NEWSLETTER
No. 63 | March 2012 | 18th Year
The Business Designers
Pharma Compliance
1– 3 What Will the 16th AMG Amendment Entail?
Operational Excellence
4 – 5 High Asset Utilization Due to EGO
Medtech Compliance
6 – 7 How Compliant are Your Medical
Devices?
The Technology Designers
Laboratory Planning
10 – 11 Labs Planned for Transformation
Pharma Design / Qualification
12 – 13 The Hospital Pharmacy as a
Pharmaceutical Manufacturer
The Business Designers
Career
14 – 15 Through Diploma Thesis to the
Job
Chemgineering Group
Qualification / Validation
8 – 9 Qualification and Validation Alla
Turca
QuickNews
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What Will the 16th
AMG Amendment
Entail?
Important changes to pharmaceutical drug safety for manufacturers
Since December 2011, the ministerial draft bill of the 16th Amendment of the
Pharmaceutical Law (AMG) and other pharmaceutical regulations are on
hand. It is their goal to implement the new EU directives on pharmacovigilance,1 pharmaceutical drug safety as well as protection from falsification
into German law.
At nearly regular intervals of approximately two years, proceeding amendments of
European directives, there follows an amendment of the German laws. This is a fact
which clearly proves how important pharmaceutical safety adapted to the latest
state of the art is to legislators.
The planned update of the law is already the fifth amendment within the past ten
years. The current draft, which is currently being discussed in different bodies, focuses
No. 63 | March 2012 | 18th Year
1
Editorial: On our own account
Dear Readers,
«It is not the strongest or most intelligent species that
survive, but those who adapt most quickly.» The
significance of Darwin’s law can be observed not only
in nature but also in day-to-day business life.
Equally Chemgineering Group continuously adapts to
the needs of clients and the market. Thus our business unit engineering –
The Technology Designers – now has strengthened its cross-border market
orientation by being led as one entity. In doing so, we achieve an efficient
engineering organization as well as a harmonized know-how development
in specialist disciplines across state and company borders.
In addition, Chemgineering has boosted market activities in Austria. We
successfully acquired some significant projects and expanded our
engineering team with new professionals as well as experienced employees from Chemgineering Group. With their help we are intensifying our
on-site support for you.
You can only benefit from this novelty: With overall more than 150 experts
we are a large and competent partner for your projects. Due to fast and
simply available resources we are able to rapidly meet your demand or
implement changes. Moreover, we expect having the ability to start projects
more quickly. At the same time, your local and global project support is
ensured – with the same people of contact, the same standards and the
same quality. We are convinced to respond to your needs even better in the
new constellation and are looking forward to a continuing good cooperation.
Our cross-border performance is being represented from the year one in
our Chemgineering Newsletter, whose on-hand edition carries you off to the
Bosporus. Please enjoy now the specialist articles of our consulting and
engineering professionals who use their scarce time apart from projects to
share with you valuable information from market development and project
practice.
Wishing you an inspiring reading,
Dr. Armin Mayer
Head of Engineering Chemgineering Group
2
No. 63 | March 2012 | 18th Year
on the topics of pharmacovigilance
(Directive 2010/84/EU) and falsification
of drugs (Directive 2011/62/EU). As part
of this amendment of the AMG, among
other things amendments and updates in
the Pharmaceutical and Active Agent
Restoration Ordinance (AMWHV), the
GCP ordinance2 and the DIMDI Pharmaceutical Ordinance3 are included. You
can read the content focus areas in the
following passages.
Chapter: Pharmacovigilance
The tenth section of the Pharmaceutical
Law, which previously encompassed the
paragraphs 62 and 63 under the heading
«Observation, Collection and the Effect
of Pharmaceutical Risks», has now been
placed under the headline «Pharmacovigilance». Here the specifications of
the European directive are completely
applied so that extensive adaptations of
the aforementioned paragraphs occur.
The terms upon which the law is based
are supplemented by the following items:
· Risk management system,
· Risk management plan,
· Pharmacovigilance system
· Pharmacovigilance master documentation.
The marketing authorization holder is
obligated to oversee market observations to record pharmaceutical risks with
an individual pharmaceutical risk
management system. In other words, an
adapted risk management system
should be established for each pharmaceutical product. As a further innovation,
the marketing authorization holder is
responsible for the regulation to perform
audits of his pharmacovigilance system.
In this regard, also the term «secondary
effects» is made broader: A secondary
effect is defined as all dangerous and
unintentional effects which occur in the
new definition also regardless of the
dosage. In order to considerably improve
the recording of secondary effects and
to thereby ensure the security of pharmaceuticals, special emphasis is placed
on the patients. In the future, on package
inserts they must be explicitly instructed
to directly report suspicious cases
of secondary effects to their physicians,
pharmacists or other members of
healthcare professions or even the
Higher Federal Authority. A similar
request should also be applied in the
field-specific information.
Drug safety increased
To increase the protection against falsifications of drugs, safety
characteristics should be attached on all pharmaceuticals
which require prescriptions (§ 10 AMG). Thus, the genuineness
and the identification of the individual packaging are reviewed
and if necessary real manipulations must be proven.
As part of the authorization process, also a statement by the
pharmaceutical manufacturer must be submitted which
provides information on supplier audits (result and date). In the
newly formulated provisions on the inspections by the monitoring authorities, in addition to good manufacturing practice
(GMP) also good distribution practice (GDP) is listed without
details being described on this. Here reference is also made to
the explanations in Directive 2011/62/EU, which basically states:
1. The commission shall adopt principles and guidelines of
good manufacturing practice for active substances.
