Medicine for the pharmaceutical industry
The
pharmaceutical industry is under pressure from a number of sources. Spending
on pharmaceuticals has grown significantly in recent years and continues
to rise as diseases can be treated earlier and more effectively and, as
a result, the cost of healthcare is spiralling, with new "lifestyle" drugs bringing an additional burden. Whilst governments are taking steps
to control the rising cost of healthcare, the pharmaceutical industry
needs to replenish a pipeline of blockbuster products that will lose patent
protection over the next few years. Generic manufacturers with their low
cost manufacturing operations are ready to capitalise on these opportunities
so the major pharmaceutical manufacturers need to place increased emphasis
on manufacturing efficiencies.
Over the course of the last 20 years in the US, pharmaceutical sales have
increased by around 12% per year1. China, the world's seventh largest
pharmaceutical market with sales of $9.3 billion in 2000, is also growing
at an annual rate of 11%, according to a recent study by McKinsey &
Company1. The combination of the introduction of over-the-counter-sales
in 1999, together with more Chinese paying for their healthcare, and
a move towards increased distribution of pharmaceutical products provides
a major opportunity for pharmaceutical companies.
Increased regulation
Meeting increased regulation is a major challenge for pharmaceutical manufacturers.
In the US, all drugs must be manufactured in accordance with current Good
Manufacturing Practice (cGMP) regulations, governed by the Food and Drug Administration (FDA). The company
manufacturing the drug must therefore prove that they have been in compliance
with the regulations at every stage before a drug can be released to the
market.
Process Analytical Technologies (PAT) is a new initiative established by the FDA for the pharmaceutical industry to improve both drug product quality and manufacturing efficiency. The PAT initiative is intended to facilitate the introduction of modern process analytical technology tools and concepts to the manufacturing sector of the pharmaceutical industry. The FDA believes that using more modern methods of production would reduce costs and get more medicines to market more quickly.
According to the Centre for Drug Evaluation and Research (CDER), a current good manufacturing process allows about 10% waste - an error rate that would be unacceptable in many other industries. When compared to other manufacturing sectors, such as the automotive and semiconductor industries, internal production efficiency in the pharmaceutical industry is not high, with significant batch rejection rates (often up to 30%) due in part to a lack of true process understanding.
The main goals of PAT are to provide additional regulatory attention to those aspects of manufacturing that pose the greatest potential risk and to ensure continuous quality assurance and safety. Although many companies are already using process technologies to some extent, PAT will bring opportunities for real-time monitoring, rather than batch formula processing, to reduce the risk of poor process quality and out of specification materials. This should benefit Spectris companies: for example, particle characterisation systems from Malvern, X-ray analysis instrumentation from PANalytical and near-infrared systems from NDC Infrared Engineering are expected to play a key role in helping pharmaceutical companies to meet the demands of the new PAT initiative.
Reducing development costs
Another key issue is research
productivity. The need to measure ever-smaller particle sizes or more
parameters, as well as increase sample throughput through automation,
is driving investment by pharmaceutical companies in particle technology
equipment. New drug formulations and delivery systems place increasing
emphasis on understanding physical properties such as size and shape.
With the average cost of developing a new prescription medicine reaching over
$800 million2, there are significant opportunities for improving processes
and reducing costs.
Providing instrumentation
to improve manufacturing and development processes
Spectris involvement in the pharmaceutical industry starts with the development
of new products. Particle size and shape are critical to the integrity
of a drug, whether this is a powder, a spray or an emulsion. The performance
of a drug depends on the known interaction of the ingredients in order
to provide the required dose in a precise location and every batch of
drugs produced must be identical in formulation. Alterations in the particle
size distribution can lead to poor quality of the end product, as well
as material wastage and reduced throughput. Malvern's Insitec system
monitors particles continuously, on-line, enabling particle size distribution
to be improved and inconsistencies in product quality reduced compared
to conventional off-line sampling methods. Conventional methods are limited
by slow response times feeding back into the process and the potential
for changes in the sample once it has been removed from the process stream.
Using Insitec, product quality can be controlled within 2-3 minutes of
start-up rather than the 20-30 minutes required previously.
"Each
gram saved is a real gain and we can now perform much better
in a sector where high quality is crucial."
Hubert Müller, Siemens Axiva GmbH, Malvern
Insitec user
Use of the Insitec system also plays a part in improving safety in the manufacturing process. Many powders are toxic and by enabling samples to remain in the process line, rather than exposing operators to powder emissions by manual sampling, the system is both safer and reduces product wastage.
Drug development
and quality control
PANalytical's main applications are in drug development and quality
control. During the manufacturing process small variations in, for example,
temperature or pressure may change the morphology or crystalline state
of the active ingredient in the final product, influencing the effectiveness
of the drug. There is thus an increasing need to analyse the final oral
dosage form.
