The hydrophilic matrix system continues to be the most popular and widely used strategy to achieve extended drug release. Hypromellose (hydroxypropylmethylcellulose [HPMC]) is typically the polymer of choice for the rate-controlling carrier in these systems. 

Table 1 Three model drugs used in the development of HyperStart. 			

In its simplest form, a hydrophilic matrix is a compressed powder mixture of a drug with a water-swelling viscous polymer. A variety of other excipients may be included in the formulation to aid its tableting properties, as well as to modulate the release rate of the active. Key factors in the popularity of hypromellose matrices are: 			

The ease of manufacture using traditional techniques, such as direct compression and granulation on conventional equipment.  

The ability to achieve reliable and consistent drug release when a robust matrix formulation has been developed.

A large array of drug delivery technologies is available to formulators, but hydrophilic matrices remain the most commonly used oral extended release (ER) systems. These devices are easy to manufacture, robust, flexible and reliable. Various water-soluble or water-swellable polymers with high molecular weight have been used in hydrophilic matrices, such as HPMC, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO). HPMC, however, is by far the most popular polymer in matrix applications because of its safety, availability, global compliance and physicochemical/mechanical characteristics.

HPMC has been widely studied for its applications in hydrophilic matrices.

  It hydrates rapidly on contact with water and forms a gelatinous barrier layer around the wetted tablet. Drug release occurs by diffusion of the active through the gel layer and/or by gradual erosion of the gel, exposing fresh surfaces containing the drug to the dissolution medium.  

Diffusion is the dominant mechanism controlling the release of water-soluble actives, and erosion of the matrix is the dominant mechanism controlling the release of water-insoluble actives. Typically, however, drug release occurs by a combination of these two mechanisms.

The most basic matrix formulation consists of the active, polymer, flow aid and a lubricant. Developing a formula that can produce the exact required release profile is quite challenging. The pharmaceutical scientist is confronted with a large number of variables that can influence the processing of the HPMC ER formulation and drug dissolution.  

The release rate from the matrix is dependent upon factors such as polymer type and level; drug solubility and dose; polymer:drug ratio; filler type and level; polymer:filler ratio; particle size of drug and polymer; porosity and shape of the matrix.

Traditional approaches to new product development rely on a slow iterative process that includes experimental programs to identify desirable formulation ranges. These processes require significant investment in manpower and time. 

A number of model drugs with a range of solubilities and concentrations (may not represent therapeutic doses) have been utilized in the development of HyperStart.

  Here, three examples of the actives are illustrated (Table 1), with water solubilities ranging from freely-soluble through to practically insoluble.  

Fillers are generally used to improve processing of tablet formulations (such as flow, compressibility and bulk) and may have a significant impact on the release profiles from HPMC matrices. In the HyperStart model, four commonly used fillers (lactose monohydrate [soluble], microcrystalline cellulose [insoluble], dicalcium phosphate [inorganic-insoluble] and pregelatinized starch [partly soluble]) were investigated. 

Figure 1 shows nine formulations in a simple decision tree that were used to obtain release profiles for three drug solubility and three dose ranges. The experimental study conducted to develop HyperStart included HPMC (Methocel; The Dow Chemical Company) polymers with various chemistries and viscosity grades, as well as different fillers to achieve release profiles ranging from a few minutes to 24 hours. This design acknowledged the complexity associated with developing these systems, but also provided a wide experimental space for later definition by statistical modelling. 

Figure 1 Initial HPMC decision tree system.			

All powder blends were prepared by a standardized process to minimize any random error introduced through formulation preparation variation. The drug, HPMC, filler and 0.5% w/w flow aid (fumed silica, Aerosil 200; Degussa) were mixed in a Turbula blender (Model T2C, Willy A Bachofen UK Ltd)  for 5 min. Magnesium stearate (0.5% w/w) was then added as a lubricant and the formulation was mixed for a further minute. Tablets were manufactured using an instrumented 10 station rotary tablet press (Piccola; Riva) at 20 rpm and a compression force of 10 kN.  

Drug release was measured in a Sotax dissolution bath using USP Apparatus II (paddles) at 100 rpm with sinkers. The dissolution medium was 1000 mL of purified water at 37.0 °C ± 0.5 °C. A dual beam spectrophotometer (Lambda 25, Perkin Elmer) was utilized for drug detection. 

Table 2 f2 values of release profiles calculated from HyperStart compared with experimental data.			

Predictive modelling and analysis were conducted using the Design of Experiments (DoE) Fusion Pro (S-Matrix Corporation) software package. DoE assisted in understanding complex interactions and relationships that may exist between the raw materials in all the tested formulations. With the help of this software, the effects of individual raw materials and the boundaries of operation were explored by progressing in two phases.  

Initially, a screening study primarily examined the boundaries of useful inclusion levels for the raw materials, followed by a second phase of optimization. Both phases involved generating and testing several formulations, and the results from these experiments were recorded as dependant variables (i.e., responses). These were interpreted by the software to produce predictive formulations based on desired parameters in the final product.  