2. The principles of good distribution practice (GDP) for active
substances shall be adopted by the commission in the form
of guidelines.
3. The commission shall adopt guidelines for the formalised risk
assessment for ascertaining the appropriate good manufacturing practice for excipients.
Import regulations tightened
A series of alterations is included, also in the import of active
ingredients:
In § 72a «Certificates», the WHO standard for GMP as a
permissible standard is removed again so that de facto the
requirements become stricter as required in Directive 2011/62/
EU: «… the standards specified by the Union are at least
equivalent.»
In addition, the authorities of the exporting countries should
regularly monitor the manufacturers of active ingredients,
including repeated and unannounced inspections. In the event
Impact for marketing authorization holders and manufacturers:
· A risk management system, as it is known in the medical devices
industry with the ISO 14971 guideline, is now to be implemented by
the marketing authorization holders – beginning with the development, over manufacturing up to market observation.
· Secondary effects are to be identified, documented and reported
more intensively according to the pharmacovigilance system.
· The requirements for purchase of active pharmaceutical ingredients
and excipients for manufacturing pharmaceutical products are
going to increase significantly in the future.
of deviations, the local (European) authorities should be
informed. We have to wait and see how this is implemented in
practice.
By suspending no. 4 in paragraph 1a of the AMG, the requirements placed on import have also proved effective for plant
materials in a state until initial extraction. The import restrictions
should not apply to active substances which are imported from
countries that are on a yet to be published list of the European
Commission.
Audits extended according to AMWHV
In the Pharmaceutical and Active Agent Restoration Ordinance
(Arzneimittel- und Wirkstoffherstellungsverordnung), the
changes of §11 «Self-inspections and Supplier Qualifications»
should be specified as follows:
· The manufacture and sale of the active pharmaceutical
ingredients (API) should be audited.
· Audits by suitable third parties should also be permitted
according to the rules of the QM system of the pharmaceutical
manufacturer.
· Audits should also be extended to importers or sellers of
the API and include the verification of the registration with the
relevant authority.
· A formalised risk assessment for excipients should also
include the audit of the compliance with an appropriate good
manufacturing practice (GMP).
· The specifications for drugs and active agents should include
the accepted manufacturers and suppliers.
Outlook
After the associations and bodies were required to submit their
observations and notes in January, the new law and its formulations must be finalized in by mid-2012. Experience has shown
there will still be some review cycles before the final adoption in
Parliament occurs.
For active agent and commodity traders:
· More information has to be reported to the authorities.
· Due to the new requirements to the competent authorities in the
manufacturers’ countries the import of active agents is supposed
to be tightened.
· The requirements for excipients are approximating those for active
pharmaceutical igredients.
1 Pharmacovigilance is the same as pharmaceutical safety. WHO defines pharmacovigilance as the «science and activities relating to the detection, assessment, understanding
and prevention of adverse effects or any other possible drug-related problems.» (In: WHO 2002: The importance of pharmacovigilance, safety monitoring of medicinal products.
http://whqlibdoc.who.int/hq/2002/a75646.pdf)
2 GCP: Good Clinical Practice
3 DIMDI: German Institute of Medical Documentation and Information
Dr. Friedrich Elstner
Dr. Jan-Carsten Hempel
Senior Consultant GMP-Compliance & Medical Devices
Leiter Q/V Compliance
Chemgineering – The Business Designers
Chemgineering – The Technology Designers
[email protected]
[email protected]
No. 63 | March 2012 | 18th Year
3
The Business Designers
High Asset Utilization
Due to EGO
How you can boost your effectiveness and persuade investors
In the last two issues of the Newsletter, you were introduced to the Chemgineering approach for an efficient
business organization – EGO – and learned about possible uses in the first sample applications. In this edition, we will
show you how to manage or improve the capacity utilization.
Part
3
Figure 1 shows the assignment of the loss types of availability,
rate and quality and the resulting effect in the calculation of the
components.
Using Available Time
In addition to recording interference factors, it is critical to
define the available time for your OEE concept. We make a
distinction between the net OEE, the actual capacity of the
equipment and the gross OEE for the actual effectiveness of the
production. As shown in Figure 2, it is important to distinguish
between planned and external losses.
Overall Equipment Effectiveness
If it is a question of equipment utilization, your investors will
pose three questions to you as an operator:
1. How high is the current capacity?
2. How long can existing equipment cover needs?
3. What can you do to improve the capacity situation?
To provide information here in a qualified manner, a concept for
overall equipment effectiveness (OEE) will be helpful to you.
This key indicator represents the acknowledged measurement
for the value added by a piece of equipment. The indicator itself
is calculated as the product of the availability of the equipment,
its speed or ratio with which the equipment runs and the quality
of products (number of yields) and is expressed in percent:
OEE = Availability × Rate × Quality
Making Interference Factors Visible
In order to improve the equipment utilization and thereby the
value added, the first most important thing is to record the
interference factors. The resulting losses are usually assigned
to six loss types which, experience has shown, cover the entire
spectrum. Table 1 shows the loss types and the respective
goal. The available time for a system in which it can optimally
produce is reduced due to the effect of the interference factors.
By calculating the OEE, these interference factors are visible
and will provide you with the first approach for improvement.
