1. business and industrial
2. pharmaceutical industry

european
INDUSTRIAL
PHARMACY
FEATURES
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18
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THE POTENTIAL IMPACT OF ICH Q8, 9 & 10 ON THE
QUALIFIED PERSON
The QP is attracting more and more duties and responsibilities
which will require more delegation and management involvement
by Richard Smalley
FRAMEWORK FOR A CONTINUING PROFESSIONAL
DEVELOPMENT (CPD) – A UK PERSPECTIVE
UK pharmacists wishing to register with the new General
Pharmaceutical Council will need to commit to CPD and submit
regular records. This article tells you why and how.
by Fred Ayling
HOW TO ACHIEVE EFFECTIVE COMPLIANCE WITH
EU GMP PART II IN API MANUFACTURE
Dealing with practical aspects of compliance – an auditor’s tour of
the QC laboratories.
by Norman Franklin
NEAR-INFRARED SPECTROSCOPY: A POWERFUL
TOOL FOR PAT/QBD
NIR has a wide range of applications in the pharmaceutical industry
in production and quality assurance.
by Emil W Ciurczak
THE NEXT FIFTY YEARS: DEVELOPING OUR CORE
VALUES FOR A CHANGING WORLD
Report from PGEU symposium, Stockholm, 15 June 2009.
by Pär Tellner
THE INDUSTRIAL PHARMACIST’S ROLE IN
PROVIDING PATIENT INFORMATION
The importance of the pharmacist is emphasised.
by Roland Schots
SAFER MEDICINES SUPPLY – ANTICOUNTERFEITING USING 2-D BARCODING
The Data Matrix 2-D code is described.
by Inger Näsman
REGULARS
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EDITORIAL COMMENT
REGULATORY REVIEW
NEWS FROM THE EIPG
PHARMACEUTICAL FORUM
BOOK REVIEW
JOB VACANCIES
DATES FOR YOUR DIARY
ISSUE 4 • OCTOBER 2009
www.industrialpharmacy.eu
www.eipg.eu
Associate Editors
european
INDUSTRIAL
PHARMACY
Belgium: Philippe Van der Hofstadt
Bulgaria: Valentina Belcheva
Issue 4 October 2009
Czech Republic: Miloslava Rabiskova
ISSN 1759-202X
Denmark: Michiel Ringkjøbing Elema
EDITOR
Joe Ridge, MRPharmS
PRODUCTION
Sue Feather
Finland: Tuula Lehtela
France: Jean-Pierre Paccioni
SUBSCRIPTIONS
Jill Monk
Germany: Armin Hoffmann
EDITORIAL BOARD
Michael Anisfeld
Michael Gamlen
Linda Hakes
Larry Hurst
John Jolley
Pär Tellner
Great Britain: Jane Nicholson
Greece: Kiriasis Savvas
Hungary: Sylvia Marton
European Industrial Pharmacy
is published three times a year by:
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Italy: Piero Iamartino
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Netherlands: Ineke Kleefsman, Michiel Storimans
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Tel: +44 (0)1428 752222
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european
INDUSTRIAL
PHARMACY
Spain: Mercé Pujol
discussion group:
www.pharmweb.net/gmp.html
Sweden: Pär Tellner
Switzerland: Renato Kaiser
GMP Forum
The online discussion group for industrial pharmacy
www.pharmweb.net/gmp.html
Views expressed in European Industrial
Pharmacy are those of the contributors and
not necessarily endorsed by the Publisher,
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©2009 Euromed Communications Ltd
Cover picture: Representation of microwells used for protein quantification assays.
european INDUSTRIAL PHARMACY
is the official publication of the European Industrial
Pharmacists Group (Groupement des Pharmaciens de
l’Industrie en Europe) www.eipg.eu
2
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
E D I TO R I A L C O M M E N T
Dear Colleagues
I would like to welcome you to the
fourth issue of the European
Industrial Pharmacy journal which is
dedicated to informing all
Pharmacists working in this sector
throughout Europe.
You will notice that we have
introduced a new format with the
following features:
♦ A selection of GMP related
questions and answers
originating from the GMP Forum
which our publisher, Euromed,
sponsors. It is hoped that such
Q&A will be an informative
resource for many Pharmacists
and Pharmaceutical Scientists
working within a GMP, quality or
regulatory setting.
will change and provide what you
would like to see, so please feel free
to send us your suggestions and
ideas to either myself
([email protected]), to Jane
Nicholson, Executive Director for
EIPG ([email protected] ) or
directly to Euromed
([email protected]).
From the EIPG perspectives we have
been very busy in responding to a
number of working parties and
European Commission Directives
and we are working closely with
EFPIA, on the variability in the
interpretation and implementation
of GMP initiatives. IPG has made it
a priority to aid EFPIA and other
related bodies in contributing to the
following workstreams:
♦ Developing the role of the
Qualified Person
♦ A job postings board to
encourage firms and recruiting
agencies to display opportunities
within the sector. It is clear that
during these challenging times
we must continue to extol and
advertise the skill sets of the
pharmacy degree and the
Industrial Pharmacist. A
Pharmaceutical Industry without
Pharmacists would be a very
sorrowful state of affairs. We
hope that the vacancy board will
encourage more opportunities
for Pharmacists.
These changes have been created in
response to feedback from you the
readers. We intend to make this
Journal a ‘living journal’ in that we
♦ Harmonising the implementation
of new guidances and regulations
originating from the Commission.
EIPG has made representation to the
following European institutions:
♦ Submission to the Commission
on their proposals to amend
Directive 2001/83/EC (anticounterfeiting measures)
EIPG working parties have produced
the following:
♦ Final draft of the EIPG Guidelines
on Good Distribution Practice of
Medicinal Products led by Claude
Farrugia (Malta)
♦ Revisions to the EIPG Code of
Practice for Qualified Persons led
by John Jolley (Great Britain) and
Piero Iamartino (Italy)
♦ Of particular note has been
EIPG’s Continuing Professional
Development guidance
document for the regulatory
affairs professional which has
received widespread praise. I
would like to thank the truly
pan-European efforts of Valerie
Lacamoire (France), Kelsey Mower
(Great Britain) and Ursula
Schickel (Germany) who have
worked together extremely well
and made this document the
success it is.
I would like to thank you all for
your continued support and once
again would encourage your
feedback; this is truly your journal.
With very best wishes
♦ Representation to the Committee
for environment, public health
and food safety and to the
European Council on the
Commission’s legal proposals on
the provision of information to
patients on prescription products.
Gino Martini FRPharmS
President, EIPG
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european INDUSTRIAL PHARMACY • Issue 4 October 2009
3
THE POTENTIAL IMPACT
OF ICH Q8, 9 & 10 ON
THE QUALIFIED PERSON
by Richard Smalley
T
he International Conference on Harmonisation has created and finetuned the series of inter-connected GMP guides ICH Q8, Q9 and Q10.
These are possibly the most wide-ranging and influential GMP guides to
have been written. They represent both a clear step-change in approach
AND a more aligned strategy between the world’s biggest
pharmaceutical markets. The intention of this article is not to review
the detail of the guides, which most people are familiar with by now,
but to identify the potential impact of implementing these on the
European Qualified Person (QP).
Conférence internationale sur l’Harmonisation a
LQ10arédigé
et mis au point la série de guides ICH Q8, Q9 et
de BPF (GMP) interdépendants. Ils pourraient s’agir
des guides de BPF les plus exhaustifs et les plus influents
jamais rédigés. Ils représentent à la fois un changement
progressif évident dans leur approche ET une stratégie
plus concertée entre les plus grands marchés
pharmaceutiques du monde. Le but de cet article n’est
pas d’examiner les guides en détail, qui sont déjà bien
connus par la majorité des personnes, mais d’identifier la
portée potentielle de leur mise en œuvre sur la « Personne
qualifiée » à l’échelle européenne.
As some background information,
different bodies including the EFPIA
Adhoc GMP Team have focused on the
growing challenges to the role of the QP
and view the situation with concern. GMP
developments are resulting in increased
regulatory responsibilities and often more
pressure on Quality Assurance
departments. As a general trend,
increased automation/instrumentation
means more data are generated and
potentially there is more to review. Whilst
Annex 16 allows QPs to delegate routine
duties to appropriate personnel,
increasing delegation does not mean
abdication of accountability.
RICHARD JOHN SMALLEY is
Associate Director, Global
Quality Assurance, UCB
Pharma SA, Brussels,
Belgium. He is a member of
the PQG team creating a
guide for Supply Chain Risk
Management for publication
in 2009.
4
It is now universally recognised that the
economic and regulatory environment in
which the pharmaceutical industry exists
is fundamentally different to that 20
years ago. The pressure on manufacturers
to provide consistent profits in the face of
falling numbers of new blockbuster drugs
and the reduced prices that national
health services/governments will pay for
medicines have provided the impetus for
making cost savings. In parallel with this
has been strong encouragement, from
the FDA in particular, of key initiatives
that could change the way that
companies develop, control and release
their products.
All of this describes the “what” relating to
the ICH guides, but the “how” is in
practice somewhat trickier. A big part of
the “how” problem is “who” will be
responsible for leading, managing and
making key decisions? There are
differences in the breadth of
responsibilities and management
seniority of QPs across Europe, with some
being limited to batch review and others
taking the senior role of a manufacturing
site. Commonly the QP is regarded as the
most senior Quality Assurance person in
any manufacturing site’s organisation
with direct responsibility for all aspects of
both the effective operation of the quality
system and product quality. Therefore, for
the implementation of the ICH guides,
the QP as usual will be the meat in the
sandwich between “operations” and the
Competent Authorities; it is expected that
they will feel a lot of pressure as both the
“arbitrator of common sense” and the
“protector of the patient”.
ICH Q8 implications
The agreed “Desired State” will result in:
♦ Specifications being based on a
mechanistic understanding of how
formulation and process factors impact
product performance.
♦ A continuous “real time” assurance of
quality.
♦ QPs should have more confidence as
patient safety is being protected by
more robust manufacturing processes
firmly based on robust knowledge of
the product.
In order to do this, QPs in future must
understand the whole process at this
level and use their knowledge to make
decisions. To do this effectively, QPs
increasingly must have a strong
understanding of statistical techniques
since these are necessary to extract
information from data. Whilst they might
not perform this step, they must
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
THE POTENTI AL IMPAC T OF ICH Q8, 9 & 10 ON THE QUALIFI ED PERSON (Cont.)
understand it and then the
information must be evaluated by
the QP to obtain knowledge. Finally
such knowledge can then be used to
make effective decisions (Figure 1).
