Issue 76 | July 2019
Contents
Welcome
Greetings from all
at Pharmig. We
are over halfway
through the year so
roll on Christmas.
Please don’t
groan or smile
for that matter
but consider, for
a moment, whether you see the above
statement as positive or negative?
As social media fills up with references to
negative energy, or some other such guff,
I can’t help but think the way you hear or
read a statement underlines the way you
are feeling, not the person who delivered
the message. Talk of Christmas now, to
me, means an end to summer and sitting
outside and the onset of dark wet weather.
An Australian, on the other hand, sees the
reverse. On that random note I shall begin
(yes it was a convoluted way of talking
about the weather!).
The committee have drafted out the 2019
November Conference and have already
secured the majority of speakers including
Phil Rose (MHRA), Jeanne Moldenhaeur,
and the magnificent and inexplicable mind
of Willy Verstraete. More good news is I’m
not speaking! The November Conference
will also see Pharmig launch its latest
publication: A Guide to Isolators for Sterility
Testing. Pre-orders can be taken now if you
contact the Pharmig office.
This year all committee positions are up for
re-election and, as I mentioned in earlier
missives, we are looking to expand. More
detailed information on how to apply is
outlined in this newsletter. As we seek to
maintain a balance in the committee, we
are looking for industry members both
experienced and newer.
1 Design & Printed by Preview Design • www.preview-design.co.uk • info@preview-design.co.uk
David Keen
Pharmig Chair
I am also delighted to announce that
Pharmig are preparing to launch an
annual award given in recognition of an
outstanding contribution made by an
apprentice working as a microbiologist in
the pharmaceutical or healthcare industries.
More details will be available in the
October newsletter with a full launch at the
November Conference. Watch this space!
Additionally, Pharmig are now offering
Rapid Microbiological Methods Workshop
free membership to students in full
time education studying pharmaceutical 17th September, Birmingham
microbiology or related subjects with a view
to working in Industry. If you know anyone
that would benefit from this, please ask
them to contact the Pharmig office in the
first instance at info@pharmig.org.uk
Looking back over the last few months,
we have run some successful meetings
in Ireland and the team are now actively
working on module 2 of the Pharmig online
training portal.
It is not all plain sailing however: owing to
time constraints, monsoons and Committee
availability, we have now moved Pharmig
Rapid Microbiological Methods Workshop
India to October (15th/16th) and have
finalised the programme to be mailed 19th September, Dublin
out shortly. Please forward to any Indian
colleagues you may have.
Best Wishes….
Pharmig Chair
Pharmig’s 27th Annual Conference
13th & 14th November, Nottingham
 Contents
CONTENTS
Issue 75 | July 2019
01 02 03
Creating ‘smart’
microbial bionsensors:
An interview with a
Los Alamos National
Laboratory researcher
Compiled by Tim Sandle -
Pharmig Committee
New research shows that protein-based
biosensors can detect the presence of
a desired enzyme target and respond
by physically lighting up and enabling
researchers to immediately identify cells
with increased overall enzyme yield.
This involves taking advantage of the
molecular tools that naturally reside
within microbial cells. Membrane proteins
are essential components of biological
membranes and have a central role in
detection of various environmental stimuli
(Misawa et al, 2018). Scientists can use
these tools to produce fuel precursors and
bioproduct building blocks.
Engineered bacteria have been shown to
be effective due to a versatile metabolism
housed in a relatively simple cell structure.
A challenge that arises, however, is
that when bacteria are engineered for
producing a new product, it can prove
hard to locate the best performers in a
pool of bacterial cells. To overcome this
challenge researchers have leveraged
longstanding capabilities in protein design
and computational modelling of ligand
binding pockets in proteins. This enables
scientists to engineer custom biosensors
that detect intracellular concentrations of
2 CREATING ‘SMART’ MICROBIAL BIONSENSORS: AN INTERVIEW WITH A LOS ALAMOS NATIONAL LABORATORY RESEARCHER
01 Chairman’s Section
02 ‘Smart’ Microbial Sensors
03 Environmental Monitoring Meeting
04 Pharmig Ireland - Summary
04 06
a specific precursor or building block as
a target. These protein-based biosensors
for small molecules detect the presence
of the desired target and respond by
accumulating another molecule that
physically glows/lights up, enabling
scientists visualize the productivity
(McDonald et al, 2018).
Smart microbial cell
colonies “light up” when
enzyme activity is high.
Photo: Los Alamos
National Laboratory
The implications of this smart microbial
cell concept are to offer an advanced
platform for high throughput screening
for enzyme discovery, design, and
evolution. Such technology can be
particularly useful when it comes to the
production of biofuels. A biofuel is a term
applied to a fuel that is produced through
biological processes (such as agriculture)
as opposed to geological processes
(like fossil fuels). Renewable biofuels
either involve carbon fixation, such as
those that occur in plants or microalgae
through the process of photosynthesis;
or, they are created by the conversion of
plant material (Sandle, 2017).
06 Notice of AGM
07 Pharmig News Corner #44
11 Introducing Pharmig’s Social
Media Channels
07 11
One reason for considering biofuels
to address future energy needs is
due to the depletion of fossil fuels
as a result of the activities of the
petrochemical industry. A second reason
is the environmental impact that the
continued use of fossil fuels is having
on the planet, especially in relation
to the emission of greenhouse gases
(like carbon dioxide), leading to global
warming. A third factor is sustainability,
given that the raw material for many
biofuels is self-renewing (such as plant
biomass). A fourth factor is efficiency
and the better integration of biofuels
with new technologies.
The new approach, which comes from
Los Alamos National Laboratory, can be
translated to screening of metagenomic
samples, rational enzyme design, or
directed evolution of known enzymes.
The technology is adaptable to a
single enzyme, or a pathway, or global
optimization of an industrial strain. To
discover more about this technology,
Pharmig committee member Tim Sandle
spoke with researcher Dr. Ramesh Jha,
who works at the university’s
bioscience division.
Tim Sandle: How important are biofuels
in terms of addressing energy demand?
Ramesh Jha: Biofuels and commodity
chemicals made from renewable
biomass using enzymes or microbes
are considered sustainable routes and
their use circumvents dependency on
fossil fuels. Added to that, fuels and
commodity chemicals come with a high
carbon footprint while biofuels and
biocommodities from renewable sources is
an efficient recycling of carbon and leave
a low carbon footprint.
Examples of biofuels include bioethanol,
which is an alcohol made by fermentation other proteins for function (OPF) . If TF is
of carbohydrates produced in sugar
from a crop like corn. The bioethanol
can be used as a fuel for vehicles or as a
gasoline additive. A similar example is with
biodiesel. A third use with the generation to the fluorescence response in the cell.
of methanol, which is a liquid and easy to