In some cases, where particular variables could impact the release rate of specific actives, corrective algorithms were applied to the formulations that did not perform exactly as expected. The representative drug release profiles were then fed back into the model for fine-tuning of the system where necessary. 

After conducting the required experiments, numerous relationships between formulation parameters and the release profiles of the actives were established, that is: 			

Drug solubility and drug:polymer ratio are the most important factors.  

Release rate is faster with more soluble drugs compared with low solubility drugs. 

Release is faster with a soluble filler compared with an insoluble excipient. 

Based on these relationships, a mathematical model was produced that would offer a HPMC ER formulation with the desired drug release, taking into account solubility and the dose of the active. This model is a valuable tool that can accelerate the hydrophilic matrix development cycle and reduce the time required for a product to reach the market. 

The model was validated by comparing predicted drug release with experimental data. Figures 2 and 3 show model validation for formulations with a soluble drug, various amounts of HPMC (10%, 25% and 40% w/w) and either soluble or insoluble filler. 

Figure 2 Model validation for formulations containing soluble drug, soluble filler and various amounts of the polymer (10%, 25% and 40% w/w).			

Predicted drug release profiles were compared with the experimental data using the 

 value between 50 and 100 indicates that the two dissolution profiles are similar. 

For both filler types, it was found that formulations with the higher polymer concentrations (25% and 40% w/w) exhibited significantly better correlation between predicted and experimental drug release profiles compared with tablets containing only 10% w/w HPMC.  

Figure 3 Model validation for formulations containing soluble drug, insoluble filler and various amounts of the polymer (10%, 25% and 40% w/w).			

These results confirmed that the HyperStart model prediction is reliable, particularly for formulations with moderate to high polymer level (25% or 40% w/w). This range is within current understanding of a reliable HPMC ER matrix system. Our practical experience in the development of HPMC drug delivery devices has identified that polymer concentration has a significant effect on the robustness of a given formulation. With polymer inclusion levels greater than 30%, the effects of any small variations in any of the individual raw materials (including the active principal) are suppressed or eliminated. This then ensures more reliable clinical performance.

The following case studies are presented to illustrate the effectiveness of HyperStart in generating robust formulations with desired release profiles for two drugs, a high solubility/high dose and a low solubility/low dose. 

Table 3 HPMC ER formulation of metformin HCl 500 mg recommended by HyperStart.			

Case study 1. Hypromellose matrix with a freely soluble, high dose drug: 500mg metformin HCl.

 Metformin HCl was used as a typical, freely water-soluble, high dose (50% w/w) model active with poor inherent compressibility (Palmer et al, 2005).

  The solubility and dose (500 mg) of the drug were used as the input parameters by HyperStart to suggest a 12 hour extended release matrix formulation (Table 3), with a release profile similar to the marketed reference product Glucophage XR (Bristol-Myers Squibb). 

Microcrystalline cellulose and fumed silica were screened through a 500 μm sieve. All ingredients, with the exception of the magnesium stearate, were then blended in a Turbula mixer for 5 min. Magnesium stearate was then added and the formulation mixed for an additional minute. 

Caplets with a target weight of 1000 mg were manufactured using an instrumented 10 station rotary tablet press (Piccola; Riva), fitted with 7 × 18 mm tooling; at 20 rpm and 28 kN compression force. Tablet mechanical strength was determined using automatic tablet (Dr Schleuniger-Pharmatron) and friability testers (Copley). 

The drug release profile was measured in a United States Pharmacopeia (USP)-compliant dissolution bath (Vankel) using apparatus II (paddle method) at 100 rpm. The dissolution media was 1000 mL of purified water at 37 °C ± 0.5 °C. A dual beam spectrophotometer (Agilent) fitted with 0.01 mm cells was used for detection of metformin HCl at a wavelength of 233 nm. 

The formulation exhibited good powder flow properties resulting in a low tablet weight variation (<1%). Matrices with a high breaking force (20.8 ± 1.5 kp) and low friability (<0.01%) values were produced. These results were similar to the reference product (<1% weight variation, 19.0 ± 0.2 kp breaking force, 0.01% friability). 

The drug release profile from the formulation manufactured was compared with that of Glucophage XR (Figure 4). The calculated 

 value was 70, indicating good similarity between the two formulations. 

Figure 4 Metformin HCl release from the formulation suggested by HyperStart and Glucophage XR tablets (n = 6).			

The metformin HCl HPMC ER formulation generated by HyperStart produced tablets with good physical characteristics and a drug release profile similar to the reference product. This case study demonstrates that HyperStart can be utilized to develop reliable hydrophilic extended release matrix formulations for high dose/high solubility drugs. 			

Case study 2. HPMC matrix with a practically insoluble/low dose drug: 10 mg nifedipine.

 Nifedipine was used as a typical practically water-insoluble, relatively low dose (10 mg) active.

  The solubility and concentration (10% w/w) of the drug was used by HyperStart to suggest an 8 hour extended release matrix formulation (Table 4), with a release profile within pharmacopoeial specifications.

