To help maintain product safety, quality, and efficacy, a general approach to designing extractables and leachables studies should include evaluating and qualifying bioprocess materials used in a disposable manufacturing environment. This paper presents a systematic approach to the evaluation, identification, quantitation, and specification setting of extractables and leachables that builds product quality into the manufacturing process. It also discusses analytical thresholds of extractables for the evaluation of disposable materials.

The evaluation of extractables and leachables has become an increasingly important aspect in the Quality by Design (Qbd) initiative of FDA in the area of drug product design, including the selection of materials used in the drug product production process and the selection of container and closure systems used for product packaging to help maintain product safety, quality, and efficacy. This paper describes a general approach to designing extractables and leachables studies—based on the Product Quality Research Institute (PQRI) recommendations to FDA for Orally Inhaled and Nasal Drug Products (OINDP)—to evaluate and qualify the bioprocess materials used in a disposable manufacturing environment.

In the method described here, disposable materials are extracted with solvents of various polarities, using various extraction techniques. The resulting respective extractions then are evaluated with various techniques, including liquid chromatography/mass spectrometry (LC/MS), gas chromatography/mass spectrometry (GC/MS), high-performance liquid chromatography (HPLC), gas chromatography (GC), and inductively coupled plasma/mass spectrometry (ICP/MS). This paper also presents analytical thresholds of extractables for the evaluation of disposable materials. In addition, case studies are presented to exemplify the specific study designs and procedures that can be used to fully evaluate, characterize, and qualify certain specific disposable materials used in the bioprocess industry. 

As pharmaceutical and biological technologies move into the twenty-first century, emerging global regulations are focusing on risk management and integrated quality systems.

 The FDA, the International Conference on Harmonization (ICH), and other regulatory bodies have joined forces to promote and facilitate discussions about and the implementation of risk management and integrated quality systems into pharmaceutical and biological manufacturing processes.

The consideration and evaluation of extractables and leachables is a key aspect in the development of disposable bioprocess materials because these compounds, which can originate from the pharmaceutical container and closure packaging's processing and bulk storage supply systems, may adversely affect the safety or efficacy of the final drug product. Extractables are compounds that can be extracted from source materials using appropriate solvents under vigorous laboratory conditions. Leachables are compounds present in drug products caused by leaching from container, closure, or processing components. Therefore, leachables can be considered a subset of extractables. 

The process begins with the judicious selection of manufacturing components, and with the proactive design of process qualifications and validation requirements for materials in a disposable bioprocess. The majority of disposable materials used in single-use bioprocesses are various types of plastics which tend to leach out foreign materials over time; therefore, a detailed extractables and leachables study that is designed from an analytical point of view is needed. This paper presents a roadmap to guide the manufacturing process. This roadmap begins with the selection of components in terms of the extractables and leachables (E/L) reports and documentation. Reports and documentation are required to support viable, valid, and qualified processes that meet current good manufacturing practice (cGMP) requirements for a disposable bioprocess. 

 the Bio-Process Systems Alliance's classification identifies consensus quality tests for each of the four most commonly used classes of disposable components: 					

Selecting the right material acceptable for use in a disposable bioprocess for components in any of these subclasses can eliminate most potential extractables and leachables because of the removal of materials that fail to satisfy such standards as listed in the 

Biological Reactivity Tests, In Vivo: Classification of Plastics, Class VI.

In addition to wisely selecting components in a disposable bioprocess, fully qualified or validated single-use systems are imperative. Core validations should be performed for all essential components in a single-use system, i.e., filters, bags, tubing, and connectors. A critical part of process qualification or validation involves data about the component's qualification for a complete sterilized system. The data comes from a complete extractables and leachables study design or experiment based on the actual manufacturing process, including specific filling (surface area:solvent ratio), storage time or temperature, and formulation components. Table 1 shows typical extractables for acceptable materials used in a disposable process. 

Table 1.  Typical extractables for acceptable materials used in disposable bioprocess manufacturing systems			

GENERAL EXTRACTABLES AND LEACHABLES STUDY APPROACH 

Although PQRI's recommendations to the FDA are specific to orally inhaled and nasal drug products,  the general approach presented therein can be applied to materials used in disposable bioprocess manufacturing systems. Figure 1 shows a step-by-step approach for performing extractables and leachables studies for materials used in disposable bioprocess manufacturing systems. 

Figure 1.  A step-by-step approach for performing extractables and leachables studies for materials used in disposable bioprocess manufacturing systems			

Stage One: Compiling and Evaluating Information

Because studies of extractables and leachables (E/L) require a thorough understanding of the materials and the drug to construct an effective study plan, the first stage entails compiling and evaluating the following information: 

1. Drug dosage form and formulation composition, including excipients and the active pharmaceutical ingredient. 

2. Understanding the manufacturing process, including process conditions; evaluating which materials the drug formulation comes into contact with during the manufacturing process; and assessing the duration and types of interactions with these materials. 

3. Understanding vendor-supplied disposable product components and the compositions of those materials; evaluating information from the manufacturers of these materials as to material matrix compositions; and assessing any extractables data that already may have been generated about these vendor-supplied materials. 

The dosage regimen and the volume of product administered per unit time are the critical information required in calculating an analytical evaluation threshold (AET). The AET defines the required sensitivity of the analytical methodologies (instrumentation) for acceptably monitoring E/L at a specified safety threshold. PQRI defines a safety concern threshold (SCT) for OINDP of 0.15 µg leachable per day. (Note that the SCT for other delivery systems has not been specified by PQRI.) Therefore, based on the amount of product exposed to the patient per day, the leachable quantity per material can be calculated and the method sensitivity requirements in µg/mL of extracted solvent can be obtained based on the extraction study design.  

Stage Two: Designing the Extraction Methods

The next stage involves designing the extraction methods for the applicable process and disposable product materials. Typically, at least three extraction solvents that bracket the polarity of the drug are chosen. For some studies it is advisable to include the drug vehicle or placebo, itself a fourth extraction solvent. Extraction conditions such as temperature, pressure, extraction time, and material-to-solvent ratios should be chosen to provide a thorough, complete extraction profile for the materials under evaluation, and to provide sufficient sensitivity per the analytical evaluation threshold (AET) calculations performed. The most common extraction technique is refluxing. Alternatives include Soxhlet extraction, which exposes the sample to less extreme temperatures and can be chosen for materials that may degrade under standard reflux conditions; and time-abbreviated techniques, such as the use of an accelerated solvent extractor, sonication, or extraction in a sealed container placed in an oven or autoclave. 

