The Importance of Leachables and Extractables Testing for A Successful Product Launch

By Frances L. DeGrazio

© PHOTOGRAPHY: BONNIE JACOBS, ISABEL POULIN | AGENCY: DREAMSTIME.COM

PACKAGING REQUIREMENTS

THE FDA GUIDANCE FOR INDUSTRY, "Container Closure Systems for Packaging Human Drugs and Biologics," addresses the review and evaluation of packaging requirements. According to this document, each new drug application (NDA) or abbreviated new drug application (ANDA) should contain enough information to demonstrate that a proposed container closure system and its components are suitable for its intended use.

The type and extent of information required will depend on the dosage form and route of administration. Qualification and quality review is applied to packaging materials and to the actual dosage form. Packaging suitability is based on four attributes; protection, safety, compatibility and performance (function and/or drug delivery). For injectable dosage forms, the document outlines the tests required to show that interaction is not a problem. Associated components, such as those used only at the time a dosage is administered, self-adhesive labels and secondary packaging materials are also included in the review process.

Inhalation and injection drug products have the highest requirements. There are product-specific draft guidelines for metered dose inhalers (MDI), dry powder inhalers (DPI), nasal sprays and inhalation solutions, suspensions and spray drug products. The identity and concentration of leachables in inhalation and nasal drug products must be monitored throughout the dosage form's shelf life since the product consists of the dosage form and container closure system.

INDUSTRY RESPONSE

Numerous types of guidance (Table A) mention the appropriate evaluation of packaging components. The guidance recommends that the safety and compatibility of the dosage form with the primary container closure system be established early in the development process. Specific focus is on the potential for drug/biologic interaction with the container or closure because of leaching or absorption.

Industry-based working groups have been established to assess extractable concerns and other scientific issues. The Product Quality Research Institute (PQRI; Arlington, Va.) was established to conduct research that generates scientific information to support the development of regulatory policy. PQRI is driven by its member organizations, which include, but are not limited to, the American Association of Pharmaceutical Scientists (AAPS), the Pharmaceutical Research and Manufacturers Association (PhRMA), the Generic Pharmaceutical Association (GPhA), the Parenteral Drug Association (PDA) and the FDA Center for Drug Evaluation and Research (FDA/CDER). PQRI is a nonprofit foundation that serves as a vehicle for FDA, industry and academia to collaborate on key issues in pharmaceutical product quality through research and expert analysis. Currently, PQRI's working group for leachables and extractables is attempting to better define and clarify analytical and toxico-logical issues relating to these key areas.

"EXTENSIVE TESTING FOR EXTRACTABLES SHOULD BE PERFORMED AS PART OF THE QUALIFICATION OF THE CONTAINER/CLOSURE COMPONENTS. TESTING UNDER STRESSED CONDITIONS SHOULD DEMONSTRATE THAT THE EXTRACTABLE PROFILE IS ACCEPTABLE FOR THE SPECIFIC DOSAGE FORM AND THAT LEVELS OBSERVED WILL NOT BE APPROACHED OR EXCEEDED DURING THE SHELF LIFE OF THE DRUG PRODUCT."

Another industry group, the International Pharmaceutical Aerosol Consortium on Regulation and Science (Washington, D.C.) and the Inhalation Technology Focus Group of AAPS developed a Points-to-Consider document in reference to leachables and extractable testing as defined in the MDI/DPI draft guidance and the Nasal Spray/Inhalation Solution draft guidance. The concept recommends identification and qualification thresholds for extractable and leachables along with other suggested points clarification.

EXTRACTABLE AND LEACHABLES IN PRIMARY CONTAINER/CLOSURES SYSTEMS

Primary container/closure systems, as well as other packaging components, have the potential to interact with the dosage form. Factors that must be considered in evaluating container closure systems are materials of construction of the container/closure system, surface treatments and/or processing aids, dosage form active ingredient and excipients, sterilization and/ or other related processing, and storage conditions.

The presence of extractables is determined through artificial means. An extractable is a chemical species that can be released from a container or closure material of construction that has the potential for contaminating the dosage form. Under certain exaggerated solvent, temperature and time conditions, an extractable may be generated through an interaction with the closure system.

Extractable testing studies are recommended even if containers or closures meet compendial suitability tests. Extensive testing for extractables should be performed as part of the qualification of the container/closure components. Testing under stressed conditions should demonstrate that the extractable profile is acceptable for the specific dosage form and that levels observed will not be approached or exceeded during the shelf life of the drug product.

A leachable is a chemical species that has migrated from packaging or other components into the dosage form under normal conditions of use or during stability studies. Leachables are substances identified in a defined laboratory regimen by simulating use conditions. The industry is focused on potential problems associated with extraction of chemicals from packaging materials into drug product. Leachables are a subset of extractables.

TESTING CRITERIA

Testing criteria includes:

• Materials of construction of the container/closure components are safe for their intended use. This is usually done via chemical analysis for extractables, and if necessary, toxicological evaluation of the extractable substances.

• Container/closure components are compatible with the dosage form by demonstrating that the dosage form does not interact sufficiently with the container/closure components to cause unacceptable changes in the quality of either the dosage form or the packaging components. Such reactions might include degradation of the active ingredient induced by a chemical leached from the packaging component; or a reduction in the concentration of an excipient due to absorption, adsorption or leachable-induced degradation.

