It has been estimated that reducing inventory levels across the pharmaceutical industry to those already achieved by the very best pharmaceutical manufacturing facilities could deliver a one-off cash release of $76 billion. A further reduction to inventory levels achieved in other manufacturing industries would be worth another $15 billion.

  Process analytical technology (PAT) is a key enabling technology to deliver these savings. 

During the last 20 years, the use of on-line spectroscopic techniques for process monitoring and control has become commonplace in the petroleum, petrochemical and chemical industries.

  This is not true for the pharmaceutical sector, which has been slow to adopt on-line analysis and advanced process control techniques. Even though robust process analysers are available, the use of spectroscopic techniques such as Fourier transform infrared (FTIR), near infrared (NIR), mass spectrometry (MS) and Raman together with chemometric multivariate analysis tools remains primarily the domain of specialist analytical groups and isolated quality assurance (QA) laboratories in the pharmaceutical industry. Implementation on-line has been led by innovative groups of analysts and engineers who have recognized the potential of these techniques to improve understanding, help resolve existing manufacturing problems and decrease operating costs. Their successes are notable in view of the conservatism of the pharmaceutical industry as a whole, which has tended to act as a barrier to innovation and change, particularly in the manufacturing domain.  

The climate for on-line analysis and advanced process control in the pharmaceutical industry is currently undergoing rapid and radical change. "

Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach

Innovation and Continuous Improvement in the Pharmaceutical Industry

" highlight the support of FDA for continuous improvement in pharmaceutical manufacturing.

  At the same time, the requirement to reduce costs is becoming a high priority in Big Pharma boardrooms.

  The resistance to change of a traditionally conservative industry has been much reduced by this combination of a supportive regulatory environment and external cost pressures.  

The PAT concept is completely aligned with the wider FDA goal of a science and risk-based approach to current good manufacturing practices (cGMPs). PAT is defined as "a system for designing, analysing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality".

  As a direct consequence of the "cGMPs for the 21st Century" initiative, the pharmaceutical industry is experiencing pressure from the regulator to address concerns around limited process understanding, process inefficiencies and continuous process improvement through the adoption of PAT. This paper will describe four key elements of a PAT implementation: 								

 building a science-based knowledge base 

 implementing a PAT system — regulatory strategies. 

The PAT guidance emphasizes the need to develop a deep understanding of the underlying scientific principles behind pharmaceutical manufacturing processes to determine the parameters critical to process and product quality. The knowledge base provided by the PAT approach is valuable in three main ways: 								

 It is a foundation for robust process and product design. 

 It supports and justifies flexible regulatory paths for innovative new approaches. 

 It facilitates continuous learning throughout the product life cycle. 

The design of experiments, and the capture and evaluation of analytical measurement data are essential parts of building the knowledge base.  

Knowledge capture is recommended at all stages of the product and process life cycle, beginning at the preformulation stage and extending through formulation, lab-scale production, scale-up, pilot plant and full-scale manufacturing (Figure 1). 

 Figure 1 A knowledge base is the foundation upon which a PAT system is based.			

In R&D, the PAT approach is concerned with the capture and evaluation of information from research studies on synthesis characterization, stability and alternative dosage forms using new and conventional methods of analysis. Examples of relevant data include records in laboratory notebooks; measurements recorded by analytical equipment; the results of process modelling; and results from laboratory and pilot-scale experiments. Networked IT systems and data management and analysis software provide the means to store, access and mine the information in a practical and, crucially, traceable manner. 

Data collected from scale-up production batches and manufacturing batches is added to the knowledge base as it becomes available during the product life cycle. Typically, this includes data on raw material attributes, process parameters, product quality attributes and environmental conditions, and with time, the full range of variability is represented. Examples of sources of variability that are often only fully revealed with time include  										

 Variations in the raw material supplier manufacturing processes that impact the chemical and physical attributes of the supplied materials. 

 Time-based variations in manufacturing performance (e.g., between equipment maintenance events). 

 Long-term equipment ageing and degradation effects. 

 Effects linked to planned changes to equipment/analyser hardware and software. 

 Individual ways of working (i.e., variations attributable to people). 

 Changes in the local environment (e.g., temperature and humidity). 

This type of PAT knowledge base is of most benefit when it provides a means to evaluate the applicability of the established multifactorial relationships between process and product attributes in different scenarios; for example, by enabling the prediction of the effect of different combinations of process attributes on product quality. This capability is underpinned by general developments in IT technology, which have led to the decrease in costs for hardware and software, and the increasing availability of sophisticated statistical analysis, data modelling and knowledge management applications. As a consequence, establishing and maintaining a knowledge base is well within the reach of all pharmaceutical companies. 

Key differences between current practice in pharmaceutical manufacturing and a PAT approach can be summarized as:  									

 The use of novel analytical technologies.  

 The establishment of multifactorial relationships between materials, process and environmental conditions, and an understanding the consequences of these relationships for product quality and process robustness.  

