This article is part of a special feature on cleanrooms that was published in the December issue of PTE Digital, available at http://www.pharmtech.com/ptedigital1210.

The current expectations for cleanroom operations are those found in the FDA's 2004 

Guideline on Sterile Drug Products Manufactured by Aseptic Processing

. These documents are reasonably well harmonised with each other with respect to environmental monitoring expectations, media fill requirements and other areas, but they differ with respect to classification of the core aseptic processing environments, where the EMA employs Grades A and B, and the FDA adheres to the more general ISO classification scheme. USP is about to formalise a new chapter <1116> 

Microbial Evaluation of Clean Rooms and Other Controlled Environments

 that differs markedly in approach by eliminating numerical limits and suggesting incidence rates. USP cites analytical variability and limit of detection with respect to numerical quantification, especially in the cleanest environments as a major part of the reason for changing their approach. 

Before validating a new cleanroom facility, I think it best to first consider the functionality of the facility and then define the desired capabilities that it is intended to satisfy. It is essential to understand:  

the types of products and the expected volumes

the processes necessary for their manufacture

the equipment to be utilised in those processes, with special attention to the extent of automation and operator involvement

the materials and components necessary for the manufacturing processes.

With this defined, one can progress through the design exercise in an orderly manner.  

With respect to environmental monitoring, the expectations of both the FDA and the EMA do not consider the realities of aseptic processing and as a consequence, they overemphasise environmental monitoring to the point where they may actually be causing more problems than they are endeavouring to prevent. There are several aspects that the regulators seem to ignore:  

Aseptic processing is not 'sterile' processing; those terms don't mean the same thing. The environments have never been, nor do they need to be 'sterile'. We don't require a 'sterile' environment to make a 'sterile' product. 

Methods to precisely measure the microbial level in the air or on a surface do not exist. This is particularly true in the cleanest environments.

You cannot sample your way to 'sterility' in a processing environment. Even the most aggressive sampling schemes fall way short and increase risk more than any insight gained.

Sampling is an intervention and subject to adventitious contamination.

There have always been (and always will be) viable but nonculturable species, we cannot detect everything, but then again we shouldn't have to.

Expectations for perfection in performance may seem reasonable considering the label claim, but is quite unrealistic and unprovable from a scientific perspective. Unfortunately, these scientifically unrealistic expectations result in impractical acceptance criteria and the arbitrary and capricious rejection of product. The cost of monitoring, investigations and identification efforts is borne by the end user, and in many instances fails to bring any real benefit in reduction of product risk. 

Can sterility ever be completely assured?

Sterility can never be guaranteed, and this represents a major technical disconnect between current regulatory policy and scientific reality. The sterility test as we know it today dates to the 1930s when processes were markedly less capable. In today's aseptic processing, its utility is highly questionable. The sampling limitations are well documented and, unfortunately, unfixable. Until such time as we have a universally accepted nondestructive sterility test for products, there is simply no means to assure sterility.  

The media fill test is also, as many scientists and engineers have noted for years, merely a snapshot in time and not a method by which an aseptic process can be truly validated. It is important to remind ourselves that we can neither test nor monitor sterility (an attribute that can't be analytically measured) into our aseptically produced products. 

My recent paper with Jim Akers entitled "The Myth Called Sterility" reviews this in some detail. It outlines what we called 'Sterility by Design', which is a group of interrelated design concepts that can at least assure 'safety' if not 'sterility'.

  If we were honest with ourselves, that is really all we have ever needed to have with respect to parenteral products. 

Regulations should not reflect narrow-minded opinions

I've always been a minimalist with respect to the need for regulation, and I also believe that all regulation should be based strictly upon science and should be vetted through a rigorous peer review process. Regulation should not reflect narrowly drawn opinions. I respect that we must have regulations, but I find they are often outofdate before they are even published.  

For example there's a continued expectation for unidirectional air flow in manned cleanrooms; however, it is important to remember that there are no metrics for the assessment of the degree to which unidirectional air flow actually exist. Smoke tests — although heavily emphasised — do not actually provide definitive information regarding "sterility assurance", as is often assumed. In fact, since all production environments contain horizontal and complex surfaces, the presence of turbulence is assured and unavoidable. Also, regulations and guidance documents continue to expect air velocities of 90 FPM (0.45 m/sec) ±20%. That specification was removed from FS 209C (now replaced by ISO 14644) in late 1987. The FDA had cited FDA 209B from 1972 as the rationale for that velocity in early 1987. It was carried over into the FDA 2004 aseptic guidance and Annex 1. So why are we dealing with a 'requirement' last accepted nearly 40 years ago, and considered arbitrary and useless more than 20 years later as an expectation for performance? The entire 5 µm particle fiasco that transpired in Annex 1 was another example of regulatory over reach. There has never been a shred of evidence that 5 µm particles bore some special significance in contamination control and no one would or should attempt to use 5 µm particle counts to classify an ISO 5 environment because the counting statistics do not allow that. Finally, it is hard to imagine how anyone would deem it appropriate to set a limit of zero for any monitoring attribute or presume that a finding of a value other than zero should require an investigation when said investigation is impossible to really conduct in a meaningful manner. 

I suppose my philosophy with respect to regulation is tell me what you want me to do, but don't tell me how to do it. When regulations go beyond that the result is to reward complacency, prevent innovation and accomplish little for the patient. 