As noted above, the calculated AET is based on the total daily intake (TDI) of the potential leachables or extractables in the drug product. Depending on the dosage regimen and administered amount, achieving the required instrument sensitivity may be a challenge. Sample extracts may also require treatment or modification to be appropriate for analysis using the specified analytical technique.  

Stage Three: Designing the Sample Preparation

The third stage in constructing E/L studies is designing the sample preparation to achieve the AET, and the possible conversion of extracts to appropriate solvents for instrumental analysis. Liquid to liquid extraction is often used to make solvents more appropriate for GC analysis (volatiles and semivolatiles). Extracts may also be concentrated by evaporation for improved sensitivity, or, for solvent exchange, dried and reconstituted in an appropriate solvent for the analysis. 

Stage Four: Analyzing Extracts, and Evaluating and Compiling Data

The next stage involves analyzing material solvent extracts, and evaluating and compiling data to identify extractable compounds. Multiple analytical techniques are typically used to fully profile the material extract solutions. Headspace GC/MS is used to analyze the extracts for volatile compounds, direct liquid injection GC/MS for semivolatiles, and LC/MS for nonvolatiles (typically by both atmospheric pressure chemical ionization [APCI] positive and negative modes of detection). If applicable, metals screening is performed by  ICP/MS. Compounds of special concern to the FDA because of their carcinogenicity, such as formaldehydes, polyaromatic hydrocarbons, mercaptobenzothiozole, and nitrosamines, are analyzed using specialized instrumentation and detection, sample derivatization, or other techniques. The headspace and direct injection GC/MS extractables data are evaluated by a library compound software search, and these data, as well as the LC/MS spectral pattern data, are reviewed and evaluated for tentative compound identification. Tentative peak confirmations and semi-quantitative amounts typically are confirmed by obtaining commercial standards of the known extractable compounds (if available), and by injecting these compounds to confirm retention times and spectral patterns.  

A toxicological evaluation of extractables data is critical in determining which compounds need to be tracked as potential leachables in the drug product. Typically, TDI values calculated for the confirmed, known extractable compounds are provided by the analytical laboratory to the board-certified reviewing toxicologist. The toxicologist evaluates the compounds and amounts observed for toxicological concern or structure alert. The resulting information, along with knowledge of the intended use of the product, is applied when deciding which of the identified extractable compounds should be tracked as potential leachables in the drug product, and what extractable compounds should be tracked in routine methods for raw material quality control screening (quality control release methods for vendor-supplied materials). 

Methods are developed next for monitoring leachables. The methods are selective for identified leachables and for expected, unidentified leachables. The methods separate these peaks from drug product or process impurity chromatographic peaks. The leachable methods are developed to provide sufficient sensitivity, accuracy, precision, and linearity across a suitable range, to quantitatively determine the amount of leachable components present. Because these procedures are for routine, quality control (QC) use, they typically use high-performance liquid chromatography/ultraviolet visible (HPLC/UV) and gas chromatography/flame ionization detector (GC/FID) techniques, as opposed to mass spectrometric detection.  

At this stage, it is also advisable to develop methods for monitoring extractables in incoming vendor raw material batches before these are used in the build process for a final product. To develop the most efficient process, the results of the controlled extraction studies should be used to optimize the routine extraction procedures applied to the incoming materials testing. 

CASE STUDY 1: EXTRACTABLES AND LEACHABLES STUDY DESIGN FOR DISPOSABLE BAGS 

Disposal bags intended for bioprocessing must be qualified for extractables and leachables before use to support manufacturing process qualification and validation. Data collected for the respective materials also can be used to compile a knowledge base and enhance scientific understanding which, in preparation for a future paradigm shift into quality by design per ICH Q8 (pharmaceutical development), will support ICH Q9 (quality risk management) and ICH Q10 (pharmaceutical quality systems). The entire extractables and leachables qualification for a disposable bag is described here for a one-liter solution disposable bag with a two-doses-per-day regimen. 

 (Component selection and final formulation determination). An appropriate bag should be chosen for the intended storage and use of the disposable drug product. The properties of the material the bag is made of (such as pH tolerance, thermal resistance, tensile strength, and other related chemical and physical properties), and the processes and additives used in the bag-making process, including how the plastics polymer is made, are crucial information to gather. 

The final formulation and the bioprocess conditions (holding time, temperature, pH, etc.) are gathered when they are determined. For example: the drug placebo is a saline solution; the bags hold 1 L of the drug solution for at most 3 months; the bags are processed at 35 °C; and the dosage for the final drug product is 1 mL/dose and 2 doses/day. 

 Based on information collected in Step 1, the AET can be calculated for each extractable per bag (the SCT of 0.15 µg/day is being used per PQRI recommendation for OINDP; however, the value could be different for other dosage forms):  

Extractables above the AET should be evaluated, but extractables below the AET are of no significant safety or toxicity concern. 

Extraction solvents should include a placebo buffer, a buffer with a lower pH (such as pH 3), and a buffer with a higher pH (such as pH 9). In addition, an organic solvent (such as methanol, ethanol, or isopropyl alcohol) should be used to cover a worst-case scenario. For analysis of metals, a dilute acidic solution should be used. 

The extraction temperature and time equal 50 °C for 24 hours. The extraction technique is as follows: for the aqueous extraction, a sealed container is used; for the methanol extraction, reflux is used. For the material/solvent ratio, the important consideration is the AET. For example, if one bag is extracted with 500 mL of solvent, the AET for the extraction solution is 75 µg/500 mL = 0.15 µg/mL, which is within the analytical detection and quantitation limit of the GC/MS and LC/MS techniques. 

Extraction solutions should be analyzed with headspace GC/MS, direct injection GC/MS, and LC/MS (APCI in both positive and negative modes), as well as with ICP/MS to screen trace metals extractables. Aqueous extractions should be converted to suitable solvents, such as methylene chloride and hexane for the direct injection GC/MS analysis. The amounts of extractables are quantified with appropriate standards. 

The analytical evaluation should include extractables identity, amount, and potential TDI, as well as a toxicological evaluation. These evaluations can qualify or disqualify the bag, based on extractables or leachables, from its intended use as a bioprocess disposable bag. 

Step 5: Leachables Method Development and Validation. 

