QUALITY

1. QUALITY

2. We can do something about our problems, or we can continue the way we are. - W. Edwards Deming

3. Program Outlines What is Quality? How Quality is defined in Pharmaceutical Industry History of GMPs Essentials of GMPs GMPs - Future Regulatory requirements for APIs. Future of GMPs

4. What is “Quality”? "Degree to which a set of inherent characteristic fulfills requirements" – ISO. "Conformance to requirements" - Phil Crosby. "Fitness for use". - Joseph M. Juran "Quality and the Required Style of Management" - W. Edwards Deming

5. How Quality is defined in Pharmaceutical Industry? Quality in Pharmaceutical Industry is a much broader expression which encompasses the diverse elements of expectations and characteristics which a product should offer to its customers. Quality in Pharmaceuticals is not merely demonstrated by product characteristics, but also it is expected that product meets certain laid down specifications.

6. Genesis of Pharmaceutical Quality Management • Biological Control Act, 1902 • Sulphanilamide Elixir Tragedy, 1937- • Thalidomide Disaster in 1958- 1960

7. Chronology of GMPs:

8. What is Quality Assurance ?? Quality assurance is a wide ranging concept covering all matters that individually or collectively influence the quality of a product. With regard to pharmaceuticals, quality assurance can be divided into four major areas: • quality control, • production, • distribution, • and inspections.

9. Why is GMP important? • Poor quality medicines are not only a health hazard, but a waste of money for both governments and individual consumers. - WHO

10. What Is ICH? International Conference on Harmonization Of Technical Requirements for the Registration of Pharmaceuticals for Human Use

11. What Is ICH? • Established in 1990 between the European Union, Japan, and United States • Committed to reducing duplication during research and development of new drugs while safeguarding quality, safety and efficacy • Developed over 40 guidance documents mostly addressing technical/regulatory requirements for registering new human drug products

12. Japan USA Europe ICH Members • Regulatory agencies EMEA - European Union MHLW - Japan FDA - US • Trade associations EFPIA - Europe JPMA - Japan PhRMA - US

13. Status Of Q7A With Respect To Other Documents PhRMA Guidelines for Production, Packing, Repacking or Holding of Drug Substances is insufficient 21 CFR 211 does not apply to manufacture of APIs Q7A is the definitive GMP guidance for APIs! FDA’s Draft Guidance for Industry: Manufacturing, Processing or Holding APIs will not be finalized FDA’s Guide to Inspection of BPCs is obsolete

14. What Is an Intermediate? • A material produced during API processing that undergoes further molecular change or purification before it becomes the API • May or may not be isolated

15. What Is an Active Pharmaceutical Ingredient? • The intended use clause: Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.

16. What Is an Active Pharmaceutical Ingredient? • The pharmacological activity clause: Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

17. Uniqueness of API Processes • Process water quality • Blending of intermediates and APIs • In process controls • Process validation • Reprocessing/Reworks • Recovery of materials and solvents

18. Uniqueness of API Processes • Does not influence GMP expectations for laboratory controls and documentation • No significant differences between a laboratory testing dosage forms and one testing APIs

19. Essentials of GMPs

20. THE BASIC RULE QUALITY SHOULD BE DRIVEN & DERIVED BY: • STRONG R&D / DEVELOPMENTAL BASE • SOUND & VALIDATED SYSTEMS IN PLACE • CONTINUOUS ADHERENCE TO GMP RULES NOT BY MERE TESTING OF END PRODUCT

21. Quality Control API Excipients Pkg. Materials Manufacturing QUALITY Materials Management Engineering Men

22. Essentials of GMPs: • Buildings and Facilities • Process Equipments and Cleaning Validations • Documentation and Records • Production and In-Process Controls • Materials Management, Storage & Distribution. • Laboratory Controls • Process Validation • Change Controls • Complaints & Recalls

23. 4.1 Design & Construction • Buildings & facilities should be designed and constructed • to facilitate cleaning and maintenance • to minimize potential contamination • to limit exposure to objectionable microbiological contaminants • where micro specifications established • with adequate space and flow of materials and personnel to prevent mix-ups and contamination

24. 4.2 Utilities • Utilities that could impact quality • qualified and monitored • action taken when limits exceeded • Utility systems drawings available • Adequate ventilation, air filtration, exhaust systems (where appropriate) • to minimize risk of contamination & cross-contamination • to include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, & temperature appropriate to stage of manufacture

25. 5.2 Equipment Cleaning • Equipment and utensils should be cleaned, stored, and where necessary, sanitized, to prevent contamination or carry-over of materials • Equipment assigned to continuous production or campaign production should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants • Non-dedicated equipment should be cleaned between production of different materials to prevent cross- contamination

26. Documentation & Records • Why so much of Documentation & Records ?

27. 7.1 Materials Management -General • System for evaluating suppliers of criticalmaterials • Specifications for materials • Suppliers approved by quality • Name & address of manufacturer known (for materials supplied through intermediaries) • Change control for changing source of critical raw materials (Section 13)

