Quality? Who Decides? Mitzi M. Rettinger Vice President, Sales & Marketing Cerilliant Corporation Round Rock, TX

Transcription

1 Quality? Who Decides? Mitzi M. Rettinger Vice President, Sales & Marketing Cerilliant Corporation Round Rock, TX

2 Harmonize Methods by Raising the Bar on Calibrators A significant contributor to variability in the accuracy of reported results is the quality of the calibrators used. Laboratories can begin by purchasing calibrators or critical starting materials from accredited companies. Accreditations like ISO Guide 34 and ISO ensure consistency in quality from manufacturer to manufacturer, right? 2

3 Quality ISO Definition: Degree to which a set of inherent characteristics fulfils requirements Explained in plain English: The quality of something can be determined by comparing a set of inherent characteristics with a set of requirements. If those inherent characteristics meet all requirements, high or excellent quality is achieved. If those characteristics do not meet all requirements, a low or poor level of quality is achieved. According to this definition, quality is a relative concept. By linking quality to requirements, ISO 9000 argues that the quality of something cannot be established in a vacuum. Quality is always relative to a set of requirements. source: 3

4 Chevrolet Are these the same? V-6 V-8 4

5 Viagra Are these the same? Source: Internet Source: US Pharmacy 5

6 Grass Which did you mean? Grass Grass 6

7 Beef hamburgers The Same? Fresh Ground Beef Contains Pink Slime 7

8 Milk Are these the same? Milk Organic Milk 8

9 Paris Where do you prefer to go? Paris, Texas Paris, France 9

10 Accreditations interpretations and implementations vary do you know what you are getting?

11 ISO Guide 34 what s in the scope? General requirements for the competence of reference material producers Accreditation to ISO Guide 34 does not mean the manufacturer is producing CRMs The 3 rd edition provides two designations Certified Reference Materials (CRMs) Non-certified Reference Materials Requirements for non-certified reference materials are less stringent and do not require: Detail of stability reporting Detail of homogeneity reporting Characterization of the material Assignment of property values and their uncertainties Establishment of uncertainty budgets Establishment of metrological traceability (SI units) What products are in-scope? Were products produced at the accredited site? Accreditations are site specific. Products produced before the manufacturer s accreditation are not covered. It is very important to look beyond page 1 of the manufacturer s ISO certificate 11

12 ISO/IEC what s in the scope? General requirements for the competence of testing and calibration laboratories What materials are covered? Organic vs. inorganic Neat vs. solution What specific tests are covered? Identity / Purity / Residual content What analytical techniques and methods are covered? Compendia methods Internal methods Is the product you are buying in the scope? Were products certified at site of accreditation? Are any elements of the certification out of scope? It is very important to look beyond page 1 of the manufacturer s ISO certificate 12

13 Characterization ISO Guide 34, Section It should be recognized that a reference material needs to be characterized mainly to the level of accuracy required for its intended purpose What techniques are used? Are these techniques suitable? Is TLC or chromatographic purity sufficient? Do the techniques fully characterize the material? Have non-chromatographic impurities been considered? Water? Solvent? Inorganic content? What controls are used to ensure a robust process? Are the techniques validated or verified? Is calibration equipment properly qualified and calibrated? Is instrument performance sufficiently verified? Are multiple methods / techniques / run conditions used? Up to the manufacturer to determine what is appropriate Not required for non-certified Reference Materials 13

14 Material grade & appropriateness of characterization must be considered Important to understand manufacturer s intended use and how material was certified Compound : Reverse T3 (3,3,5 -Triiodo-L-thyronine) Material Grade & Value Assignments Purity (%) Residual Solvent Content (%) Trace Inorganic Content (%) Residual Water Content (%) Purity Factor for Quantitative Use (%) PF Difference from Purity (%) Research Grade Manufacturer Assigned 97 (TLC) NA NA NA 97 NA Research Grade Cerilliant Assigned ** ** Difference between manufacturer assigned purity value and Cerilliant assigned Purity Factor (wt %) Certified Reference Material Synthesized at Cerilliant

