New directive
Pharmaceutical outsourcing : when only the best will do
Practical aspects of validation
Facilitating the Audit Process
Service Providers - Partners in Prime

New Directive - choosing the correct clinical
trial service provider will prove crucial to non-EC sponsors

Mike Parker, Quality Assurance and Technical Director, Brecon Pharmaceuticals Ltd, Hay-on-Wye, UK

Summary
An EC Directive to be implemented in May 2004 will have a profound effect on the way clinical trials are carried out within the Community. There are three major changes: the use of a Qualified Person (QP) for release; the requirement for Investigational Medicinal Products to be manufactured, assembled and packaged in accordance with GMP guidelines; and the necessity for various authorisations before a trial can commence. The QP’s role in satisfying these regulations will be pivotal and sponsors will be required to have at least one QP “permanently and continuously” at their disposal. This will result in a substantial increase in the subcontracting of European clinical trial service providers by sponsors outside the EC. Many will be calling on these services for the first time and there are number of points to be aware of when choosing a service provider, not least the QP’s training, experience and availability.

Following implementation of Directive 2001/20/EC next May, new regulations will apply to the way clinical trials involving human subjects are carried out within the European Community. Prior to this point, there has been no coordinated legislation or control over clinical trials in the EC, with local legislation applying in most cases. However, Germany, France, Spain and Belgium have opted to implement the Directive early and are already conducting trials which abide by its requirements. It is likely too that other Member States will phase in the Directive before May 2004.

The overall objective of the Directive is to introduce the application of GxPs to clinical trials. Much of the Directive concerns Good Clinical Practice, but manufacturing, packaging, labelling and release are also affected. While the legislation will cover all clinical studies originating from within the Community, it will have particular impact on studies carried out by sponsors based outside the EC.

The most significant change for these sponsors will be the mandatory use of a Qualified Person for the release of the studies. This means that supplies manufactured, assembled or packed outside the EC will have to be QP released on entry after appropriate analysis and manufacturing site authentication. To comply with this requirement, sponsors must have at least one QP “permanently and continuously” at their disposal.

Another major change is that the Directive requires that Investigational Medicinal Products (IMPs) are manufactured, assembled and packaged in accordance with GMP guidelines and that new minimum labelling requirements are adhered to, as detailed in Annex 13 of the “Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002”. The QP is responsible for checking compliance with all these requirements.

For products where manufacture, packaging and analysis take place outside the EC, and there has been no QP release, the only practical way for the QP to verify compliance with GMP is by site familiarisation. This requirement also applies to comparators and placebos, which means they will be subject to the same level of regulation and inspection if they are unlicensed in the EC.

The third significant change is that a sponsor company must have a trial authorisation - on which the release site must be specified - for a trial before it can commence supply of an IMP. If the IMP is to be imported into the EC, authorisation must also be sought for each individual trial import. In addition, a product specification file must be produced which should include manufacturing and product analysis details as well as ethics approval. Again, the QP will be responsible for checking compliance with these authorisations and with the product specification file.

The Directive contains a number of other changes concerning infringements or suspensions of the studies, reporting of adverse reactions and other guidance, but it is the three points outlined above - the necessity for QP release, adherence to GxPs and the various authorisations required - which will have the biggest impact on how trials must be conducted.

Clearly, sponsors outside the EC will need access to the services of a European QP if they wish to conduct trials within the Community. This will naturally result in an increase in the use of European clinical trial service providers and also reflect the importance of their role, as it is they who will take the weight of responsibility for authorisation compliance with respect to GMP.

The new Directive will consequently usher in a period where many non-EC organisations will seek to form relationships with European service providers for the first time and there are a number of considerations to be taken into account when choosing a partner.

QP Resource
The importance of the QP role in the authorisation process with regard to GMP compliance cannot be overemphasised. Ideally providers should be able to call upon a number of QPs with experience in all dosage form areas to ensure exclusive use of the provider for the duration of the trial. The broader the spectrum of QP experience, the greater the versatility that can be offered.

QP Training
The Directive requires QPs to undergo “appropriate training” with respect to experience, knowledge and formal education. However, there is still some debate as to what exactly constitutes appropriate training for clinical trials release. This will need careful formulating between sponsors, authorities and release/compliance personnel.