Lactose and Methocel E15 LV were blended in a polyethylene bag for 3 min. The drug was screened through a 420 μm sieve to break up any aggregates, added to the mix and blended for 3 min. Methocel K15M CR was then added and blending continued for a further 3 min. Magnesium stearate and fumed silica were screened through a 150 μm sieve, added to the mixture and blended for a further minute. 

Articles

Drug Delivery

The hydrophilic matrix system continues to be the most popular and widely used strategy to achieve extended drug release. Hypromellose (hydroxypropylmethylcellulose [HPMC]) is typically the polymer of choice for the rate-controlling carrier in these systems.

Application of a modelling system in the formulation of extended release hydrophilic matrices

The total share of industrial investment in European R&D is insufficient and explains the poor positioning of the European industry in high-growth technology fields. The gap is widening, not only with the USA, but also with Japan, jeopardizing the future growth and financing of the European social model.  

Biotechnology drugs already amount to 10% of world pharmaceutical sales, 20% of total newly registered products and 50% of the product pipeline. Apart from the health sector, life science research contributes to the growth of numerous key sectors such as energy, the environment, the food industry and several others.  

With a comparable number of biotechnology companies, the US has twice as many jobs in this sector, invests three times as much in R&D (in 2005, over a quarter of the $110 billion invested in R&D by the federal state was allocated to life sciences) and generates twice as much revenue as Europe . 

Both these sectors were the first recipients of venture capital investments, both in Europe and the USA, but investment in biotechnology companies was four times higher in the USA than in Europe in 2004 ($3.8 billion in the USA compared with $1.4 billion in Europe), with European companies failing to benefit from the increase. At the end of 2005, total investment (venture capital and stock market) in biotechnology again increased on either side of the Atlantic, but once again over three times more was invested in American biotech. 

France only ranked third in Europe for venture-capital investment in biotechnology companies in 2004 (€242 million), behind Germany (€258 million) and the UK (€393 million). France only had four listed companies, as opposed to 15 in Germany and 42 in the UK in August 2005. 

It was not until the end of 2005, when there had been no initial public offering (IPO) in this sector in France since 1999, that the French stock market began to open up to biotechnology companies with the initial public offerings of BioAlliance Pharma and ExonHit Therapeutics. With 48 strategic alliances established by French biotechnology companies in 2004, France was still behind its German and UK neighbours, with 103 and 105 alliances respectively in 2004.  

An effort on the scale made by the USA and Asia needs to be made now for the French biotechnology industry to succeed in entering the maturity phase and continue to be a driving force.  

France Biotech, the Strategic Council of Innovation (SCI) and several associations identified several key factors for success. 

Stimulating the stock market for high-tech SMEs. 

By enabling French SMEs to finance their international growth using the French–European stock market and by whetting the investors' appetite by means of tax incentives, an initiative called Jeune Entreprise Innovante Cotée (JEIC) status will boost private research and hopefully lead to the emergence of leading companies. 

JEIC status will therefore contribute to a new impetus to all the innovation financing chains and to preventing delocalization of technological SMEs to the US. There are currently about one hundred listed biotechnology companies in Europe: 6 are in France, 42 are in the UK and 15 are in Germany, compared with 319 in the USA!  

The savings of French people, particularly in life insurance and pension funds, should be increasingly directed towards all innovative SMEs, including biotech SMEs; the commitment by insurance companies to invest €6 billion more in SMEs with high-growth potential between now and 2007 should now be backed up by substantial investments in specialized venture capital funds.  

Dynamizing research and improving research finance. 

Our new Agence Nationale de la Recherche (ANR) must receive substantial additional resources — at least €1 billion a year — and set up good international practices of grant agencies (peer review, independency and transparency). This agency must allocate at least 40% of its funds for projects that come directly from and are managed by innovative SMEs or innovative SME consortiums, and not reserve its funds for projects managed by a few large groups.  

The creation in the Paris Region (Ile-de-France) of a multidisciplinary European Institute of Technology (IET de Paris) will bring together the best researchers in world, innovative SMEs and the research centres of large industrial groups. Financed on projects by European grant agencies, it will enable French biomedical and biotechnological research to gain a leading position on the international scene.

is chairman of France Biotech, the French biotechnology industry association. 

Bio News

The creation in the Paris Region of a multidisciplinary Institute of Technology will bring together the best researchers in world, innovative SMEs and the research centres of large industrial groups.

Financing the French future

Although it has recently been surpassed by Mexico in terms of value, the Brazilian pharmaceutical market remains of key importance to companies establishing themselves in Latin America. The Brazilian government has focused heavily on improving the healthcare system and this should lead to long-term benefits for its citizens. The Ministry of Health has also attempted to decentralize the management of the healthcare system to more regional and local levels. This has been necessary to account for the different healthcare priorities in different parts of the country. 

Figure 1 Life expectancy in Latin America.			

The population is growing and ageing rapidly (Figure 1), which will result in increased demand for new medicines and thus provide the pharmaceutical industry with great opportunities; for example, between 1970–1991, the Brazilian population grew from 93.1 million to 146.8 million — an increase of nearly 58%.

