For most products, and especially f

For most products, and especially for a successful one, the transfer of analytical methods during development is inevitable. Method transfers are often needed as a consequence of sequential activities (e.g., methods transferred from discovery to pre-clinical, to clinical manufacturing and finally to commercial manufacturing) or parallel activities (e.g., multiple testing sites including formulation and process development, stability and release testing). As such, methods transfers are a natural part of project progression. It is important that Analytical Methods Transfer Exercises (AMTE) are designed taking into consideration factors such as the development stage of the method and project, type of method and its intended use, and sites involved in the transfer. Table 1 lists key considerations and components for AMTEs.

Table 1 - Key considerations and components of AMTEs

Zoom In
Major goals of methods transfer to a new lab are to avoid release of product that does not meet specifications (safety impact) as well as avoid rejection of good product (economic impact). Because of these potentially high-impact implications, an assay cannot be used by the new lab until transfer is successfully completed.

A transfer exercise is the process of establishing a qualified analytical test procedure that originates in another laboratory. It documents that assay performance is equivalent across testing sites. Since each transfer situation is unique, a planned approach tailored to each project is required.

Zoom In
Figure 1 - A hypothetical example of data trending. The white circles represent AMTE results from the transferring and receiving labs. The difference in results is well within the variability of the assay thus, the AMTE is deemed successful, but if the historical data is analyzed for trends, a shift can be detected. When more data points are collected from the receiving lab, it could be determined if the change is real.

Like validation, methods transfer is an exercise that provides a static picture of the process at a given moment in time. When performing this type of activity, it is necessary to keep in mind that processes are dynamic (i.e., things change over time). For that reason, it is important to revisit and monitor assay performance even after completion of a successful transfer. It is also risky to rely on methods transfer as the sole means to approve method use. AMTEs should be complemented by methods validation (depending on the stage of development this could be ICH validation, qualification or verification), training (including records and protocols) and subsequent monitoring of the assay (continuous monitoring). Post-transfer method changes initiated by the transferring lab should be communicated to the receiving lab. Figure 1 illustrates one of the dangers of transferring assays using a single set of experiments.

The transfer should result in the generation of regulatory documentation, including training records, transfer study design, data analysis plan with pre-defined acceptance criteria, experimental work, and a report.

CONSIDERATIONS FOR AMTE DESIGN

When performing methods transfer, the stage of development for both the method and the project should be considered. Obviously, late-stage transfers tend to be more stringent. Thus, an evaluation is recommended to define and identify risk level, the assay history and complexity, method validation status, experience at both transferring and receiving laboratories, etc. Based on the outcome of these evaluations, the approach for methods transfer may vary. The use of the method (e.g., release, stability, characterization, in-process monitoring, raw materials testing, registered or additional tests) should also be considered. As for most aspects of development, a careful evaluation of the ultimate risk to patients must be performed (i.e., the AMTE should be more stringent for assays that may result in higher patient risk).

The type of assay transfer, the experimental design and data analysis options should be adapted to different situations in order to meet regulatory expectations. Some factors that simplify (or eliminate) an AMTE include receiving laboratories with extensive experience in the use of a closely related method, new dosage strengths or dosage forms of the same product, compendial methods, use of a co-validation approach, and a very early stage of product development (e.g., before the start of clinical trials).

The probability of a successful AMTE increases with the degree of understanding of the methods (i.e., know your assay before you transfer). Two method characteristics that complicate transfers are variability and lack of robustness. Besides their effect on obtaining reliable values during normal usage, variability impacts setting meaningful AMTE acceptance criteria and may cause the acceptance criteria limits to be too wide to ensure the assay is working properly in the new laboratory. Lack of robustness jeopardizes success because many of the variables evaluated during validation (e.g., reproducibility, inter-instrument, inter-analyst, inter-day, instrument-to-instrument, sample/reagent stability, etc.) come into play during transfer. To ensure easier methods transfer, it is necessary to minimize assay variability and ensure assay robustness is well understood.

It is also important to ensure adequate understanding of the performance of impurity assays by including spiked samples at the lower and upper limits during pre-transfer exercises. As for instruments, equivalent equipment may not be an option (e.g., transfer to national laboratories), thus, if possible, validation of the method prior to transfer using multiple instruments (different vendors) should be considered. Identify “equivalent” instruments and provide correction factors for non-equivalent equipment (to address bias). As for process validation, design of experiments (DOE) and multivariate validation method robustness may uncover links that need to be accounted for during transfer.

