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GMP and preparation in hospital pharmacies

Yvonne Bouwman,1 Lilli Møller Andersen2

The suitability of good manufacturing practice (GMP) for the quality assurance of the preparation in hospital
pharmacies is investigated. It is expected that the recent expansion of GMP with quality by design (QbD) and quality
risk management (QRM) will significantly improve the applicability for all types of preparation in hospital pharmacies.
QbD and QRM acknowledge the importance of targeting the need of the patient, of a good design and of risk
assessment, thereby offering more flexibility to the hospital pharmacist to respond to everyday requests for patient
care.
For European hospital pharmacy an elaboration of GMP principles for specific preparation processes is desirable.
The development of models for risk assessment will also be very helpful. The usefulness of the Council of Europe
Resolution for these aims is discussed. This article aims to provide a small contribution towards a transparent,
predictable though flexible and cost-effective pharmacy preparation.

Introduction manufacturing practice (GMP) in relation to relevant for pharmaceutical manufacturing

In January 2011 the Resolution on quality
and safety assurance requirements for
medicinal products prepared in pharmacies
for the special needs of patients (Council
of Europe (CoE) Resolution) was adopted
by the Committee of Ministers of the
CoE. In the introduction it is emphasised
that patient safety and the achievement of
the therapeutic aim require that medicinal
products prepared in pharmacies meet
appropriate and specific criteria for quality,
safety and added value.1
Basically this Resolution is an
approach to enforce a standardised quality
system for preparation in pharmacies. The
initiative has been expected but when
available the possible consequences of
enforcement have given some hospital
pharmacists reason for doubts and
concerns. These seem mainly related to
a foreseen loss of flexibility to prepare
individual highly needed medications
and a concern about the extra cost, time,
personnel, knowledge and skills needed
to apply the requirements. The primary
task for the hospital pharmacist is to take
care of patients and if patients really need
medications any quality concerns have to
be considered against this need.
In light of this we take a closer look
at the general implications of good
1
Laboratory Dutch Pharmacists, KNMP, Den Haag,
The Netherlands
2
Department of Quality Assurance, Region
Hovedstadens Apotek, Herlev, Denmark
Correspondence to  Yvonne Bouwman,
Laboratory Dutch Pharmacists, KNMP,
Alexanderstraat 11, Den Haag 2514 JL,
The Netherlands; y.bouwman@knmp.nl
preparations in hospital pharmacies. processes, such as that undertaken in
hospitals’. In the Netherlands this statement
GMP in general and its origin triggered the development of GMP guidelines
GMP as a paradigm stands for incorporating for hospital pharmacy preparation. In
documented quality into products by Denmark the authorities basically expect
enforcement of GMPs contrary to ensuring hospital pharmacies to be fully compliant
quality by simply assaying the final with GMP. A survey among European
product. The modern history of GMP countries3 shows a wide range of quality
started in the 1960s and laws and guidelines assurance and standards. Therefore the
have subsequently been expanded as a authorities of different European countries
consequence of new experiences and appear to enforce GMP requirements to
acknowledged quality problems. In Europe, different extents, from inspections on a
GMP requirements are primarily described regular basis similar to pharmaceutical
in EudraLex Vol 4 (EU GMP),2 the European industries to no inspections at all.
Pharmacopoeia and in national requirements.
In EU GMP each chapter starts with a Changes in GMP
formulation of a principle that is important for In recent years fundamental changes in
building in quality; see examples in table 1. the GMP paradigm have taken place in the
The principle of each chapter is regime of the International Conference on
elaborated in several guidelines, some of Harmonisation of Technical Requirements
them rather general, some of them detailed for Registration of Pharmaceuticals
and directed at the production environment for Human Use (ICH) guidelines.
in the pharmaceutical industry. Table 2 These changes refer to pharmaceutical
shows a few examples. development/quality by design (QbD)4
Hospitals are mentioned in the and quality risk management (QRM).5
introduction to EU GMP: ‘The principles of Principles from these guidelines are
GMP and the detailed guidelines are . . . also integrated in a revised EU GMP chapter 16
Table 1  Examples of EU good manufacturing practice (GMP) principles
Chapter 2: Personnel ‘The establishment and maintenance of a satisfactory system of quality
assurance and the correct manufacture of medicinal products relies upon
people. For this reason there must be sufficient qualified personnel to
carry out all the tasks which are the responsibility of the manufacturer.
Individual responsibilities should be clearly understood by the individuals
and recorded. All personnel should be aware of the principles of GMP
that affect them and receive initial and continuing training, including
hygiene instructions, relevant to their needs’.
Chapter 3: Premises/equipment ‘Premises and equipment must be located, designed, constructed,
adapted and maintained to suit the operations to be carried out. Their
layout and design must aim to minimise the risk of errors and permit
effective cleaning and maintenance in order to avoid cross contamina-
tion, build up of dust or dirt and, in general, any adverse effect on the
quality of products.’

