Update on the

PDA Discussion Forum on

Rapid Microbiology Methods

21 September 2009
Frankfurt, Germany

(c) Moldenhauer
Photo courtesy of Texwipe
2009

Agenda
Implementing Rapid Microbiology Methods: Experiences and
Expectations from Regulatory Authorities
Riccardo Luigetti, EMEA, Reviewer and on the PAT Team
Gustavo Marco, MHRA, Reviewer
Paul Hargreaves, MHRA Inspectorate

Industry Perspective: What Needs to be Done to Simplify

Implementation? These presentations will not be addressed due to
time constraints
Gilberto Dalmaso, A&L Co
Marco Gut, Applied Biosystems

Questions to the Regulators

(c) Moldenhauer 2009 2
 European Medicines Agency

Regulatory Framework for Rapid

Microbiology Methods – an EMEA
view

Riccardo Luigetti – EMEA

Frankfurt 21 September 2009

The views presented here are those of the author and should not be understood or quoted as being made on
behalf of the EMEA

3
Photo courtesy of Texwipe

Marketing Authorization Procedures

in the EU
• National Procedure
• Mutual Recognition Procedure (MRP)
• Decentralised Procedure (DCP)
• Centralised Procedure (CP)

4
Ph. Eur. chapter 5.1.6 (1)

• Ph. Eur. chapter 5.1.6 Alternative methods

for control of microbiological quality
ƒ Publication in Supplement 5.5 in January 2006
for information
ƒ Implementation 1 July 2006

Variations Regulatons: The revision project

• Current regulations considered considerable burden

for both authorities and industry
• Objectives:
ƒ Clearer, simpler, more flexible, reduce administrative
burden, adapt to ICH concepts, further harmonisation,
without compromising human and animal health
• Scope
ƒ Harmonisation (common set of rules regardless of
authorisation route)
ƒ Content of the regulations
6
Variations Regulatons revision: Status

• New Regulation EC No 1234/2008 published on 18 Dec 08

in the EU Official Journal
http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:33
4:0007:0024:EN:PDF
• Regulation will apply from 1 January 2010 (Except Art 5
from 1 January 2009) to centralised and mutual recognition
products only
• Proposal + impact assessment presented by the European
Commission for applicability of the revised regulation also
to nationally authorised products
7

Implementation preparation

• External consultation on Commission

guideline on classification of variations
ended in July 2009; comments received
currently under evaluation
• Publication by the end of 2009

8
Main changes (1)
• Changes inside the Design Space are not
considered a variation
• Type IA variations to be notified by 12 months
after implementation (“do and tell”, similar to
FDA’s CBE process) e.g. through annual reports
• Unlisted variations type IB by default
• Possibility to request an EMEA/CMDh
recommendation on unclassified variations

Main changes (2)

• Grouping of variations
ƒ Group of variations for the same MA to be submitted and
assessed at the same time
• Work sharing
ƒ Same variation or group of variations which applies to
different MAs of the same MAH to be submitted at the
same time (common assessment)
• The possibility of having pre-authorised post
approval change management plans and protocols
and their applicability is currently under discussion
10
 Opportunities for scientific dialogue with regulators
EMEA Scientific Advice (1)

• The EMEA Scientific Advice (SA) procedure can be requested for all medicinal
products irrespective of eligibility for the centralised procedure or not
• The Scientific Advice procedure is used for scientific issues concerning quality,
non-clinical and clinical aspects relating to the proposed future development of
the medicinal product
• Scientific Advice focuses on development strategies rather than pre-evaluation
of data to support a MA application
• Scientific Advice received from the EMEA is applicable throughout the EU
• A SA consultation does not preclude the possibility of consultations with
national competent authorities
• Results in a written document from the EMEA Working Party
• SA is not legally binding with regard to any future marketing authorisation
application of the product concerned
• There are fees associated with this service

11

EMEA Scientific Advice (2)

• EMEA SA is subject to a fee, reductions are granted to small and medium
enterprises (SMEs)
• EMEA SA is subject to a fee, reductions are granted to small and medium
enterprises (SMEs)
• EMEA has established a Scientific Advice Working Party
• It is possible to request a parallel scientific advice with FDA; this is not intended
to provide a combined or joint advice from the two regulatory authorities, but is
an opportunity for increased dialogue, each agency will provide their
independent advice to the applicant, according to their usual procedures and
timelines. The advices may still differ after the discussion
• The requesting company can be invited for a discussion meeting at EMEA
• Companies may ask for clarification after a SA letter has been received and/or a
"follow-up" to the initial request for Scientific Advice