Whatever the outcome, ongoing in-house training to the highest standards will be of paramount importance. It is therefore essential to ensure the provider has the necessary infrastructure in place to support this, as well as an ethos which demands “best practice” training procedures are maintained.

Validation Experience
A service provider’s experience in validating processes, through the operation of commercial manufacturing or packaging activities, will also be critical. Validation, whether of machinery or an operative’s work, is a discipline which must be instilled in a company’s working procedures. Companies which already operate under GMP guidelines will be much better placed to ensure compliance with the Directive.

Knowledge of validation procedures will initially be particularly relevant to Phase III and Phase IV studies, where volumes will typically be inherently larger, and the validation requirements consequently higher. As time goes by, however, it is likely that the requirements for validation of stages I and II will be strengthened - the earlier processes are validated, the greater the potential savings in due course.

Quality System and SOPs
Standard Operating Procedures (SOPs) are an essential part of the provider’s modus operandi and an established contractor with commercial and clinical trials experience will have procedures that have been developed over a long period and draw on the experience of numerous audits. The SOPs will have been diligently scrutinised by both commercial and government agency auditors from around the world and developed accordingly - such excellence is difficult to come by any other way.

Auditing Experience
Audit experience and a keen knowledge of regulatory requirements are valuable commodities, as it is highly likely that the service provider will be called upon to provide an auditing service to ensure GMP compliance.

Labelling Issues
Direct experience of commercial packaging provides the contractor with an immediate benefit concerning the new labelling requirements. Although they are relatively straightforward, the requirements vary from country to country and it is important for the service provider to be able to comply with these, or offer the appropriate advice.

Breadth of Experience
It is advisable to consider a contractor with a full complement of capabilities and facilities which encompass import and release services - including analysis, process validation, method transfer and stability testing - together with appropriate storage and distribution and returns management. If required, experience of sourcing EC licensed comparators and placebos should also be checked.

The new Directive represents a radical change in the way non-EC sponsors must now approach and conduct clinical trials held in the Community, and sponsors should not delay in determining their future strategy. At a fundamental level, the Directive’s requirement to name the release site when applying for authorisation for a trial means that the whole life cycle of the trial will have to be considered at a very early stage. It will therefore be necessary to establish a relationship with the service provider and its associated QPs well before the trial is scheduled to begin. This is particularly relevant if the service provider will be required to conduct audits.

This is not a process to be rushed and by beginning now sponsors will be more likely to secure the services of a provider with whom they feel comfortable and in whom they have confidence.


First published in the Autumn 2003 issue of “Global Outsourcing Review”


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Pharmaceutical outsourcing:
when only the best will do

The changing complexion of the global pharmaceutical market is creating a climate of great potential for the contract services sector. But, says John Bath, Chief Executive of Brecon Pharmaceuticals, to capitalise on these opportunities, companies must invest time, money and effort into every aspect of their business.

The character of the global pharmaceutical industry has undergone radical change in the past decade and the resulting impact on the outsourcing community has been significant. Contract services organisations in particular are having to rethink the way they do business. Traditionally services such as packaging might have been outsourced for products perceived as being of lesser importance or lower value to the brand owner, or to supplement in-house packaging capabilities on an ad hoc basis. Faced with an unforeseen surge in demand or with production problems in-house, a pharmaceutical manufacturer might employ a contract house simply as a means to solve a short-term problem.

Although this model certainly serves a purpose, it is not necessarily the most satisfactory means of doing business for either party. While getting the job done on time, short-term, short-notice requirements do not allow the contractor to develop an optimum process and for the customer, additional costs might be incurred or certain compromises may have to be made. In this scenario, neither party is able to optimise cost savings, efficiencies or performance.

There will always be some demand for contingency operations such as this but the general trend now is for companies to outsource as part of a strategic plan. As the contract sector matures, it is increasingly apparent that in many instances, the decision to outsource provides access to facilities, expertise and cost savings not readily available in-house. Outsourcing is now an added-value rather than a stopgap service.