• Container/closure systems provides the dosage form with adequate protection from factors that can cause a degradation in the quality of the dosage form over its shelf life; these factors include seal integrity and the ability to reseal when applicable.

• The container/closure system functions in the manner for which it was designed.

• Leachables have the potential to interfere with drug product as-says. For instance, leachables might have the same retention time as a drug in an HPLC assay. Leachables also may interfere with medical diagnostic tests, increase the impurity level of a drug product to an unacceptable range or increasing the toxicity of a drug product. If leachables react with one or more drug product components, they could cause a precipitate or pH change.

TESTING PROCESSES

Extractable screening during safety studies is an important part in choosing the appropriate container or closure for a dosage form. It can minimize the time and money needed for future suitability studies. Because test methods must be specific to the extractable, the laboratory performing the testing must use the correct techniques. Test methods must be specific to the drug product and placebo in order to evaluate interferences, linearity and other critical factors. In addition, evaluators must test the final packaging/drug combination for leachables during stability studies.

Prescreening procedures should begin with a basic evaluation of container/closure options. The protocol can involve multiple temperatures and conditions for acceleration. It should be designed to identify the appropriate container/closure candidate for inclusion in stability programs. Identification of extractables can be achieved through analytical testing, such as liquid chromatography/mass spectrophotometry (LC/MS), gas chromatography/mass spectrophotometry (GC/MS), inductively coupled plasma (ICP) and infra red (IR). Suppliers of these systems may be able to provide some information on testing procedures. The testing laboratory can then develop methods and complete validation of them.

Using rubber closures as an example, the laboratory would identify a potential extractables list for the rubber formulation. This list would include chemicals that can leach into the product from the base closure formulation. These extractables have a direct relationship to the ingredients of the rubber closure. If the laboratory has prior experience with certain potential extractables, previously used methods are chosen for the study. Otherwise, the laboratory will engage in methods development and conducts an assessment to determine the potential for analytical interference, the limits of quantification (LOQ), and typical percentage of recovery of spiked extractables in non-degraded and degraded product and placebo.

If there is significant interference during method feasibility testing, such as HPLC column deterioration evidenced by peak fronting, peak splitting, retention time shortening and poor recovery after multiple injections for extractables, the laboratory determines that these extractables cannot be detected by that particular method. If issues with column performance are noted, dilution of drug product with an organic solvent and cleanup injections between sample injections may be investigated, and analysis of these extractables by other methods with a new sample preparation technique may be attempted.

Typically, methods development would be required to address leachables. Sometimes methods development studies are expanded to improve sample preparation before analysis with a particular instrument. In one case of certain extractables analyzed by HPLC, it has been determined through several organic solvent investigations that client samples require dilution with an equal volume of tetrahydrofuran (THF) to enhance the solubility of the extractables. Samples must then be centrifuged at a preset time and speed to allow presence of a clear THF top layer. The laboratory then analyzes this layer and allows for proper detection of compounds at required concentrations. It has also been determined that the cleanup step in-between sample injections must be made with acetonitrile in order to maintain column performance. For some extractables, new sample preparation techniques are investigated.

THIS "NEXT PHASE" TESTING ALLOWS FOR MONITORING OF LEACHABLES DURING LONG TERM STORAGE CONDITIONS AND WILL ASSESS ANY NEGATIVE OR POSITIVE IMPACTS THAT MAY OCCUR WITH THE PRIMARY PACKAGING COMPONENTS.

Once appropriate methods are developed and verified through multiple sample preparation repetitions and varying factors, formal procedural methods are written in detail for method validation.

Methods validation for detection of leachables in placebo and dosage form are based and recommended on industry practice and International Conference for Harmonization (ICH) Guidelines. A validation plan for each identified test method is developed and approved by the client. Each plan includes detailed standards and sample preparation techniques, system suitability, validation criteria and pass/fail specifications.

Once the appropriate test methods are validated, samples are analyzed for leachables.

Then testing of development and stability lots is performed under accelerated and long term conditions. If leachables are found, toxicological evaluation should be conducted and routine testing or testing of the annual stability lot may be necessary. Three lots of each strength are tested at predetermined conditions. The extractables testing may be incorporated into the master stability study protocol. This "next phase" testing allows for monitoring of leachables during long term storage conditions and will assess any negative or positive impacts that may occur with the primary packaging components.

CONCLUSION

The FDA's June 1999 Container Closure Guidance has accelerated the requirements for extractable and leachable testing of container/closure packaging components.

Obtaining this information may require testing methods not previously completed within the manufacturer's environment. Further, additional testing will require time and money that must be built into the qualification and stability studies of the container/closure system early in the product development cycle.

Container/closure prescreening assures suitability for use with the dosage form and establishes appropriate methodology to test leachables using validated methods. These tests minimize risk and allow for a successful product launch in a timely manner. -PFQ

Frances L. DeGrazio is vice president of marketing and strategic business development for West Pharmaceutical Services, Inc. (Lionville, Pa.). Reach her at 610-594-3190 or fran.degrazio@westpharma.com.

TECHNOLOGY AUGMENTS STRINGENT DESICCANT QUALITY CONTROL

NEW PRODUCT LAUNCH

THE MANUFACTURING TECHNOLOGY behind the newly launched DRI-MAC 100 percent non-dusting desiccant canister from Silgel Packaging (Telford, England) was developed specifically to manufacture DRI-MAC canisters and is fully automated to ensure a 100 percent component check.