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No. 63 | March 2012 | 18th Year
The net OEE for equipment running in single shift mode can be
between 25 and 30%. The gross OEE of the same equipment
will be between 75 and 90%. The first key figure will show you
that you still have reserves in production which, for example,
can be used with an alternative shift model. The second key
figure shows you how good the capacity of the equipment is
when it is running. Based on this information, it is possible to
calculate how much more product the equipment can produce
with less interferences.
Design Your OEE Concept Pragmatically
The increase in the net OEE immediately becomes clear
through the reduction of costs and thereby in the improvement
of your margins. To do this, your individual OEE concept must
be coordinated with management, the staff must be trained in
data recording and a continuous improvement process (CIP)
must be established. Once the OEE concept and the accompanying CIP are established, the investors’ questions mentioned
at the start can be answered at any time objectively. We will
gladly assist you during implementation.
Dr. Thomas Lellau
Managing Consultant
Chemgineering – The Business Designers
[email protected]
Loss type
Goal
Explanation
Machine damages
0
> 1 min, must be reduced to zero for all machines
Set-up and adjustment
minimization
As short as possible: shorter than 10 minutes without other adjustments
Reduced speed
0
Should meet the machine specifications, or, with improvements,
even exceed them
Short idle times
0
< 1 min, must be reduced to zero for all machines
Defects and refinishing
0
The size can vary but should be expressed in parts per million
(e.g. under 300 ppm)
Start loss
minimization
Is in competition with 2 and is sometimes difficult to separate from 5
Table 1
Available time
Availability
losses
(1) larger machine breakdowns, idle times,
maintenance (>1 min)
(2) Installation, refitting and adjustment
Production time
at maximal rate
Availability
Available time – idle times
Available time
= 90%
×
Performance
losses
Production time
Rate
(3) Short idle times (>1 min)
Actual output
max. output during
production time
(4) Loss of speed (incl. starting time)
= 95%
×
Quality
losses
Production time
at maximal rate &
quality
Quality
(5) Quality issues during the process, rework
Actual output
–
waste
actual waste
(6) Waste at the starting
= 99%
OEE = 85%
Figure 1: Calculation of OEE. A value from 85% – as shown in this example – is considered excellent.
· 365 days × 24 hours
· Pro rata within a year, with new installations
Gross time available
Planned
losses
Scheduled time available
External
losses
Net available time
· Adaption to shifts (e.g. 230 days × 8 hours)
· Inspections, etc.
· Losses which are not in the control of the production site
(e.g. power failure, strike-actions, etc.)
The goal must be to find a reasonable and traceable definition of the available time. This must not lead to a random adaptation of the planned and
external losses.
Gross OEE
Net OEE
=
=
OEE vs. gross available time
OEE vs. available time
=
=
actual plant utilization
actual production effectiveness
Figure 2: Distinction between gross and net OEE. By defining planned and external losses, a realistic net OEE can be calculated.
No. 63 | March 2012 | 18th Year
5
The Business Designers
How Compliant are Your
Medical Devices?
New Patient Rights Law and Its Effects
The German federal government wants to reinforce patient rights. In a joint initiative of the Ministries of Health and Justice,
a «patient rights law» is to be created. Among other things, it obligates the insurance companies and public health
care entities to support the insured in claims for damages. This would also have consequences for the manufacturers
of medical devices.
What does strengthening patient rights mean for the manufacturers of medical devices? Which scenarios can develop from
the initiative? Are even the rumored «American conditions» in
product liability menacing? Do manufacturers have to be
prepared to a flood of complaints?
A glance on the website of the relevant authority in Germany,
the Federal Institute of Pharmaceuticals and Medical Products
(BfArM), shows a growing number of incidents with medical
devices. An incident means: «Every malfunction or every
change in the characteristics and/or the performance as well as
any improper behavior in the labeling or the instructions for use
6
No. 63 | March 2012 | 18th Year
of a product can result in or has resulted in the death of a
patient or a severe deterioration of the health state of a patient
or a user …» (Directive 93/42/EEC, Article 10, section 1, paragraph a).
The Two Sides of the Same Coin
This does not necessarily mean that the quality of medical
devices or medical care has gotten worse. Rather, different
forces propel this development: On the one hand, there are the
growing expectations of today’s patients that they can fully
recover from following treatment or at least have major
improvements in the circumstances which have caused their
illness. This expectation is reinforced by the demands we as
people place on mobility – a loss of mobility is considered a
major restriction in life quality.
On the other hand, there is the rapidly increasing maturity of
today’s patients. This is partially accelerated by the change in
generation and with the associated self-awareness of younger
generations. This is pushed by the dynamic of the media
to bring damage claims to light quickly and in detail, often
peppered with a fundamental mistrust against industrial
companies. What is more obvious than attributing possible
errors to the failure of medical devices? The wave of complaints
is almost pre-programmed and here people forget that 100%
safety cannot be achieved or at least not at all costs.
Not to disregard the growing cost pressure on all parties
involved (health insurances, hospitals, or nursing care insurances). In case of a complaint generally costs occur for the
subsequent treatment of the patient.
Quality Audit Required
The positive approach to strengthening patient rights will
hardly pass by medical devices manufacturers without a trace.
In particular patient safety and thereby the quality assurance
system and the proof of quality assurance will still be more in
focus than previously. How persuasive are your test records?