transport. Biodiesel is made from rapeseed
oil and other plant oils. It can be used in
diesel-powered vehicles without needing
any modifications to the engine. The
fourth major biofuel is biobutanol, which
has slightly less energy than gasoline,
but can run in any car that uses gasoline
without the need for modification to
engine components.
Sandle: What are the different types of
biofuels and how do they differ in terms
of production?
Jha: Various biofuels, biocommodities and can be easily visualized using a flow
bioplastics can be ‘drop in’ or ‘functional cytometer with ultra-high throughput and
replacements’ of the existing fuels,
Pharmig Best
Practices in
Environmental
Monitoring Meeting -
Summary
Compiled by Tim Sandle -
Pharmig Committee
Back in February Pharmig’s one-day
meeting explored best practices in
environmental monitoring. The theme
of the event was on risk-assessment.
The meeting took place at the Nailcote
hotel and country club, located on the
outskirts of Birmingham.
PHARMIG BEST PRACTICES IN ENVIRONMENTAL MONITORING MEETING - SUMMARY
commodity chemicals or polymers mostly Sandle: Has industry shown an interest in
derived from petroleum sources. this development, in relation to biofuels?
Sandle: Are biofuels ‘clean’ forms of Jha: Industries are interested in testing
energy? millions of variants of microbial strains or
enzymes. Since the biosensor technology
Jha: Yes, they leave a low carbon footprint. can be easily adapted for high-throughput
screening, industries are getting interested
Sandle: How did you develop your in this technology.
protein-based biosensors?
Sandle: Are there any other practical
Jha: Our protein-based biosensors applications for this technology?
are inspired by nature, where a class
of proteins called transcription factors Jha: This technology can be applied
(TF) gets activated in the presence of a to optimization of enzymes or
molecule and regulate the production of microbial strains with applications in
biomanufacturing as well as medical
engineered to interact with an enzymatic therapeutics and environmental clean-up.
product and the OPF is a fluorescent
protein reporter, then the enzymatic References
activity in a microbial cell can be correlated McDonald, R.E. and Jha, R. K. (2018)
Lighting the way to bioproducts: Smart
microbial biosensors for conversion
Sandle: How do the biosensors identify pathway design, Los Alamos National
the desired enzyme target? Laboratory, white paper LA-UR-18-30606
at: https://permalink.lanl.gov/object/
Jha: Enzymatic activity results in a chemical tr?what=info:lanl-repo/lareport/LA-
product. This product activates the UR-18-30606
biosensor, which responds by producing
and accumulating a fluorescence Misawa,N., Osaki T. and Takeuchi,
“reporter.” The enzymatic activity is S. (2018) Membrane protein-based
visualized by the presence of light. biosensors, J R Soc Interface. 15(141):
20170952
Sandle: What are the practical benefits of
this identification? Sandle, T. (2017) Making more efficient
biofuels, Digital Journal at: http://www.
Jha: What we see, we believe. Cellular digitaljournal.com/tech-and-science/
fluorescence due to the enzymatic activity science/essential-science-making-more-
efficient-biofuels/article/490993
sensitivity. Measuring the product in a cell
is otherwise a tedious and slow step.
The day monitoring program, including the key
began with a elements to include and some of the
presentation concerns with monitoring programmes
delivered by Edel expressed by regulators. Edel expanded
Fitzmaurice on on the different types of samples that
the basis of the should be taken and how the samples
environmental and the resultant data should be
3
processed once the samples are taken
and processed in the laboratory.
This was followed by a presentation
from Tim Sandle that looked at
the concept of risk; the main types
of hazards affecting cleanroom
environments; and three case studies
of how risk assessment can be applied.
The case studies looked at Hazard
Analysis Critical Control Points (HACCP)
for selecting locations; risk filtering,
for setting monitoring frequencies;
and Failure Modes and Effects Analysis
(FMEA) to assess processing equipment,
focusing on a sterility testing isolator.
From nudge theory
to sound science,
Pharmig Ireland -
Summary
Compiled by Tim Sandle -
Pharmig Committee
From nudge theory, to the importance AbbVie (and a former medicines
of looking at the science behind
processes and procedures, the
Pharmig conference in Ireland (May)
featured some of the hottest topics
in the industry. This was followed on
from a one-day meeting focusing on
pharmaceutical water systems.
The Irish conference is one of the
highlights of the microbiology
(and Pharmig calendar). The 2019
conference was chaired by Pharmig
chair David Keen and it took place
at Portmarnock Hotel & Golf Links,
Dublin. The first presentation was
delivered by Andrew Hopkins,
who is the Director, Operation
Quality, QA Audit and Compliance,
4 FROM NUDGE THEORY TO SOUND SCIENCE, PHARMIG IRELAND - SUMMARY
Tim Sandle gave a second presentation
on incubation strategies and culture
media selection, linking these choices
to the Human Microbiome Project.
With incubation Tim considered the
appropriate types of agar to select and
the appropriate order of incubation,
offering case studies of how this can be
assessed in order to satisfy regulators.
This was followed by a presentation
from Anna Lovatt about the approach to
microbial identification and the different
technologies that are available to assess
microorganisms. Anna offered advice on
how far to take samples for identification
and how many identifications to
undertake for both sterile and non-sterile
manufacturers.
The sessions then moved to a workshop,
presented by Monica Di Mattia and
inspector at the MHRA). Hopkins
looked at the developed of sterile
product manufacture guidance and
the importance of developing a
contamination control strategy. While
the concept of a contamination control
strategy is not new, the importance
of a holistic approach to reducing all
forms of contamination is now clearly
being spelt out in regulatory guidance
documentation. In the presentation it
was emphasised that such a document
needs to be a ‘living’ document, one
that is frequently revised and added to
through a review of any changes made
to the manufacturing process.
Prabhjot Parahr (from BPL), which
explored the selecting of sample
locations based on risk assessment
in two different cleanrooms (special
environments served by filtered air
and supported by the application of
disinfectants).
This was followed by a session on data
integrity from bioinformatics specialist
Sinead Cowman, where measures to
ensure data security and data robustness
were considered, especially in relation
to electronic capture systems. The final
presentation was delivered by Edel
Fitzmaurice, which looked at microbial
data deviations and the importance of
thorough investigations that holistically
consider contamination within facilities
and which are underpinned by good root
cause analysis.
The take-home messages for the
delegates was use risk assessment, but
use it wisely, understanding its systematic
advantages and subjective weaknesses,
and to ensure that data is properly
captured, reviewed and controlled.
The second presentation of the day was
delivered by Tim Sandle (Pharmig) and
focused on the microbiological aspects
of cleaning validation. Most cleaning
validation strategies look at the ability of
a process, through the combination of
chemicals and rinses, to remove chemical
contamination. Sandle’s presentation
