Metrology in pharmaceutical production

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1 Metrology in pharmaceutical production 22/05/ Metrology in pharmaceutical production Metrologidag 2013 Lorenzo Carli, Ph.D. lzcl@novonordisk.com Contributions from: Jan Lasson Andreasen (R&D) Kirsten Byrialsen (Global metrology)

2 Metrology in pharmaceutical production 22/05/ Table of contents Novo Nordisk A/S: Facts and Figures Global Metrology at Novo Nordisk Metrology and Calibration at Device, Manufacturing and Sourcing (DMS) site Hillerød Novo Nordisk need for comparability and traceability

3 Metrology in pharmaceutical production 22/05/ Novo Nordisk at a glance Novo Nordisk is a global healthcare company with 90 years of innovation and leadership within diabetes care Thanks to dedicated research into proteins, Novo Nordisk also holds leading positions within: Growth hormone therapy Hormone replacement treatment Haemophilia

4 Metrology in pharmaceutical production 22/05/ Our global presence (ca employees) Global headquarters Denmark Regional headquarters China, Japan, Switzerland, US Strategic manufacturing Brazil, China, Denmark, France, US R&D facilities China, Denmark, US International Affiliates or offices in 75 countries

5 Financial performance Metrology in pharmaceutical production 22/05/2013 5

6 Metrology in pharmaceutical production 22/05/ Why do we measure at NN? Obtain knowledge of production processes Form basis for calculations Identify non conformities (NCs) Document quality to regulatory bodies To secure patient safety product quality process performance compliance with external requirements To provide data for making decisions In God we trust; all others must bring data. (W. Edwards Deming) "If you cannot measure it, you cannot improve it." (Lord Kelvin)

7 Metrology in pharmaceutical production 22/05/ Measurands at NN: some examples Voltage Volume Lenght Frequency UV absorbance Pressure Concentration Air flow Liquid flow Air humidity Force ph Conductivity Colour

8 Metrology in pharmaceutical production 22/05/ How do we ensure that our instrument measures correctly?

9 Metrology in pharmaceutical production 22/05/ Calibration Definition: International Vocabulary of Metrology Basic and General Concepts and Associated Terms JCGM 200:2012 In short : process where the value of a measurement equipment is compared to a value of a standard with documented uncertainty and metrological traceability

10 Metrology in pharmaceutical production 22/05/ Why do we calibrate? Calibration provides documentation for: The error of the measuring equipment Important input for the quality of the measurement results Traceability provides documentation for: comparability of measurement results

11 Measurement uncertainty Metrology in pharmaceutical production 22/05/ The estimate of the difference between a measured value and the true value. ISO :1998 Geometrical Product Specifications (GPS) -- Inspection by measurement of workpieces and measuring equipment -- Part 1: Decision rules for proving conformance or non-conformance with specifications

12 Metrology in pharmaceutical production 22/05/ Metrological traceability Definition: property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations, each contributing to the measurement uncertainty International Vocabulary of Metrology Basic and General Concepts and Associated Terms JCGM 200:2012

13 Traceability in Novo Nordisk Metrology in pharmaceutical production 22/05/

14 Metrology in pharmaceutical production 22/05/ International definition of the temperature scale DK US FR BR CNR National standard Technol. Institute NIST LNE InMetro NIM NN Working Standard Site DK Site Clayton Site Chartres Site MOC Site Tianjin Operator with measuring instrument

15 Metrology in pharmaceutical production 22/05/ No mutual recognition of Reference Standards

16 Metrology in pharmaceutical production 22/05/ Some key messages Measuring equipment cannot be traceable in and of itself. What is traceable about the equipment is the determination of its errors during calibration. Only the result of a measurement or the value of a standard can be traceable. Traceable equipment= equipment potentially able to produce traceable measuring results. A standard cannot be traceable, but the value assigned to it can.