Articles

Special Feature

What are the current expectations for cleanroom operations? And are these realistic?

Are Cleanroom Regulations Realistic?

Editor's Note: This article is part of a special feature on cleanrooms that was published in the December issue of PTE Digital.

A review of warning letters from the last 10 years relating specifically to cleanrooms has indicated several concerns with the appropriateness of cleanroom design — primarily regarding air flow and laminarity. Additional citations have been made about area maintenance, e.g., in need of repair, presence of "rust", peeling or damaged surfaces, and so forth. Meanwhile, additional observations have related to monitoring plan inappropriateness/insufficience and the poor aseptic behaviour observed within the cleanroom. 

To reduce the chance of receiving a warning letter, companies must review the design features of a cleanroom on a regular basis and take appropriate corrective actions to ensure that both airflow and laminarity are maintained, especially when personnel are operating in the area. Maintenance issues could be mitigated by conducting routine and frequent checks of both the condition of the area and the equipment, ensuring that concerns are quickly repaired. Cleanroom monitoring programmes should also be routinely reviewed to determine whether they reflect current, stateofthe art thinking. If not, the programmes should be updated as appropriate. Finally, poor aseptic behaviour must be mitigated with training and retraining of operators. This should be supplemented with supervisory oversight and coaching, as appropriate. 

It is important that a group or person within a company is responsible for keeping abreast of current regulatory trends, e.g., by reviewing recent warning letters, benchmarking against other companies, reviewing literature, and assessing the company's performance against current trends and standards. 

Best practice for environmental monitoring

It is a little more difficult for companies to meet all of the requirements for environmental monitoring. First, one must understand which regulatory requirements are applicable. There are compendial monographs in the USP, JP and EP; guidance in various regulatory documents; GMP requirements for Europe; GMP requirements in the US FDA's Aseptic Guidance; ISO Documents; and World Health Organisation documents, to name a few of the applicable requirements. 

Many traditional companies use programmes that were established more than 10 years ago. While the programme may still evaluate a state of control, it may not appropriately implement the current regulatory expectations.  

In order to define an appropriate environmental monitoring programme, it is advisable that companies use risk assessments to determine the appropriateness of sample locations, monitoring equipment and control levels, as well as in determining the types of organisms that should be considered "objectionable" to the process. Once these parameters have been defined, the process of developing an effective environmental monitoring can begin. 

A review of warning letters from the last 10 years relating specifically to cleanrooms has indicated several concerns with the appropriateness of cleanroom design - primarily regarding air flow and laminarity.

Passing Cleanroom Inspections

Biotech has had a profound impact on the pharma industry by helping to develop new medicines that treat patients more effectively; however, despite its achievements, it hasn't made a significant difference to the number of new treatments reaching the market. According to PricewaterhouseCoopers' (PwC) research paper, 

, biotech hasn't met the industry's expectations and will need to change its business model if it is to survive. Crucially, biotech hasn't reduced the inherent risk in drug discovery and development; the overall success rate is still only 9.1% for biotech drugs compared with 6.7% for a smallmolecule drug.  

Unfortunately, biotech's situation worsens.  

"The current business model on which biotech has relied is flawed," Simon Friend, Global Pharmaceuticals and Life Sciences Industry Leader at PwC, said in a statement. "Due to poor rates of return, investment has dried up and many of the external conditions that have allowed companies to thrive are vanishing." 

In particular, the research base is shifting geographically, moving further East, and the emerging economies are competing more aggressively. Importantly, these new economies aren't just copying the West, but learning from past mistakes; they're doing away with the costly infrastructure and creating leaner business models.  

An additional problem for biotech is the fact that financial investors are being more cautious in light of the recession. In 2008, for instance, biotech in Canada, Europe and the US raised 45% less funding compared with previous years. The situation did improve in 2009; however, 10 biotech firms still filed for bankruptcy in the US and a further 9 closed without being officially bankrupt.  

All of these issues mean it's time for the industry to change. According to PwC, the boundaries between biotech and pharma are already blurring with the emergence of biopharmaceutical companies, but all companies — whether biotechnological or pharmaceutical — need to adopt a new business model. In particular, there is great potential in a more united front that makes use of collaborations.  

"Efficiency is the name of the game," said Friend. "Working with others accelerates and facilitates innovation, discovery and development, which in turn can reduce costs and benefit both large and smaller companies." 

Indeed, a number of precompetitive discovery federations — public–private partnerships where biopharm companies exchange knowledge, data and resources with each other, as well as other organisations — have already been formed. There is also potential for close collaborations in more competitive development, with rival biopharm companies joining forces with each other, as well as with CROs and platform technology providers. Although Big Pharma has traditionally shied away from such arrangements, AstraZeneca and Merck recently entered into a partnership to develop a combination therapy for cancer. Under the terms of the deal, the companies will share the decision rights and costs, as well as any intellectual property that is developed as a result.  

One of the main issues regarding these collaborations, however, is that data aggregators will be needed that can collect and synthesise all the necessary data. At the moment, no such organisations exist, although solutions are beginning to emerge slowly; for instance, the Human Proteome Organisation's Proteomics Standards Initiative has released standards for representing and exchanging proteomic data.  

