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Risk-Based Analytical Method Transfer: Application to Large Multi-Product Transfers Christina S. Raska,* Tony S. Bennett, and Scott A. Goodberlet GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709 As pharmaceutical companies adapt their business models, a new approach to analytical method transfer is needed to efficiently handle transfers of multiple products, associated with situations such as site consolidations/ closures. Using the principles of risk management, a riskbased method transfer approach is described, which defines appropriate transfer activities based on a risk assessment of the methods and experience of the receiving unit. A key step in the process is detailed knowledge transfer from the transferring unit to the receiving unit. The amount of transfer testing required can be streamlined or eliminated on the basis of a number of factors, including method capability, receiving unit familiarity, and method past performance. The issues currently facing the pharmaceutical industry are significant: erosion of profits due to increasing patent expiry and generic competition, pricing pressures, higher regulatory barriers to market entry, and declining research and development (R&D) productivity.1 The idea to simplify operations and maximize efficiency is even more timely, given the current economic downturn. Several articles describe sea-changes which may be employed in R&D,1-3 but similar approaches can also be introduced into the parts of the business whose focus is supplying approved products to the marketplace. Although current moves in R&D are toward creating smaller groups and centralizing all activity at a small number of hubs, for the largest global pharmaceutical companies, manufacturing activities are concurrently performed at multiple sites across the world. There are clear tactical advantages to maintaining a network of sites, such that manufacture of key products is likely not adversely affected by issues at a single site, therefore ensuring continuity of the supply chain. In light of the spreading pandemic H1N1 flu, where manufacturing is concerned, this strategy makes good business sense and guarantees patients continue to have access to critically needed medications. Throughout a product’s lifecycle, manufacture and analysis is often moved to different locations, for example, when a product transitions from early to late phase development, from R&D to commercial manufacturing, or between commercial manufacturing sites. From an analytical method perspective, the scope of a * To whom correspondence should be addressed. E-mail: christy.s.raska@ gsk.com. Phone: 919-483-3020. Fax: 919-315-6501. (1) Garnier, J. P. Harv. Bus. Rev. 2008, 86 (5), 68–70. (2) Sewing, A.; Winchester, T.; Carnell, P.; Hampton, D.; Keighley, W. Drug Discovery Today 2008, 13 (5-6), 227–33. (3) Federsel, H. J. Drug Discovery Today 2006, 11 (21-22), 966–74.
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conventional product transfer is a small number of methods needed for testing a single product or family of products, approximately three to six methods. Prior to moving the product, a method transfer exercise takes place, where the transferring unit passes on the knowledge and experience accumulated from a long period of product testing to the receiving lab.4 Following this information exchange, both laboratories perform a fairly extensive study to establish comparable performance, typically analyzing a sufficient number of representative samples to appropriately power any statistical analysis needed to qualify performance of the method at the receiving unit.5 More recently, due to transformative changes within the pharmaceutical industry, transfers of multiple products are occurring more frequently, in situations such as site closures, mergers/acquisitions, and creation of centralized testing hubs. In these cases, it is not uncommon for large numbers of methods (200-400) to be simultaneously transferred, far exceeding the scope of traditional analytical transfer. For such a large number of methods, the resource required to perform traditional method transfer for each method would be prohibitive. This paradigm shift drives the need to develop a new approach to multiple product analytical transfer. Incorporating the key aspects of risk management, a risk-based strategy to analytical transfer is presented, which allows the transferring and receiving units to focus resources on the key tasks required to ensure consistent performance of all of the methods after transfer has been completed. Though more complex strategies could be envisaged, the benefit of the proposed strategy is a relatively simple three level approach for risk classification and corresponding transfer type while providing considerable advantages over one fixed approach to method transfer. Depending on the situation in which this strategy will be used, other