  The changing epidemiological profile of the population has been accompanied by a rise in chronic diseases, particularly cardiovascular and respiratory conditions, and a persistence of diseases associated with poverty and social inequality.

Despite the potential opportunities for pharmaceutical companies, the Brazilian market will present several challenges, given the government's tough line on pharmaceutical pricing, intellectual property and cost containment. Nevertheless, companies focused on the future will benefit from remaining committed to the Brazilian market. 

Brazil's size makes the provision of affordable healthcare for all citizens a difficult commitment for the government to fulfill. It has been described as a country that exhibits some of the most profound social inequalities to be found across the world. According to figures from the UK's Department for International Development Health Resource Centre, across Brazil there is a 63.4% degree of income inequality.

  The scale of the difference is highlighted by the fact that the median income of the wealthiest 10% of the Brazilian population remains 30 times greater than that of the poorest 40%.  

Successive Brazilian governments have attempted to improve this situation and a key step forward was the 1988 constitution that created a new health system, the Sistema Único de Saúde ([SUS] literally the Single Health System).

  The SUS brought together a number of healthcare institutions and hospitals across the nation under a single body of control for the first time.

  In 1990, Brazil's Congresso Nacional (National Congress) passed additional legislation that detailed how the new system would operate. 

Public health services, in conjunction with the private sector, work under contract to the government and it is estimated that healthcare coverage is now about 75%.

  Much of the work being carried out by the government to improve healthcare services is focusing on the poorest sections of the population in areas such as combating vitamin deficiencies and reducing child mortality rates. Over 75% of the financing for the public health sector comes from the Brazilian treasury, with the remainder provided by states and municipalities.  

Although much has happened since the establishment of the SUS, the healthcare situation in Brazil is changing slowly rather than dramatically. This is partly because of factors such as the country's economic crisis, which disrupted the government's more ambitious plans. In 2002, Brazil's healthcare spending as a percentage of GDP was only 5.2%. This put it behind countries such as Argentina (8.0%), Chile (6.0%) and Mexico (5.5%).

  Brazil's per capita spending on healthcare was estimated at $50 per annum, which put it far below the $500 recommended by the World Health Organization. 

The economic problems that Brazil suffered during 2002 contributed to significant disruption of healthcare services and stagnation of the pharmaceutical market.

  At one point during August 2002, the Brazilian currency, the Real, lost 13% of its value.

  The weakening of the currency made it more difficult for the country to pay its debts and growing unemployment led to further uncertainty. The persistence of this uncertainty contributed heavily to the election of a new President in the subsequent elections, but his social policies appeared to alienate foreign investors. Economic troubles in neighbouring Argentina and Uruguay only served to prolong any recovery in the Brazilian economy, as investors moved funds out of Latin America.  

The economic problems naturally affected the funding of healthcare and the pharmaceutical market. In 2002, Brazil's pharmaceutical net sales were estimated at $3.9 billion, whereas in 2001 they had been around $5.7 billion.

  However, currency fluctuations are reported to have made the drop in pharmaceutical sales appear more dramatic. In December 2002, the government appeared to address some of the pharmaceutical industry's worries by allowing an 8.63% price increase for many products sold in pharmacies.

  Furthermore, although Brazil has now slipped behind Mexico as the leading market in Latin America, it is recovering strongly. IMS Health reported that in the twelve month period leading up to February 2005, sales through retail pharmacies in Brazil rose by 19%, which surpassed the 9% sales increase seen in Mexico and the 13% increase in Argentina.

  The most popular therapeutic categories in terms of sales were cardiovascular, central nervous system (CNS) and alimentary/metabolism. 

There is no doubt that the Brazilian pharmaceutical market offers considerable commercial opportunities to the pharmaceutical industry, but what is of concern to companies is the attitude that the government has taken towards pricing issues and intellectual property. The immense scale of the AIDS crisis in Brazil has largely driven this process (Figure 2) as the country has the highest number of AIDS cases in Latin America.

Figure 2 Expenditure by the Brazilian government on antiretrovirals.			

Brazil has implemented one of the most effective anti-AIDS strategies in the world by making affordable treatments available to sufferers despite opposition from the global pharmaceutical industry on the strategies employed. The pharmaceutical industry has been critical of the Brazilian government's attempts to produce its own generic versions of antiretroviral drugs. Brazil exploited a time lag until international patent rules applied in the country. This has meant that a generic version of an antiretroviral combination cocktail that sells for $10000–15000 a year in the USA can cost $3000 in Brazil.

  This situation came about from enacting a law that "guaranteed every AIDS patient [in Brazil] state-of-the-art treatment".  

In August 2001, there was controversy when Brazil's health minister threatened to strip Roche pharmaceutical's patent on the anti-AIDS drug Nelfinavir after six months of negotiations failed to lower the price. By manufacturing the drug locally, the minister estimated that the price could be reduced by 40%. Although Brazil has manufactured generic versions of antiretrovirals, it was the first time it had openly threatened to strip a patent.  