Every canister is photographed several times during production. In addition to passing through four vision systems, all canisters undergo 14 quality control tests to confirm that the components are assembled correctly and consistently. Any canister not meeting the exacting specifications is automatically rejected.

This assembly technology and other factors, such as a canister sealing and laser printing processes, all serve to ensure that the DRI-MAC is approved by all key quality standards. Compliant with FDA 21 CFR Part 11, the new canister is also manufactured to BS EN ISO 9001:2000 and BS EN ISO14001 and has a Drug Master File listing. This means that DRI-MAC canisters are fully approved for direct contact with packaged drugs.

Other developments behind DRI-MAC include a distinctive sonic welding technology, which effectively embeds the Tyvek end caps into the main body of the DRI-MAC canister, ensuring a completely robust seal and total product integrity. In addition, the DRI-MAC canister requires no label that may fall off or move. This is due to the development of laser printing technology that uses an FDA approved laser sensitive additive to etch the required safety and product information permanently onto the canister.

DRI-MAC canisters have been specifically designed, in complete compliance with 21 CFR Part 11 and other major quality standards for direct contact with drugs, to meet the high specification drying and packaging needs of pharmaceutical companies.

The safe, non-toxic canister is used for high speed automatic desiccant insertion to eliminate moisture and odour from product packaging. Not only does the canister shape produce a 5-fold increase in automatic insertion throughput over traditional desiccant sachets, but it also totally removes the risk of loose desic-cant contamination.

A sonic welding technology, which effectively embeds the Tyvek end caps into the main body of the DRI-MAC canister, ensures a completely robust seal and total product integrity. Additionally, the fully breathable Tyvek membrane at both ends of the canister ensures excellent gaseous transmission whichever way up the canister is.

The DRI-MAC canister does not require a label that may fall off or move. Laser printing using an FDA approved laser sensitive additive etches the required safety and product information. This and the distinctive nature of the DRI-MAC canister ensure that it is easily distinguished from the packaged product to prevent accidental ingestion. �

GMP NOTEBOOK

EFREM H. ZARET, PH.D.

Quality Control Laboratories

Control of testing laboratories is a never ending concern

Laboratory error is a significant cause of recalls and FDA Inspectional Observations (483s). Inspection of quality control laboratories therefore requires special consideration and care. The Guide To Inspections Of Pharmaceutical Quality Control Laboratories (www.fda.gov/ora/inspect_ref/igs/pharm.htm) begins as "In addition to the general approach utilized in a drug cGMP inspection, the inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with cGMPs and to specifically carry out the commitments in an application or DMF. When conducting a comprehensive inspection of a laboratory, all aspects of the laboratory operations will be evaluated."

Recent warning letters provide insight into the Agency's expectations with respect to operation of quality control labs (visit www.labcompliance.com for details). This list of horrors is an eye opener given the current state of sophistication that exists in our industry.

List of Horrors

Recent warning letters provide insight into the Agency's expectations with respect to operation of quality control labs (visit www.labcompliance.com for details). This list of horrors is an eye opener given the current state of sophistication that exists in our industry.

• Insufficient detection of impurities, inadequate analytical methods validation, missing raw data, lack of scientifically sound test procedures, failure to identify unknown peaks during the testing for organic volatile impurities, lack of adequate training for laboratory analysts and manufacturing employees;

• Failure to perform the required USP testing on each production "batch" of the product Anhydrous Caffeine USP;

• The (HPLC test) method currently used to assay caffeine has not been shown to be equivalent to, or better than, the current USP method;

• The primary caffeine USP reference standard is not used, and the secondary reference standard in use has not been qualified;

• The reference standards used to perform the caffeine tests are not stored under adequate conditions;

• Laboratory notebooks do not document critical information including test methods, reagents used, weights of samples, and drying times and temperatures achieved during testing;

• The equipment used to analyze the caffeine product was not calibrated prior to use;

• The laboratory hood is not certified;

• Laboratory equipment maintenance logbooks are not maintained;

• The laboratory bench, sample jars and equipment are dirty and covered with a white powdery material;

• There is no established GMP training program for the firm's employees;

• No or insufficient method validation, expiration dates and storage conditions;

• No chromatographic system suitability testing;

• Missing laboratory records, missing chromatograms and spectra, missing stability test records;

• Standard weights, sample weights and calculations are not recorded;

• No written procedures for any micro-biological tests are performed;

• Balances have not been calibrated against ASTM conforming weights;

• No established calibration specifications for the infrared spectrophotometer exist when the spectrum of polystyrene is recorded;

• Raw data has not been reviewed and maintained;

• Test records are released before review and approval;

• Results of stability testing are not traceable to the batches produced at the manufacturing site, missing raw data, no testing of detector linearity, no testing of accuracy of temperature settings for column heater and detector, inadequate calibration procedure for GCs and GC headspace unit, calibration raw data and results obtained for performance qualification of analytical instruments not checked for accuracy and completeness by a second analyst or supervisor; and

• The calibration procedure for HPLC systems is inadequate in that it did not include integrator and detector's linearity, injector's reproducibility and accuracy of temperature settings for column heater and detector.