Following a PAT approach, the understanding of the interaction between process and product is the basis for the design of the process monitoring, process control and QA strategies used in manufacturing.  

It is important to realize that process analysers and PAT tools that are used only for monitoring incoming raw materials, process variables and process end-points do not constitute a PAT approach. Rather, PAT is an integrated approach in which the results obtained from the real-time analysis of critical process control points are used to control the process in some way. During manufacturing, process parameters are adjusted (within clearly defined limits) to produce the desired product quality attributes at the process end-point (this may mean a process unit operation or the process as a whole). The automation systems required for this level of process control are available today and are used extensively in the chemical and petrochemical industries. Figure 2 shows an example of the degree to which the integration of process control sensors has already been realized. Indeed, the same automation systems are already in use in the pharmaceutical industry, but they are rarely integrated with process analysers. Data management is also extremely fragmented, with individual storage, analysis and review tools for each process analyser, preventing the evaluation of trends, and cause and effect relationships. 

Figure 2 Advanced extended process control systems are available and can be integrated with process analysers to realize integrated PAT systems for manufacturing.			

Another outcome of using a PAT approach in manufacturing is a move away from end product quality control to a real-time QA approach, which gives rise to a change in the definition of quality decision criteria, and this includes acceptance criteria. The most important differences are: 									

 A move away from time-based end-points towards the attainment of defined quality attributes. 

 The use of rigorous statistical principles to define acceptance criteria for product attributes based on the nature of the test and the sample size. 

Figure 3 shows the installation of a NIR process analyser probe in a fluid bed dryer. The drying time is controlled by the measurement of the moisture content of the product, moving away from a time-based end-point. Taking the PAT approach a stage further, the dryer operating parameters can be controlled within predefined process limits to ensure that the dryer is operating in the most efficient drying regime. With this approach, drying cycle times can be reduced by 25–50% while delivering product with a more repeatable particle size distribution, as well as moisture content, to the next processing step. 

Figure 3 NIR probe mounted in a fluid bed dryer used to monitor and control the drying process (photo courtesy of Glatt Air Technologies).			

An example of the use of rigorous statistical principles is the real-time release (RTR) of final product based on on-line or in-line analysis. The PAT guidance indicates that on-line analytical methods for real-time release should be managed as an alternative analytical procedure for product release according to existing guidelines and regulations, and a number of pharmaceutical companies are investigating or have already submitted NIR-based methods for release testing to FDA. It follows that batch records will also need to be reported using methods of evaluation that are appropriate for this type of data; that is, as acceptance ranges, confidence intervals and distribution plots showing variation between and within batches. 

FDA encourages the use of the PAT approach for new drug applications (NDAs) and for approved products. In the case of approved products, data can be collected during manufacturing from process sensors and on-line analysers, and evaluated using PAT tools to establish the scientific basis for moving to a PAT approach. The PAT guidance indicates a variety of risk-based approaches to managing the introduction of on-line analysers into existing processes with the aim of minimizing the regulatory burden for the manufacturer and encouraging innovation. The guidance clearly states that data collected in this way from existing processes, for the purpose of improving process understanding, would be considered research data and would not normally be relevant for regulatory inspections. 

To demonstrate the validity of the in-process measurement results and process monitoring and control systems, the elements of the PAT system will need to be validated according to the appropriate GxP regulations. Existing FDA guidelines on computer systems validation and software validation are applicable to PAT systems.

  The International Society for Pharmaceutical Engineering's (ISPE) good automated manufacturing process (GAMP) guide for the validation of automated systems also provides relevant information on good practice.

  ISPE is setting up a Community of Practice specifically to consider PAT systems. The validation plan for a PAT system will typically include the validation of process analyser hardware and software; software packages for data analysis; process control software; and IT systems for the management, storage and backup of results.  

In comparison with laboratory-based methods, analytical method validation for in-process analysers requires the consideration of a greater breadth of sources of error arising from the measurement system and on-line sampling issues: various approaches are required depending on the analytical technique and sampling method used. The PAT guideline highlights the value of using ASTM standards, citing various standards for the multivariate statistical analysis of analytical data, for standard practice for the comparison of test methods and for the on-line spectroscopic analysis of petroleum and petrochemical products in a process stream. The US Pharmacopeia includes general information on a number of spectroscopic techniques that are highly appropriate for the measurement of powders, intact tablets and solid samples on-line; for example, NIR spectroscopy. However, the analyst must currently rely on the scientific literature for guidance with respect to on-line implementation and appropriate statistical measures for system performance. Currently, there is no standardized approach and in each case the validation approach must be justified based on scientific principles and solid statistics. The ASTM E55 committee has been established to provide further guidance on good practice in this area.

The PAT guidance specifically discusses novel analytical techniques that measure and evaluate a process signature, which would be the characteristic response of the system to a given stimulus. Acoustic spectroscopy is perhaps the most familiar of these techniques. In such cases, comparison with the analytical method to a conventional compendial method is often difficult and even inappropriate, and the PAT guidance clearly indicates that test-to-test comparisons are not mandatory in such circumstances. The regulatory agency is prepared to review the use of such techniques based on a comprehensive statistical and risk analysis supported by additional information such as a mechanistic explanation of causal links between the measurement results and observed process variability. The predictive ability of the established correlation functions and multifactorial relationships is considered a key indicator of process understanding in such cases. 