addressed the more overlooked area of
microbiological risk, especially the risk
that time introduces. The longer a process
is held for, especially where soil (such as
protein) is present, the greater the risk
there is of microbial proliferation and
the harder it becomes to remove these
microorganisms due to the phenomenon
of irreversible attachment where
extracellular products are excreted, and
biofilms are formed.
The third talk of the day came from
Donald C. Singer, who is a Senior
Fellow at GSK and a member of
the United States Pharmacopeia
Microbiology Expert Committee.
The presentation looked at the
latest developments related to
the committee cycle in terms of
microbiology. Here new guidance
chapters are emerging on the testing
of bacterial endotoxins (which can
cause pyrogenic reactions) and for
prions (folded strands of protein that
can cause fatal neurodegenerative
diseases). Singer also introduced the
new monograph on the testing of
the bacterium Burkholderia cepacia,
which is an objectionable organism
that most often causes pneumonia in
immunocompromised individuals with
underlying lung disease.
Interspaced between these
presentations were open forum
sessions, allowing delegates to
discuss matters of microbiological
interest (chaired by David Keen), rapid
microbiological methods (chaired
by Edel Fitzmaurice), and bacterial
endotoxin (chaired by Tim Sandle).
These sessions led into the fourth
presentation of the day, which
was delivered by consultant Tony
Mayhall, who looked at hygienic
design in pharmaceutical facilities
for manufacturers of both sterile
and non-sterile medicines. Mayhall
looked at common design pitfalls,
such as the use of ball-valves (which
hold contamination) and dead-
legs in pipework which slowdown
water velocity and affect turbulence,
leading to an increased risk of
microbial adhesion.
FROM NUDGE THEORY TO SOUND SCIENCE, PHARMIG IRELAND - SUMMARY
The fifth presentation was delivered
by Sinead Cowman of Lonza, and
looked at digital methods for handling
laboratory data so that trends can be
detected, and problems reacted to
before they become adverse events.
The importance of data security and
data integrity featured strongly in the
presentation, including a warning
about common software (such as
Microsoft Excel) which cannot be
easily validated. The emphasis was
placed on purpose designed digital
laboratory data capture and analysis
software packages.
The sixth presentation came from
Gordon Farquharson, a consultant
specializing in cleanrooms and
pharmaceutical engineering.
Farquharson looked at the importance
of understand the science that
underpins many of the activities that
take place within pharmaceuticals and
how this can sometimes be overlooked,
leading to myth emerging which are
not based on empirical evidence.
Several examples were drawn relating
to aseptic processing. Farquharson
stressed the importance of using barrier
technology to product products from
contamination, and ultimately patients.
The final presentation of the day
was from David Keen who looked at
nudge theory and how this can help
to reduce human error and encourage
good operator practices. Starting
with examples drawn from wider
society, Keen moved on to look at how
operators can contaminate healthcare
products through becoming distracted
or through boredom. Thinking about
how people move and act, and
keeping them engaged were among
the examples put forward to help to
reduce human error.
Key messages from the day,
which focused on the latest issues
being flagged by pharmaceutical
regulators like the U.S. Food and
Drug Administration (FDA), were the
need to stand back and looked at the
manufacture process overall and assess
how risks are interconnected and then
trying tackle these risks head-on rather
than simply attempting to score them
as inconsequential for even the smallest
incidences can become significant and
lead to a loss of microbial control.
The second day was around the topic
of pharmaceutical water systems andy
was chaired by Pharmig committee
member Tim Sandle. The first
presentation was delivered by Gordon
Farquharson – Managing Director,
Critical Systems Ltd. This presentation
looked at the regulations surrounds
pharmaceutical water systems and
how these differed and to a degree
did not always provide the necessary
clarity. The presentation moved on to
look at some design issues required to
keep water in a state of microbiological
control, covering aspects like the
need for water to move at a sufficient
velocity through a pipe so that the
shear forces were sufficient to prevent
microbial surface attachment and the
formation of a biofilm.
The second talk was from Andrew
Gravett, who is an Associate Director
at the Global Quality Audit Group for
AstraZeneca. Gravett drew on his years
of experience of auditing different
pharmaceutical facilities to outline
the requirements and expectations to
audit against, including how to best
structure a water system audit and to
detail the common findings.
The third presentation was from
Tim Sandle and it looked at bacterial
endotoxin risks to water systems.
Endotoxins are complexes released
from the cell walls of Gram-negative
bacteria (an organism morphological
type associated with water). In sufficient
concentration these toxins can, if they
entered the human blood system,
trigger a pyrogenic response (fever)
or endotoxic shock (sepsis). Sandle
5
described three case studies where surface, plus available nutrients (including microbiology. This included discussion
poorly designed or maintained systems a carbon source). The nutrient levels around a group of bacteria called
presented a contamination risk. need only be relatively low. However, Burkholderia cepacia complex, which
once present these communities can lead is of concern to regulators especially to
The fourth address to the meeting came to continual recontamination through the U.S. Food and Drug Administration
from David Keen, who is a contamination cells being siphoned off and biofilms, (FDA) due to the risk of causing
control consultant at the disinfectant as Keen explained, are very difficult to pneumonia in immunocompromised
supplier Ecolab. This presentation looked remove requiring a combination of individuals (especially when introduced
at a grade of pharmaceutical water high heat and chemicals (and into the air passages of a susceptible
called purified water, focusing on its sometimes the removal of an entire population, which can happen
manufacture and associated risks. Keen branch of pipework). through medicines contaminated with
spent time on the filtration process pharmaceutical grade water of poor
used to create appropriately graded microbial quality).
water, demonstrating how water flows
through numerous filtration systems The day ended with an interactive
made of sand, charcoal and gravel. exercise where the delegates were
This removes contaminants like dust, presented with a series of engineering
bacteria, chemicals and viruses. Keen, designs relating to a failing water
in a separate presentation, looked at system and attempted to solve a
biofilms and the risk these complex microbial contamination issue. The
structures pose to water systems. The This was followed by a presentation exercise brought together the main
requirements for biofilm formation reads from Edel Fitzmaurice (Quality Director, themes of the event, focusing on
like a simple recipe: a given concentration Fitzmaurice Scientific Ltd.) which the importance of good design and
of planktonic bacteria, plus water, plus a looked at ‘hot topics’ relating to water maintaining control.

