Online Exclusive from PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE
January/February 2012, Vol. 32 No. 1
www.PharmaceuticalEngineering.org
©Copyright ISPE 2012
This article
presents a
perspective on
what the Facility
of the Future
will look like
as envisioned
by ISPE’s API
community.
The concepts
in the article
will form the
basis of a series
of planned
ISPE Guidance
Documents.
Facility of the Future
Facility of the Future
by the Active Pharmaceutical Ingredients Community
of Practice (API COP)
T
Introduction
his article provides the API COP’s perspective on what it thinks the Facility of
the Future will look like. While some of
it is serious and some tongue in cheek,
the key concepts discussed will form the basis
of a series of ISPE Good Practice Guides being
planned by the API COP.
If you read this and think “No, it won’t look
like that,” then don’t hesitate to put pen to paper
or digit to keyboard! This article is intended
to initiate discussion and debate among ISPE
Members. You are invited to take a survey (the
link can be found at the end of this article) to
help the API COP further clarify and focus on
specific areas where the development of a Good
Practice Guide or other industry resources could
be useful and influential.
What Does the Facility of the
Future Look Like?
We believe that high volume API blockbusters
will be exceptions; the trend will be toward
smaller volumes and increased potency. Manufacturing sites will need the ability to manufacture small batches and have the flexibility
to run small campaigns. We will see increasing
cost of goods pressures driven by more complex
molecules and market price pressures. This
will increase the pressure to deliver processes
with innovative and cost-efficient chemistry
and technology.
The key drivers for the next generation of
facilities, equipment, and processes include:
• capital cost – compete globally considering
the increasing cost of transportation
• operational costs – compete with low cost
locations
• process robustness
• application of continuous monitoring/design
space
• approvals for product platforms rather than
individual compounds
• risk-based approach – quality focus on the
appropriate areas (including equipment
qualification/process validation)
• safety (high energy reactions nitrations,
etc.)
• environmental costs – going green (low energy use, recyclable materials)
The Facility
Traditional Build
Much as we may like to think of the high quality of traditional craftsmanship, there is really
little likelihood of a timber frame facility. It may
be sustainable, it may be durable, but it is not
resistant to pests, it changes shape with the
climate, and (most importantly) takes a little
while to construct and finish.
• capability for high potency, lower volume
products as well as traditional high volume
products
• rapid build and commissioning – pre-commissioning of packaged equipment
• flexibility – modularity/ease of configuration
of equipment modules
• portability
• agility – speed of response to market changes
January/February 2012 PHARMACEUTICAL ENGINEERING Online Exclusive
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Facility of the Future
Rapid Build
No to all of the above; well, it’s not really likely, is it! What
is more likely is a standard rapid build form of construction,
such as tilt up or pre-stressed concrete or steel frame with
precast panels – this use of “standard” modules would allow
a very rapid construction of a weathertight enclosure so that
internal work can take place regardless of external weather
conditions.
Internal construction can then proceed using:
• traditional methods – metal studwork and sheetrock with
suitable finishes
• standard panel cleanroom systems
Tudor (1500's) Timber Frame House in York (UK).
Other options that are potential solutions to the requirement
of minimum times on site:
• Internal fit out with premade process modules; each box
containing a platform standard module.
• The main building may provide the administrative and
general support areas with the transit corridor allowing
prefabricated modules with all the process equipment to
be located and placed onto the main building.
• Another option may be the use of “standard” size open areas
dedicated to a production line – all standard size with an
opening that will allow dedicated process modules to be
exchanged depending on the market demand.
The Manufacturing Environment
Brickmaking in the UK!
What about a slightly more modern approach – put up a
brick kiln and build a brick building. No chance there then –
slower to build and more expensive, but perhaps more robust
and attractive.
Modern Brick built house (1714) York (UK).
2
• API manufacturing is done with closed processes, obviating
the need for controlled environments, except for control of
chemical and potent product exposure.
• Biotech processes are completely closed with true-aseptic
sampling that again minimizes the need for controlled
environments.
