Production and Process validation

1. Production and Process validation 17 January 2006 by...Wiriya charoenkunathum

2. References: • GMP for pharmaceutical products: main principles; WHO TRS No. 908,2003 • GMP for biological products; WHO TRS No.822,1992 • A WHO guide to GMP requirements, part 2:validation; WHO,1997

3. GMP • The good practices outlined are to be considered general guides and they may be adapted to meet individual needs.

4. GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production • Cross –contamination; unexpected contaminants • Mix-ups; confusion (false labels)

5. Good practices in production • Principle: production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.

6. Production of Vaccine GMP Master seed Working seed Inoculum Media/Cell culture Single harvest Excipients Validation - process - method Stability studies Pool/Concentrated material Purified/Bulk material Final lot Final bulk

7. Good practices in production:General • All handling of materials and products; • receipt • cleaning • quarantine • sampling • storage • labelling • dispensing • processing • packaging • distribution • should be done in accordance with written procedures and recorded.

8. Good practices in production:General • Any deviation from instructions or procedures should be avoid as far as possible. • If deviations occur: should be done in accordance with an approved procedure • approved in writing by a designated person

9. Good practices in production:General • Checks on yields and reconciliation of quantities to ensure that there are no discrepancies outside acceptable limits.

10. Good practices in production:General • Operation on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix-up or cross-contamination.

11. Good practices in production:General • At all time during processing • all materials • bulk containers • major items of equipment • rooms • packaging lines • being used should be labeled or identified

12. Good practices in production:General • Access to production premises should be restricted to authorized personnel. • Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.

13. Good practices in production:General • In-process controls are usually performed within the production area. • The performance should not have any negative effect on the quality of the product or another product.

14. Good practices in production: Prevention of cross-contamination during production • When dry materials and products are used in production, special precautionshould be taken to prevent the generation and dissemination of dust. • proper air control e.g. supply and extraction of air of suitable quality

15. Good practices in production: Prevention of cross-contamination during production • Contamination of a starting material or of a product by another material or product must be avoid. • accidental cross-contamination arises from • uncontrolled release of dust, gases, particles, vapours. sprays or organisms from materials and products in process • residues on equipment • intruding insects • operators’ clothing, skin, etc. • most hazardous, highly sensitizing materials • living organisms, hormones, cytotoxic substances, and others

16. Good practices in production: Prevention of cross-contamination during production • Avoided by taking appropriate technical e.g. • carrying out production in dedicated and self-contained areas • conducting campaign production followed by appropriate cleaning in accordance with a validated cleaning procedure • providing appropriately designed airlocks, pressure differentials and air supply and extraction systems

17. Good practices in production: Prevention of cross-contamination during production • minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air • wearing protective clothing • using cleaning and decontamination procedures of known effectiveness • using a closed system in production • testing for residues • using cleanliness status labels on equipment

18. Good practices in production: Prevention of cross-contamination during production • Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOP • Production areas periodic environmental monitoring

19. Good practices in production: Processing operations • Before any processing operation • work area and equipment • clean and free from any starting materials, products, product residues, labels or documents not required for the current operation

20. Good practices in production: Processing operations • Any necessary in-process controls and environmental controls should be carried out and recorded • Indicate the failures of equipment or services (e.g. water, gas) to equipment • defective EQ withdrawn • after use, production EQ • cleanedwithout delay, • stored underclean and dry conditions in separate area

21. Good practices in production: Processing operations • Time limits for storage of EQ after cleaning and before use • Containers for filling should be cleaned before filling • Any significant deviation from the expected yield • recorded and investigated

22. Good practices in production: Processing operations • Checks • pipelines and other pieces of EQ used for transportation of products • Pipe used for conveying distilled or deionized water • sanitized and stored according to written procedures (action limits for microbiological contamination and measures

23. Good practices in production: Processing operations • EQ and instruments • serviced and calibrated at prespecified interval • records maintained • checked daily or prior to use • clearly indicated the date of calibration and servicing, recalibration (label attached to instrument) • Repair and maintenance operations • not present any hazard to the quality of the products

24. GMP for biologicalproducts :Production • SOP for manufacturing operations: available, up date • Starting material: source, origin, method of manufacture, QC • Media and culture shall be added to fermenter and other vessels under carefully controlled conditions, avoid contamination

25. GMP for biologicalproducts :Production • Media should be sterilized in situ. Inline sterilizing filters for routine addition of gases, media, acids, alkalis, deforming agents, etc. to fermenter should be used where possible. • Validation of sterilization. • Inactivation process: measures should be taken to avoid risk of cross-contamination between treated and untreated products.

26. GMP for biologicalproducts :Production • A wide equipment used for chromatography • should be dedicated to purification of one product • should besterilized or sanitized between batches • define the life span of columns and the sterilization method

27. In-process controls play a specially important role in ensuring the consistent quality of biological products because certain deficiencies may not be revealed by testing the finished product. • Tests that are crucial for quality control but that cannot be carried out on the finished product shall be performed at an appropriate stage of production.

28. Samples of intermediate and final products shall be retained in sufficient amount and under appropriate storage conditions to allow the repetition or confirmation of a batch control. • Certain operations require the continuous monitoring of data during a production process e.g.monitoring and recording of physical parameters during fermentation.