A Control System for Labs

The Compliance Program Guidance Manual dealing with drug manufacturing inspections (CPM 7356.002) discusses the control system for laboratories and lists a number of areas that should be covered. These include change control, standard operating procedures, personnel training, calibration and maintenance of laboratory equipment, validation of computers, control of reference standards, system suitability checks on chromatographic equipment, representative sampling plans, validation/verification of and adherence to written analytical methods, OOS investigations and documentation, adherence to the written OOS procedure, raw data retention and complete analytical records of all tests and summaries of results, and demonstration that analytical methods used in the stability testing program are stability indicating.

Some of these areas are part of general cGMP compliance for all aspects of drug product manufacturing, but others are specific to laboratories.

Control of raw data is critical, and a laboratory is no better than its data. Laboratory SOPs should ensure that data is traceable from its acquisition through its verification by a second person and preparation of the data summaries. The SOPs should also specify the data retention policies and prescribe the data retention procedures. Chromatographic data should refer to the sample analyzed, the system used and the electronic data file that is stored on the system. If a paper printout of the data has been produced, that should be cross-referenced to the notebook or datasheet that was used to describe sample preparation, analysis and the results. If an electronic file is maintained, the SOPs should discuss compliance with Part 11.

While on the subject of laboratory data, we must consider out-of-specification results. Every laboratory generates unexpected data, and the evaluation of that data must be done according to a well-defined, rigorous procedure that can separate laboratory error from defective product or materials. The SOP(s) dealing with investigation of unexpected and/or OOS results must provide sufficient information for the decision as to whether the data is truly OOS or just an error in the laboratory. OOS investigations must be timely and complete; they must be completely and thoroughly documented and properly reviewed. The investigation must consider the root cause of the OOS or lab error, and it must include consideration of corrective and preventative actions.

Equipment not Qualified/Calibrated

I am constantly amazed at laboratories utilizing equipment that has not been qualified and calibrated (21 CFR 211.160 (b) (4)). Although it is unusual to find balances that are out of calibration, I often find that the check weights that are used daily have not been certified or are not regularly certified.

Calibration of chromatographic systems often is incomplete because the individual modules have not been calibrated, or flow rates, pressures, temperature controls, etc., have not been calibrated individually. Thermometers are often not routinely calibrated against certified standards.

All of these observations should be prevented by compliance to SOPs that are specific to the laboratory. The SOPs should discuss the routine validation/qualification of lab equipment, and must include consideration of preventative maintenance. For chromatographic equipment, the SOPs should also describe the use of system suitability testing to verify a system's proper and reproducible operation. System suitability procedures are a required part of the analytical test method.

While on the subject of lab equipment, I must mention equipment log books. Records of the use and non-routine maintenance of laboratory equipment is basic and should be covered in the laboratory SOPs. The use of chromatography columns should also be recorded and be traceable for any given column.

Another common problem involves the storage and handling of analytical standards. Primary analytical standards must be stored and handled according to their specifications, and those procedures should be documented in SOPs. It is not uncommon to find USP standards stored in a controlled humidity chamber, which is, however, not monitored to ensure that the humidity and/or temperature are within specification. Quite often, the storage conditions are not recorded or logged.

If primary standards are used to prepare secondary analytical standards, the procedures and methods used to qualify the secondary standards must be fully documented and be covered by SOPs. The storage of secondary standards requires the same care as the primary ones.

Handling Test Samples

Procedures for storage and security of test samples submitted to the lab are another topic that should be covered by SOPs. Is the receipt logged with time and date? Where are the samples kept before, during and after analysis? Is there sufficient sample to provide an adequate reserve sample and how long will the reserve sample be kept after its analysis is completed? Do not forget that some samples require special storage conditions and protection from humidity, light and oxygen.

The last aspect of this brief review of laboratory compliance deals with analytical test methods. It is surprising to find an adequately trained laboratory analyst who does not know that test methods must be validated or verified. However, it is also surprising to often find analysts who perform procedures on which they have not been qualified.

Slightly less often, you also find experienced lab personnel who have developed little "tricks" they use in the performance of an analysis. These "tricks" frequently constitute changes to the method that have not been approved by accepted change control procedures or validated to show they have not affected the performance of the method. This occurs with both compendial and noncompendial procedures, and control requires extra scrutiny and diligence on the part of laboratory management. Needless to say, such unauthorized "tricks" are unacceptable and should be forbidden by both policy and procedure.

In summary, control of testing laboratories is a never ending concern. Well run labs have tight and adequate SOPs, good training, effective change control, quality oversight and review, and control of equipment, standards and samples. Operating a laboratory that is in compliance and control is hard work and a continuous challenge. �

Efrem Zaret, Ph.D., president of EZ Associates Inc., consults in GMP compliance and training, quality assurance and control, clinical supplies, logistics, regulatory affairs and product and package development. Reach him at 908-753-8566 or ef@ezassociates.com.

IT TO SPEED DEVELOPMENT

DR. MARTIN SUMNER-SMITH

Making IT Work

If a system does not benefit you and your colleagues, it will fail

IT project managers are told to make sure that a proposed product will meet the needs of business users-that it will solve a critical business problem-that's why software vendors now describe their products as solutions to problems rather than extolling the technology.

Here's a typical scenario: A software vendor comes in to demonstrate a particular product. Staff members either volunteer or are "volunteered" to come and hear the pitch, but they could probably write the script for the first 10 minutes themselves.

"We are the leading vendor of software that will make you more efficient, will save you money, get you to market faster and make sure you comply to FDA regulations," the earnest sales rep says.