12
EU PAT Team
• A forum for dialogue and understanding between Quality
and Biologics Working Parties and GMDP Inspectors
Working Group to prepare a harmonised approach in Europe
on assessment of applications and inspections of
products/systems/facilities for Process Analytical
Technology, including Quality by Design principles and
manufacturing science in the context of PAT
• Companies are regularly invited to PAT Team meetings in
order to present and discuss their development strategies and
the techniques they intend to use
• If RMMs are used in a QbD/PAT context, dialogue with the
PAT Team is a possibility
13

Conclusions (1)
• The regulatory system in the EU is complex, it is
advisable to involve regulatory affairs experts if it
is planned to introduce a RMM method
• The Ph. Eur. chapter 5.1.6 Alternative methods for
control of microbiological quality provides the
regulatory basis for the introduction of RMMs in
the EU; the introduction of such methods are in
general supported by the regulatory competent
authorities in the EU

14
Conclusions (2)

• The implementation of the revision of the

variations regulation will simplify the
introduction of changes to the MA
• The SA procedure provides for scientific
dialogue with authorities on any scientific
aspects related to medicinal products; the
outcome of the SA is official, even if not
legally binding 15

Development / Scientific Advise

How to compare RMMs and traditional methods
• Please give a judgement on growth based RMMs and where
their usages were beneficial.
• Lengthy discussion by Dr. Hargreaves on the inappropriateness of
growth based methods for sterility testing, unless you have at least a
10-14 day incubation period. (needed for a single damaged cell to
grow to 103 level needed for detection)
Development / Scientific Advise
• Some RMMs are based on fully different technologies than
the actual growth based referee test. How to compare the
results needs to be addressed in development. What
possibilities are offered to discuss the strategy prior to
perform the experiments with Competent Authorities or
EMEA?
• Use of the Scientific Advise Procedure

Development / Scientific Advise

How to compare RMMs and traditional methods
• If a destructive sterility test method was chosen, for instance
the ChemScan RDI, with whom would it be possible to
discuss the ID strategy? (With this method it is not possible
to ID the exact same sample in case of a positive sterility
test)
• Use of the Scientific Advise Procedure
Development / Scientific Advise
How to compare RMMs and traditional methods
• ID is not always possible with available RMMs. How to
address this situation in a development programme?
• The key to this one is adequate explanation in the Quality Expert
Summary Report which should include a risk-benefit analysis of
why this is or is not an issue.
• Other questions could be addressed in the Scientific Advice
Procedure

Development / Scientific Advise

How to compare RMMs and traditional methods
• Please advice on where you would actually see the best contribution /
value for pharmaceutical customers to implement rapid technologies.
ƒ Sterile/non sterile applications
ƒ Raw material
ƒ in-process controls, final product controls, environmental
monitoring.
ƒ Answer: Dr. Hargreaves: Where you can gain information on your
process
Development / Scientific Advise
How to compare RMMs and traditional methods
• Sample sizes might not be corresponding to the one of
traditional methods. What possibility exist to discuss the
rational of the sample size with the Authorities in advance?
• Use of the Scientific Advice Procedure

Development / Scientific Advise

How to compare RMMs and traditional methods
• For testing performed by customers for comparability
(traditional method compared to a new RMM) how much
data in terms of replicates is needed to be statistically
significant? For example, when qualifying a new RMM for
environmental monitoring in clean environments (e.g., ISO
5) or for sterility or bioburden testing where the counts are
historically zero.
• It may be necessary to do more replicates to meet your need for
statistics.
• You need to actively involve your statisticians in the process
Development / Scientific Advise
How to compare RMMs and traditional methods
• How is it possible to demonstrate equivalence or superiority
for new culture-independent RMMs when the golden
standard culture-techniques are heavily biased?
• The standard methods have been used for many years. You need to
show that you are equivalent, or better to these methods. The
regulators recognize weaknesses associated with these methods.

