HPLC for Pharmaceutical Scientists 2007 (Part 16)

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Analytical technology transfer and manufacturing is the mechanism by which knowledge acquired about a process for making a pharmaceutical active ingredient or dosage form during the clinical development phase is transferred from research and development to commercial scale-up operation or shared between internal groups or with third parties. Analytical technology transfer guarantees that laboratories can routinely execute tests, obtain acceptable results, and be able to accurately and independently judge the quality of commercial batches. One of the most important analytical technology transfers is high-performance liquid chromatography (HPLC) methods. ...

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Nội dung Text: HPLC for Pharmaceutical Scientists 2007 (Part 16)

16 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING Joseph Etse 16.1 INTRODUCTION Analytical technology transfer and manufacturing is the mechanism by which knowledge acquired about a process for making a pharmaceutical active ingre- dient or dosage form during the clinical development phase is transferred from research and development to commercial scale-up operation or shared between internal groups or with third parties. Analytical technology transfer guarantees that laboratories can routinely execute tests, obtain acceptable results, and be able to accurately and independently judge the quality of com- mercial batches. One of the most important analytical technology transfers is high-performance liquid chromatography (HPLC) methods. The success or failure of analytical technology transfers are judged on the merits of data gen- erated using HPLC. Consequently, a major focus of regulatory authorities [1–3] is on methods transfer as a critical link in the drug development con- tinuum. Depending on the structure of the pharmaceutical organization, trans- fer of analytical technology and manufacturing may occur at the end of the phase II clinical studies or during the transition from phase II to phase III. However, for a successful transfer of analytical technology to occur, the exis- tence of HPLC methods that have been fully validated in accordance with the ICH guidelines on validation will be required [4–7]. A full description of method validation is provided in Chapter 9. HPLC for Pharmaceutical Scientists, Edited by Yuri Kazakevich and Rosario LoBrutto Copyright © 2007 by John Wiley & Sons, Inc. 735
736 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING 16.2 PREREQUISITES FOR TRANSFER OF HPLC METHODS 16.2.1 Availability of Either Fully or Partially Validated Methods A prerequisite for the transfer of analytical technology is the establishment of fully validated methods in accordance with the International Council on Har- monization (ICH) [4, 5], United States Pharmacopeia (USP) [6] and European Pharmacopeia (EP) [7] guidelines for method validation, the existence of a ﬁnal synthetic process for the active pharmaceutical ingredients (APIs), and ﬁnal market image of the pharmaceutical dosage form. Method development and validation usually parallels the API and pharmaceutical dosage form development. It progresses from very rudimentary Tier 1 methods with limited validation as shown in Table 16-1 through to Tier 2 methods and culminating in Tier 3/registration-type methods [8–10]. Differences between methods from Tier 1 through Tier 3 are due to the extent of validation of the analytical ﬁgures of merit that is performed [3]. During early development of the active pharmaceutical ingredient and early dosage form development, emphasis is placed on speed and quantitation of the API. At this stage, methods rely on the use of short columns, fast ﬂows, and very minimum validation to quickly identify the most desirable synthetic route for the API that will produce an adequate impurity proﬁle (overall yield may not be optimized at this stage) and most desirable prototype formulations and excipients that will ultimately lead to the selection of the ﬁnal formula- TABLE 16-1. Progressive Validation of Analytical Figures of Merit Progressive Method Development Discovery/ Phase I Phase II Phase III Phase IV Analytical Figures of Merit Tier 1 Tier 2 Tier 3 Registration 1. Linearity √ √ √ √ 2. Range √ √ √ √ 3. Accuracy — √ √ √ 4. Speciﬁcity/stress studies — √ √ √ 5. Precision • Repeatability (injection) √ √ √ √ • Intermediate precision (API) — √ √ √ • Intermediate precision (RS) — — √ √ 6. Robustness — — √ √ 7. Solution stability √ √ √ √ 8. Limit of detection (LOD) — — √ √ 9. Limit of quantitation (LOQ) — √ √ √ √, Validated; —, not validated; R&D, discovery research, API, active pharmaceutical ingredient; RS, related substance. Source: Reprinted from Am. Pharm. Rev. Vol. 8(1), (2005), 76, with permission.
PREREQUISITES FOR TRANSFER OF HPLC METHODS 737 tion. Typically, Tier 1 and Tier 2 methods include validation of some, but not all, of the analytical ﬁgures of merit as shown in Table 16-1. Tier 1 methods are the simplest methods in the sense that only linearity and precision may have been validated. As the synthesis scheme for the API becomes optimized with respect to improving the overall API yield and as the dosage form devel- opment evolves from prototype formulations to the more robust ﬁnal market image formulations, the analytical methods employed also evolve and become increasingly robust and optimized for the quantitation of the API as well as degradation products and related substances. Once the ﬁnal synthesis is set and ﬁnal formulations are selected, more robust and fully validated Tier 3 methods [3] are established to ensure the successful transfer of analytical tech- nology from research and development to commercial operation. Supple- mentary to this prerequisite is the identiﬁcation of the commercial production site or launch site where the pharmaceutical dosage form will be manufac- tured. This is usually the stage in which all the drug development activities come together in a New Drug Application (NDA) for regulatory approval (Figures 16-1 and 16-2). Phase IV methods are usually slight variations of Tier 3 methods which include but are not limited to calculation formulas, the number of sample preparations for API, and the number of dosage units. Figure 16-1. Drug development and method transfer continuum for pharmaceutical active ingredients (APIs).
