisms“ and

– FDA dislike of Burkholderia cepacia

Pharmacopieal Concerns

• The pharmacopieas indicate that the purpose of the compendial test is not to demonstrate the absence of „objectionable organisms“

• They are designed to detect a number of indicator / potentially pathogenic micro-organisms in specific material mongraphs

• If there is a requirement for detection of specific organisms then it is up to the QC microbiologist – FDA- BAM methods, EPA, AOAC etc

So how can an organism be determined as „objectionable“ and „limits“ set ?................

Determining if an organism is “Objectionable”


See also Luis Jimenez article in PDA J. Pharm. Sci. Technol. (2007) 61 (5), 383-399.


• The FDA suggest an approach to identifying “objectionables”:

– Identify all microorganisms recovered from a product on total plate counts (bacteria and fungi)

• i.e. understand your endemic flora !!

– The QC microbiologist performs a risk assessment on the presence of the microorganism in the preparation

– The risk analysis looks at:…….


• Absolute number of organisms recovered

• Micro-organisms Characteristics

• Product Characteristics

• Potential Impact on Patients


• Absolute number of organisms recovered:

– High numbers of non-pathogenic microorganisms may not be a health hazard but may affect product efficacy, chemical and physical stability

– High numbers of microorganisms may also indicate:• Production problem• Raw material problem• Ability of the organism to live in the product

– If preserved then maybe the preservative system is not working, wrongly formulated, or even missing !!!


• Microorganisms Characteristics- Literature search

• Conduct a thorough literature search with textbooks, the internet or at the library

• Use several databases during this literature review process. Do not limit the scope or range of literature citations to just the pharmaceutical journals and books



• Target journal titles that cover e.g. food, clinical, cosmetics, environmental and basic research

• Multi-national sources. Good data is available in the global scientific community– Many abstracts and journal articles have been translated into

several languages



• During the literature search be sure to use both the new and the older name for the microorganisms of interest.

– That is …………………

Determining if an organism is “Objectionable”:

• Pseudomonas species used to be called:• (Burkholderia) Ralstonia pickettii• Burkholderia cepacia• Brevundimonas diminuta• Stenotrophomonas maltophilia• Methylobacterium mesophilicum• Sphingomonas paucimobilis• Hydrogenophaga pseudoflava• (Flavobacterium) Sphingobacterium multivorum• Nitrosomonas• Comamonas



– Determine if the organism is a known pathogen• Look at Centre for food safety and nutrition website (CFSAN),

especially the…

• FDA “bad bug book”– Evaluate the list of organisms in relation to your product

and its use to determine if “objectionable”


• Microorganisms Characteristics- Nutritional /growth requirements:

– What are suitable substrates for the organism can it spoil the product ?

• Use literature data • Identification data i.e. Biolog / Vitek substrate utilisation

– Evaluate tolerance to growth conditions e.g.• pH ranges• High salt / sugar • Water activity • Growth temperature etc……


• Product Characteristics:– Dosage form (anhydrous / aqueous) ?– What is the product water activity ?– Container / closure system designed to minimise

contamination • Designed for in use stability e.g. prevent extraneous

contamination from microbes / moisture

– Route of administration• Organisms in an oral preparation may not be tolerated in

a topical and vice versa.• Organisms recovered from Inhalants should be

evaluated carefully


• Product Characteristics:

• Other areas for review include:– Production records / environmental monitoring

trends and the microorganisms encountered.– Customer complaints / adverse events

contamination issues, what microorganisms involved / frequently found


• Potential Impact on Patients:– It is difficult to control use of a pharmaceutical

product by the patient

– As part of the microbial risk analysis the risk to the patient population if exposed to the microorganism should be evaluated e.g.

• Route of Administration (eye, nose, etc)• Method of Application• Intended Recipient (infants, immunocompromised)• Use of Immunosuppressive Drugs (corticosteroids)• Presence of Disease, Wounds, Organ Damage


BUT BE PRAGMATIC !!!

Example - Objectionable Organisms for Oral products ?

• When the microbial count is exceeded (>100 cfu/ml as per USP monograph)

• Candida spp.• Aflatoxin Producing Aspergillus spp• Bacillus cereus• Burkholderia cepacia (Pseudomonas

cepacia)• Enterobacteriaceae Family (see next slide)

Enterobacteriaceae Family- listed below (one major firm)

This list includes, but not limited to, the following microorganisms:

Arizona, Cedicea, Citrobacter, Edwardsiella Enterobacter, Erwinia, Escherichia, Hafnia, Klebsiella, Kluyvera, Morganella, Obesumbacterium, Pectobacterium, Proteus, Providencia, Rahnella, Salmonella, Serratia, Shigella, Tatumella, Xenorhabdus, and Yersinia

What have others done !!!!

Pharmaceutical Industry survery ....• 21 Pharmaceutical companies were asked:

1.Do you identify typical and atypical isolates on selective media ?1. 70% Identify typical isolates only

2. If you identify atypical isolates do you have a quantitative limit for atypicals ?1. 33% identify and evaluate all atypicals from plates and broth

2. 33% have a target limit of 100 CFU / g or ml

3. 33% identify and evaluate only if the total count is above alert limit

Is this acceptable ?

Pharmaceutical Industry survery ....• 21 Pharmaceutical companies were asked:

3. Do you routinely test solid orals microbiologically ?

1. 80% test solid orals routinely

4. What rationale do you apply to release or reject a product with an atypical isolate ?1. reject if the isolate is a human pathogen or able to survive or grow in the product

Is this logical ?

Threshold Limits for Identifying and evaluating microbial isolates

• A decision making process to determine threshold limits of when to identify and evaluate the significance of microbial isolates in non sterile oral products based upon:

– Type of dosage form• Non aqueous / Solid oral versus aqueous

– Health of intended user• Immunocompromised / paediatric versus Normal immune system

» Pathogens in paediatrics require 100cfu for infection compared to 10۸6 CFU healthy person

W. Manu-Tawiah PDA J. Pharm. Sci. Technol. (2001) 55 (3), 171-175.

BUT... Going forward Consider....

Consistency of Requirements

• Regulatory requirements have a consistent approach

• Internal approaches are often inconsistent between products

• Testing should be on a rationale basis: “more is not better”

So What Can We Do ?

ICH Q6A and QCB

• ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

• ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological products

Remember Ph Eu 5.1.4 / USP <1111>.........

Ph. Eur. 5.1.4 / USP<1111>

ICH Q6A and Q6B.......

ICH Q6A

Is the drug substance/excipient capable to support growth / viability ?

Provide supporting dataMicrobial Limits acceptance criteriaand testing may not be necessary

Is the drug substance/excipient sterile?

No further microbial limit testing or acceptance criteria necessary

yes

yes

Does production processinvolve steps that reducemicroorganisms?

Establish microbial limit acceptancecriteria as harmonized pharmacopoeial monograph

no

yes

no

to next slide to next slide

no

ICH Q6A

Does scientific evidence demonstratethat reduction steps result in lowermicroorganism levels TVC + indicatorin the drug substance/excipient?

Are monitoring microorganismindicator levels constantly belowacceptance criteria levels?

Establish microbial limit acceptance criteria asharmonized pharmacopoeial

Test lots ona skip basisTVC + indicator

Test each lotTVC + indicator

yes no

Provide supporting data Microbial limit criteria and testing may not be necessary

yesno

ICH Q6A

Thank You

Questions ?

Documents

„Objectionable Organisms“ Dr Robert Johnson. Objectionable Organisms Agenda: –Pharmacopieas versus regulators Regulators concerns Pharmacopieas concerns