HPLC for Pharmaceutical Scientists 2007 (Part 16)

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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HPLC for Pharmaceutical Scientists 2007 (Part 16)16THE ROLE OF HPLC IN TECHNICALTRANSFER AND MANUFACTURINGJoseph Etse16.1 INTRODUCTIONAnalytical technology transfer and manufacturing is the mechanism by whichknowledge acquired about a process for making a pharmaceutical active ingre-dient or dosage form during the clinical development phase is transferredfrom research and development to commercial scale-up operation or sharedbetween internal groups or with third parties. Analytical technology transferguarantees that laboratories can routinely execute tests, obtain acceptableresults, and be able to accurately and independently judge the quality of com-mercial batches. One of the most important analytical technology transfers ishigh-performance liquid chromatography (HPLC) methods. The success orfailure 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 thephase 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 theICH guidelines on validation will be required [4–7]. A full description ofmethod validation is provided in Chapter 9.HPLC for Pharmaceutical Scientists, Edited by Yuri Kazakevich and Rosario LoBruttoCopyright © 2007 by John Wiley & Sons, Inc. 735736 THE ROLE OF HPLC IN TECHNICAL TRANSFER AND MANUFACTURING16.2 PREREQUISITES FOR TRANSFER OF HPLC METHODS16.2.1 Availability of Either Fully or Partially Validated MethodsA prerequisite for the transfer of analytical technology is the establishment offully validated methods in accordance with the International Council on Har-monization (ICH) [4, 5], United States Pharmacopeia (USP) [6] and EuropeanPharmacopeia (EP) [7] guidelines for method validation, the existence of afinal synthetic process for the active pharmaceutical ingredients (APIs), andfinal market image of the pharmaceutical dosage form. Method developmentand validation usually parallels the API and pharmaceutical dosage formdevelopment. It progresses from very rudimentary Tier 1 methods with limitedvalidation as shown in Table 16-1 through to Tier 2 methods and culminatingin Tier 3/registration-type methods [8–10]. Differences between methods from Tier 1 through Tier 3 are due to theextent of validation of the analytical figures of merit that is performed [3].During early development of the active pharmaceutical ingredient and earlydosage form development, emphasis is placed on speed and quantitation ofthe API. At this stage, methods rely on the use of short columns, fast flows,and very minimum validation to quickly identify the most desirable syntheticroute for the API that will produce an adequate impurity profile (overall yieldmay not be optimized at this stage) and most desirable prototype formulationsand 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 IVAnalytical Figures of Merit Tier 1 Tier 2 Tier 3 Registration1. 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 permissi ...