15 Mass balance orthogonal approach Cerilliant Process Residual Water USP<921> Validated Residual Solvent GC Headspace Cerilliant validated method or USP<467> Chromatographic Purity Purity & related substances Use at least 2 techniques NMR evaluation Purity Factor/ Potency Residual Inorganic Content Micro ROI based on USP<281> Validated NMR evaluation EA or other PurityFactor 100 ( wt% Solvents) ( wt% H [ 2 15 ChromPurity O) ( wt% Inorganics)]* 100

16 Complete characterization critical Use of chromatographic purity alone can impact instrument/assay performance and introduce significant error into the concentration of the solution Compound Chrom. Purity (%) Residual Solvent Content (%) Trace Inorganic Content (%) Residual Water Content (%) Purity Factor for Quantitative Use (%) PF Difference from Chrom Purity (%) Aldosterone Oxazepam glucuronide 99.9 None Detected (±)-Metanephrine HCl α,25-Dihydroxyvitamin D < Cyanocobalamin (Vitamin B12) None Detected Lorazepam glucuronide T3 (3,3,5-Triiodo-L-thyronine)

17 Impact of hygroscopicity Changes in residual water content over time during storage and handling can impact accuracy of the reference solution concentration and analytical variability Compound First Analysis Date Second Analysis Date First Analysis Water (%) Second Analysis Water (%) Months Stored Between Analyses Change in Water Content Morphine 10/2007 5/ % Vardenafil di HCl 10/2008 1/ % Digoxin (e.g. of Sample Handling) 6/2/2006 Bench top 6/4/2009 Glove box 1.15% 0.56% NA -51% Is it practical to check moisture content before each use? Materials were stored under normal freezer conditions in sealed, screw-cap amber vials. Water content was analyzed by Karl Fisher Coulometry based on USP method <921>. 17

18 Uncertainty neat material purity factor Residual Water Analysis Analysis u kf H2 = O = % w/w Residual Analysis Solvent Analysis Residual Solvent u ovi solvents = = % w/w Chromatographic Purity Purity 0.25% 0.144% u ChromPurity ( ) 0.25% u ( ChromPurity) 0.144% 3 Method repeatability Method repeatability u Appropriate methods Sensitivity, robustness, accuracy robustness, accuracy Specifications Tolerances Mass measurement Inorganic Content Analysis 0.4% ( wt % Inorganic) % Cerilliant Model Purity Purity Factor Uncertainty Factor Uncertainty u pf = 0.292% 18

19 Uncertainty neat material purity factor Residual Water Analysis Analysis u H2 u kf kf O = % w/w w/w Chromatographic Purity Purity 0.25% u ( ) 0.25% u ChromPurity 0.144% ( ChromPurity) 0.144% 3 Method repeatability Appropriate methods Sensitivity, robustness, accuracy robustness, accuracy Specifications Tolerances Purity Factor Purity Uncertainty Factor From Uncertainty Method repeatability u pf = 0.292% Mass measurement to Residual Solvent u pf = 0.165% Analysis Solvent Inorganic Content It would Analysis be easy to ignore and improve the u solvents Analysis Analysis ovi = = % uncertainty calculation. But 0.4% w/w u ( wt % ROI ) Oxazepam 0.231% glucuronide example 3 concentration would be low by 2.37% 19 What is the impact if we didn t consider inorganic content?

20 Uncertainty neat material purity factor u Chromatographic Purity 0.25% ( ChromPurity) % Appropriate methods Sensitivity, robustness, accuracy Specifications Uncertainty would be greatly improved. But Oxazepam glucuronide example concentration will be low by 11.33% What is the impact if we didn t consider any residual content? Purity Factor Uncertainty From u pf = 0.292% to u pf = 0.144% 20

21 Measuring equipment ISO Guide 34, 5.10 measuring equipment shall be properly calibrated, verified, & maintained. Where appropriate, performance checks shall be carried out and recorded The frequency of performance checks shall be determined by experience and based on the type and previous performance of the equipment. ISO/IEC 17025, Equipment and its software used for testing, calibration and sampling shall be capable of achieving the accuracy required. Calibration programs shall be established for key quantities or values of the instruments where these properties have a significant effect on the results Before being placed into service equipment, shall be calibrated or checked to establish that it meets the laboratory s specification requirements.it shall be checked and/or calibrated before use.. 21

