Mr Michael Stubbs

1. Mr Michael Stubbs Presentation for ALMAC 16 November 2006

2. Observed Many Changes • Medicines Inspector on arrival: “Here’s Your Certificate. Where are you taking me for Lunch?”

3. Michael Stubbs • Managerial Skills • Communication Skills • Technical Skills and Experiences

4. Multi-tasking, Quick Thinking, Direct & Decisive Keep abreast of Global Picture and Priorities Budgeting, Capital Expenditure Introduction of New Technologies to Improve Quality, Turn Around and Efficiency Control of Health & Safety, COSHH assessments Compliance with GLP, GMP, GCP, SOPs, Company Policy Project Planning and Allocation of Resources Setting of Objectives and Agreed Deadlines Delegation of Tasks and Responsibilities, where appropriate Time Management Compilation of Master Schedule Experimental Design Mentoring, Professional Development & Training Excellent Motivational and Communication Skills Supportive of Staff and their Problems Encourage staff NOT just to do, but to LEARN Interviewing and Appraisal Skills Managerial Skills

5. Communication Skills • Excellent open communicator – Report ALL news promptly – Good AND Bad • Policy of answering ALL requests and e-mails within 24 hours • Open door policy and cooperative • Preference for personal contact to gather complete information, ensuring work is carried out right first time and on time • Careful listener, provide feedback, excellent problem solver • Mentored over 60 analysts, patient, understanding, constantly using “W” questions to check understanding • Clear unambiguous English

6. Technical Skills & Experiences • Worked to varying high quality standards: GLP, GMP and GCP • Updated Quality Management System for US Laboratory (GMP) • Introduced Evaluation for Certified Reference Standard Characterisation and Issue (in excess of GLP, all methods using weights not volumes: CV limit for HPLC was 0.5% n=5, 95%CI = 0.7%) • Raw Materials Evaluation and CT approval (BP, Ph.Eur., USP, DAB, JP, GCP) • Literature Searches (esp. German) • Related Substances (Synthetic and potential degradation products, LC-MS) • Method Development and ICH Validation (GMP) • Formulation Development (GLP) and CT Support (GCP) • ICH Stability Studies and Evaluation (GMP and GCP) • Registration Support, answering Technical Questions • Technology Transfer (GMP) • Cleaning Verification and Validation (GMP) • Preparing, Editing, Reviewing and Approving of Documentation • Excellent IT Skills (Office, HTML, VB Script)

7. Training Courses • Leadership Skills • Time Management • LIMS • Introduction to Statistics • Statistics for Analytical Chemists • Experimental Design • ICH conferences • Capillary Electrochromatography • Statgraphics • MSOffice, Advanced Word, Advanced Excel, Outlook, Visual Basic • HTML, Java

8. Method Development • Identification • Titrimetric • UV-VIS Spectrophotometric • HPLC • Dissolution (UV-Vis & HPLC) • GC • Karl Fischer

9. Method Development • Consideration of cost of goods • Ease of use – keep it simple and quick • Automate where possible to minimise analyst error and maximise efficiency • Specificity, sensitivity, linearity, accuracy, precision, robustness • Future proof – think ahead – consider likely potential degradation routes, contaminants, solution stability, constituents • Minimise analytical potential error by ensuring control of critical parameters to maximise confidence

10. Ph.Eur. Assay for 4-Aminophenol • Ordinary laboratory analysis showed 4-Aminophenol content in Acetaminophen (Paracetamol) increased with time • Result – all analyses carried out with immediate preparation and injection • Cleaning Verification – look for Acetaminophen OR 4-Aminophenol?

11. Nifedipine Related Substances • Erroneous results obtained even under Sodium lighting with immediate preparation and injection • Evaluation of film coat layer from Nifedipine marketed products showed they ALL absorbed at 450 nm • A search revealed Methyl Orange also absorbed at 450 nm, when added to sample solvent preparation no photolytic degradation occurred allowing analysis to be performed in ordinary laboratory conditions

12. Dispute of NCE Impurity • GMP Manufacturer passed NCE material for CT, C of A showed no impurity • On examination, material was yellow, analysis and re-analysis provided an identical impurity result of 0.2% • Manufacturer refused to believe, I asked them to provide a chromatogram, and spotted they had used a DAD detector with 360 nm as the reference wavelength, effectively removing the yellow coloured impurity content • As a result the material FAILED and was returned

13. HPLC or HPTLC for (±) Naproxen • HPLC – interfering reagent peak, expensive column, long analysis time • HPTLC – quick, cheap plates, easy analysis

14. Fast Method for Vitamin A • Previous 2 day method: Saponification, Column Chromatography, Colorimetric – dubious results • Minimal sample preparation – dissolve 5 g of cream in 25 ml of THF • Rapid separation of Vitamin A esters in <5 minutes • Addition of Cetrimide restores column efficiency negating any effect of waxes • Recovery 100.3% using Vitamin A Stearate as internal (prepared from Vitamin A Alcohol and Stearoyl Chloride)