• The biotech area of the facility is designed with open spaces,
cleanable finishes, coved floors and ceilings to maintain
the appearance of a high quality manufacturing facility,
with no "pre viral" and "post viral" facility separation. All
separation is in the equipment trains.
• The process equipment is made up of close coupled equipment, with a mobile Laminar Air Flow (LAF) that can be
moved down the line to provide high quality protection to
any open ports where addition is required.
• In normal operation, the equipment is pressurized by
nitrogen or clean air after Clean-in-Place (CIP) and Steamin-Place (SIP), providing protection of the product.
• The charging operation is fully contained within an isolator, equipped with CIP/SIP.
• The charging operation could also be Blow/Fill/Seal (BFS),
fully contained in a low grade background.
• The charging equipment is fully robotic - no glove ports,
no operator interventions.
• Lighting and HVAC occupied/unoccupied set points are
controlled by occupancy detectors.
• Open process cleanrooms utilize adaptive control of airflow
and velocity.
PHARMACEUTICAL ENGINEERING Online Exclusive January/February 2012
Facility of the Future
• 100% OA units are no longer used for any application except hazardous gases. Appropriate filtration and particle
monitoring control cross-contamination and operator
exposure where necessary.
Process Technologies
The introduction of innovative technology and continuous
processing brings with it many new opportunities in the area
of operations. In the recent past, the pharmaceutical industry
has almost exclusively focused on batch processing due to the
flexibility of multipurpose batch manufacturing plants. The
ideal API process would implement the best and lowest cost
process and process equipment for each unit operation.
Should the plant of the future be constrained to
a single processing philosophy?
Batch process technology is flexible, widely available, and
applicable across a range of scale. It has been used successfully for many chemistries and for many unit operations.
Limitations in mixing, heat transfer, and mass transfer make
it less than optimal for many operations, yet the performance
is frequently adequate and in some cases very good.
Fully continuous processing replaces the batch paradigm
with a flow paradigm, utilizing operation specific technology
at each step of the process. The ultimate vision for continuous processing has raw materials entering the process and
fully tested drug product discharging at the other end, even
moving directly to packaging. This vision eliminates all areas
where the process is not actively moving forward to the final
product.
Or can we have the best of both worlds?
Hybrid processing can be thought of as a combination of
standard batch technology with new/innovative/continuous
technology. Specific operations are targeted for improved
performance utilizing technology designed for that specific
process requirement. A hybrid process might use new technology for a single, specific operation or for an entire portion of
a process. Examples of hybrid processing include:
a. Coupling a continuous reaction with batch work-up, crystallization, and isolation.
b. Coupling a batch reaction with a continuous work-up step
(separation, extraction, distillation), followed by additional
batch processing.
c. Coupling batch processing with continuous crystallization.
With multiple options available, it is important to determine
which choice will achieve the best cost/benefit ratio for the
Facility of the Future. This requires discerning which benefits
are available (because the technology enables improved chemical/productivity outcomes) and which benefits are inherent
in the application of new technology (even if the chemistry/
productivity outcomes remain the same).
Potential Areas of Focus
This includes:
• Use of portable or single-use equipment.
• Robust equipment design and lower in-situ total system
energy to enable safe operation of chemistry deemed too
hazardous for traditional batch equipment.
• PI/continuous processes to offer increased concentration,
better selectivity, and improved yields resulting in less
waste.
• Green guidelines including capabilities for recycling operations and use of energy-efficient equipment.
• Contained manufacture of highly potent or toxic drug
substances.
• Process control to provide enhanced process knowledge
and facilitate.
• Real time release in lieu of end product testing.
Process Development and Design
Pharmaceutical companies are looking at process design differently these days. With the addition of new technologies and
continuous processing come new opportunities to integrate
chemistry, engineering, and process modeling to achieve lower
cost and better process understanding. The development and
design of these processes will require a multidisciplinary approach. A variety of design and modeling tools will be necessary
to make process development most efficient. Leveraging the
strengths of both research and manufacturing during process
development and design will drive down manufacturing costs
earlier in the product lifecycles, but require integrated working across departments.
Utility Systems
• The site potable water is monitored to ensure that it
remains in the expected seasonal range for conductivity,
TOC, and microbial levels.
