Cleaning validation in the pharmaceuticals industry:

Alleviations through innovative, modular centrifuge technology

Good pharmaceuticals manufacturing practice requires from pharmaceuticals companies that rooms and apparatus such as centrifuges and other devices must be cleaned according to written methods (“Good Manufacturing Practice” or GMP).

The most suitable method must be validated by the respective pharmaceuticals company on the basis of regulatory requirements [1] and their own expertise and technological advances in apparatus engineering. This takes place as part of cleaning validation; and this is precisely where the innovations of Ferrum in the area of vertical scraper centrifuges offer further alleviations.

Not without “my” risk assessment

The word cleaning validation represents a real challenge to the pharmaceutical, apparatus and plant engineering industries. This does not just simply involve complying with regulatory standards. The safety of pharmaceuticals, feasibility and efficiency are main aspects.

At the start of every cleaning validation is the validation plan, which can be divided into three phases, see also [2], [3]. The providers of centrifuge technology solutions can make an essential contribution in all three phases towards realisation and efficiency. This can only be achieved by working together and harnessing all available relevant knowledge available.

The three phases can be briefly described as follows:

1)Internal status inspection of planned production line
This concerns the question of which active and inactive ingredients are to be produced or used? The product change frequency has a considerable influence on the efficiency. One must therefore know which cleaning agent and method should or can be used.

This is where the latest innovative VBC centrifuge technology comes in; based on the expertise of the machine supplier in apparatus engineering and construction in line with the latest advances in mechatronics as well as design aspects and process sequences of solids-liquid separation and cleaning. The machine supplier is not responsible for the active ingredients however.

2)Risk assessment of products and facilities
The internal pharmaceuticals status inspection must be followed by risk assessment for all products, the aim being to identify substances that are a particular hazard. Responsible is the pharmaceuticals company, see graphic “worst-case” analysis according to Borchert [6].
Centrifuge manufacturers can make a valuable contribution with their expertise and years of experience in the assessment of design-related cross-contamination (e.g. difficult to access or absorbent surfaces, dead ends in pipes and extraction points, etc.).

3)Determination of extent of validation
On completion of the internal status inspection and joint risk assessment (machine supplier and pharmaceuticals company), the extent of validation can (must) be determined by the pharmaceuticals company, see also [4].

In this phase, Ferrum is able to offer the possibility of validating design-related critical points in its own assembly halls following assembly and so reduce by this verification item, time-consuming validation within the pharmaceuticals company. By means of a so-called riboflavin test, for example, the effectiveness and wettability within the centrifuge can be verified or also the effectiveness of CIP cleaning of inert material at “critical points”.

It is therefore in the interest of the pharmaceuticals company to complete validation quickly and if possible in the phase prior to commissioning. This is only possible in cases where existing facilities are duplicated. As maximum flexibility in the manufacture of pharmaceuticals is of the essence today, apparatus such as centrifuges must be appropriately flexible in design.

Precisely this step was taken at Ferrum with the latest VBC vertical pharmaceutical centrifuge. The processes of rinsing, washing, spraying, measuring, analysing, scraping, blowing out and even flooding have been greatly improved in the new generation of centrifuges over that which was state of the art a few years ago. The special advantage of Ferrum centrifuge technology solutions is that many of the different function modules can be integrated flexibly both in the initial design of the machine as well as retrofitting. The cleaning process can be optimally adapted to the respective production sequence in a highly flexible manner.

It is therefore extremely important that the experienced and innovative centrifuge supplier is included in process selection already in the planning phase.

Cleaning procedure validation and selection

In order to locate fouling on machine parts, specific samples are taken before and after the cleaning procedure. In the PIC document PI 006, sampling procedures using the wipe or swab test and flush or rinse test are considered suitable. [5]

One advantage of the swab test is that it provides information on where the fouling is located, e.g. in bends or branches of pipe systems.