The audience smiles with fixed smiles and pretends to pay attention-they've heard it all before. After a while, the presentation moves to the demonstration phase, probably by a sales engineer, who really knows the product. At that point the audience divides between those who try to follow along and those who have more information than they want.

In the end, pharmaceutical companies will buy some of the software. Attempts will be made to use most of what they buy, but not all systems will ever be rolled out, and many of those systems that are will meet considerable user resistance, leading to deployment failure.

It's easy to say that software and information technology are over-hyped and doomed to fail, but in fact, the right systems for the right purposes can be indispensable. A word processor was used to author this article and e-mail to submit it; things we really use become "part of the furniture."

Project managers have developed some standard approaches to improving the chances of software deployment success. Looking at such approaches as a potential end user on the business side, what contributions are going to be asked of you, and more importantly, can you have a role influencing future success while minimizing unproductive use of your time?

From Validation to Success

We need to distinguish between software for single individuals working largely alone, departmental software for groups of people and enterprise software that is intended for most or all of an organization. If you are the end user of a single-user system, you are best able to determine if it is going to benefit you. But group software assessment is much harder and is proportionate to the number and types of users.

Software vendors usually talk about operational efficiency benefits, which is a message that appeals to management. In fact, experience has shown that end users of group systems are far more concerned about whether a given piece of software makes their job easier, than the overall benefits to their company. If it doesn't make their jobs easier, they will usually resist efforts to implement it, which means that neither management nor staff will achieve the purported benefits. The more different users from different departments there are, the greater the challenge to successful deployment.

IT project managers are told to make sure that a proposed product will meet the needs of business users-that it will solve a critical business problem-that's why software vendors now describe their products as solutions to problems rather than extolling the technology.

Software used in the pharmaceutical industry must be validated if it is applied in critical applications that might put patient health or business continuity at risk. Readers may well be familiar with this approach either as quality managers or as they have seen it is used for control systems, but now it is applied more broadly to include most critical business software. The aim of validation is to ensure that the software and associated systems perform as required and that risks are identified and mitigated.

A first step in validation is to collect and document user requirements to produce a user requirement specification (URS). IT project managers will solicit end user input. This information is incredibly important and is used as a basis to select software vendors and products in the early stages and ultimately to test the performance of the implemented system (performance qualification; PQ).

URS documents can vary widely in quality. Sometimes they are clearly the result of asking very different groups for their input and then making a master list with little integration. In worst-case situations, some individual requirements may be contradictory or even mutually exclusive! Thought should be given to better processes that might be enabled or optimal system design as URS documents are reviewed and finalized.

Often users give their input based on past experience and assumptions and do not know of alternatives. If you can, take the time to educate yourself about alternative technologies and other options, most importantly, consider whether a proposed software system will provide incremental benefit to a current process, or possibly a different and better process. Will the design of a proposed system force you to do things differently and if so will that be an improvement? Ideally an organization will recognize the importance of bringing all participating users up-to-speed before embarking on developing a URS.

There's one warning: Often, companies use validation expense and complexity as excuses to maintain the status quo or justify slow roll-outs. User enthusiasm and support rapidly wane. Ultimately, an inflexible or infrequently updated, but validated, system may become invalid as it fails to address evolving business and regulatory requirements. A validated, but unused, system may even encourage non-compliant user behaviors.

Deployment

If you are asked about a new software system, make sure you give it proper consideration early on-if a given product is not going to unambiguously help you and your colleagues, say so. Later on, you'll likely be asked to participate in a pilot implementation project. If you never really believed in the product, then it will be a waste of time to be trained participate and report that the product was of no benefit when you suspected that all along.

If a pilot software project goes well, then IT managers will look for "power" or "angel" users to help roll it out to their colleagues. This is a proven approach to optimize user adoption: I am far more likely to listen to a colleague who has found genuine benefit in a product than to an IT manager.

On the other hand, if a given product makes your job easier and your efforts more productive, do you really want to spend a lot of time promoting it to your colleagues? Fortunately, for software deployment, many users enjoy the challenges and different experiences that promoting a new system can give-make sure you're likely to be one of them before you get heavily into a new software project.

Often, companies use validation expense and complexity as excuses to maintain the status quo or justify slow roll-outs. User enthusiasm and support rapidly wane. Ultimately, an inflexible or infrequently updated, but validated, system may become invalid as it fails to address evolving business and regulatory requirements.

Effective IT project managers are trying to address end user resistance and reduce the fear of failure, while looking for visionaries who can see the long-term benefits while accepting the near-term workload.

Executive sponsorship is essential. These days, IT project managers will look to get a senior business executive as a sponsor who can help overcome internal hurdles and encourage adoption. Also a steering or oversight committee will be formed and will meet on a regular, but not necessarily, frequent basis.

Without such sponsorship, ultimate project success is much less likely, no matter how much enthusiasm there is among potential business end users. Before volunteering valuable time with a proposed software project, make sure the internal assessment and implementation efforts are well run.

Configuration and Customization

While sometimes a software product, touted as a "complete solution," can do everything required to meet your needs, often it cannot. Simple configuration or customization may be required or software products may need to be acquired and integrated to achieve the required functionalities-so called "best-of-breed" systems. There are many options and forces at play.

In mature software sectors, an out-of-the-box product may fit your needs perfectly. Often some simple configuration options serve to optimize the software. But in less mature sectors, and in specialty applications, further customization may be required.