Additionally, organisations will also have to learn to work with one another. "Biotech executives and academics sometimes complain of Big Pharma's 'arrogance', for example," says PwC. "But size isn't everything and the biggest pharma companies can't expect to have everything their own way. So they'll need to become more flexible." 

At the same time, research institutes and biotech firms will need to have more "realistic" expectations as it's all too easy for a biotech company to over value a single platform technology or molecule. 

"There are some considerable cultural, behavioural and practical hurdles, and some of them may be difficult to overcome," says PwC. "But we believe they're well worth resolving, given the rewards." 

Industry has recently been paying close attention to the biosimilars hearing in the US, which discussed the implementation and regulation of a followon biologics pathway. Trade associations PhRMA, BIO and GPhA also gave their input. 

Industry executives have revealed their biggest worries for global supply chain management in a new report. Half of the respondents to a survey said the biggest area of risk is raw materials sourced outside of the US. Sixty one percent said contaminated or nonconforming raw materials was the top threat in the next 5 years. 

Biopharmaceutical manufacturers have successfully patented isolated DNA molecules for some time, but a new development in a federal court case, however, could redefine what legitimately can and cannot be patented.  

Pfizer has stepped into the biosimilars market 

a strategic agreement with India's Biocon for biosimilar versions of insulin and insulin analog products. The move is also consistent with the Pfizer's strategy of partnering with domestic companies to access emerging markets. 

News

Biotech has had a profound impact on the pharma industry by helping to develop new medicines that treat patients more effectively; however, despite its achievements, it hasn't made a significant difference to the number of new treatments reaching the market.

In November 2008, the first-ever European Antibiotic Awareness Day took place across Europe.

  Its success has led to plans for this to become a regular fixture, with the third European Antibiotic Awareness Day held in November 2010. Although there have been previous efforts to tackle the problem of antibiotic resistance in Europe, the organisers behind the first European Antibiotic Awareness Day believed that improvements need to be made in sharing information and best practice.

The ongoing campaign has been promoted by the European Centre for Disease Prevention and Control (ECDC), an EU agency whose goal is to strengthen Europe's defences against infectious diseases. The campaign is also backed by the World Health Organisation (WHO), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Standing Committee of European Doctors (CPME), as well as a number of European healthcare professionals.

This broad, international participation has enabled the organisers to run a series of events held in different European member states during European Antibiotic Awareness Day. In 2008, for example, the inaugural campaign started with a scientific briefing and press conference at the European Parliament in Strasbourg (France), followed by national press conferences rolled out in EU countries ranging from Estonia to Greece. In a number of these countries, the Ministers of Health took part in the briefing sessions. As part of the campaign, leaflets and factsheets prepared in conjunction with local prescribers were distributed and a multilingual website was also launched. 

The European Federation of Pharmaceutical Industry Associations (EFPIA) has welcomed the European Antibiotic Awareness Day initiative, but has also used the occasion to remind governments that the current drugs available are thanks to the historic efforts of the pharmaceutical sector.

  It hopes that greater awareness of the issues surrounding antibiotic resistance will translate into support for the industry to produce next generation antibiotics. Given the high investment needed and the time lag to product launch in the existing regulatory and economic environment, however, it has been lobbying the European Commission to provide specific incentives to enable it to fast track its efforts. These moves appear to have had some impact; in 2009, Sweden used its Presidency of the EU to promote more open discussion of the industry's concerns on the matter.

What has alarmed European governments, regulators and industry is that despite a growing availability of public information regarding antibiotic resistance, there continues to be a surprising level of misinformation and complacency around Europe.  

In 2009, a pan-European survey was conducted on behalf of the European Commission to assess antibiotic awareness across the region.

  A total of 26761 facetoface interviews were carried out across 27 EU member states between November and December 2009. The timing of the interviews was designed to reflect the periods before and after European Antibiotic Awareness Day. The initial intention was to evaluate progress in public awareness and behaviour following a similar, although briefer survey, in 2002.

  Overall, however, the 2009 survey revealed worrying gaps in people's understanding of the issues surrounding antibiotic resistance even among those indicating exposure to previous public awareness initiatives.  

As in 2002, around 40% of respondents indicated that they had taken antibiotics over the previous year, with greater usage being found in southern European countries. However, in the 2009 results, it was found that onethird of European respondents had taken antibiotics for a viral infection such as a cold or the flu.

  A disappointing outcome was the fact that a large number of respondents stated that new information provided on antibiotics did not change their initial viewpoint.  

The lack of knowledge retention following public campaigns on antibiotic awareness is also problematic. A recent paper in the 

 examined the effect of the 2008 English public antibiotic campaigns.

  Among respondents in England, there was only a small increase in recollection of campaign posters. In light of these results, the authors called for better auditing of the effectiveness of public campaigns and for better planning of such initiatives. They recommended targeting patients in physician waiting rooms and involving physicians themselves to relay the information. 

Despite such disappointing outcomes, some national awareness campaigns have been reported as successes. In Belgium, a series of national public campaigns have been running since 2000, primarily over winter periods, and the initiatives have been given a high profile.