Useful is the inclusion of global analytical methods. An example is TOC determination for organic loading, conductivity measurement for ionic residues and ph measurement for cleaning agent residue detection. These analytical methods can be included as online measurements or installed in the centrifuge. Such analytical methods can be used for multifunction systems to provide maximum flexibility during commissioning, as all possible active and inactive ingredients are often not known. Offered is a retrofitting option; this is usually possible in the majority of cases without redelivery to the manufacturer’s workshop due to the modular design of the VBC.

Modularity in use

Passive contribution towards cleanliness in scraper centrifuges

It may sound simple, but good access to the centrifuge is a precondition for its cleaning and analysis, even when fully automatic CIP systems are usually installed. The modular design of the VBC vertical pharmaceutical centrifuge takes this into account. The design of the cover opening, the position of the outlet and the basket drive can be selected in a wide range of variants and combinations. This enables the machine to be optimally adapted to local space conditions at the site of installation without additional expenditure; this is something that will be appreciated by structural engineers and plant constructors as well as those responsible for maintenance.

Until now, only so-called horizontal centrifuges where considered suitable for installation in a clean room. With the introduction of the VBC, a vertical scraper centrifuge now meets all requirements for installation in a clean room concept, as the complete drive can be arranged below the vibrating plate. This allows the technical area to be separated from the clean room area by means of a membrane in the floor/ceiling.

This method of installation complies with the wishes of many pharmaceuticals companies as the entire production flow takes place gravimetric vertical. The VBC vertical scraper centrifuge thus requires less space than a conventional horizontal centrifuge, as this additional clean room area is required for opening the horizontal housing and positioning the pipes with respect to the vertical product flow into the horizontal machine.

A further important item in the design of the VBC is the one-piece concept of the housing and base plate, avoiding numerous edges and transitions with the advantage of less fouling.

Active contribution towards cleanliness in scraper centrifuges

The function modules that contribute towards active cleanliness include CIP nozzles. The principle applies: As much as necessary, as little as possible. Especially in the case of multifunction systems, the use of an additional CIP nozzle may be necessary. In the modular concept of the VBC centrifuge, this does not present a problem as the CIP nozzles are flanged and easily retrofitted (during production) without welding. It goes without saying that these flanges are all provided with GMP compliant seals.

Those responsible in pharmaceuticals companies can face a far greater problem if the cleaning process must subsequently be changed from CIP cleaning to flood cleaning with a change of product, see “worst-case” analysis. This is another problem that can easily be solved with the design concept of the VBC, as the complete bearing and sealing system is in a modular design. The so-called bearing cartridge can be prefitted as a floodable version and exchanged for the fitted cartridge (during production); and all this without removing the complete centrifuge and sending it to the manufacturer’s works. After the conversion, the complete centrifuge can be flooded up to the cover.

A further important innovation measure was achieved by the optimal use of pneumatic drives for operating the scraper and cover, whereby movement is effected by self-locking spindle drives. All hydraulic oil is thus banned from the pharmaceuticals area and a further risk factor eliminated.

Conclusion

Innovation in the engineering industry today is based on a large proportion of modularisation of functional units. An innovative and modular design in combination with the latest control concept enables users in pharmaceuticals production to adapt machines precisely to suit their individual requirements and to bring function and costs into accord.

A technical feature does not often produce the best result with regard to reducing consumption costs. Only the sum total of all activities in one solution enables costs to be minimised within a production plant. In short, Ferrum “Centrifuge Technology Solutions.

SMOL Schneider; Dipl. Phys. ETHZ, Ferrum Marketing& Sales, Business Unit Centrifuge Technology /29.2.04

Bibliography
[1] EG-GMP Guide, Appendix 15

[2] Jörg Koppenhöfer; Efficient and cost-saving cleaning validation in the area of active ingredients and substances in multifunction systems, gempex, GmbH, Mannheim, Source: http://www.gempex.com/

[3] Dr. Bernd Köhler und Dr. Carsten Richling; Planing, implementation and documentation of cleaning validation in the pharmaceuticals industry, SWISS PHARMA 25 (2003) No. 9.