15. Stability Method for Morphine • Validation Report held up at ICH Conference by MHRA Speaker as “Ideal” • Morphine isomers, N-oxide, Codeine – UV max 211nm • Morphinone – UV max 205nm, unstable in solution • Pseudomorphine – UV max 233 nm, absorbs onto glass • 10-Oxomorphine – UV max 350nm, affected by light, column temperature • Mass balance 100%

16. Formulation Development • Addition of plasticizer DBP to product during formulation development necessitated increasing the organic content and higher chain length of ion pair agent

17. Developed GC Method for Malathion in a Shampoo • Old method used non-polar OV-1 phase • Increasing the polarity of phase to OV-225 retained Malathion on column, improving specificity, accuracy and analysis time

18. In-vitro Dissolution Testing • UV-VIS DAD Spectrophotometric – Single Stream gave precision values of <0.3% released with compete data storage across UV-VIS region • HPLC online – Two baths, one HPLC • For one product development over 1,000 40 hour dissolutions, 8 formulations each day • Full validation: Justification of Parameters, Effect of pH, Discrimination, Specificity, Linearity, Accuracy, Precision, Robustness, Sensitivity • 2 Stage for Enteric Coats • Flow Through (Open and Closed) for compounds which do not meet “in sink” conditions • Baskets, Paddles, Fine Mesh, Sinkers (Tablet and Capsules), Transdermal Patches • Also useful for timed compound stability in different solutions as part of method development or forced degradation studies

19. Effect of constant error on cumulative in-vitro dissolution profile

20. Effect of Variable Tablet Contents • A variable active content results in increasing standard deviation values with percentage released • This effect is also observed where interference occurs (e.g. UV-VIS) though the final release is >100%

21. Effect of Bead Size on the In-Vitro Dissolution Profile

22. Effect of Formation of Clumps during Coating of Cores

23. Problem with Marketing Choice of Film Coat • Methods were developed for the core products • Marketing decided on a range encompassing 5 strengths with grey, purple, green, orange and blue film coats • The purple and orange film coats contained Erythrosine, which reacted with the active via a free radical mechanism during sample preparation causing high level of degradation product • Two solutions, first was to scrape off the film coat – time consuming, not analyst friendly • I was reminded of my classical training for Vitamin A analysis where Quinol is added to prevent oxidation during saponification. Addition of 0.001%w/v to the solution used to prepare standards and samples prevented oxidation and restored the method.

24. Excipient Compatibility • Forced degradation studies (in solution: weak and strong acids/bases, oxidising agents, photodegradation, heat, humidity) • Simulated product and mixes (both dry and wet) • Chemistry is a wonderful subject – you should never be surprised by the reactions that can occur – oxidation, free radical, hydrolysis, keto-enolisation • Forced degradation studies MAY NOT be indicative of what happens in Product!

25. Method Validation • Summary, Specificity, Linearity & Range, Accuracy, Precision, Sensitivity, Robustness • Statistical Experimental Design for Accuracy, Precision, Robustness – Day, Analyst, Instruments, Stability of solutions

26. Example Precision Data

27. Example Stability Data with Reference Standard Error

28. Stability Data for Capsule Strengths • All the strengths were filled with Batch 1 and Batch 2 • Only the 2 mg product exhibited unsatisfactory stability • Both batches of the 2 mg product were filled with the same batch of capsule shells. A previous batch exhibited satisfactory stability • Conclusion: The quality of the batch of capsule shells affected the stability of the 2 mg encapsulated product necessitating further investigation

29. Technology Transfer • Although mean active is within limits precision for the Transfer Laboratory is too high. Why? • The sensitivity is insufficient in the Transfer Laboratory for related substances. Why are they unable to detect them? • Result: FAILS, investigation required

30. Research to QC Transfer • Results for a controlled release tablet were 69.6 mg/tablet from Research (claim = 70.0 mg/tablet) and 72.3 mg/tablet when transferred into QC. Samples were extracted with methanol • Why was there a difference? • In Research the method was followed and the result was comparable to the input value • QC had a policy of centrifuging ALL samples in open tubes, this was contrary to the procedure specified in the method and caused a concentration effect

31. Excel Skills • Creation, presentation, protection and validation of spreadsheets - statistical tests, linearity, specificity, accuracy, precision, dissolution, certification of reference materials • Different modes of calculation – e.g. normalisation, authentic standards, 0.1% versus 100% reference standards; for Content Uniformity – corrected or uncorrected for product weight • Error messages for failures against limits in Method or Product e.g. System Suitability: Standard Check, Repeatability of Injection, Reproducibility, Sensitivity • Automated macros in Visual Basic to calculate, validate and print • Data formatted ready for importing into Word • Formulas e.g. =IF($a$1=“”,”Error! Please Enter Data! ”,IF($a$1=$b$4,”Pass”,”Fail”)) • Automated macros – each spreadsheet can be fully validated at any time even when all raw data has been entered as all processing is performed by hidden and protected sheets • Once data is entered, checked and approved, the spreadsheet is password locked

32. Example Validation of Equation • Equation: • Excel Spreadsheet • Use test data and =IF(“Validate”=“ON”,VLOOKUP(“Test”,”Test Data”,”Row”,True),”Data Value”)