Manufacturers who have validated their test methods may rest
easy! Manufacturers that did not see tests in the light of a
validation will probably come in the compulsion to act. Not to
disregard the control and storage of the test protocols,
especially with electronic systems this calls for computerized
systems validation (CSV).
In the very regulated pharmaceuticals industry, the «Batch
Record Review» is considered a tried-and-tested means to
scrutinize your own quality records. In US law for pharmaceutical products (21 CFR Part 820), this corresponds to the claims
in the «Device History Record» (DHR). Here, «state of the art» is
to link the product release for sales or implementation to the
review of the manufacturing and test protocols. Apart from this,
it is important with this review to recognize possible quality
issues or their patterns at an early stage.
In the future, manufacturers will subsequently have to pay
much more attention to the meaningfulness and unambiguousness of their quality records, known as proof documents. In
addition, the focus will be on the controllability of the production processes – how safe and reproducible is the production
result? Manufacturers who possess an efficient risk manage-
ment system over the whole production cycle of their medical
devices may probably rest here easy, too!
Is your QM system fit for authorities?
Would you present/make available your quality records to
an attorney or court with a clear conscience? Depending on
the implementation of the established quality assurance
system – on paper or in reality? – this may have major consequences, including imprisonment.
The fact that many companies have not yet arrived at a
compliant QM system is actually hard to understand. Since the
entry into effect of today’s legal ruling on medical devices –
90/385/EEC on active implantable medical instruments
(AIMDD), 93/42/EEC on medical devices (MDD) and the 98/79/
EC on in vitro diagnostics (IVDD) – 17 years have now passed.
That left enough time to optimize the established processes
and boost efficiency.
Meanwhile the required tools should be established by each
medical devices manufacturer in his organization. To be
mentioned in particular are risk management, qualifications
and validations, deviation management and the system for
corrections and preventative actions.
Fit for New Demands
The demands and rights of the patients are growing and
thereby also the effort and risk for medical devices manufacturers. How well prepared is your company for future challenges?
What about conformity of your pharmaceutical products?
Have you decided for a careful check or a rapid market launch?
The Chemgineering Business Designers gladly assist you in
implementing a future-proof system.
Martin Rümke
Senior Consultant Medtech Compliance
Chemgineering – The Business Designers
[email protected]
No. 63 | March 2012 | 18th Year
7
Chemgineering Group
Qualification and
Validation Alla Turca
Personal experiences when building a new pharmaceutical manufacturing plant in Turkey.
Chemgineering provided qualification and validation support for a Turkish pharmaceutical company in building a
new plant for contract manufacturing. Read the experience report of two participants from Business and Technology
Design here.
In the past few years, countries in southeastern Europe have
made economic and industrial progress, especially Turkey.
The country between the two seas has linked the Orient and
Occident for centuries and has rich natural and industrial
resources. Due to its strong and modern industry, the state is
attracting more and more investors and manufacturers.
Pharmaceutical production has played a major role in the
general industrialization for quite some time. In the past
two years, there have been several green field investments in
this area in Turkey, each valued at over 50 million Euros.
The desert lives
Chemgineering was awarded to accomplish design reviews in
the newly constructed plant of a pharmaceutical manufacturer,
8
No. 63 | March 2012 | 18th Year
to qualify the HVAC facilities and to validate the computerized
systems (CSV). The client’s production site is located in central
Turkey, far away from the port cities like Istanbul, Izmir or
Antalya.
As the perfect host, our client organized an exclusive hotel
accommodation and the efficient transport from the hotel to the
construction site with small mini-vans. The construction site
was located in an industrial zone comprised of several thousand hectares which went to the horizon and seemed endless.
Supposedly, this land was still a desert without asphalt and
traffic just a decade ago. Also the relatively new highway,
streets and buildings could be developed on it. Clearly large
amounts were invested here and certainly others are planned.
There must be quality
Design reviews and qualification could be performed without
interference. The design model was on a high level and required
a lot of care and experience. We communicated in English,
which the employees on the client side spoke rather well. Their
written English was even much better than verbal expression,
which was very important for creation of the documents. The
client employees were nice and very extroverted in terms of the
collaboration and about learning new things, particularly in the
area of qualification, a relatively new topic in Turkey.
The client tried to procure as much as possible of the equipment from domestic manufacturers but not at the cost of
quality. For example, AIR HANDLING UNITS FROM LOCAL
MANUFACTURER WERE INSTALLED. They were manufactured with the high quality as it is required in the pharmaceutical
industry. Equipment components such as HPW plants
or blister machines which are not produced in Turkey in the
needed quality were from EU manufacturer ordered and
installed. This means that our client was able to combine
domestic and foreign products of the highest quality for this
project respecting the local authorities, the EU laws and
the GMP guidelines.
Corporate management with SAP®
The construction of a new production facility also required
the redesign of the company processes and thereby also the
company software which should be used to control these
processes. Chemgineering was entrusted with assisting in the
validation of the SAP® system. This task included validation
coaching, validation planning and document review according
to GAMP 5®.
For handling the finance and controlling tasks the SAP® module
FI/CO was used which the company had been taken over from
the parent company. The topic of computer validation was
essentially new territory for the departments involved. At a joint
on-site workshop at the Istanbul headquarters, the validation
strategy was set with the most important milestones and
the tasks were prioritized. There was already some preliminary
work with the local implementation partners based on the
standard SAP® introduction method ASAP (accelerated SAP).