In future Marketing Authorisations
will define a ‘Design Space’, but who
will Regulatory Agencies/Competent
Authorities hold accountable for
ensuring that there is a system for
managing changes within the Design
Space? The simple answer is
probably the Qualified Person! Also
in future, changes made within the
Design Space will not require
regulatory submissions, so who will
approve changes within the Design
Space? Other questions are:
♦ How is the QP going to manage
their knowledge when batch
process settings can be changed
within the Design Space?
♦ How will this be managed in
practice by the “Pharmaceutical
Quality System”?
And the answers to all of these are
(probably) that it is up to the QP to
decide…
On a highly positive note,
specifications will be based on the
mechanistic understanding of how
formulation and process factors
impact product performance.
Therefore, with a greater “knowledge
window” and clearer scientific
justifications for the specifications,
this should mean that fewer greyarea decisions need to be made by
the QP, since fewer grey areas will
exist. One thing that will not change
is that whilst it may also be easier to
make decisions if the required
knowledge exists, the regulatory
position will probably remain that
“Out Of Licence is Out Of Licence !”
ICH Q9 implications
Many of us have already experienced
much more emphasis on formal risk
management than ever in the past.
The MHRA have commented (Ian
Trussell, MHRA speaker at the QP
Symposium 2008) that many
troubles anyone who has experience
of the Risk Assessment tools being
applied (eg. in other industries, in
n
Decisio
Safety departments or within
forward thinking companies). It is
dge
dependent on the training and
Knowle
experience of the people, the tool
used and the accuracy of the data /
tion
Informa
information (to name just a few).
Will there be standard or accepted
tools for Risk Analysis? …And if you
don’t use these (but an alternative)
will you be criticised? Will these tools
Data
be quick enough? eg. standard FMEA
is thorough but time-consuming.
When will a preliminary hazard
Figure 1. Understanding the implications of analysis approach be enough?
ICH Q8.
companies inspected in 2007/2008
were still using Risk Assessments to
“justify bad decisions” or incidents that
had occurred but were not paying
sufficient attention to the use of a full
Risk Management process for
proactively working on prioritised risks
(Figure 2).
The normal process of Risk
Assessment and Risk Control will
conclude with a final risk
acceptance decision, leading to the
question “Who is going to be the
final approver of Risk Acceptance
documents?” Once again the EU
regulatory authorities may well be
tempted to say “The Qualified
Person”, if the decision has the
potential to impact product quality,
safety or efficacy. (Just try and prove
that it doesn’t and even then you’ll
probably still need a QP to sign this
justification.) Therefore it is
important that a company’s internal
procedures are clear on where the
responsibility lies. This is somewhat
helped by Annex 20 being issued
but the bigger question of “Will this
fully clarify the ‘QP discretion’
conundrum?” is still unanswered.
Risk Management is a process, so in
principle the QP need not get
involved but could just review the
output. The potentially variable
standard of the output is what
european INDUSTRIAL PHARMACY • Issue 4 October 2009
There is obviously still work to do
here, but the answers are capable of
being generated from this guidance.
The problem can be pre-existing
regulatory positions that could be
seen as being “exceptions to the
rule” or taking precedence over the
logic of balanced risk. There are
efforts being made to clarify the
what, when and how, which are
questions not clearly answered by
ICH Q9:
♦ BARQA guide to implementing
Quality Risk Management has
been issued.
♦ PQG guide for Supply Chain Risk
Management (for use by both
pharmaceutical company
supplier management
departments and by suppliers to
the pharmaceutical industry) will
be circulated for consultation in
Q2 2009.
On a final note it is good to see that
MHRA accepts the benefits of Risk
Management (see Hampton Report
and MLX 345 consultation) for its
risk-based inspection programme,
covering high and low risks for GLP,
GCP, GPvP, GMP, GDP.
ICH Q10 implications
Existing, established GMPs require
that:
♦ The QP should be involved in the
implementation and
5
THE POTENTI AL IMPAC T OF ICH Q8, 9 & 10 ON THE QUALIFI ED PERSON (Cont.)
maintenance of the Quality
Management System.
Initiate
Quality Risk Management Process
♦ The QP should ensure that the
Product Quality Review is
performed in a timely manner
and is adequate.
Risk Identification
Risk Analysis
Risk Evaluation
unacceptable
Risk Communication
ICH Q10 very clearly requires that
“senior management” is ultimately
responsible for the Quality System.
However, the task of developing and
maintaining an effective quality
system is going to be delegated and
the obvious (but overloaded)
recipient would be yet again “The
Qualified Person”. My personal hope
is that the QP should NOT have to
be the architect and guardian of the
Pharmaceutical Quality System
(PQS), but rather the QP should be
an auditor of the PQS. To achieve
this, the QP must monitor and be
able to influence the content and
implementation of the PQS.
Risk Assessment
Risk Control
Risk Reduction
Risk Acceptance
Output/Result of the
Quality Risk Management Process
An area that is of great interest to
many in the changing environment
we now work in is subcontractor
control. Here, the QP needs to
assure the basics of:
Risk Review
Review Events
♦ The existence of a written
contract.
♦ Any proposed changes are in
accordance with the MA.
♦ A system has been used to assess
the competence of the contract
acceptor.
♦ All products delivered by the
contract acceptor comply with
the specification and are released
by a QP.
The QP needs to manage this risk
and ensure that the quality system
includes:
♦ Formal agreement of “Must Haves”.
♦ Excellent systems for
communicating changes.
♦ Excellent systems for review.
Details which still need to be
worked out, and we can only
speculate on them, including how
this will affect Annex 16 of EU GMP.
We can also hope that universal
6
Figure 2. Risk management.
acceptance of the Q10 standard will
help MRAs between US and EU.
Key messages
The ICH Quality guides that are now
in place and being developed mean
that QPs must, in future, have a
good understanding of statistical
techniques for data interpretation.
The QP if not accountable for Design
Space changes, the QRM process, the
final Risk Acceptance decision and
the effectiveness of the PQS, will
certainly be seen by Competent
Authorities to hold a key role.
It is clear that the regulators will
take action against irresponsible,
negligent and unprofessional QPs,
and this is only right and proper in
order to protect patients. However,
with involvement and responsibility
increasing further, the risk of QPs
being over-worked, over-stressed
and not supported adequately
becomes greater than ever before.
It is therefore vital for QPs to keep
up with the evolving expectations in
order to be able to assist in
implementing the new paradigm.
Due to the demands on their time,
the role of QP will require even
more delegation and even more
management activities.
GMP Forum
The online discussion group for industrial pharmacy
www.pharmweb.net/gmp.html
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
FRAMEWORK FOR A
CONTINUING
PROFESSIONAL
DEVELOPMENT (CPD) –
A UK PERSPECTIVE
by Fred Ayling
2010, a new regulator, the General Pharmaceutical
InewnCouncil
(GPhC), will be established in Great Britain. This
body will take over the regulatory functions currently
undertaken by the Royal Pharmaceutical Society of Great
Britain. As part of these functions, the GPhC will implement
mandatory CPD requirements for pharmacists and
pharmacy technicians.
The approach taken to CPD for
pharmacists in Great Britain is
significantly different to elsewhere in
Europe. It is based on one that the RPSGB
has been developing since 1998 and has
been made available to pharmacists since
2002. At the point at which CPD remained
voluntary, more than 20,000, over half of
the membership, had made a start at
recording their CPD. This is in comparison
to other professions, where voluntary
uptake has been informally reported at
being in only single figure percentages.
For a number of years the RPSGB’s Code
of Ethics has required pharmacists to
undertake and keep records of their CPD.
It is anticipated that later this year the
RPSGB will start asking pharmacists to
submit their CPD records for review.
When the GPhC is established in 2010 it
will be able to ask pharmacists for CPD
records dating back to 2008 and it is
anticipated that it will require pharmacists
to submit a record once every five years.
What is different about CPD in
Great Britain?
FRED AYLING is Director of
CPD Services, Ltd. He was the
Royal Pharmaceutical
Society’s CPD Manager from
1998 to 2007.
email: [email protected]
Most pharmacists will be used to an
approach of accumulating a set number of
points for hours of attendance at formal
events over a period of time. These events
may or may not be accredited. In Great
Britain, this approach is referred to as
continuing education rather than continuing
professional development.
european INDUSTRIAL PHARMACY • Issue 4 October 2009
Continuing professional development is
different in a number of ways. It is
perhaps best understood as an approach
adopted by pharmacists for the selfmanagement of their development, based
on a four-stage cycle. At the first stage of
the cycle each pharmacist is expected to
identify personal learning objectives that
are specific, measurable, achievable,
relevant and timed; they should also have
a clearly identified performance outcome;
that is, something the pharmacist will be
able to do, either differently or better in
some way. This approach is important
because it helps the pharmacist to take
ownership of their learning and it means
that they focus their development on what
is actually going to make a difference.
Although this reflection stage of the
management cycle is self-directed, it does
not mean that pharmacists necessarily act
in isolation when setting these objectives.
Indeed, it would be best practice to
ensure, where appropriate, that they
involve others, such as colleagues, peers
and those who use their services. This
method of setting objectives fits well with
an employer’s performance review
systems, although it should be stressed
that a pharmacist’s development will
extend beyond this. Each person will have
their own career aspirations and there
may be aspects to their development that
an employer is not interested in. Also
there may be issues that a pharmacist
would not be comfortable discussing with
the person undertaking their
performance review, or with their
employer generally. It is also important to
remember that many pharmacists in
Great Britain are self-employed, or are an
employee-owner without a line manager
to undertake a performance review.
It is at this reflection stage of the
management cycle where competences
may play a part. Competency audit may be
used to identify learning objectives.
Competences for industrial pharmacists
have proved something of an issue in Great
Britain. The RPSGB has published a set of
‘competences’ which are really just a high
level list of the types of things that
industrial pharmacists should know
something about. There are only seven
items in the list and it is not really detailed
or thorough enough to be of much
practicable use. Fortunately, the RPSGB’s
7
F R A M E W OR K F OR C P D – A U K P E R SP E C T I V E (C o n t . )
through discussion, observations and
other means of learning-by-doing.
That’s to say, we learn through
experience every bit as much as we
learn through attending courses.
Reflection
Evaluation
Planning
Action
Figure 1. The learning cycle.
electronic recording systems allow
pharmacists to add their own
competences into the system. These
additional competences may be
provided or set by an employer or by
a relevant organisation, such as those
for competent persons that are
published by the European Industrial
Pharmacy Group (EIPG).