Notice is hereby given of Pharmig Ltd Annual General Meeting (AGM)

The AGM will be held between 13.00 and 13.30 on Wednesday 13th November 2019 at The Nottingham Belfry Hotel.
Please note that the AGM is open to all fully paid up Pharmig Members of 2019 including Commercial/Allied companies.

The AGM will consist of four sections:

(i) 2019 Reports from present: (ii) Election of Chairman and Committee (current Committee
Chairperson (David Keen), and positions are listed below - all are up for re-election):
Treasurer / Company Secretary (Andy Martin) Name: David Keen - GlaxoSmithKline Role: Chair
Andy Martin – ABM Consulting Treasurer

Each current Committee member has significant input in all of the following roles within Pharmig:
• Technical advisors & presenters • Membership development • Social Media • Communications
• Marketing/ branding / strategy • Development of meetings, conferences, training courses, publications

Rachel Blount – Ecolab Andy Brack – PZ Cussons (stepping down at the November 2019 AGM)
Edel Fitzmaurice – Fitzmaurice Scientific Ltd Laura Guardi – Astra Zeneca
Julie Roberts – J Roberts Associates Ltd Tim Sandle – BPL
Paige Shelley – Wockhardt

All positions listed are up for election this year. Pharmig is also looking to expand the Committee in line with its current strategy
and are looking for additional industry members, both experienced and newer, to put themselves forward for consideration.

For those interested in being considered for any of the roles listed – please contact the Pharmig office in the first instance
to obtain a full job description(s). A CV with covering letter should then be sent to the Pharmig office outlining reasons of
suitability etc (for the role being applied for) no later than Friday 30th August 2019.

These will be reviewed by the current committee who will also be asked to state if they want to stand again for another
term of two years.