22 Measuring equipment Analytical instruments All instruments fully qualified & calibrated IQ by vendor OQ annually System suitability daily good for 24 hours Example: GC System Suitability Separation/resolution Column adsorptivity Injection/column reactivity Cerilliant Approach Identical 5-place balances in 2 different locations can have different minimum weighings assigned Balances Qualified/calibrated in their installed state semi annually by vendor to factory tolerances Calibration verifications weekly across range of balance Calibration daily Calibration verification pre-use for range of weighing NIST-traceable weights Minimum weighings assigned to ensure NMT 0.1% relative error 22

23 Measuring equipment Cerilliant Approach Are you weighing the right amount of material on your balance to ensure an accurate weighing with minimal uncertainty? Cerilliant Minimum Weighing Requirements Balance 7-place 6-place 5-place 4-place Balance Resolution mg mg 0.01 mg 0.1 mg Minimum Weighing 1 mg 3 mg 20 mg 125 mg Cerilliant sets minimum weighings to ensure 0.1% or less relative error 23

24 Control contamination ISO Guide 34, Section shall identify, preserve and separate (i.e. from other chemicals and samples) all candidate materials and reference materials, from the time of processing through to their distribution to users. Synthesis Process controls to control residual impurity profile and ensure homogeneity Cross contamination controls Solution standard manufacturing & dispensing Line clearance / product segregation 100% fresh tubing for each dispensing run Disposable or dedicated syringes Line purge ensures consistency of fill use of solution being filled ensures concentration consistency Evaporation controls Validated cleaning process for all contact parts Segregated and sampled according to a random stratified sampling plan Post ampouling testing to ensure no degradation and verification of homogeneity Validated glassware washing on qualified washers; verified annually DI water system qualified monitored; requalified annually Nitrogen system qualified and medical grade filters on use ports 24 Cerilliant Approach

25 Stability and integrity ISO Guide 34, The reference material producer should ensure that the integrity of the reference material is maintained until the seal has been broken, or up to the point when presented for analysis ISO Guide 34, the reference material producer shall have procedures and service facilities, where appropriate, for ensuring appropriate transport arrangements ISO Guide 34, h the producer shall have a quality system that covers the following arrangements for ensuring adequate storage facilities. ISO Guide 34, Section shall ensure adequate packaging and provide secure storage areas/stock rooms which prevent damage or deterioration of any item or material between characterization and distribution Not required for non-certified Reference Materials 25

26 Stability assessment & reporting Cerilliant approach Accelerated stability studies performed at various conditions One to four week studies at 2-8 C, RT, and 40 C to determine transport requirements (ambient or dry-ice) o Purity changes are assessed o Also supports normal lab use and accidental mishandling o Shipping studies to various locations provided information on transport time and maximum temperature during transit o Validated shipping configurations used Real-time studies establish shelf life Purity and concentration changes assessed New products tested annually until 3-5 years shelf life is established Older lots tested upon release of new lots Cerilliant COA includes stability assessment data to support regulatory requirements. Updates or changes are automatically provided to end-users. 26

27 Stability and integrity storage Cerilliant approach Secure storage with limited access Dedicated material management team Storage units/areas are qualified and thermally mapped All units/areas assigned acceptable temperature range Continuous electronic temperature monitoring with validated system Electronic notification of any trending and excursions to facilities and QA Electronic systems supported by UPS to ensure no loss of data Critical systems and storage units supported by a back-up generator generator performance verified weekly Full electronic traceability of where materials are stored and temperature profiles for life of the product. Storage Temp USP ranges Refrigerate 2 to 8 C Freezer -25 to -10 C Room temperature 15 to 30 C Temperature excursion allowances are based on USP General Notices 10.Preservation, Packaging, Storage, and Labeling 27