With efficiency and profit maximisation the drivers for much of the recent M&A activity in the pharmaceutical sector, the role of the outsourcing community has become more prominent. While sales growth and pooled R&D resource are often primary objectives for any merger, investors also appreciate that rationalisation is a key to maximising profit. Therefore if each partner involved in a merger has a production or packaging facility operating significantly below capacity - a fairly common state of affairs in the pharmaceutical sector hitherto - there will undoubtedly be rationalisation. A single unit operating close to capacity is ostensibly more efficient and carries fewer overheads. However, the flipside here is that the manufacturer’s ability to react to sudden peaks in demand utilising in-house resources is considerably diminished.

There is a laudable trend in all areas of business towards focussing on core competencies. For ‘big pharma’ these are research & development and - once a product has gained regulatory approval - capitalising on market presence and brand identity to maximise sales. Critical mass is therefore concentrated in these areas, with intermediate activities often regarded as peripheral. Nowhere is this more starkly illustrated than in the case of virtual pharmaceutical companies, which have never had and never intend to have anything other than R&D and marketing functions.

To a greater degree than ever before, pharmaceutical companies now stand or fall by the perceived strength of their drug pipeline. It used to be the common perception that once marketing approval for a new drug had been obtained, its developer could relax and reap the fruits of his labour in the form of fat profits during several years of exclusivity. Whether this was ever the case is open to debate but it is certainly not an accurate depiction of the current situation.

There are several pertinent factors here. The already huge costs of drug development continue on an ever-upward spiral, against a background of sustained pressure on healthcare costs from governments around the world. Nor is it any longer the case that the quest is necessarily over when one company patents a treatment for a particular condition. Recent court actions have shown that patents for competing products are valid, provided that the therapeutic action is demonstrably different. So the race for an effective treatment for ‘lucrative’ conditions continues, even after one or more companies has crossed the finishing line.

With the value of companies so closely allied to the health of their respective pipelines, it is not surprising that no stone is left unturned in the search for a new blockbuster. This has extended to the revival of projects previously shelved. Whether deemed too costly, or not providing sufficiently strong indicators for success, many studies are now under review. Scientific advances such as the genome project may rejuvenate the prospects for some, while others may be shown to be applicable to different medical conditions from those for which they were originally intended. The aim here is to avoid the daunting costs associated with developing a new drug ab initio and, crucially, to maximise sales under patent by cutting development time.

Reduced time to market has become something of a mantra for the pharmaceutical sector. Typically seven out of seventeen years of patent protection are spent in researching and developing a new drug; any reduction in this time equates to increased profits through greater sales during the period of exclusivity. Some of the initiatives being undertaken to achieve this goal are described above; a further trend is for concurrent multi-market launches, as opposed to the sequential territory launches seen previously. The involvement of a range of contract organisations can make a significant contribution towards achieving this objective.

In summary, therefore, the contract sector now has the opportunity to offer a wider range of services to its pharmaceutical industry customers and to become involved at an earlier stage in the drug life cycle. Business commitments of several years’ duration are commonplace, with the attendant advantages of better planning and greater efficiencies for both parties.

So what do we need to do to earn our place in this exciting scenario? Whatever service we offer, from formulation development right through study management to commercial packaging, there is one commodity in which we must trade above all other - confidence. We must inspire confidence in our expertise, to the extent that customers would feel able to walk away from a contract, once awarded, knowing that it is being handled by the best in the business and that the results or goods will be delivered on time and in a professional manner.

In practice, of course, customer involvement is usually extensive. Close lines of communication and a partnership approach are the key ingredients for a successful and enduring relationship, whatever the volume of business involved. Much like a marriage, the relationship works best when each party needs the other in equal measure.

The issue of core competencies is significant here. The contract organisation must invest time and money in developing expertise complementary to that of its customers. At Brecon, for example, we have built up a business based on excellence in packaging for solid dose products. Having worked for over 100 major pharmaceutical companies worldwide, we can offer unrivalled experience in packing thousands of products into blisters, sachets and bottles. We have invested in people and infrastructure to ensure that we can fulfil our commitments in the best possible manner. Our range of equipment gives us the flexibility to respond to any requirement quickly and efficiently. Few of our customers have had the opportunity to develop such expertise in-house, for the simple reason that their product range is limited. In this way we graduate from simply the contract packer supplying extra capacity on an ad hoc basis to the status of valuable business partner.

Yet the contract services sector is fiercely competitive, with many companies offering outwardly similar competencies and capacity. How, then, do we differentiate ourselves?