All nominations must be proposed and seconded by an existing Pharmig Member at the AGM

(iii) Open floor for Members to air views / pose questions (iv) Any other business

6 NOTICE IS HEREBY GIVEN OF PHARMIG LTD ANNUAL GENERAL MEETING (AGM)

 PHARMIG NEWS
CORNER #44

Compiled by Tim Sandle - Pharmig

Committee

Updated Technical Guide for In order to guide experts on the
elaborating monographs on information to be included in European
vaccines and sera for human use Pharmacopoeia (Ph. Eur.) monographs,
At its 162nd session, the European and also to harmonise the style of the
Pharmacopoeia (Ph. Eur.) Commission different monographs, a Guide for
approved a new edition of the the elaboration of monographs on
Guide for the elaboration and use radiopharmaceuticals was published
of monographs on vaccines and by the EDQM in 2010. This Guide has
immunosera for human use. now been updated to include a section
on the validation of methods used in
the analysis of radiopharmaceuticals,
reflecting the validation requirements
applicable to analytical methods
included in Ph. Eur. monographs. The
new validation section in the revised
Guide is the result of a joint effort by
The Guide provides guidance to Ph. Eur. experts on radiopharmaceuticals
experts on the information to be and the members of the European
included in Ph. Eur. monographs Association of Nuclear Medicine’s
related to vaccines and sera for human (EANM) Radiopharmacy Committee.
use, and to harmonise the style of the
different monographs. In the course of method development
for the quality control of active
The new edition of the Guide pharmaceutical ingredients in non-
takes into account the experience radioactive, “traditional” chemicals,
gained in recent years in elaborating validation of analytical methods
monographs in this field, and reflects according to ICH Q2 (R1)1 has been an
recent developments in the Ph. Eur. integral part of the process for decades.
The Guide is primarily designed for Ph. In the field of radiopharmaceutical
Eur. experts drafting monographs on preparations, commercial manufacturers
vaccines and sera, but it also provides have been performing validation
useful information to help users better activities for a long time, whereas
understand the requirements and small producers sometimes face
structure of these monographs. difficulties in preparing validation
protocols. This is mainly due to the fact
For details, see: https://www.edqm.eu/ that the evaluation of the validation
sites/default/files/tg_vaccines_en.pdf characteristics must be adapted to the
special case of radiopharmaceuticals:
Revised guidance for the short half-life of the radionuclides,
elaborating monographs on non-availability of radiochemical
radiopharmaceutical preparations impurities and radiation protection
Monographs and general texts on need to be considered in the study
radiopharmaceutical preparations are design. The Guide gives in-depth
elaborated by experts in the field. guidance on the evaluation of validation
characteristics adapted to radioactive
compounds. It is designed by and
for Ph. Eur. experts responsible for
elaborating and revising monographs
on radiopharmaceuticals, but it can also
serve as a useful guidance document
for other parties interested in the quality
control of radiopharmaceuticals.
See: https://www.edqm.eu/en/
node/16651
ICH Q12 revision process
The EMA has published industry
comments gathered during its
public consultation for the ICH draft
guideline on pharmaceutical product
lifecycle management (ICH Q12).
This new guideline is proposed to
provide guidance on a framework to
facilitate the management of post-
approval chemistry, manufacturing
and controls (CMC) changes in a more
predictable and efficient manner across
the product lifecycle. This guideline aims
to promote innovation and continual
improvement, and strengthen quality
assurance and reliable supply of product,
including proactive planning of supply
chain adjustments. The guideline strives
to promote, for regulators (assessors and
inspectors), an improved understanding
of the Applicants’ pharmaceutical quality
systems (PQSs) for management of
post-approval CMC changes. This new
guideline is intended to complement the
existing ICH Q8 to Q11 guidelines.
For details, see: https://www.ema.
europa.eu/en/ich-q12-technical-
regulatory-considerations-
pharmaceutical-product-lifecycle-
management