• The Purified Water (PW) system operates on a stop start
basis with online monitoring of the microbial levels – if
increases are seen on system start up, then the system is
heat sanitized. The total microbial levels as well as conductivity and TOC are monitored continuously and used
to confirm that the system is fit for use.
• The WFI is generated from an additional UF stage on the
PW system, with independent monitoring systems.
• WFI recirculated after use in areas where there is no product exposure, e.g., vial washing is recycled back through a
ceramic UF to the WFI polish stage.
• The compressed air system uses water lubricated high efficiency compressors to supply the site demand, the heat
generated from compression is used to regenerate the
desiccant dryer. The air is continuously monitored for total
particulate, pressure dew point, and hydrocarbon levels.
• The majority of the controlled valves in the utility systems
are electrically driven. Any adverse trends in system performance will cause a local alert alarm in the production
areas, with an action alarm if the system performance
exceeds acceptable limits.
January/February 2012 PHARMACEUTICAL ENGINEERING Online Exclusive
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Facility of the Future
Conclusion:
What About the Ultimate Vision?
It is helpful to have an ultimate vision of where innovative
technology might lead (with respect to equipment, process,
plant, and organization). Without an ultimate vision, barriers (real and imagined) can result in inertia providing the
greatest barrier of all. Vision provides the impetus to keep
moving. The vision in this case is integrated API and drug
product manufacture. A single-factory manufacture of Drug
Product (DP) starting from excipients and API intermediates.
This would be an integrated facility with real time release
of API into DP, minimum or zero API storage, and very fast
supply chain response. Processes would be developed by a
single development team enabling them to deal with linkages
between API and DP without organizational barriers.
Could there even be more to the ultimate vision? When
thinking about the future of the pharmaceutical industry as
a whole, we cannot forget the growing focus on personalized
medicines. This could lead to much greater numbers of very
low volume products. These APIs are likely to be complex
and difficult to make. How will our facility of the future look
like in order to meet this demand? A highly automated unit
or skid capable of making a myriad of minor changes, either
individually or in multiple combinations, would be highly
desirable. This also could then lead to more production on
demand where the medicines are not made until the prescriptions are written.
About the API COP
The API COP proactively advocates the importance of API
in the drug product delivery process with the objectives of
providing a forum for members to discuss issues of common
interest.
Image Sources
Photo 1: http://www.hearthstonehomes.com/commercial_
structures.html
Photo 2: http://www.yorkhistoryinpictures.co.uk/tudor_stuart.html
Photo 3: http://www.google.com/imgres?q=hand+brick+m
aking+in+the+UK&hl=en&sa=X&rls=com.microsoft:en-u
s&biw=1920&bih=952&tbm=isch&prmd=imvns&tbni
d=_yURbJLzQl8_5M:&imgrefurl=http://madpotter-oldcanalpottery.blogspot.com/&docid=MpBf2L8EmnlJNM&imgurl=h
ttp://1.bp.blogspot.com/-_IP_KVR-ODs/Tg9U8bvO32I/AAAA
AAAAAdo/2NvV2v7Q4wM/s1600/todd%25252527sbrick1910.
JPG&w=1600&h=1227&ei=JPYET-uLN8mriAKon7CUDQ
&zoom=1&iact=hc&vpx=1279&vpy=304&dur=296&hovh=
197&hovw=256&tx=173&ty=146&sig=11528888516088437
5757&page=1&tbnh=136&tbnw=177&start=0&ndsp=45&v
ed=1t:429,r:15,s:0
Photo 4: http://www.yorkhistoryinpictures.co.uk/tudor_stuart.html
Take the Survey, Shape the Industry
We want your feedback on the concepts discussed in this article. Take the survey
and help guide the industry toward your vision of the API Small Molecule Plant
of the Future. There is a dedicated section at the end of the survey for your own
serious or tongue in cheek comments.
Here is the link to the survey:
http://apismallmoleculeplantofthefuture.questionpro.com/
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PHARMACEUTICAL ENGINEERING Online Exclusive January/February 2012