X-ray powder diffraction (XRPD) has many applications in the pharmaceutical industry - from drug discovery, pre-formulation and formulation, through to manufacturing and quality assurance. In all of these areas, XRPD is used to determine the crystallographic constitution of the sample from which the physical properties of an active pharmaceutical ingredient or an excipient can be derived. In contrast to other commonly used techniques, X-ray analysis is non-destructive.
In addition to the major pharmaceutical manufacturers, drug development departments of "smaller" generic drug manufacturing companies are increasingly introducing XRPD techniques into drug development. There is also a growing trend towards introducing XRD techniques in production control as a result of the increasing need to analyse the final oral dosage form and to trace small compound amounts. An example is the use of PANalytical's X'Celerator detector to analyse the crystal structure of aerosols to quantify small amounts delivered by an inhaler. One of the most important problems with inhaler-delivered drugs is dosing uniformity. Previously, X-ray diffraction measurements on final aerosol products were difficult due to specific sampling techniques, small quantities of sample and very long measurement times. However, PANalytical's X-ray diffraction systems, with the high-speed data collection offered by the X'Celerator detector, can be used effectively for measurements on aerosol formations.
Quality control is critical to drug safety
Particle Measuring Systems supplies instrumentation to satisfy the US current Good Manufacturing Processes regulations that the products have been manufactured in a controlled environment. Known as cleanrooms, these environments are rigorously monitored to ensure non-contamination. Particle counters from PMS are used by the major pharmaceutical manufacturers to ensure that their cleanrooms meet the required standards. Continuous monitoring is carried out for air-borne and surface particulates which may cause contamination.
Providing instrumentation
for packaging and labelling
Pharmaceutical manufacturers use bar codes to track work in progress and
for labelling, in conformance with the FDA's Good Manufacturing
Processes. In addition, in March this year the FDA announced a proposed
rule to require pharmaceutical packaging to be labelled with the National
Drug Code number encoded in a bar code. The FDA also proposed allowing
pharmaceutical manufacturers to include other information in this bar
code, for example batch number and expiry date.
Many manufacturers already
do this, as it facilitates accurate and automatic recording of information
at any stage in the production process and enables them to isolate quality
or compliance problems or to subsequently recall products. Microscan's
bar code scanners are used by manufacturers in a variety of pharmaceutical
research and production applications ranging from automated pipetting
stations to integration onto robotic arms and liquid dispensing equipment.
Microscan's latest product, the MS-3 laser scanner, can read bar
codes on test tubes, reagent packs and microtitre plates within a distance
of 40mm. The scanners have been specifically designed for integration
into clinical analysers and instruments, meeting regulatory as well as
budgetary requirements without compromising performance. (Click here to view article in last issue of Perspectives) Laser scanners also minimise the possibility
of inadvertent contamination in production areas where cleanliness is
critical.
NDC's near-infrared instrumentation (NIR) is widely used in the pharmaceutical industry, with its main application to determine the level of moisture and process end point in fluid bed drying pre-tabletting. Achieving correct end point moisture is critical: too high a moisture level and the tablets will crack in the tablet press. Too low a moisture level and they may crumble in the process. Additionally, overdrying may cause product damage with the consequential loss of a batch worth as much as £2.5m. Traditionally, control of fluid bed dryer end point with NIR has been unsatisfactory due to contamination of the sight glass window which prevents the instrument from seeing the product changes. NDC have developed a patented vision system, PharmaView, which allows unimpeded viewing of powders in a fluid bed drying process and allows accurate process control. This represents a major leap forward in solutions engineering and also meets the PAT objectives of dependable process monitoring.
At the end of the manufacturing process, Loma's checkweighing and inspection equipment ensures quality control of the final product. One customer, Allergan Pharmaceuticals, uses Loma's checkweigher for its contact lens solutions line. Contact lens solutions vary greatly in composition and suitability for different types of lenses and it is vital that a box contains the correct quality and quantity and also an instruction leaflet to protect the customer. Loma's checkweigher examines packs of products to ensure they contain the correct number of items and can adapt to the 30 different variations of packaging and size that the products are available in. Around 60 packs per minute are checked on the production line, equating to some 5 million tablets and 80 million bottles per year.
Conclusion
The growing demand for safer, more effective medicines to treat an ageing
population, together with an increasing focus on "lifestyle"
medicines in response to consumer demand, provides a strong foundation
for continued growth in the pharmaceutical industry. However, increasing regulation, higher costs, and greater competition bring challenges for pharmaceutical manufacturers. With their ability
to provide instrumentation to help manufacturers to meet
these challenges, significant opportunities exist for Spectris companies
in the future.
References
1. Nathaniel J Cosper, McKinsey & Co.
2. Journal of Health Economics 22 (2003)
Glossary
FDA - US Food & Drug Administration
PAT - Process Analytical Technologies initiative
cGMP - current Good Manufacturing Processes
NIR - Near Infrared Radiation
XRD - X-ray Diffraction
XRPD - X-ray Powder Diffraction