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Michael J. Miller, Ph.D.

Rapid Microbiological Methods:

Overcoming the "Barriers”

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© Michael J. Miller, Ph.D. 2022

• In reality, there are NO barriers!

• However, there are perceptions that rapid methods 

cannot be validated or implemented, due to . . .

§ Lack of knowledge (e.g., QA/QC, manufacturing, 

regulatory)

§ Not being visible or important to senior management

§ No commitment to change, unless forced to do so

• Let’s discuss the most prevalent “perceived barriers”

Barriers to Rapid Microbiological Methods (RMM)

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© Michael J. Miller, Ph.D. 2022

• Yes, they are.

• FDA, EMA, TGA, PMDA, others around the 

world

• Many validation and implementation approvals

• Regulatory policy changes encourage RMM use, 

especially for ATMPs in the US and EU

“RMMs are not accepted by regulatory authorities.”

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© Michael J. Miller, Ph.D. 2022

• Yes, they have.

• Currently, RMMs are alternatives to compendial 

testing and usually require regulatory approvals 

• Numerous authorities have approved RMMs to 

replace compendial sterility and bioburden tests

• Firms have provided robust validation protocols 

and data to support equivalence/non-inferiority

“RMMs cannot replace compendial assays.” 

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© Michael J. Miller, Ph.D. 2022

• Of course, there is!

• PDA Technical Report #33, Evaluation, Validation 

and Implementation of New Microbiological Testing 

Methods (new revision in the works)

• USP <1223>, Validation of alternative microbiological 

methods

• Ph. Eur. 5.1.6, Alternative methods for control of 

microbiological quality

“There is no guidance on validating RMMs.”

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© Michael J. Miller, Ph.D. 2022

• Yes, they can; some large and some small.

• Return on investment (ROI) should not be the most 

important factor in implementing a RMM

§ e.g., faster results, medical need, short shelf-life of product

• Perform a ROI calculation to determine if the cost 

savings outweigh the initial investment (e.g., capital 

expense, validation)

“RMMs do not provide a return on investment.”

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© Michael J. Miller, Ph.D. 2022

• Yes, you can, when supported with data

• e.g., correlate existing CFU data with an 

alternative signal (e.g., fluorescent count) 

• Revision to Annex 1 specifically allows this

§ “Manufacture of Sterile Medicinal Products” of the EU 

Guideline for good manufacturing practice for drug 

products and drug substances

“You cannot change acceptance levels or the signal (cfu).” 

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© Michael J. Miller, Ph.D. 2022

• Quality Control section:

• For products with short shelf life, the environmental data for 

the time of manufacture may not be available; in these cases, 

the certification should include a review of the most recent 

available data. Manufacturers of these products should 

consider the use of rapid monitoring systems.

• Where rapid and automated microbial methods are used for 

general manufacturing purposes, these methods should be 

validated for the product(s) or processes concerned.

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Revision to EU Annex 1

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© Michael J. Miller, Ph.D. 2022 8

Revision to Annex 1: Limits During Manufacturing

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© Michael J. Miller, Ph.D. 2022

• Advanced therapy medicinal products

§ ATMPs, cell and gene therapies

• COVID-19 vaccines

• Sterile compounded products

• PET drugs

• Current regulatory policy encourage RMMs . . .

The Need for Rapid Methods

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© Michael J. Miller, Ph.D. 2022

• The compendial sterility test may not be suitable for 

products with a limited shelf life or immediate need

• Examples of alternative methods include:

§ Rapid sterility, mycoplasma (including PCR-based tests) 

and endotoxin tests

• For these non-compendial tests we recommend that 

you qualify/validate them to ensure they are fit for 

their intended use

2020 FDA Final Guidance on Gene Therapy for INDs

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© Michael J. Miller, Ph.D. 2022

• The sterility test may not be appropriate due to 

the scarcity of materials available, short shelf-life 

or medical need

• Validated RMMs may be considered when 

method suitability for the product has been 

demonstrated

2018 EU Guidelines for ATMP

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© Michael J. Miller, Ph.D. 2022

• Discusses limitations of the compendial sterility test 

(shelf-life and availability of product)

• Can use automated growth-based methods or 

alternative methods

• Allows sterility testing of 1% of the total batch

• If testing the final product is not possible, surrogate 

samples, such as liquids last in contact with cells 

being processed, may be analyzed

Ph. Eur. 2.6.27, Microbiological Examination of Cell-Based Preparations

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© Michael J. Miller, Ph.D. 2022

• Provides guidance when the compendial sterility 

test is unsuitable for product release due to short 

shelf-life or immediate need

• Allows for a 1% total batch size sampling plan

• Also refers to CFR 610.12, where one could test 

an in-process sample when it is not possible to 

test the finished product

USP <1071>, Rapid Microbial Tests for Release of Sterile Short-Life 

Products: A Risk-Based Approach

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© Michael J. Miller, Ph.D. 2022

• Understand available RMM technologies

• Match a RMM technology with your user 

requirements

§ e.g., time to result, level of sensitivity, types of organisms 

to be detected

• Develop and execute the validation plan

§ Includes statistical analyses of the data

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A Strategy for Implementation

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© Michael J. Miller, Ph.D. 2022

Example: Validation of Rapid Sterility Tests

• Specificity

§ Relevant panel of microorganisms; e.g., slow growers and 

stressed organisms for growth-based systems

• Limit of detection

§ e.g., single cell level

• Method suitability

§ No false positives or false negatives with the test sample

• Equivalence/non-inferiority to compendial sterility test

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© Michael J. Miller, Ph.D. 2022

Summary

• Regulatory policies and compendial chapters have been 

revised to meet the needs of rapid testing requirements

§ New medicines with an immediate medical need

§ Short shelf-life

§ Challenges with conventional, compendial assays

• Many companies have utilized these changes to validate 

RMMs and gain regulatory approval for routine use

• There are NO barriers! 

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© Michael J. Miller, Ph.D. 2022

• rapidmicromethods.com

• Validation strategies

• Regulatory overviews

• Technology tutorials

• Extensive reference list

• Product comparison matrix

• Current news articles

For More Info on Rapid Methods

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© Michael J. Miller, Ph.D. 2022

Thank you!

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• microbiologyconsultants.com

• mjm@microbiologyconsultants.com

• LinkedIn: drmichaelmiller

• +1 72743 72743 (RAPID-RAPID)

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