[4] FDA Guide for inspection of the validation of cleaning processes; http://www.fda.gov/ICECI/Inspections/default.htm

[5] PIC/S PI 006; Recommendations for validation master plan; GMP Consultant, GMP-Verlag, Schopfheim (2003)

[6] D. Borchert; Cleaning validation (Bd. 1, Chapter 8.B-8.K), GMP Consultant, GMP-Verlag, Schopfheim (2003)

Author Information - Mr. Sandro M.O.L. Schneider Dipl. Phys. ETH

Head of marketing and Sales

Mr. Sandro M.O.L. Schneider, a certified physicist ETH, worked for many years in research and development after completing his studies. As head of research and development at a Swiss based Sensor Company, he was responsible for the efficient application of sensor technology in many machines of the process industry.
He headed than Global Marketing for sensor and instrumentation technology at an international company active in process automation.
At Ferrum he is responsible for the active sales and marketing of the Centrifuge Technology Solutions in the global market. His experience in process and automation engineering is at disposal now to the Ferrum customers.

Methods for practical validation of surrogate endpoints

Along with the development of different definitions of a surrogate endpoint, methods for verifying whether the definitions hold for a biomarker have been proposed. Recently, a new methodology, known as the “meta-analytic” validation approach, has been developed (Buyse et al., Biostatistics 2000). This method uses data from multiple randomized clinical trials and aims at assessing directly the precision of prediction of treatment effect on the true endpoint from the effect on the surrogate. Thus, it allows to assess whether “the effect of treatment on a surrogate endpoint is reasonably likely to predict clinical benefit”, as required by the Biomarkers Definitions Working Group definition. As such, it is a powerful tool that makes it possible to assess the suitability of candidate surrogate endpoints and to prevent erroneous use of them.

A big advantage for such a structured approach is that it allows quantifying the evidence in favor or against the use of a surrogate. The methodology has been already used, e.g., to evaluate the validity of using response rate and progression-free survival as surrogates for overall survival in colorectal cancer (Buyse et al., Lancet 2000; Sargent et al., Journal of Clinical Oncology 2005; Buyse et al., Journal of Clinical Oncology 2007); the validity of using PSA as a surrogate for overall survival in metastatic prostate cancer (Collette et al., Journal of Clinical Oncology 2005); or the validity of using response rate, disease control rate, time to progression, and progression-free survival as surrogates for overall survival in metastatic breast cancer (Burzykowski et al., Journal of Clinical Oncology 2007). Some of these results have been taken into account in the “FDA Project on Cancer Drug Approval Endpoints”, launched by FDA “to evaluate potential endpoints for cancer drug approval” (http://www.fda.gov/cder/drug/cancer_endpoints). Within the project, FDA holds public workshops to identify important issues that are discussed in meetings of the Oncologic Drugs Advisory Committee (ODAC). Subsequently, guidance documents are published describing FDA's view on endpoints for cancer drug approval. Thus far, workshops for multiple myeloma, ovarian cancer, primary brain tumors, lung cancer, colorectal cancer, prostate cancer, and acute leukemia, have been organized.

Conclusions

One needs to be aware of the fact that, even if a surrogate has been validated for a particular class of treatments in a particular disease, this does not automatically mean that the use of the surrogate is valid in another disease, or for another class of treatments. This is because the mechanisms of action of different treatments may differ, and their relevance for different diseases may also vary. Thus, the use of a surrogate endpoint will most likely always require a careful consideration whether the result of a validation exercise can apply to a particular situation.

Facilitating regulations and increasing throughput

Nerviano Medical Sciences is one of the largest oncology-focused, integrated discovery and development companies in Europe. It is a private company owned by the Congregazione dei Figli dell’Immacolata Concezione (CFIC). Almost 700 highly skilled and experienced scientists, technicians and managers are involved in oncology R&D projects, from target validation through to clinical phase IIa. NervianoMS aims to discover and develop innovative medicines for the treatment of cancer, and to establish partnerships with the biopharmaceutical industry and the scientific community.