In contrast to the increased requirement for analyser and IT system validation and more sophisticated statistical approaches for analytical method validation, it can well be imagined that the current practice of '3 batch' process validation will be rendered superfluous by the PAT approach. Using a PAT approach, the process will be continuously validated in real-time through control of the process critical control points and process critical end points.  

Implementing a PAT system — regulatory strategies

To facilitate innovation and encourage the adoption of the PAT approach, FDA has consciously sought to remove the perception that technological innovation inevitably carries a heavy regulatory burden. PAT is a joint initiative of the Center for Drug Evaluation and Research (CDER), Office of Regulatory Affairs (ORA) and the Center for Veterinary Medicine (CVM) within the "cGMPs for the 21st Century" framework. A PAT policy development team of four subject matter experts has been established to work with industry to facilitate discussion on proposed PAT approaches at an early stage and support FDA's science and risk-based approach to PAT. Additionally, a PAT review and inspection team has been established, which includes reviewers, compliance officers and inspectors who have been trained and certified in the PAT approach. 

The PAT guidance emphasizes that PAT implementation plans should be risk-based and the risk is regarded as being significantly lower when the process is well understood. This is considered to be the case when: 							

 All critical sources of variability are identified and explained. 

 Product quality attributes can be accurately and reliably predicted. 

Articles

The PAT guidance indicates a variety of risk-based approaches to managing the introduction of on-line analysers into existing processes with the aim of minimizing the regulatory burden for the manufacturer and encouraging innovation.

A practical approach to PAT implementation

Human plasma provides a rich source of therapeutic medicines, including gamma globulins, coagulation factors, albumin, alpha anti-trypsin and others. In 2001, sales of immuno gamma-globulin (IgG) were estimated at $2 billion with a production rate of 50 metric tons for the year.

  A number of therapeutic products have been introduced including Gammimune from Bayer, RhoPhylac from ZLB Behring and Octagam from Octapharma.  

Hyperimmunes (IgGs with high levels of antibodies targeted at a specific antigen such as a virus) are also under development for biodefence applications such as anthrax or smallpox. These are useful as either therapeutics or preventative measures. 

In the past, contamination of source plasma by enveloped viruses (HIV, HCV) has led to the contamination of plasma products and patient infection.

  In response, the industry adopted a multilayered virus safety strategy that includes source plasma control (donor screening, plasma testing), product manufacturing (plasma pooling, clearance steps in plasma product manufacturing, current good manufacturing practice [cGMP]), product testing and pharmacovigilence [patient monitoring, recalls]). The enveloped virus problem has been addressed by the adoption of virus clearance technologies such as solvent detergent, heat, low pH, caprylate, chromatography and large virus filtration. Regulatory authorities have issued regulations describing requirements for marketing approval.

Plasma product safety concerns are focused on the smaller nonenveloped viruses (HAV, B19) and new agents (TSE, WNV, SARS). These small, nonenveloped viruses can be more difficult to inactivate or remove.

  The solvent detergent method, which is effective in preventing enveloped virus replication (through dissolution of their lipid envelope coating), is ineffective at inactivating nonenveloped viruses. The severe treatment conditions required for some nonenveloped virus inactivation (for example, 100 °C for PPV) can lead to significant product losses and potential formation of neo-antigens. 

Virus filtration is a useful clearance method for nonenveloped viruses.

  Filters are inert and do not degrade the product or add any foreign substances requiring removal. They are also capable of providing high product yield, can be validated using scaledown models and in-process integrity tests, and can be conveniently integrated into manufacturing processes. 

Virus filtration is a well-established unit operation in biopharmaceutical processes and has been implemented in a number of approved products dating back to the mid 1990s. Mononine, a Factor IX product developed by Armour Pharmaceutical Company, was approved in 1992 using an ultrafiltration process for viral reduction.

The Millipore Viresolve NFP is a normal-flow parvovirus-removal filter with a patented membrane structure for strength and high flow. The NFP filter contains three layers of a highly asymmetric membrane as shown in Figure 1. The filter retains 4 ≥ logarithmic reduction value (LRV) of 20 nm diameter parvoviridae with high flows (75–150 L/m

 /h at differential pressure of 30 psi [2.1 bar]) and high capacities (100–200 L per 0.5 m

  area filter). Features of the filter are listed in Table 1.  

The development of a parvovirus filter process requires examining how the design variables (for example, feedstock and operating conditions) affect the performance parameters (for example, sizing, product recovery and LRV). Filter sizing is determined by capacity and flux. Capacity can be conveniently characterized by the 

 model, based on the gradual plugging of filter pores.

  When the volume of a batch is fixed at 

 and the allowable time to process a batch is fixed at 

, the required area will be described by Equation 1.  