  The campaign was in two parts; one aimed at providing information to the public on the main issues (e.g. booklets and TV campaigns) and another providing specific clinical recommendations to healthcare professionals. The 2002 public campaign pieces had titles such as "Use antibiotics less frequently, but better", "Save antibiotics, they may save your life", and "Talk to your doctor, talk to your pharmacist". In 2004 it became more specific with one campaign piece entitled "Antibiotics are ineffective for common cold, acute bronchitis and flu". For healthcare professionals, the Belgian Antibiotic Policy Coordination Committee (BAPCC) produced evidence-based guidelines using scientific methodology for the appropriate use of antibiotics in particular conditions, such as sore throat and acute cystitis in women. All general practitioners received copies. Each year a consortium, including scientific colleges for general practitioners and the Federal Knowledge Centre for Healthcare, examined antibiotic prescribing data and provided feedback to GPs on their conclusions. All these primary care physicians were also invited to discuss these feedback reports with their peers in specially convened sessions. 

Outpatient use of antibiotics, expressed in the number of reimbursed packages per 1000 inhabitants per day, dropped by a third between the 1997–1998 and the 2006–2007 winter seasons in Belgium. Apart from antibiotic usage, some benefits could also be shown in terms of actual resistance levels. This was most apparent when examining the proportion of nonsusceptible isolates of Streptococcus pneumoniae. For example, between 2000 and 2008, penicillin resistance decreased from 18% to 10% and macrolide resistance from 36% to 25%.

The positive outcome in Belgium was followed by similar measures in France in 2001 through a campaign designed to counteract the idea that antibiotics should be used for viral infections.

  The campaign used the slogan "Antibiotics Are Not Automatic". As well as distributing information to the public, the authorities promoted better testing measures and guidelines directly to physicians through a process known as "academic detailing". When the two winters before the campaign were compared with five winters following the campaign, a dramatic effect was noted. A decline by 26.5% in the number of antibiotic prescriptions was achieved, which was more than the desired 25% target and the drop was seen in all French regions and age groups. 

Such positive results appear to show that an effective and ongoing public campaign can have a real impact, but it still raises important questions about how such campaigns should be organised. From the Belgian and French experiences, a multi-faceted approach that focuses on both public and professional awareness has been recommended.

  However, given different medical practices across the EU, as well as patient attitudes and behaviour, it would be presumptuous to assume that a campaign that has been successful in one country can automatically achieve success elsewhere. This is why European Antibiotic Awareness Day initiative has the potential to break new ground, as it takes into account the variations across the EU. 

Raising awareness of antibiotic resistance is aimed at preserving the effectiveness of the currently available agents, but there is an urgent need to develop a new generation of antibiotics for the future. While some of the major pharmaceutical companies, such as Pfizer, GlaxoSmithKline and Merck, have maintained some interest in antibiotic R&D, most innovative research in this field is now being carried out by smaller companies.

During the mid- to late-1990s, many large pharmaceutical companies reduced or abandoned antibiotic R&D programmes because the market was considered too crowded and financially unrewarding.

  The experience of Lilly, who developed daptomycin, convinced some companies that their efforts would be better spent in other areas.

  Daptomycin proved to have antibacterial activity, but was not considered particularly potent compared with existing agents on the market. In addition, it was found to have a narrow therapeutic window. During trials to examine higher doses, some volunteers developed muscle damage. Since Lilly already marketed vancomycin, an immensely popular broad-spectrum antibiotic, there was limited interest in funding another risky antibiotic R&D project. Even if successful, a new antibiotic might have ended up eroding the market for vancomycin.

  As a result of commercial nervousness, Lilly shifted its emphasis to other therapeutic areas considered more financially secure. 

At the end of 2009, the Swedish government commissioned a study by the European Observatory on Health Systems and Policies to look at ways to provide new R&D incentives to pharmaceutical companies to carry out antibiotic research.

  As well as confirming that antibiotic R&D was considered a financially unattractive field for companies, it revealed underlying problems that would hamper any attempts to set up new research programmes.  

According to the study, apart from commercial factors, antibiotic research in the pharmaceutical industry began to tail off partly due to a feeling that bacterial infectious diseases had been "conquered." As a result, many scientists chose to pursue research in other areas, believing them to be medically under-served. Over time, this shift in emphasis left a lack of industry personnel with the scientific experience to maintain the focus on antibiotic research.

  A number of well-funded training programmes have been initiated to give European scientists the necessary training to pursue antibiotic research, but trainees will still lack hands-on experience in dealing with infectious bacterial diseases. The European Observatory on Health Systems and Policies report concluded that as well as recruiting new scientists, efforts must be made to leverage the experience of older scientists. This may even necessitate asking retired scientists to mentor the next generation of antibiotic researchers. Only then will the pharmaceutical industry have the necessary pool of scientific talent to draw upon for new antibiotic R&D projects. 

The report authors supported the idea that tax incentives could stimulate new industry antibiotic research.

  They recommended incentives to be focused on the earlier stages of R&D, as they felt that any measures linked to marketing or sales would weaken efforts to preserve current antibiotics on the market. As an example, it cited the policy approach of the French government in 2008, which was designed to make the country a more attractive environment for pharmaceutical R&D. The French Finance Act featured a reduced rate of corporation tax, but also provided preferential tax measures for various activities involved in the R&D process. For example, outsourced activities, expenses related to compliance with regulatory standards and social costs for employees with the necessary R&D expertise all had the potential to qualify for tax relief.  