The preclinical development unit (PCD) of NervianoMS, Accelera, is committed to predicting and managing potential toxic, pharmacokinetic and metabolic issues of new compounds and to supporting all stages of drug discovery and development. Based outside Milan, Italy, Accelera has successfully developed and applied state-of-the-art technologies and ad hoc approaches to ‘pick the winner’ among potential drug candidates for all therapeutic areas. Currently employing approximately 120 scientists, Accelera provides a range of PCD services, including preclinical discovery and profiling, development services and consultancy, clinical and preclinical bioanalysis and oncology drugs research services.

GLP compliance
The IT group of NervianoMS manages and maintains complex IT infrastructure architectures, information system networks and software applications, and supports more than 1000 workstations across the organisation. The group must also maintain processes in line with GLP and FDA Computer Validation Guidelines, as well as other regulations relevant to the pharmaceutical environment.

Both GLP and FDA guidelines require drug makers, medical device manufacturers, biotechnology companies and other regulated industries to implement control processes, including regular audits, validation programs and full documentation of products and systems. GLP guidelines help to assure regulatory bodies that data submitted by manufacturing companies are a true reflection of the results obtained and can therefore be relied upon. In order to comply with this wide range of regulatory requirements, it is essential that companies undertaking sample analysis implement carefully validated software systems.

As part of its R&D activity, Accelera carries out Enzyme-Linked ImmunoSorbent Assay (ELISA) experiments, with a large focus on GLP compliance. In 2001, the company began to receive both internal and external requests for bioanalytical support for ELISA data in preclinical and clinical regulated studies. The main business requirements for such a support system were: a validated process and statistical tool to generate and manage ELISA data, and the capacity to electronically manage and store study information and ELISA data that was compliant with regulatory guidelines. In order to meet these requirements, the company began to look for a Laboratory Information Management System (LIMS).

Smooth implementation
Accelera traditionally used vendor-specific instrument analysis software for the management of ELISA data, as well as Microsoft Excel and paper-based procedures, but began to investigate the installation of a LIMS. NervianoMS looked at several alternative systems for Accelera, but found that none matched the capabilities of Thermo Scientific Watson LIMS in terms of integration, development for the analytical field and guaranteed GLP compliance.

Thermo Scientific Watson LIMS is a highly specialised protocol-driven system, which has been specifically developed to support drug metabolism and pharmacokinetics (DMPK) and bioanalytical studies in drug development. It is installed in 18 of the top 20 global pharmaceutical organisations, and is widely used in leading biotechnology and contract research organisations worldwide.

NervianoMS already had an established relationship with Thermo Fisher Scientific, as the company uses a range of Thermo Scientific instruments. Thermo Fisher’s proven track record of support for Watson LIMS was attractive, as well as the company’s ongoing dedication to developing and integrating its systems in the analytical field. Additionally, Watson LIMS has been expressly built to promote compliance with GLP and 21 CFR Part 11 regulations.

During the Accelera implementation, Watson LIMS was configured to use a central Oracle 92 database on a Linux operating system. The LIMS offers a simple, point-and-click graphical interface that resulted in minimal training for the 50 Watson users at Accelera. To aid GLP compliance, the system security and audit trail are designed to provide maximum flexibility and configurability while preserving data integrity. Watson LIMS is the ideal system for Accelera, as it is capable of handing and storing complex study protocols and tracking deviations to each study.

Since its installation, Watson LIMS has been a key component of all GLP activities, and as a result almost all experimental data must be organised and managed by the LIMS. In addition to implementing the LIMS, Accelera required a method to import ELISA data files directly from its fluorometer into Watson LIMS. To accomplish this, Accelera uses a program compiler to interface Watson LIMS with the software for the microplate reader, ensuring Watson support for the determination of large molecules. Watson’s interfacing drives a range of activity, from study information and sequence plans to the final results reports in Accelera’s fully compliant environment.

Significant impact
Since the implementation of Watson LIMS, Accelera has experienced considerable benefits, including enhanced regulatory compliance, as well as increased laboratory productivity and accelerated sample turnaround.