When the stream is relatively nonfouling and the batch time is low, the size will primarily be determined by the initial flux, 

. With longer batch times and dirtier streams, 

 determines the size. The concept is easier to grasp by using the sizing index a, a dimensionless term shown in Equation 2 that indicates whether membrane area requirements will primarily be determined by membrane flux or membrane capacity. 

The sizing equation can be simplified to Equation 3 when using the sizing index. 

The sizing index provides a simple indication of the factors that determine membrane area requirements for a process. When α is greater than 10, the process is flux-limited — more than 90% of the area required is determined by the initial flux. When the value of α is less than 0.1, the process is capacity-limited — more than 90% of the area required is determined by the capacity. 

Table 1 Features of Viresolve NFP filter.			

As shown in Figure 2, filters with low α (Filter A) outperform filters with high α (Filter B) at short process times. This allows NFP filters to offer manufacturing flexibility, such as operating in series with other process steps. Most small virus filters on the market have low flux and high capacity and, therefore, have high α values. These filters are only economical at extended process times. 

Figure 1 Magnified image of Viresolve NFP membrane.			

Increasing pressure can improve filtration throughput, which is why 50 psig (3.5 bar) is usually the optimum operating point. Representative data showing this effect is shown in Figure 3, where using an average flux incorporates the effects of both a high initial flux and a high capacity. NFP devices are rated to 80 psig; most customers prefer not to run above 50. 

Protein concentration in the feedstock impacts capacity. Test data in Figure 4 show the effect. This relationship can be modelled as shown in Equation 4. 

 is subjected to various levels of dilution to improve the 

 the filtration sizing can be determined in terms of the process concentration. Equation 5 is a mass balance. Plugging this into Equation 3 allows the size to be determined as in Equation 6. 

Filtration

Human plasma provides a rich source of therapeutic medicines, including gamma globulins, coagulation factors, albumin, alpha anti-trypsin and others. In 2001, sales of immuno gamma-globulin (IgG) were estimated at $2 billion with a production rate of 50 metric tons for the year.1 A number of therapeutic products have been introduced including Gammimune from Bayer, RhoPhylac from ZLB Behring and Octagam from Octapharma.

Viral filtration of plasma-derived human IgG

Clean rooms are areas in which it is essential that microorganisms are not allowed to proliferate because they could contaminate pharmaceuticals and directly affect human health. 

The infrastructures being coated are diverse, creating demands on a coating to cope with anything from old, possibly damp substrates, to modern synthetic surfaces. They must also allow for moisture vapour pressure, give excellent adhesion even if steam-cleaned daily, be resistant to cleaning chemicals or contamination from chemical splashing and continue to provide a seamless film-protected environment. 

To ensure this, the coatings must be part of a system approach that recognizes substrates — particularly old, previously uncoated ones — will be contaminated with microorganisms and require sterilizing before a hygiene system is applied. Following this, the specific situation may demand that the coating can be reinforced to resist impact damage and that a fully seamless approach is provided over existing or potential joints and cracks. 

Industry requires the system to give long-term protection from microorganism growth and this will usually be seen as the main requirement. A further requirement is that the coating system will do this without exuding contaminating chemicals. If biocides, which leach to the surface, are used to protect the film, they will be short-lived and will potentially contaminate the environment.  

There are additional specialty requirements. Pharmaceutical industries demand clean rooms whose surface finishes will not attract and retain dust, and are easily cleaned. Rooms can be prone to condensation and this emphasizes the point that film-protective agents must be nonleaching. 

 Table 1 Properties of hygiene topcoats for different applications.			

Time restraints mean a room must be ready to be used 24–48 hours after the application of a hygiene coating. To comply with this, water-borne agents are best as they can be applied without contaminating the environment with high levels of volatile organic compounds (VOCs).			

Manufacturers will have in-house demands from their own hygienists and environmental managers, and external legislation regarding validation and performance of hygiene measures. When considering what legislation prevails at a given time, we truly enter a field for experts. A simple look at some relevant extracts from the European Directive (93/43/EEC) is useful: 

"Surfaces must be maintained in a sound condition and they must be easy to clean and, where necessary, disinfect. This will require the use of impervious, non-absorbent, washable and non-toxic materials, and require a smooth surface up to a height appropriate for the operations."

The European Biocidal Products Directive demands that any biocide or product containing a biocide, such as a hygiene coating, shall be subject to regulation. Most European countries have adopted this position. 

Finally, VOC regulations are decisive. It is highly desirable to use water-borne coatings, which have as low a content of VOCs as possible.  

What coating systems are available? What are the key benefits and properties, and what advantages are there over conventional paints? 

 The choice is often made from remarkably few criteria: 				

 Is the system perceived as safe to use and does it carry any approvals to verify efficiency? 

 Has the system been validated to recognized standards by an independent third party?  

 Can it be used in the given process area? 

 Can it be applied by brush, roller or spray as may be convenient or dictated by process considerations? 