At the next stage of the
management cycle, the pharmacist
is asked to plan how they are going
to address the learning objective
they have identified. There are two
aspects to this, firstly prioritising the
objective and secondly, identifying
appropriate activities. Clearly the
pharmacist will have a number of
learning objectives at any one time
and so prioritising is important.
They will need to provide a realistic
target date for meeting the objective
and to think about the degree of
impact their learning objective will
have on them, their employer or
contracting body, colleagues and the
users of their services or products.
In terms of identifying appropriate
activities, the RPSGB is not
prescriptive. If the appropriate
activity is informal, such as having a
discussion with someone, reading a
book or undertaking a web search,
that is fine. If it is formal, such as
attending a course, it does not need
to be accredited. What is important is
that the pharmacist describes why
one activity is more appropriate than
another. This provides great flexibility
for the pharmacist and reflects the
way we learn. We often learn
8
At the action stage of the cycle, the
pharmacist undertakes the activities
they have identified and then sums
up the key learning points. This
‘summing up’ is important as it has
been demonstrated that we only
retain a fraction of the information
that we are told when engaging in a
learning event, whatever that may
be. Two pharmacists engaging in the
same learning event will take away
different things. That is because
they will come to the event with
different levels of existing
knowledge or skills and they will
have different expectations in terms
of what they want to go away with.
Reflecting on their learning has a
twofold benefit; it reinforces the key
points they have learnt and provides
a list that can be used in the future
as a handy reference.
In the final stage of the management
cycle, the pharmacist evaluates their
learning. Have they successfully
addressed the learning objective they
identified? If not, why not, and what
are they going to do next, if anything?
If the learning objective has been
successfully addressed, how have they
been able to apply what they have
learnt in practice? What are they now
doing that they didn’t do before? What
feedback or indicators do they have on
the effectiveness of their learning? Do
they need to build on this; perhaps
identify a new objective and so start
the management cycle again?
The CPD cycle?
The management cycle described
above is referred to as the CPD cycle.
But in simple terms it is a
management cycle that those
involved in research or project
management will be familiar with:
identify, plan, act and evaluate.
The RPSGB presents this cycle as in
Figure 1. It refers to the identification
stage as reflection. This is because the
RPSGB wishes to promote a reflective
approach to pharmacists’
development. This is based on the
observations made by Donald A Schon
in his book: The reflective practitioner:
how professionals think in action.
Schon observed that faced with the
same event and the need to take
action (make a decision, give certain
advice, provide a solution and so on)
professionals acted differently. This
was because they brought their
personal and professional
experiences to bear when acting.
Different professionals would provide
different advice or come to different
conclusions or solutions. It was not
necessarily the case that one action
was better or more right than
another. It does follow though that if
there are a range of actions in a given
situation, some actions may be better
than others and indeed some may be
poor. The idea behind reflective
practice is that it encourages the
pharmacist to step back and
understand that there are a range of
actions and that the one they choose
will be based, for good and bad, on
their own experiences. By thinking
this through, it is hoped that the
pharmacist may be more objective
and so make better decisions.
So, at the identification stage, the
RPSGB regards a pharmacist as
reflecting on events to help them
find the right or best learning
objectives that arise out of them.
A number of issues have arisen from
this. Although pharmacists who have
qualified in recent years will have
been taught about reflective practice,
GMP Forum
The online discussion group for industrial pharmacy
www.pharmweb.net/gmp.html
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
F R A M E W OR K F OR C P D – A U K P E R SP E C T I V E (C o n t . )
those who have been qualified longer
may be less familiar with this concept
and have less understanding of the
term ‘reflection’. Also, it is not always
the case that much reflection really
needs to go on when identifying
learning objectives. It is often quite
clear and self-evident what learning
needs to be undertaken as a result of
a certain event. If someone asks us a
straightforward question, we don’t
need to do much or any reflection to
realise what we need to know and
that we need to go away and look the
answer up!
opportunity that you may learn
something.
On a personal note, I tend to simply
refer to this stage of the CPD cycle as
identification. I also regard reflective
practice as happening at any stage, as
at each stage I find myself making
decisions that I have reflected on. For
example, at planning I am reflecting
on what I anticipate the impact of my
learning will be and which activities
are going to be appropriate based on
previous experiences.
Why CPD instead of CE?
A common misconception about the
CPD cycle is that it is an annual
exercise; the pharmacist would sit
down once a year, identify their
objectives and spend the next year
addressing them. Although taking
time out once a year to do just this
is good practice, learning objectives
will arise at any time throughout the
year and may need to be addressed
in a couple of months, weeks, days
or hours. So a CPD record is a live,
ongoing document and it is possible
to move through the cycle in hours
or years, depending on the learning
objective.
When the RPSGB piloted CPD and
launched it nationwide in 2002, it
also allowed pharmacists to start
their CPD at the action stage of the
cycle. This meant that pharmacists
could record CPD that occurred
when a learning objective had not
previously been identified, for
example, reading a journal or
attending a routine seminar without
a learning objective in mind, but
simply because there was an
In 2007, the RPSGB allowed
pharmacists to start their CPD at the
planning and evaluation stages.
Although a few pharmacists had
requested this, the feedback I have
received from most of the trainers
supporting pharmacists is that this
has added confusion and given no
real benefit. It can be quite difficult
to find examples of CPD that starts
at these stages and my advice is to
ignore this option unless you can
see any specific benefits.
When we looked at the research that
had been undertaken in the area of
continuing education, it was clear
that there was no evidence that
attending courses actually made a
difference.
One of the leading authorities in this
area is Dave Davis and his team from
the Faculty of Medicine, at the
University of Toronto. In their review
of the literature1, they made the
observation that there is a
‘diminished impact of CME along this
continuum’.
The thinking in the field was that it
was more important to accredit the
learner rather than the course. A
learner who is motivated and
committed may attend a course that
is poor but will not leave it at that; he
or she will instead find another way
of learning what needs to be learnt.
This is not to say that courses are
not an important part of
professional development and,
indeed, that some form of quality
assurance is required. Continuing
Education should not be relegated
as CPD’s poor cousin but instead
regarded as part of a wider process
of CPD. The suggestion is that it is
Skills
Knowledge
Attitudes
european INDUSTRIAL PHARMACY • Issue 4 October 2009
important for pharmacists to take
ownership of their learning and that
each pharmacist will have his or her
own starting point in terms of their
knowledge, skills or competences
and their own end point of where
they need to be. It is also important
that the approach to CPD
encompasses all the manners in
which we learn, including informal
learning, as not to do so could lead
to pharmacists not appreciating and
engaging in all the development
opportunities available to them. To
bring about more effective
development pharmacists were also
encouraged to think about learning
that would make a difference as
they moved through the cycle.
A professional develops over time.
There are rarely big leaps, but more
commonly it is the accumulation of
lots of little bits of learning that can
add up to something quite
significant. CPD should be about
continuous improvement and in
developing their approach the RPSGB
wanted to encourage pharmacists not
just to think about what they don’t
do well but what they already do well
and how they could build on that.
How can it be recorded?
Pharmacists can record their CPD in
three ways. There is an online
recording system, CPD Online; PCbased software, CPD Desktop; or a
paper-based system using a format
provided by the RPSGB or a format
accredited by them.
CPD Online is by far the best format in
terms of its functionality. More than
50% of pharmacists are recording
their CPD in this way, that’s over
20,000 people.
CPD Online allows pharmacists to
tailor various aspects of the
recording system, including
competences and options from
Skills
Performance
Attitudes
Patient
outcomes
9
F R A M E W OR K F OR C P D – A U K P E R SP E C T I V E (C o n t . )
other menus. It also allows pharmacists to share
aspects of their CPD with others online. These may be
friends and colleagues or their employer, so making it
easier to integrate into employers’ HR systems. The
pharmacist is in control of who sees what and when.
Regular backups also mean that the pharmacist cannot
accidentally delete their CPD record or lose it if their
computer system crashes.
A personal development plan that interacts with their CPD
record is also provided to help the pharmacist identify
learning objectives.
Recording consists of a mixture of free text and
selections made by means of checkboxes and
dropdown menus. Once familiar with the system, it
should take about 30 minutes to record one entry in a
CPD record, taking in all four stages of the CPD cycle.
Review and feedback
CPD will be reviewed according to the good
management practice described by the RPSGB
reviewers. They will consider whether the learning
objectives are specific, measurable, achievable,
relevant and timed; whether there has been a thoughtthrough option appraisal at the planning stage; and
whether the CPD has actually made a difference.
The purpose of the review is primarily to look at how
the pharmacist has been managing his CPD and to
provide him with meaningful and formative feedback.
Some of it will be used to establish whether the
pharmacist has met the required standards, but most
aspects will simply be used to provide feedback. For
example, when receiving feedback the pharmacist will
be able to see at a glance where his CPD has been
focused in terms of competences. For good reasons, it
may be quite narrow or broad and there is no reason
why any two pharmacists should have the same focus.
The intention is simply to provide feedback to help the
pharmacist understand where they may take their
professional development in the future.
Although the RPSGB is taking a formative approach,
they and the GPhC will need to set a minimum
requirement. I do not expect it to be terribly taxing but
then the intention is to engage pharmacists in a
formative way and not to be heavy-handed.
Reference
1. Davis D, O’Brien MAT, Freemantle N, et al. Impact of formal
continuing medical education – do conferences, workshops, rounds
and other traditional continuing education activities change
physician behaviour or healthcare outcomes? JAMA 1999; 282:
867–874.
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10
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
HOW TO ACHIEVE
EFFECTIVE COMPLIANCE
WITH EU GMP PART II IN
API MANUFACTURE –
An auditor’s tour of the QC
laboratories
by Norman Franklin
This article describes an auditor’s tour of the Quality Control laboratory
areas, covering analytical standards, OOS results, impurities, batch release,
etc. ending with a walk through the laboratories.
I
f an audit team is conducting the audit, and this team consists of two
specialists, one with a production background and one with a quality
control background, they will already have split up, and the person
with the quality control background will have transferred to the lab
area whilst his (her) colleague was covering production.
NORMAN FRANKLIN was a
member of the ICH Q7a
Expert Working Group and is
now a Principal Associate of
Interactive Consulting
Associates GmbH, a GMP
training and contract auditing
company in Zug, Switzerland.