Company ethos is a rather nebulous concept but judging by the frequent customer audits carried out here at Brecon, nonetheless significant. We are passionate in our belief that each member of every team must take responsibility for his or her part of the process to ensure that the end result is never less than excellent and this certainly comes across in the majority of audit reports. Training is therefore at the heart of our business strategy, to the extent that we would be confident of any of our employees being challenged on GMP or protocol issues and coming through with flying colours.

This commitment to training carries considerable costs but the rewards can be surprisingly tangible. In our case, it has been a significant factor in helping us to win contracts packing product for the Japanese market, acknowledged as the most demanding in the world. Training has enabled us to identify and retain the staff best-suited to carrying out the rigorous product inspection routines essential to these contracts.

Developing and maintaining best practice is vital to the continuing success of a contract organisation and the external audit fulfils a valuable function in this context. Growth in demand for outsourcing has turned these into a regular fixture, which we at Brecon welcome. With 20 years’ experience working with scores of pharmaceutical companies, we have established protocols and procedures which are an amalgamation of the industry’s best. Nevertheless, there is always opportunity for improvement and so we view audits and the fresh view they bring to our business not as a test but rather as one of the best ways to improve further.

This is a highly-regulated industry and as such, the outsourcing community must always remain abreast of changes in the regulatory environment. One issue currently taxing all those involved in the clinical studies sector is the impending implementation of the EU Clinical Trials Directive 2001/20/EC. Member States must adopt and publish laws, regulations and administrative provisions to comply with the Directive by May 2003 and must have applied these provisions by May 2004. The objective of the legislation is to ensure the application of GxPs to all clinical trials involving human subjects and it will have particular impact on studies whose sponsor is based outside the EU area, since release of study materials by a European QP will be mandatory.

With just eight months to go before the due date for publication of laws, some of the detail is still to be resolved, causing headaches for the regulators, the pharmaceutical industry and the outsourcing community alike. A major issue is the appropriate training of QPs: article 23 of Council Directive 75/319/EEC (2001/83/EC) sets out the threefold requirement of formal training, practical experience and professional assessment. However, with the legal issues not yet finalised, there are clearly difficulties in determining what constitutes appropriate training, experience and assessment. In these circumstances, the GxP protocols will certainly need to be formulated in close consultation with the authorities and the study sponsors; ongoing in-house training to the highest standards will be of paramount importance.

One effect of the Directive is the recognition of the globalisation of the pharmaceutical outsourcing community, reflecting that of the industry it serves. Contract organisations based outside the EU must have access to the services of a European QP if they are to continue to offer a comprehensive international clinical trials service as required by their customers. The Directive notwithstanding, this requirement is one which all service providers should be seeking to address.

With this in mind, Brecon established a joint venture in 1998 with ProClinical Pharmaceutical Services Inc (Philadelphia, PA). ProClinical’s services include formulation development of Phase I-IV clinical supplies in various dosage forms, analytical testing, packaging, labelling, storage and distribution. Again this is a relationship based on equal need, with ProClinical having access to a European QP release facility via Brecon and Brecon gaining a point of entry to the North American market. Most importantly, however, the relationship benefits the customers of both parties, putting at their disposal a broader portfolio of services in a wider geographical area.

The question of the extent of services on offer is a moot point for the outsourcing community. With less infrastructure in-house, our pharmaceutical customers are understandably looking to one-stop shopping to reduce administration. So how do we expand our offering without diluting our expertise, or losing focus on our core competencies? How do we retain the personal touch of a small organisation, while expanding to satisfy the requirements of our business partners?

Yet again, company ethos is the key. Continuing personnel development is essential and we must establish a set of customer-focused values, transmitted throughout the organisation, which ensure that every team member understands the vital role he or she plays. However large we grow and whatever services we add to our portfolio, maintaining our reputation for quality, service and dependability must remain our foremost objective.

First published in Manufacturing Chemist, September 2002

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Practical aspects of validation

“We are looking to establish a practical, standardised approach to validation,” says David Woolley, who joined Brecon recently in the key post of Validation Manager.