METHODS AND PROJECT CONTINUITY, SELECTION OF CRITICAL SAMPLES

Establishing continuity is a key activity during analytical and general project development and during methods transfers. Continuity is seldom addressed, but when ignored, it can result in serious problems in future project activities. For method continuity, appropriate bridging studies must be performed whenever a method is replaced or heavily modified. This can be achieved by using both the original method and modified method over a period of time to evaluate similarity/equivalence. It is important to include key samples (e.g., analytical reference standard, tox lots, clinical lots) when major method changes are adopted and, if appropriate, run samples side-by-side to minimize assay variability when comparing results. Since it is difficult to predict when new methods may be required, it should be common practice to bank samples by establishing and maintaining a sample retain system. This bank will be more useful if the most stable conditions in addition to preferred storage are used. As a rule, never discard important or representative samples for each stage of project, method, or manufacturing development.

Selecting the appropriate samples for AMTEs is critical. Consider inclusion of samples that cover accuracy and linearity for the main product and impurities when appropriate. When demonstrating quantitation limits (QL) or detection limits (DL) as part of the exercise, keep in mind that QL and DL are often instrument dependent. Samples from method validation forced-degraded samples, as well as purified impurities are all useful for method transfer. As previously mentioned, evaluate the need to use samples that contain relevant impurities.

If clinical or commercial samples are used for AMTEs, Out-of-specifications (OOS) results during methods transfer cannot be dismissed or ignored. Needless to say, if the transfer fails due to a sample OOS result (unless OOS samples were used and identified by pre-acceptance criteria in the protocol) a full OOS investigation should be performed to determine the failure cause. The investigation should determine which set of results is correct. Inclusion of OOS samples should be carefully evaluated (case-by-case basis).

KEY COMPONENTS OF AN AMTE

Table 1 lists key components of an AMTE, but it does not specify the factors involved in the decision making for defining what is included in each of the components. In the following sections, typical approaches to compendial, internal and external transfers are discussed.

TYPES OF AMTES

AMTEs can be classified by several characteristics, including method type and origin (e.g., compendial methods and product-specific methods), and transferring and receiving laboratories (e.g., external and internal transfers).

COMPENDIAL METHODS

For compendial methods, transfer is from the compendia to the “receiving” laboratory. Keep in mind that compendial methods are validated and should not be changed. The most common practice for compendial assays is to verify their performance in the hands of the receiving lab.

When the assay is used in multiple laboratories, an inter-laboratory comparison should be a more common practice. To avoid discrepancies, a gap analysis evaluation should be performed before the initiation of the transfer that includes analyst training and experience, state of the equipment (qualified instruments), information on known issues or product-specific requirements (e.g., sample prep or equipment compatibility), and identification of appropriate samples for the verification exercise.

PRODUCT SPECIFIC ASSAYS

Two common approaches to AMTEs for product-specific assays are Comparative Testing and Co-Validation.

Comparative testing is performed by comparing results from the analysis of the same samples by the transferring and receiving labs. One of the main advantages of comparative testing is the control and flexibility it al

ผลลัพธ์ (ไทย) 1:

