Document Systems Validation

1. Document SystemsValidation BIT 230 Chapters 3 and 4 (Huxsoll)

2. cGMP • Biotech companies coming to GMP like large pharma difficult transition • Problems due to: • tight budgets • limited (trained) personnel • R & D scientists only

3. Documentation for cGMP • Provides project planning • Record of what and how was done- plus any changes implemented • IT IS REQUIRED THE cGMP

4. Biotech and Documentation • Overlooked in early stages • Viewed as cumbersome and time consuming • From this, delays in early development occur • Need top down commitment to documentation

5. Types of Documentation • Early on, scope and project goals • timeline or Gantt chart • http://www.netmba.com/operations/project/gantt • http://searchcio.techtarget.com/sDefinition/0,,sid19_gci331397,00.html

6. Gantt chart • Planning tool • timelines showing duration stages of the project in chronological order • interrelationship between various stages of the project • responsible parties for each phase of the project • Figure 3.1, Page 29

7. Areas of Documentation • Process overview • explain major process steps • detail sufficient so personnel at each step knows how the product is made and what their role is • blueprint of project • process targets

8. Areas of Documentation cont’d • Parts of the process overview: • 1. Purpose, including cell type and purification steps • 2. Required resources - raw materials, facilities, equipment, personnel requirements, test methods • 3. Process outline- step-by-step outline • 4. Product characterization- tests to assure quality • 5. Change authority - how and who

9. Areas of Documentation cont’d • Research notebooks • what you have kept in my courses • great support for process validation • detailed experimental results • anyone picking up notebook can repeat your steps • lots of info about the preclinical material and its properties

10. Areas of Documentation cont’d • 5 parts to a research notebook: • 1. Introduction • 2. Experimental plan (include alternate plans) • 3. Observations and data (raw data) • 4. Discussion and results • 5. Conclusion

11. Areas of Documentation cont’d • SOPs • preclinically after stabilization of process • REPRODUCIBILITY (again, anyone who knows the techniques can produce the product) • however, not too rigidly written • differ from lab notebooks - HOW?

12. Areas of Documentation cont’d • SOPs cont’d - Value • while being written, forced to think of problems- may avert costly errors this way • standardize technician training • minimize misunderstandings about the process • if changes are made to the process, SOP history will be available by end user for review • tells the user what to record

13. Areas of Documentation cont’d • Testing Documents • SOPs standardize test methods - include equipment, methods and reagents • minimize variation from operator to operator (“pilot error”) • include use of positive and negative controls • outline data and test values that need recording

14. Areas of Documentation cont’d • Batch Production Records (BPRs) • provide lot information- critical in production (recalls often by lot number) • develop lot-specific forms for each appropriate step in the SOP • Pages 33-34- CFR-required batch record sections • go over batch records given in class

15. GLP documentation • Preclinical operations • user-friendly document numbering system (needs to accommodate many doc types) • index should contain 3 parts: • functional group (testing vs. processing) • stage of process (scale-up, purification) • type (general item, specific procedure, etc.)

16. GLP docs cont’d • Each doc reviewed by a person in each functional unit (process dev., QA, production) • use document review record (Page 35) • format of document standardized • BPRs- data and text together or separate- find consensus (see page 36 Figure 3.3)

17. GLP docs cont’d • Raw material documents • catalogue materials used • list all required raw materials • assign identity numbers to each reagent • inspection of raw materials; visually, chemically and microbiologically- WHAT are you looking for? • USP or ACS

18. GLP docs cont’d • Sampling documents • create early in process also • purity, integrity, yields • types of tests: • endotoxin • microbiological • ELISA • PAGE • HPLC

19. GLP docs cont’d • Laboratory documents • raw material and in-process testing • detailed info, such as time when and amount of sample to be taken, lot number, date, etc. • how precise and accurate from original test data (accepted standard deviation) • location of original test data

20. GLP docs cont’d • Laboratory documents cont’d • necessary calculations to arrive at data • logbooks for instruments and reagents • calibration records • lab personnel training docs • Page 39 Figure 3.4- document of a simple lab procedure

21. GMP documentation • Extension of docs begun in preclinical lab • includes prompts were information needs to be entered • need QA tested raw materials (remember, the product is now going into a person!) • record expiration date- cannot use 1 day past that date (not so in a research lab)

22. GMP documents • Contain process limits (maintains control of process) • limits include process parameters • pH • temperature • volume • concentration • WHAT are some other limits?