738 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING Figure 16-2. Drug development and method transfer continuum for pharmaceutical dosage forms. 16.2.2 Availability of the Finalized Pharmaceutical Active Ingredient (API), Known Degradation Products, By-products and Reference Standards Besides the existence of validated HPLC methods, the availability of a ﬁnal- ized API synthetic scheme and optimized formulations is another prerequisite for ensuring a successful transfer of analytical technology from research and development to commercial operation (Figure 16-1). Evaluation of data gen- erated from the HPLC analysis of the API provides the means by which deter- mination is made about whether a validated API synthetic scheme exists and if the API can be made reproducibly during commercial operation. Conﬁrmation of the existence of a validated API synthetic process is based on the interpretation of acquired nuclear magnetic resonance (NMR) spec- trum of the API in conjunction with deﬁnitive molecular formula for the API and its components based on mass spectroscopy (MS). Concluding that a reproducible API manufacturing process exists is based on whether purity proﬁles of subsequent drug substance batches retain the same proﬁle of the API and its related substance peaks as was in the reference material. In that sense, data generated using HPLC and hyphenated HPLC techniques such as HPLC/MS, HPLC-MS/MS, and HPLC/NMR serve as the foundation for declaring the existence of reproducible API manufacturing process [11–13].
PREREQUISITES FOR TRANSFER OF HPLC METHODS 739 16.2.3 Availability of Drug Products Made by the Deﬁnitive Manufacturing Process Once the API has been selected for further development, a clear deﬁnition and demonstration of the validated status of the manufacturing process for the pharmaceutical dosage form is required in order to initiate transfer of ana- lytical technology and manufacturing process. Development of the phar- maceutical dosage form consists of a series of experimental activities that ultimately result in the transformation of the API into a dosage form (i.e., tablet, capsule, suspension, injectable, patch, creams, inhalation product) suit- able for human use [14]. This is achieved through the manufacture of batches at the chosen commercial site for scale-up production (Figure 16-2). As the formulation development process evolves into the ﬁnal market image dosage form, more robust HPLC methods as shown in Table 16-1 are established [3]. Assessment of whether or not the transfer of manufacturing process has been successful is usually done by sampling and analyzing batches for blend uni- formity [15, 16]. Sampling of the batches can be done in a number of ways. Sampling by variables or the Bergum approach [17] are examples of sampling techniques that can be used to measure the quality characteristics of the batch on a continuous statistical scale. A simple method of measurement used to judge the quality of the batch is the sample mean value (SMV) and its corre- sponding percent relative standard deviation (%RSD). A sample mean value that is close to the expected target value of 100% with a corresponding low %RSD serves to prove the attainment of a homogeneous product that is uniform and not variable in the content of the API. Assessment of product quality using the Bergum approach relies on whether selected samples of a batch has an SMV and %RSD that match the Bergum acceptance criteria. The process is rejected if the SMV and %RSD lie outside the allowable Bergum acceptance criteria [17–19]. An example of how the Bergum acceptance crite- ria are applied for evaluating content uniformity data generated using HPLC is shown in Figure 16-3. A sample with an SMV of 95% will pass the Bergum criteria, provided that its corresponding %RSD is less than or equal to 3.5. Similarly, a sample with a %RSD of 2.0 must have a corresponding SMV of either 90% or 109% to pass the Bergum acceptance criteria. The general trend as seen with Bergum acceptance criteria is that an increase in the magnitude of the %RSD and its corresponding sample mean value (SMV) follow a bell- shaped distribution in such way that %RSD decreases to zero as the SMV becomes greater than or less than 100%. 16.2.4 Availability of Suitable Instruments and Personnel A critical activity that precedes the start of analytical technology transfer is to assess whether suitable instrumentation and qualiﬁed personnel are available at the receiving laboratory. The receiving laboratory is the laboratory to which the analytical methods are transferred to. This assessment is accomplished through the organization of an analytical challenge meeting. The purpose of
740 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING Figure 16-3. Bergum acceptance curve for evaluating content uniformity (CU) data. Note: The curve shows that for a relative standard deviation (%RSD) of 4.5%, a sample mean value (SMV) of 100% must be achieved for the manufacturing process to be judged as validated. this meeting is usually to open up channels of communication between the participating laboratories to discuss the methods that are going to be trans- ferred, to share and exchange knowledge about the idiosyncrasies of the methods, and to agree on the types of tests to perform and samples that will be used for the cross-over testing. Because of the potential impact of sample- to-sample variability on the agreement between data generated, participating labs should agree to use identical batches and also decide on the number and types of batches that should be tested [17–20]. Additionally, identiﬁcation of key contact persons and assignment of responsibilities are other items that can be agreed upon during the analytical challenge meeting. 16.2.5 Availability of a Protocol Containing Predetermined Acceptance Criteria The methods transfer protocol is the main driver that governs the conduct of the experiments and ensures that assessment of results generated is not unduly inﬂuenced by biases due to either (a) the analytical method or (b) inherent batch-to-batch variability of the active pharmaceutical ingredient or pharma- ceutical dosage form. The methods transfer protocol establishes the predeter- mined acceptance criteria by which results will be judged to have either passed or failed the methods transfer. The criteria for assessment of success or failure contained in the methods transfer protocol is achieved through an iterative