The package approach is important to guarantee the coordination of the system, and should include the following products: 

 One- or two-pack materials based on the most modern liquid or spray-dried polymers in conjunction with cement and microsilica technology.  

 Specific water-based acrylic sealants are available. These are internally film protected in a similar way to the coatings, in sealing around door/window frames, and between coatings and skirting boards, for example. 

 Typically a biocidal wash is water-based and supplied as a concentrate for use as-is in known areas of contamination, or diluted with water as a sterilizing wash.  

 Water-borne primers are available to provide the functions of substrate binder (where friable), for metal primer and to ensure top coats strongly adhere.  

 These may be used alone, in combination with each other as defined by the manufacturer or as part of a reinforced system. Table 1 shows details of five types of top coats, all water-borne with low-VOC levels, fire retardancy and defined physical test data. In most cases, two coats can be applied in a day. 

Figure 1 Procedure for producing smooth crack-bridging finish.			

These features allow a full range of substrates to be coated, though some demand a system approach rather than any single coating. For example, a tailor-made system would include lining board substrate, which incorporates  						

 primer to kill suction and prevent absorption of the coating resin binder into the substrate, thereby ensuring film integrity 

 product A set with glass-fibre woven reinforcement

This gives a tough impact-resistant system, which covers the joints in between the boards to give the required seamless finish. 

Other reinforcements include knitted nylon reinforcement tapes for specific joint treatments, which may be used locally as shown in Figure 1 — in this case the crack could be static or dynamic. 

Hygiene coatings versus traditional materials. 

Traditional materials include conventional fungicidal paints, tiles and wall cladding systems.  

 These are designed to 'quick kill' microorganisms with biocides that are in excess on the surface of the dried paint. The drawback is that they leach potentially toxic chemicals into the environment. 

Figure 2 Construction of a seamless hygiene cladding system.			

Grouting is the weak link with growths usually seen in that area. They can only be used on ideal substrates. 

 These are inert, but expensive and require specialist installation. They do not provide a seamless finish and usually have no inherent 'surface protection', unlike hygiene coatings. However, they can be used as the basis of a seamless system (Figure 2). 

The threat here is from the contamination of products and cultures from (mainly) airborne bacteria. Equally, it would be disastrous to have fungal/mould growth giving potential cross-contamination. It requires only low levels of opportunist pathogens such as salmonella and pseudomonas to cause spoilage. 

Figure 3 Changes in bacterial count over time (arbitrary units, bacterial 	count 3106). 			

Combating the proliferation of microorganisms. 

What is needed from a hygiene coating to prevent proliferation and how is this achieved? A comparison on a life cycle graph illustrates the point in Figure 3. On the unprotected film, bacteria proliferate until, in the closed test system, they run out of space and food. The contact/quick kill paint swiftly kills bacteria until the active runs out and growth recommences. The correctly formulated hygiene coating shows a growth pattern as it neutralizes more slowly, but then eliminates growth to virtually zero proliferation. 

Any individual organism must be neutralized by a process that is nonsite specific (for example, multisite) to avoid the risk of resistance developing. This can be simply summarized as: 

The biocide chemically disrupts the metabolism of the microorganisms preventing life processes. 

 Respiration; spore forming; protein/enzyme synthesis; reproduction; and energy assimilation. All these are sites or areas where the reproduction processes are attacked and this results in a neutralized microorganism by the following process:  

Aseptic Technologies

Clean rooms are areas in which it is essential that microorganisms are not allowed to proliferate because they could contaminate pharmaceuticals and directly affect human health.

Pharmaceutical clean rooms: specialty hygiene coatings

Online shopping has become something of a phenomenon during the past decade. Why bother trawling through shops when you can order just about anything online — you don't even have to leave the comfort of your own seat, let alone the house. A few clicks and it's completed. OK, so your purchase may take a couple of days longer to arrive compared with going to a shop, but the savings far outweigh the delay. And besides, it's always nicer and much more exciting to get parcels through the post. 

I am happy to admit that I do most of my shopping online — a favourite is grocery shopping. Not that it gives me any pleasure; far from it. But, it's a lot easier than going to a supermarket full of screaming kids, unhelpful staff and coming out with 'beep beep beep' from the tills ringing in your ears. It takes less than 30 minutes to do a weekly shop online and they deliver right to my door. Perfect. 

One of the best things to happen to online shopping has been web-based auction sites. There's something for everyone on these, and if you're quick enough you can grab an absolute bargain. But they have become more than just online auction houses; they are now proper market places, fully fledged institutions. 

So could the online auction formula be extended to the pharmaceutical industry? For me, the customer should always come first and this would be a great way to make some big savings. Vendors needn't worry either — the auction process would help the best vendors make some good money. Something for everyone then!  

Of course, the reality is that this would never happen. The market may witness cheap imitations and rip off merchants — though judging by some comments that I have heard recently, this is happening to a degree anyway. I guess the regulatory authorities wouldn't be too pleased either. 