28. 7.1 Materials Management -General • Each container (or group of containers) visually examined • labeling, damage, seals, tampering • Held under quarantine until sampled, examined/tested & released • including mixing into existing stock (e.g. solvents)

29. Samples Representative Methods specify number of containers part of container amount of material Sampling plan based on material criticality material variability quality history quantity analyzed 7.3 Sampling & Testing • Sampled at defined locations & by procedures to prevent contamination • Sampled containers resealed & marked

30. Stored/handled to prevent degradation, contamination & cross-contamination Stored off floor, suitably spaced for cleaning/inspection Normally “FIFO” 7.4 Storage of Materials • Outside storage in suitable containers OK if labels remain legible and containers cleaned before opening/use • Rejects identified and controlled

31. Section 8.1Weighing/Measuring of Materials • Raw materials should be weighed or measured under appropriate conditions that do not affect suitability for use • Weighing and measuring devices should be of suitable accuracy for intended use

32. Section 8.1Subdividing of Materials • Materials subdivided for later use should be stored in suitable containers identified with • Material name and/or item code • Receiving or control number • Weight or measure of material in new container • Re-evaluation or retest date if appropriate

33. Section 8.1Critical Operations • Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control • Other critical activities should be witnessed or subjected to an equivalent control Equivalent control means confirmation by a second independent means, e.g. printout from electronic or mechanical source.

34. Section 8.3In-Process Sampling & Controls • In-process controls and acceptance criteria should be defined based on information gained during development stage or from historical data

35. Section 8.3In-Process Sampling & Controls Less stringent in-process controls may be appropriate in early processing steps Tighter controls may be appropriate for later processing steps (e.g., isolation and purification) A B C D D E E F F API API Increasing GMPs

36. Laboratory Controls • General Controls • Testing Intermediates & APIs • Validation of Analytical Procedures (12.8) • Certificates of Analysis • Stability Monitoring • Expiry & Retest Dating • Reserve/Retention Samples

37. 11.1 Specifications • API specs • include control of impurities • organic, inorganic, residual solvents • if API has spec for microbiological purity, appropriate action limits established for • total microbial count • objectionable organisms • if API has spec for endotoxins, appropriate action limits established

38. Solvents Water Metals Salts Organics 11.2 Testing APIs & Intermediates An impurity is any component present in the intermediate or API that is not the desired entity Impurities • Byproduct • Degradants • Reactants, Intermediates, Catalysts, Ligands, Process Aids

39. 11.2 Testing Intermediates & APIs • Impurity profile (identified and unidentified) for API should be established • identity (or some qualitative analytical designation) • range observed • classification (inorganic, organic, solvent, etc) Impurity profile is for typical batch produced by specific controlled production process Normally not necessary for APIs from herbal or animal tissue source. Biotech covered in ICH Q6B

40. Definition Of Critical • “A process step, process condition, test requirement, or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.” Usually critical if: Narrow range High probability of deviation Deviation likely to impact quality of the API

41. Example of an API Process made up of many steps A B C1 D1 Final Intermediate C2 E D2 Crude API Final API Note: this is only an example for discussion purpose

42. Example of Criticality Analysis

43. Examples ofProcess Parameters • Temperature • Pressure • Vacuum • Time (Duration) • Flow Rate • Cooling Rate • Agitation Speed • Quantities of materials • Order of addition • Equipment type / material of construction • Sequence of unit operations • ….

44. Process Validation “Process validation is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting pre-determined specifications and quality attributes.” (Q7A 12.4)

45. Process Validation • Documented = Protocols and records • Evidence = Good science and extensive sampling • Consistency = Multiple batches produced by the same process • Predetermined = Knowledge of the API

46. Process ValidationIs Not! • An experiment • Optimization study • Process improvement program • Process capability study • “Worst case” tests

47. 12.4 Approaches to Process Validation • Prospective Validation is normally performed for API processes. (12.42) • Validation of API process should be completed before commercial distribution of the final drug product manufactured from that API (12.42)

48. 12.4 Approaches to Process Validation • Concurrent Validation(12.43) • Can be conducted when data from replicate production runs are unavailable because • Only a limited number of API batches have been produced (e.g., clinical or orphan drugs) • API batches are produced infrequently (e.g., limited market demand, complex multi-step processes) • API batches are produced by a validated process that has been modified

49. 12.3 Qualification • Before initiating process validation, appropriate qualification of critical equipment and ancillary systems should be completed (12.30) • DQ = Design Qualification, • IQ/OQ and PQ = Installation, Operational and Performance

50. 12.3 Qualification • DQ - documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose • IQ - documented verification that the equipment or systems as installed or modified, comply with the approved design, the manufacturer’s recommendations and/ or the user requirements.