Because Watson LIMS fully supports unit management and allows data consolidation across studies and projects, it has been quickly accepted by Accelera’s analytical community. By expanding the use of the electronic format across Accelera’s traditionally paper-oriented environment, Watson LIMS has had a significant impact on laboratory productivity, and enables laboratory analysts and ELISA study directors to easily consolidate sample and instrument data. Watson LIMS has also had a significant impact on the level of compliance of Accelera’s laboratories by providing a clear audit trail for GLP compliance for the execution of regulated studies.

In a global pharmaceutical manufacturing company such as NervianoMS, it is essential that processes and practices be compliant with strict regulations such as GLP and the standards set by the FDA. However, newly implemented systems must be flexible in order to interface with Accelera’s wide range of instruments and the associated data. By using Watson LIMS, Accelera has put in place an easy-to-use system which improves laboratory productivity and turnaround time, as well as guaranteeing simple regulatory compliance in a cost-effective way.

Watson LIMS has fulfilled the initial requirements of Accelera, and through its security control and server qualification, provides a fully compliant system for the management of ELISA data. With the capability to support a validated statistical tool for ELISA data as well as being the driver of automated data processes, Watson LIMS is an electronic repository for ELISA data across multiple studies and projects.

NervianoMS initially chose Watson LIMS because of the development of the system within the analytical field, into which Watson is perfectly integrated. The company was also impressed by Thermo Fisher Scientific’s dedicated approach to solving problems. Watson LIMS is extremely easy to use and was quickly accepted by our 50 users.

Watson has met all of our requirements and was easily configurable to enable interface with our instruments. Since implementing the LIMS, all of our processes have been validated and all points of the NMS Computer Validation Policies have been applied, in agreement with the FDA Computer Validation Guidelines. As a result of the increased productivity of our laboratories and the guaranteed compliance of Watson, we cannot do without it.

Thermo Scientific Watson LIMS is now used as the standard LIMS across Accelera’s PCD laboratories.

Bio:

Stefano Cavanus is the informatics system manager at Nerviano Medical Sciences, one of the largest pharmaceutical research and development facilities in Italy.

About Thermo Fisher Scientific
Thermo Fisher Scientific markets its leading informatics solutions, including Laboratory Information Management Systems (LIMS), Chromatography Data Systems (CDS) and Spectroscopy Software, under the Thermo Scientific brand. Thermo Scientific LIMS and CDS can meet the most demanding data management needs, with purpose-built solutions to reduce implementation risk and total cost of ownership. With more than 1500 systems sold, its informatics solutions command the market and serve as the corporate standard at leading companies.

For more information, visit www.thermo.com/informatics.

Playing ball with the Pharma 'Big Boys

Entrepreneurs trying to penetrate the fast-moving pharmaceutical industry are often lost in the background noise of the global competition. Do-Coop Technologies has discovered that you can level the playing field with just a bit of smart business strategy.

If “insanity is doing the same thing over and over again and expecting different results,” as Albert Einstein was rumored to have said, then many entrepreneurs should have their heads examined. Fully convinced that their innovation will “speak for itself”, a startup will knock on the Pharma door, expecting admission to the labs of the Big Boys... only to be lost among hundreds from around the world with the same ambition.

Meanwhile, the doorkeepers of this competitive industry look out over the sea of eager faces, waving signs and clamoring voices. They might well be interested in your technology. But you need to give them a reason to notice your face in the crowd and grant you a hearing.

At Do-Coop, we applied Added-Value Elements that sweetened the deal for potential partners, giving us that edge. You can use these keys to unlock the Pharma door for yourself, where sustained, profitable relationships could be waiting.

A-V Element 1: Perform the business and technology validation yourself.

A small company seeking to enter the Big Boys' playing field faces a double hurdle. The more innovative your technology claims to be, the more skepticism you will face about its potential success. Regarding a newcomer to the industry, that skepticism naturally increases.

A technology doesn't stand on slick public relations but on verifiable results. The global Pharma players achieved their market position through a track record of such results; they are as difficult to fool as Nature itself. They distinguish "breakthrough technology" from "science fiction" through the reality check known as business and technology claims validation.