Development / Scientific Advise

How to compare RMMs and traditional methods
• What guidance does EMEA have on determining
comparability, especially, when for the traditional methods
no validation data of today's standard exist.
• Similar to the previous question, the regulators feel that the long use
of the methods in the EP “validate” them for use.
• You need to show that you are equivalent or better to these methods.
• They recognize that weaknesses exist in the methods.
Development / Scientific Advise
How to compare RMMs and traditional methods
• The development of a “comparative protocol” that demon-
strates equivalency is accepted by the FDA as an approach
to the validation of an RMM. What is the intention of
EMEA to structure the dialogue with potential applicants?
• There are no current plans to legislate a comparability protocol for
Europe.
• You could use the Scientific Advice Procedure to discuss your plans
with the regulators and get information from the Working Party,
however, this information is not legally binding.

Development / Scientific Advise

Communication with EMEA / Competent Authorities
• Would the EMEA PAT team and/or member states welcome
presentations from RMM vendors and/or pharma companies
to introduce new technologies? Who can be contacted to
arrange these presentations?
• They do not really want this type of presentation. They prefer that
the technology be presented in peer reviewed journals, like PDA’s.
They feel that many “sales oriented” claims are not valid.
Development / Scientific Advise
Communication with EMEA / Competent Authorities
• Who is the identified EMEA PAT team individual(s) that
RMM vendors and end-users of RMMs can contact with
questions? Who at EMEA would be the RMM contacts, that
are available to review the validation strategy approach and
methodology before starting with any studies?
• The PAT Team would only review if it is related to QbD. You can
contact Dr. Luigetti for this process.
• Basically, the PAT does not automatically include review of rapid
microbiological methods.

Development / Scientific Advise

Communication with EMEA / Competent Authorities
• How to get scientific advice and keep the risk for a failure
low? How could pharmaceutical companies get in touch
with the regulatory agencies before full validation and
implementation of RMM?
• Use of the scientific advice procedure
Development / Scientific Advise
Communication with EMEA / Competent Authorities
• What guidelines exist regarding comparability studies when
we want to change to a RMM?
• Recommended submission of the variation, provided it is to collect
data that is in the dossier.
If not in the dossier, recommended discussing with the local
inspectorate

Development / Scientific Advise

Communication with EMEA / Competent Authorities
• How and when to contact European regulatory bodies to
discuss the strategy chosen for changing a filed method?
• The Scientific Advice Procedure is the only available method. As
soon as possible.
Development / Scientific Advise
Communication with EMEA / Competent Authorities
• To what types of RMMs feedback to the validation plan is
given prior to running the validation and performing the
submission (e.g., meetings with regulators, written
proposals)? Does this include Rapid Mycoplasma testing?
• Use of the scientific advice procedure or meet with the local
inspectorate. Mycoplasma testing is included.

Development / Scientific Advise

Communication with EMEA / Competent Authorities
• Without establishing a “comparability protocol”-type of
agreement upfront the risk that a RMM is not approved due
to scientific dispute is high. What is a way out of this that
EMEA or Competent Authorities can propose?
• Use of the Scientific Advice procedure or meet with the local
inspectorate.
Development / Scientific Advise
Communication with EMEA / Competent Authorities
• How are RMMs seen in the the QbD strategy, especially
within the Control Strategy? As all agree RMM can make
make medicines safer, what programs are in place to
prioritize their review and how to apply to participate in
those?
• There are no provisions for prioritized review of RMMs or PAT
submissions.

Validation

Role of supplier
• Is there a way RMM manufacturers can submit equipment
validation tests and results to EMEA to be referenced by
pharma companies similar to FDA’s Type V Drug Master
File? If not, is there a plan to develop something like the
Drug Master File?
• The option of submitting the information was discussed.
• They do not currently plan for a DMF option.
• MHRA does allow the vendor to confidentially submit a package for
review with the submission.
 Validation

Role of supplier
• Can validation information generated by the RMM
manufacturer be used by pharma companies in lieu of
repeating the same type of testing, for example, during
standardized accuracy, precision and similar validation
studies?
• There was not an issue with “who” does the testing, but the pharma
company is responsible for the testing performed, must be able to
explain the testing, and is liable for the quality of the testing. They
should also have copies of the testing data either at their site or in
their submission.