PREREQUISITES FOR TRANSFER OF HPLC METHODS 741 process of exchange of ideas and comments between the originating lab and the participating or receiving labs. Since the aim of the protocol is to ensure the mitigation of problems, the essential elements of the protocol consists of sections that include (a) an Introduction, (b) treatment and disposition of data, (c) types of methods being transferred, (d) materials, reference standards, and reagents being used, (e) recommended type of equipment, (f) sample handling, (g) predetermined acceptance criteria, and (h) an Acknowledgment section. An example of a typical table of contents (TOC) of an analytical methods transfer protocol is discussed in Table 16-2. TABLE 16-2. Table of Contents of an Example of Analytical Transfer Protocol Section Description 1. Introduction • Aim and scope of the protocol • Brief description of dosage forms • Arguments for waivers, bracketing, and matrixing (if applicable) 2. Treatment and disposition of data • Format for reporting data (i.e., number of decimal places • Archival of data • Handling and resolution of OOS or OOT results 3. Materials, standards, and reagents • Batches to be tested including batch- speciﬁc data (storage conditions, shelf life, etc.) • Reference substances (including storage conditions and expiry dates) • Special handling instructions or precautions (if applicable) • Reagents and source of supplier(s) 4. Test methods and speciﬁcations • Lists all applicable test methods and speciﬁcations • List methods that will not be transferred by cross-over testing 5. Acceptance criteria • Lists pass or fail requirements • Enumerates the release acceptance requirements • Stipulates the number of required replicate determinations • Establishes the statistical assessment requirements 6. Method acknowledgment • Feedback from participating labs • Signature of acceptance/approval (receiving and transfer laboratory) OOS, out-of-speciﬁcation results; OOT, out-of-trend results. Source: Adapted from Am. Pharm. Rev. 8(1) (2005), 76, with permission.
742 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING 16.2.5.1 Introduction. The introduction section lays down the purpose of the transfer and clearly identiﬁes the originator lab where the method was developed as the reference lab (also designated as center A or originator lab) and identiﬁes all the other labs participating in the transfer as participating or receiving labs. A brief description of the pharmaceutical dosage forms being transferred as well as any arguments for bracketing and matrixing of the testing plan is included in this section. Because a minimum of three batches of each dosage strength of a pharmaceutical dosage form is normally required to be to tested during the transfer activities [17–19], any argument that serves as justiﬁcation for omitting the testing of certain dosage strengths through the application of bracketing and matrixing strategies becomes an important con- sideration that is addressed in this section. Bracketing and matrix testing is the approach in which only the highest and lowest dosage strengths are tested in the cross-over experiments and carry the beneﬁts of reducing the amount of testing required. When this approach is applied to a pharmaceutical dosage form consisting of 50-, 75-, 100-, 125-, and 150-mg dosage strengths, cross-over testing is performed using only the 50-, 100-, and 150-mg dose strengths. In that sense, passing results generated for the 50-, 100-, and 150-mg strengths automatically becomes surrogate and proof of the transfer for the 75- and 125-mg dose strengths. Usually, arguments for bracketing and matrixing are easier to justify if the analytical sample prepa- ration steps for all dosage strengths are similar and if the dosage strengths are made from similar or identical granulation and the excipient-to-drug content ratio is dose and/or weight proportional. 16.2.5.2 Treatment and Disposition of Data. This section discusses treat- ment and disposition of data and establishes the mechanism by which data will be assessed as having passed or failed the predetermined acceptance criteria. It is important that this section also address (a) the mechanism by which out- of-speciﬁcation (OOS) or out-of-trend (OOT) results will be handled and (b) procedures for reporting and archiving of data. Stipulation of how assessment of reported results and the archival and disposition of data will be handled should also be discussed under this section. Clear rules governing how assess- ment of data is handled takes on an ever-increasing signiﬁcance because of the intense scrutiny regulatory agencies apply when reviewing any docu- mented report that claims equivalency based on data comparison between different laboratories [20–22]. 16.2.5.3 List of Materials, Standards, and Reagents. The impact that batch-to-batch variability of a pharmaceutical dosage form can have on the interpretation of results can be very challenging [17, 18]. The same challenges are also present for the API because different vendors may be used for the raw materials that may lead to different impurity proﬁles of the API. Hence, the purpose of this section of the protocol is to describe in unequivocal terms