more appropriate factors can be used to classify and categorize risk for multiple product transfers. For newer products which have been developed using a quality by design (QbD) approach, the design space and the variability of the associated analytical methods are well characterized. The quality critical attributes of the methods are established, and it is understood how changes to method attributes affect method performance, due to detailed measurement systems analyses, robustness evaluations, and other design space mapping exercises performed during the method development and validation. Given this wealth of background knowledge, the transfer of testing from one location to another location should be a relatively simple (4) Scypinski, S.; Roberts, D.; Oates, M.; Etse, J. Pharm. Technol. 2002, 26 (3), 84–89. (5) Schwenke, J. R.; O’Connor, D. K. J. Biopharm. Stat. 2008, 18 (5), 1013– 1033. 10.1021/ac1008892 2010 American Chemical Society Published on Web 06/17/2010
exercise, as the work has been performed up-front to fully understand method performance. However, the vast majority of currently marketed products were developed prior to the advent of QbD, and thus, the rigor of knowledge management tools used in evaluating method variability and other method attributes is likely not to the same standard as methods developed using the QbD approach. The approach presented in this paper was designed with these legacy products in mind, although the concepts may also be applied to legacy drug substance and newer drug substances and drug products whose methods have been developed using QbD. In addition, although multiple product analytical transfers were the driver for developing this new strategy, the tenets may be equally valuable for traditional single product transfers as well. RISK MANAGEMENT Historically, the pharmaceutical industry has been very risk averse, and this is fitting, given the nature of the business, providing patients medications which ensure continuation of both life and quality of life. However, as the industry has evolved, a more balanced approach to risk management is gaining acceptance, as evidenced by recent ICH and FDA publications.6,7 Rather than a “one-size fits all” model, where the same tasks are performed regardless of the situation, a risk-based approach is a “custom-designed” model. The fundamental steps in risk management8 are (1) identifying risk, (2) evaluating risk, (3) mitigating risk, and (4) recording and managing risk. The identified risk is evaluated to determine the probability of occurrence and the severity of occurrence. As necessary, appropriate mitigation activities can be defined. After these steps are completed, the risks and corresponding evaluations and mitigation plans are recorded. Mitigation activities tend to align into three categories, depending on how probable and/or severe the risk is: risk acceptance, risk mitigation, or risk avoidance. If the probability and/or occurrence are low enough, no action may need to be taken after the risk evaluation is performed. If the probability/occurrence is high enough or the results from the risk occurring are severe, then appropriate activities should be defined to avoid the risk if possible. For cases falling into the middle, appropriate mitigating activities which can lessen either the probability and/or occurrence are appropriate. For purposes of due diligence, periodic review of the risk management plan ensures that the original risk analysis is still accurate and allows the opportunity to introduce new mitigation activities as necessary. RISK-BASED METHOD TRANSFER PROCESS Analytical technical transfer is the term that is used to describe the process of transferring knowledge between different analytical groups and of demonstrating that a method has comparable performance when operated by the different groups. Applying the principles of risk management to analytical technical transfer, there is a risk of the two sites generating noncomparable data either during transfer or post-transfer. Risk-based thinking can (6) ICH. ICH-Topic ICHQ9 Quality Risk Management; 2005. (7) U.S. Food and Drug Administration. Pharmaceutical cGMPs for the 21st Century-A Risk Based Approach, 2004. (8) Bartlett, J. Managing Risk for Projects and Programmes; Project Management Today Publications: Hampshire, 2006.
Table 1. Activities for Traditional vs Risk-Based Method Transfer phase
traditional method transfer
risk-based method transfer
preparation information/knowledge transfer familiarization/training of receiving unit staff
execution
a
information/knowledge transfer familiarization/training of receiving unit staff method review and risk assessment protocol creation protocol creation a9 comparable performance appropriate laboratory testing by both transferring testing as dictated by and receiving laboratories risk and associated protocol data evaluation data evaluation
Typically performance equivalence.