“A great deal is written and spoken about this subject and to the uninitiated, it might seem to be one of enormous technical complexity. What we are aiming to do here at Brecon, however, is to demystify validation and approach the subject in a very down to earth fashion. By breaking it down into core disciplines such as cleaning, operation, maintenance and calibration, we are creating transparency for ourselves, our suppliers and for our customers.”

In essence, validation is about verifying that equipment and associated software is capable of fulfilling its stated purpose. The process should therefore begin well before equipment is specified, with the first step being the compilation of a URS (User Requirement Specification) detailing exactly what the user - and, in many cases, its customers - want the equipment to do and how. At this stage the document represents an ideal scenario, a series of benchmarks against which the candidate equipment can be measured. The next step is to check off the items in the URS against the features of the various pieces of equipment under consideration and through this process of elimination, to identify which option most closely matches the specification. It would be a fortunate buyer indeed who was able to locate his ideal machine through this process but nevertheless, a leading contender should emerge.

Once the choice has been made, the URS will again be used as the basis for a second process - that of Design Qualification (DQ). This involves checking off the various aspects of the URS against the machine specification to identify positives and negatives and possibly giving the prospective vendor the opportunity to address the negatives.

Following order placement, the process moves to its practical stage with Factory Acceptance Tests (FATs). It is at this stage that the vendor must prove to the purchaser’s satisfaction that the equipment does indeed match up to its specification.

Once accepted at the equipment supplier’s site, the equipment is installed at the user’s site, at which point Operational Qualification (OQ) is carried out. The purpose of these tests is to confirm on site that the equipment is operating safely and correctly. Confirmation of calibration here is essential, as are cleaning, maintenance and training.

Further specific testing is performed during Performance qualifications (PQ’s). This process confirms the operation of the equipment in specific applications and is the major area of challenge as far as the customer is concerned.

“As a validation professional, it’s my job to convey to colleagues and customers that validation has clear practical advantages which can help us all,” says David Woolley. “Initially it is about proving the equipment can do what it claims to do. However, PQ’s should not be seen to be the end of the process: validation should continue throughout the life of the machine to ensure that it continues to perform safely, securely and at optimum levels. This can be as simple as establishing and adhering to a routine for calibration of critical functions such as temperature and pressure, or as complex as software change control when a sophisticated system is upgraded.”

“Well-maintained and validated equipment has benefits for all parties. For the user, it ensures that productivity is maximised. For the equipment supplier, it reduces the incidence of spurious breakdown callouts. And for the customer, it means that his product is packed to consistently high standards and that he can expect a reliable service. The establishment and maintenance of good practice in the area of validation, such as documented cleandown between batches, has a direct impact on the quality of the finished product and minimises the potential for reject packs.

First published in Packaging Today, August 2002

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Facilitating the Audit Process

External auditing of suppliers is a time consuming exercise, but there are ways to ease the process. A Veteran of over 500 audits, Mike Parker of Brecon Pharmaceuticals, explains how.

External audits are an expensive business, both for the auditing company and the supplier or contractor under scrutiny. The time involved in preparation, the audit itself, subsequent questions and clarifications and, for the auditing company, the writing up of the report, is not inconsiderable.

Even for a small facility, the hours involved for the total process will tie up the personnel involved for upwards of three days and for larger sites it could be considerably longer. Times this by the number of suppliers a typical pharmaceutical house has - plus the number of internal audits carried out - and it comes as no surprise that large pharmaceutical houses have teams of dedicated auditors and even small concerns will have some staff seriously distracted from their “real jobs” by the auditing process.
Of course, these personnel are carrying out a vital role in ensuring that those supplying goods and services to the company are of a standard. Their role in maintaining internal procedures will also reflect positively on the quality of their end products. This, in itself more than justifies their cost to the business and over time it is likely they will save the company considerable sums by helping to avoid the repercussions associated with, for example, reject products, late deliveries, or even recalls.

So while audit teams may not be considered a direct contributor to the bottom line, they can be instrumental in maintaining it and in some circumstances, preventing it getting badly dented. Nonetheless, the fact cannot be avoided that audits represent a considerable cost to businesses and it is in the interest of both the auditing company and the audited supplier to make the process as efficient as possible in terms of both time and effectiveness.

