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PAT & QbD SUPPLEMENT


the product and its manufacturing process can create a basis for more flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided in the registration application’1


. The USP has started a similar approach in its


draft General Chapter on inorganic impurities and heavy metals20


, where a performance-based


approach has been introduced for selection of appropriate analytical technology. Flexibility is intended in the choice of method as long as the technique can meet the defined accuracy, sensitivity and specificity. The proposed concept is intended to


stimulate further discussion and engagement within industry and especially between industry and regulatory authorities regarding QbD for analytical procedures. For the next steps, regulatory perception and possible concerns needs to be discussed and addressed appropriately. A lot of details still need to be clarified and experience gained, such as the establishment of ATPs for a wider range of CQAs, clarification of how a Quality by


References


1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) http://www.ich.org/products/guidelines/quality/ article/quality-guidelines.html ICH Q8 (R2): Pharmaceutical Development (2009)


2. ICH Q9: Quality Risk Management (2005) 3. ICH Q10: Pharmaceutical Quality System (2008)


4. ICH Q11: Development and Manufacture of Drug Substances


(chemical entities and


biotechnological/biological entities) Draft Pre Step 2 (2010)10


5. P. Borman, P. Nethercote, M. Chatfield, D. Thompson, K. Truman, The Application of Quality by Design to Analytical Methods. Pharmaceutical Technology, October 2007, 142-152


6. P.F. Gavin, B.A. Olsen, A quality by design approach to impurity method development for atomoxetine hydrochloride (LY139603). J.Pharm.Biomed.Anal. 46 (2008) 431-41


7. M. Schweitzer, M. Pohl, Implications and Opportunities of Applying QbD Principles to Analytical Measurements. Pharmaceutical Technology, Feb. 2010, 2-8 http://pharmtech. findpharma.com/pharmtech/article/articleDetail.jsp? id=654746


8. European Medicines Agency: Compliance and Inspection Report: Results of the Sampling and Testing Programme for the year 2009. (Nov. 2010) EMA/INS/S&T/477571/2010 http://www.ema.europa.eu/docs/en_GB/document_ library/Report/2010/08/WC500095740.pdf


9. ICH Q2 (R1): Validation of Analytical Procedures: Text and Methodology (2005)


10. United States Pharmacopeia, Section <1010> ‘Analytical Data – Interpretation and Treatment


24


European Pharmaceutical Review Volume 16 | Issue 3 | 2011


Acknowledgements I would like to acknowledge the entire EFPIA ADS topic team, the PhRMA ATG group and all colleagues contributing to the described concepts. In particular, many thanks to Phil Nethercote (GlaxoSmithKline) for helpful comments and suggestions to this paper.


Dr. Joachim Ermer is currently Head of Quality Control Services Chemistry at sanofi-aventis in Frankfurt, Germany, which includes also the global sanofi- aventis reference standard unit. He studied Biochemistry and completed his PhD studies in enzymology in 1988 at University


of Halle, Germany. Following a post-doc fellowship in Cambridge, UK, Joachim Ermer joined Hoechst AG, Frankfurt in 1991 as Head of Laboratory in R&D. In 2001, he changed to a global position as Director of Analytical Processes and Technology. From 2005 to 2010, Joachim Ermer worked as Head of Quality Control Frankfurt Chemistry.


11. Consensus paper of the Working Group Quality Control/Pharmaceutical Analysis of the German Pharmaceutical Society (DPhG); http://www.pharmchem.tu-bs.de/forschung/ waetzig/englisch/dphg_pospapier_eng03.pdf


12. EURACHEM/CITAC Guide: Quantifying uncertainty in analytical measurement. 2nd edition. 2000. http://www.measurementuncertainty.org


13. D. Hoffman, R. Kringle, A total error approach for the validation of quantitative analytical methods. Pharm.Res. 24 (2007) 1157-64


14. J. Ermer: Chapter 2.3 Accuracy in: J. Ermer, J.H.McB. Miller (Eds.) Method Validation in Pharmaceutical Analysis. A Guide to Best Practice. Wiley VCH, Weinheim (2005) 77-79


15. J.B. Crowther, M.I. Jimidar, N. Niemeijer, P. Salomons: Chapter 15 in: J.M. Miller, J.B. Crowther, eds.: Analytical chemistry in a GMP environment. John Wiley, New York (2000) 448-9


16. European Pharmacopoeia: Technical Guide for the elaboration of monographs, 5th Edition (2010)


17. ISO 5725-2, Basic method for the determination of repeatability and reproducibility of a standard measurement method (1994)


18. J. Ermer et al., Precision from drug stability studies. Investigation of reliable repeatability and intermediate precision of HPLC assay procedures. J. Pharm. Biomed. Anal. 38/4 (2005) 653-663


19. European Medicines Agency, GUIDELINE ON THE USE OF NEAR INFRARED SPECTROSCOPY BY THE PHARMACEUTICAL INDUSTRY AND THE DATA REQUIREMENTS FOR NEW SUBMISSIONS AND VARIATIONS (Draft) Feb. 2009


20. United States Pharmacopeia, General Chapter on Inorganic Impurities: Heavy Metals (Draft http://www.usp.org/pdf/EN/USPNF/2008-04- 10InorganicImpuritiesStim.pdf


Design approach should be described in a regulatory submission, or further under- standing the implication of a Quality by Design approach on current method validation and transfer guidance.


GLOSSARY


Analytical Target Profile (ATP) The combination of all measurement performance criteria that direct the method development process. An ATP would be developed for each of the attributes defined in the control strategy and defines what a method has to ‘measure’ and to what level the measurement is required (i.e. performance level characteristics: e.g. precision, accuracy, working range, sensitivity and the associated performance criterion)7


Control Strategy (Process) A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control3


Critical Quality Attribute (CQA) A physical, chemical, biological or micro - biological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality1


Lifecycle All phases in the life of a product from the initial development through marketing until the product’s discontinuation1


Method Operable Design Region (MODR) Range of method factors and parameters, within which the performance of the analytical procedure is demonstrated to conform to the requirements (e.g. ATP, or validation acceptance criteria)


Process Analytical Technology (PAT) A system for designing, analysing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality1


Quality by Design (QbD) A systematic approach to development that begins with predefined objectives and emphasises product and process under - standing and process control, based on sound science and quality risk management1


Quality Target Product Profile (QTPP): A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product1


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