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www.biopharminternational.com Quality and Regulatory Sourcebook March eBook 2023 BioPharm International ® 23 Validation and allow for regulatory f lexibility, possibly reduc- ing the burden on industry. Q14 mentions that ATP could also form the basis of a PACMP, which would allow changes between technologies to be reported at a lower reporting category, provided that the pre- viously established performance requirements for a change are met (1). Although Q14 does not clearly emphasize the role of the MODR in the PACMPs, this element could build the basis for allowing suitable risk management, enabling comprehensive analyt- ical changes management within the qualified op- erating ranges while identif ying which conditions meet ATP requirements without running additional experimentation or validation. From a compendial perspective, the inclusion of validated MODR in com- pendial monographs can provide a certain degree of f lexibility for risk management to ensure fitness for use ("operating range procedure" instead of "tradi- tional fixed-point procedure"). Other analytical QbD (AQbD) elements may be potentially incorporated into monographs, such as the ATP, replication strat- egy (e.g., number of injections; sample and standard preparation) and analy tical control strateg y (ACS [e.g., system suitability and any relevant attribute/ requirement]). The ATP and AQbD principles were introduced by joint working groups of the European Federation of the Pharmaceutical Industries and As- sociations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) in 2010 (2,3), and later in a few USP stimuli articles (4–9) and USP <1220> (10). The MODR was introduced by several authors in 2010 (11,12), in USP <1220> (10) and in ICH Q14(1). The first official mention of MODR by health authorities was in the European Medicines Agency (EMA)–FDA pilot program report (13). Key aspects in Q14 include the following: • Minimal (traditional) or enhanced approaches to a n a ly t ica l procedu re de velopment ca n be applied. • The enhanced approach offers a systematic way of developing analytical procedure and manag- ing knowledge. This approach is similar to stage 1 described in USP <1220>. • Knowledge and quality risk management (QRM) are presented as key enablers of the enhanced approach as well as the definition of ATP. • Other elements included in the enhanced ap- proach are the use of multivariate experiments, establishment of an analytical procedure con- trol strategy, and definition of reporting catego- ries of ECs, proven acceptable ranges (PARs), or MODR. All this information can be used to build the lifecycle change management plan and can be shared in the regulatory dossiers. • Q14 highlights the important role of robustness assessment during procedure development. • Q14 emphasizes the importance of establish- ing analytical procedure control strategy and recommends ongoing monitoring of selected analytical procedure outputs to look for any trends considering the analytical procedure control strateg y as major enabler. However, little guidance is given on how to conduct on- going monitoring. • Q14 brings a section dedicated to develop- ment of mu lt iva r iate a na ly t ica l procedure and real-time release testing (RTRT), building off existing guidance (e.g., Q2(R2) and Q13). It presents the multivariate model lifecycle and provides support for the use of multivariate prediction models for risk assessment. • A section on submission of analytical proce- dure–related information has also been in- cluded to facilitate harmonization of the level of details submitted by applicants. As discussed in Part I of this article, the ICH Ex- pert Working Group (EWG) decided to split the APLC stages into Q14 and Q2(R2) guidelines, attempting to not significantly change the structure of Q2(R2) from its previous version (14). Although both guide- lines present some level of interconnectivity, stron- ger con nec t iv it y cou ld have been bui lt to faci l i- tate the knowledge management. QRM should be emphasized, because this is what connects all stages. Tables I and II show a comparison of terminology and elements between Q14 and USP <1220>. Q2(R2) Draft Guideline: Validation of Analytical Procedures ICH Q2(R2) applies to new or revised AP used for re- lease and stability testing of commercial drug sub- stances and products (chemical and biological/bio- technological). However, it can be applied to support clinical studies development, as well as other types of products, with appropriate regulatory authority con- sultation as needed (15). Q2(R2) can also be applied to other analytical procedure used as part of the control strategy (Q8–Q10) following a risk-based approach (15), enlarging its scope to validate procedures to be used for manufacturing process monitoring and other stages involved in the pharmaceutical product life cycle. Q2(R2) can be seen (in part) as similar to stage 2 described in USP <1220>; however, the two documents have the following significant differences: • Q2(R2) does not include guidance for proce- dure transfer and verification, which are part of stage 2 in USP <1220>. • The concept of "analytical procedure valida- tion" differs between Q2(R2) and USP <1220>. • As per USP <1220>, "Analytical procedure per- formance qualification" (APPQ) refers to all ac- tivities performed in APLC stage 2, conducted