Here, it is important to strike a balance. Too often, one or more constituencies demand changes in a proposed software product, but will the proposed changes really produce a business benefit? The downside of any software customization is that it costs more money upfront, and continues to cost more money downstream, while making maintenance updates harder or often impossible. People realize this based on past failed projects or because the burden of validating systems increases dramatically with customization. Astute IT project managers choose to minimize customization to key features that are going to increase user acceptance and business benefit in a very tangible and measurable way.

As a business end user, you are the most important player in software assessment and deployment because in the end, if a system does not benefit you and your colleagues, it will fail. You should leverage that position to maximize the most effective use of your time while supporting efforts that will bring real benefits to your company. �

Martin Sumner-Smith, Ph.D. is vice president of Pharmaceutical and Life Sciences Solutions at Open Text (Ontario, Canada). Reach him at 905-762-6214 or msumners@opentext.com.

Pump It Up

By Peter Lambert

New peristaltic pump designs mean more accurate dispensing of biopharmaceuticals

All images courtesy of Watson-Marlow Pumps Group

An automated peristaltic aseptic filling system at work. 

Over the last decade, the pharmaceutical industry has had to adapt to major changes and challenges, driven mostly by the fact that many of the blockbuster drugs are running out of patent. The industry has had to focus more on research and development (R&D) with a greater interest toward developing biopharmaceutical products, a trend that has highlighted the need for efficient, small batch, aseptic liquid processing and fill operations. In addition, ever-increasing Food and Drug Administration (FDA) demands have forced the industry to look for more efficient and safer production technologies.

Traditional filling technologies are piston pumps and time-pressure filling systems, but new challenges and more stringent validation requirements have put the focus on peristaltic filling technology. Innovations in peristaltic pump design are already reducing the cost of bringing new drugs to market and are demonstrating changes that may be made in the way products are mass-produced.

Peristaltic pumps, which are extremely convenient to use, are often the preferred choice for fluid transfers in all types of environments, including both the laboratory and the heavy chemical industry. Piston pumps are also very popular and have proven themselves over the years. Unfortunately, piston pumps have drawbacks in some applications. For example, because piston pumps are designed with many mechanical parts such as valves and seals that are in direct contact with the product, these components—which will wear out—need to be taken apart, cleaned, and reassembled between uses. Even the high-end valveless ceramic piston pump comes into direct contact with the product. Additionally, diligent care is required to prevent damage to the piston in these extremely fragile pumps.

In peristaltic pumps, product only comes in direct contact with a single piece of tubing, which can easily be cleaned or replaced after use. This single-use feature makes the peristaltic pump an attractive alternative to piston pumps for dispensing of biopharmaceutical injectable drugs, which are quickly becoming the most promising new biopharmaceuticals.

Pulsation-Free Peristaltic

After two tubes drawing product through the pump head merge into a single tube, the pulses add up to cancel each other out, resulting in a pulsation-free flow.

Technology

An innovation in the accuracy of peristaltic pumps occurred 21 years ago when Flexicon A/S of Denmark created the "pulsation-free" peristaltic pump. The removal of pulses made it possible to achieve high accuracy dispensing. Today, five generations of improvements later, peristaltic dispensing pump accuracy rivals piston pumps down to micro fill volumes.

Two key design features allow the peristaltic pump to dispense accurately: the use of multiple rollers and the use of offset rollers to remove the typical peristaltic flow pulses. Optimal configuration for a pump head design is two sets of six rollers, with each set of rollers offset with respect to one another. The two tubes drawing the product through the pump head merge into a single tube via a Y-connector, after which the pulses add up to cancel each other out (see Figure 1). The resulting pulsation-free flow is then controlled using a precise positioning motor and special software that ensures accurate dispensing.

A huge selection of tubing is available—made of many materials and in various sizes, many of them made specifically for peristaltic pump use. Nonetheless, to allow for consistently accurate dispensing down to microliters, it is imperative that the tubing and pump head work together from the beginning and that they both have close dimensional tolerances.

Key mechanical characteristics in the selection of peristaltic pump tubing include uniform wall thickness, consistent material hardness, and high mechanical "memory" after compression. Finally, and in consideration of dispensing injectables, the silicone tubing must be of the highest quality to meet the FDA’s current good manufacturing practices requirements (cGMP).

The Benefits

An automated closed-loop weight-check system used in conjunction with peristaltic pumps assures that fill volumes remain within tight tolerances.

When compared to piston pumps and other dispensing technologies, peristaltic pumps offer several benefits.

• One pump can fill a wide range of fill volumes: A single peristaltic pump can fill volumes between 0.1 ml and 250 ml, with just a simple change in the tubing size. More than one piston pump would be required to meet a similar fill range.

• Fast setup and calibration: It can take less than five minutes to load the tubing, purge the system, make one calibration, and begin filling.

• Cross-contamination: Peristaltic pumps do not require cleaning when utilized for single-use dispensing, because each batch is produced with new tubing that creates a new fluid path or set of contact parts. In comparison, on a traditional piston filling line for injectable drugs, it is not uncommon to buy dedicated piston pumps for each product in order to prevent cross-contamination between batches. Those pumps require cleaning, sterilization, and maintenance.

• Greatly reduced cleaning validation: Cleaning validation is a cGMP requirement that demonstrates and documents that the equipment used for processing an injectable drug is clean and free of contaminants. For a multiple-use piston pump filling system, cleaning validation typically requires two qualified employees up to four months to write up and execute the protocols. For each subsequent production batch, cleaning in accordance with the validated procedures has to be maintained and properly documented each time throughout the drug’s commercial life. These labor costs are added to other costs associated with the use of water for injection; for washing, rinsing, and sterilization using pure steam; and, finally, for the cost of detergents and water disposal.