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patient with the risks from an unvalidated

Table 2  Examples of GMP guidelines
or even a consciously suboptimal design or
Chapter 4: Records should be made or completed at the time each action is taken and in preparation process.
Documentation such a way that all significant activities concerning the manufacture of medicinal
This brings us to the conclusion that
products are traceable.
There should be written policies, procedures, protocols, reports for the following
GMP seems to be applicable to pharmacy
examples: preparation on the condition that QbD and
▶ Validation and qualification of processes, equipment and systems; QRM are included. However, this leads to
▶ Equipment assembly and calibration;
the challenge of elaborating principles into
▶ Maintenance, cleaning and sanitation
Chapter 5: Production All handling of materials and products, such as receipt and quarantine, sampling,
guidelines for specific pharmacy processes
storage, labelling, dispensing, processing, packaging and distribution should be and to meaningful risk assessments.
done in accordance with written procedures or instructions and, where necessary, Activities should be directed at a
recorded. At every stage of processing, products and materials should be pro- significant improvement in quality
tected from microbial and other contamination
assurance. Improvements have to be
implemented in a formalised way,
and will certainly be integrated into other documentation, training, qualification of taking into account that changes may
chapters as well. facilities and equipment, and prevention be necessary in premises and equipment
QbD is about quality built into the design of contamination are of importance for before full compliance is achieved.
of the product, the formulation and the pharmacy preparations. The requirements Consequently the necessary GMP
design of the preparation. QbD starts when related to training of people and prevention improvements will very often be a
the need for a therapeutic product emerges, of contamination are inevitable. yearlong process (light green line in
for example, due to a particular clinical Furthermore, preparation has to follow figure 1). The usual limited resources in
problem (‘target product quality profile’) and standard procedures and critical aspects healthcare (blue line) will on the one hand
thereby stresses the importance of meeting should be well documented as it enables slow down this implementation; on the
patient requirements. A control strategy reconstruction of what happened if quality other hand, they will hopefully prevent
needs to be defined and in-process controls defects or even adverse events are reported. going beyond the optimal quality for
planned correspondingly in connection with Qualification of critical equipment like the patient (dark green line) by irrelevant
the design of the preparation. balances and autoclaves is also important in (orange line) or even destructive activities
The manufacturing and subsequent use a pharmacy to ensure continuous control. (red line). Healthcare quality experts regard
of a medicinal product will always entail Some of the GMP principles have to be this as a too common phenomenon.7
some risk of harm to the patient. With the enforced differently when processes typical
new paradigm the authorities acknowledge for pharmacy preparation are apparently Specific guidelines for pharmacy
this risk; consider the very definition of harm: not foreseen in EU GMP. Examples of these preparation processes
‘Harm—damage to health, including the processes are given in box 1. Alongside the general GMP requirements
damage that can occur from loss of product The basic principles of GMP inclusive regarding an appropriate quality assurance
quality or availability’.5 of the new initiatives—QbD and QRM—are system and reporting of quality and safety
QRM provides a framework to manage well known by preparation pharmacists issues, the CoE Resolution gives specific
and document this risk. QRM has to be as assays of the numerous preparations requirements for pharmacies. Examples
based on scientific knowledge and should and small batches are too expensive include:
ultimately link to the protection of the and often technically not feasible. For
patient. The level of effort, formality and extemporaneous preparations an assay is XX requirements for reconstitution of
documentation of the QRM process should not possible within acceptable timeframes. medical products;
be commensurate with the level of risk. Consequently, the pharmacists have to XX products dossier for stock preparations;
The authorities acknowledge the risk of base their professional responsibility on XX before preparation the pharmacist
loss of product quality as well as the risk of knowledge, appropriate designs, experience, should verify whether a pharmaceutical
loss of availability of the product. It would in-process controls, the application and equivalent is available on the national
be interesting to know whether lack of validation of model preparation processes market, taking into consideration the
availability for economical reasons in the and QRM. In addition, the pharmacist has pharmaceutical form and the strength;
pharmaceutical industry is also included always balanced the medical need of the if not, availability as a EU-licensed
in this definition. If so, it may pressure medicine should be investigated;
a pharmaceutical company not to cease XX the professionals involved in patient care
Box 1 Preparation processes typical for should jointly assume responsibility
production if there is no alternative for hospital pharmacies
the patient. If not, it might emphasise the for determining whether a pharmacy
professional task of the hospital pharmacist XX Preparation of small batches, of preparation could be of added value.
to prepare a necessary medicine, even if capsules and suppositories
The requirements are very high level
the quality system may not be targeted for XX Manipulating or adapting authorised
or very detailed. As an example, the risk-
preparation of this product. More about this medicines, like converting tablets into
based decision matrix for the preparation
is covered in the section ‘Meaningful risk mixtures for children
process is very detailed compared with
assessments’. XX Aseptic handling at reconstitution or
general QRM principles, whereas demands
diluting injections for infusion
for documentation are only mentioned
GMP in relation to preparation XX Release of a prepared medicine
indirectly. Some of the requirements have
immediately after preparation
in hospital pharmacies to be specified nationally according to
XX Unique preparation for an individual
From the current GMP regulations, national requirements, for example, section 7
patient
especially requirements related to regarding labelling.