28 Short term stability: a summary of accelerated stability findings examples from COAs Testosterone Storage Condition Freezer Mean Kinetic Temperature (MKT) -15 C Time Period Refrigerator 4 C No decrease in purity was Room Temperature 21 C noted after one week. 40 C 40 C Transport/Shipping : Stability data supports transport of this product at ambient conditions. Short Term Storage: Stability data supports short term storage up to 1 year at Refrigerate conditions. Cyclosporin D Mean Kinetic Temperature Storage Condition (MKT) Sub-Freezer -70 C Freezer -15 C Refrigerator 4 C Room Temperature 21 C Time Period No decrease in purity was noted after one week. 40 C 40 C Transport/Shipping : Stability data supports transport of this product at ambient conditions. Short Term Storage: Stability data supports short term storage for no more than 1 month at Freezer conditions. 17 Estradiol Storage Condition inetic Temperatur Time Period Freezer -15 C Refrigerator 4 C No decrease in purity was Room Temperature 21 C noted after one week. 40 C 40 C Transport/Shipping : Stability data supports transport of this product at ambient conditions. Short Term Storage: Stability data supports short term storage up to 1 year at Refrigerate conditions. Sirolimus Storage Condition inetic Temperatur Time Period -70 C Freezer -70 C -15 C No decrease in purity was noted after four weeks. Refrigerator 4 C 3% decrease in purity was Transport/Shipping : Stability data supports transport of this product at MKT not exceeding -15 C over a period of one month. Provides data for transport and normal lab use 28

29 Accelerated stability study example: 25-Hydroxyvitamin D2 & D3 % Purity Hydroxyvitamin D2, 50 µg/ml in ethanol freezer refrigerator Room Temperature 40C Demonstrated instability at RT and elevated temperatures special handling instructions on COA and shipment on dry ice Hours Hydroxyvitamin D3, 100 µg/ml in ethanol Multiple temperatures: RT, Freezer, refrigerate, & 40 C 2 hours to 7 days % Purity freezer refrigerator Room Temperature 40C Hours 29

30 Accelerated stability example: gemfibrozil Stability exhibited at all storage conditions mau VWD1 A, Wavelength=276 nm (LC11008\M D) Catalog Product: G-012, 1 mg/ml in methanol Analysis Method: HPLC/UV Column: Betasil Phenyl 4.6 x 150 mm Mobile Phase: Acetonitrile::0.1% H 3 PO 4 in Water Flow Rate: 1.0 ml/min Wavelength: 276 nm Calibration Curve: Linear Regression Number of Points: 3 Linearity (r): mi Storage Condition/ Test Interval Initial (t=0) 99.9 Freezer (-1 to -25 C) Gemfibrozil solution purity(%) 1 week weeks weeks 99.9 Refrigerate (1 to 15 C) 1 week weeks weeks 99.9 Ambient (18 to 30 C) 1 week weeks weeks 99.9 Elevated (40 C) 1 week weeks weeks

31 Stability real-time stability studies Cerilliant approach Compound Age of Stability Sample Original Purity % Stability Interval Analyzed Conc (mg/ml) Stability Original Interval Testosterone (1.0 mg/ml) Cyclosporin A (1.0 mg/ml) 17ß-Estradiol (1.0 mg/ml) Sirolimus (1.0 mg.ml) 4 years 99.5% 99.4% months 99.9% 99.9% months 99.9% 99.9% years 99.2% 98.9% Concentration acceptance criteria for each of the examples = + 3% and incorporates variability of the analysis. Performed to establish shelf-life 31

32 Uncertainty ISO/IEC 17025, Section all uncertainty components which are of importance in the given situation shall be taken into account using appropriate methods of analysis Guide 34, reference material property needs to be characterized mainly to the level of accuracy required for its intended purpose (i.e. appropriate measurement uncertainty for a property value of a certified reference material). shall define their scope of activities in terms of the types of reference materials (including their sample matrices, if applicable), the properties to be certified and the ranges of the assigned values (and their uncertainties) of the reference materials produce, and their involvement in the performance of testing, calibration and measurements in relation to homogeneity, stability and characterization assessments and their use of subcontractors in these tasks. Not required for non-certified Reference Materials 32

33 Uncertainty Guide 34, shall include, as appropriate: a) details of the experimental designs and statistical techniques used; b) policies on treatment and investigation of statistical outliers and/or the use of robust statistics; c) whether weighting techniques are used for contributions to assigned property values derived from different methods with different measurement uncertainties; d) the approach used to assign uncertainties to the property values; e) any other significant factors which may affect the assignment of property values." Guide 34, shall carry out an assessment of the measurement uncertainties to be included in the assignment of the property values any uncertainties resulting from between-unit variations and/or from possible doubts on stability (both during storage and during transportation) shall be assessed and shall be included in the assigned uncertainty. A statement of the measurement uncertainty is mandatory for certified values. In case values are assigned to non-certified reference materials (e.g. indicative values or information values ), a statement of uncertainties is highly recommended to improve the use of the material. Up to the manufacturer to determine what is appropriate 33