Based on the extractables profile and the profile evaluation, potential leachables are determined and one or more methods for analyzing the potential leachables are developed. These methods must separate the potential leachables from drug products such as the active pharmaceutical ingredient (API), additives, and degradants. The methods are validated per ICH guidelines in terms of method selectivity and specificity, accuracy, precision, linearity, range, and sensitivity. 

Step 6: Leachables Analysis of Stability Samples.

 Leachables are monitored in at least three lots of stability samples at time points of initial, 1, 3, 6, and 12 months, if needed. 

Step 7: Leachables Trending, and Extractables and Leachables Correlation Analysis.

 At the end of the leachables test program, a trending analysis of the leachables should be performed. Additionally, a correlation analysis of the leachables amount and the extractables amount should be demonstrated. If the leachables are more than the extractables, the extractables must be revisited. 

Step 8: Routine Extractables Method Development and Validation.

 Based on the extractables profiles, routine extractables methods, which are usually GC/FID or HPLC/UV, are developed and validated for purposes such as sample preparation. The routine extractables methods should be robust, efficient, exhaustive, and simple to operate. 

Step 9: Bag Release for Use Through Routine Extractables Testing.

 Different lots of incoming bags should be tested before they are filled with drug solutions. This will ensure that the bags meet the criteria for potential extractables, and that the bags are suitable for their intended use. 

Articles

Features

Two case studies illustrate a systematic approach.

Extractables and Leachables Study Approach for Disposable Materials Used in Bioprocessing

Twenty years of increasing assignments and declining budgets has changed the US Food and Drug Administration from the world's gold standard for drug regulation into a "debilitated, under-performing organization," according to the agency's advisory Science Board. In a scathing analysis issued last December (2007), the panel described how FDA suffers from "serious scientific deficiencies" and cannot meet its regulatory responsibilities.

The main culprit is inadequate funding, according to the Science Board subcommittee that prepared the report. FDA lacks the staff and resources needed to support regulatory functions and to keep up with scientific discoveries important to ensure the safety of medical and food products. Fast-expanding user fees have made up for some of the deficit, but increased reliance on industry payments has created inequities in FDA. An analysis by panel member and attorney Peter Barton Hutt reveals that any budget increases over the last 20 years have been lost to inflation. FDA has gained only 700 appropriated staffers during this period, even though its work was expanded by hundreds of statutes, executive orders, and other mandates.  

A key FDA need is an information technology (IT) system that is able to process and integrate vast amounts of scientific information. FDA's IT budget runs about $200 million, but it would require at least another $200 million to be able to assess reams of clinical trial data and track thousands of manufacturing sites around the world. Senate Health Committee Chairman Edward Kennedy (D-MA) termed the analysis a "wake-up call" to provide FDA with adequate resources to do its job, and Rep. Henry Waxman (D-CA) called on FDA and administration leaders to tackle these problems.  

Only a few days after the meeting, however, Congress approved long-delayed federal government funding legislation for fiscal year 2008 (which began on October 1, 2007) that boosted FDA's total budget funding to $2.2 billion—$1.7 billion without user fees. In view of heavy spending cuts across the federal government, FDA did well to receive any budget increase at all. Agency advocates seek to boost FDA appropriations to $2 billion in five years, but this year's budget falls short of this goal. Much of the $145-million increase in appropriations, moreover, will support food safety programs, with little left for other regulatory initiatives. 

The Center for Drug Evaluation and Research (CDER) has a $682.8 million budget for 2008, almost half of which ($356 million) comes from user fees. Much of CDER's increase will go to drug safety activities and the rest to regulate generic drugs, direct-to-consumer advertising, and FDA's Critical Path initiative. The Center for Biologics Evaluation and Research (CBER) will have a $237-million budget, including $81 million from user fees. Its $12-million gain supports pandemic influenza preparedness and other popular initiatives.  

As usual, Congress uses the appropriation process to micromanage FDA policies. The legislation seeks an assessment of FDA's MedGuide program for riskier therapies and instructs the agency to produce studies and reports on everything from Ketek safety to microbial resistance. Several provisions reflect ongoing concerns on Capitol Hill about pharmaceutical and biotech industry influence on FDA policies. Congress reminds FDA to reduce the number of advisory committee members with conflicts-of-interest, and undermines the launch of the Reagan-Udall Foundation by stipulating that FDA cannot use any appropriated funds to support this new organization. Rep. Rosa DeLauro (D-CT), chair of the House Appropriations subcommittee that oversees FDA, has objected that Reagan-Udall provides an avenue for manufacturers to shape FDA safety initiatives.  

While FDA officials hope to assuage DeLauro's concerns, the rift may interfere with efforts to help establish an active surveillance system for drugs. Former FDA Commissioner Mark McClellan, recently named to chair Reagan-Udall, is a leading advocate of using health system databases and advanced IT systems to detect and analyze drug safety signals earlier and faster to prevent safety problems and facilitate new drug development. Establishing such a system is no easy task and will require new data standards and collaborative efforts, a task appropriate for Reagan-Udall. 

A much larger influence on FDA operations is the expanding role of user fees in agency funding: almost one-fourth of FDA's $2.2-billion 2008 budget will come from user fee revenues and most of that ($460 million) from pharmaceutical and biotech manufacturers. At the December Science Board meeting, attorney Hutt lamented the funding "desperation" that has forced FDA to rely increasingly on user fees to shore up its depleted coffers.  

Yet members of Congress find it too easy to tap this ready source of revenue to support FDA programs, minimizing the likelihood that the fees will be reduced or eliminated. In fact, the FDA Amendments Act (FDAAA) boosted drug user fees by another $25 million for each of the next five years to support additional drug safety initiatives, and pending legislation proposes to raise millions more through fees on food and drug imports.  

Congress is likely to enact food and drug import legislation because FDA's Office of Regulatory Affairs (ORA), which operates the agency's field inspection force, has suffered from depleted resources even more than the rest of the agency. FDA officials unveiled a major field consolidation plan two years ago that proposed to close regional offices, reduce the number of district offices from 20 to 16, and shut seven of 13 field laboratories. But Congressional leaders blocked the closures, and ORA officials agreed to "take a fresh look" at how to meet its challenges. 

Meanwhile, scandals over contaminated food and medical products from abroad have focused public attention on the inadequacies of the current system for ensuring safe food and drug imports. In the past year, FDA had to contend with contaminated pet food and toothpaste from China, along with fears about tainted blood substitutes and liquid medicines laced with diethylene glycol.  