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of risk assessment that is typical for an

everyday situation in hospital pharmacy.
Therefore we provide here some more
materials, applying general QRM principles.
First is the chapter ‘Risk management’
in the textbook by Jackson and Lowey.9 It
describes practical ways to avoid preparation,
specific extemporaneous preparation
errors, therapeutic risks, and so on. The
risk management puts quality risks, safety/
efficacy risks and health and safety risks into
a matrix to get a risk rating.
The second tool is a form that is in
use in the Netherlands for assessing a
request for a non-standardised preparation
(figure 2). A similar form is used for stock
Figure 1  The relation between quality improvement in healthcare and increasing requirements and audits
(adapted with permission from Peters7).
preparation, just replacing individual

We recommend the topics of the

Resolution and the typical processes
mentioned in box 1 as a sort of working list
to the EAHP working group on guidelines
that has been started recently.

Meaningful risk assessments

How do we balance the need of the patient
against a potential risk connected with the
pharmacy preparation?
The CoE Resolution says: ‘For
extemporaneous preparations, however,
the pharmacist and the prescriber should
always consider the risks for the patient,
which include the risks posed by a medicinal
product without documentation specifying
the added value of the pharmacy preparation
and the quality assurance system applied to
its production versus the risks related to the
unavailability of this medicinal product.
The draft European Pharmacopoeia
monograph ‘Pharmaceutical preparations’8
states: ‘In developing an unlicensed
pharmaceutical preparation, an appropriate
risk assessment is undertaken, which
includes consideration of the suitability and
fitness for purpose of the pharmaceutical
preparation. The risk assessment also
considers the contribution of the excipients
and containers to the safety profile of the
unlicensed pharmaceutical preparation’.
We think it is right that this monograph
specifies that all unlicensed medicines
require a risk assessment instead of just the
extemporaneous pharmacy preparations.
However, using the QRM principle ‘The level
of effort, formality and documentation of the
QRM process should be commensurate with
the level of risk’ will generally lead to more
quality investments in stock preparation
compared with extemporaneous preparations
due to the higher number of patients that will
be exposed .
The Resolution does not provide a tool,
a framework or a checklist for this type Figure 2  Form for the risk assessment of a request for an individual non-standardised preparation.