34 Uncertainty solution standards Cerilliant approach Technical studies performed on each part of the manufacturing and dispensing process led to the development of process controls Every aspect of the solution standard manufacturing process was thoroughly evaluated Weighing adjustment purity factor Weighing and dilution process neat material and solvent addition Dispensing and sealing Technical Studies TR006 - Measurement of Methanol Evaporation and its Predicted Effect on Nominal Solute Concentration during Standard Solution Dispensing Processes TR029 - Sampling Plan for Homogeneity TR030 - Initial Study to Develop a Statistically Based Sampling Plan TR009 - Evaluation of Line Clearance and Homogeneity in the Cozzoli Filling/Sealing Process TR038 - Cleaning Validation of the Cozzoli and Hamilton Dispensing Pumps 34

35 Uncertainty weighing Cerilliant approach Weighing instrument tolerance and performance of balance in place using a controlled weighing process Repeatability studies were completed to determine process status, process improvements were instituted and repeatability repeated Studies included using multiple balances, multiple operators, over multiple days, utilizing a defined & controlled weighing procedure Upgraded balances & refined and documented weighing procedure IQ/OQ (minimum weighing) Gravimetric approach Use of static bars Use of tongs vs gloved hands Balance equilibration time Sample and solvent temperature Proficiency testing used to qualify technicians on each balance in use - Passing criteria=100% (all 5 preps must pass accuracy criteria) Improper balance selection can lead to high levels of uncertainty Importance of Balance Selection and Mass Uncertainty Sample Mass Mass Uncertainty 5-place Balance 4-place Balance 1 mg 8.0% 45.0% 10 mg 0.80% 4.5% 100 mg 0.080% 0.45% 1000 mg % 0.045% Cerilliant studies indicate that when gloved hands are used as opposed to tongs for handling sample vials, uncertainty of mass measurement increased approximately 10 fold. 35

36 Uncertainty mass measurement Cerilliant approach Balance Repeatability Experiments for Cerilliant Preparations Using Different Balances XP6400 XP1230S XP205 XP5 6 UMX2 1 Place 3 Place 5 Place 6 Place 7 Place Process Scale 1-10 Liters ml 2 5 mg--1 0 g 5 mg 1 mg Approx. Gross M ass 1 kg 200 g 2.1 g g 41 mg Tare Container none none 2 mlglass vial 2 mlglass vial aluminum micro weigh pan Ref./ N et Mass (g) Mean Standard Deviation %RSD (s p ) % % % % % 20 replicates per test; two to three operators; multiple days Repeatability experiments were used to determine uncertainty for weighing operations 36

37 Uncertainty solution standard preparations C ( m v a ( m f s m ) dp v mf ) U Neat Material Purity Factor u pf = 0.292% Cerilliant Model Solvent Addition Solution Density ud = g/ml Mass measurement Temperature Instrument Tolerances Chromatographic Purity Residual Water Analysis Residual Solvent Analysis Inorganic Content Analysis Weighing Techniques Balance Sensitivity & Linearity Uncertainty of Solution Concentration u c = 0.315% U = 0.63% (k=2) Balance Selection, Qualification Minimum Weights Mass Measurement um = 0.035% 37

38 COAs & traceability ISO Guide 34, Section 4 Details given may permit the user to make a judgment of quality & integrity of CRM ISO Guide 34, 5.17 shall issue a certificate for certified reference materials and provide appropriate documentation for non-certified reference materials in the form of a statement, analysis report, or information sheet... If the certificate also contains non-certified values, a clear distinction shall be made between certified and non-certified values. ISO Guide 31, Section 6 name of the material; producer and producer s code for the material; general description of the material; intended use; instructions for proper use; instructions for appropriate conditions of storage; certified property value(s), each accompanied by a statement of uncertainty; method(s) used to obtain property values (with full details where values are dependent on the method of measurement); period of validity, if appropriate. ISO Guide 34, shall provide documentary evidence on the metrological traceability, of the measurement results to a stated reference metrological traceability shall be achieved through an unbroken chain of calibrations, all having stated uncertainties. Not required for non-certified Reference Materials 38