be beneficial for analytical technical transfer in the evaluation of the product and associated analytical methods prior to method transfer, to determine the probability of the risk occurring. A product which tightly adheres to the middle of its specification range and is evaluated with robust methods has a low probability of a post-transfer difference in quality control. A product which has higher inherent variability and/or is evaluated with more variable methods has a higher probability of the risk being realized. Therefore, risk management would suggest that, with limited resource, it makes more sense to focus the resource on mitigation/avoidance of the high probability risk and accepting the low probability risk. The challenges in creating a risk-based method transfer process are to retain the key activities which are critical for successful transfer and proper identification of the activities which are nonvalue adding and can, thus, be eliminated. Many of the steps involved in risk-based method transfer are similar to the traditional method transfer approach, as shown in Table 1. However, the risk-based approach requires more up-front work to understand the products and their associated methods. At first glance, it seems counterintuitive to perform more work, when the approach is being driven by resource constraints. However, the investment up-front will increase the likelihood of successful transfer testing exercises and will reap dividends for years to come, as the in-depth knowledge gained can help avoid unnecessary laboratory investigations in the future. Knowledge Transfer. Knowledge transfer is the key step to a successful method transfer. In many ways, method transfer is similar to training a new analyst in an existing laboratory, although method transfer has the added complexity of potential differences in instrumentation. To train a new laboratory analyst, there is an extensive period of individualized training, where product knowledge, method technique, and best practices are passed on, prior to the analyst beginning any hands-on work in the laboratory. This knowledge transfer process is often less robust during a method transfer. Although there may be many potential root causes, the end result is a missed opportunity to pass along the rich experience and intimate product knowledge which the transferring unit staff have gained. Ensuring that the expertise is captured and transferred to the receiving unit staff is the most critical activity in a successful (9) Hauck, W. W.; DeStefano, A. J.; Cecil, T. L.; Abernethy, D. R.; Koch, W. F.; Williams, R. L. Pharmacopeial Forum 2009, 35 (3), 772–778.
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Table 2. Transfer Activities per Transfer Type transfer type
risk mitigation assignment
information/ knowledge transfer
lab testing by transferring unit
lab testing by receiving unit
data evaluation/ analysis
knowledge alone method confirmation comparable performance
acceptance mitigation avoidance
X X X
X
X X
X X
Table 3. Example of Risk Assessment Output method type
technique
familiar API/ dose form
technique complexity
risk
rationale
assay and impurities
isocratic RP-HPLC
yes/yes
simple
low
assay and impurities
gradient RP-HPLC
yes/no
complex
low
assay and impurities
gradient RP-HPLC
no
complex
high
Receiving site has extensive experience with this product, and the method in use is identical. Receiving site has experience with the API formulated as a tablet but not in this dosage form. Method has a history of capable performance at the transferring site. Receiving site does not have experience with this API or method. Transferring site indicates that meeting resolution requirements can require validated modifications to mobile phase composition.
simultaneous method transfer for multiple products. Along with the methods, the transferring unit should provide copies of the method development, validation reports, investigation history, and any other relevant product and method information. Additionally, preliminary information from the expert analysts is invaluable. The instructions provided in analytical methods developed prior to QbD often do not fully reflect the intricacies of how the method is executed in routine practice. While the method may state “shake until dissolved,” the analysts who routinely use the method can indicate that this step actually takes at least 30 min of very vigorous shaking, and incomplete dissolution yields assay results which are at least 5% below the expected value. Failure to capture these details can lead to increased variability, differences in data obtained post-transfer, or out of specification results. To be successful, the process requires full engagement from both the transferring and receiving units. In addition to the technical considerations involved with the analytical transfer, differences may exist between the transferring and receiving sites due to location factors. These include the transferring and receiving sites being in separate divisions or different countries within the same company (e.g., R&D, manufacturing) or when transferring to an external company (e.g., transfer to a contract research organization). Differences in site standard operating procedures (SOPs), standard ways of working, language, and local regulations can all subtly influence how the method is carried out in the laboratory. When language and/or cultural differences exist, it is beneficial for the receiving site to understand the customs and conventions of the transferring site prior to engaging in the method review process. In these transfer situations, it is critical to form a team as early in the process as possible and to explore some of the general differences between the groups before beginning the method risk assessments. Sharing the transferring sites SOPs with the receiving site can help identify these differences. Additionally, use of 5934
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transfer type knowledge alone
method confirmation
comparable performance
Lean tools10 such as process flowcharts and value stream maps can help the receiving site understand not only the technical aspects of the method but also the order of execution of steps in the method. Method Review and Risk Assessment. The analytical methods, specifications, validations, and any relevant product knowledge are key inputs into the review and risk assessment process. To risk assess the methods, a team of analysts from the transferring unit and the receiving unit is formed to review and risk assess the analytical methods. The complexity of the technique, and thus by inference the transfer process, is categorized as either simple or complex. Incorporating feedback from the transferring unit, the probability to affect quality control post-transfer, e.g., result in a step change in the data, is also evaluated as low or high. This probability is determined using a variety of factors such as: input from the analysts at the transferring unit; receiving unit staff experience with the dose form and technique; past method performance, e.g., laboratory investigation history; product stability trends; and method/product capability data11 (e.g., ppk). Assignment of the Transfer Strategy. On the basis of the combination of the complexity and probability assessment and the familiarity of the receiving unit with the dose form and product, the appropriate method transfer activities can be defined. It is impractical to create a simple guideline to be used a priori for all cases to define what level of method transfer activities should be applied. This risk-based approach requires a new evaluation for each situation, as the products and expertise of the receiving unit with the dose forms and specific products will necessarily influence the assignment of risk and complexity. (10) Adams, M.; Kiemele, M.; Pollock, L.; Quan, T. Lean Six Sigma: A Tools Edition; Air Academy Associates, LLC: Colorado Springs, CO, 2004. (11) Montgomery, D. C. Introduction to Statistical Quality Control, Sixth ed.; John Wiley and Sons: New York, 2008.