Notice that it isn't enough to prove that the technology works; it must be a workable business idea – meeting a sufficient market need, adaptable for mass production, and transportable to the market (all for a profit).

Claims validation is an expensive, time-consuming process, a risk in itself. Therefore, an unknown company with an unvalidated technology is perceived as carrying more risk than opportunity.

You can lower the risk and enhance the opportunity by presenting the claims validation as an established fact. This is what Do-Coop did with Neowater.

Neowater is applied Nanoscience – molecular-level particles – one of today’s most important research frontiers. Nanoparticles are of great interest because all properties of a material (such as melting point, electronic and optical properties) change when particles in the material become nanoscopic.

In Biotechnology, nanoparticles are used in nanometer-scale equipment for probing the real-space structure and function of biological molecules. Auxiliary nanoparticles, such as calcium alginate nanospheres, have also been used to help improve gene transfection protocols.

Our Neowater technology was radically innovative - even for Nanoscience. It gave ordinary water unprecedented properties, demanding a paradigm shift in Pharma thinking.

We knew this would provoke initial skepticism. The opportunity represented by Neowater would be considered a high risk by any sane corporation. Our company overcame that skepticism, and built confidence in the viability of Neowater, by performing the claims validation ourselves.

Recognizing the risk that still remained, we further bridged the gap with business structure deals that cater to customer needs.

A-V Element 2: Reduce business risk by resolving regulation issues.

In the Pharma business, nanoparticles are used for drug delivery, and the list of applications based on nanostructure is continually growing... as are the regulations that must be addressed.

Do-Coop Technologies resolved these issues before approaching customers, a proactive step to reduce the penetration barrier to the clinical stage. Interested customers can cross-reference our Type IV Drug Master File for Neowater (DMF# 20503) with the FDA, eliminating the need for a separate group in the study of Neowater. By saving them the cost of a customer study, we sweetened the deal considerably.

A-V Element 3: Offer to share the IP wealth.

To remove another barrier to market penetration, our company limits the scope of its Intellectual Property holdings to the Neowater production process and its composition (one family of applications). We allow the customer the right to own the use of Neowater in the customer's IP portfolio, which ensures that we will not be competing with our future customer and partners, and ultimately enhances their potential profits. (The right to use our IP is granted to companies that own IP for the product under evaluation.)

A-V Element 4: Share the burden of product validation with your partner.

Yet another risk is the customer’s cost of validation in specific product development using your technology. This includes Proof of Concept: clinical criteria to be met before the company can add a new product to its portfolio.

Do-Coop has adopted the position that we are not a service provider for our technology, but rather a full partner in R&D. After all, no one knows the technology better than its creators, and our willingness to provide risk-free Proof of Concept greatly eases the process for companies to license Neowater technology for their product portfolio. It also increases their confidence in the business viability of Neowater.

Upon request, our company team sits with the customer team to discuss the modifications they need. The first step is to determine the Proof of Concept success criteria. After agreement on these, and a Statement of Working Relationship, we offer the company the option to sign a contract with us to license the Neowater technology (including milestones and royalties).

The business strategy of Value-Added Elements has opened important doors for Do-Coop in the Pharmaceutical, Biotechnology and Chemical industries.

As satisfying as these successes are, they represent only our first target markets. The physical properties of Neowater, and particularly its heat-management thermodynamic capabilities, provide a very broad technology platform that will benefit many industries. We will be adding value to each application, ensuring a smooth playing field for all partners.

Achieving GLP Compliance Through Deployment of LIMS

In 1997, the Organization for Economic Co-operation and Development (OECD) published the revised principles of Good Laboratory Practice (GLP) to regulate the non-clinical safety testing of test items contained in pharmaceuticals, pesticides, cosmetics, veterinary drugs, food and feed additives and industrial chemicals. These test items are frequently synthetic chemicals, but they may also be of natural or biological origin and, in some circumstances, may be living organisms.

The purpose of the principles of GLP is to promote the development of high quality, validated test data. Comparable quality and validation of test data forms the basis for the mutual acceptance of data among countries. If individual countries can confidently rely on test data developed in other countries, duplicative testing can be avoided, thereby saving time and resources. The application of these principles should help to avoid the creation of technical barriers to trade and further improve the protection of human health and the environment.