• Flow control: It is easy to adjust flow speed with the peristaltic pump interface in order to prevent foaming or splashing of the product. It is also possible to adjust how fast the fill speed is reached using the ramp-up and ramp-down feature. This is helpful in optimizing overall fill time to permit greater throughput from the filling machine.

• Gentle handling for shear-sensitive products: The valve system in the piston pump generates high-speed flow through small orifices, potentially damaging biological products. Even valveless piston pumps generate higher pressures and higher shear factors and produce, by design, a "dead volume" with each stroke. Peristaltic pumps are valveless and apply only low pressure to move the product.

High-end peristaltic dispensing pumps, which dispense product upon demand, can fill volumes at higher speeds.

• Better accuracy: The typical industry standard for fill volume accuracy is ±0.5%. Peristaltic dispensing pumps meet this requirement for fill volumes as small as 0.5 ml. Below that fill volume, accuracy can be as good as ±1% (see Figure 2, p. 35). When peristaltic pumps are integrated into high-speed filling machines, an automated closed-loop weight-check system assures that fill volumes remain within tight tolerances.

• Fill time: While piston pumps need to cycle through a recovery or suction phase between each dispensing stroke, peristaltic pumps require no such downtime. Consequently, peristaltic pumps dispense product upon demand. High-end peristaltic dispensing pumps are designed to run at high revolutions per minute to minimize fill time (see Figure 3, above). This feature, along with a control system that provides an immediate response from a filling machine input signal, means that using a peristaltic dispensing pump instead of a piston pump will not slow down the filling process. It is now commonplace to have high-speed filling lines with peristaltic pumps that fill at rates over 400 bottles per minute.

• Viscosity limitations: Peristaltic pumps have limiting capabilities for dispensing viscous products. In general, a product with the viscosity of olive oil can be dispensed using peristaltic pumps. Slightly higher viscous products will also work but may exhibit loss in accuracy and flow rate. While piston pumps have the capacity to generate significantly greater pressure for dispensing more viscous products, high-end peristaltic dispensing pumps do not. In fact, one of the underlying principles in achieving accurate peristaltic dispensing down to micro fill volumes is the application of very little pressure on the tubing. When used for micro filling, peristaltic pumps are calibrated to provide no more than approximately 1.3 bar of pressure.

Single-Use Bioprocessing

In recent years, biotech companies have embraced single-use technology, an efficient method for developing and bringing new drugs to market. Single-use process components such as small reactors, filters, mixers, and fluid handling bags have been available for the last few years. Peristaltic pumps and single-use tubing are also becoming more commonplace because they allow for simple fluid transfers with no cleaning and no risk of cross contamination.

New drugs, biopharmaceuticals in particular, are often designed for a specific population. Therefore, they are more likely to be made in relatively small batches than are general application "chemical" drugs.

As new drugs evolve to offer a more specific spectrum of applications, batch sizes are shrinking, increasing the need for efficient production changeovers on the filling lines.

As new drugs evolve to offer a more specific spectrum of applications, batch sizes are shrinking, increasing the need for efficient product changeovers on the filling lines. Benefits of single-use technology include reduced labor, equipment, and energy costs, increased plant flexibility, and faster turnaround with significantly less risk of contamination.

Just as with R&D, the fill/finish side of biological drug mass manufacturing now requires greater reliability and efficiency. Therefore, it is expected that single-use technology will make its way into production facilities where accurate peristaltic dispensing pumps can eventually replace pistons and other mechanical dispensing systems, potentially allowing for 100% single-use drug manufacturing.

Until now, the pharmaceutical industry has used single-use silicone tubing and fittings for peristaltic dispensing but has not had access a single-use filling nozzle. In an effort to offer a tool for single-use aseptic filling, Flexicon developed a plastic nozzle for single-use applications. It is now possible to purchase single-use ready-to-use tubing set assemblies. These sets include the required pharmaceutical-grade silicone tubing, connectors, and single-use filling nozzles. The assembly is double bagged and gamma irradiated and includes a complete validation package.

Various single-use tubing set configurations are available. These may include a sterile filter, septic quick-connect fittings, and a pre-filled product bag. In most cases, tubing and connectors bring the product directly from the product holding tank to the filling nozzle for dispensing on the filling machine—making the entire process single use.

Lambert is manager of the biopharmaceutical division at Watson-Marlow Pumps Group. For more information, e-mail support@wmbpumps.com or call (802) 657-3232.

Cram For the Implementation Test

By John Dickinson

A screen shot from Darwin, a laboratory information management system for pharmaceutical manufacturing, which features tools for environmental monitoring, stability testing, and content uniformity.

SOURCE: THERMO FISHER SCIENTIFIC

Pass the IT Implementation Test

A best practice approach helps when implementing an IT system

In the pharmaceutical industry, where validation and compliance with 21 CFR Part 11 is mandated, information technology (IT) system implementations can be fraught with difficulty and, in some instances, associated with a high failure rate. Nevertheless, the benefits these systems offer ought to heavily outweigh their costs. One critical success factor, which affects all other factors, is assembling an optimal project team with the right mix of skills, knowledge, and experience.