The study also identified a lack of information over how much new antibiotic research programmes might cost, which therefore complicates efforts to develop government policies for financial incentives. Generally, clinical trials for antibiotics are considered less complex than in other therapeutic areas, as the therapeutic endpoint is clear i.e., patient recovery from infection.

  This would suggest that R&D costs for antibiotic trials are less than say, for example, an oncology programme. Future trials, however, might involve additional costs as they might need to include a significant number of subjects with resistant pathogens.

  Since industry critics believe that pharmaceutical companies already generate excessive profits, financial incentives to kickstart antibiotic research might be publicised in the media as being unnecessary. However, the conclusions regarding the financing of antibiotic R&D programmes are based on historical data. 

Antibiotic resistance remains a very serious threat due to the limitations of current agents and poor public knowledge about bacterial infections. The European Antibiotic Awareness Day campaign represents a continuing effort to combat these problems across the region, but measures are also needed to boost new pharmaceutical industry R&D efforts. Although the 2009 European Observatory on Health Systems and Policies report was a welcome step forward in summarising thinking of how to stimulate new industry research, it has not yet prompted governments to implement specific incentives. In 2009, a survey among European intensive care physicians found that 53% had treated at least one patient infected with a bacterium totally or almost totally resistant to available antibiotics during the previous 6 months.

  Worrying developments such as these are a warning that governments must bring a sense of urgency to incentivising new antibiotic R&D efforts. 

1. About European Antibiotic Awareness Day (2008). antibiotic2008.ecdc.europa.eu 

2. The overuse of antibiotics — Eurobarometer statistics. 

3. E. Mossialos, et al., Policies and incentives for promoting innovation in antibiotic research (2010).  

, Eurobarometer 72.5 (2009). ec.europa.eu  

, Eurobarometer Special (2003). ec.europa.eu 

8. B. Huttner. Antibiotics Are Not Automatic Anymore — The French National Campaign To Cut Antibiotic Overuse. 

Industry Insider

A European-wide awareness initiative hopes to tackle the issue of antibiotic over-prescription, but industry must also be encouraged to make further investments.

Europe Addresses Antibiotic Resistance

So 2010 is nearly over and what a year it's been for our industry. We've borne witness to the dramatic changes that have been spurred by the financial crisis of 2008/09: the spate of announcements regarding job losses; the myriad of headlines hinting at or confirming still further M&A activity; the restructuring/diversification/divestiture of underperforming divisions; the rising interest in biologics, generics, outsourcing, the emerging markets; the continued drive to curb counterfeits and improve supply chain security, to name just a few of the recurring trends of 2010. 

For the pharma/biopharma industry, I would define this year as one of refocusing and reprioritising. It will be interesting to see what these changes will yield moving into 2011. It's likely that companies will continue looking to the emerging countries as high growth markets and generics and biologics as potential acquisition targets, for those not already active in those areas. But I do hope that we'll see more investment in R&D in the next 12 months, and perhaps an increase in focus in personalised medicine and stem cell therapy research, seeing as both are hoped to play a greater role in the future of patient care. There's no doubt that originator companies will remain focused on protecting their valuable brands from generic competition, more likely through improved administration routes, so drug delivery and innovative dosage form manufacturers are set to reap the rewards of this trend.  

There is one thing that I can guarantee for 2011 and that is that we at 

will be there to continue reporting on all of the latest trends, innovations and issues that matter to you through our magazine, website, eNewsletters, digital magazine and Twitter feeds. We will also continue listening to you and encouraging you to share your views with your peers through our LinkedIn group which, at the time of writing, now has 1130 members! It's clear that you want to share ideas with like-minded peers so why not join our group, if you haven't already done so, and start sharing (

I would like to thank you for your continued support of 

 in 2010 and I look forward to an eventful 2011. 

So 2010 is nearly over and what a year it's been for our industry.

A year of ups and downs

Risk assessment is a frequently used term and today almost every industry sector has adopted this in some form as a standard working practice. The bio/pharma industry must manage the balance between increased regulation and the need to be more efficient and effective at each stage of drug development and manufacturing, with both factors being driven by the need for continuous improvement. In particular, it is important to understand what truly represents a risk to a patient or critical information that is ultimately associated with the care of a patient. If done correctly and consistently, however, business, regulatory and legislative requirements can be aligned. 

The process of identifying and quantifying a GXP risk within any component of drug development and manufacturing is often done inefficiently, most often due to the focus of the exercise not being correct or as welldefined as it could be. In many cases, this can be attributed to the risk assessment process being inappropriate and/or over-complicated. The purpose of the process is not to generate comprehensive reports, but to identify where there is potential risk to the patient and then to eliminate or minimise this risk.  

The International Society for Pharmaceutical Engineering (ISPE) Baseline Guide and Good Automated Manufacturing Practices (GAMP) documentation provides an excellent foundation upon which to base risk assessment. In accordance with these guidelines, it is necessary to conduct an objective assessment of each system and activity. It is important to challenge the way things have been done historically, as well as the way things are done in different parts of the organisation, as these may not always be the most appropriate solutions.  