PREREQUISITES FOR TRANSFER OF HPLC METHODS 743 the analytical methods, test samples, standards, and reagents that should be used.An approach that greatly helps to alleviate potential differences that lead to non-agreement of data between the participating and originator labs due to the potential impact of batch-to-batch variability is to use either freshly manufactured or well-characterized batches. This can be accomplished by pro- viding all the participating labs with identical samples derived from previously prepared composite samples or aliquots from the same batches of drug product (DP) and drug substance (DS). The prepared composite samples for the DP or DS are subdivided evenly into smaller lots that are distributed to all participating laboratories. Because the ultimate goal of the technical trans- fer is the transfer of analytical test methods and not the identiﬁcation of inher- ent batch-to-batch variability that may exist among batches, it is essential to stipulate the lot number, date of manufacture and the required storage con- dition of the batches selected. For example, a storage condition of “5°C” or “Do not store above 30°C,” together with any special handling instructions, and the appropriate “Re-test” or “Expiry date (i.e., 2 years, etc.),” should be provided [23, 24].Additionally, it may also be necessary to stipulate and restrict the number of vendors/suppliers of reagents and reference standards as a means by which potential biases from such sources on the results generated can be eliminated or minimized. For example, if in-house reference standards are used, it may be necessary to quarantine that particular lot of reference standard material to ensure that adequate supplies are available at all times for the duration of the analytical methods transfer. Material Safety and Data Sheet (MSDS) classiﬁcation of the reagents, standards, and the API should be provided to assure the types of adequate precaution that should be taken to avoid unintended exposure of analysts to potentially dangerous materials [23, 24]. 16.2.5.4 Test Methods and Speciﬁcations. This section tabulates all the test methods and speciﬁcations that are being transferred via an interlaboratory cross-over testing plan. In addition, a discussion of the rationale for transfer- ring the methods should be provided in this section. When transfer of related substances methods is required, a number of steps should be considered to ensure that data generated will be reasonable and meaningful for the purposes of comparing data between the different laboratories. Transfer of related sub- stances methods often presents a challenging situation because related sub- stances tend to occur in low levels, especially in recently manufactured batches, or may be present at levels that are close to the quantitation limits of the method. To circumvent this, a very well-deﬁned strategy can adopted by the participating labs to mitigate difﬁculties associated with the transfer of related substances. For example, clear instructions regarding whether a spike experiment involving the use of pre-prepared samples containing a known amount of the degradation product or the use of samples containing well- characterized amount of the degradation product of interest can be stipulated. Also, clear deﬁnition of the sample preparation in regard to sonication (power
744 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING output, water level in batch), shaking, ﬁltration steps, and so on, must be communicated [25–29]. Another aspect of this section of the protocol is to discuss the rationale for not transferring certain methods. In general, test methods such as microbial limit tests (MLT) and other types of test methods based on universally accepted pharmacopeia procedures are not typically subjected to interlabora- tory cross-over testing. Instead, such methods are validated locally by demon- strating suitability for their intended purpose. Similarly, test methods that rely on the use of well-established techniques that are considered routine such as “appearance by visual examination” and “uniformity of dosage units by weights” are not normally subjected to interlaboratory cross-over testing. However, if some of the more common tests such as “Appearance of Solution” tests require special pharmacopeia procedures that are not routine, it may be necessary to consider the inclusion of such methods in the interlaboratory cross-over testing scheme. Any decision that is contemplated to either include or exclude a test method or methods from conventional cross-over testing should clearly be justiﬁed on the basis of sound scientiﬁc argument(s). 16.2.5.5 Acceptance Criteria. A most important section of the protocol is the section that outlines all the acceptance criteria by which results generated for each method being transferred will be judged as having fulﬁlled the requirements of the transfer. Since the interpretation of acceptance criteria is often based on the application of some type of statistical value, an important aspect of this section is to include clear instructions regarding the number of batches and the number of replicate determinations that has to be performed [18, 19]. Table 16-3 shows examples of acceptance criteria that may be applied TABLE 16-3. Example of Acceptance Criteria for Assay, Content Uniformity, and Dissolution Test Replicates (n) Acceptance Criteria Assay 3 • Mean difference ≤ 2.0% [%RSD, n = 6) ≤3.0%] Content uniformity (CU) 10 • Results meet current USP and/or harmonized USP, JP, and EP 2.6.1 requirements. • If %RSD at either site is >4.0%, then [STDev (Lab B)/STDev (Lab A)] ≤2.0% • For each site, SMV = ±3% of the mean assay within each site Dissolution 12 • Mean difference ≤7.5% SMV, sample mean value; RSD, relative standard deviation; n, number of replicates; USP, United State Pharmacopeia; JP, Japanese Pharmacopeia; EP, European Pharmacopeia. Source: Adapted from Am. Pharm. Rev. 8(1) (2005), 77, with permission.