Although the approach that the Brazilian government has used is highly controversial, its effects have been dramatic. The decline in hospitalizations from opportunistic infections from 1997–1999 is estimated to have saved the country $422 million.  

Another challenge for the pharmaceutical industry is the overt attempt by the government to promote the usage of generics to drive down healthcare costs. In public hospitals, doctors are required to prescribe generically and the government has been running a public campaign to educate consumers about generics.

  The official backing of generics has also been seen in the approval process. The Agencia Nacional de Vigilancia Sanitaria (ANVISA) has visibly increased the number of generic applications that it has approved. 

Brazil represents an important market for the pharmaceutical industry. There is a strong demand from the growing population for new medicines, but any commercial opportunities in this area will be strongly affected by the government's attempts to drive down prices through cost containment measures. Pharmaceutical companies will need to carefully assess the market for their products to deal with these difficult challenges. Dealing with government cost control measures is not a new experience for international companies, and so overall Brazil still has plenty to offer the pharmaceutical industry. 

1. L. Lobato, Reorganizing the health care system in Brazil in S. Fleury, S. Belmartino and E. Baris (Eds.) 

Reshaping health care in Latin America: A comparative analysis of health care reform in Argentina, Brazil, and Mexico

 (International Development Research Centre, Ottawa, ON, Canada, 2000). 

2. UK's Department for International Development Health Resource Centre, Brazil health briefing paper (2004). 

www.dfidhealthrc.org/shared/know_the/publications.html

Financing Health Policies in Brazil: Achievements, Challenges and Proposals

 (The UN Development Programme Poverty Centre, Brasilia, Brazil, 2002). 

5. Brazil: Country Health Profile. The Pan American Health Organization (2001). 

6. E. Sandullo, Latin America lagging behind in health care provision (IMS Health, 2003). 

7. Brazil's looming economic crisis (BBC News, London, UK). http://

8. J. Oliveira, Brazil: Market overview of drugs and pharmaceuticals (US & Foreign Commercial Service and US Department Of State, 2003). http://

9. L. Miranda, El aumento de precios de medicamentos en las farmacias tendrá lugar en diciembre (2002). 

10. IMS Retail Drug Monitor: Pharma Sales Growth Continues at 6 per cent Pace in 13 Major Markets (IMS Health, 2005). 

12. F. Kermani, Neglected and Emerging Diseases: The Next R&D Challenge (Chiltern International, 2004).  

13. AIDS drugs policy — Ministry of Health/Brazil (2000). 

www.aids.gov.br/assistencia/aids_drugs_policy.htm

14. Generics take off in Brazil (IMS Health, 2004). http://

Spotlight

Although it has recently been surpassed by Mexico in terms of value, the Brazilian pharmaceutical market remains of key importance to companies establishing themselves in Latin America. The Brazilian government has focused heavily on improving the healthcare system and this should lead to long-term benefits for its citizens. The Ministry of Health has also attempted to decentralize the management of the healthcare system to more regional and local levels. This has been necessary to account for the different healthcare priorities in different parts of the country.

Pharma battles in Brazil

This column provides a practical perspective and recommendations for applying a risk-based approach within the guidance-regulated biotechnology industry, an approach that can affect time-to-market. Focusing on the implementation of a risk management strategy encompassing the regulatory framework is not at all new, at least not to pharma manufacturing. The operationalization of the strategy and subsequent deployment is difficult, however. In particular the biotechnology industry has first seat in the value chain, or what FDA has defined as the critical path for new drug development. 

Table 1 Three dimensions of the critical path.			

To further enhance understanding, the column focuses entirely on regulation and biotechnology. This is a rather simplistic and academic approach, as other stake holders of course engage in this collaborative work. Furthermore, it has a sole focus on validation and documentation only, even though it is noted that in the very early stages of discovery and development, to a certain extent these compliance activities are optional and not enforced as in pharma. This transformation should result in earlier trial completion, earlier regulatory approval, earlier marketplace introduction and thus longer patent utilization — resulting in significant financial and competitive advantages. 

From a biotechnology industry perspective, the definition and deployment of the traditional legal interpretation of risk-assessment is particularly timely. It is required for a variety of reasons, but primarily because this era's new business paradigm forces the integration of new approaches and technologies to secure compliance with regulations and fast-track initiatives. This means validation and documentation resources need to be prioritized. The biotechnology industry's own challenges and the legal challenges of how to secure safe and efficient new drugs faster are intimately connected. 

The science-based regulatory framework for development of new drugs is dynamic in that public health objectives may change in response to patient needs and society's interests. In this column no distinction is made between traditional chemically synthesized drugs and respective biological drugs derived from living sources (such as humans, animals and micro-organisms). Most biologics are complex mixtures that are not easily identified or characterized and many are manufactured using biotechnology. FDA has traditionally regulated biologics and traditional drugs in different centres, but this separation is being rapidly accentuated by organizational changes. 

Given the dynamic character of these factors and also the fact that the process involves many different parties — pharmaceutical sponsors, the scientific and healthcare communities, the government and society at large — a potential synergy exists where these parties could collaborate to improve methods, approaches and technologies for development of new drugs. And it all begins with biotech (Figure 1). 