• system suitability tests pass • typical chromatography obtained • TOST or other comparability performance measure specified in protocol is successfully achieved. Two analysts prepare samples from a single batch, with n ) 6 replicates. Two analysts prepare samples from a single batch, with n ) 6 replicates. knowledge transfer, walk-through method at transferring site, training of receiving site analysts at transferring site comparable performance
acceptance criteria
N/A • system suitability tests pass • typical chromatography obtained • expected content/impurities value none One analyst prepares samples from a single batch, at the degree of replication specified in the method. none none knowledge transfer knowledge transfer
transfer testing required for receiving lab transfer testing required for transferring lab pretransfer activities transfer type
knowledge alone method confirmation
(12) Quattrocchi, O.; Martin, G.; Runser, D.; Iser, R.; Xi, F.; Pappa, H. Pharmacopeial Forum 2009, 35 (5), 1380–1382.
Table 4. Example Testing Performed and Acceptance Criteria per Testing Type
For the transfers with the lowest probability of realizing the risk (simple method, low risk of an effect on quality control, familiarity to receiving unit staff), method transfer will consist of exchanging information with the transferring unit, to ensure that all practical knowledge and expertise is passed to the receiving unit. Methods categorized as lowest risk are sufficiently simple, familiar, and/or robust so that there is no value added in performing any laboratory work. For methods which may be unfamiliar to the receiving unit but where the other risks are still low, the receiving unit alone will perform sample analysis to confirm suitable method performance at the receiving unit, and the data will be reviewed by the transferring unit and compared to historical data on that batch. For methods which are sufficiently complex, unfamiliar, or less robust, sufficient testing will be performed to ensure comparable performance between the transferring and receiving units. These three categories of method transfer activities are summarized in Table 2. The level of testing for method confirmation and comparable performance strategies is described in the section entitled Transfer Testing to Demonstrate Competence. An example of the risk assessment output for a representative method can be found in Table 3. If multiple unfamiliar products and/or dosage forms are involved in the transfer, the outputs from the risk assessments may need to be rereviewed during the transfer process. After the first unfamiliar products are transferred and the receiving unit gains experience with the new products/dosage forms, the probability of risk realization for the subsequent transfers is likely to decrease. Therefore, it may be more appropriate to reclassify the remaining methods as either knowledge only or method confirmation transfers. There is a published precedent for a varied strategy to analytical method transfer. The United States Pharmacopoeia has published a stimulus article12 which describes different ways of demonstrating method transfer from statistical comparative testing down to transfer waivers where conventional method transfer may be omitted under certain circumstances. In the latter case, the receiving unit is considered to be qualified to use the analytical test procedures without comparison and generation of interlaboratory comparative data. This would be comparable to the knowledge only transfers proposed above. Method Familiarization. The level of familiarization should be based on the specific method details and outputs from the risk assessment. For a simple method such as moisture determination (e.g., Karl Fischer or loss on drying), transfer of appropriate validation reports and product stability trends as part of the knowledge capture may be sufficient. To greatly enhance the potential for successful method transfer of the more difficult and complex methods, either on-site or teleconference walk-throughs should be scheduled, depending on the output from the risk assessments. Video demonstrations may also be helpful in sharing local ways of working and capturing best practices. Due to the large number of methods involved in these types of transfers, the transferring and receiving unit analysts should prioritize the methods for the on-site walk-throughs. Additionally, the sessions should focus on the specific aspects of the method (e.g., suspen-