GLP is a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. Non-clinical health and environmental safety studies covered by the principles of GLP include work conducted in the laboratory, in greenhouses and in the field. These studies are undertaken to generate data on the properties of test items and assess the hazards and risks to users, consumers and third parties, including the environment. GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments for the purpose of registering or licensing pharmaceuticals, pesticides, cosmetics, veterinary drugs, food and feed additives and industrial chemicals.

Work that does not constitute a regulatory study is not required to be conducted in compliance with the principles of GLP. For example, work undertaken by Quality Control (QC) laboratories in support of final product release or laboratory work in support of human clinical trials do not require to be conducted in compliance with the principles of GLP.

The principles of GLP require that study plans, raw data and final reports should be systematically archived for secure record keeping, reporting, storage and retrieval. Archive design and archive conditions should protect contents from untimely deterioration. All data generated during the conduct of the study should be recorded directly, promptly, accurately and legibly. Any change in the raw data should be made so as not to obscure the previous entry, should indicate the reason for change and should be dated and signed or initialed by the individual making the change.

The Need for LIMS

Manual capture, calculation and verification of raw data result in a tremendous drain on human resources while also jeopardizing the integrity of the information. The administration of paper records is particularly inefficient and expensive and data cannot be easily integrated with other technologies employed by the organization. As a result, complying with the strict principles of GLP can prove a very time consuming and expensive process.

There emerges a need to employ sophisticated, enterprise-wide Laboratory Information Management Systems (LIMS) capable of addressing the complexity of the regulations, ensuring compliance with current best practice and satisfying the concerns and expectations of the regulators.

Data generated from an instrument electronically and captured as a direct computer input can be identified at the time of the input by the individual(s) responsible for direct data entries. An efficient computerized system design always provides for the retention of full audit trails to show all changes to the data without obscuring the original data. It is also mandatory to associate all changes to data with the persons having made those changes by use of timed and dated electronic signatures. The justification of changes can be also recorded and saved with each entry.

LIMS solutions can also generate the final report of the study automatically providing a comprehensive description of the methods and materials used and a presentation of the results, including calculations and determinations of statistical significance.

Validation

When it comes to computerized systems, the principles of GLP also demand the existence of relevant validation documentation. This is because a validated system ensures accurate results and prevents fraud as well as failure of the system.

Validation costs vary enormously even within the same industry. These can range from 5% of the total project cost for a multi-site, worldwide, industry standard Enterprise Resource Planning (ERP) central server deployment to up to 75% of the total project cost for a bespoke customized system. In general, validation costs are higher when it comes to the implementation of one-off systems, new technology or complex applications. On the contrary, validation costs are lower for multiple rollouts of the same system, or when Commercial Off-The-Shelf (COTS) solutions are employed that have been specifically designed to meet industry standard GLP requirements. In conclusion, best validation practice constitutes spending between 15 and 25% of the overall project cost.

Cost-Effective Validation StrategiesOne of the most cost-effective validation strategies is to follow the Good Automated Manufacturing Practice (GAMP) Guide for Validation of Automated Systems. The Guide draws together key principles and practices and describes how they can be applied to determine the extent and scope of validation for different types of automated systems. The principles of GAMP concern five different software categories, namely operating systems, hardware and instrument embedded software, COTS, configurable systems and customized LIMS. Following the Guide provides significant cost benefits by aiding the production of systems that are fit for purpose, meet user and business requirements and have acceptable operation and maintenance costs. The time and effort taken to achieve compliant systems is also reduced and compliance with regulatory expectations is improved by defining a common and comprehensive life cycle model. Thermo Fisher Scientific offers purpose-built or COTS solutions -- such as Darwin LIMS™ for pharmaceutical manufacturing R&D and QA/QC and Watson LIMS™ for Bioanalytical laboratories -- to reduce the complexity and risk of system validation.