However, it was quickly clear that the procedure needed to be
more focused on the process. This required a lot of explanation
and persuasion. But this was the only opportunity to get a grip
on this complex project and to keep the test and documentation costs in hand based on risk.
Validating with a high level of motivation
The goal was, based on system-oriented specifications
(business blueprints – BBP’s), to divide the business processes
within the planned SAP® modules into main and sub-processes
in a practical manner and to develop the respective validation
documentation according to GAMP 5®. A universal multi-level
risk assessment provided information on the test scope and
depth. The Chemgineering expertise from comparable projects
was extremely beneficial. The time-consuming document
creation process was supported by new client employees who
were prepared in Istanbul for their future duties in the plant in
central Turkey. As consultants, we were very impressed by the
high level of motivation and the ability to grasp new information
quickly as shown by these young college graduates.
Soft skills demanded
All project members spoke somewhat fluent English. At the
same time, the communication turned out to be one of
the greatest challenges. A SAP® validation is per se no trivial
matter and it is not always easy to express special issues and
contexts in a foreign language in a direct and understandable
manner. In addition, for the purpose of a review, relevant
documents had to be translated into English or Turkish. Most of
all in e-mail communication this requires patience from both
sides. While the project was underway for well over a year, there
were status meetings every two to three months in Istanbul to
clarify unanswered questions personally, something which was
essential despite all modern communication technologies.
A decisive factor for the tasks as a consultant was a healthy
portion of human empathy. That is because there were situations which made it necessary to respond to a sense of
insecureness at some stages, to communicate between
departments or simply to motivate people.
Due to the high level of commitment of everyone involved,
the validation could ultimately be successfully concluded
and the SAP® system can begin operation with the official
go-live.
Ready for New Projects
Our client as well as other pharmaceutical companies are
planning the expansion of existing plants and building new
ones. Thus, various new investments are to be expected in
Turkey in the near future. Due to the positive experiences of the
Business and Technology Designers, Chemgineering is looking
forward to new projects in Turkey.
Dr. Peter Schober
Andrija Marinkovic
Senior Consultant
Project Engineer
Chemgineering – The Business Designers
Chemgineering – The Technology Designer
[email protected]
[email protected]
No. 63 | March 2012 | 18th Year
9
The Technology Designers
Labs Planned for
Transformation
Functional and future-oriented workspaces thanks to the experience of industry architects.
How does the general public define the term «lab planner»? The answer in most cases is: «A lab planner is comparable to a kitchen planner – he just draws equipment layout designs.» That is not entirely accurate, as there are
fundamental differences between planning a kitchen and planning a lab.
For example, a kitchen planner only goes into action when the
building has already been completed and he has to adapt to
existing situations. A lab planner, on the other hand, accompanies the planning process from the start. An industrial building
is planned from the inside out, the building design is tailored to
fit the interior. Ergo: Design follows function. The complex
planning of a lab requires the skills of a generalist who serves as
the interface between future users and all persons participating
in the planning process. He also has detailed knowledge of
relevant laws, ordinances and directives.
Start With A Dialogue
Lab planning does not begin with an inventory of existing
equipment and locations, but rather with a dialogue. This
dialogue with future users:
· helps getting to know the people and their individual needs
and
· benefits their work method in and around the lab.
In this, the most important thing is to understand the steps
required, to ask follow-up questions and to optimize, if necessary. These are the initial steps on the exciting journey from
project start-up to moving into the new lab. It is only after the
completion of this dialogue phase that the assessment and
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No. 63 | March 2012 | 18th Year
analysis of the information gathered can begin, eventually
resulting in a condensed picture of all relevant matters.
The result is an optimized planning basis in the form of a
diagram of all production steps, using short routes in the lab
and to required secondary rooms. The illustration is also used
to show possibilities for an effective work method. This diagram
allows «outsiders» – i.e. the planner and users – to get a
different perspective of the daily work in the lab. This «revelation» constitutes the basis for the start of planning and the
recording of technical data. Taking this and other influencing
factors into account, it is now possible to start layout development.
In line with requirements
Three key groups of factors have considerable impact on
laboratory planning (see Fig. 1):
· client requirements,
· requirements of construction laws / ordinances,
· lab requirements.
Among these, the client specifications are the most complex
influence group. Client interests and perceptions must be
brought into harmony with the respective legal regulations and
the specified budget must be met in the process. The other two
influence groups provide a framework which serves as a kind of
playing field. The planner is able to move relatively freely within
the boundaries of this playing field, which enables him, through
the creative interpretation of relevant laws and regulations,
to develop appropriate solutions despite narrow guidelines.
The incentive and the challenge for the planner lie in fully
utilizing this predefined framework to find innovative solutions
for every new and unique project.
Mastering interfaces
In addition to the influence factors listed above, there are many
interfaces between individual participants (client, user, architect, TGA, professional planner, fire protection, etc.) that must
be taken into account and coordinated (Fig. 2). This is both a
tricky and intense matter which becomes easier to control
using intuition and suitable tools.
The architect for lab planning becomes a «juggler» who
considers the pros and cons of all factors before designing a
tailor-made layout for the user. However, as stated above, the
number one influence factor is the client request.
A Perfect Solution: Everything from A Single Source
Simultaneous work is recommended in order to quickly achieve
planning results. Under the direction of the architect for lab
client
planning, the design team is divided into smaller teams, each of
which begins to develop the bases for individual project areas
independently. A regular exchange of information between the
planners is essential in order to communicate and present
established bases and possible concepts. An intensive
exchange results in the best possible result for the client at a
relatively early date in the project. The planning phase results in
a concept which combines the best of all areas and serves as
the basis for further planning. It is also an inestimable advantage that the client gets all planning services from a single
source and only has one contact person.