It's a shame really, because it would be quite exciting to watch pharmaceutical companies from across the globe battling it out to find the cheapest raw materials and process equipment. The serious point is that it would certainly bring our heavily fragmented industry much closer together — it would also be a lot more fun, and that never hurts anybody. 

Editorial

So could the online auction formula be extended to the pharmaceutical industry? It might be a great way to make some big savings.

Online auctions

The safety of medicines concerns us all. Everyone is confronted sooner or later with situations where a medicine can make the difference between life and death for ourselves or for those who are close to us. The possibility of a quality defect of the medicine that may lead to unexpected, detrimental effects in such situations may be something that would not normally cross our minds. Nevertheless, especially regarding older, well-established medicinal products, there are indications that such possibilities may be increasing. 

"...it is estimated that annually about 70000 tons of paracetamol (acetaminophen) are consumed worldwide, representing a total of 150 billion tablets. A sub-standard product could have a more lethal impact than an atomic bomb in such cases!"

Active pharmaceutical ingredients (APIs) give medicines their pharmacological activity. If it were not for the API a medicinal product would be as likely to cure a patient as a placebo. Several synonyms of the acronym 'API' are in use today: 'drug substance' is the traditional term in the US, and 'starting material' and, more recently, 'starting material used as an active substance' is preferred in Europe. However, the world seems to have adopted 'API' as the unofficial, but harmonized term. 

APIs are manufactured worldwide using many types of production processes to a precise specification agreed with national governments. APIs may be produced by  				

 extraction from plants or other natural sources 

Substandard APIs either result from poorly controlled, though approved manufacturing processes or from processes, that have not been approved by national authorities. 

To help protect EU citizens from such APIs, the rules governing the manufacture of APIs destined for the EU market have just been tightened to ensure they are made to the highest possible industry standards, a quality management system in the pharmaceutical industry known as good manufacturing practice (GMP). The quality of the API is fundamental as it predetermines the essential, approved pharmacological properties of a medicinal product, especially its safety and efficacy at prescribed dosages. 

To make the final medicine (powder, pill, injectable etc.), the API is mixed with other pharmacologically inactive substances (called excipients). As excipients do not normally change the intrinsic properties of the API, provided the quality of the API is as specified, the patient will be safe at the prescribed dose. However, if the quality of the API is not as specified (is substandard) then the patient's health could be affected. For example, the substandard API may contain a nonspecified toxic substance. The medicinal product containing the API would then be unsafe to prescribe, if not lethal. The question is how would a doctor know that? 

Examples of major API quality defects that may occur are the presence of dangerous quantities of toxic impurities, inadequate physical properties or insufficient stability. Each of these quality defects may give rise to health problems for the patient taking the medicine: 			

Toxic impurities may result in short- or long-term side-effects that may range from minor to lethal. 

Inadequate physical properties, such as incorrect particle size or crystal form, may either impede the action of the medicine or result in dangerous overdosing, because the API either dissolves too slowly/quickly directly impacting the rate of absorption in the organism. 

 If the API is not sufficiently stable, it may have degraded by the time the patient takes the medicine, resulting in too low a dose of the API and the possible presence of dangerous quantities of toxic degradation products.

To protect patients against possible API-related health risks, the EU authorities have developed and implemented a large number of laws and regulations with supporting guidelines for the pharmaceutical industry. These are extensive and very detailed. They include the requirement for thorough documentation — on site as well as to be submitted to the authorities — running from many hundreds to even thousands of pages. To comply with the laws, a producer needs to employ an appropriate level of skilled staff. In the case of API manufacture, the law aims to ensure that APIs are manufactured in a way that will consistently guarantee their high quality. 

EDQMÃÂ´s API inspections: the results are reason for concern			

Regulatory compliance in API manufacture is fully auditable by a qualified party and should normally be audited and inspected regularly. 

The manufacturing process used for an API's production is a crucial factor determining its quality. An API of the required quality and specification can only be produced based on in-depth knowledge and rigorous control of this process and its capabilities. If either a different or an uncontrolled process were used, deviations from the desired result would probably occur and the API may have — detected or undetected — quality defects. It is important to emphasize that such uncontrolled situations may pass completely unnoticed despite the analytical quality control testing of the API: the analytical testing for impurities is performed with methods that have been developed and chosen because of their suitability to detect the impurities that are expected to be present in the API. However, they can easily miss any unexpected impurities. Therefore, because uncontrolled processing and processes have a high chance of giving rise to unexpected impurities, the resulting API will be of an unknown, undefined quality even after analytical testing and can, therefore, be a danger to the patient.  

The rules that are in place to protect an EU patient against these risks can be divided into two essentially different categories: 

 Rules for the registration and authorization of the final medicinal product, including the API. 

. Rules for the systems to be used to ensure controlled and consistent manufacture of the API. 

The API manufacturer has to submit a document to the health authorities (in many cases a so-called Drug Master File [DMF]) that describes in full detail all the manufacturing aspects of the API. This includes analytical testing methods, product specifications, raw materials specifications, in-process controls and API stability. The information is to be assessed by expert reviewers from the health authorities. They will only approve use of the API if the submitted information complies with all the rules. The time between filing of the document and approval can range from one to a few years.  