Selecting the Right IT System

IT system implementations, such as Laboratory Information Management Systems (LIMS), have evolved significantly over the past few decades, particularly with regards to their approach to 21 CFR Part 11 compliance. This could not be more evident than it is in today'S pharmaceutical companies, whose IT business requirements place significant demands on a system'S responsiveness, complexity, and ability to comply with government regulations.

The debate over build versus buy-whether to craft a LIMS or IT system in house or purchase them from an external vendor-has largely been decided in the pharmaceutical industry. In-house development is not a core competency of drug discovery or pharmaceutical organizations and is inevitably a costly and slow approach. The most compelling reason these systems are generally purchased externally, however, is that vendors now offer "purpose-built" systems that are designed to meet requirements specific to the pharmaceutical industry, including drug discovery, clinical trial management, research and development, and manufacturing.

Another question many organizations have asked over the years is whether the IT system should be monolithic or best of breed. For example, should LIMS functionality be provided by a module of an enterprise resource planning application, such as the quality module of the R/3 system from SAP AG (Walldorf, Germany)? Other options include a dedicated LIMS application like Darwin LIMS for pharmaceutical manufacturing, Watson LIMS for drug metabolism and pharmacokinetics labs, Galileo LIMS for in vivo testing, and Nautilus LIMS for high-throughput labs, all from Thermo Fisher Scientific (Waltham, Mass.).

The monolithic approach brings great advantages in consistency and efficient messaging between business areas, but best-of-breed applications from LIMS vendors offer significant advantages themselves. "Purpose-built" LIMS solutions are designed to meet a very high percentage of business requirements for pharmaceutical applications in the core product out of the box. For example, key functionality for pharmaceutical manufacturing, including environmental monitoring, stability testing, and content uniformity, is already built into the Darwin LIMS. Costly customizations, upgrades, and validation are practically eliminated with a group of software systems; upgrade activities can be subdivided into manageable chunks. Indeed, the same is true for initial system implementation, where prioritization and a low-risk approach with a phased rollout is an attractive option.

Project Team Selection

Whichever option is chosen, a critical success factor in the system rollout is assembling the optimal project team. In-depth knowledge of the business is vital; therefore, full-time assignment of in-house business area experts to the project team is highly recommended. In addition, with systems purchased from vendors, in-depth knowledge of the software is critical to success, and accumulating this in-house expertise can be a burden. A better solution by far is to acquire this expertise by hiring an external consultant. This can be a much more efficient and effective approach in spite of the initial bottom-line cost.

Regulatory compliance is mandatory in the pharmaceutical industry. There have also been seismic changes in the 21 CFR Part 11 landscape in recent years due to the Food and Drug Administration'S (FDA) risk-based initiative and court rulings, both of which add to the complexity of IT systems. The FDA is committed to revising Part 11, as stated in their 21 CFR Part 11 Final Guidance document. The same document also makes clear that, in the interim, the FDA intends to exercise enforcement discretion and a narrow interpretation of Part 11. Ensuring electronic record integrity, availability, and, where appropriate, confidentiality-as demanded by Part 11-is required to comply with numerous other best practices regulations. Employing a purpose-built LIMS solution that is designed to meet Part 11 compliance can greatly facilitate the process.

With systems purchased from vendors, in-depth knowledge of the software is critical to success, and accumulating this in-house expertise can be a burden.

Another factor to consider is the Utah Medical court ruling. Although Utah Medical is a medical device company, the court decision is significant for the pharmaceutical industry as a whole. United States Senior District Judge Bruce S. Jenkins ruled that the FDA can't dictate how regulated business will meet regulations. Enforcing "industry best practice," although it is not explicitly required by regulation, is an attractive option for a regulator with broad industry experience and has, in fact, been widely used by regulators in many industries and many countries. But such an approach would seem problematic in the light of this decision.

In the validation area, project team composition is, again, a vital consideration. Key areas of knowledge and experience include in-depth comprehension of business requirements, proficiency in the application area, command of the purchased software package and, finally, expertise in validation. Because finding all these attributes in one individual is unlikely, the optimum team is likely to comprise in-house specialists and external consultants.

Outside Advice

The use of external consultants is particularly relevant because the compliance landscape is shifting dramatically, and companies need to stay abreast of the latest changes to meet requirements. A validation expert can help a project navigate to a low-risk yet efficient route to compliance with knowledge of the various approaches that have been taken by others in the pharmaceutical industry.

Another aid that can be used to help organizations determine the best path to achieve Part 11 compliance is to obtain the Good Automated Manufacturing Practice (GAMP) forum'S Good Practice Guide, "A Risk-Based Approach to Compliant Electronic Records and Signatures," available at www.ispe/gamp.org. The GAMP forum includes representation from the pharmaceutical industry and software vendors and has close relationships with regulators in Europe and America. The aim of the GAMP guidance documents is to provide a unified reference source for regulatory compliance and industry best practices in the IT arena.

Many of the challenges inherent in selecting and implementing an IT system can be overcome with a best practice approach in place. While managing risk, utilizing GAMP guidance, and selecting a system that is purpose-built for your application needs are all important factors, perhaps the most critical is assembling an optimal project team with the right mix of skills, knowledge, and experience. �

Dickson is a consultant with the Informatics Services Group specializing in validation services at Thermo Fisher Scientific. For more information, call (866) 463-6522 or e-mail marketing.informatics@thermofisher.com.