TYPES OF TECHNICAL TRANSFER 745 for comparing assay, content uniformity, and dissolution data between par- ticipating labs. For the purposes of comparing assay, content uniformity, and dissolution data, simple statistics such as sample mean value (SMV) and relative standard deviation (%RSD) derived from experience of performing the tests over long periods of time can be used as acceptance criteria. Alternatively, more sophis- ticated statistics such as the z-test, F-test or t-test as shown in Table 16-4 can be applied [17–19, 25]. In the case of evaluating CU data, it can be concluded that results from two labs are equivalent based on applying the simple statis- tics of the difference between the SMV from Lab A and Lab B (Table 16-4) not to be more than 2.0%. In the other examples where the more sophisti- cated statistics such as z-test, F-test, or t-test are applied (Table 16-4), results from two labs are considered to be equivalent because the calculated statis- tics in each case (z-calculated values of 0.32/0.64, F-calculated value of 0.14, or T-calculated values of 0.30/0.60) are less than the predicted statistics (z-critical value of 1.64, F-critical values of 3.18, or T-critical value of 1.73) [19, 25]. 16.2.5.6 Method Acknowledgment. Since the goal of the transfer is to achieve an efﬁcient and an issue-free transfer, a meeting to discuss the HPLC methods with the participating labs prior to the start of the transfer activities is highly recommended. As previously discussed, the meeting provides oppor- tunities for the participating labs (or receiving labs) to be made aware of any special features or idiosyncrasies of the methods. Hence, the primary focus of this section is to capture feedback and suggestions from discussions with the participating labs prior to the start of the transfer activities. Sometimes based on feedback from the discussions, methods can be further optimized to address special concerns or to accommodate well-established procedural practices at the receiving labs. For example, the test method for assay can be changed to permit the use of 20 instead of 10 sample composite for assay in order to rec- oncile practices in AR&D with quality control (QC). In other cases, a stipu- lated column oven temperature of 30°C can be changed to 35°C, and the initial isocratic hold time in a gradient method can also be modiﬁed in order to accommodate differences in instrument capabilities (dwell volumes) between QC and AR&D. Additionally, this section stipulates who needs to approve the protocol from both the participating and originator labs. 16.3 TYPES OF TECHNICAL TRANSFER 16.3.1 From Analytical Research and Development (AR&D) to Quality Control (QC) Lab of the Commercial Organization Technical transfer from AR&D to QC constitutes the majority of technology transfers that are performed. It is the process by which a laboratory is
746 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING TABLE 16-4. Role of HPLC in the Comparison of CU Data Between Two Labs Test Sample # Lab A Lab B 1 99.4 99.0 2 99.8 99.6 3 100.0 101.0 4 101.0 100.0 5 97.9 98.8 6 99.9 99.3 7 99.5 99.6 8 100.0 99.9 9 101.2 100.0 10 102.0 101.2 Average 100.1 99.8 Standard deviation 1.1 0.8 Mean difference 0.30 z-Test: Two Sample for Means Lab A Lab B Minimum value 99.4 99.0 Mean 100.1 99.9 Known variance 1.27 0.6 Observations 9 9 Hypothesized mean difference 0 z 0.46 P(Z ≤ z) one-tail 0.32 z Critical one-tail 1.64 P(Z ≤ z) two-tail 0.64 z Critical two-tail 1.96 F-Test Two-Sample for Variances Mean 100.1 99.8 Variance 1.27 0.60 Observations 10 10 df 9 9 F 2.11 P(F ≤ f ) one-tail 0.14 F Critical one-tail 3.18 t-Test: Two-Sample Assuming Equal Variances Lab A Lab B Mean 100.1 99.8 Variance 1.27 0.60 Observations 10 10 Pooled variance 0.94 Hypothesized mean difference 0 df 18 t Stat 0.53 P(T ≤ t) one-tail 0.30 t Critical one-tail 1.73 P(T ≤ t) two-tail 0.60 t Critical two-tail 2.10
TYPES OF TECHNICAL TRANSFER 747 qualiﬁed to utilize analytical methods for the routine release of products to the marketplace [20]. This type of transfer guarantees that commercial organization can routinely perform the tests and obtained acceptable results. From that perspective, the timely transfer of methods from AR&D to QC is regarded as providing a competitive advantage in accelerating the commer- cialization of the drug products. Transfer from AR&D to QC guarantees the proper training of QC chemists in the use of the analytical methodologies and avoids unnecessary delays due to analytical issues in the timely release of products to the marketplace [20]. For this type of transfer to occur, it is usually the originator of the method (AR&D) who undertakes the full validation of the methods and also initiates the transfer of the methods. Though timing of the transfer generally occurs prior to the regulatory submission of a New Drug Application (NDA), the transfer can also take place earlier in the drug development continuum around the time of ﬁling an Investigational New Drug Application (IND). Transfer during the IND ﬁling phase can occur if a project is transferred from one development center to another. A distinguish- ing feature of this type of transfer is that fully validated Tier 2 or Tier 3/ registration method (Table 16-1) must be available before the transfer can begin. The assessment of success or failure of the transfer under this type of transfer is usually based on extensive interlaboratory cross-over testing and comparison of results against predetermined acceptance criteria [26, 29]. 16.3.2 Transfer from AR&D to Another AR&D Organization Transfer from one AR&D organization to another AR&D unit occurs when projects are transferred mid-stream during the drug development continuum. There may be a number of reasons that could lead to this type of transfer. Notable among these are; (a) Realignment of project portfolios due to signiﬁcant reorganization of a company. (b) Merger/acquisition situation requiring the divestiture of projects to avoid creation of monopolies. (c) Change in a company’s therapeutic area of focus or interest leading to either out-licensing or in-licensing of new development activities to bolster pipeline depreciation issues. Unlike transfer from AR&D to QC, methods available at this time may not have been fully validated and may either be Tier 1 or Tier 2 methods (Table 16-1). Depending on the status of the project at the time of the transfer, the receiving lab may have to redevelop and revalidate the methods. Transfer under this mode can be prompted by legally mandated timeline, especially in a merger situation, to ensure the timely and complete transfer of technology to the receiving lab. Assessment of success or failure of transfer may not be