Figure 1 Cooperation, interdependency and individualisation demands new approaches and technologies			

Most of the contemporary debate on regulatory topics is in fact old news presented in more modern vocabulary. Controversies are inevitable. From an industry perspective, revision of the regulatory context under FDA is challenged more so today than at any time since the 1962 amendments to the Food, Drug and Cosmetic Act recreated FDA by mandating it to require proof of efficacy as well as safety when approving new drugs.

One main 'safety' criticism is that FDA favours the pharma industry by placing too little focus and weight on safety when approving new drugs and monitoring them afterwards, a chief criticism mainly grown upon Merck's withdrawals of Vioxx September, 2004 and Pfizer's withdrawal of Bextra in April, 2005. Alternatively, academic medical communities (also great supporters) have criticized the agency for being too slow to approve new drugs or too quick to remove them. 

FDA balances risks and benefits for the intended population and the drug's intended use as it decides that a drug is sufficiently safe and effective for marketing, and obviously the stringency of FDA approval standards ultimately has an effect on the pace with which new molecular entities (NMEs) are developed (Figure 2, Table 1). 

Figure 2 The critical path value chain.			

Rapid advances in basic and applied science pose a great challenge for FDA. Of course, the same logic applies to good manufacturing practice (cGMP) regulation as pharma manufacturing has become increasingly obsolete even as the advent of biotechnology cries out for radical changes. Despite technological progress and the adoption of new technologies in high-tech industries, such as petrochemical, software, hardware, communication etc. this industry routinely accedes to requirements that have become obsolete because of the costs for obtaining regulatory approval for changes. 

In March 2004, FDA published the report "Innovation or Stagnation? — Challenge and Opportunity on the Critical Path to New Medical Products", which examines the critical path needed to bring therapeutic products to fruition. It highlights how FDA can collaborate in the process from laboratory to end-use, to make medical breakthroughs available to those in need as quickly as possible.

  This report analyses the "pipeline problem", that is, the slowdown in innovative medical therapies reaching patients as a result of the current new drug development path becoming increasingly challenging, inefficient and costly, and this has manifested itself in a lower number of new drug approvals and biologic applications (Table 1). 

Only scientific and technical dimensions are included in the table, and all three dimensions are interdependent and none guarantee success. In January 2006, FDA published the Exploratory IND3 Studies.

  The guidance is to build in line with the critical path initiative and will facilitate very early exploratory scientific studies in people before the standard safety studies (Phase 1) begin, though limited to drug and certain well-characterized therapeutic biological products. One of the biggest barriers research and academic institutions face is the ability to get discoveries made in the lab into clinical testing. Because only small amounts of drugs are used in these early studies, they represent fewer potential risks for people in these trials. FDA makes recommendations about safety testing, manufacturing and clinical approaches that can be used in these very early studies. 

The guidance explains how medical researchers can take full advantage of the flexibility built into existing regulations in the amount of data needed when asking FDA's permission to proceed with such a study, enabling more rapid delivery of innovative products to patients. 

FDA has previously articulated its commitment to ensuring the appropriate flexibility is applied when patients with a serious disease and no satisfactory alternative therapies are enrolled in a trial with therapeutic intent.

It is expected that all preclinical safety studies supporting the safety of an exploratory investigation new drug (IND) application will be performed in a manner consistent with good laboratory practices (GLP) (21 CFR Part 58).

  The GLP provisions apply to a broad variety of studies, test articles, and test systems.  

In related draft guidance, INDs — Approaches to Complying with CGMP During Phase 1, FDA outlines a suggested approach to complying with current good manufacturing practice (cGMP) requirements for drugs intended for use solely in Phase 1 studies.

With this new guidance and an accompanying regulation, FDA formally recognizes specific standards for the manufacture of small amounts of drug product for Phase 1 studies and formulates an approach to cGMP compliance that is appropriate for the particular stage of drug development. 

Taking FDA initiatives even further from a regulatory perspective, the deployment of a risk-based, process-oriented approach would allow biotechnology to analyse and monitor their processes and implement appropriate controls to mitigate GxP risks. 

In that sense, following a four-step model that covers both the scope and selection of appropriate, supporting new technologies and controls, can be deployed: 				

Define overall responsibility for project team, i.e., system, business, quality assurance (QA). 

Define and identify critical GLP, good clinical practice (GCP) and good manufacturing GMP. 

GLP/GCP/GMP processes that could potentially compromise product safety, efficacy and quality 

Categorize all validation activities (Priority Plan). 

Non-critical processes (GLP/GCP/GMP) should be carefully analysed, and non-valuable adding processes (ideally) eliminated. 

Implement controls commensurate with the risk identified. These controls should be documented and justified with reference to the identified risks. 

This top-down and very pragmatic, public-acknowledged approach needs to be transformed to operational, intuitive measures easily deployable in the biotech environments.  