These crises prompted hearings on Capitol Hill. The Bush administration established an import safety task force headed by Health and Human Services Secretary Mike Leavitt to map out improvements in the US food and drug import system, which produced a report in November. House Energy & Commerce Committee Chairman John Dingell (D-MI) proposed user fees on imported food and drug shipments to bolster US inspections and field laboratories. The Senate Finance Committee has interest in tackling import safety this year, and Senator Kennedy is working on a comprehensive food safety bill. The resulting legislation is likely to enhance FDA's authority to mandate product recalls and halt imports, boost penalties for illegal activities, and require foreign manufacturers and importers to certify product compliance with quality standards.  

Reformers seek a lifecycle approach to import regulation that follows products through the supply chain and delivers assessments of product risk to border inspectors, compliance offices, and electronic screening systems. A recent proposal is for FDA to establish regulatory offices in China and India to manage the rising volume of drug exports to the US. FDA signed a memorandum of agreement with China in December that encourages safety certification of exported drugs and information sharing related to inspections. It will focus initially on designated high-risk products including insulin, blood screening diagnostics, human growth hormone, and others. 

It remains to be seen if FDA will gain the resources needed to really modernize its field force, foreign inspection capability, and outdated IT systems. There is some concern that policy changes could open US borders to more counterfeit and unregulated products without a major overhaul of current policies and operations. Congress is providing some funding increase for food monitoring, but it's not clear whether that will translate into broader improvements in how the agency oversees imported drugs and biotech therapies. 

's Washington editor, Chevy Chase, MD, 301.656.4634, 

1. US Food and Drug Administration. FDA Science and Mission at Risk. 3 Dec 2007. Available from: http://

www.fda.gov/ohrms/dockets/ac/oc07.htm#ScienceBoard

Columns and Departments

The much needed modernization of the agency's IT systems and inspection capabilities will likely fall prey to budget shortfalls.

Limited Resources Challenge Regulators

The biopharmaceutical industry is less than 30 years old. It has evolved during a period of rapid change, both in the science base and the manufacturing technologies. In the early days, we did not have biopharmaceutical-specific manufacturing technologies and we borrowed equipment from other industries (the disk stack centrifuge from the dairy industry, for example) or relied on scaling up laboratory techniques, such as chromatography. 

A revolution is currently taking place in our industry: we are now seeing rapid development of disposable technologies (sometimes referred to as single-use technologies). Much of this growth has been in the last five years, although disposables have been around a lot longer. Plastic blood bags were developed for blood collection in the 1950s and for the delivery of total parenteral nutrition (TPN) to sick patients in the 1960s. Even in the early days of biopharmaceutical manufacturing, we used plastic and silicone tubing. However, disposable bag technologies as we know them today came into being in the early 1990s. 

In collaboration with you, the readers, I hope to investigate the benefits and drawbacks of disposables and identify the factors driving their dramatic growth in the industry. Through this analysis, we will better understand how to get the best out of disposable technologies. In this column, I will address the issues that the industry faces as users, designers, regulators, and suppliers. This column's purpose is to stimulate discussion and debate about the role and limitations of disposable technologies, and look into the future impact of this technology on our industry. Therefore, I seek from you feedback, ideas, and concerns, which you can email to 

.In the industry today, we have widespread acceptance of the use of disposables. As a result, we have all the major suppliers running disposables development programs and investing substantially in the technology. Increasingly, there is consolidation in the suppliers as they strive to offer integrated whole process platforms; each supplier wants to be a one-stop-shop. The disposables revolution has only just started and there are significant challenges ahead that relate to standardization, implementation, regulation, environmental impact, supply chain management, technology functionality, and so on. For example, is it feasible or desirable to have a totally disposable manufacturing process? If so, is it all going to be single use? These are themes to which I will return in later columns. 

It will be useful to look back to see how far we have come and to look to the future. To get a supplier's and a user's perspective, I consulted the joint co-chairs of the ISPE Community of Practice (COP) for disposables

—Miriam Monge, former director of marketing for Stedim Biosystems, and Adam Goldstein, a senior manager at Genentech's Oceanside facility.  

Miriam has worked for Stedim since 1994 and was instrumental in raising awareness of the benefits and uses of disposable fluid handling systems. Stedim was an early developer and promoter of disposable bag technologies: this grew out of its TPN bag business and was driven by customer demand, e.g., wanting larger bags manifolded together. In those early days, the move to bags larger than 50 L required a radical rethink of the conventional two-dimensional bag design. This led to the development of the three-dimensional range comprising bag and the containers in 1998. To develop the business, it was important to work with end users: in Stedim's case, this involved working in partnership with the GlaxoSmithKline biologics vaccines division to achieve solutions we now take for granted, such as how to make aseptic connections, improving ergonomics of the bag containers, and working with the regulatory affairs department to define standards for disposables interaction studies in compliance with worldwide regulatory requirements. The major challenges in those early years were people related: the industry is conservative about novel technologies and adoption of disposables was a radical departure from traditional stainless-steel systems. But there were early adopters and a lot of these early adopters were driven by specific process needs in existing facilities that were not easily addressed by conventional technologies.  

Miriam's experience with Stedim mirrors both my and Adam's experience. In my case, at Lonza in Slough, we had a big problem with buffer handling in stainless-steel containers. The use of hold bags for buffers streamlined the whole operation and freed up production floor space for more capacity. Early in his career, Adam worked for a small biotech company that did not have the money to put in a conventional facility. Adam worked with Biowhitakker, a bag supplier, to look into using them to provide bags for holding buffers. However, the challenges he faced were considerable: the bag designs were rudimentary and he had to work with Colder Products to sort out the methods for making aseptic connections. Adam used this experience to challenge the likes of Stedim and Pall to offer something better. 

As the industry has matured and the suppliers have developed technologies for sterilization, design, and integration of components (filters, tubing, and aseptic connectors), acceptance for the use of disposables for handling solutions has become widespread. We have reached the point where handling solutions in bags is commoditized and every supplier must have the capability of providing solution-handling systems. The future challenges are technical, business, and cost related. From Adam's perspective, the technical focus for the future has to do with development of the disposable downstream components such as GE Healthcare's disposable column. This will complement the advances in disposable cell culture bioreactors and contribute to achieve a totally disposable process.  