PHARMIG NEWS CORNER #44 7

FDA: Immunogenicity Testing of a global public health concern that Food, Drug, and Cosmetic Act (FD&C Act)
therapeutic protein products threatens the effective treatment and 21 CFR part 314, subpart H, or 21
FDA have issued a new draft guidance of infectious diseases. Combatting CFR part 601, subpart E. More specifically,
for developing and validating assays for this threat, particularly resistance to this guidance focuses on indications for
anti-drug antibody detection. antibiotics, is a high priority for the drugs approved via accelerated approval
European Medicines Agency (EMA) on the basis of a surrogate endpoint or
and the European medicines regulatory a clinical endpoint other than survival
network. Antimicrobial resistance is or irreversible morbidity. This guidance
when a microbe evolves to become also addresses labeling considerations
more or fully resistant to antimicrobials for indications that were approved under
which previously could treat it. accelerated approval and for which
Antimicrobials include antibiotics, which clinical benefit subsequently has been
kill or inhibit the growth of bacteria. verified and the FDA terminates the
This guidance provides recommendations conditions of accelerated approval under
to facilitate industry’s development 21 CFR 314.560 or 21 CFR 601.46. In
and validation of assays for assessment addition, this guidance addresses labeling
of the immunogenicity of therapeutic considerations when the FDA withdraws
protein products during clinical trials. approval of an indication that had been
Specifically, this document includes approved through the accelerated
guidance regarding the development approval pathway while other indications
and validation of screening assays, A well-known example of a bacterium for the drug remain approved.
confirmatory assays, titration assays, and that is resistant to a number of antibiotics
neutralization assays. For the purposes of is meticillin-resistant Staphylococcus See: https://www.fda.gov/downloads/Drugs/
this guidance, immunogenicity is defined aureus (MRSA), which has caused GuidanceComplianceRegulatoryInformation/
as the propensity of a therapeutic protein infections that are difficult to treat across Guidances/UCM390058.pdf
product to generate immune responses to the European Union (EU).
WHO guidance on testing of
itself and to related proteins or to induce
“suspect” falsified medicines
immunologically related adverse clinical The emerging and steady increase in the
This new World Health Organization
events. The recommendations for assay occurrence of bacteria that are resistant
document provides technical guidance
development and validation provided in to multiple antibiotics has become a
on laboratory testing of samples of
this document apply to assays for the global public health threat due to the
suspect deliberately falsified medical
detection of one or more anti- drug lack of therapeutic options to treat
products detected on the markets
antibodies (ADAs). This guidance may also certain infections in humans.
of WHO Member States and related
apply to some peptides, oligonucleotides,
aspects of sampling and reporting. This
and combination products on a case-by- Specific advice has also been added with
guidance should be read in conjunction
case basis. regards to the EU regulatory requirements
with the guidelines on sampling and
to develop medicines for the treatment
market surveillance.
See: https://www.fda.gov/downloads/Drugs/ of uncomplicated urinary tract infections
GuidanceComplianceRegulatoryInformation/ and gonorrhoea. The draft revised See: https://www.who.int/medicines/
Guidances/UCM629728.pdf guideline was adopted by EMA’s human areas/quality_safety/quality_assurance/
medicines committee (CHMP). TRS1010annex5.pdf?ua=1
Global approach to development
of new antibacterial medicines See: https://www.ema.europa.eu/
Antimicrobial resistance is a global en/news/revised-guideline-aims-
public health problem. Regulators in strengthen-global-approach-
the EU, the USA and Japan have had development-new-antibacterial-
extensive discussions over the last few medicines
years to explore and agree how to align
as much as possible their respective FDA guidance: Labeling for human
data requirements so that medicine prescription drug and biological Particle counter calibration
developers can design clinical trials that products approved under the standard updated
meet the evidence needs of multiple accelerated approval regulatory The international standard for the
regulatory agencies. The revised pathway calibration of particle counters
guidance reflects the outcome of New FDA guidance, which is intended has been update to: “ISO 21501-
these discussions. In addition, it offers to assist applicants in developing the 4:2018 Determination of particle size
clarification on the clinical development INDICATIONS AND USAGE section of distribution -- Single particle light
of antibacterial agents that are expected labeling for human prescription drug and interaction methods -- Part 4: Light
to address an unmet medical need, in biological products has been issued. scattering airborne particle counter for
accordance with experience. clean spaces.”
This is for drugs that are approved under
The emerging and steady increase the accelerated approval regulatory This document describes a calibration
of microbes that are resistant to pathway (hereafter accelerated approval) and verification method for a light
antimicrobial treatments has become as defined in section 506(c) of the Federal scattering airborne particle counter