In operational terms this means a strong focus on failure investigation (falsification, fabrication, compromise to subject protection) and the documentation, monitoring and reporting to authorities. In other terms, this means traceability and classification of deviations: 			

Overall, the risk-based approach should be implemented in processes as follows: 				

clinical research methodologies, including protocols and regulatory compliance (documentation) 

assessment and evaluation of safety/toxicity and efficacy. 

Development of the necessary information to document safety, efficacy and utility involves a highly complex set of scientific and QA activities not commonly used in biotech, at least when entering fast-track programmes and partnering with pharma companies. For the biotechnology regulatory executive selecting the right compliance levels and systems supported by new technology (electronic record-keeping) is in today's collaborative environment essential, not least in the effort of securing a shorter cycle time. In fact one could argue, that GMP actually also yields significant benefit for biotech. Early implementation and education in compliance issues scaled and supported by using a risk-based approach towards this vital issue is resulting in synergism for all actors in the value chain, ultimately the patient and society. 

Furthermore, with the deployment of new technologies (knowledge-sharing based), for example, electronic documentation, biotech companies will comply with the requirements for electronic applications that will become mandatory in the EC in 2009, as is already the case in Belgium, The Netherlands and the UK 

is the director and co-founder of QAtor A/S, Denmark. 

1. S. Peltzman (1974), "Regulation of Pharmaceutical Innovation: The 1962 Amendments". Evaluative Studies. Washington: American Enterprise Institute for Public Policy Research. 

2. FDA (2004, March), "Innovation or Stagnation, Challenge and Opportunity on the Critical Path to New Medical Products", US Department of Health and Human Services. 

3. FDA (2006, January), "Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies". US Department of Health and Human Services, CDER. 

4. FDA (2006, January, rev. 2), "Guidance for Industry. Fast Track Drug Development Programs — Designation, Development, and Application Review" US Department of Health and Human Services, CDER and CBER. 

5. FDA (2006, January),"Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies". US Department of Health and Human Services, CDER. 

6. FDA (2006, January), "Guidance for Industry. INDs — Approaches to Complying with CGMP During Phase 1". US Department of Health and Human Services, CDER and CBER.

Regulatory Report

One of the biggest barriers research and academic institutions face is the ability to get discoveries made in the lab into clinical testing. Because only small amounts of drugs are used in these early studies, they represent fewer potential risks for people in these trials.

A risk based approach to biopharmaceutical manufacturing

Creation and qualification of scale-down models is essential for performing several critical activities that support process validation and commercial manufacturing. This article is the second of two parts covering scaling down biopharmaceutical operations, Part I was published in April 2006 and detailed fermentation. In this segment, we present some guidelines and examples for scale-down of common downstream unit operations used in biotech processes — chromatography and filtration. 

In theory, chromatography is one of the more straightforward unit operations to scale down. Factors at the large scale such as column-header design and packing can be difficult to control and may result in reduced accuracy of the scale-down model. This section presents a review of general guidelines for scaling down.  

Use representative feed streams, preferably from full-scale manufacturing. First perform a complete analysis of product concentration, quality attributes and other feed stream characteristics (such as pH and conductivity) to ensure a good match. If possible, use feed streams from different lots at small scale to learn about the effect of feed stream quality on the performance. In addition, acquire some knowledge of the storage and stability of the feed stream material. Storage-related degradation of the inventory could affect the outcome of the small-scale runs. 

Use a representative chromatography resin. It would be ideal to have resin from the lot being used at full scale. If you can't obtain GMP-released resin, then make a match based on the vendor's certificate of analysis. 

 Figure 1 Chromatographic profiles of small- and large-scale columns. Raw material is a proprietary aqueous solution that has undergone one step of preliminary purification. The small column (green data) is 1.6 cm diameter by 12 cm. The large column (black data) is 63 cm diameter by 12 cm.			

Buffers and other solutions should be made up and released by manufacturing. If it is not possible to obtain these, mix solutions with GMP-released raw materials, or material of an equivalent grade from an approved vendor. Follow exactly the solution recipes from manufacturing. The pH, temperature and conductivity probes that check buffer properties must be comparable with those used at the large scale. Measure pH and conductivity at the same temperature spelled out in the recipe. The pH and conductivity standards should also be comparable (preferably identical) to those used in manufacturing. 

 Our experience has been that an automated small-scale chromatography system, such as the äKTA Explorer, excels at small-scale studies. It offers precise, accurate and reproducible control of flow rates and gradients. However, you still have to check and calibrate the accuracy and precision of in-line detectors (pH, conductivity, temperature) by using off-line probes.  

The type of column is generally not a major issue; however, whenever possible use the same bed support material. We prefer to not use column diameters of less than 1.0 cm since the ratio of system dead volume to column volume can result in pool concentrations significantly lower than those seen at large scale. The packing procedures and solutions should be similar to those used at large scale.  

Controlling temperature at small scale to mimic that of cold rooms or cold-boxes can be a challenge. The use of water baths with column jacketing can provide precise temperature control, but the tubing leading up to the column can frequently act as a mini heat exchanger, making it difficult to control the actual inlet temperature. Using heat exchangers on the inlet tubing and column jacketing may be necessary for accurate, consistent and precise temperature control. 