For instance, the classification of environmental conditions for a work area can have a significant cost impact in terms of design, installation, validation and ongoing monitoring. For pharmaceutical companies, it is important to consider whether reducing the classification across elements of drug manufacturing can have an impact on product safety. By challenging the classification necessary to conduct GMP/GLP operations within an environment that is adequate for the operation, companies may be able to achieve significant savings. A value engineering study must challenge all areas of drug development and manufacturing, including quality, and must not be restricted to new facilities, as the robust review of existing facilities is also often beneficial. 

Lean compliance involves clearly identifying what an organisation does to achieve GXP compliance. This includes factors such as how the organisation measures success; what can be measured to quantify success and improvement; and identifying tools to seek better and more efficient ways of either improving performance or maintaining performance with less resources. In terms of quality and compliance, this means driving a bigger margin between the resources needed to achieve and demonstrate the appropriate and applicable level of compliance. Using the manufacturing analogy, improvements in efficiency can be driven through economies of scale; for example, having more products in the development pipeline or marketed products that are managed by the quality and compliance functions. However, this presents a number of challenges because not every company is a multinational, multiproduct organisation capable of achieving savings in this way. Secondly, larger organisations with manufacturing capabilities have already seen the benefits of applying lean thinking to their production operations, so it is important to examine how this can be applied to other parts of the business. In other words, how can the same level of resources be used to support an increasing pipeline or increasing regulatory requirement? Or, how can a reduced level of resource support the current level of regulatory requirement? This is represented in 

Figure 1: Lean compliance resource savings identification and cost benefit diagram. 			

Lean compliance is a means by which all parts of an organisation are aligned to contribute to achieving optimal performance. Each component of the business process is also made truly accountable. Lean compliance addresses the costs and return of QA compliance and how this improves the quality or confidence in a product or process. It also questions how much effort is given to ensuring the ultimate safety of the patient, and whether the applicable regulations and corporate policy are fulfilled and can be demonstrated. It should also identify and challenge those non valueadding components where regulations and policy are generally fulfilled to provide a feeling of security rather than being driven simply by necessity. 

The focus of such a process is to conduct an objective assessment of the quality, compliance and validation functions in order to categorise each process and subsection of a process, as shown in 

Table 1: Summary of function value categorisation.			

To maximise the value of this overall process, it is essential that the focus be on the identification and elimination of waste. As demonstrated in 

, the savings of waste prevention will typically far exceed the savings from efficiency improvements. To achieve this, it is necessary to challenge the quality and compliance activities that the business is performing. For example, if a new enterprise resource planning (ERP) system is to be deployed within an organisation, it must be considered which components will have any impact on GXP and require validation. It is also important to determine how many 'Business Value' elements are truly necessary and whether any can be downgraded to waste. This approach can quickly facilitate real savings in cost and time, both in terms of implementation and ongoing use of systems within the GXP environment. Therefore, it is important for the risk assessment to look not only at what is required to ensure compliance, but also to enable clear identification of what is not required. 

As with any quality system, the route to success involves setting out 'policies' to communicate what the organisation wishes to achieve, the 'guides' for how this should be done (principles), the details of how this must be completed (methods) and the measurement system and expected results by which success and adoption will be measured. Fundamental to the success of any lean compliance programme is buyin from the organisation and readiness to change. This is a change management project and must be managed appropriately — a brilliant idea will remain just an idea if it is not clearly communicated and adopted with the necessary understanding of its purpose and benefit.  

The objective of lean compliance is to enable organisations to focus on those elements that truly impact patient safety and eliminate those that do not. If an organisation successfully adopts a leaner approach to compliance then they will have a significant commercial advantage over competitors. 

Figure 2: Lean Compliance process overview.			

Whilst traditional lean methodologies can be easily transposed to a manufacturing operation for a marketed product, this is not always the case with clinical manufacture or GLP and GCP operations. These processes require smart adaptation of tools that can be customised, as there will be a level of uniqueness in each study, project and activity performed. 

Recent debate: eCTD demonstrating lean compliance 			

In order for the lean compliance process to be successful, it is essential to have the correct blend of internal knowledge and ownership of the operations, combined with the right amount of sympathetic expertise to drive overall success. Depending on the size and internal capabilities of an organisation, this may require secondment of personnel from a different business unit, or the use of third party GXP consultants. This is a people process that requires expert guidance to ensure communication, coaching, cooperation, consistency and a collective and clear understanding of the results and success. The roadmap to success is shown in 

The following real life example demonstrates how lean compliance can result in significant cost and time savings for the release of Clinical Trial Material (CTM).

A lean compliance initiative has been implemented within a leading CMO to reduce the time and cost needed to review and release CTM. To be successful, the quality approval process was mapped, documented and explained to all key stakeholders to create a collective understanding of the operation. Through the use of lean methodologies, the quality control/quality assurance cycle time was reduced from more than 200 days to 56 days — a reduction of 72% of the original time taken. These recommended process improvements — based around changes to the quality function within the business, e.g., review, approval and communication of quality records and data — were incorporated into standard operating procedures (SOPs) for release of CTM and have enabled knowledge sharing between different sites of the CMO, significantly enhancing business processes, knowledge sharing and profitability. 

Using a true riskbased approach to quality and compliance is an essential component of ensuring that an organisation not only fulfils its regulatory requirements, but also does so with a clear understanding of the priority and relative resources that should be given to each element. It also enables identification of those areas that do not have any notable impact on patient safety or GXP data integrity, providing justification for eliminating or ignoring these. 