Validation

Role of supplier
• How should this information be shared with the pharma
companies (e.g., in a briefing package, with what content?)
so that the companies can then provide to EMEA for
review? If there was this option, what information and
documentation should come from the supplier and what
should be done by the pharmaceutical company?
• This again is an issue of the pharma company being responsible for
the results of the package and needing to have the data to explain
either in the submission or at the site during an inspection (depends
on the type of information)
 Validation

Role of supplier
• If the supplier was the source of some validation data, what
responsibilities would this include? For example, would the
supplier then be subject to inspection and would need to
receive a GMP certificate and if so whom to address this to
and who would inspect?
• There are no provisions in the EU regulations to allow
inspection of the vendor.
• The pharma company would be liable for all issues related to
the inspection.

Validation

Validation guidance
• As the original microbiological methods have never been
validated to the scrutiny of today's requirements, how can
comparability been shown? Would it be expected to do an
“after the fact” validation that would only prove the previous
method was never valid?
• The old methods are considered validated by the fact that they are in
the compendia.
• The Agency recognizes that there are weaknesses in some of these
methods.
 Validation

Validation guidance
• What types of RMMs have to be validated following Ph Eur
Monograph 5.1.6? For those new RMMs used to monitor
viable contamination when performing environmental
monitoring what additional testing (other than IQ, OQ) was
needed and what situations/ strains should be included
during PQ?
• The emphasis from the regulators was the use of stressed organisms
in the PQ testing.

Validation

Validation guidance
• For the use of RMMs in environmental monitoring, what
additional studies have to be conducted against other
standards for viable air samplers, such as ISO 14698-1?
What testing by the manufacturer would be appropriate to be
used by the end user?
• This answer was somewhat ambiguous since there was not clear
information on whether the ISO standard must be followed.
 Validation

Validation guidance
• Does EMEA have any preferred study design, statistical
tools or other data analysis process to compare two methods
for being equivalent?
• It’s up to your statisticians to prepare these methods.
• In case we detect better results with RMM either in terms of
sensitivity or trend analysis than the ones obtained with
conventional methods, can the RMM be justified to the
authorities based on this results?
• The authorities recognize that some new methods are superior to
older methods.

Approval

Regulatory Bodies and contact points

• Who are the RMM approval groups within EMEA (e.g.,
PAT team, reference member state)?
• The PAT team only will look at them if they are part of a QbD
approach.
• For a PAT approach, you can contact Dr. Luigutti.
 Approval

Variation / Submission scenarios

• Is a formal submission required (e.g., type variation) for new
RMMs if the intended use is for in-process control, such as
in-process bioburden or environmental monitoring?
• If the requirements are in a dossier, you need to do a submission.
• If the test being performed is not in the dossier, you should review
the new method with the appropriate local inspectorate.

Approval

Variation / Submission scenarios

• Can a single validation/submission of a RMM cover
multiple manufacturing process changes (i.e., multiple drug
products) and for multiple manufacturing facilities if the
RMM is for in-process control testing, such as
environmental monitoring or bioburden analyses? Would
there be a difference if the method being replaced was or
was not in a marketing authorisation? Are you going to
develop a similar route of change control like the FDA with
their comparability protocol?
• Multiple issues can be covered in the updated variation procedure to
be implemented in 2010.
• No plans for a comparability protocol are planned.
 Approval

Variation / Submission scenarios

• Will RMM need to be justified for each and every plant
making the same products using the same test method?
Why can't they be similar to an HPLC in terms of
registration?
• There is some level of validation that must be performed at each site
for the equipment, IQ, OQ, PQ.
• There was some discussion about method transfer, but you have to
show that the entire procedure will work at your site with your
people, equipment and reagents.

Approval

Variation / Submission scenarios

• It seems that there are questions back from the Authorities
based on little or incomplete understanding of the
technologies used. This is more an educational then a
technical issue. What plans exist to create experts within the
authorities that handle RMMs and by this accelerate the
approval process.
• The panel members felt that it was not lack of understanding on their
part, but rather poorly written submissions that did not “tell a story.”
The story should have a beginning, middle and an end.
• The regulators want to see the technologies discussed in peer
reviewed journal articles as their way of learning more about
“The Research Exemption”
• Are there any plans to implement a research
exemption program in Europe?
• A QP looks at the whole program, and should
not in good conscience overlook data that
indicates the process may be ….