Any changes to the manufacturing process and/or operations require the API manufacturer to provide the authorities with an amendment to the DMF while at the same time the holder of the marketing authorization for the medicinal product must submit a 'variation' document to the authorities. Many variations require assessment and prior approval from the authorities before the change is allowed to be implemented. In conclusion, difficult regulatory hurdles first have to be overcome before the implementation of a change in API manufacturing operations is permitted. 

The API manufacturer has to execute its operations in full compliance with a specific GMP. In October 2005, the EU adopted this principle into law for API manufacture — a principle already applied by FDA since the early 1960s.

  A harmonized standard for API–GMP now exists in the form of the so-called ICH/Q7A Guideline.

Compliance with these regulations requires additional costs. Studies published in recent years have concluded that the 'cost of compliance' forms an important part of pharmaceutical production costs. The cost of reaching and maintaining the required Category 1 and Category 2 compliance level for the API operations may be 20–25% of a site's operating cost, less the cost of raw materials.

  In addition, depending on the types of technologies involved, over time, the high registration-related thresholds to implement improvements in API manufacture will increase the cost gap between APIs manufactured in full compliance of GMP rules compared APIs manufactured without full compliance with the rules. So strict adherence to compliance also implies significant inflexibility to change and reduces time-to-market — so it provides 'noncompliers' with significant competitive advantages. 

We need to compare the additional cost of GMP and regulatory compliance with the 'costs' of noncompliance. The latter may vary from just replacing 'rejected' material to multiple fatalities.

  The issue may be a matter of negligence, but may sometimes be one of wilful misconduct. Indeed, the profit motive should not be ignored. The API contributes a small percentage of the overall cost of the medicine, a level out of all proportion with its enormous quality impact. So the higher costs of using better quality, compliant APIs ought not to be a deterrent to their use. But for APIs that have become 'commodities', the cost and price differences are of great importance. 

This cost difference, therefore, puts a heavy responsibility upon the competent authorities. The new law on GMP compliance requires the EU inspection, enforcement and penalty system should provide for the guaranteed protection of the EU citizen against the supply of medicines made from illegal, nonGMP-compliant APIs. Otherwise, such noncompliant APIs would continue to have the competitive advantage of being available in the EU at significantly lower prices! 

The adoption into law of the API–GMP standard ICH/Q7A is a major milestone for making available to the EU patients safe, reliable, effective and affordable medicines. However, to judge whether this will be sufficient it is important to first assess the situation in today's EU API market. 

Until October 2005 only Category 1 rules were in force for medicines sold in the EU and no adequate API manufacturers' inspection system was in place. Consequently, until October 2005, the EU system was based almost solely on assessing paperwork, and trusting the authors of the DMFs that they reflected what actually occurs in the manufacturing plant. This meant that there was little incentive for API manufacturers, API brokers, traders and users of APIs to comply with the rules. However, many API manufacturers in the EU were already complying with the GMP standards because FDA required them before their products were approved for sale in the US. FDA not only demanded high standards, but it provided the necessary regulatory oversight and inspections to ensure their enforcement. 

Unsurprisingly, for those APIs not covered by FDA oversight there is a relatively high incidence of noncompliance with such strict GMP standards. In the past few years, evidence has begun to emerge confirming that a significant percentage of, in particular, the older medicines in the EU market may contain noncompliant APIs from obscure and/or unknown origin. They present a significantly increased risk of containing potentially dangerous impurities. 

Quantitative estimates are difficult to make. However, as a first example that would indicate that the situation is quite serious, published scientific research results on the fingerprinting of samples of the antibiotic API gentamicin are now available. This product is known to have caused fatalities in the US as a result of the use of substandard API material.

  The published results suggest that in the EU market the percentage of gentamicin API from unknown origin is significant.

  This conclusion has been confirmed to be a representative picture for many older APIs on the EU market, by presentations and publications on fraudulent and grossly negligent API practices, published by API traders during 2004 and 2005.

  In conclusion, estimations made by some sources that for older medicinal products 'at least 33% of the total API volume in the EU may be from unknown sources' do not seem exaggerated.

The EU has now created the legal basis for the worldwide inspection of API manufacturers whose products are destined for the EU market. However, the directives and guidelines make clear that API inspections will not be performed on a routine basis. Inspections will only be triggered either by suspicion of noncompliance or by a request of the API manufacturer. Without a random factor and a high enough probability of inspection the law has no teeth. EU law now places the prime responsibility and burden of proof that GMP-compliant APIs are being used, on the holders of the EU manufacturing — and of marketing authorizations for medicinal products. This responsibility will be challenged during inspections at their sites. The question is whether this new law will effectively lead to the use of only GMP-compliant and safe APIs in EU medicines. It seems likely that this can only be achieved if strong enough deterrents and potentially business-damaging sanctions as well as penal sanctions against the responsible individuals are put in place by the health authorities.  