Rely on Experience
Practical experience shows that labs – especially research labs –
are usually modified, modernized and put to use again within
record time every two or three years. The rapid progress of
technology as well as frequent changes in the composition
of the user groups require flexible and convertible labs which are
quickly available for new work. Even in existing labs, this
flexibility can be realized to a large extent. Nonetheless, a small
amount of modification actions, particularly in the media supply
area, is always required to adjust the lab situation to new needs.
Leave nothing to chance and put your lab into the hands of
experienced lab planners and architects such as the Chemgineering Technology Designers. We will be happy to advise you.
· Internal Standards
· URS
· Cost
Client
Technical
Planner
Lab
Laws/
Regulations
Lab
· LBO
· EN / DIN Norms
· Fire Control
· ArbStättV
· BGV
Lab
Labor
Fire
Control
· Lab Guideline
· GMP / GLP
· GenTG / BioStoffV
· GefahrstoffV
User
Architect
Authority
Figure 1: Major demands placed on lab planning
MEP
Figure 2: Interfaces
Antonio Condemi
Abbreviations
TGA: Technical Building Equipment or MEP: Mechanical, Electrical and Plumbing
LBO: State Construction Ordinance
URS: User Requirements
ArbStättV: Workplace Ordinance
BGV: Professional Association Ordinances
GenTG: Gene Technology Law
BioStoffV: Bio-Materials Ordiance
GefahrstoffV: Hazardous Materials Ordinance
Architect and specialist for fire protection structural and
property monitoring (EIPOS)
Chemgineering – The Technology Designers
[email protected]
No. 63 | March 2012 | 18th Year
11
The Technology Designers
The Hospital Pharmacy
as a Pharmaceutical
Manufacturer
Prepare well for the inspection by the authorities
New rules determine when public and hospital pharmacies fall under the Regulation on Operating Instructions for
Medicinal Products (Arzneimittelbetriebsordnung). Thus the requirements for the manufacture, control and storage of
drugs in the pharmacy are tightened.
Have you already asked yourself whether your pharmacy is
bound to demonstrate an operational approval in accordance
with the Pharmaceutical Products Act (AMG)? According to this
law, pharmaceutical products which are transferred to other
public or hospital pharmacies in frequency, number and
quantity that go beyond regular pharmacy business have to be
recorded. If the regular limit for pharmacy businesses is
exceeded,1 the basic legal conditions for the manufacture of
pharmaceuticals change. In addition to the Pharmacy Practice
Order, the Pharmaceutical and Active Ingredient Manufacture
Ordinance (Arzneimittel- und Wirkstoffherstellverordnung) will
become the legal basis, and an operational approval is required
12
No. 63 | March 2012 | 18th Year
according to the Pharmaceutical Product Act (Arzneimittelgesetz). In most cases, the manufacture of cytostatics and aseptic
manufacture are involved.
Following Safety Regulations
In general, the law requires sufficient personnel protection
(workplace protection) and product protection in manufacturing of pharmaceuticals. Whereas aseptic manufacture poses
special demands on product protection, the preparation
of cytostatics, on the one hand, must comply with workplace
safety regulations and, on the other, meet pharmaceutical
standards. When manufacturing cytostatics, the greatest care
is to be taken in terms of personnel protection which may result
in conflicts between personnel protection and product protection. Here the interpretation of the spatial and technical
requirements raises questions as before. These safety requirements are summarized in particular in the cytostatics directives
of the federal states. In addition, for the manufacture of
cytostatics in pharmacies, the Pharmacy Operations Ordinance
(ApBetrO), the Pharmaceutical Products Act (AMG) and
the requirements of the EC GMP guideline including Annex 1
«Manufacture of Sterile Medicinal Products» should be
followed.
Clean Room Design
According to the GMP rules, aseptic manufacturing steps are to
be implemented in clean room class A with an environment
of clean room class B. Product and personnel protection can be
achieved in a simple way by installing an isolator. A high level
of protection can be achieved among other things by producing
in a closed system and maintaining a negative air pressure
difference. The air may not be recirculated or carried into other
areas. In addition, HEPA filters must be used for release of the
air into the environment.
Through such a closed system the environment can be reduced
to clean room class C and the costs for operation and monitoring can be considerably reduced. Via a controlled environment
the connection to other zones is established. Moreover,
separate air lock systems are to be set up for staff and materials. Thus, it should be ensured that the doors of the air lock
cannot be opened simultaneously. In addition, the rooms must
be protected from the access by unauthorized persons.
Qualifying Efficiently
Within the qualification steps it is reviewed whether all user and
GMP requirements in the planning and execution phase have
been taken into account and whether, following completion, the
required specifications can be met under production conditions. The qualification concept should therefore consistently
follow the approach of «slim qualification». If documents and
the experience of suppliers and qualification experts such as
Chemgineering are integrated, the time and personnel costs
are reduced considerably. This process can be flexibly adapted
to different tasks and project-specific concerns as required by
the operator.