Obviously, there are no tablets of stone, as the concept of a “standard” audit is by and large a misnomer. A number of variables - not least the nature of the job the third party is carrying out - will ensure that each audit is likely to be unique in some way. However, there are predictable elements of every audit which can be pre-planned and basic tenets which can be followed which will make the process more efficient.

The following is particularly applicable when auditing suppliers of contract services, but it also has relevance to those looking at component and material suppliers. Some of the points made may appear obvious, but often it is the simplest of things which cause misinterpretations and delays.

Firstly, it is frequently the case that certain information - from both sides - can be supplied ahead of audit day so pre-preparation is maximised and any questions or required clarifications can be properly considered. Information that is not pre-supplied should be readily at hand on audit day. It is therefore useful to make the company to be audited aware of your requirements.

For example, you will want to discuss the organogram of the company structure to assure yourself that the potential supplier has the required skill-sets and procedures to cope with the demands of the contract. Similarly, you will need to see all relevant SOPs.

A word to the wise here too. Please do not be tempted to apply your own SOPs to a third party’s operation. Contractors will have aspects of their SOPs that can be modified, within limits, to incorporate particular needs - say with differing limits on reconciliation for bulk product - but it is not recommended that you insist on changing them entirely to dovetail with your own internal procedures as the operational personnel’s unfamiliarity with them could lead to difficulties.

It may help to reassure you if you remember that most contractor’s SOPs have been developed over a long period and are the result of hundreds of audits which equates to months’ worth of “free” consultancy. They have been diligently scrutinised by both commercial and government agency auditors from around the world and adjusted appropriately - they are effectively as good as you get.

It is also important to ensure that all the personnel who are key to the project on the contractor’s side are available during the period of the visit, as it may be that questions will arise that only they can answer. However, if you make this request, try not to make a habit of changing the date of the audit as this will obviously cause friction with the contractor who may have rescheduled the diaries of various senior personnel to comply with your demands.

There are also a number of things you can do to ease the process and save everybody time. You have presumably checked the company’s accreditations and testimonials and seen its work, so the basis of your visit should be co-operative rather than confrontational. As such the audit should not be treated strictly as an exam, but more as an investigation to ascertain whether, with the necessary input from you, the contractor can provide the right quality product within the specified time schedule. If the audit is successful a number of variables may then come into play when negotiating the contract.

It is important that the contractor knows exactly what the job entails so that they can be confident they can meet your needs (It may appear very obvious, but those carrying out the audit on the day should also be fully briefed on the requirements).

For example, it helps if the contractor knows if they will be required to supply materials and components and who will apply controls to these items. Other areas to consider include the type and design of the pack, especially if it is an unusual format which may need specialist forming or handling. The nature of the labelling and language requirements should also be disclosed to ensure they can comply with your needs.

Most contractors will also be able source analytical services if you required them to, but it is worth checking that they have the experience and contacts to fulfil this need. Similarly, if you want the contractor to handle final release, make sure they are happy to take on this responsibility.

It is useful too if the audit plan is supplied prior to the site visit so that the contractor can carry out some preparatory planning for specific issues that may arise. This is not a case of “making it easy” for the contractor, it is a way of ensuring they are as best prepared as they can be to respond to your requests.

Indeed, the more pre-knowledge a prospective contractor has about the job, the more relevant and effective the audit will be. Moreover, should the contractor be awarded the project, less discussion and planning will be needed at a later stage when time will undoubtedly be more pressing.

In order to process this information in as quick and clear a way as possible, it is also vital that both sides establish firm channels of communication for both commercial and technical information.

It may also be pertinent to contact colleagues ahead of the audit to check if the company to be visited is being considered for any other contracts, in which case you could save a re-visit by covering specific points they may wish to be raised.

As mentioned, at the audit itself, adopt a positive attitude towards your prospective partner and the day will run much more smoothly without altering the result. If things are not what they should be, it will soon become apparent anyway and if everything is up to spec, you will not have put a potential strain on the relationship. How the company applies standards can be gauged by close observation of operatives and procedures during the visit. Conversing with staff at all levels is also useful to gain an insight into the company’s philosophy and modus operandi.

The most crucial part of any audit is the summary session - if there are any concerns from any party, they must come up at this point. All facts should be agreed at this session before the report is written-up and as a final measure to ensure it is a true account, the report should be sent to the audited company for checking before it is finalised.