E: norman.franklin@
interactive-consulting.ch
Some of the checking of the “Laboratory
Controls” (see Chapter 11) can, and
should, be done before arriving on site,
for example checking whether the API
specification, the extent of the tests and
the limits applied comply with the
pharmacopoeia requirements (see
§11.13). In particular it should have been
checked if the impurities listed and
limited are those listed in the
pharmacopoeia and are ones liable to
arise from the route of synthesis (see
§11.13). If there are discrepancies here
between the route of synthesis and the
impurities tested this is a HIGH RISK for
the patient. If the solvents used in the
synthesis are not given in the flow sheet
supplied with the Pre-Audit questionnaire
it must be noted which solvents are used,
from start to finish of the synthesis, and
what limits are being applied; this can be
compared later against the ICH limits for
solvents. It is not usual in the Pre-Audit
questionnaire to ask for copies of the
specifications of the critical starting
materials, but this should be reviewed on
site (see §11.12).
Analytical standards
One of the topics that received very little
attention in earlier GMP guides was the
european INDUSTRIAL PHARMACY • Issue 4 October 2009
use of analytical standards. The FDA
pointed out to other members of the ICH
Q7 Expert Working Group (EWG) that,
particularly in Asia, there was a lack of
understanding of the administration and
use of analytical standards. This author
can only confirm that this problem is not
limited to Asian API manufacturers, and
lack of compliance with these sections is
a HIGH RISK for the patient. Thus the
auditor should check very carefully where
the QC labs obtain their primary
standards (see §11.17 and 11.18) and,
even more important, how do they
ensure that their secondary (or daily
working) standards maintain the assigned
assay value.
It must always be remembered that if the
secondary standard has lost 1% of its
assigned value, but this has not been
compensated for, then every batch of API
test against this standard will have an
assay value 1% higher than the true value
(which can mean the batches are released
with an assay value of 98.7% when in
reality the true assay value is only 97.8%).
The EU GMP Guide Part II gives, in §11.17
to 11.19 detailed advice to API
manufacturers as to their responsibilities,
and perhaps the most important
sentence which the auditor should check
is “Secondary reference standards should
be periodically requalified in accordance
with a written protocol” (see §11.19). In
this context it is not acceptable to
reanalyse the secondary reference
standard just twice against the primary
standard every 24 months just because
the product is known to be stable for 24
months. Even a loss of 0.3% in the assay
over this period, whilst acceptable in a
stability study, will result in production
batches being released with an assay
value 0.3% higher than the true value.
Out-of-specification results
Knowing that the assay results are reliable
is a prerequisite for knowing whether
these (or any other results) are “Out-ofSpecification” (OOS). For the first time the
concepts arising out of the BARR
Judgement1 have been incorporated into
an international GMP guide and are now
an essential part of EU GMP. Thus it is
NOT ACCEPTABLE just to repeat an
analysis twice and accept the results if 2
out of the 3 test results meet the
11
EFFECTIVE C OMPLIANC E WITH EU GMP PART I I IN API MANUFACTURE (Cont .)
specification limits. The principle of
the Barr judgement is that if an
analytical result does not meet the
specification, either the product
itself is out-of-specification and thus
needs to be rejected, or the
analytical results are incorrect.
Each API manufacturer must
therefore have a procedure for
dealing with such OOS results (see
§6.53 and §11.15). It is usual (and
correct) for an auditor to ask to see
a “flow sheet” which identifies the
decision points and actions to be
taken – step by step – if there is an
OOS result. If an auditor has not
found an OOS result when reviewing
the laboratory records (the luck of
the draw) then the procedures taken
to resolve an specific OOS case as
suggested by the API manufacturer
can be used.
However it must be remembered
that this may be a “polished case”
which does not reflect the
investigations actually carried out in
daily practice. It must also be
remembered that an OOS can arise
because the specification itself is too
tight, or is not related to the
capability of the process. The API
manufacturer should have
considered this possibility and
reacted accordingly if the OOS is
found time and time again. It must
be remembered that OOSs are
“critical deviations” because they
could reflect the lack of quality of
the batch of API involved. Thus they
need to be resolved (see §2.22-4).
In spite of some earlier comments
to the contrary, it is not now
necessary to treat the
discontinuation of an analytical test
as an OOS because no results were
obtained to compare with the
specification limit2. Nevertheless,
such a discontinuation should be
treated as a “deviation” and be
explained. If a certain analytical test
often needs to be discontinued then
the reason for this needs to be
thoroughly investigated (see §6.53)
and an auditor should check this. It
12
is a RISK situation if certain tests
need to be frequently re-run – can
one rely on those which ran
smoothly?
Impurity profiles
Very few API manufacturers have
appreciated the implications of §11.2
particularly §11.21 and §11.22. This
author frequently finds that API
manufacturers confuse the “GMP
Impurity Profile” with the impurity
profile included in a Marketing
Application (MA). Although the
impurity profile in the MA will be
part of the “GMP impurity profile”
this latter is more of a “total
fingerprint” of all the impurities
detected even down to 10 or less
ppm if they can be detected. For the
manufacturer this “GMP impurity
profile” is the fingerprint of the site
where the product is made, and if it
is suspected that material may be
supplied from several different sites,
but all carrying the name of the
same exporting or importing
company, then one needs to
establish this “GMP impurity profile”
for the site audited. Under such
circumstances the auditors may be
asked to take a sample themselves of
the API in question at the site they
are auditing (see §11.22). Such site
switches are not only fraudulent but
could be a HIGH RISK for the patient
if a different synthetic route is
followed with new and unknown
impurities.
The review of the Certificates of
Analysis should have been carried
out before leaving the home office,
and thus the review on site should
consist of checking the raw data
“It is not acceptable just to
repeat an analysis twice
and accept the results if
only 2 out of the 3 test
results meet the
specification limits”
generated for the batches in
question. This topic will also be
covered later in this paper.
Responsibility for batch
release
Coupled with the review of the
Certificate of Analysis (CoA) should
be the review of who is responsible
for the release of the batches of API
(see §2.14) and are these persons
adequately educated and trained
(see §3.10). It is also important to
determine how this release is done
(see §6.70), because basically, as the
user of the API, the MP
manufacturer places considerable
trust in the persons and the
procedures used at the API
manufacturer. These topics are
therefore HIGH RISK situations.
Firstly, who carries out the release?
These people are generally known,
but there is not always a formal act
to confirm this, nor are their
signatures always on record to be
checked against the signatures on
the CoA. The auditor should be
checking this carefully. It must be
remembered that in the Haiti
poisoning affair it was not possible
to determine who had actually
signed the CoA for the “Synthetic
Glycol” and therefore this
requirement was added by the
members of ICH Q7a EWG (see
§11.43).
Knowing who these persons are
enables one to check the education
and experience of such persons (see
§3.10). In spite of the Japanese
requirement that these persons
must be trained pharmacists (and
the request by other competent
authorities to only use a “Qualified
Person” for such an assignment), the
members of the EWG did not follow
these requests and left the
education and experience
qualifications open.
Thus an auditor can only record
what education and training the
“release persons” possess, but it may
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
EFFECTIVE C OMPLIANC E WITH EU GMP PART I I IN API MANUFACTURE (Cont .)
be difficult to openly state “The
qualifications and experience of the
persons authorized to release
batches of API are inadequate” as
this is an “opinion” and not a “fact”
and experienced auditors always try
and just present the “facts” as found
during the audit. It would however
be possible to list the education and
training of the persons responsible
for release so that the MP
manufacturer himself can judge
whether he is willing to accept a
CoA signed by such persons or this
could be a HIGH RISK situation.
As part of this assessment it should
be checked HOW the release of a
batch of API is carried out. There
should be a “Check List” of
documents which must have been
reviewed and signed before release,
eg. the laboratory reports with the
signatures of the analyst who
checked the records for accuracy
(see §6.60); the BMR signed by
production that they have checked
these (see §2.3-3 and §6.52); the
review of the BMRs by the Quality
Unit (QU) for the correct and
completed critical steps and
parameters (see §2.22-3); the
recorded check that the deviations
have been reviewed (see §6.72) and
closed out (see §2.22-4); and the
check that any OOS investigations
have been completed and resolved
(see §6.72 and 11.15); and that the
data finally required for the issue of
a CoA is accurate and complete, (see
§11.42), then the release procedure
is a HIGH RISK situation because
batches may be released without
adequate control of the relevant
data.
Stability
The auditor needs to cover the
procedures and facilities used to
monitor the on-going stability of the
APIs produced on site. Although it is
admitted that for inorganic APIs
such as KCl, such studies have little
relevance for the behaviour on
storage (the natural stability
programme was initiated some 50
“It is a risk situation if
certain tests need to be
frequently re-started”
million years ago and has not yet
been completed), nevertheless there
should be an on-going stability
programme in place, even if this is
being carried out under contract.
It important to check whether
selected batches are being placed
on stability (see §11.54), particularly
if the audit of the change control
system indicates that there have
been major process or even
equipment changes such as a new
type of dryer for the API (see
§13.16). If the stability testing
programme is not being carried out
in-house, where the auditor can
check if the principles of ICH Q1A
(RS) are being followed, then the
contract with the stability testing
laboratory should be checked (see
§16.12) as should the evidence that
samples have been shipped there
over the last 15 months (see §11.54);
preliminarily reports from the
testing labs can also be checked, if
they are available (see §11.55 and
11.56). This should be the case,
otherwise it is a RISK situation as it
is not known if the current batches
of the API are as stable as the
development batches.
Retention samples
Another section of the GMP guide
for APIs that has also not always
been understood is that on reserve
or retention samples, in spite of the
clear statement in the guide that
the purpose of the reserve or
retention sample is NOT for future
stability testing. It is this statement
which makes it clear that the
packaging used to store the reserve
or retention sample should protect
it as far as possible from change
during storage, so that when it
comes to the future evaluation of
european INDUSTRIAL PHARMACY • Issue 4 October 2009
the quality of the sample this should
as far as possible reflect the quality
AT THE TIME of RELEASE (see §11.70).
Although incorrect packaging of the
reserve or retention sample is not a
real risk for the patient, it does
indicate a lack of understanding of
the EU GMP Guide Part II, (which may
then be the case with other
requirements, as was discussed
earlier under the “GMP impurity
profile).
A walk through the
laboratories
It is usual to take a walk though the
laboratories. Most laboratory
managers are proud of their new
equipment and like to demonstrate
its capabilities – or may complain
about their lack of space to the
auditor(s) – (NEVER take sides
during an audit – report the facts).