29. Validation: Definition • Validation is the documented act of proving that any procedure, process, equipment, material,activity or system actually leads to the expected result.

30. Validation studies • analytical test • equipment • facility systems (air, water, steam, process; manufacturing processes, cleaning, sterilization, sterile filling, lyophilization) Separate validation for lyophilizer/ lyophilization process cleaning of glassware/ cleaning of facility sterilization process/sterility test

31. Validation studies • verify the system under test under the extremes expected during the process to prove that the system remains in control. • Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control.

32. Type of validation • Prospective • pre-planned protocol • Concurrent • base on data collected during actual performance of a process already implemented in a manufacturing facility • suit manufacturers of long standing, have well-controlled manufacturing process • Retrospective • for production for a long time, but has not been validated according to a prospective protocol and concurrent validation is not realistic option • is not generally accepted

33. Type of validation • Laboratory-and pilot-scale validations • some production processes cannot be carried out in production facility removal of impurities by individual purification steps in process - not acceptable to bring unacceptable impurities (endotoxin, unwanted protein, contaminating bacteria and virus) spike into process

34. Facility systems and equipment: Stage of validation • Design qualification (DQ) • Installation Qualification (IQ) • Operational Qualification(OQ) • Performance Qualification (PQ) Systems and EQ; PQ=validation Depending on the function and operation of some EQ

35. Facility systems and equipment • Design qualification (DQ) • necessary when planning and choosing EQ or systems to ensure that components selected will have adequate capacity to function for the intended purpose, and will adequately serve the operations or functions of another piece of EQ or operation.

36. Facility systems and equipment • Installation Qualification (IQ) • written for critical processing EQ and systems • list all the identification information, location, utility requirements, and any safety features of EQ • verify that the item matches the purchase specifications

37. Facility systems and equipment • Operational Qualification(OQ) • outlines the information required to provide evidence that all component of a system or of a piece of EQ operate as specified. • should provide a listing of SOPs for operation, maintenance and calibration • define the specification and acceptance criteria • include information on EQ or system calibration, pre-operational activities, routine operations and their acceptance criteria

38. Facility systems and equipment • Performance Qualification (PQ) • performed after both IQ and OQ have been completed, reviewed and approved • describes the procedures for demonstrating that a system or piece of EQ can consistently perform and meet required specification under routine operation and, where appropriate, under worst case situations • include description of preliminary procedures required, detailed performance tests to be done, acceptance criteria • other supporting EQ used during qualification have been validated.

39. Facility systems and equipment pH meter, incubator, centrifuge, freezer; IQ,OQ system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ EQ: autoclave, oven, lyophilizer,continuous flow centrifuge; IQ, OQ, PQ

40. Process validation • A process is a series of interrelated functions and activities using a variety of specified actions and EQ which is designed to produce a defined result.

41. Process validationstudies • examine a process under normal operating conditions to prove that the process is in control • re-validation • modification to the process • problems occur • EQ or systems are changed

42. Process validation • To validate the reproducibility and consistency of a process • full defined process is carried out using validated EQ • at least 3 times, under established procedure • process must successfully and consistently meet all acceptance criteria at all steps throughout the procedure at least 3 times consecutively Validated process Worst case: to ensure that process is acceptable in the extreme case

43. Process validation • Example • cleaning • sanitization • fumigation • depyrogenation • sterilization • sterile filling • fermentation • bulk production • purification • inactivation • filling, capping, sealing • lyophilization

44. Process validation • specific process clearly described in Master formula or in SOP • all EQ; identity, code number, construction, operation capacity, actual operating range • processing parameter; sufficiently detailed to permit complete reproducibility (time period, pH, volume, temp.etc.) • specification at each step

45. Process validation • Very important • specifications for a process undergoing validation be pre-determined • all critical processing parameters for which specifications have been set, there must be equipment to measure all of those parameters during the validation study

46. Typical content requirements for process validations • Cleaning, Fumigation, Sanitization Process • collecting liquid and swab samples for testing of residual product • residual protein • endotoxin tests • microbial tests (bioburden) • chemical tests (chlorine and phosphoric acid) • residual cleaning agents • conductivity tests • pH As relevant to the cleaning process All analytical tests must be validated before

47. Typical content requirements for process validations • Sterilization • sterilization filtration of solutions • microbial challenge • filter integrity tests • performance tests

48. Typical content requirements for process validations • Depyrogenation process (dry heat, column chromatography, other) • endotoxin content reduction of 3 logs

49. Typical content requirements for process validations • Sterile filling • test filling process • perform filling process with nutrient media • run at full scale for at least one fill size • worst case; large volume and number of vials • filled vials incubated, observed and test for contamination by validated sterility test • must be sterile for 3 consecutive runs • media fill performed twice a year • size of run must be large enough to detect low levels of contamination e.g. contamination rate of 1/1000, 3000 units are needed to provide 95% confidence

50. Typical content requirements for process validations • Mock fermentation • full scale fermentation of a representative fermentation process • to validate the parts of process involving connections, sampling, and additions of nutrients etc. • fermentor prepared and operated in simulated process with uninoculated nutrient media • process follow the full fermentation process • 3 consecutive runs at each stage