1 According to the German Pharmacy Operations Order (Apothekenbetriebsverordnung,
ApBetrO), this number is 100 transferrable packages per batch or the corresponding
quantity in one day. In addition, in Austria, in collaboration with the Federal Ministry of
Health (BMG), AGES PharmMed, the Austrian Chamber of Pharmacists as well as
committed pharmacists, an assessment grid has been developed which allows a fair
and yet simple and practice-oriented (self-)evaluation despite the numerous
possibilities of each individual pharmacy due to a general approval obligation (§ 63
Arzneimittelgesetz, AMG). In accordance with Art. 19 c of the Swiss Pharmaceutical
Practice Order (VAM), there can be at most 3,000 transfer-ready packages
manufactured per calendar year as a subcontractor in accordance with Art. 9
paragraph 2b HMG with a total of maximum 90,000 individual bottles of a medication
according to Art. 9 paragraph 2 letters a–c HMG (Federal Law on Medications and
Medical Products or also the Pharmaceuticals Law, HMG). Every aspect of this
requires a certification and risk check of the relevant authority.
In Great Shape for Inspection
Does your existing documentation and quality planning
withstand inspections by the authorities? Due to the additional
requirements, an expansion to the GMP-oriented documentation can be necessary. Benefit from our experience from numerous pharmacy projects on the way toward operating approval.
Within just a few hours, a Chemgineering Fitness Check will
show you whether there is a need for action at your company.
Secure your market position now!
Dr. Gerald Banko
Project Manager Qualification
Chemgineering – The Technology Designers
[email protected]
No. 63 | March 2012 | 18th Year
13
The Technology Designers
Through Diploma Thesis
to the Job
Degree theses at the Chemgineering Technology Designers’ elaborate viable solutions to basic questions in the business. With
their herewith presented papers two graduands started their track at Chemgineering.
The Path of the Water
Since his degree thesis in 2009 at Chemgineering Technology
AG in Pratteln, the bio-engineer Thomas Peter (Dipl. Ing. FH
Bingen) has been involved with the topic of «Selective handling
of endocrine-active waste waters from biotechnology.»
According to the European Water Directive, water is «[…] no
conventional commercial good but rather an inherited material
which must be protected, defended and handled correspondingly […].»1 The goal of this is to protect and improve the
sustainable handling of water resources and the eco-systems
which directly depend on the water. However, the use of
chemicals and the handling of waste waters are being discussed publicly again and again.2
One of the best known groups of synthetically organic compounds (SOC’s) are the alkylphenols which were used for
decades in every branch of industry in large quantities. As a
result of their incomplete decomposition by the microorganisms at a sewage treatment plant, they get into the aquatic
environment as persistent (hard-to-decompose) and endocrine
(hormonally active) substances and with clearing sludge they
get into agriculture, too. To dam up these problems, the EU
decided in 2003 that the nonylphenol concentration in products
should be less than 0.1 mass %.
Also in the biotechnology industry, chemicals were used, e.g.
octylphenolethoxylates (OPEO) in downstream processing to
manufacture virus-free medicines. For this purpose, a threshold
limit value of 1 kg per plant and year was determined. This
forces companies to resolve the question: Which strategy to
14
No. 63 | March 2012 | 18th Year
clean or dispose of accumulated waste water is both environmentally as well as economically implementable? This issue
was the subject matter of my degree thesis. As the biological
and physical cleaning capabilities in the SOC’s do not offer any
satisfactory solution, the waste water current is often collected
separately in practice and later burned. Thermal oxidation of
the waste water under stress is therefore used as a benchmark
for strategy development.
The development of a concept for waste water treatment can
be subdivided into two phases: In the first phase of the selection process, the goal is to check for the effectiveness of
cleaning technologies in terms of the material-specific and
legally required threshold limit values. To approximately assess
this, in particular the know-how of planning specialists and
previously obtained experience were used as resources
besides trade literature. This analysis quickly shows which
methods get on the shortlist from the technical and financial
perspective. As alternative technologies for thermal oxidation,
first microbial decomposition possibilities, then advanced
oxidation processes (AOP) and adsorption possibilities were
taken into account in the degree thesis.
In practice, the composition of the waste water often cannot
be compared with the theoretical conditions. In a second
phase, this circumstance makes lab tests with the pre-selected
processes and the waste water to be cleaned essential. The
results obtained clearly show whether the tested technologies
can actually maintain the required decomposition values. They
also allow the acquisition costs and the later operating costs
of the respective systems to be reliably estimated or calculated.
Here it should be noted that the «chemical cocktail» in the
waste water can not only influence the effectiveness of the
process but also the analytics to be performed. In this phase,
it is a good idea to enter into a dialogue with the relevant water
authority and discuss the analytics.
The described procedure of the systematic concept development makes it possible to develop an action strategy which
gives the client both environmental as well as economic added
value. Major cost differentials can be achieved rather between
different technologies than between the technology providers.
Therefore, particularly an innovative strategy development
as the Technology Designers’ is a basis for sustainable waste
water cleaning which both takes the legal requirements for
environmental protection and the economic interests of the
client into account.
comparison and the conversations with the authorities, in this
case it was possible to define an AOP which decomposes the
endocrine material residual-free and can therefore meet the
required decomposition values. Due to the complete destruction of the OPEO and octylphenol (OP) during decomposition,
the client can now forego the unecological and expensive
combustion of the waste water.
1 Bmu.de; last update: March 2011
2 For example «Sewage treatment plants let through toxins, retrofitting is necessary»
in Tagesanzeiger.ch of March 18th, 2011 or «The hazardous chemical bisphenol A
could create erection problems» in Spiegel.de of November 12, 2009.