17 Metrology in pharmaceutical production 22/05/ Metrology and Calibration at Device, Manufacturing and Sourcing (DMS)

18 Metrology in pharmaceutical production 22/05/ Keywords and challenges Innovation High volume Complexity Outsourcing Regulations Safety

19 Metrology in pharmaceutical production 22/05/ Overview of devices (durable and prefilled) 1994 NovoFine 30 World s first 30 gauge insulin pen needle 1996 NovoPen Innovo 2002 NovoPen Jr 2001 InnoLet 2002 FlexPen

20 Metrology in pharmaceutical production 22/05/ New metrology Lab in fall 2011 (at site Hillerød) 5 Zeiss CMMs and a Zeiss Metrotom CT scanner (plus a GE Phoenix Nanotom located by R&D). GE Phoenix Nanotom Zeiss Metrotom 1500 Zeiss CMM Accura II

21 Range of dimensional CT tasks Injection needles (SS) Ø 0.3 mm x 20 mm Complex plast components max Ø 20 mm x 150 mm

22 Metrology in pharmaceutical production 22/05/ CT-scanning in NN Device Development Ready for assembly? Part geometry inspection Material Interior analysis Ready for test? Assembly analysis Why does it not work? Failure analysis

23 Metrology in pharmaceutical production 22/05/ Relevance of Metrology at NN 1. Product development (CT-scanner) 2. Mould validation (CMM and CT-scanner): geometrical and dimensional measurements of all the cavities and of a few shots to verify tolerances and process repeatability. 3. Shrinkage tests (to determine time related variations of plastic component dimensions) 4. In line process control (specifically designed fixtures for key-measurements to test the goodness of the moulding process or of a certain batch) 5. Visual inspection (by operators, to verify presence of defective components in a specific batch) 6. Quality Control (specifically designed fixtures for measuring key parameters on large number of components) 7. Special tasks (CT scanner): failures investigation, internal features measurements and assembly analysis 8. Vision systems (cameras): in-line measurements during assembly phase

24 Traceability Action Metrology in pharmaceutical production 22/05/ Dimensional and geometrical Metrology* Mould validation INJECTION MOULDING Sampling TIMELINE 0 Visual inspection Few min. IPC Key Meas. 1 or 2 h Quality Control (QC) 1 or 2 days

25 Metrology in pharmaceutical production 22/05/ Novo Nordisk need for comparability Production in DK, USA, France, Brazil, Japan, China Same product quality regardless of production site Same quality requirements for analytical results regardless of production site Need for global comparability of measurement results in order to document the quality over time and between regions Without traceability no comparability

26 Metrology in pharmaceutical production 22/05/ Novo Nordisk needs for improved metrology 1) Uncertainty evaluation for industrial metrology: New methods/standards/strategies when few or no information about measuring repeatability and reproducibility. 2) Uncertainty evaluation of plastic components: Software tools for uncertainty evaluation based on computer simulations: Reducing cost and time. 3) CT scanner traceability : Lack of calibrated artefacts, standards and procedures. Validation is needed. 4) Data fusion (and intelligent data processing): Merging high resolution (Magnification) CT-scanner point cloud with low resolution ones of the overall component shape. 5) Multisensor Metrology: Merging information obtained by CMM measurements with dense information point clouds obtained with CT-Scanner. 6) GPS and Tolerancing: Tolerance chain is usually very complex. The overall GPS system should be re-considered to be adapted to real industrial metrology i.e. a more simplified approach.

27 Metrology in pharmaceutical production 22/05/ JRP IND59 Multi-sensor metrology for microparts in innovative industrial products (Microparts) Start date: 01 June 2013 The overall goal of JRP IND59 is for a significant improvement of state-of-the-art measurement capabilities of multi-sensor coordinate measuring machines for microparts used, e.g. in automotive, medical and optical applications.

28 Metrology in pharmaceutical production 22/05/ Yes, it is a mammoth! Lorenzo Carli lzcl@novonordisk.com