39 Expiration/Retest Date Expiration Dates are established through real-time stability studies. Retest Dates are assigned to ensure products are continually evaluated during the expected period shelf-life. Refer to Expiration/Retest policy for additional information. Solution Purity Extensive process controls are employed during manufacturing to ensure no degradation or contamination occurs. Analytical verification of solution purity post ampouling provides absolute confirmation. Concentration & Uncertainty Concentration of the gravimetric preparation expressed as ± mg/ml Represents the actual concentration (not theoretical) based on material weighings and material Purity Factor Uncertainty Statement Provides details of what standards were used to develop the uncertainty value, the confidence interval, the coverage factor and the processes or steps incorporated in the uncertainty value. Uncertainty of the concentration is expressed as an expanded uncertainty in accordance with ISO and ISO Guide 34 at the approximate 95% confidence interval using a coverage factor of k = 2 and has been calculated by statistical analysis of our production system and incorporates uncertainty of the purity factor, material density, and mass. Analytical Verification of Concentration & Ampoule to Ampoule Consistency The gravimetrically prepared concentration is verified analytically by comparison to an independently prepared calibration solution. Lot-to-lot consistency is demonstrated through analysis of the previous lot (where available). Ampoule-to-ampoule consistency, or lot homogeneity, ensures consistency in recovery and is demonstrated through analysis of ampoules pulled from across the lot. Lack of variability is demonstrated through the tight %RSD reported for the analysis. Acceptance criteria incorporates variability of the analysis. Traceability Statement describing traceability to SI units & NIST Gravimetrically prepared using qualified balances calibrated semi-annually by Mettler Toledo using NIST traceable weights. Calibration verification performed weekly and prior to each use utilizing NIST traceable weights. Each balance has been assigned a minimum weighing by Mettler Toledo taking into consideration the balance and installed environmental conditions to ensure weighing complies with USP tolerances of no more than 0.1% relative error. Manufacture of Cerilliant standards is fully documented in a detailed batch record capturing all equipment utilized providing traceability to equipment calibration records. Calibration verification weigh tapes are included in each batch record. In addition, each neat material utilized has been identified and thoroughly characterized through 39 the use of multiple analytical techniques. Spectral data is provided on subsequent pages of the COA. 39

40 Solution Standard Assay Shows method used to assay solution to an independently prepared calibration solution and calibration solution qualification data Neat Material Characterization Summary and Purity Factor Assignment Cerilliant Certified Solution Standards begin with full characterization of the neat material including chromatographic purity and analysis for residual content including: water, solvent, and inorganic content. This approach ensures accuracy of the standard and its suitability for demanding quantitative applications. Summary table shows results of all analyses performed and the calculated Purity Factor. Chemical information about the compound and its lot number is also provided for complete traceability. Chromatographic Purity Cerilliant utilizes multiple techniques to determine chromatographic purity. Results must agree within 0.5% of each other. The Primary purity method is used for purity factor calculations. The Secondary purity method is utilized as a confirming method. This approach ensures proper resolution of impurities and related substances and protects against random analytical error that could result in improper purity assignment. Isotopic Purity Includes isotopic distribution and purity by SIM. Purity Factor The purity factor (PF) mass balance measurement equation is used to calculate the amount of analyte required to achieve an accurate concentration of the solution standard, accounting for chromatographic purity and residual water, solvent, and inorganic content. Identity Cerilliant utilizes multiple methods to determine neat material identity, usually two of the following: NMR, LC/MS, GC/MS, FTIR. Each result must be consistent with compound structure. Spectral data is provided on subsequent pages of the COA This approach is consistent with ISO Guide 34 requirements and protects against random analytical error that could result in improper identification and ensures complete traceability of the reference standard

41 Neat Material Characterization Details Details of all neat material testing performed is provided along with run conditions and spectra. 41

42 Neat Material Characterization Details Details of all neat material testing performed is provided along with run conditions and spectra. 42

43 Stability Data A summary of accelerated stability findings to support transport conditions, normal lab use and short-term storage. 43

44 THANK YOU!!