สำหรับผลิตภัณฑ์มากที่สุด และโดยเฉพาะอย่างยิ่ง สำหรับหนึ่งประสบความสำเร็จ การถ่ายโอนของวิธีการวิเคราะห์ในระหว่างการพัฒนาจะหลีกเลี่ยงไม่ได้ วิธีโอนย้ายจำเป็นมักจะเป็นลำดับของกิจกรรมต่อเนื่อง (เช่น วิธีการโอนย้ายมาจากค้นพบก่อนคลินิก คลินิกการผลิตการผลิตเชิงพาณิชย์ไปในที่สุด) หรือกิจกรรมแบบขนาน (เช่น หลายทดสอบไซต์กำหนดและกระบวนการพัฒนา ความมั่นคง และปล่อยทดสอบ) ดัง วิธีโอนเป็นส่วนหนึ่งตามธรรมชาติของความก้าวหน้าโครงการ จึงควรวิเคราะห์วิธีการโอนย้ายการออกกำลังกาย (AMTE) ถูกออกแบบโดยใช้พิจารณาปัจจัยต่าง ๆ เช่นระยะการพัฒนาวิธีการ และโครงการ ชนิดของวิธีการใช้ และเว็บไซต์ที่เกี่ยวข้องในการโอนย้าย ตารางที่ 1 แสดงรายการสำคัญและส่วนประกอบสำหรับ AMTEsตาราง 1 - พิจารณาคีย์และคอมโพเนนต์ของ AMTEsขยายเป้าหมายสำคัญของการถ่ายโอนวิธีการปฏิบัติใหม่เพื่อ หลีกเลี่ยงการนำผลิตภัณฑ์ที่ไม่ตรงกับข้อมูลจำเพาะ (ผลกระทบด้านความปลอดภัย) รวมทั้งหลีกเลี่ยงการปฏิเสธผลิตภัณฑ์ดี (ผลกระทบทางเศรษฐกิจ) ได้ เนื่องจากผลกระทบเหล่านี้อาจสูงผลกระทบ ไม่สามารถใช้การวิเคราะห์ โดยห้องปฏิบัติการใหม่จนกว่าโอนเสร็จเรียบร้อยแล้วการออกกำลังกายถ่ายโอนคือ กระบวนการกำหนดวิธีวิเคราะห์ทดสอบคุณสมบัติที่เกิดในห้องปฏิบัติการอื่น เอกสารทดสอบประสิทธิภาพเทียบเท่าในอเมริกาการทดสอบ เนื่องจากสถานการณ์การโอนย้ายแต่ละไม่ซ้ำกัน เป็นแนวทางวางแผนให้แต่ละโครงการจะต้องZoom InFigure 1 - A hypothetical example of data trending. The white circles represent AMTE results from the transferring and receiving labs. The difference in results is well within the variability of the assay thus, the AMTE is deemed successful, but if the historical data is analyzed for trends, a shift can be detected. When more data points are collected from the receiving lab, it could be determined if the change is real.Like validation, methods transfer is an exercise that provides a static picture of the process at a given moment in time. When performing this type of activity, it is necessary to keep in mind that processes are dynamic (i.e., things change over time). For that reason, it is important to revisit and monitor assay performance even after completion of a successful transfer. It is also risky to rely on methods transfer as the sole means to approve method use. AMTEs should be complemented by methods validation (depending on the stage of development this could be ICH validation, qualification or verification), training (including records and protocols) and subsequent monitoring of the assay (continuous monitoring). Post-transfer method changes initiated by the transferring lab should be communicated to the receiving lab. Figure 1 illustrates one of the dangers of transferring assays using a single set of experiments. The transfer should result in the generation of regulatory documentation, including training records, transfer study design, data analysis plan with pre-defined acceptance criteria, experimental work, and a report.CONSIDERATIONS FOR AMTE DESIGNWhen performing methods transfer, the stage of development for both the method and the project should be considered. Obviously, late-stage transfers tend to be more stringent. Thus, an evaluation is recommended to define and identify risk level, the assay history and complexity, method validation status, experience at both transferring and receiving laboratories, etc. Based on the outcome of these evaluations, the approach for methods transfer may vary. The use of the method (e.g., release, stability, characterization, in-process monitoring, raw materials testing, registered or additional tests) should also be considered. As for most aspects of development, a careful evaluation of the ultimate risk to patients must be performed (i.e., the AMTE should be more stringent for assays that may result in higher patient risk).The type of assay transfer, the experimental design and data analysis options should be adapted to different situations in order to meet regulatory expectations. Some factors that simplify (or eliminate) an AMTE include receiving laboratories with extensive experience in the use of a closely related method, new dosage strengths or dosage forms