This should not engender a debate unless the contractor believes there are blatant errors in the findings. The primary reason for this exercise is simply that factual inaccuracies do find their way into reports. These may be down to simple misinterpretations on the auditor’s behalf, or poor communication from the audited company. Whatever, it makes sense to avoid embarrassment all round by passing it in front of the eyes of all senior personnel involved.

This co-operation in getting a true and correct result should reflect the overall manner in which the relationship between client and contractor is conducted, as there is an inevitable link between the nature of this relationship and the degree of success of the project.

The more information exchanged and the more the client takes the contractor into their confidence, the better the result will be. By fostering a “partnership” approach, the contractor will accept a degree of ownership of the project which ensures a high level of service and, if required, innovation. Indeed, given the right brief, we find we can often provide added value way beyond the simple fulfilment of the contract through application of the experience and expertise we have gained over the years.

So what of the future of audits? The most glaringly obvious fact about current practice is the duplication. Every major pharmaceutical company in the world and numerous middle-sized and small concerns, have passed through Brecon’s doors, all basically to check the same equipment, procedures and general competency.

A central database of approved contractors held and monitored by an industry body or government agency and backed up by the agreed use of testimonials and references would seem to make perfect sense. The funding of such a body would only represent a fraction of that spent by drug houses annually on external audits.

Of course, audits can have differing emphases, or be very product specific and if the database does not hold the required information, individual audits could still be carried out. New audits and re-audits at specific intervals would also continue, but the total number would be radically reduced which would ultimately cut the time to market for many products, a crucial factor nowadays for most companies.

To rationalise the audit process itself and to ensure a full and frank exchange of information between the parties, standard - though flexible - pre-audit questionnaires could also be compiled. One would be completed by the contractor to save time at audit and the other by the client to ensure the audit is as relevant as possible.

For the nearer future though, I believe the industry will increasingly move away from the traditional sponsor/contractor relationship and the trend towards constructing partnerships and even co-sponsorships will strengthen, which will inevitably change the nature of the audit process for the better.

Top ten tips for an effective audit
Make the contractor aware of your full information needs pre-audit
Get as much information as possible supplied prior to audit
Inform colleagues of the audit as it could save a re-visit
Supply a full job specification and audit plan in advance
Ensure all the contractor’s key staff are on-site on the day
Determine responsibilities of each party at an early stage
Establish firm channels of communication
Adopt a partnership approach to maximise contractor’s commitment
Ensure all concerns and questions are aired at summary session
Give the contractor sight of the report before finalising it

This feature first appeared in the Spring 2002 issue of PMPS magazine

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Service Providers - Partners in Prime


Today's pharmaceutical services companies face the most challenging of tasks, as they are required to offer speed, flexibility and competitive pricing combined with impeccable standards. Yet, says Steve Kemp, Business Development Director of Brecon Pharmaceuticals, this ideal can be achieved when a partnership approach is adopted.



The rash of mergers and acquisitions over the past decade has transformed the research-based pharmaceutical sector. Almost without exception, the top companies in the sector are shedding 'non-core' functions such as manufacture and packaging, as a diverse range of operations is increasingly viewed as a hindrance rather than an asset in today's aggressive global market.

Traditionally, large companies existed to reduce transaction costs - that is, to retain the profit generated by each stage of product development, manufacture and sale. However, current business models suggest that focussing on core competencies is more desirable, and with improved communications and the globalisation of the economy, it is easier to identify the most suitable suppliers and the best prices for services on the open market. The attraction of variable rather than fixed costs is also considerable.

Many mergers and acquisitions have been justified on the basis of aggressive sales forecasts, which can only be achieved if companies are able to increase the number of new drugs coming out of their pipelines. Several of the world's top-selling drugs will come off patent in the next few years and these must be replaced by New Chemical Entities (NCEs) if revenue streams are to be maintained and increased. Most companies in this sector now have a clear strategy to focus on their core competencies of drug development and marketing, pledging publicly to increase the amount of sales revenue they spend on R&D and to cut typical time to market for NCEs by as much as 30%.

These are ambitious targets indeed but in the context of the average of £350m development costs for each NCE and £1m sales revenue each day during patent protection, they are understandable enough.