As an auditor, however, one must be
careful that one is not blinded by
such advances in equipment design
or capability unless the equipment
can be correctly calibrated, and has
been adequately qualified on
installation.
One can, however, use this tour to
check simple items such as
adequate identification of reagent
containers, adequate records of
calibration of equipment such as
spectrophotometers, etc. (see §5.30
to 5.35), and that analytical
procedures are easily accessible to
the staff. One can also see at the lab
bench what system is used to record
the laboratory raw data, such as lab
notebooks, preprinted sheets, or
even test procedures where the
analyst enters, in the empty boxes,
the values read off or to be used in
calculations (see §6.14).
References
1. USA FDA v Barr Laboratories. Judgement
and reasoning given by Judge Wolin on
Feb 4 1993 in US NJ Circuit Court.
2. FDA Guidance for Industry. Investigating
Out-of-Specification Test Results for
Pharmaceutical Production US DHSS, FDA,
CDER October 2006.
13
NEAR-INFRARED
SPECTROSCOPY: A
POWERFUL TOOL FOR
PAT/QbD
by Emil W Ciurczak
A
lthough near-infrared (NIR) was the first wavelength
region outside of the visible to be discovered (by Sir
William Herschel in 1800), it was not really used much for
the first 150 years. By 1970, there were only a dozen or so
papers published utilizing the technique. When Karl Norris
(US Dept of Agriculture) introduced methods for
determining moisture, oil, starch, and protein in the late
1970s and early 1980s, the interest in NIR soared. By the
early 1980s, all shipments of grain from the US were
analyzed by NIR. Since agricultural products are produced
by, in essence, uncontrolled chemical processes, it was
assumed that pharmaceutical products, manufactured by
stringently controlled processes, should be easily
monitored.
DR EMIL W CIURCZAK has
advanced degrees in
Chemistry from Rutgers and
Seton Hall Universities and
has been in the
pharmaceutical industry since
1970. Most of his research
has been on pharmaceutical
applications of NIR where he
has published over three
dozen articles in refereed
journals and presented nearly
two hundred technical
papers.
email:
[email protected]
14
In the early 1980s, quantitative work was
being done at Glaxo (UK) by Ken Leiper.
In the US (spurred on by EMEA
suggestions), Sandoz (East Hanover, NJ,
USA) was qualifying all its incoming raw
materials by NIR: 100% testing of all lots!
This was made possible by the
Mahalanobis distance software developed
by Dr. Howard Mark of Technicon. In
1987, Principal Component Analysis and
Partial Least Squares software was
introduced. Applications soared from that
point. Some of these applications are
highlighted by category.
Basic theory
Near-infrared spectra are the overtones
and combinations of vibrations
originating in the conventional or midrange infrared (2500 to 25,000nm or 4000
to 400cm-1). The main absorbances are
from C-H, N-H, or O-H bonds, the skeletal
modes being too small to be significant.
As a consequence, hydrogen bonding
strongly affects the spectra. Since most
NIR spectra are generated on “as is”
materials, scattering from powders and
suspended solids is also a major
contributor to sample spectra.
Absorptivities in the NIR are much
smaller (10-1000 times lower) than in the
mid-range infrared (MIR), while the
sources of radiation are stronger and the
detectors orders of magnitude lower in
noise. This combination allows analysts to
use pure samples, yet allow them to
measure low levels of analytes in
complex samples.
Since NIR samples were originally
complex agricultural samples, where
synthetic standards were impossible to
create, new computational methods were
needed. One of the greatest contributions
of Karl Norris was his introduction of the
Multiple Linear Regression algorithm. In
his calculations, a decade before complex
mathematics and computers were
available several wavelengths were used
as an extension of classical Beer’s law
calculations. The wavelength most
representing the analyte of interest is
found and placed in a linear regression
equation. Often, this wavelength does not
represent a “pure” peak and therefore the
linear function does not completely fit. In
that case one or more other wavelengths,
often representing the matrix, are added
as either secondary factors or divisors,
allowing an equation to be generated
that gives satisfactory results.
In 1987, Principal Components Analysis
(PCA) was introduced. This matrix-algebra
based computation uses all (or most) of
the wavelengths of the spectra to
generate equations describing the
differences between materials. Thus, the
fact that single wavelengths are difficult
to isolate for a property of analyte
became irrelevant. Adding chemical
values to the equations generated
quantitative equations capable of very
fine work. Later that year, Partial Least
Squares (PLS) was introduced.
PLS, is similar to PCA, but uses the
chemical values to produce “factors” for
the equation rather than spectral
differences. In short, PCA uses spectral
difference, making it excellent for
qualitative uses, while PLS measures how
the spectra change with chemical or
physical property changes, making it
better at quantitative analyses.
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
NEAR-INFRARED SPEC TROSCOPY: A POWERFUL TOOL FOR PAT/ QbD (Cont .)
Identity and quality
While agricultural applications were
usually quantitative, the first
widespread application of NIR in
Pharma was for qualifying incoming
raw materials. While NIR spectra are
not as “crisp” as the mid-range
infrared (MIR) spectra with which
analysts were accustomed, the ease
of using as-is samples outweighs all
the sample preparations. Using
available software, the reflectance
spectra of disparate raw materials
(see Figure 1) can be used to
generate domains in computer-space
for estimation of both identity and
quality of a material (Figure 2). Since
the resultant NIR spectrum of any
material is dependent upon both its
chemical and physical properties, use
of some variant of PCA gives, in
essence, the “quality” of a material as
well as its identity. What is meant by
“quality?”
Figure 1. NIR Reflectance Spectra of Several Common Pharma Raw Materials.
[orange = mannitol, red = lactose, pink = povidone, green = starch)
Using the spectral shifts, the physical
properties of a “proper” raw material
may be determined. There is no need
to identify (at first) why a material is
rejected by the software, a rejection
simply means that it is not similar to
previously analyzed samples. A
library of acceptable materials,
including all allowable variations of
moisture, particle size, polymorphic
form, degree of crystallinity and so
forth is constructed. The software
(available from nearly every
instrument manufacturer) generates
an equation which is then used to
determine whether a new material is
within acceptable parameters or not.
[If not, compendial or functional tests
may be run to ascertain acceptability;
if acceptable, the spectrum is added
to the library and a new equation is
generated.]
Quantitative applications
Since NIR was originally used for
quantitative analysis, it is not
surprising that there are so many
applications in Pharma. The leading
application is for water. Not
surprising, since water has the highest
Figure 2. Cluster Analysis of several calcium and sodium salts of small acids. [For instance,
calcium salts of propionate (orange), lactate (light blue), formate (green), and acetate (dark
blue), sodium salts of acetate (purple) and propionate (brown).] Similar acid anions are
easily separated by cation differences. Spectral differences are also based on crystal
structure.
european INDUSTRIAL PHARMACY • Issue 4 October 2009
15
NEAR-INFRARED SPEC TROSCOPY: A POWERFUL TOOL FOR PAT/ QbD (Cont .)
absorptivity, as in MIR. However,
unlike MIR, water is a nuisance in NIR
and aqueous analyses are also
routinely performed.
First, in water analyses, the level of
detection and quantification
depends on the matrix. In a freezedried matrix, NIR can easily
determine values below 0.1% water.
In a fluid bed drier (FBD), several
tenths of a percent are easily
determined in a moving matrix.
Since FBD moisture levels are
usually set as “below 1.0%”, this
level is most often sufficient.
Tablets may be assayed for their
active pharmaceutical ingredient
(API) either in transmission or
reflection mode quite easily. Again,
the levels are best detected well
above 0.1% API. One advantage is
that all excipients are determinable;
this allows determination of the
true content uniformity of all the
components within a tablet or
capsule.
Physical changes can also be easily
quantified. Figure 3 shows a series
of calibration samples made to
quantify polymorphic changes in an
API. Similar work has been done to
determine the degree of crystallinity
in excipients and drugs, even during
a mixing or granulation process.
This is an important feature, since
crystalline changes during
processing can affect the dissolution
and/or bioavailability profile of a
solid dosage form or its
manufacturability.
Using the proper models, a large
number of analytes/physical
parameters may be measured
simultaneously in a single sample.
This means that a raw material can
simultaneously be identified and
have its moisture, polymorphic
form, and average particle size
measured from a single sample
scan. Work is being done on other
physical parameters, important to
PAT, such as porosity, crushability,
surface area, and density in order to
add these to the toolbox for routine
screening of raw materials.
Counterfeiting or
adulteration
Figure 3. Calibration curve for two polymorphic forms of an API (Active Pharmaceutical
Ingredient)
Figure 4. NIR chemical Image of tablet; various excipients and API are highlighted with
false colors. The chemistry of each particle as well as its distribution are easily determined.
(Courtesy of Malvern Instruments.)
16
The ability to determine all the
materials within a material allows
an analyst to determine counterfeit
products. Using techniques such as
NIR Chemical Imaging (Figure 4),
the excipients can be determined as
well as the active ingredient. Using
PLS or PCA software, the physical
attributes of a tablet (in QbD terms,
the “process signature”) may be
determined. The hardness, speed of
production, etc. are all part of the
“goodness” of a tablet, leading to
changes in dissolution profile,
degradation, etc.
Recent problems with raw materials
and intermediates from developing
countries, caused by outsourcing
strategies of the larger companies,
can be addressed by NIR, as well. An
example is the recently discovered
lots of heparin contaminated
(possibly on purpose) with oversulfated chondroitin. The FDA
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
NEAR-INFRARED SPEC TROSCOPY: A POWERFUL TOOL FOR PAT/ QbD (Cont .)
packaged in larger quantities,
however, so the 84 remaining
tablets in the 100 tablet bottle stay
unknown after the 16 are used for
testing. As with end product testing,
nothing is learned about the
process.
Figure 5. 2nd Derivative NIR spectra of oversulfated chondroitin (blue) and heparin (red).
Figure 6. Increasing Levels of melamine (monomer) in gluten.
discovered what the adulterant was
by use of capillary electrophoresis
and two-dimensional NMR. While
this is a good research project, it is
cumbersome for a routine
approach. Using NIR on
contaminated heparin samples
shows obvious differences (Figure 5).
The check for heparin quality may
be performed more quickly and on
a routine basis with NIR. Any
unexplained differences could then
be investigated by more
sophisticated means.
Another adulteration problem was
the use of melamine to raise the
protein assay (by chemical means,
such as Kjeldahl digestion) in milk
and imported gluten. Figure 6
shows the NIR determination of
melamine in gluten.