748 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING based on extensive interlaboratory cross-over testing. Instead, the timely trans- fer of all available relevant documentation and the comprehension of the doc- umentation by the receiving laboratory may be sufﬁcient proof of the successful transfer of the analytical methods. 16.3.3 Transfer from AR&D to Contract Research Organization (CRO) Transfer from AR&D to CRO is becoming an increasing means by which com- panies faced with severe capacity constraints ﬁnd external partners to off-load some of their routine activities to free-up capacity from performing routine activities such as testing of stability samples and manufacture of compara- tor/positive control batches. Additionally, companies may engage in this type of transfer when they place greater emphasis on the performance of only certain activities such as early proof concept screening of compound and dis- covery support activities. Transfer under this category can be similar to the transfer from AR&D to QC or the transfer from one AR&D unit to another. When transfer is similar to the transfer from AR&D to QC, the originator of the method (AR&D) undertakes the full validation of the methods and initi- ates the transfer. A facet of this transfer is that methods at this stage can span the whole gamut from Tier 1 methods to the fully validated Tier 3 methods. When Tier 2 methods are involved, the CRO undertakes the task of complet- ing the validation of the method with either full or partial participation in the validation efforts by the originator lab. Successful transfer in this case is based on the CRO completing the validation exercises in accordance with criteria deﬁned in a protocol. With regard to transferring fully validated Tier 3-type methods, assessment of success or the transfer is similar to the transfer from AR&D to QC in the sense that success or failure of the transfer is predicated on the generation of results from extensive interlaboratory cross-over testing and the agreement of the results with a set of predetermined acceptance criteria. 16.4 DIFFERENT APPROACHES FOR TECHNICAL TRANSFER AND MANUFACTURING 16.4.1 Comparative Testing Comparative testing is the most common approach employed for ensuring the transfer of analytical methods. Because this approach usually requires the availability of fully validated Tier 3/registration-type methods, a prerequisite for this approach is that the originator lab and participating laboratories agree to use the same fully validated methods and preselected and mutually agreed- upon products sourced from identical batches of the material. Considerations that are paramount to the success or failure of this approach are the precau- tionary measures that must be taken to either eliminate or at least minimize
DIFFERENT APPROACHES FOR TECHNICAL TRANSFER 749 the potential impact of any inherent batch-to-batch variability on the results. To achieve this goal, material used for the interlaboratory cross-over testing is sourced from the same batch/lot of drug product or drug substance. One of the most popular means employed to ensure the elimination of potential inﬂu- ence of batch-to-batch variability on data interpretation is that the originator lab prepares a composite sample of the material to be tested. The composite sample is split into equal portions that are then supplied to the participating labs. Results generated by the participating labs are compared to the origina- tor lab’s results as the reference or gold standard lab [18–20]. Assessment of agreement of results is done by using a variety of statistical approaches [20, 25]. The simplest statistical approach that is often used is to compare results based on predetermined relative standard deviation (%RSD) and difference between sample mean value (SMV). Selection of the %RSD and SMV crite- ria can be based on accumulated historical data generated from analyzing several batches at the originator lab. Table 16-5 shows data generated for the transfer of an HPLC assay method from Lab A (the originator lab) to Lab B (the receiving lab). In this case, a predetermined acceptance criteria of differ- ence between the SMV as ≤2.0% for assay was established prior to the start of the transfer activities. In addition, a %RSD criteria of ≤2.0% was also estab- lished. For the three dosage strengths (250 mg, 500 mg, and 750 mg tablet) tested in the interlaboratory cross-over testing, data generated by both labs agreed with the predetermined SMV and %RSD acceptance criteria, and so the transfer is judged to have been successful. In other cases of determining whether a transfer has been successful involves the use of sophisticated statistical means (Table 16-4) such as the Student t-test, testing of equality of means from two groups (two sample TABLE 16-5. Comparison of Assay Results for Three Replicates of Three Dosage Strengths Drug Product Batch: A B C Dosage strength: 250 mg 500 mg 750 mg Participating labs: Lab A Lab B Lab A Lab B Lab A Lab B First value: 101.1 99.5 101.4 101.2 101.3 99.6 Second value: 100.4 98.9 101.3 100.7 100.6 100.5 Third value: 99.8 98.5 101.1 101.1 100.9 100.2 Mean value: 100.5 99.0 101.3 101.0 100.9 100.2 RSD: 0.7 0.5 0.1 0.3 0.4 0.7 Mean difference: 1.5 0.3 0.7 Note: Lab A is the reference or originator lab. Acceptance criteria based on three replicate deter- mination are as follows: Sample mean value (SMV) = 95–105%; Difference between the SMV (i.e., mean difference) is ≤2%; RSD (n = 3) ≤2.0%. In this example, the transfer was successfully completed because all predetermined acceptance criteria were met.