Leaving aside the technical challenges, Miriam's view is that although standards may be being set in the arena of extractables and leachables, and sterility requirements, there is currently little attempt by the suppliers to standardize across product ranges. Such standardization would allow the end user to interchange bags between two suppliers working with the same support container. Lack of standardization complicates both the qualification of multiple suppliers and supply chain management. Such cost and business-related issues will come into sharper focus as disposables integration becomes the norm. There is a need for an industry forum where interested parties can debate competing claims: the ISPE is to be commended for setting up a Community of Practice for disposables. I will be returning to these and other issues in the future columns and welcome your input. 

 is the managing director of Biopharm Services, Chesham, Bucks, UK,  +44  (0) 1494 793 243, 

.1 International Society of Professional Engineers (ISPE) set up a Community of Practice for disposables in 2007 whose mission aims to create a global focal point of support for biopharmaceutical professionals working with single-use disposable technologies. http://

The use of disposables has changed significantly in the biopharmaceutical industry.

The Disposables Revolution

As the US biopharmaceutical industry and regulators debate new requirements for biosimilars, industry leaders are already turning to analytical science to define intellectual property and business development strategies. Emerging techniques are providing previously unseen protein characterization details in turn giving both innovators and generics new weapons in the battle for future market share. 

The impact of generic small-molecule medicines on the pharmaceutical industry is well documented. The current debate over large-molecule generics therefore is no surprise. 

Currently, there is no regulatory pathway for generic versions of biopharmaceutical drugs in the US market. However, history shows the US Food and Drug Administration (FDA) has embraced biopharmaceutical policy change guided or even driven by new analytical techniques. In 1996, the FDA promulgated the concept of the well-characterized biologic product (WCBP), which acknowledged that analytical techniques could definitively determine a biologic product's identity, purity, potency, and stability. This statement allowed the agency to approve biologic products, compared to the previous requirements, which permitted approval of the biologic manufacturing process. 

An outcome of the WCBP concept was that companies could use comparability protocols to support manufacturing changes (improve yield, add manufacturing capacity, etc.) without additional clinical testing. Comparability protocols ensure that the product manufactured with a new process is similar to the product of the original process. This component to WCBP opened the door to the argument that because innovator companies use comparability protocols to support manufacturing changes, the same analytical approach could be a pathway to new biosimilar product approvals. 

With an additional 10 years of analytical science innovation since the WCBP concept was first publicized, how far away can we be from new FDA biosimilar policies?   

Today, new techniques for studying higher-order protein structure are emerging that provide rapid and accurate therapeutic protein batch comparisons. Higher-order structure is a critical quality attribute of a biopharmaceutical protein. Slight changes in these structures can dramatically impact the safety and efficacy of a given molecule. Unfortunately, today's methods for determining higher-order structure can require days of analysis—but this is changing. For example, ion mobility spectrometry coupled with mass spectrometry shows great promise for determining differences in high-order structure in just minutes of analysis time.

  This methodology could be used to rapidly demonstrate that every batch of a given protein has the same higher-order structure as the reference batch. 

Another example is analysis of glycosylation, which plays a critical role in the safety and efficacy of many therapeutic proteins. Heterogeneity resulting from differences in glycosylation is difficult to measure because of its tremendous complexity. New methods that integrate specific enzymes, advanced analytical techniques, and mathematical modes can provide much more detailed analysis of glycosylation heterogeneity.

Both innovator and generics companies are quickly adopting these kinds of techniques, but with very different business objectives in mind. Innovator companies are depending on analytics to demonstrate the inherent complexities of their products. Their goal is to protect patents by fingerprinting biologics to the extent that they cannot be exactly copied, thus making a match of the approved biologic unachievable. However, the risk in such a strategy lies in the innovator's capacity to reproducibly manufacture the same fingerprint. A careful balance between differentiation and manufacturability must be weighed. 

Generics companies are maximizing analytical science to fully characterize proteins to show equivalency and structural comparability. Demonstration of structural comparability potentially means avoiding the need for extensive clinical trials comparing the biosimilar product to the innovator product. Minimizing the need for extensive clinical trials is important for generics companies to keep development costs low, so that pricing advantages can be sustained. The risk in this strategy is that, as more powerful tools are used to compare the biosimilar to the innovator drug, at some point differences must be found.  

Analytics have played a key role in moving the biopharmaceutical industry forward and will continue to play a central role in the ongoing biosimilar debate. Both innovator biopharmaceutical companies and biosimilar developers must align their business strategies with the best available analytical technology for characterizing protein therapeutics. For the biopharmaceutical industry, good science means good business. 

 is the biopharmaceutical business director at Waters Corporation, Milford, MA, 508.482.3462, 

 1. Smith, D, et al. J Am Soc Mass Spectrom. 2007(18):2180–2190. 

2. Cormac Sheridan. Commercial interest grows in glycan analysis. Nature Biotechnol. 2007;25(2):145–146.  

Both innovator and generics companies are using analytics to support comparability arguments.

The Role of Analytical Science in the Debate over Biosimilars

Last November, the Oversight and Investigations subcommittee of the US House of Representatives' Energy and Commerce committee met to discuss the FDA's foreign drug inspection program. The opening statements of Chair Bart Stupak cited disturbing data and trends: 

 Approximately 80% of active pharmaceutical ingredients in the US come from abroad. India and China account for more than half of these imports. India's pharmaceutical imports to the US have increased 2,400% from 1996 to 2006. China doubled its pharmaceutical imports to the US over the last five years. 

Lack of requirement for periodic foreign inspections

. Federal law requires that US manufacturing sites be inspected every two years. No law specifies how often the agency must inspect foreign drug firms. 

The FDA isn't sure how many foreign firms export to the US.

 Over three months, the FDA provided the subcommittee with a variety of counts of the foreign firms the agency needs to inspect—ranging from 2,100 to 13,800 foreign firms. (The agency's risk model counts about 3,300). 

The agency's IT systems are woefully inadequate

. As the agency's uncertainty about the number of foreign facilities indicates, the FDA needs an IT overhaul. The need for greater IT investment was also a major recommendation in the November 2007 report by the FDA Science Board. 

Meanwhile, the number of FDA inspections is decreasing. The number of inspections carried out by CDER (in the US and abroad) dropped by 279 (to 2,411) from 2006 to 2005, and those conducted by CBER dropped by 126 (to 1,826), according to a March 2007 report from the FDA's Office of Regulatory Affairs. Information from the subcommittee meeting indicated that current resources allow foreign firms to be inspected only once every 12–13 years. And according to an October 31 

 article, the number of overseas inspectors is expected to drop in 2008 to 102, from 149 in 2002.  