Stability
One other application, beginning to
be investigated is stability testing.
Under QbD/PAT, thousands of units
of product are examined (if not
100%). Under cGMP, a minimal
number of units is tested at stability
time points: six tablets/capsules for
dissolution and ten for assay or
content uniformity. Most drugs are
european INDUSTRIAL PHARMACY • Issue 4 October 2009
One paradigm being tested is to
scan all the tablets/capsules in a
bottle at each stability time point.
The analyst could then use the
software to identify which of any
units are different. If any outliers
are noted, these could be subjected
to further testing on a “for research
purposes only” basis (avoiding
adverse FDA or EMEA scrutiny). With
a number of batches recorded,
statistic-magic can be performed. As
an example, results from the 100%
scrutiny can be compared with
batch records (QbD/PAT measures
many parameters to acquire design
space).
As a hypothetical case, assume that
at the expiry date for lot “A,” 10% of
the units show “differences” by NIR,
while batch “B” shows 25%. This
begs the question “what happened
during production to cause this
difference?” Over time, the design
space could be tweaked to give
longer and more predictable
expiration times. There is even a
possibility of using this data to
extend the expiration date for a
product, potentially saving sample
recalls and increasing profits.
Summary
In essence, NIR is a tool that can be
used before and after production as
well as being a production monitor.
The chemical and physical attributes
of raw materials, intermediates, and
products can be measured and
controlled with existing hardware
and software.
The added benefit of screening for
counterfeits and adulterated
materials makes NIR a powerful ally
for the Pharma industry in its
pursuit of assuring quality
medication.
17
THE NEXT 50 YEARS: DEVELOPING OUR
CORE VALUES FOR A CHANGING WORLD
REPORT FROM PGEU SYMPOSIUM, STOCKHOLM, 15 JUNE, 2009
by Pär Tellner
T
he first presentation was
given by Professor Claire
Anderson, from The Centre for
Pharmacy, Health and Society
at the Nottingham School of
Pharmacy, who gave an
overview of factors
influencing the
pharmaceutical sector. She
also referred to a study made
in UK on community
pharmacist core values, which
found that the most common
core values were patient best
interest and respect for
medicines. She also thought
that pharmacy will focus more
on personalized treatment
and prevention.
Thomas Lönngren from EMEA talked
about the regulatory system, the
role of the EMEA and future
challenges. The Commission will
reflect on the Clinical Trial Directive
and the fact that there is no
harmonization of the national
approvals of clinical trials in Europe.
He also told us about the recent
positive opinions on OTC-switches
(Alli and pantoprazol) and negative
opinion on an OTC-switch for Viagra.
Thomas clearly indicated that the
different security level of the
national pharmacy system is a very
important factor for CHMP when
deciding if they should approve an
OTC-switch or not. He wonders if
and how PGEU could help CHMP
with that assessment.
Thomas brought up the challenges
on how to control manufacturing
and clinical trials, when these
important activities are to a much
greater extent performed in the
growing economies, eg. China, India
and South-east Asia. He also
18
discussed the problem that
although we invest more in R&D,
the number of new substances is
decreasing. He thought that further
harmonization of regulatory
requirements, better advice in early
development and how to better
reward innovation could be of some
help. However, he believes that the
failures seen are a result of more
complex targets. Finally he said that
EMEA need to give scientific advice
and issue clinical guidelines in close
collaboration with Health
Technology Assessment bodies, in
order for industry not to have
different clinical development
programs. EMEA also need to
develop how they come to their
conclusions on risk/benefit in the
EPARs, to facilitate the HTA bodies’
work.
Dominique Monnet from the
European Centre for Disease
Prevention and Control (ECDC) gave
a presentation on “The potential of
pharmacists to contribute to
infectious disease prevention and
control”. He thought that
community pharmacists could
identify infectious diseases, inform
the patients, participate in public
awareness campaigns and vaccinate
against seasonal diseases. In
Portugal, community pharmacists
have started to give vaccinations.
The interest from the population is
huge, despite the fact that they have
to pay for the service at the
pharmacies, while the service is free
of charge at the health care centres.
40 % of the administrations of flu
vaccine in Portugal were made at
pharmacies.
Dominique also informed us that
ECDC will arrange the 2nd European
Antibiotic Awareness Day, 18
November 2009 and that
pharmacists could contribute to
decrease the resistance problems by
responsible dispensing of
antibiotics.
Balázs Hankó from Hungary
informed us that the Hungarian
government has decided to give all
Hungarian pharmacists a PharmD
degree. The decision is valid
retrospectively.
Professor David Taylor gave a
presentation of UK Pharmacy
developments. He told us that for
example over 2 million Medicines
Use Reviews have been made in
2009, good results with pharmacists’
prescriptions, NHS Health checks,
smoking cessation programs, etc.
Richard Bergström, Director General
of LIF Sweden, who today
represented EFPIA, questioned
whether the industry and
pharmacists are collaborating
enough. They have a lot in
common, he said. They are both in
business to make money by helping
people but unfortunately there is no
common agenda. Richard believes a
new collaborative approach is
needed with patient support and
disease management programs,
follow-up systems, new channels of
delivery and joint recruitment of
patients for clinical research.
Somewhat surprisingly, this
presentation was seen as
provocative.
Anders Olauson from the European
Patient Forum gave a presentation
on” How should the profession
move forward”. Anders told us that
pharmacists have an active role in
patient advice and medication
therapy management, and could
give patient care services ranging
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
THE NEXT 50 Y EARS: DEVELOPING OUR C ORE VALUES (Cont .)
from monitoring to nutrition
support. Anders also said that
pharmacists are the most accessible
and trusted HCP. In contrast to
PGEU’s opinion, EPF sees a role for
industry to give quality secured
information to patients, eg. via
public private partnerships.
The PGEU is the Pharmaceutical Group
of the European Union (Le Groupement
Pharmaceutique) a European
association representing Community
Pharmacists. PGEU members are the
national associations and
representative bodies of community
pharmacists in 30 European countries
including the EU member states and
EEA members. www.pgeu.eu or
www.gpue.eu (in French)
Pär Tellner is Compliance Officer and
Director of Veterinary Medicine at LIF
the research-based Pharmaceutical
Industry in Sweden
THE INDUSTRIAL PHARMACIST’S
ROLE IN PROVIDING PATIENT
INFORMATION
by Roland Schots
Medical information impacts most key operations in
the pharmaceutical industry including Regulatory
Affairs, Medical information and promotion,
Pharmacovigilance, Manufacturing, Quality
Assurance.
Regulatory Affairs comes first because the
information to the patients must reflect accurately
the particulars of the medicinal preparation as
approved by the Health Authorities. This means that
any Product Information (reference for the Patient
Information Leaflet) must be in compliance with the
Marketing Authorisation granted by the responsible
Authorities. Wording, layout and readability have to
meet European and national regulations (QRDtemplate – EMEA). This is also the case for veterinary
drugs.
Product information may only be changed postapproval by the Health Authorities. The valid texts
are provided by Regulatory Affairs to the Medical
information and promotion department. The
approved Product information also is the reference
when clinical or quality complaints are reported
(clinical complaints are managed by the
Pharmacovigilance department). Medical
information and promotion to patients is allowed
for non-reimbursed drugs but the information is
subject to strict restriction and is even prohibited for
some classes of products (eg. cytostatics, narcotics,
etc.).
The right product information has to match with the
right product and this means a well organised QAsystem that reduces risks of mislabelling in the
Packaging unit.
This brief survey emphasises the role pharmacists,
by their education, have to play at several stages of
patient information. They are indeed active at the
different steps leading to the final information
communicated to the patients.
Mr Roland Schots is a QP for radiopharmaceutical
manufacturing and adviser for Regulatory Affairs to
Belgian and multinational companies.
GMP Forum
The online discussion group for industrial pharmacy
www.pharmweb.net/gmp.html
european INDUSTRIAL PHARMACY • Issue 4 October 2009
19
REGULATORY REVIEW:
Review of major developments in GMP and the regulation
of medicines in the EU and on the International Scene,
July to September 2009
by Steve Fairchild
The last review period saw the issue of
a statement of intent from the United
States FDA for more robust enforcement of serious non-compliances with
GMP. The FDA also issued important
guidance on dealing with potential
melamine contamination in
pharmaceutical starting materials and
on anti-counterfeiting measures for
finished products.
In Europe we saw a climb-down on
proposals for legislation to impose
GMP on “certain” pharmaceutical
excipients.
Europe
Conclusions on the EC study on
pharmaceutical excipients
The European Commission (DG Ent.)
announced that it does not intend
to develop a new directive applying
GMP to “certain” pharmaceutical
excipients, as foreseen in earlier EU
legislation.
Whilst DG Ent. has accepted the
need to apply GMP to certain of
these materials, the responsibility
for identifying them and ensuring
compliance with GMP will now rest
primarily with pharmaceutical
manufacturers (and presumably
their Qualified Persons).
EudraGMP database
This database was set up by the
EMEA 2 years ago to provide a
common resource for EU GMP
inspectorates to use in planning and
performing GMP inspections.
The EMEA has now made certain
fields in the database available for
public scrutiny. However, it is
unlikely to be of much use at
present due to the limited fields
covered (eg. GMP deficiencies
cannot be accessed) and lack of
data from the Member States’
regulatory authorities.
However, there is some sign of
progress with data entries as the
20
MHRA has announced that in future
it will transmit data into EudraGMP
automatically.
Common deficiencies from UK GMP
inspections
The UK’s MHRA has published a
package of information on its
website derived from the analysis of
follow–up correspondence for GMP
inspections carried out in 2007 and
2008.
Whilst this information is interesting
it is difficult to draw any conclusions
from them about either compliance
or inspection trends.
Communication of serious GMP
deficiencies and rapid alerts for
product defects
A new procedure has been issued by
the EMEA according to which the
regulatory authorities of the EU
Member States will exchange
information about serious deficiencies
found during GMP inspections,
together with recommended actions.
In addition, the existing procedure for
communicating serious product
defects (rapid alerts) has been updated.
British Pharmacopoeia 2010
The 2010 edition of the BP has been
published recently with an effective
date of January 1st 2010. It contains
several new monographs and
standards along with material from
the European Pharmacopoeia 6th
Edition Supplement 6.5.
