Organization of QA cGMP compliance

1. Organization of QAcGMP compliance BIT 230 Chapters 1 and 2 (Huxsoll)

2. TQM • Total Quality Management • Approach a company uses day to day • 7 strategies • Leadership • Information and analysis • Strategic planning • Human resource development and management

3. TQM • Strategies continued • Process quality management • Quality and operational results • Customer focus and satisfaction • Often focus is on the customer – so last but not least- customer driven success

4. Quality Assurance • A unit that is part of the whole • US CFR – United States Code of Federal Regulations- defines the quality unit’s job • Approve or reject all materials associated production of any product – includes containers, components, labels, other packaging materials

5. Quality • Ensure purity- # 1 goal • Also strength and quality • New biotech lose site of quality – develop science first, then quality • Should be done in parallel to have less problems later • Role of QA better established in large pharma

6. Quality Control (QC) within QA • QC is a testing function • Defined as fitness for use • Need to be integrated throughout process • Fitness for use divided into several components - next slide; these 4 major components subdivided into further categories - THESE important regardless of product

8. Manage from the top down • Upper management sets tone for company style and compliance • Biopharm products complex- therefore need “quality of manufacture” • CFR definition of QA unit - 7 points

9. QA function(pertaining to a non-clinical lab) • 1. Maintain master schedule sheet • 2. Maintain protocol records • 3. Inspect each phase of study • 4. Submit periodic written status reports • 5. Ensure SOPs are followed • 6. Review final study report • 7. Prepare a signed statement (with inspection dates, etc. for final study).

10. QA vs. QC • Will discuss more later, but major point of confusion • QC function limited - testing methods • “Controls the product” in production • CFR does not clearly define QC- more of a QA definition

11. Product production • QA defines systems and methods to ensure quality of a product- QC tests various aspects of a product as it is being developed

12. Which function: QA or QC? • SOP for measuring pH of a production run • measuring pH of a production run 3 X daily • filling in batch records • developing batch record • signing and dating batch record • confirming integrity of raw material • defining raw material to be used in production

13. Routine functions of QA • Testing • Documentation • Labeling • Vendor audits • Vendor approval

14. Routine QA functions cont’d • Raw material receipt • Product release • Product Specifications • Training • Validation

15. Other QA Functions • 1. Company awareness • long and short term goals • QA part of business involvement team • if QA operates as a separate group company not as successful • upper management must commit to QA • sometimes overlooked in biotech

16. Other QA Functions cont’d • 2. Product knowledge • without it failure is likely • know the product, process used to develop it, support systems, and product use (e.g. target population- FOSAMAX example - older population, people with arthritis, people with difficulty sitting up) • AGAIN, product defined by systems established to assure its consistency

17. Other QA Functions cont’d • 3. Facility knowledge • function of equipment • function of local environment of production facility • need personnel expertise in these areas - proper training, etc. • don’t work in a vacuum

18. Other QA Functions cont’d • 4. Networking through outside organizations • regulatory agencies • other companies with similar product line • conferences • understand industry and regulatory standards

19. Other QA Functions cont’d • 5. Risk analysis/decision making • analyze situations • make recommendations- if so, assure proper modification of SOP • risk/benefit ratio to modification of SOP • Page 8 - quality systems functions and percentage at various companies http://www.mtm-laboratories.com/janusmtmportal/portal/template/Home/action/news_4.html

20. Establishing QA • Define the function of QA (chicken and egg problem) • Should start before production of material to be used in Phase 1 clinical trials • Start when biotech company is small • What quality systems are needed • Risks of leaving out some QA functions?

21. New company QA • What type of product • Complexity of end material • Production method • Financial considerations • Stage of development • is product in-licensed? • is there some parameters for product development already determined?

22. Factors to achieve Quality • Page 9-10 (points 1-12) • Key points: • Quality indicators discussed not hidden- problem in other sectors of company, not just quality (e.g. Vioxx, was everything transparent?) • resource allocation • good exchange of dialogue • accept responsibility (e.g., Tylenol case)

23. QA functions • Assay development and validation • equipment validation • process validation • vendor qualifications • raw material and product specs • documentation • QC testing

24. People, people, people • In-house expertise (product & quality) • need for external expertise (advisory, etc.) • add staff as need arises • proper training • other company personnel should be part of day-to-day QA decisions and processes • avoid attitude that QA is not needed

25. QA organization • Figure 1.3, Page 11 • Compares organization at various stages of a company • Large pharma has a separate QA department with significant staff

26. Day-to-day goals • Setting standards • sets standards for goals for both QA group and entire company • written • especially important for process deviations • based on expectations and outcomes for product • How is the experience gained with a product?

27. Day-to-day cont’d • Implement training • can’t really do it here in class- need to be on the job; but learn the basics here (e.g., microbiological procedures - sterile technique) • ongoing training needed • make time for training (can easily be cast aside) • make training a goal (objective) of the employee’s yearly plan- reward built in

28. Day-to-day cont’d • Feedback • constructive • realistic • communication key • support time commitments and constraints • What is your time back up plan?

29. Coming into cGMP compliance Chapter 2

30. How does a company look pre-GMP? • Small company- few to a few dozen employees • mostly research scientists • very few others as administrative, production, testing and support • operating style develops quickly “corporate culture” • problems with this during mergers

31. Pre GMP company • Creative and fast • long hours for employees • good interaction • react quickly to issues - not much red tape • less documentation - many things decided verbally with no paper trail- can lead to problems as the company grows • costly

32. GMP compliant company • Large pharmaceutical companies • many employees in production, testing, support and administrative • equal or outnumber R & D scientists • follow accepted, validated, approved methods • slower to change • large volume of documentation

33. Moving from Pre- to GMP • Company has identified product to produce; plan needed to develop product under GMP • Be part of company master plan • site able to produce GMP product or must find alternate manufacturing facility • Regulatory affairs personnel - always jobs in this area!

34. Moving to GMP • Finalize plan • Determine budget (may be when a company goes public) • START the project • I’ll say it again: documentation! • How is the documentation used?

35. GMP required documents • Process variables • analytical methods used to determine quality of intermediate and final products • functioning of support systems • facility is functional and suitable • clean and functional equipment • reproducibility

36. Remember Flu Vaccine problem this past Fall??

37. Clinical production • Need GMP here, too • included to document: • raw materials • labeling • batch records • equipment/building preventative maintenance • Yields • Figure 2.1, page 19

38. GMP training • On-the-job training necessary • “validation” of personnel • trainer content expert; experience as instructor • upper management acknowledges the need for on-going training • often external trainers brought in (certified)

39. GMP training • Audits - internal and follow same GMP guidelines as external audit • written and well organized • follow approved procedures • auditors trained and from outside immediate work area • External audits include review of internal audits, although not FDA’s current policy

40. Documents for auditing • Master schedule • generated up to 2 years in advance • may be included in SOP • internal audits not surprise • but, not a time to do everything at last minute; must perform duties regularly • hold post-audit meeting • have corrective action and back-up plans

41. There’s never time to do it right, but always time to do it over!