750 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING t-test), one-way analysis of variance (ANOVA), z-test, F-test, and use of control charts [17, 25]. As previously discussed in Table 16-4, the sample mean values obtained at the originator and participating labs are considered to be equiva- lent because the calculated P-value for each lab is less than the z-critical or t- critical value. This situation is interpreted to mean that the transfer has been successful. Under this type of transfer, participating labs are certiﬁed as qual- iﬁed to perform the tests only after the results they generate unequivocally agree with predetermined acceptance criteria and with the originator lab’s data. Comparative testing is the conventional approach often used for the transfer of analytical methods from AR&D to either QC or contract research organizations (CRO). 16.4.2 Co-validation of Methods Unlike in the case of comparative testing, which requires the existence of fully validated methods, there is no requirement for the existence of a validated method for transfer based on co-validation. In other words, availability of a fully validated method is not a prerequisite for this mode of transfer. This type of transfer is usually employed for transferring methods from one AR&D organization to another ARD organization or from an AR&D unit to a QC lab. Because the receiving labs in this type of transfer participate in all aspects of the ﬁnal validation of the methods, completion of the validation is gener- ally considered proof of the successful transfer of the methods. In that regard the receiving labs become immediately certiﬁed to perform the test and do not require any formal certiﬁcation.Although this mode of transfer is not often used, it is gaining in popularity because of the beneﬁts it offers in terms of reducing the amount of time required to complete a transfer exercise. The other beneﬁts of this transfer is that the use of pre-selected batches is not required because validation experiments are shared between the labs. However, for this approach to work well, prior agreement is reached on the analytical ﬁgures of merit (i.e., linearity, accuracy, intermediate precision, etc.) that each lab will have to include or exclude from the validation (see Chapter 9 for more details on method validation). In some cases, acceptance criteria may be based on the originator’s Method validation SOP for demonstrating accuracy, linearity, precision, repeatability, range, LOD and LOQ (Table 16-6). In the example shown in Table 16-6, independent achievement of the accep- tance criteria by the participating labs is considered sufﬁcient proof for declar- ing that the transfer has been successful. 16.4.3 Revalidation of Methods Revalidation of methods is the approach by which methods are be transferred based on a complete revalidation of already existing fully validated methods. With this mode of transfer no prior agreement is required in deciding what analytical ﬁgures of merit require revalidation. Because use of preselected
DIFFERENT APPROACHES FOR TECHNICAL TRANSFER 751 TABLE 16-6. Validation of Analytical Figures of Merit; Example of Acceptance Criteria Analytical Figures of Merit Acceptance Criteria Assay Recovery (3 × 3 levels of concentration) 95–105% %RSD ≤2.0% Completeness of extraction ≤1% Linearity (n ≥ 6) Correlation coefﬁcient (r) ≥0.999 Y-intercept ≤2.0% Residual standard deviation ≤2.0% Range 70–130% of label claim Precision/repeatability n ≥ 6, %RSD ≤ 2.0% Intermediate n ≥ 6, %RSD ≤ 2.0% LOD S/N ≥ 3 : 1 LOQ S/N ≥ 10 : 1 and %RSD(n ≥ 5) = 10–20% well-characterized batches is also not required, the decision to revalidate is based solely on the requirements of prevailing SOPs at the receiving lab which do not require any tacit approval by the originator lab. The other aspect of this mode of transfer is that it does not normally require comparison of data generated at the receiving lab with data previously reported by the originator lab. The receiving labs are certiﬁed to perform the tests once they complete revalidation of the methods. This mode of transfer is sometimes employed for transferring methods from one AR&D organization to another AR&D organization or from an AR&D unit to a QC lab or CRO. Though this type of transfer can be the simplest mode of transferring methods, it may also be the most time-consuming approach because all aspects of an already existing method will have to revali- dated. On the contrary, if timing of the revalidation is coordinated in a manner that coincides with the validation of the methods by the originator lab, con- siderable time savings can be achieved because the receiving or participating labs will not have to wait for the originator lab to complete validation of the method before they start their own revalidation exercises. Both activities can occur in parallel and not in the usual sequential fashion that tends to charac- terize all the other modes of transfer. However, a potential drawback for not waiting before embarking on revalidation is that any time saving that may have been gained by the receiving lab would be erased when the originator lab decides to change the method in course of their validation exercise because of last-minute discovery of unexpected analytical issues. Under those circum- stances, both labs may now have to divert resources to perform additional experiments in order to resolve the unexpected analytical issue. Though not a necessary requirement for this mode of transfer, it may still be prudent for the