of the same product, compendial methods, use of a co-validation approach, and a very early stage of product development (e.g., before the start of clinical trials).The probability of a successful AMTE increases with the degree of understanding of the methods (i.e., know your assay before you transfer). Two method characteristics that complicate transfers are variability and lack of robustness. Besides their effect on obtaining reliable values during normal usage, variability impacts setting meaningful AMTE acceptance criteria and may cause the acceptance criteria limits to be too wide to ensure the assay is working properly in the new laboratory. Lack of robustness jeopardizes success because many of the variables evaluated during validation (e.g., reproducibility, inter-instrument, inter-analyst, inter-day, instrument-to-instrument, sample/reagent stability, etc.) come into play during transfer. To ensure easier methods transfer, it is necessary to minimize assay variability and ensure assay robustness is well understood.It is also important to ensure adequate understanding of the performance of impurity assays by including spiked samples at the lower and upper limits during pre-transfer exercises. As for instruments, equivalent equipment may not be an option (e.g., transfer to national laboratories), thus, if possible, validation of the method prior to transfer using multiple instruments (different vendors) should be considered. Identify “equivalent” instruments and provide correction factors for non-equivalent equipment (to address bias). As for process validation, design of experiments (DOE) and multivariate validation method robustness may uncover links that need to be accounted for during transfer.METHODS AND PROJECT CONTINUITY, SELECTION OF CRITICAL SAMPLESEstablishing continuity is a key activity during analytical and general project development and during methods transfers. Continuity is seldom addressed, but when ignored, it can result in serious problems in future project activities. For method continuity, appropriate bridging studies must be performed whenever a method is replaced or heavily modified. This can be achieved by using both the original method and modified method over a period of time to evaluate similarity/equivalence. It is important to include key samples (e.g., analytical reference standard, tox lots, clinical lots) when major method changes are adopted and, if appropriate, run samples side-by-side to minimize assay variability when comparing results. Since it is difficult to predict when new methods may be required, it should be common practice to bank samples by establishing and maintaining a sample retain system. This bank will be more useful if the most stable conditions in addition to preferred storage are used. As a rule, never discard important or representative samples for each stage of project, method, or manufacturing development.Selecting the appropriate samples for AMTEs is critical. Consider inclusion of samples that cover accuracy and linearity for the main product and impurities when appropriate. When demonstrating quantitation limits (QL) or detection limits (DL) as part of the exercise, keep in mind that QL and DL are often instrument dependent. Samples from method validation forced-degraded samples, as well as purified impurities are all useful for method transfer. As previously mentioned, evaluate the need to use samples that contain relevant impurities.
If clinical or commercial samples are used for AMTEs, Out-of-specifications (OOS) results during methods transfer cannot be dismissed or ignored. Needless to say, if the transfer fails due to a sample OOS result (unless OOS samples were used and identified by pre-acceptance criteria in the protocol) a full OOS investigation should be performed to determine the failure cause. The investigation should determine which set of results is correct. Inclusion of OOS samples should be carefully evaluated (case-by-case basis).