Lean compliance is a business process efficiency concept used to ensure that GXP best practice is achieved as efficiently and effectively as possible. By carefully using proven and established lean methodologies and tools, the quality and compliance functions of an organisation can be challenged. Lean compliance establishes the true valueadding operations within a business and looks at how these can be maximised. It decides which business value operations are necessary to ensure compliance, and how these can be simplified and reduced. It also highlights the non valueadding operations that can be eliminated and prevented to save time and cost. The objective is to truly challenge each component of a process and determine whether it is really essential. The main question is whether something is being validated because it has always been done that way or because it really has an impact on quality, compliance and, most importantly, patient safety. 

The key to success with any lean compliance project is the same as any good business or project management practice — establishing key objectives, clear communication throughout the group, and maintaining the focus and support needed to drive and measure success. 

1. Pharma iQ, "Do Electronic Submissions Save Pharmaceutical Companies Time? 62% says Yes!" (2010). 

Manufacturing

With the increasing need for businesses to reduce costs and demonstrate value, there is a requirement to look at all aspects of bio/pharma drug development and manufacturing to achieve efficiency improvements.

Lean Compliance And Adopting A True Risk-Based Approach To Validation

This article is part of a special feature on cleanrooms that was published in the December issue of PTE Digital.

Contamination in all its forms should be identified and reduced whenever and wherever possible. The best managed cleanrooms/critical environments start at the entrance to the building and implement a holistic contamination control programme, starting with basic entrance matting to reduce the ingress of mud, grit, water and gross contamination, and becoming progressively cleaner as you get nearer to the critical area.  

The specifics of the exact products, processes and protocols required largely depend on the class of cleanroom, number of staff, frequency of cleaning and future company improvement goals; for example, reducing environmental impact. 

Normal solutions comprise some form of workwear, such as a lab coat and work shoes, to a washable or disposable cleanroom suit with facemask, hat, gloves. There will also be one form of contamination control flooring protection system at all entrances and exits to the critical areas, such as airlocks, changing rooms, and transfer hatches. 

When selecting detergents for cleanrooms, it is necessary to rotate the solutions used at regular intervals as germs become more resistant to a specific cleaner. It takes a lot of time and money to validate a new cleaning detergent/product; this is accepted as a necessary investment because if the cleaning solution fails and contamination enters the clean area, the costs can be prohibitive.

To select the right solutions, companies must first consider how clean they need the clean area to be, i.e., what are the allowed viable and non viable counts pass fail rates? 

The cost of cleaning in the cleanroom is always far higher than cleaning 

 the cleanroom; hence everything that can be done to keep the dirt out is highly cost effective, such as the use of polymeric flooring. It is widely accepted that around 80% of all contaminants entering a cleanroom do so through entrances and exits at or near floor height (

Time is also a consideration; one must define how long one cleaning system takes 

 another. Also, how aggressive is the cleaning system? The answer is usually a trade off between killing everything very quickly, and risk ruining other sensitive and even nonsensitive equipment. I have even seen stainless steel eaten away by aggressive cleaning systems so beware! 

Before introducing new protocols, proper validation is vital as the "magic" new solution may not be quite as it first appears! 

All pharmaceutical companies place a great deal of importance on continuous good manufacturing practice (cGMP). In today's world, environmental improvement is a key goal and there is often a lot of wasted electrical energy from using HEPA or UPLA filters to control the class of cleanroom or mini environment. Also, the use of disposable or consumable products when longer term options are readily available simply seems a waste of resources. A couple of obvious examples are the use of disposable Tyvek suits 

 washable, reusable cleanroom clothing, and using peel off sticky mats instead of the environmentally friendly, polymeric contamination control systems. 

The best way of ensuring a long active life of a cleanroom and its equipment is to slightly over engineer the cleanroom and standard operating procedures in the first place so changes and upgrades can easily be accommodated. If this is not done, then companies will be continuously working hard to meet the standards needed, which is going to be both costly and time consuming. 

Contamination in all its forms should be identified and reduced whenever and wherever possible.

Selecting The Right Cleanroom Solutions

What are the three most important reasons for GMP deviations? A lack of GMP training, a lack of GMP training and a lack of GMP training! The root cause for GMP deviations most frequently listed in inspection reports is the personnel involved in API manufacture and quality assurance.

  GMP training for manufacturing personnel is essential, as defined in Chapter 2 Paragraph 2.9 of the EU GMP Guide and in 211.25 of the FDA cGMP Guide; however, GMP control is not always as good as it should be — as demonstrated by the increasing number of warning letters, import stops and other provisions by regulatory authorities in past years. 

Well-qualified employees are an essential part of GMP, and training concepts and the compliance status of personnel are always within the scope of inspections. As such, requirements for qualifications, training and development of all employees involved in GxP relevant operations must be met to ensure that employees can aptly perform their assigned tasks according to their position. The best way to accomplish this is through training programmes tailored to each employee's job. This should not just end with an induction programme, but continue with annual training plans and periodic retraining to ensure that an employee's knowledge and behaviour is maintained at the required level.  