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sion mixing, tablet disintegration, integration) which are viewed as the highest risk, to try and mitigate the risk occurring posttransfer. Protocol Creation and Risk Documentation. A method transfer protocol is created for all products transferring from the site. The results of the risk assessment, type of method transfer assigned, and rationale are all captured in the protocol. The protocol with test plans and acceptance criteria is to be approved prior to any testing.13 Transfer Testing to Demonstrate Competence. If testing is required, it will be carried out and compared against acceptance criteria which are specified in the preapproved transfer protocol. Method confirmation testing may be thought of as method trials performed at the receiving unit as a confirmation that the methods behave as expected in the laboratory environment of the receiving unit, similar to a performance qualification for a new instrument. It is a limited check on a batch previously evaluated by the transferring unit that the method continues to perform as expected, despite all the variables associated with ways of working, equipment, reagent sources, training, etc. that may be difficult to fully appreciate from a knowledge only-based transfer. System suitability requirements should be met and, as defined by the transfer protocol, the result(s) should be as expected by the transferring site, given knowledge of the analytical variability. An example of typical testing performed for each transfer type can be found in Table 4. Comparable performance is the standard fairly extensive comparative testing between transferring and receiving units.14 Historically, this has been carried out by studies assessing comparability (e.g., direct comparison of estimates of means) rather than a formal statistical demonstration of equivalence.15,16 However, a formal statistical demonstration of equivalence provides assurance of patient and producer risk and, thus, is preferred.9 The Two One Sided Tests approach advocated by Limentani and Chambers17 for use in assessing analytical method changes, is applicable in many instances, and is increasingly used by industry. (13) (14) (15) (16) (17)
Mortko, H. J. Pharm. Tech. 1999, 23 (SUPPL), 30–40. Schepers, U.; Watzig, H. J. Pharm. Biomed. Anal. 2006, 41 (1), 290–292. Chatfield, M. J.; Borman, P. J. Anal. Chem. 2009, 81 (24), 9841–9848. de Fontenay, G. J. Pharm. Biomed. Anal. 2008, 46 (1), 104–112. Limentani, G. B.; Ringo, M. C.; Ye, F.; Bergquist, M. L.; McSorley, E. O. Anal. Chem. 2005, 77, 221A–226A.
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Post-Transfer Risk Management. One of the key steps in a risk management program is periodic review of the risks. Review of system suitability performance data can provide continued reassurance the method is operating satisfactorily at the receiving unit. Thus, even for knowledge only transfers, there is an opportunity after the first time a product is tested by the receiving unit to reconfirm the original risk assessments. By performing appropriate statistical analyses, the receiving unit can ensure that the new data conform to expected trends and historical data and that nothing unexpected is observed due to transferring the testing. In the case of transferring stability evaluation, as the receiving unit begins to generate stability data with the transferred methods, an evaluation of the stability data, similar to what would typically be performed at each time point, provides this assurance. CONCLUSIONS As the pharmaceutical industry adapts to the current challenging environment, innovations to current practices will be required for sustainability. Using the principles of risk analysis, method transfer can transform into an activity which takes into account method complexity, method robustness, and receiving site experience to determine the appropriate activities needed to transfer analytical testing. In many cases, the activities needed to confirm acceptable method performance at the receiving site will not include the need to generate comparable data between the transferring and receiving units, although there will always be methods that will require this. The key activity which is required for all transfers is knowledge transfer. Using this new approach, it is estimated that the resource required at the transferring unit could range from one-quarter to half of what would be required to generate full comparability data. For the receiving unit, the resource savings will not be as great as the transferring unit but can approach half of the resource required for full transfers. ACKNOWLEDGMENT We thank Dan Szarko and John Glennon for input and feedback during the initial process development.
Received for review April 5, 2010. Accepted June 1, 2010. AC1008892