Numerous publications during the past have described the very serious problems that exist regarding fake and counterfeit medicines.11–19 The World Health Organisation and other reliable sources have estimated the annual worldwide turnover for these fake and counterfeit medicines to be approximately $35 billion (â¬29.2 billion). They expect this to nearly double by 2010.  

Publications also agree that the majority of these fake medicines are being manufactured in and exported by China and India, most of it to developing countries (especially in Africa), but also to the Western markets, either directly or indirectly. Taking this into account, it is of great concern that today more than 70% of the API volume contained within the medicines on the EU market originates from China and India. Without an FDA-style approach to significantly reducing the risk of nonGMP-compliant APIs entering the EU market (by implementing a programme of thorough frequent regulatory oversight, inspections and enforcement by our European competent authorities) the threat to the health of the EU citizens is certain to increase. 

Medicines have always had to include some level of risk. This risk has traditionally been kept at an acceptable level. However, this has now changed: the intensity of competition — especially regarding 'commodity-type APIs' — triggered by accelerating globalization has driven the risk to unacceptable levels. The rate of change in the industry has been dramatic, the regulators have not kept with the pace, they possibly are not even fully aware of it.  

APIs

The manufacturing process used for an API’s production is a crucial factor determining its quality.

APIs: Why EU authority oversight is vital

According to the US Patent and Trademark Office, 2005 was another booming year for patenting worldwide. IBM alone received nearly 3000 US patents. Electronics manufactures such as Canon and Hewlett-Packard made up the top 10 of US patent recipients. 

Absent from the top 10 list of patent recipients — and from the top 100 — were pharmaceutical companies. In contrast to their electronics industry counterparts, Big Pharma has experienced a marked decrease in technological success. New drug approvals in the US were down to less than half the number of approvals in 1996.  

This is not for want of trying. FDA data indicate expenditure by pharmaceutical companies on R&D has doubled since 1996. Why is intensive research yielding so few patented inventions and so few new drugs?  

Part of this phenomenon can be explained by the cyclical nature of pharmaceutical research. There is almost never an immediate reward from R&D investment. Rather, it takes years for R&D efforts to pay-off, with effort being bunched together over lean years and the results of that effort being seen in other years. We are going through a high investment, low return period.  

This explains some, but not all, of what is going on. While fewer new drugs are being approved lately, patent-based litigation has increased and not just between pharmaceutical companies and commercial infringers or parallel traders, but between the pharmaceutical developers themselves. This part of the problem lies with the patent system. 

Technology-intensive industries are enamoured with patents as incremental, documentary evidence that all their work and investment have paid off — at least on paper if not in commerce. The general perception is: the more patents, the better. However, as with research itself, quantity is not necessarily a substitute for quality. The drive to generate more and more patents results in incremental claims, where the patent application drafter divides the invention in issue into minute pieces. This allows for more patents to be squeezed from one inventive effort and makes each of these patents marginally safer, in that if one claim fails, either at the patent office or during litigation, others may survive. 

The problem with this approach, as opposed to using broader, smore encompassing claims, is that it can leave gaps in the technology, over which other researchers may claim priority. The result is that two or more inventors can wind up with rights in parts of the same pharmaceutical application. 

Claims relating to metabolites are a case in point. Pfizer and Schwarz Pharma are battling it out in London over Fesoterodine, a metabolite of Pfizer's DETROL treatment for overactive bladder symptoms. The question before the High Court is whether Pfizer's original claims in relation to the DETROL invention include the metabolite preparation claimed by Schwarz.  

There is no clear answer and this highlights a deeper problem in patenting: what distinguishes one invention from another. The simple, time-honoured answer is that to be a distinct invention, and so not an infringement of someone else's patent, the invention must represent an inventive step over prior technology. 

That answer, in its simplest forms, no longer works. Pfizer's product is one chemical. Schwarz's product is another chemical. Pfizer can argue that Schwarz's chemical is produced in the body automatically when a patient takes DETROL and so the Fesoterodine does not represent an inventive step. Schwarz can argue this is an over-simplification, that its work in developing the metabolite as a drug in its own right is an inventive step that is not covered by Pfizer's narrow patent claims. 

We will know this summer what the High Court thinks: it's a fact question. In the meantime, the issue of what amounts to an inventive step, especially in relation to pharmaceuticals, needs to be addressed. The UK Patent Office is taking the lead in this area. It has announced a review of the patenting process, in particular of the requirement of an inventive step. This is a legal issue, but it should receive the comments of scientists and pharmaceutical professionals, as well as those of attorneys. We need a concept of inventiveness that can accommodate quality as well as quantity. 

is a patent attorney with Lewis Silkin, UK. 

Talking Point

FDA data indicate expenditure by pharmaceutical companies on R&D has doubled since 1996. Why is intensive research yielding so few patented inventions and so few new drugs?

Pharmaceutical Technology Europe-03-01-2006

A practical approach to PAT implementation

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Online auctions

APIs: Why EU authority oversight is vital

Talking Point: The patent problem with metabolites

Biopharmaceuticals market overview