In order to achieve validation with the minimum cost possible while also speeding up the whole project, organizations should purchase validation services only from experienced providers. The ideal vendor should be fully aware of the GLP regulations, the principles of GAMP, the validation needs of the specific application area as well as the operation and usability of the specific application software that needs to be validated. Additionally, the vendor should possess relevant information technology expertise and be knowledgeable of validation industry best practice. Finally, the vendor should comprehend the internal validation procedures of the specific organization.

Effective, timely validation can be most effectively accomplished by a validation team that has been thoroughly trained through a course that brings together the different experiences of validation approaches of the team members so that everybody agrees a common approach. Furthermore, cost-effective validation can be achieved via standardization of a single LIMS solution across all laboratory facilities of an organization or via rollout of the same system sequentially. Following one of these strategies will greatly reduce validation costs as a percentage of the overall project expenditure since only minimal acceptance testing is needed at every site and most testing can be cross-referenced.
Risk analysis may be also used but always with caution. It is true that many GLP laboratories process low risk records, however only functions, not records, can be validated. In the LIMS area it is common for the same generic functions to be used across all records, whether high or low risk. Therefore all functions must be considered high risk and subject to full validation. It can be more efficient to conduct a high-level risk analysis of the entire LIMS, which acknowledges that the whole system is high risk, rather than conduct a detailed risk analysis of every function which eventually reaches the same conclusion, but with more effort(1).
Organizations should also make appropriate use of the testing that the vendor has already carried out. For this reason, they should consider purchasing a vendor-supplied validation kit and also avoid validating functionality which they do not intend to use.

Finally, organizations should ensure that the validated state of the systems is maintained. The principles of GAMP define that this is achieved by ensuring that existing operational procedures are kept up-to-date. Maintenance of the validated state is primarily the responsibility of the system owner, and is typically achieved by defined service-level agreements with, for example, the IT function. For COTS, the vendor support package is also a vital component of the overall system maintenance.

Summary

Compliance with the principles of GLP is of high importance when registering or licensing pharmaceuticals, pesticides, cosmetics, veterinary drugs, food and feed additives and industrial chemicals. LIMS solutions have emerged as the most appropriate tool to assist towards compliance with the principles of GLP. Such systems can efficiently and safely record, report, store and retrieve study plans, raw data and final reports, thereby addressing the complexity of the regulations.

In order to comply with the principles of GLP, LIMS solutions need to be fully validated. This may be a particularly expensive process but costs can be considerably minimized by following certain strategies; adhering to the principles of GAMP, sourcing validation services from experienced vendors, employing a consistently trained validation team, standardizing on a single solution and ensuring long-term maintenance of the validated state of the systems.

References

“Risk Analysis Warning – your validation costs may go up as well as down;” John Dickson, Thermo Fisher Scientific, Technical Presentation, Pittcon 2004.

For more information about Thermo Scientific informatics solutions please call +1-866-463-6522, e-mail marketing.informatics@thermofisher.com or visit www.thermo.com/informatics.

Thermo Scientific is part of Thermo Fisher Scientific, the world leader in serving science.

About Thermo Fisher Scientific

Thermo Fisher Scientific Inc. (NYSE: TMO) is the world leader in serving science, enabling our customers to make the world healthier, cleaner and safer. With annual sales of more than $9 billion, we employ 30,000 people and serve over 350,000 customers within pharmaceutical and biotech companies, hospitals and clinical diagnostic labs, universities, research institutions, government agencies as well as environmental and industrial process control settings. Serving customers through two premier brands, Thermo Scientific and Fisher Scientific, we help solve analytical challenges from routine testing to complex research and discovery. Thermo Scientific offers customers a complete range of high-end analytical instruments as well as laboratory equipment, software, services, consumables and reagents to enable integrated laboratory workflow solutions. Fisher Scientific provides a complete portfolio of laboratory equipment, chemicals, supplies and services used in healthcare, scientific research, safety and education. Together, we offer the most convenient purchasing options to customers and continuously advance our technologies to accelerate the pace of scientific discovery, enhance value for customers and fuel growth for shareholders and employees alike. Visit www.thermofisher.com.