8 PHARMIG NEWS CORNER #44

(LSAPC), which is used to measure the
size distribution and particle number
concentration of particles suspended
in air. The light scattering method
described in this document is based
on single particle measurements. The
typical size range of particles measured
by this method is between 0,1 μm and
10 μm in particle size.
Instruments that conform to this
document are used for the classification of endotoxins from gram-negative
of air cleanliness in cleanrooms and
associated controlled environments in
accordance with ISO 14644‑1 and ISO
14644‑2, as well as the measurement of new chapter as the rFC kits currently
number and size distribution of particles available on the European market and
in various environments.
The following parameters are within the
scope of this document:
• size setting error;
• counting efficiency;
• size resolution;
• false count;
• maximum particle number
concentration;
• sampling flow rate error;
• sampling time error;
• response rate;
• calibration interval;
•  reporting results from test and
calibration.
For further details, see ISO: https://www. information regarding FDA’s current
iso.org/standard/58073.html
New general chapter on test
for bacterial endotoxins using
recombinant factor C
The European Pharmacopoeia (Ph. Eur.)
has launched a public consultation on
a new general chapter, 2.6.32. Test for
bacterial endotoxins using recombinant
factor C (rFC). This is not a new topic
for the Ph. Eur. which was one of the
first pharmacopoeias to refer to rFC,
namely in chapter 5.1.10 Guidelines for
using the test for bacterial endotoxins
in Supplement 8.8 (2016), allowing the
recombinant protein to be used as an
alternative to limulus amoebocyte lysate.
Now, the Ph. Eur. is moving another
step forward by publishing a standalone
chapter on the test for bacterial
endotoxins (BET) using rFC. This is a
significant development since, for the
BET, the world currently depends on a
single source of lysate, the horseshoe
crab family, and more specifically, two
species of the crab, Limulus polyphemus
and Tachypleus tridentatus, both of
which are known to be endangered.
PHARMIG NEWS CORNER #44
This chapter describes a BET that uses a
rFC based on the gene sequence of the
horseshoe crab for the quantification
bacteria, and a fluorimetric end-point
detection method. For now, only the
fluorimetric method is described in the
most of the available scientific data are
based on this method.
It is important to highlight that for the
time being, this will be a standalone
chapter which will therefore not be
referenced in individual monographs.
See: http://pharmeuropa.edqm.eu/
TextsForComment/
FDA Issues Draft Guidance on OSD
Continuous Manufacturing
FDA has announced the availability
of a draft guidance for industry,
Quality Considerations for Continuous
Manufacturing, which provides
thinking on the quality considerations
for continuous manufacturing of small-
molecule, solid oral drug products that
are regulated by the Center for Drug
Evaluation and Research (CDER).
The document addresses areas like:
• Data storage and handling from
process analytical technology systems
• Potential approaches for
situations where direct attribute
measurement is not possible (e.g.,
low dose compounds)
• Contract manufacturers employing
continuous manufacturing
• Risk-based reporting of routine
model maintenance and updates
• Statistical approaches using large
samples (e.g., Large N).
Continuous manufacturing processes
are dynamic systems, unlike batch
manufacturing processes. During normal
operation, a set of critical process
parameters and/or quality attributes
are kept close to the target values,
rather than at a steady-state condition.
Transient disturbances may occur during
normal operation. These are usually
small enough to be controllable (i.e.,
being kept within a desired range).
Larger changes in process parameters
and quality attributes can happen when
a process is in a transient state, such as
during start-up and shutdown, a change
from one operating condition to another,
or significant deviations such as those
due to equipment failure or unexpected
change in material attributes.
Understanding of process dynamics as
a function of input material attributes
(e.g., potency, material flow properties),
process conditions (e.g., mass flow rates)
or equipment design elements (e.g.,
blade types for a continuous blender)
enables material traceability (the ability
to preserve and access the identity and
attribute of a material throughout the
system) during and after production.
See: https://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/
Guidances/UCM632033.pdf
Quality Culture: Learning from
History
The MHRA have produced an interesting
blog on quality culture in the historical
perspective, looking at some of the events
that have shaped the development of
quality (some of which have had a serious
impact upon human health).
The blog notes that a strong quality
culture is built upon:
• knowledge of what is important,
and how a process achieves critical
quality attributes
• diligence, by fostering awareness
that everyone contributes to
product quality, and understanding
that “my actions impact the patient
and the company”
• vigilance by individuals who know
what ‘right’ and ‘wrong’ look like in
their process, and a mechanism for
management to be aware of problems
• senior management commitment
to being visible and transparent in
decision-making so that positive
outcomes can be seen from the
diligence and vigilance efforts. This
is more than the company mission
statement – it’s ‘walking the talk’.
The blog can be accessed here: https://
mhrainspectorate.blog.gov.uk/2019/02/28/
quality-culture-learning-from-history/
Falsified Medicines Directive:
Safety Features
The EMA’s safety feature provisions
enter into force on 9 February 2019.
continued over...
9
 Member states are required to implement
the new falsified medicines safety
features for almost all prescription-only
medicines which aim to prevent falsified
medicinal products from entering the
pharmaceutical supply chain. The safety
features are placed on the packaging
of the respective medicinal products
by the pharmaceutical manufacturer
and consist of the following: a unique
identifier, in the form of a 2D data matrix
barcode, allowing the verification of the
authenticity and the identification of an
individual pack
of a medicinal
product anti-
tampering
device.
For further details, see the MHRA
blog: https://mhrainspectorate.blog.
gov.uk/2019/02/08/falsified-medicines-
directive-safety-features/
New sterile manufacturing
guidance published by EMA
The European Medicines Agency
(EMA) has published the final version of
“Sterilisation of the medicinal product,
active substance, excipient and primary
container” (EMA/CHMP/CVMP/
QWP/850374/2015), which first appeared plans-medicines-and-biologicals
in draft form in 2016. The document
was published on 8th March 2019 and
becomes effective from 1st October 2019. Biological Products:
The guidance describes the selection
of appropriate methods of sterilisation
for sterile products. The guidance
discusses the importance of terminal
sterilisation and the use of alternative
methods for producing sterile products
when terminal sterilisation cannot be
undertaken (that is using sterilising
filtration or aseptic processing, or a
combination of the two). Where terminal the nonproprietary names of these
sterilisation cannot be adopted, a robust products need not be revised in order to
rationale needs to be provided. For new
products, the document outlines the
appropriate decision-making process that for Industry: Nonproprietary Naming of
is to be followed and the requirements
needed for the marketing authorisation
application (or a variation application)
for a new or updated medicinal product. the naming convention described in the
Central to the decision-making process
is risk assessment and risk acceptance,
within the overall context of quality
risk management.
For details, see: http://ec.europa.eu/health/
files/eudralex/vol-4/2008_11_25_gmp-
an1_en.pdf
