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Traditional process validation ´«Í³¹¤ÒÕÑéÖ¤

5.18. In the traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility. 5.18.

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5.19. The number of batches manufactured and the number of samples taken should be based on quality risk management principles, allow the normal range of variation and trends to be established and provide sufficient data for evaluation. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.

5.19. Éú²úÅú´ÎÊýºÍÈ¡ÑùÑùÆ·ÊýÁ¿¶¼Ó¦»ùÓÚÖÊÁ¿·çÏÕ¹ÜÀíµÄÔ­Ôò£¬Èç¹ûÄܹ»Ìá

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5.21. A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge. 5.21.

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5.22. Process validation protocols should include, but are not limited to the following: 5.22.

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i. A short description of the process and a reference to the respective Master Batch Record; i.

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ii. Functions and responsibilities; ii.

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iii. Summary of the CQAs to be investigated; iii.

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iv. Summary of CPPs and their associated limits; iv.

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v. Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion;

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vi. List of the equipment/facilities to be used (including

measuring/monitoring/recording equipment) together with the calibration status; vi.

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vii. List of analytical methods and method validation, as appropriate. vii.

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viii. Proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected; viii.

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ix. Additional testing to be carried out with acceptance criteria;

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x. Sampling plan and the rationale behind it; x.

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xi. Methods for recording and evaluating results; xi.

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xii. Process for release and certification of batches (if applicable). xii.

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Continuous process verification ³ÖÐø¹¤ÒÕÈ·ÈÏ

5.23. For products developed by a quality by design approach, where it has been scientifically established during development that the established control strategy provides a high degree of assurance of product quality, then continuous process verification can be used as an alternative to traditional process validation.

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5.24. The method by which the process will be verified should be defined. There should be a science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realisation. This should also include regular evaluation of the control strategy. Process Analytical Technology and multivariate statistical process control may be used as tools. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.

5.24. Ó¦µ±Ã÷È·¹ý³Ì²ÉÓÃÄÄÖÖ·½·¨½øÐÐÑéÖ¤£¬Ó¦¸ÃÓÐÕë¶ÔÔ­¸¨ÁÏ¡¢¹Ø¼üÖÊÁ¿ÊôÐԺ͹ؼü¹¤ÒÕ²ÎÊýµÄ»ùÓÚ¿ÆÑ§»ù´¡µÄ¿ØÖƲßÂÔÒÔÈ·±£²úƷʵÏÖÒªÇóµÄÖÊÁ¿±ê×¼£¬ÕâÒ²°üÀ¨¶Ô¿ØÖƲßÂԵ͍ÆÚÆÀ¹À¡£¹ý³Ì·ÖÎö¼¼ÊõºÍ¶à±äÁ¿µÄͳ¼ÆÑ§ÊֶοÉÒÔ×÷Ϊ¹¤¾ßʹÓá£Éú²úÉÌÐèҪȷ¶¨ºÍ½»´ú±ØÐëÉú²ú¶àÉÙÅú´Î²Å¿ÉÒÔ±íÃ÷¹¤ÒÕÄܹ»³ÖÐøÉú²ú³öÓÅÖʲúÆ·µÄ¸ßˮƽ±£Ö¤¶È¡£

5.25. The general principles laid down in 5.1 ¨C 5.14 above still apply.

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Hybrid approach »ìºÏÐÍ·½·¨

5.26. A hybrid of the traditional approach and continuous process verification could be used where there is a substantial amount of product and process knowledge and understanding which has been gained from manufacturing experience and historical batch data.

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5.27. This approach may also be used for any validation activities after changes or during ongoing process verification even though the product was initially validated using a traditional approach.

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Ongoing Process Verification during Lifecycle ÉúÃüÖÜÆÚÖеÄÁ¬Ðø¹¤ÒÕÈ·ÈÏ

5.28. Paragraphs 5.28-5.32 are applicable to all three approaches to process validation mentioned above, i.e. traditional, continuous and hybrid. 5.28.

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5.29. Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated.

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5.30. The extent and frequency of ongoing process verification should be reviewed periodically. At any point throughout the product lifecycle, it may be appropriate to modify the requirements taking into account the current level of process understanding and process performance.

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