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

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. Pool/Concentrated material
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 precaution should 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. Avoided by taking appropriate technical e.g.
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
cleaned without delay,
stored under clean 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 biological products :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 biological products :Production
Media should be sterilized in situ. In line 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 biological products :Production
A wide equipment used for chromatography
should be dedicated to purification of one product
should be sterilized 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.
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีสำหรับโรงงานผลิตชีววัตถุ

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. Separate validation for
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 Concurrent Retrospective
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 validation studies
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

51. Typical content requirements for process validations
Production processes(fermentation, bulk production, purification, filling, lyophilization)
run according to approved Master formula including all raw material, personnel, equipment, and facility preparations, in-process tests, processing, through to final testing of the batch lot.
all facility systems must be monitored
3 consecutive lots must be produced and all facility, EQ, support systems, product spec, and process being validated must pass at all steps

52. Validation: Type of Documentation
Validation master plan (VMP)
Validation protocol (VP)
Validation reports (VR)
Standard operating procedures (SOPs)

53. Master validation plan (MVP)
is a document pertaining to the whole facility that describes which EQ, systems, methods and processes will be validated and when they will be validated.
provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation)

54. Master validation plan (MVP)
indicate what information is to be contained within each document
indicate why and when revalidations will be performed
who will decide what validations will be performed
order in which each part of the facility is validated

55. Master validation plan (MVP)
indicate how to deal with any deviations
state the time interval permitted between each validation

56. Validation: VMP Enables overview of entire validation project
List items to be validated with planning schedule as its heart
like a map

57. Validation: In summary, VMP should contain at least
Validation policy
Organizational structure
Summary of facilities, systems, equipment, processes to be validated
Documentation format for protocols and reports
Planning and scheduling
Change control
Training requirements

58. Validation: Protocol
Objectives of the validation and qualification study
Site of the study
Responsible personnel
Description of the equipment
SOPs
Standards
Criteria for the relevant products and processes

59. Validation: Report Title objective of the study Refer to the protocol
Details of material
Equipment
Programmes and cycles use
Details of procedures and test methods

60. Validation: changes that require revalidation
Software changes; controllers
Site changes; operational changes
Change of source of material
Change in the process
Significant equipment changes
Production area changes
Support system changes