23. GMP documents • Steps after a process is complete: • technician verifies and signs that process is complete • supervisor reviews and signs documents • independent reviewer QA’s the documents (and the process) • Therefore, each document is reviewed 3 times • have review document for this process (GETTING the picture about how much writing goes on!) • FILE docs when done for safe keeping

24. Misc. GMP Documents • Records for preventative maintenance, calibration and usage of equipment used in production • Make sure equipment functions same from run to run

25. Validation Chapter 4

26. Validation • Document that a manufacturing process is under control • Capable of consistent production of a biopharmaceutical • Begins with product specifications

27. Validation • Can’t test for quality, so validate • Therefore, each step of manufacturing process validated so you have assurance of quality product

28. Important Validation Definitions • Calibration • measuring device produces results within predetermined limits (compared to a reference standard) • Cell Seed • aliquot of cells derived from single tissue • Certification • review and approval process (final step)

29. Important Definitions, cont’d • Concurrent Validation • written evidence that process is working (by gathering data during the process) • Drug Product • a finished dosage that contains active ingredient (s) • HVAC • Heating, ventilation, and air conditioning

30. Important Definitions, cont’d • Intermediate • substance produced in one stage of production and used at another (produced by chemical, biological or physical action) • Installation Qualification (IQ) • written proof of installation according to specs • Master Working Cell Bank (MWCB) • derived from one or more ampoules of the cell seed- shown to be uniform composition (WCB)

31. Important Definitions, cont’d • Operational Qualification (OQ) • written proof that system performs as designed • Performance Qualification (PQ) • approved plan to validate a system or process • Population Doubling Time (PDL) • number of doublings that culture has undergone- Why is this important?

32. Important Definitions, cont’d • Process Validation • documented evidence that a process will consistently produce a product • Prospective Validation • written evidence, prior to carrying out a process, that the process will do as suggested • Qualification • separate validation- shows system is suitable to carry out designated process

33. Regulatory requirements • FDA - safety and efficacy of drug supply • See quote page 48 under section 4.1.3 • Parts 210 and 211 of GMPs - if FDA thinks drug is tampered they may take action against the producer • highly trained FDA personnel to carry out inspections of drug makers

34. Process Development • IF process development weak or absent, inconsistent results will appear during manufacturing runs • Involves personnel from validation, QA, QC, manufacturing and engineering • Section under change control (page 49)

35. Parameters of Process Validation • Validation of utilities • proper installation • manufacturer’s specs • moisture and airborne product contamination • purity • take samples from both inlet and outlet of unit (when testing water, steam, etc.)

36. Parameters of Validation, cont’d • Environmental control • design of facility and environmental controls keep operation within specified limits • conditions differ based process performed in that area (cold, moist, etc.)- e.g. protein purification in a 4ºC room • microbiological testing of surfaces, air, etc (do you need clean room facilities?) • facility sanitization

37. Parameters of Validation, cont’d • Cleaning methods and changeover • not only clean surfaces, but document residual detergent levels on washed equipment & surfaces • endotoxin testing (what are endotoxins?) - can use LAL test • perform assays on final rinse water- determine levels of residual products • what should be the acceptable level of residual material?

38. Parameters of Validation, cont’d • Bioinactivation • of bacterial or cell culture waste • different level of requirements based on Biosafety level • some procedures include: • inactivation of organisms prior to removal from a closed system • inactivate wastes before disposal in normal trash

39. Parameters of Validation, cont’d • Sterilization • validate process so sterility assurance level is achieved • Methods include: • filtration • autoclaving • steam-in-place (SIP - some bioreactors) • vessel heated with a solution

40. Parameters of Validation, cont’d • Sterilization, cont’d • Autoclaves - use empty chamber heat distribution studies (to determine temperature uniformity) • Biological indicators (BIs) to determine when organism is eradicated (called D-value or BI death rate) • vendor specific D-value so keep that in mind

41. Parameters of Validation, cont’d • Media hold challenge • length of time a vessel hold a liquid and remain sterile • push the procedure to see when it fails • how does manipulations (adding or removing items) affect the sterility • important if you need to make media in advance and hold a while (how about the LB we use in class?)

42. Parameters of Validation, cont’d • Depyrogenation • sterilization of heat stable materials • use an endotoxin challenge (since endotoxins are heat stable) • empty chamber and loaded chamber heat studies performed

43. Parameters of Validation, cont’d • Filtration • need to evaluate product, steps and filter media • early process uses: sterilization of media, removal of cellular debris and removal of intermediate • late stage process uses: microbial retention (with altering final product • evaluate filters themselves

44. Parameters of Validation, cont’d • Programmable logic controllers (PLCs) • computers that automate the processes - must be validated also • hardware • software • operating system • What are some problems here?

45. Bulk drug manufacturing • Making large batch of drug at once • MWCB important - do the cells and DNA remain intact during production • perform validation tests for acceptability of starting material

46. MWCB • History and morphology of cell line, plasmid, and transfection into host cell • storage, maintenance and propagation of cell line • cell markers • tumorigenicity studies • expression of endogenous retroviruses • test for presence of virus, fungi, bacteria or mycoplasma

47. MWCB cont’d • Bacterial production systems check for: • carbohydrate use • antibiotic resistance • contamination • sequence and restriction map of plasmid • growth rate of host • SDS-PAGE of product profile

48. Recovery and purification • Remove impurities from the drug substance • eliminate inadvertent contamination (Flu vaccine) • therefore, validate recovery process!

49. Pharmaceutical Manufacturing Validation • Similar to biotech manufacturing, but has special issues such as aseptic processing, lyophilization and packaging • Aseptic processing • aspects of filling of a drug product so that contamination is not introduced • fill with cell growth media as a control

50. Pharmaceutical Manufacturing Validation, cont’d • Lyophilization • freeze drying- extends shelf life and reduces moisture content • freeze-dry placebo as control; test several cycle to assure process uniformity • filling operation important to duplicate volumes in every vial