Table 1 Comparison of scale-down model with a large-scale cation-exchange column. Input material roughly 98% antibody, 3 ppm DNA, 3000 ppm CHOP and  

Biopharmaceuticals

Constraints associated with equipment can make scale-down a challenging exercise.

Scaling down biopharmaceutical operation part II: Chromatography and filtration

The era of process analytical technology (PAT) in pharmaceutical manufacturing is upon us.

  Many companies are high up on the overall PAT learning curve, but all are grappling with the more critical challenge of determining the best way to introduce PAT and to select the right tools and infrastructure.  

Companies need to address wider business issues to determine the answers to some of the key questions that arise when introducing PAT: which facilities to prioritize? How best to phase investment? How to achieve the best product quality and mitigate risks? How to migrate the control infrastructure? How best to scale-up? Determining the answers to these questions is vital for companies as they face the challenge of implementing PAT. 

The impetus for PAT stems primarily from FDA guidance issued in its final form in September 2004. In many respects, the pharmaceutical industry is way behind other industries in its adoption of PAT. This is understandable in a sector where much is conditioned by the regulatory environment. The proactive stance of FDA is only recent and the regulatory momentum in other territories is less driven. While European regulation already contains the concept of PAT and the EU has established a PAT team, the EU is expecting the industry to lead rather than taking the more pro-active stance of FDA. 

However, companies that delay PAT implementation risk being left behind on the business as well as the regulatory front. While regulation may be the catalyst it is competitive advantage that is the compelling prize. Early adopters can secure cost and competitive advantage gains. For an existing production process, PAT adoption and implementation tends to be seen in terms of reduced cost, lower inventory levels and a move towards 'just in time' production and supply.  

For new processes the benefit of PAT is the ability to quickly develop the manufacturing process, upscale to a robust process and perform validation more easily. These are tremendously important, but the full competitive advantage potential also needs to be seen in the context of the end-consumer or patient. 

The 'process understanding' that lies at the heart of PAT means that manufacturers can gain improved knowledge and production capability to create products to match the quality and therapeutic expectations of patients. Bioavailability is a critical patient variable but it is not a current production variable. PAT enables manufacturers to gain improved control of their product quality but it also enhances a company's ability to better match different patient needs. This is significant because bioavailability differences are, of course, important for drugs with a relatively narrow therapeutic index (TI) and also because of the potential of PAT to deliver competitive advantage by influencing new product development.  

However, the prize of longer term gain comes at significant short-term hazard and cost. PAT investment comes at a time when the pharmaceutical sector in general is facing significant pressure to reduce costs to maintain profitability levels. Blockbusters are rarer and the industry faces the twin challenges of price pressure from consumers and health buyers, and competitive pressure from generics. Introducing PAT investment and change in a well judged and timely manner is crucial. How can companies feel more confident and certain about their PAT journey? 

A clear understanding of the business goals of PAT implementation is a vital starting point. There are many points to consider and their exact fit with a particular company will be dependent on the company's current manufacturing base and its future strategy. 

PAT can fix or improve existing processes, speed up new product development, reduce site-to-site transfer risk and times, reduce validation costs and, through quality reliability, enhance a company's image. At the end of a drug's life cycle, PAT can help prolong patent life through the development of new formulations. 

Most companies will want to realize a blend of these business benefits but, at the same time, they will also want to take a view on which one is their most important priority. This will be determined by the current state of play of its manufacturing and wider market activities. In turn, a company's decision on which business benefit to prioritize will determine the focus and pace of PAT investment. 

A company's view on the business benefits it wants to prioritize will be the lens through which it evaluates its return on investment (ROI) in PAT. For example, a company may want to focus on improvements in existing processes. Some companies choose an easy and stable production process for PAT introduction. 

However, this may not be the choice that will yield the quickest benefits. An alternative focus might be on a troublesome process where the gains of better process understanding and control will be far higher. 

Other companies may be at a stage in their product portfolio where they may want to make new drug development the focus of their PAT investment. For these companies, the potential gains in revenue of using PAT to speed the time to market of drugs in the development pipeline may be greater than prioritizing the application of PAT to the manufacture of existing drugs.  

Each company's situation will be different and judgements on the focus and pace of PAT implementation will vary according to the ROI analysis of the different options open to them. Companies will need to carry out ROI analysis of all options to validate their prior assumptions about the lead business benefits. 

In some cases, they may decide that these prior assumptions need to be adjusted with some options, on examination, emerging as better contenders than previously expected. Such an examination of priorities is crucial since one of the key issues for companies is where and how best to start implementing PAT.  

The big challenge for pharmaceutical companies is to mathematically model their production processes, combining both data from the laboratory and the production process.

Pharmaceutical Technology Europe-07-01-2006

Application of a modelling system in the formulation of extended release hydrophilic matrices

Financing the French future

Pharma battles in Brazil

A risk based approach to biopharmaceutical manufacturing

Scaling down biopharmaceutical operation part II: Chromatography and filtration

Speeding up the move to PAT