752 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING participating labs to show that by using their versions of the methods, com- parable data with the originator is obtained for the assay of similar or identi- cal batches of the same pharmaceutical dosage form. The importance of showing comparability is borne out by the fact that subtle differences in the acceptance criterion applied for accuracy—for example, 95–105% versus 95.0–105.0% stipulated in the different local SOPs—could potentially con- tribute to instances of nonagreement of results between the originator and receiving labs. This fact is illustrated by the example of an assay criterion set to 95.0%, in which case a value of 95.1% would fail this criterion but would pass a criterion of 95% simply because values obtained must ﬁrst be rounded to the same number of decimal places as in the acceptance criteria before com- parison against the acceptance criterion can be performed. 16.4.4 Waiver of Transfer Waiver is the mode of transfer in which no interlaboratory cross-over testing is performed. This is the least used mode of transfer, and it is evoked only under certain special circumstances. An example of such a circumstance is when the method to be transferred can universally be acknowledged and accepted as relying on technologies that are considered standard and routine analytical techniques that have been in use at the receiving lab for a consid- erable period of time. Identiﬁcation by visual examination and uniformity of dosage unit by a weighing operation are two examples that merit considera- tion for waiver transfer. Another circumstance under which a waiver may be justiﬁed is when it can be proven that an earlier version of a method has rou- tinely been used to test products at the receiving lab facility. A strong case for waiver consideration is when it can be demonstrated that differences between the earlier and newer version of the method are attributable mainly to minor editorial revisions to the method and changes involving a switch from a shorter to a longer column of the same column chemistry or a change in the sample preparation procedure by changing the sequence of addition of extraction solvent or an increase in shake or sonication time to account for a more robust extraction of analytes. A poignant argument that can be made for waiver of transfer is when per- sonnel from the lab where the methods were originally developed and vali- dated are transferred to a brand new lab in a completely different facility. In this case the granting of waiver is justiﬁed because the expertise required for performing the methods already exists among the personnel at this new site assuming that any new personnel performing testing in the different facility of the same company have been adequately trained using the intended ana- lytical modalities. In spite of such arguments, it must be noted that even when a waiver trans- fer is judged to be justiﬁed and acceptable, it may still be prudent to expect a minimum interlaboratory cross-over testing to provide continued assurance that the receiving lab can reliably and competently perform the tests.
POTENTIAL PITFALLS DURING TECHNICAL TRANSFER 753 16.5 POTENTIAL PITFALLS DURING TECHNICAL TRANSFER AND MANUFACTURING Because the success or failure of any technical transfer is judged primarily on the merits of the agreement data between the originator and participating labs generated using HPLC, a number of factors must be taken into consideration to ensure the mitigation of differences in results. 16.5.1 Sample Handling The impact of sample handling as innocuous as it may appear can have a sig- niﬁcant impact on the interpretation of results. Figure 16-4 shows the presence of an unknown peak (i.e., leachable peak B) that appeared in the chro- matogram of a sample that was prepared by a chemist in a receiving lab but was absent in the chromatogram from the originator lab. Follow-up investi- gation conﬁrmed that the source of the unknown peak initially reported by Figure 16-4. Leachable peaks from nitrile gloves found in the sample. HPLC condi- tions: Column temperature 35°C, column: YMC ODS-AQ, S-3, 120A, 3.0 mm × 150 mm, wavelength, 267 nm. Gradient Mobile phase A: Water/acetonitrile/TFA (950/50/1, v/v/v). Mobile phase B: Water/acetonitrile/TFA (50/950/1, v/v/v). Injection volume, 15 mL; ﬂow rate, 0.8 mL/min.
754 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING the receiving lab as degradation peaks was indeed a leachable peak from the nitrile gloves that the chemist wore during the preparation of the samples. Inci- dents such as this goes to highlight the need to exercise caution in the choice of gloves that can be worn during sample preparation procedures [26, 29]. During the execution of sample preparation procedures, care should be taken to avoid spillage of solvents onto gloves, and steps should be taken to replace soiled gloves with new ones. Sonication is a popular sample preparation procedure that is widely used for sample preparation of solid dosage forms such as tablets and capsules. However, due to the intense sound waves that sonicators produce, different models of sonicators occasionally produce different degrees of local hot spots [26, 27]. Also, sonication may also be dependent on where the solution is placed in the bath, and the water level in the bath. The chromatograms in Figure 16-5 show increased formation of two degradation product peaks A and B that occurred in a sample as the sonication time was extended from 20 to 30 minutes. Due to the potential formation of degradation peaks that could contribute to nonagreement between results from different labs, explicit instructions about the duration of the sonication time that should be applied to the samples, power output of the sonicator, level of water in the sonicator, and where samples should be placed within the sonicator should always be provided [26–29]. Another source that contributes to frequent differences in results during technical transfers is inefﬁcient extraction. This is often attributed to the Figure 16-5. Degradation product peaks A and B formed from prolonged sonication of samples.