Risk management plans for
medicines and biologicals
10
The Australian TGA have issued a new In addition, this draft guidance describes
document titled “Risk management plans FDA’s current thinking on the appropriate
for medicines and biologicals : Australian suffix format for the proper name of
requirements and recommendations”, an interchangeable biological product
which is an update of a document licensed under section 351(k) of the PHS
originally issued in 2017. Act. For each interchangeable product,
FDA intends to designate a proper name
The new version (3.3) provides guidance is that is 30 a combination of the core
for sponsors of prescription medicines and name and a distinguishing suffix that is
biologicals making applications to enter devoid of meaning and 31 composed of
or vary Australian Register of Therapeutic four lowercase letters.
Goods (ARTG) entries. It describes the risk
management plan (RMP) requirements. FDA is also reconsidering whether
The guidance: vaccines should be within the scope of
• describes what an RMP is the naming convention.
• explains when you must submit
To access the document, see: https://
an RMP with an application for
www.fda.gov/downloads/Drugs/
registration, inclusion or variation in
the ARTG 20 years of sampling and testing
• describes what to include in an RMP programme for medicines
and the required format for RMPs EMA and the European Directorate for
• details special requirements for RMPs the Quality of Medicines & Healthcare
for biologicals and generics (EDQM) have reviewed EMA’s sampling
• outlines how we evaluate RMPs and testing programme for centrally
• explains when to submit RMP updates authorised medicines on the EU/EEA
after regulatory approval, and market, which has been organised
• describes how we monitor your yearly since 1998.
compliance with RMP commitments.
The number of centrally authorised
To view the document, see: https://www. medicines tested every year has steadily
tga.gov.au/publication/risk-management- increased from nine in the 1997-1998
pilot project to 58 in 2017, totalling
over 700 products. Most of the issues
FDA - Nonproprietary Naming of identified during the testing resulted
in EMA requiring companies to amend
The FDA has issued a new draft guidance the registered manufacturer’s control
document – “Nonproprietary Naming of methods for their medicines. In a small
Biological Products: Update”. number of cases, the tested samples
were not compliant with the authorised
This draft guidance describes FDA’s quality specifications for the medicine
current thinking on nonproprietary and required other regulatory actions
names of biological products licensed such as re-testing, inspections, recalls or
under section 351 of the Public Health suspension of supply. These are some of
Service Act (PHS Act) that do not include the key findings in a report summarising
an FDA-designated suffix. Specifically, the sampling and testing activities and
main achievements over the past 20 years.
The programme is an important part of
accomplish the objectives of the naming
the supervision of the quality of centrally
convention described in the Guidance
authorised products (CAPs) for human
and veterinary use in all parts of the
Biological Products (Naming Guidance).
distribution chain. The tests are aimed
at verifying the compliance of medicines
Similarly, FDA does not intend to apply
with their authorised specifications and
ensuring that the manufacturer’s control
Naming Guidance to biological products methods are satisfactory.
that are the subject of an approved
application under section 505 of the To access the report, see: https://www.
Federal Food, Drug, and Cosmetic Act ema.europa.eu/documents/report/20-
(FD&C Act) as of March 23, 2020, when years-sampling-testing-centrally-
such an application is deemed to be a authorised-products-1998-2017_en.pdf
biologics license application (BLA) under New EudraVigilance system improves
section 351 of the PHS Act on March 23, reporting of side effects
2020 (transition biological products). The new and improved
PHARMIG NEWS CORNER #44
EudraVigilance”>EudraVigilance as Link},
the European system for managing and
analysing information on suspected
adverse reactions to medicines that are
authorised or being studied in clinical
trials in the EU, received more than
2 million reports of suspected side
effects in 2018. This is an increase of
37% compared to 2017 which largely
reflects that from November 2017 the
national competent authorities and
the marketing authorisation holders
were required to report non-serious
cases of suspected adverse reactions to
EudraVigilance, having previously only
reported serious cases.
This was also a key driver for the
increase in the number of reports
received from European patients and
consumers through national authorities
and marketing authorisation holders,
which almost doubled between 2017
and 2018. Improvements in patient
reporting also reflect efforts at national
level to encourage patients to share
information on side effects through
information campaigns. These and
other findings are summarised in EMA’s
annual report on Eudravigilance.
evaluation is identified in the trial risk
assessment, performed prior to the
trial commencing. This could include
evaluation of data points associated with
critical/complex trial processes, in other
words, where the trial risks are. This has
led many to question whether this means
According to the report, EMA reviewed that sponsors, or indeed Clinical Research
more than 2,200 potential signals. This is Organisations (CROs) working on behalf
information on a new adverse reaction or of sponsors, need to develop a generic
new aspect of a known adverse reaction audit trail review Standard Operating
that is potentially caused by a medicine Procedure (SOP) that covers this process,
and warrants further investigation. Almost that is, an SOP not specific to a particular
80% of these signals originated from clinical trial as part of their quality system.
monitoring the EudraVigilance database.
Other signals were generated from clinical To answer this question, we would refer
studies and scientific literature. organisations back to the statement
that the need for a review of an audit
To see the report, go to: https://www. trail should be determined by a risk
ema.europa.eu/documents/report/2018- assessment based on the requirements
annual-report-eudravigilance-european- of the trial, taking into account the
parliament-council-commission-reporting- systems, procedures and controls in
period-1-january_en.pdf place to be used in the trial. Therefore,
to have a generic SOP would probably
MHRA GXP Data Integrity Guidance not add any benefit to this process and
An interesting MHRA blog post has is not mandated by the guidance or
been posted, looking at data integrity expected by GCP inspectors.”
from the GCP perspective. The blog is
from Paula Walker. Here is an excerpt: To read the whole blog, see: https://
mhrainspectorate.blog.gov.uk/2019/03/06/
“The guidance describes the need mhra-gxp-data-integrity-guidance-part-1-
for a documented audit trail review, a-gcp-perspective/
where the need for and extent of such

INTRODUCING
PHARMIG’S SOCIAL
MEDIA CHANNELS
Compiled by Tim Sandle -
Pharmig Committee
For 2019, Pharmig has reconfigured
and refreshed its social media channels.
Pharmig’s social media platforms
provide the opportunity for
members to discuss hot topics relating
to microbiology, pharmaceuticals
and healthcare.
The channels also provide the
opportunity for Pharmig to deliver the
latest news on courses, conferences and
webinars in addition to our email group.
Our social media channels are branded
with our mission statement: ‘Pharmig –
Excellence in Microbiology’.
Follow us on Twitter 
Pharmig’s growing Twitter account now
has 2,500 followers. Join us for the latest
industry news by going to
@pharmamicro.
Follow us on Facebook 
Pharmig has a Facebook group, currently
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To find the group, search ‘Pharmig’ under
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