One way the agency is attempting to deal with this problem is by seeking cooperation from foreign governments such as China. Under an agreement signed last December, all Chinese companies that export certain drug products will have to register with Chinese regulators. The FDA will also gain access to Chinese inspection records, and the two countries will conduct joint training programs on inspection methods and other regulatory procedures.  

Such efforts to strengthen cooperation with Chinese regulators are valuable, and given the FDA's insufficient resources, present a logical approach. But relying on Chinese regulators, who still have a long row to hoe to improve domestic regulation, is an interim measure at best.  

FDA Commissioner Andrew von Eschbenbach has also said the agency would place staff in long-term assignments abroad, FDA News reported. This is another good step. Permanent offices abroad would be better, but resources for that are unlikely to appear anytime soon. 

The agency has also proposed a reinspection user-fee system. Under this plan, facilities that fail to meet FDA requirements would have to pay for the full costs of reinspections and other follow-up work. Although such a system has some potential drawbacks—such as the risk that Congress would then decrease other funding to the agency—this is a worthwhile proposal. 

Given how thin the FDA's resources are stretched, these approaches all make sense. The agency still needs to revamp its IT systems, though. This is critical, not just for inspections but for all of the FDA's mission. 

In our increasingly global industry; foreign manufacturing inspections are more important than ever.

Inspections in a Global Industry

Biopharmaceutical manufacturing and cleaning equipment must be designed for effective and consistent cleaning to avoid cross-contamination and the cleaning processes must be verified as effective. A cleanability study is essential before introducing a new product into the manufacturing equipment. Part 1 of this article provides background on cleaning validation and the associated regulations, cleaning methods, and the validation strategy. It also describes Genentech's approach for new product introduction using laboratory-scale and representative-scale studies. Part 2 will cover the other aspects of the cleaning validation program such as grouping strategy, validation sampling, acceptance criteria, change control, and revalidation.

Cleaning validation refers to establishing documented evidence providing a high degree of assurance that a specific cleaning process will produce consistent and reproducible cleaning results that meet a predetermined level. A cleaning program can be divided into three phases: cleaning process and cycle development, cleaning validation, and maintenance. The program should begin with equipment design evaluation and cycle and process development that includes, but is not limited to, the following: sanitary equipment design, selection of final rinse water, approved equipment specifications that address an evaluation of the compatibility of construction materials with product and cleaning solutions, sprayball design optimization, cleaning process design studies, cleaning sample assay validation, suitability of sampling, and recovery studies for assay and sampling methods. Without these design and development activities, validation could potentially lead to unnecessary troubleshooting and cleaning verification exercises.  

The cleaning process should remove materials such as media, buffers, storage solutions, cell culture fluids, cell debris, non-active pharmaceutical ingredients containing placebos, and formulations and concentrations of drugs or active pharmaceutical ingredients (API). Selection of appropriate sampling to demonstrate that residues have been removed to an acceptable level is vital for the success of cleaning validation.  

At Genentech, Inc., design and cleaning-cycle development is considered a prerequisite for cleaning validation. The purpose of cleaning validation at Genentech for biopharmaceuticals is to: 					

Assess a new product or new equipment for cleanability before cGMP production.

Ensure that cleaning procedures are adequate for cleaning new products or new equipment.

Ensure that residues after cleaning of equipment are reduced to an acceptable level before the manufacture of the next run or the next product in the same equipment.

Provide ongoing assurance that the validated cleaning procedures are in a state of control through monitoring and periodic revalidation.

Evaluate and validate changes to cleaning processes, other manufacturing processes, and equipment to maintain these validated cleaning processes in a state of control.

Cleaning validation is driven by regulatory expectations to ensure that residues from one product will not carry over and cross-contaminate the next product. An effective cleaning program starts with appropriately designed equipment and cleaning processes, followed by validation and maintenance. The following are some good manufacturing practice (GMP) cleaning validation requirements for the biopharmaceutical industry.  

Part 211: Current GMP for Finished Pharmaceuticals

§  211.63 Equipment design, size, and location: 

Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

§  211.67 Equipment cleaning and maintenance: 

(a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. (b)(3)(5) Protection of clean equipment from contamination before use.

§  211.182 Equipment cleaning and use log: 

A written record of major equipment cleaning, maintenance, . . . and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.

Basic European Union GMP Requirements for Medicinal Products

Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice

Principle: Premises and equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.

, annex 15, Qualification and Validation:  

 Cleaning Validation: Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents, and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.

International Conference on Harmonization Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 

The ICH Q7 was developed jointly by the European Union, Japan, and the United States for active pharmaceutical ingredient manufacturing.

 API is the drug substance before final formulation; section 12.7 contains cleaning validation requirements for APIs.  

Additional guidance documents have been established by regulatory agencies and industry associations, such as the FDA, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), the Canada Health Products, and the World Health Organization .

BIOPHARMACEUTICAL MANUFACTURING PROCESSES AT GENENTECH

Genentech manufactures biopharmaceutical products from 

 and Chinese hamster ovary host cells using multiproduct, dedicated, and single-use equipment. Product manufacturing involves cell culture and bacterial fermentation processes, with the associated recovery processes (harvesting, initial and final purification), followed by formulation, aseptic filling or lyophilization, and capping. 

Genentech's manufacturing processes include steps for manufacturing and purification of the API, and steps for manufacturing and packaging of the finished drug product. Steps up to and including final purification of the drug substance are considered API manufacturing; the formulation of the drug substance into finished product and the packaging of that product is considered finished drug product manufacture. This is consistent with regulatory expectations for these different categories of manufacturing, with cleaning validation requirements including predetermined acceptance criteria, which may differ for each type of manufacturing. Two separate cleaning validation master plans have been created: one for the API and one for the finished drug product. 

Cleaning is performed to remove materials introduced into equipment during the manufacturing process. These materials may include media, buffers, storage solutions, cell debris, non-API-containing placebos, and any formulation or concentration of a given drug product or API. Manufacturing and cleaning equipment must be designed for effective and consistent cleaning. The cleaning of manufacturing equipment surfaces at Genentech uses automated, semi-automated, and manual cleaning processes. For larger, enclosed equipment, an automatic or semi-automatic clean-in-place (CIP) process is typically used. Cleaning process parameters include cleaning agent concentration, temperature, flow rates, volume, and time.  