United States of America
FDA’s “Vision” on enforcement
The FDA’s Commissioner has set out
the Agency’s commitment to
improve its regulatory and
enforcement system. This will
involve tighter deadlines for
responses to inspection findings,
streamlining of the Warning Letter
process, the possibility of immediate
action, closer collaboration with
regulatory “partners” and a more
structured approach to following up
and closing out Warning Letters.
Guidance for Industry: Pharmaceutical
components at risk of melamine
contamination
This guidance results from serious
health problems in China due to the
adulteration of milk with melamine.
It set out to alert finished products
manufacturers, compounders, repackers, and suppliers to the potential
risk of melamine contamination in
pharmaceutical components.
It also sets out specific actions to be
taken to detect and prevent melamine
contamination of “at risk” components
which include lactose and povidone.
New questions and answers on GMP
for penicillin products
The FDA updated its set of GMP Q&A
to include the manufacture of penicillin
active ingredients and finished
products. This confirms what was
generally understood to be the FDA’s
position and industry practice.
Draft guidance on drug anticounterfeiting measures
The FDA has published a draft
guidance document that facilitates
the incorporation of physico-chemical
identifiers (PCIDS) in drug products.
This guidance should provide an
incentive to protect the public from
counterfeit products.
Proposed revision of US Pharmacopoeia
(USP) monographs for excipients
The USP has published draft revised
monographs for Propylene Glycol,
Sorbitol Solution, Sorbitol Sorbitan
Solution and Noncrystallizing
Sorbitol Solution to include specific
tests for adulteration.
For further information on these and
other topics we suggest you refer to
current and past editions of “gmpreview News” published by Euromed
Communications.
(See: www.euromed.uk.com)
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
NEWS FROM THE EIPG
Pharmine meeting
A meeting of the Pharmacy
Education in Europe (PHARMINE) has
been held at the PGEU (European
Community Pharmacists Group)
offices in Brussels. Progress with the
seven working groups was discussed
and the timing for reports on
undergraduate and post-registration
in industrial and hospital pharmacy
practice was agreed.
The Pharmine consortium consists of
four universities (Brussels, Nancy,
London and Lisbon and EU partner
associations representing the
different branches of pharmacy.
Industrial Pharmacy is represented
by EIPG.
The aim is to put forward an EU
PATstandard
& QbD half
page ad education
1/9/09
for pharmacy
11:48
and training to be adopted by both
the older and newer member states
as well as candidates for EU
membership and countries in nonEU areas such as Africa, China, India
and South America.
Further information on this project
can be found on the PHARMINE
website www.pharmine.org
EFPIA meets EMEA
Contact has been made with EFPIA in
preparation for a December meeting
with the EMEA and other interested
parties to discuss variability in the
interpretation and implementation
of GMP issues.
Commission’s legal proposals on the
provision of information to patients
has been acknowledged by the
European Council. Our comments
can be found on the EIPG website.
CPD in sales and marketing
The continuing professional
development needs for staff in Sales
and Marketing are under
consideration. If you are interested in
including your ideas for discussion
within the working group, please
contact Kiriasis Savvas at
[email protected]
Information to patients
Jane Nicholson
Executive Director EIPG
Pagerepresentation
1
EIPG
on the
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PAT and Quality
by Design
www.patandqbd.com
Ensure your regulatory submission is approved first time by successfully navigating the regulatory guide lines
surrounding PAT and QbD
Establish best practice for the use of PAT and real-time-release in commercial manufacture
Build a successful change management strategy when implementing QbD across the wider business and
incorporating it into your lifecycle management programme
Establishing a watertight business case for your senior management: Where do you start?
Ensure product and process quality from the beginning by successfully building QbD into your development process
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CALL: +44 (0)20 7368 9300 / 0800 652 2363
FAX: +44 (0)20 7368 9301
european INDUSTRIAL PHARMACY • Issue 4 October 2009
EMAIL: [email protected]
21
SAFER MEDICINES
SUPPLY – ANTICOUNTERFEITING
USING 2-D BARCODING
by Inger Näsman
Background
ounterfeit medicines are a serious problem in many
Cdeveloping
countries. It is a well known and big problem in the
countries but also a growing problem in Europe
and USA. WHO estimates that about 7-10% of the world’s
pharmaceuticals are counterfeit and in some developing
countries counterfeit drugs range from 25-50%.
Counterfeit medicines are now finding
their way into the legal supply chain. For
example in the UK recalls have been
made of counterfeit Lipitor, Plavix and
Zyprexa. In USA more than 50 cases were
investigated by FDA in 2006. The
European Commission is now taking
action and proposes a means to
guarantee the integrity of product packs
along the supply chain and the possibility
to identify individual packs.
Coding and tracing
Today, authentication of individual packs
is not possible – product traceability is in
best cases ensured at batch level.
However, several countries are now
taking steps to introduce traceability
systems. Belgium, Greece and Italy are
already requesting serial numbers on
packs and Spain, Turkey and Serbia are
currently working on introducing
mandatory serialisation.
INGER NÄSMAN is a
Director of LIF – the
Research-based
Pharmaceutical Industry
in Sweden
22
Different solutions in different countries
have many disadvantages and EFPIA is
therefore proposing a standardised
system for coding and identification of
pharmaceuticals in Europe using the Data
Matrix code. The code should contain
information on Global Trade
Identification Number (GTIN), a random
serial number, batch number and expiry
date. The combination of GTIN and the
random serial number gives a unique
identification of an individual pack. Data
Matrix has been chosen because it is
robust and cost competitive and has also
been used successfully by international
Federation of Animal Health (IFAH) for
coding animal health products.
The concept is an end-to-end system and
verification should be done at the point
of dispensing to verify:
♦ The existence of the number in the
database
♦ That the product has not been
dispensed before
But the system also provides more
advantages for the quality of dispensing
in pharmacies since you can check that:
♦ The right product is chosen
♦ The product has not expired
♦ Absence of recall for this
product/batch
Pilot in Sweden
EFPIA is currently performing a pilot in
Sweden to check the concept. In the pilot
the database and the response time for
pharmacists will be checked. Twenty-five
different products has been chosen and
will be scanned in 25 different
pharmacies until at least 100,000 packs
has been authenticated. The pilot will be
finalised early 2010.
Products and labelling
Products that are sold in several packs
were chosen and applications to allow
additional labelling with the 2-D code
were sent to MPA. The distribution to the
selected pharmacies was made by the
two one-channel distributors in Sweden,
KD Pharma and Tamro, who were also
responsible for making the extra
labelling. Of course when the system is
up and running the labelling will be
conducted at the point of manufacture.
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
SAFER M EDI CINES SUPPLY - ANTI-COUNTERF EI TING USING 2-D B ARCODING (C ont.)
Scanning
Better patient safety
In Swedish pharmacies the personnel scan a barcode
on all packs to check that the right product is selected
and therefore makes scanning of the new 2-D code
only a small change in routine. The additional software
is incorporated into the pharmacy software to make
the check as easy as possible. Swedish pharmacies are
currently under deregulation but only pharmacies
belonging to the State-owned chain, Apoteket, has
been chosen for the pilot, therefore only one software
needed to be altered.
There is no perfect solution to guarantee safety and
eradicate counterfeits, but the use of the Data Matrix
can help fight counterfeits and the technology can be
implemented quickly and at an acceptable cost.
Authentication at the point of dispensing, together
with e-prescriptions would also reduce dispensing
errors and allow more effective and efficient product
recalls and automatic detection of expired products.
GMP Forum
The online discussion group for industrial pharmacy
www.pharmweb.net/gmp.html
european INDUSTRIAL PHARMACY • Issue 4 October 2009
23
PHARMACEUTICAL FORUM
The following questions and responses are a selection
of those published on an open online discussion group
www.pharmweb.net/gmp.html. The Forum serves as a
means of exchanging views on international
regulations affecting the pharmaceutical industry.
Readers of European Industrial Pharmacy are invited to
contribute to the Forum.
BSE/TSE free certificate
Is it a requirement of MHRA that all the
Q
raw materials used in drug product
manufactured for the UK should have a
Response 4 – I agree that is most unusual to
perform a physical audit of a manufacturer of common
excipients. The previous responder referred to audit
data which could mean a questionnaire to obtain basic
information. Obviously if it was found that materials of
bovine origin were being used in common equipment,
an audit or alternative supplier would be necessary.
I was present at an EU Inspection when this topic was
discussed. It was easy to state that the excipient in
question was BSE/TSE free, but the Inspector
mentioned that he knew that the site processed bovine
materials – would the company please check, that
bovine materials were not processed in the equipment
used for that particular excipient. Note: a check was
required, not necessarily an audit.
certificate of freedom from BSE/TSE? I
understand that a BSE/TSE free certificate is
required for only those materials
manufactured from animal origin.
Response 1 – You’ll need to do a supplier
evaluation first to be confident the supplier does not
manufacture other products with animal materials.
Response 2 – The issue of potential contamination
with prions needs to be addressed in your risk
assessment for materials to be used in any product,
wherever they will be marketed.
Relation between GMP and ISO standards
I would appreciate advice on how to
Q
manage the existence of both GMP and ISO
standards in the same company. The company
is a manufacturer of medicinal products, but
there is also production of medical devices,
dietetic supplements, etc.
Please keep in mind that materials of animal origin
may be used in the manufacture of materials even if
they are not supposed to be present in the finished
material. This includes active ingredients, excipients
and materials used in the manufacture of container
components.
Response 1 – According to today’s GMP regulations,
Your suppliers should be asked to confirm whether or
not materials of animal origin have been used in the
manufacture of each material you use. When you have
this information you are then in a position to consider
whether you need a TSE certificate for any of those
materials or if you can change the supplier to obviate
this need – eg. where there is a source of the material
concerned that uses vegetable rather than animal
materials. If there is no animal material used (and you
have audit data to support this) then there no need to
obtain a TSE certificate.
Response 3 – Audits could targeted at sites with a
excipients production where there is use of potential
animal derivatives – eg. tallow derivatives, gelatin,
collagen, etc. Note that I used the word ‘use’ – this
could be in the production of materials which might
not contain animal derivatives themselves when placed
on the market but were exposed to them during the
manufacturing process. The frequency of audit would
depend on the extent of use of animal derivatives in
the plant. There might be less need for audit if the
materials are covered by a current, valid EDQM CEP.
24
API sites should be audited anyway regardless of the
type of material if the output is to be used in the EU
due to QP obligations.
the differences are not so big. Actually ICH Q10:
Pharmaceutical Quality System, is based on the ISO
9001 standard. On the other hand, ISO 13485 for
medical devices follows the principles of GMP. I was
involved in the establishment of a quality standard for
a biotech company which complied with ISO 9001, ISO
13485, GMP and biologics, I can advise you to go
through an in-house harmonization process.
