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www.biopharminternational.com Quality and Regulatory Sourcebook March eBook 2023 BioPharm International ® 25 Validation to confirm that the procedure is fit for its in- tended purpose, and may include "traditional" procedure validation, transfer, and verification (10,16). APPQ is inspired by the term "process performance qualification" included in FDA's guidance on process validation (17), referring to activities that confirm that the commercial ma nufact ur ing process design a nd per for- mance are as expected. • As per USP <1220>, "AP validation" refers to a broader concept that encompasses all activi- ties that confirm that a procedure is suitable for use a nd t hat ta ke place over t he ent ire APLC, not just activities restricted to stage 2 and "traditional validation." Q2(R2) still de- scribes the "traditional" procedure validation concept only. The more holistic concept of val- idation introduced in USP <1220> expands the well-known activities to integrate them into the procedure life cycle and include them in a process that incorporates the ATP. Q2(R2) does not mention ATP and does not emphasize: the link between the ATP performance character- istics and the intended purpose of the report- able value; and the probability assessment of making a wrong decision. A high-level summary of new principles included in Q2(R2) is provided in the following sections. TABLE II. Comparison of terminology and elements between International Council for Harmonisation (ICH) Q14 and United States Pharmacopeia (USP) General Chapter <1220>–Stages 2 and 3. APLC is analytical procedure life cycle. Stages of APLC (<1220>) APLC Elements ICH Q14 USP GC <1220> Stage 2: Analytical Procedure Performance Qualification Procedure Validation This stage is not covered in Q14. For procedure validation, refer to ICH Q2(R2). In USP <1220>, the framework proposed to manage procedure life cycle encompasses stage 2 Analytical Procedure Performance Qualification. This may include procedure validation, transfer, and verification. In USP <1220>, "procedure validation" has a broader meaning than in Q2(R2), since it encompasses all activities that take place to ensure that the procedure is fit for use throughout the procedure life cycle. Stage 3: Ongoing Procedure Performance Verification Ongoing Procedure Performance Verification "Ongoing monitoring of selected analytical procedure outputs is recommended to look for any trends. Review of analytical procedure outputs facilitates the procedure lifecycle management and enables proactive intervention to avoid failures." Little guidance is provided on stage 3, which is an essential piece of the analytical procedure life cycle. Stage 3: Ongoing Procedure Performance Verification "ensures that the analytical procedure remains in control during routine use and thus continues to meet the ATP criteria. This stage includes both routine monitoring of data linked to the performance of the analytical procedure and evaluation of the procedure's performance after changes to determine if the analytical procedure continues to be fit for purpose." Life Cycle Management — "Changes to analytical procedures can occur throughout the product lifecycle and could involve modification of existing procedures or a complete replacement including introduction of a new technology. The tools and enablers discussed in ICH Q12 are applicable to analytical procedures." "Changes to analytical procedures may be needed over the life cycle and can be prompted by several events including needed changes identified through a routine monitoring program, the adoption of new technology, or changes to the ATP. Such changes should be risk assessed for their impact to determine the appropriate activities required. In addition, appropriate change management approaches and documentation should be used when making changes to a procedure." Lifecycle Management Post-Approval Changes of Analytical Procedures "The use of different elements of the enhanced approach can facilitate management and regulatory communication of post-approval changes." This is not described. However, <1220> discusses quality risk management as a comprehensive process to allow for managing procedure life cycle and analytical condition changes. All Stages Development of Multivariate Analytical Procedures Section 8. Development of Multivariate Analytical Procedures Not described in <1220>. Few elements are described in USP <1039>, which requires review to become better connected to USP <1220> and provide more guidance on development and validation of multivariate procedures and the multivariate model life cycle. All Stages Development of Real Time Release (RTR) Testing Section 9. Development of Analytical Procedures for Real-Time Release Testing: Special Considerations Not described in <1220>. Few elements are described in USP <1039>, which should be revised to provide guidance for RTRT and process control strategies using process analytical technologies (PATs). These should all be connected to USP <1220> at some point.