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Figure 2  (Continued)
patient characteristics by a description of an
indication or care situation.
Some of the rationales behind this form
are as follows. The risk of unavailability
can also be defined as the assumed added
therapeutic value for the patient. This added
value will be documented in some way or
another, as is common practice in at least
some countries.
To be more specific about the assumed
added value one can discern:
1 unique therapeutic value as there is
no comparable authorised medicine
available;
2 improved patient friendliness and with
this better compliance to therapy;
3 improved safety of healthcare processes;
4 improved health and safety of healthcare
personnel.
472
Several medical products are only
available as a pharmacy preparation. The
number certainly differs among European
countries as it is influenced by the expected
Figure 3  Balancing added value with therapeutic and pharmaceutical risks.
European Journal of Hospital Pharmacy 2012;19:469–473. doi:10.1136/ejhpharm-2012-000194
financial benefit for the pharmaceutical
industry of the country and by traditions.
Properties of the preparation that might
improve patient friendliness are, for example,
individually targeted strength, different
dosage frequency, easier to swallow dosage
form, better taste and/or handier packaging.
The safety of the healthcare process will
improve if one diminishes opportunities
that a nurse, caretaker or patient makes an
error during the process of reconstitution
and administration of a medicine or causes
microbial contamination. Health and safety
risk of care personnel will be reduced if the
preparation is done by pharmacists and
technicians trained for the purpose and
with premises and equipment designed to
protect the staff against chemicals, just as in
pharmacies.
To be more specific about the risks for
the patient one can discern:
1. uncertainty about therapeutic safety and
efficacy;
2. design failure causing, for example,
poor bioavailability or poor content
uniformity;
3. preparation risk: the actual
pharmaceutical quality system cannot
guarantee that the preparation will fully
meet relevant specifications.
Specifying the various risks is a
prerequisite for a transparent risk assessment
and transparent design of product and
processes. Pharmacists are professionally
trained to weigh these different risks (figure 3)
and they are experienced in fulfilling this
task. Documentation of the process and the
risk balance is necessary for transparency
and clarifies which professional is allowed
to decide whether to prepare the product. In
addition, documentation makes knowledge
sharing, targeted training and continuous
improvements possible.
Conclusion
Establishment of common quality
requirements for pharmacy preparation in
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all EU countries seems to be feasible using
principles of current GMP, including the
new paradigms introduced with QbD and
QRM. For products prepared for stock, GMP
should be implemented to a further extent
than for extemporaneous preparations.
In addition, GMP principles have to be
elaborated for specific pharmacy preparation
processes and situations. Risk assessments,
using the principles of QRM, should
be developed for assessing requests for
extemporaneous preparations and for stock
preparations.
The CoE Resolution was prepared
simultaneously with the new EU GMP
initiatives and with the draft monograph
of the European Pharmacopoeia
‘Pharmaceutical preparations’. Consequently,
these documents are not fully integrated.
Beyond this, the principles in QbD and
QRM are not used in the Resolution and
the detailed requirements still need some
elaboration to take into consideration
national and cultural differences.
An EAHP working group will start the
elaboration of the Resolution on a European
level. Hopefully this will result in a common
professional EU framework for GMP/
QbD/QRM in hospital pharmacies. Such a
common, targeted approach should provide a
backbone for detailed national requirements
and provide a tool to deal with the very
European Journal of Hospital Pharmacy 2012;19:469–473. doi:10.1136/ejhpharm-2012-000194
different situations regarding healthcare
finances. For hospitals such a way of
implementing GMP will require huge efforts
but the long-term gain is predictability in
quality, cost effectiveness and transparency
of hospital-based preparations.
Key messages
 GMP principles including the new paradigms
QbD and QRM can be utilised for pharmacy
preparation quality systems.
 The importance of the design of the prepara-
tion and the preparation process, as well as
the risk of unavailability have to be included in
risk assessment models that should be part of
the quality system.
Competing interests  None.
Provenance and peer review  Commissioned;
internally peer reviewed.
Received 24 August 2012
Accepted 28 August 2012
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Cover story
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GMP and preparation in hospital pharmacies

Yvonne Bouwman and Lilli Møller Andersen

Eur J Hosp Pharm 2012 19: 469-473 originally published online October
2, 2012
doi: 10.1136/ejhpharm-2012-000194

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