Equipment cleaning procedures use cleaning agents to aid removal of process soils. The cleaning agents may be categorized as caustic, acidic, neutral, or oxidizing. Some equipment at Genentech is cleaned with water for injection only, using no cleaning chemicals. A typical CIP process includes an initial water pre-rinse, a washing step with one or more cleaning agents, and a final rinse. Before conducting residue removal testing in cleaning validation, installation qualification and operational qualification are performed on the equipment to be cleaned and on the equipment used for the cleaning process. Manufacturing equipment is exposed to cleaning solutions by fully submerging the component (i.e., clean-out-of-place washer or manual cleaning methods); by fully flooding the product-contacting surfaces (i.e., transfer lines or manually cleaned tanks); or by directing fluids by use of spray devices such as spray balls, spray wands, and washer nozzles.  

For equipment containing a spray device, qualifications include identifying and documenting the device, noting its proper orientation and alignment, and performing a spray coverage test to assure complete coverage. Spray device coverage verification testing for vessels that are cleaned in place is conducted according to an approved procedure. This procedure involves the use of a visual marker (e.g., riboflavin solution, which fluoresces under ultraviolet light) and spray devices. For glassware that is cleaned in washers, verification of coverage may be conducted with process soils, rather than riboflavin, if process soils are readily visible against translucent glass surfaces. 

The cleaning processes for product-contact surfaces for all products manufactured in GMP equipment must be demonstrated to be effective. Product-contact surfaces are surfaces that make direct contact with product or materials introduced into equipment as part of the normal manufacturing process by their very design. Indirect-product-contact surfaces (such as buffer tanks), where there is a significant risk of residues on surfaces contaminating a subsequently manufactured product, also undergo cleaning validation.  

To demonstrate the effectiveness of a cleaning process, the process is challenged. This challenge involves at least three consecutive successful cleaning process runs, after which residues are measured and results are compared to predetermined acceptance criteria.  

Mock soiling is also used. Mock soiling refers to the soiling of equipment by a process other than routine manufacturing that creates a dirty equipment state equivalent to that following routine manufacturing. Mock soiling of equipment for validation purposes can be performed when equipment is not available for manufacturing soiling. Mock soiling procedures must be adequately described to simulate normal manufacturing processes.  

Cleaning validation includes the establishment of dirty hold times and clean hold times. Dirty hold time is the amount of time between the end of the use of the equipment and the start of equipment cleaning. Clean hold time is the amount of time between the completion of the equipment cleaning and the next cycle of use. Cleaning processes are challenged for maximum dirty hold times during cleaning validation runs.  

For clinical products, infrequently made products, or infrequently used equipment, a cleaning verification approach may be used in lieu of cleaning validation.  

Single-use product-contact equipment (used once and then discarded) is excluded from cleaning validation. Single-use items include beakers, pipettes, weigh boats, silicone tubing, sample tubes, storage bags, and normal-flow filtration filters. 

Product-dedicated refers to equipment that is used for a single product and then is removed as part of changeover procedures. Product-dedicated items, such as chromatography resins and tangential-flow filtration membranes, are used with one product only. The requirement for residues in dedicated equipment may differ from that for residues in equipment used for multiple products; nevertheless, the cleaning of product-contact surfaces of dedicated equipment requires cleaning validation. The validation of product-specific resin and membrane cleaning is captured in process validation protocols.  

Multi-use equipment may be used to process one or more products or media components. At Genentech, the main emphasis of the equipment cleaning validation program is on multi-use equipment, because this equipment type has the highest risk of process contamination (run-to-run or product-to-product).  

Before introducing a new product into equipment used for manufacturing a marketed product, a cleanability study is performed to determine the effectiveness of the cleaning process, using the new product on similar equipment surface types. The new product introduction (NPI) method has two purposes: to avoid cross-contamination of commercial products, and to collect development data on new products.  

The cleanability study is divided into two parts: the laboratory-scale study, and the representative-scale runs. The cleanability study starts with an evaluation of the characteristics of the product and soiling at laboratory scale to determine the effectiveness of the rinse, swab, and visual inspection methods. Results of the laboratory-scale study are verified at representative scale. Representative-scale runs include three successful consecutive cleaning runs, conducted on equipment used for marketed products, which include sampling and analysis for residues, and comparison to predetermined acceptance criteria. 

Best practices from Big Biotech, including how to handle new product introductions.

Cleaning Validation for Biopharmaceutical Manufacturing at Genentech, Inc. Part 1

This article is the first in a four-part series on essential statistical techniques for any scientist or engineer working in the biotechnology field. Though many of the techniques seem trivial, they are often misused or misunderstood in practice. Future topics will include hypothesis testing, confidence intervals, Design of Experiments, and analysis of variance. This column deals with the ways data can be presented to maximize effectiveness, including  methods to summarize data sets. 

There are two main types of data: quantitative and qualitative. Quantitative, or numerical, data are continuous data sets with an infinite number of possible values. For example, protein concentration is considered continuous data, because its value is limited by the sensitivity of the measurement device. Qualitative, or categorical, data have a finite number of possible values. For example, the number of defective vials in a lot is considered qualitative because its values range from zero to the number of vials in the lot incremented in whole units. 

Each of the data types has different statistical methods used for summarizing and reporting.  

Qualitative data are usually presented in tabular format or as a percentage. Graphically, a bar graph can be used to present the data. A bar graph can be used to present a single variable or to compare two or more variables. Figure 1 and Table 1 show a presentation of the reasons for a lot failure. 

It is not enough just to plot the data to compare the frequencies by year. If the number of lots each year is different, it is preferred to plot the percentages to make a better comparison. Figure 2 shows the preferred graph. 

Table 1. The reasons for a lot failure			

The comparative graph in Figure 1 does not show the vast improvement between 2007 and 2006 that can be seen in Figure 2. Additional statistical tests such as the chi-squared test can be used to show that 2007 showed a statistically better percent defective when compared to 2006 (p = 0.005). 

Figure 2.  A preferred bar graph for comparing data from two years. The table below the bar graph makes it clear that the number of lots was different.			