KEY COMPONENTS OF AN AMTE

Table 1 lists key components of an AMTE, but it does not specify the factors involved in the decision making for defining what is included in each of the components. In the following sections, typical approaches to compendial, internal and external transfers are discussed.

TYPES OF AMTES

AMTEs can be classified by several characteristics, including method type and origin (e.g., compendial methods and product-specific methods), and transferring and receiving laboratories (e.g., external and internal transfers).

COMPENDIAL METHODS

For compendial methods, transfer is from the compendia to the “receiving” laboratory. Keep in mind that compendial methods are validated and should not be changed. The most common practice for compendial assays is to verify their performance in the hands of the receiving lab.

When the assay is used in multiple laboratories, an inter-laboratory comparison should be a more common practice. To avoid discrepancies, a gap analysis evaluation should be performed before the initiation of the transfer that includes analyst training and experience, state of the equipment (qualified instruments), information on known issues or product-specific requirements (e.g., sample prep or equipment compatibility), and identification of appropriate samples for the verification exercise.

PRODUCT SPECIFIC ASSAYS

Two common approaches to AMTEs for product-specific assays are Comparative Testing and Co-Validation.

Comparative testing is performed by comparing results from the analysis of the same samples by the transferring and receiving labs. One of the main advantages of comparative testing is the control and flexibility it al

ผลลัพธ์ (ไทย) 3:

สำหรับผลิตภัณฑ์ส่วนใหญ่ และโดยเฉพาะอย่างยิ่งสำหรับการประสบความสำเร็จ , การโอนของวิธีการวิเคราะห์ในระหว่างการพัฒนาเป็นสิ่งที่หลีกเลี่ยงไม่ได้ โอนเงินวิธีมักต้องการเป็นผลของกิจกรรมต่อเนื่อง ( เช่น วิธีการโอนย้ายจากการค้นพบก่อนทางคลินิก เพื่อการผลิตทางคลินิกและสุดท้ายที่จะผลิตเชิงพาณิชย์ ) หรือกิจกรรมแบบขนาน เช่นการทดสอบหลายเว็บไซต์ รวมถึงการพัฒนาสูตรและกระบวนการความมั่นคงและการทดสอบปล่อย ) เช่น วิธีการโอนย้ายเป็นส่วนหนึ่งของธรรมชาติ ความก้าวหน้าโครงการ มันเป็นสิ่งสำคัญว่า แบบฝึกหัดการวิธีการวิเคราะห์ ( amte ) ได้รับการพิจารณาปัจจัยต่างๆ เช่น การพัฒนาขั้นตอนของวิธีการและโครงการ , ประเภทของวิธีการและวัตถุประสงค์ที่ใช้มันและเว็บไซต์ที่เกี่ยวข้องในการถ่ายโอน ตารางที่ 1 แสดงรายการหลักพิจารณาองค์ประกอบและ amtes

โต๊ะ 1 - คีย์ข้อพิจารณาและส่วนประกอบของ amtes


ที่สำคัญซูมเป้าหมายวิธีการโอนไปยังห้องทดลองเพื่อหลีกเลี่ยงการปล่อยใหม่ของผลิตภัณฑ์ที่ไม่เป็นไปตามข้อกำหนด ( ผลกระทบต่อความปลอดภัย รวมทั้งหลีกเลี่ยงการปฏิเสธของผลิตภัณฑ์ที่ดี ( ทางเศรษฐกิจ )เพราะผลกระทบผลกระทบอาจสูงเหล่านี้ ไปใช้ไม่สามารถใช้แล็บใหม่จนกว่าการถ่ายโอนเสร็จสมบูรณ์เรียบร้อยแล้ว

การออกกําลังกายโอนเป็นกระบวนการของการสร้างผ่านกระบวนการทดสอบในห้องปฏิบัติการวิเคราะห์ว่าขึ้นอีก เอกสารที่ใช้ในการปฏิบัติงาน คิดเป็นเว็บไซต์ทดสอบ ตั้งแต่การถ่ายโอนแต่ละสถานการณ์เฉพาะวางแผนวิธีการที่เหมาะกับแต่ละโครงการต้องใช้


รูปที่ 1 - ซูมสมมุติตัวอย่างข้อมูลแนวโน้ม วงกลมสีขาวแสดงผล amte จากการโอนและได้รับห้องปฏิบัติการ ความแตกต่างในผลเป็นอย่างดี ในการวิเคราะห์ ดังนั้น amte ถือว่าสำเร็จ แต่ถ้าข้อมูลประวัติศาสตร์ วิเคราะห์แนวโน้มการเปลี่ยนแปลง สามารถตรวจพบเมื่อข้อมูลเพิ่มเติมจะถูกเก็บรวบรวมจากการรับ Lab , มันอาจจะกำหนดถ้าเปลี่ยนจริงๆ

ชอบการตรวจสอบวิธีการถ่ายโอนเป็นแบบฝึกหัดที่ให้ภาพแบบคงที่ของกระบวนการในช่วงเวลาในเวลา เวลาที่แสดงประเภทของกิจกรรมนี้ จะต้องระลึกไว้เสมอว่า กระบวนการแบบไดนามิก ( เช่น สิ่งที่เปลี่ยนแปลงตลอดเวลา ) สำหรับเหตุผลที่มันเป็นสิ่งสำคัญที่จะทบทวนและตรวจสอบประสิทธิภาพการทดสอบหลังจากเสร็จสิ้นการประสบความสำเร็จ มันก็เสี่ยงที่จะพึ่งพาวิธีการถ่ายโอนเป็นหมายถึง แต่เพียงผู้เดียวที่จะอนุมัติวิธีใช้ amtes ควรจะครบครันด้วยวิธีการตรวจสอบ ( ขึ้นอยู่กับขั้นตอนของการพัฒนานี้อาจจะได้รับการตรวจสอบคุณสมบัติหรือการตรวจสอบ )