Thomas Peter
Project Engineer Special Technologies
Chemgineering – The Technology Designers
[email protected]
It has been shown in just a short period of time that this topic
is in no way «only» a theoretical task. For a client we could
create a concept for successful on-site treatment of the waste
water stream polluted with OPEO. As a result of the technology
Process Validation Guide
As part of her degree thesis completed in 2010 at Chemgineering in Pratteln, Sabrina Flad (Dipl. Ing. Pharmaceutical
Engineer Polytechnic Albstadt-Sigmaringen) created an
«Internal Guide for Process Validation» which is still consulted even today in projects.
The life sciences market is heavily shaped by authority and
market requirements in the GMP area (Good Manufacturing
Practice). In addition to the legal specifications, there
are additional influence factors which have to be taken into
account in the GMP area, such as directives, guidelines,
standards and the current market standard. They give planners
the following challenges when implementing GMP projects:
· There are various laws and guidelines which are continuously
further developed.
· In laws there are often no clear statements, only rough
descriptions of the requirements.
· There are different definitions of the terms for the same or
similar activities.
· The described requirements and content of the steps which
ensure quality can be interpreted in different ways in a GMP
project and the overall project life cycle.
· The GMP activities, quality assurance of the Good Engineering Practice (GEP) and the tests required by law are not clearly
differentiated from each other.
· There are many conceptual methods provided by numerous
publications.
· There are also different client concepts which sometimes do
not account for the company size, the product range and the
previously indicated requirements.
The research revealed that a structure is required for the whole
validation. This helps to clearly differentiate the system
qualification from the process validation as well as to clearly
and distinctly describe the definitions and the contents of
qualifications and validation steps with the respective activities
(see Fig. 1).
The resulting Chemgineering guideline «Process Validation» is
used for internal training, project implementation, consulting
assignments, service delineations in the offer phase between
the client and the service provider as well as for concept
proposals to clients who still do not use an established qualification concept.
Validation
Equipments, Facilities
Processes, Procedures, Methods
Qualification
Process Validation
· Design Qualification DQ
· Installation Qualification IQ
· Operational Qualification OQ
· Performance Qualification PQ
· Validation of Methods
· Process Validation
· Validation Batches
· Cleaning Validation
· Sterilisation Validation
· Transportation Validation
Figure 1: Classification of Validation
Sabrina Flad
Project Engineer Pharma Design
Chemgineering – The Technology Designers
These requirements were analyzed in greater detail as part of
the degree thesis and all were combined into a uniform guide.
The creation of this guide first required extensive and thorough
research in the different bodies of legislation and their correlations.
[email protected]
No. 63 | March 2012 | 18th Year
15
QuickNews
Chemgineering Group
The Business Designers
The Technology Designers
Chemgineering Business Design AG
Güterstrasse 107
4133 Pratteln 1 | Switzerland
T +41 61 467 89 00
Engineering Strongly Positioned for Your Projects
The Power of 150,000 Volt
From 2012 on, the business unit Engineering of Chemgineering Group has strengthened their market orientation by transnationally organizing themselves in specialist
disciplines. Overall more than 150 Technology Designers are available as strong and
flexible partners for your projects.
The following chart gives you an insight into the new structure: «Project Delivery» is
now being led as an own department. In addition, the lineup of the project directors
strengthens the meaning of projects. We primarily develop our employees in a
so-called know-how management pool. Depending on their expertise, our people
contribute to the corresponding specialist groups within six further departments.
The Technology Designers
In this new constellation, we are looking forward to provide you with «viable solutions for life sciences» in 2012 and beyond!
Project
Delivery
Project
Directors
Project
Managers
Construction
Managers
Pharma
Design
Solida
Liquida
Packaging
Process
Design
Process 1
Process 2
Process 3
Energy/
Infra
HVAC
E+I
Automation
Building
Design
Q/V
Compliance
Q/V
Compliance 1
Q/V
Compliance 2
Special
Techn.
Biotech
Clean Media
Logistics
Simulation
Plant Design 1
Plant Design 2
Maintenance
CAD
Plant Design
Project
Support
Chemgineering
Business Design GmbH
Kreuzberger Ring 13
65205 Wiesbaden | Germany
T +49 611 77 88 70
Chemgineering
Business Design GmbH
Gusshausstrasse 22
1040 Vienna | Austria
T +43 1 255 74 13
The Technology Designers
Chemgineering Technology AG
Güterstrasse 107
4133 Pratteln 1 | Switzerland
T +41 61 467 54 54
Chemgineering Technology GmbH
Kreuzberger Ring 13
65205 Wiesbaden | Germany
T +49 611 77 88 70
Energy &
Infrastructure
Chemgineering Technology GmbH
Gusshausstrasse 22
1040 Vienna | Austria
T +43 1 255 74 13
Chemgineering d.o.o.
Suboticka 23
11000 Belgrade | Serbia
T +381 11 241 25 55
Publishing information
Editor: Chemgineering Holding AG
Corporate Communications, Uta Ünal
Güterstrasse 107 | 4133 Pratteln 1 | Switzerland
www.chemgineering.com
Design: WOMM Werbeagentur AG, Basel
Print: Schwabe AG, Muttenz/Basel
Circulation: 1500 copies
Printed on FSC-certified paper
16
No. 63 | March 2012 | 18th Year