Quantitative, or continuous, data are preferred because of their ability to estimate and predict the true population values. Though qualitative data can be used to estimate and predict the true population values, they typically require larger sample sizes to accomplish the task. There are several summary statistics that are used with quantitative data. The most common is the mean or average of the data. Another estimate for central tendency is the median, or 50th percentile of the data. Even though the mean is the most widely used, it is not appropriate for highly skewed distributions and is less efficient than other measures of central tendency when extreme scores are possible. The median is useful because its meaning is clear and it is more efficient than the mean in highly-skewed distributions. Another good estimate for the central tendency is the geometric mean if all the values are positive and the distribution has a positive skew. The geometric mean is computed by taking the average of the logarithms of all the values and raising the base of the logarithm used to the resultant average. If the distribution is skewed positively, the mean will be larger than the median; if it is skewed negatively, the mean is smaller than the median. When a distribution is symmetrical, the mean and the median are equal. 

The standard deviation or the square root of the variance is by far the most widely used measure of spread. The variance is the average squared deviation from the mean of the data. A key point to remember is that the variance can be averaged but the standard deviation cannot. 

The range is another estimate of the dispersion of the data, but it takes into account only two scores, the maximum and minimum value. A very handy method for comparing variability is the coefficient of variation (CV), sometimes called the relative standard deviation (RSD). The coefficient of variation measures variability in relation to the mean and is used to compare the relative dispersion in one type of data with the relative dispersion in another type of data. The data to be compared may be in the same units, in different units, with the same mean, or with different means.  

There are several methods to graphically display quantitative data. The most common methods include the line plot, box and whisker, and histogram. 

Graphing data makes it easier to see patterns in the data and to confirm assumptions about the distribution of the results. A line plot is a two- dimensional plot of data, usually over time, used to detect trends in the data. Line plots are used in conjunction with other statistical techniques such as control charts for process control. A control chart is a line plot with statistical limits set at ±3 standard deviations from the mean. Based on the normal distribution, 99.7% of the data should be within these limits. Figure 3 is an example of a line plot. The horizontal line is the mean of the 30 lots. 

Figure 3.  An example of a line plot. The horizontal line is the mean of the 30 lots.			

A box and whisker, or simply a box plot is a graphical representation of dispersion of the data. Figure 4 represents the lower quartile (Q1), upper quartile (Q3), and median. The box includes the range of scores falling into the middle 50% of the distribution. The whiskers i.e, the vertical lines extending from the box usually are set at 1.5 times the interquartile range (Q3–Q1). Points that are outside of the whiskers are usually candidates for outlier analysis. The box plot also can be used to compare different lots or batches. A t-test would be used to statistically compare two different lots. If you have more than two lots to compare, a one-way analysis of variance (ANOVA) would be used. 

The histogram plots the frequency of events where categories are ordered by x-values. If the data are continuous, they can be "binned" to create the cut points for the histogram. There is no best number of bins and different bin sizes can reveal different features of the data. Sometimes experimentation with different bins sizes can highlight the salient points of the data. A histogram shows the shape of the data distribution, which is useful for checking the assumption of normality of the data. A popular method for testing normality is the Andersen-Darling method, which can be found in most statistical software. Figure 5 shows how two data sets can be compared. The top graphic shows the two separate histograms; in the bottom graph, the two distributions have been overlaid. 

Figure 5.  Two examples showing different ways to compare data sets. In the bottom graph, the two distributions have been overlaid.			

CONVERTING QUANTITATIVE TO QUALITATIVE DATA

Typically, continuous data are converted to qualitative or binary response. For example, the specification for pH is between 6.9 and 7.1 but we code values within the limits as pass and those outside the limits as fail. Though this makes for an easier disposition of the lot, it does not allow for extensive data analysis during an investigation. Another common problem with data analysis occurs when the measurement system is inadequate so data is binned into a few unique values. For example, we measure a weight to the closest 0.1 mg, although the measurement device can measure to the closest 0.01 mg. This is commonly done to adhere to significant figures in a specification, but can lead to poor data analysis. 

Data presentation should be designed to ensure the correct conclusions. Though graphical methods give an overview of the data, more rigorous statistical methods help to separate normal variability from special cause variability. The key to a good graphical presentation is to select the method that best fits the data. 

 is the president of Statistical Outsourcing Services, Olney, MD, 301.325.3129, 

steven@statisticaloutsourcingservices.com

The key to a good graphical presentation is to select the method that best fits the data.

Presenting Data Effectively

India's pharmaceutical manufacturers currently sell close to 30% of the world's generic therapeutics. Sales of generic versions of biologicals in India have grown rapidly, and that growth will likely expand into export sales over the next decade, according to the joint study, 

Advances in Biopharmaceutical Technology in India

, (February 2008) by BioPlan Associates, Inc., and the Society for Industrial Microbiology. 

Biogenerics represent a high-growth sector in India, where recombinant insulin, granulocyte cell stimulating factor (G-CSF), interferon alpha, erythropoietin (EPO), monoclonal antibody (MAb) products, and recombinant vaccines are manufactured by a number of domestic biotech companies. The costs of Western-made biopharmaceutical products places them out of reach of much of the world, and many of these products are close to losing their patent protections. To assist the Indian biotech industry in seizing this opportunity, the Indian government has streamlined some of its drug application and review procedures, and has offered strong tax incentives. As a result, India's biotech industry has been investing heavily in the development of facilities. It is expected that Indian biogenerics makers will soon receive their first approvals to manufacture products for the European market. 

"Indian companies such as Biocon, Dr. Reddy's Laboratory, Intas Pharmaceuticals, MJ Biopharma, and others have the skills to develop and manufacture recombinant biotech products," says  Ashesh Kumar, PhD, head of Medipolis GMP. These products include hepatitis B vaccine, streptokinase, human insulin, G-CSF, EPO, human growth hormone (HGH), interferon alpha-2a, and MAbs for cancer and Hodgkin's lymphoma.  

Following the success of its generic pharmaceutical industry, Indian policy makers plan to repeat this in the biogeneric sector. Indian biotech revenues, currently at about $2 billion, are projected to reach $5 billion by 2010. Already, nearly 60% of these revenues are from exports.

  The year 2005 was an important milestone for Indian biotechnology as revenues crossed $1 billion.

The success demonstrated by India's small molecule generic drug industry may not be a easily duplicated, however, for several reasons.  

The research infrastructure, academic network, and overall talent pool are small compared to those supporting the traditional pharmaceuticals industry.

There have been greater regulatory hurdles for biologics in major markets, in particular, the lack of bioequivalence laws in the US, and the lack, until recently, in Europe.

Indian biogenerics could form a major piece of the global biotherapeutics market in the future.

BioPharm International-02-01-2008