Response 2 – Except for some common areas
linked to “systems” like quality manual, complaint
handling, annual review, etc. where you will have to
check that both referentials are matched, there is no
real opposition to implementing both standards in the
same company. There is, in my opinion, no place for a
litigious situation between them.
Response 3 – The main reason for any business to
exist is to create profit by providing a service or
product.
Fulfilling of GMP requirements ensures (or attempts to
ensure) product quality directly. ISO is more a
disciplined way of working to and to continuously
evolve the working practices for betterment of the
services provided.
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
P H AR M A C E U T I C A L F O R U M ( C o n t . )
Once GMP requirements are fulfilled, the customer can
be satisfied he has a good product. Once ISO
requirements are fulfilled, the customer knows he is
working with a disciplined and reliable organisation.
Top priority must be given to GMP and then align it to
match ISO requirements. GMP requirements lay down
what is required and these have to be incorporated
into the system by addressing them with respect to the
ISO clauses.
Response 4 – While not disagreeing with any of the
previous correspondence about the relevance of ISO
and GMP, it has to be stated that ISO standards in many
cases are not policed, so they are used and often
abused. On the other hand, GMP is policed by your
regulators and you will be quickly closed down for
persistent non-compliance.
Response 5 – For medical devices in the EU, ISO
standards are widely used for quality systems. Their
implementation is monitored by Notified Bodies (and
the Notified Bodies are monitored by the Competent
Authorities).
Audit of ISO standards can be done effectively in other
sectors too. There needs to be reliable third party
auditor rather than just a statement from the company
that they are implementing ISO standards.
Response 6 – It should be remembered that ISO
documents are ‘standards’ while EU GMP ones are LAW.
Ozone sanitization in HVAC
Let’s say that every Sunday evening, we
Q
added ozone into the air handling units
(AHU) and made it circulate for 2 hours. Then
flushed with fresh air and started working
again on Monday morning. This will help
control microbial growth and has the same
effect as periodic hot water sanitization.
Lets forget the human safety issue. Are there any
quality issues with this? What’s FDA’s attitude?
Response 1 – I don’t know about the FDA’s attitude
but why do you suggest this? What is your process and
what is the concept of your HVAC system? What are you
seeking to achieve? Is it really necessary? There are
other and better ways of controlling the
microbiological environment of a clean area without
such a draconian treatment. If the HVAC system is
correctly designed, installed and operated you should
not need the type of treatment you mention.
Why choose ozone? What would be the long term
impact of very frequent oxidizing agent contact on the
physical properties/structure of the system/components
(ventilator, ducting, extractors, etc).
Some companies working with infectious or
transmissible agents use hydrogen peroxide as a
precaution to disinfect the AHU at the end of a
production campaign. That can be a validated process
using BIs. However, whilst aggressive, this is an
occasional treatment that is not done every day.
Response 2 – Apart from both ozone or hydrogen
peroxide, formaldehyde fumigation during shutdowns
will work very well and effectively. This procedure is
validated for effectiveness and recirculation of
fumigated air will disinfect all the ducting and HVAC
system.
Response 3 – I built and validated a facility that
included three four-room suites, one of which was
sterile. They were periodically sterilised using a design
that included special dampers in the HVAC system that
allowed the system to run on total recirculation. The
program was PLC controlled and quite simple. On
initiation the HVAC dampers ran and transformed a
total loss system into a total recirculation system. This
was allowed to run and stabilise for around 30
minutes. In each room there were wall mounted,
pressurized containers of formaldehyde, each one
fitted with an electrical solenoid valve, which the PLC
could activate. Once the recirculation flow was
established, the PLC initiated a set program of
sequential discharge from these containers. This would
continue for approximately six hours, exhausting the
supply of formaldehyde. The PLC would then revert the
HVAC flow to total loss and dump everything into the
countryside. I managed the build and validation, but
left the quality control to production.
Response 4 – Formaldehyde gassing can work quite
efficiently and was widely used, certainly in the EU. It’s
a rather unpleasant and dangerous product whose one
advantage is that you can smell it at very low air
concentration. Some people’s sense of smell is better
than any Draeger tube. It was banned by the EU in 2007
via a previously issued European Directive concerning
the placing of biocides on the (European) market. I
don’t believe it has been used in the USA. These days,
companies should use alternatives such as hydrogen
peroxide. However, it would be interesting to know if its
use is tolerated in other regions of the world.
Readers are invited to send their Q&As to
www.pharmweb.net/gmp.html
european INDUSTRIAL PHARMACY • Issue 4 October 2009
25
BOOK REVIEW
Patient Safety
By Ivana Silva
Published by: The Pharmaceutical
Group of the European Union (PGEU)
Price: Freely downloadable at
www.pgeu.eu in English and French
atient Safety is one of the
PPharmaceutical
priorities of the
Group of the
European Union (PGEU) and
several initiatives have taken
place in the past three years
to highlight community
pharmacists’ engagement in
this particular field.
In March 2007 we published a
brochure entitled “Maximizing
Patient Safety in Europe through the
safe use of medicines”, available in
English and French and
downloadable from the PGEU
website (www.pgeu.eu).
The publication stresses the place of
medicines safety within the overall
topic of Patient Safety, a central
issue on the current EU health
agenda. It sets out some of the key
issues that must be addressed if
medication errors are to be avoided.
The publication calls for a
systematic approach to patient and
medicine safety issues across all
health professions and in all health
care settings. The publication also
describes some of the initiatives
undertaken at member state level in
the field of medication safety,
highlighting the contribution
community pharmacists make to
promoting medicines safety, while
recognising that there is still scope
to achieve more.
It is interesting to note that this
document was mentioned within
the European Commission Work
plan 2008 in relation to its roadmap
for a Regulation amending
Regulation (EC) 726/2004 and a
Directive amending Directive
2001/83/EC on Modernising
Pharmacovigilance for
26
Pharmaceuticals as a relevant data
source.
Building upon this work, PGEU also
published in May 2008 its booklet
on “Targeting Adherence: improving
patient outcomes in Europe through
community pharmacists’
intervention”, outlining relevant
research in this area and several
community pharmacists’ initiatives in
different EU countries to tackle nonadherence to medicines, a problem
estimated to cost the European
Union 125 billion Euro annually.
In the past two years PGEU was also
involved in the discussions leading
to the Patient Safety
Communication and Council
Recommendation proposal prepared
by the European Commission,
published last December 2008.
PGEU’s main points were the need
to take into account all sectors of
healthcare (primary, secondary, and
tertiary) and all healthcare
professionals, and to involve not
only Member States but also
stakeholders both in European and
National initiatives aimed at
developing and implementing
Patient Safety strategies. The final
Council Recommendation was
published this year, in June, and
PGEU was pleased to see that focus
has been given to medication errors
as an area that needs to be given
more attention.
Currently PGEU is also involved in
the EU-funded project EUNetPaS,
which started in 2008 and will end
in 2010. PGEU has been particularly
active in the project’s work-package
dealing with medication safety.
PGEU’s message has been focused
on the need to ensure a systemic
approach to all healthcare settings
which are part of the patient
journey in the healthcare system,
and underlines the importance of
avoiding medication errors
occurring at the interface of hospital
and ambulatory care.
Ivana Silva works within the
Pharmaceuticals and Profession Affairs
division of the PGEU.
email: [email protected]
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009
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DATES FOR YOUR DIARY
OCTOBER
26-28 October 2009 – Antalya, Turkey
3rd BBBB Conference on
Pharmaceutical Sciences
(EUFEPS)
www.bbbb-eufeps.org
27-28 October 2009 – Barcelona, Spain
BioProduction 2009
(Informa)
www.bio-production.com
N OV E M B E R
3 November 2009 – London, UK
The 11th Joint Conference on the
Qualified Person
(RPSGB)
www.rpsgb.org
4-5 November 2009 – Dessau, Germany
Disposables in biopharmaceutical
development and manufacturing
(APV)
www.apv-mainz.de
10-11 November 2009 – London, UK
APS Vaccines 2009
(APSGB)
www.apsgb.org
16-18 November 2009 – London, UK
Shelf life and stability testing of
pharmaceuticals and biotechnology
products
(ECEC)
www.ECEC.co.uk
9-12 November 2009 – Manchester, UK
Essential elements of a quality
management system
(DBA)
www.dba-global.com
17-18 November 2009 – Manchester,
UK
GMP and good distribution practice
symposium
(MHRA)
www.mhra.gov.uk
18-20 November 2009 – Venice, Italy
12th APIC/CEFIC European
Conference on Active
Pharmaceutical Ingredients
(APIC)
www.api-conference.org
23-25 November 2009 – Cambridge,
UK
Tabletting technology for the
pharmaceutical industry
(RPSGB/APS)
www.rpsgb.org
24 November 2009 – London, UK
Supplier quality management
(Management Forum)
www.management-forum.co.uk
2-3 December 2009 – Amsterdam,
The Netherlands
HVAC systems and the
pharmaceutical manufacturing
environment
(VIP)
www.vipltd.co.uk
7-10 December 2009 – Amsterdam,
The Netherlands
Pharmaceutical GMP
(DBA)
www.dba-global.com
8-9 December 2009 – London, UK
4th Annual Operational Excellence
(IQPC)
www.opexpharma.com/gmpdm
9-11 December 2009 – Edinburgh,
Scotland
DDL20 – celebration twenty years of
drug delivery to the lungs
(DDL)
www.ddl-conference.org.uk
JANUARY
D E C EM B E R
18-20 January 2010 – London, UK
PAT and quality by design
(IQPC)
www.patandqbd.com
1-2 December 2009 – Manchester, UK
Practical application of quality by
design
(DBA)
www.dba-global.com
27-28 January 2010 – Amsterdam, The
Netherlands
Cool Chain Europe 2010
(IQPC)
www.coolchaineurope.com
World Leader in GMP gap analyses,
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that every single one of our clients has
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• Fundamentals and Essentials of Validation
• Effective Investigations and Corrective Actions
• Effective Quality Assurance Auditing
We have wide expertise in evaluating GMP and
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For full details and registration check our website at:
www.globepharm.org/seminars.html/course
Let us assist you. Speedily and cost effectively.
Contact us at: [email protected]
28
performing third-party supplier and contract
manufacturer audits
eur opean INDUSTRIAL PHARMACY • Issue 4 October 2009