With drug companies avowedly focussing on the beginning and the end of the product cycle, a wide range of services once performed by full- time employees is now outsourced. Estimated at £13bn in 1998, the pharmaceutical outsourcing market continues to grow at some 20% p.a.

Outsourcing creates access to expertise and production capacity and can be a major factor in reducing time to market for a new product. It also allows pharmaceutical companies to be fast and flexible, while avoiding the financial risk associated with investment in facilities and personnel. It is attractive because it provides the flexibility required, whatever the degree of success achieved by the product in question.

Providers of outsourced services take many and varied forms but they must all offer in common speed and flexibility of response. The degree of regulatory control applicable to the production of pharmaceutical products, however, means that no corners must be cut, whatever the pressure to offer flexibility and fast turnaround combined with a competitive price.

The nature and extent of outsourcing also varies widely from company to company and from product to product. The linchpin of many such arrangements is the contract research organisation (CRO). Established initially to take drugs through the clinical trials procedure, many CROs have now expanded the range of services they offer, with some now moving into early stage R&D, while others are offering production, packaging or sales and marketing services. Others in turn contract out requirements such as the preparation of packs for clinical trials to companies with expertise in this area.

The growth in the outsourcing sector and the increased range of services it offers is engendering a new spirit of partnership with the pharmaceutical industry.

In common with most companies in the field, Brecon Pharmaceuticals has experienced significant changes in the past decade. A decade ago, outsourcing was generally viewed as something of an emergency measure, and certainly not a long-term option. Over the years this perception has changed and ongoing partnerships are now more the rule than the exception. Teamwork has replaced the old approach of simply handing over aspects of research, manufacture or packaging and naming a date by which the finished product must be delivered.

For example, on the packaging side, many pharmaceutical companies use contract houses as an extension of their in-house facilities. As order patterns become less predictable, these companies can remain efficient and competitive by outsourcing small orders and those requiring rapid turnaround, for which their in-house facilities are not always appropriate.

Most recently, the emergence of 'virtual' pharmaceutical companies, established for the sole purpose of drug discovery, has given a further boost to the sector. These companies require production on demand, with no overhead for production and packing facilities or personnel.

Selecting the right service provider is a lengthy and complex process - each company and each project has different criteria. However, there are certain requirements which are common to all and which should be addressed at the earliest stage of discussion.

Can the supplier demonstrate experience relevant to the project in hand?
Does the company have a track record of delivering on time and to the agreed specification?
Can it provide the required degree of flexibility, in terms of availability of suitably qualified personnel and relevant equipment?
Is it accredited by all the authorities appropriate to the project?

The level of expertise available in service companies is typically extremely high, as most tend to focus on a specific area of the supply chain. Moreover, established companies will have been audited many more times than their counterparts in the research-based pharmaceutical industry and be adaptable to the exigencies of their many different customers. Brecon, for example, has in the past developed a number of new services and facilities in direct response to customer requirements.

It may also be true that as service companies rely exclusively on fulfilling specific tasks and, ideally, retaining clients, the levels of service and quality are often greater than those achieved in-house. In certain circumstances, particularly when a partnership approach is adopted, the service provider can add value way beyond the simple fulfilment of the contract through the application of their experience and expertise.

A major contributing factor in the success of any such relationship is the degree of openness existing between the parties. A key aspect here is the audit process, conducted before any work commences. The more information provided by the Contract Giver at the audit stage, the better the Contract Acceptor will be able to perform, if and when an order is forthcoming. Many contract projects are undertaken in pressure situations, so time is of the essence.

Auditors should also be briefed by their employers on the precise nature of the project for which the potential supplier is being considered. A focused audit will produce much more satisfactory results for both parties than a non-specific one. Any perception of the audit as a negative process is now outdated: one the one hand, auditors should be looking to save their employer time and money by find a suitable supplier as quickly as possible, rather than seeking minor non-compliances. On the other, the potential supplier must view it as an opportunity to demonstrate the extent of his capabilities.

Successful outsourcing reduces costs, improves flexibility and enlarges the pool of expertise available to the research-based pharmaceutical sector. As such, it is now generally part of a strategic plan rather than an emergency measure. And long-term business relationships are most fruitful when founded on mutual trust and confidence.


First published in Manufacturing Chemist, September 2001

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