Training should be planned, scheduled, conducted and documented using a very systematic approach, particularly in large companies. In 2006, a publication by Schaffer/Schmidt described how a pharmaceutical company established key performance indicators (KPIs) to calculate the ratio between the total number of trainings planned/needed, and the total trainings conducted, which helped management to assess and assign the necessary resources.

  The overall conclusion of this publication was that a companywide training management system is needed to manage the training needs in a pharmaceutical company. The administration of resources, as well as the involvement of the management, is a new requirement defined in ICH Q10 

To plan and monitor GMP training in a pharmaceutical company, a lot of operational information is required. In the past, companies often kept an archive of training certificates or lists of participants signed by each individual, or used spreadsheets, but this approach may not be appropriate for a facility with well over 100 employees. Instead, many large companies are now implementing a software control system to monitor the GMP compliance status and training of their employees. Such a system is more than just a piece of software: it is a general approach to managing the complete process of GMP training, starting with assigning individual training needs to each employee, through to an efficient documentation procedure. The system enables management to easily identify training needs, provides reports regarding the overall training status and also enables the complete tracking of training conducted per employee, which is useful for regulatory requirements. 

The following case study describes how a GMP training management system (Pharmschul; Concept Heidelberg, Germany) was introduced at Hoffman La Roche in Basel (Switzerland) to achieve the complex task of managing the GMP training of employees. The software linked with Roche's document management system (DMS) to provide up-to-date information about the status of relevant training documentation. 

For a company the size of Roche, which has many different objectives for employees, such as global guidance or company-specific GMP standards, it is necessary to merge employees to groups either in organisational or functional areas. From there, appropriate training can easily be set up. On the other hand, however, there are also local requirements that are pre-defined for a specific job. Today, Roche creates groups and assigns profiles to them using Pharmschul

to develop suitable trainings. Different roles and functionalbased assignments can be combined to receive a complete set up for each employee.  

Operating a packaging line, for example, presumes the employee has very special and detailed knowledge of technical documents tailored to one unit. Using the control system software, the company groups documents to document profiles according to different needs, or attributes certain documents to a specific job profile. Once a new document version is available in the DMS, a new draft training record is automatically created by Pharmaschul, and the training coordinator can then create the new record for the assigned group immediately. Different document profiles can be assigned directly to groups or persons, but the system can also connect document profiles to job profiles, which simplifies administration. It is also possible to group global guidance documents to dedicated global profiles, which can be applied to an entire organisational unit. 

As Roche operates globally, employees will sometimes assume new responsibilities and training for such employees must be adapted accordingly. In this case, the training manager can easily assign the new, appropriate functional group to the person. The employee's 'old' specific job profile can then be attributed to another staff member and the required training is immediately visible. An additional interface between Pharmaschul and Roche's human resources database also ensures that when an employee leaves the organisation, he/she is automatically removed from all profiles and all planned training sessions to avoid confusion. 

We also use the profiles to prepare annual staff training plans, which are created and assigned to the relevant groups. A formal report template is also available to print an annual training plan for a single employee, manually signed by line manager and employee.  

Making sure employees know about new or updated SOPs 

Standard Operating Procedures (SOPs) are necessary to introduce GMP standards into company-wide quality systems, and all employees need to be informed when a new or updated SOP is published. While this is easy in a small company, it is a rather more complicated task in a global entity like Roche. Because of this, we also introduced an additional web-based front-end for Pharmschul, called PharmschulWEB, which provides a validated solution for the completion of self-studies on procedures/SOPs, with electronic signatures.  

When a new document in the DMS has been issued for training, the training manager attaches it to the relevant group, and an integrated email function then informs employees about the training. The email will contain a link to a web interface and the assigned document, which the employee can open, read and countersign with an electronic signature. In their personal screen, users can also obtain detailed information about their training status, including performed, planned and open trainings. We also use the web interface for refresher information about GxP and regulatory requirements or issuedriven training, such as retraining in response to deviation, defects or complaints.  

A reporting system provides oversight of all training required and performed. One of the reports most frequently needed by management is the evaluation of training of one specific document; for example, to verify if all persons who need to be trained in a certain SOP have already been trained in the current version of the SOP. This functionality may seem basic, but it is extremely helpful in providing an overview about the training status of specific jobs, mapped with job profiles. Roche established such a matrix with an integrated Pharmschul report, which is a graphical list where compliance and (hopefully no) gaps are visible at a glance. The actual training status of employees is automatically reported periodically to management, providing line managers with transparent information of their responsibility in ensuring personnel are trained accordingly. We have found that this information has led to a high status of compliance. 

A KPI report for the higher management is also regularly used. Our higher level management forces the monitoring of KPIs, with all employees having a dedicated amount of training to be performed per defined period. The ratio between the total number of trainings, and the planned/required training has to be reported regularly, and helps to justify adequate resources for the technical and GxP training of staff. 

Managing GMP training is a complex task, particularly in large companies where Excel spreadsheets and certificate archives are not feasible. Because of this, Roche implemented a professional GMP training system that helps to identify and evaluate training needs, and assign these to each individual in the company. Only with a complete system in place can large companies ensure that every employee receives the necessary information and training. 

1. ECA Foundation, FDA Warning Letter Report (2010). 

Regulation

A case study describes how a software control system can manage training needs across an international company and improve GMP compliance.

Pharmaceutical Technology Europe-12-01-2010