1. Overview of Validation Requirements Pharmaceutical Industry
Kaushik Desai
Chairman,
Industrial Pharmacy Division
Indian Pharmaceutical Association

2. Agenda A definition Where did validation come from ? Why do it ?
What are the benefits ?
How far do we have to go ?

3. Definition ( FDA)
“ Establishing the documented evidence which provides a high degree of assurance that a specific process will consistently produce a product of predetermined specifications and quality attributes.”
(FDA Guidelines 1987)

4. Definition ( FDA)
“Process validation is defined as the collection & evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that process is capable of consistently delivering quality product.”
(FDA Guidelines, 2011)

5. Definition (EU GMP)
“Action of proving, in accordance with the principles of Good Manufacturing Practice (GMP), that any procedure, process, equipment, material, activity or system actually leads to expected results.”
(EU GMP 1997)

6. Where did validation come from ?
Began in 1970’s
Originally sterilized based.
Now evolved into all Product, Process and Facility matters.

7. Why Validate ? Assures Quality Regulatory Requirement Reduces Cost
It’s the LAW !

8. Benefits Validation can reduce costs by reducing, Rejects Reworks
Reliance on In-process controls
Down time

9. When it goes wrong …..? Reliance on product testing Loss of confidence
Possibility of adulterated products
Inspection : Observations / 483’s

10. Validation Terminology
User Requirement Specification (URS)
Design Qualification
Impact Assessment
Factory Acceptance Testing
Installation Qualification

11. Validation Terminology
Calibration
Site Acceptance Testing
Operational Qualification
Standard Operating Procedures
Performance Qualification
Process Validation
Change Control

12. Validation Terminology
User Requirement Specification (URS)
A description of the requirements of the facility (project) in terms of product to be manufactured, required throughput and conditions in which the product should be manufactured.
Approved statements prepared by the user which defines what is required by the project.

13. Validation Terminology
Design Qualification (DQ)
Documented review of the design, at an appropriate stage in a project, for conformance to operational and regulatory expectations.
(Note : Not an obligation)

14. Validation Terminology
Impact Assessment
The process of evaluating the impact of the operating, controlling, alarming and failure conditions of a system on the quality of a product

15. Validation Terminology
Factory Acceptance Testing (FAT)
Inspection and static and/or dynamic testing of systems or major system components to support the qualification of an equipment system conducted and documented at a supplier site.
(Note : Not an obligation)

16. Installation Qualification (Definition)
Documented verification that all aspects of a facility, utility or equipment that can affect the product quality adhere to approved specifications and are correctly installed.
The process of checking/verifying the installation to ensure that the critical components meet the approved specifications and that they are installed correctly in accordance with design documentation.

17. Installation Qualification (PURPOSE)
To establish that the critical components are installed correctly and in accordance with design documentation requirements (i.e. PO’s, Contracts etc.), that supporting documentation is in place and of suitable quality.
To record the checks and verifications for critical components in Direct Impact Systems.

18. IQ Protocol (Contents)
Approval Page
Objectives
System Description
Responsibilities
Acceptance Criteria
Engineering Documentation Requirements
Records of Signatures
Qualification Test Equipment/Instrument List
Product Contact Materials Review
Utilities Verification
Control System Verification

19. IQ Protocol (Contents)
Instrument/Control Devices Verification
Equipment Verification
Piping Installation Verification
Discrepancy/Justification and corrective Action
As built P&I Diagrams
Specifications
Conclusions
References
Modification/ Change Control
Attachments / Appendices

20. Basic IQ – Mfg. vessel Parameters
Does the vessel meet the design specification?
Does the agitator assembly meet the design specification?
Is the motor housing earthed?
Is the motor over current device set to correct setting?
Is all the pipe work connected?
Are all instruments installed as per P&I diagram?
Have all the temperature indicators been calibrated?
Is calibration procedure available?
Are operation and maintenance manuals available?
all electrical connections securely and safely fitted?
Is insulation complete?
Is vessel clean and free from dirt?

21. IQ Protocol Approval
After protocol execution is complete and deviations evaluated, post execution approval is required.
Requires sign off by original signatories.
IQ execution should be complete and approved prior to the start of OQ.

22. Validation Terminology
Calibration
Demonstrating that a measuring device produces results within the specified limits of those produced by a reference standard over an appropriate range of measurements.
The devices are normally tagged and supported by a maintenance procedures.

23. Validation Terminology
Site Acceptance Testing (SAT)
Inspection and dynamic testing of systems or major system components to support the qualification of an equipment system conducted at a client site.
(Note : Not an obligation)

24. Operational Qualification (Definition)
Documented verification that all aspects of a facility, utility or equipment that can affect product quality operate as intended throughout all anticipated ranges. It is the process of testing to ensure that individual components and systems operate as specified, and how that information is recorded.

25. Operational Qualification (PURPOSE)
To establish through documented testing, that all critical components and direct impact systems are capable of operating within established limits and tolerances.
To test parameters that regulate the process or product quality. To verify the proper operation of controllers, indicators, recorders, alarms and interlocks, is performed and documented during the operational qualification testing.

26. Operational Qualification (Protocol)
Approval page
Pre-requisites
Objectives
System Description
Responsibilities
Acceptance Criteria
Records of signatures
Qualification test Equipment/Instruments list
Alarm and Interlocks test
Operation testing
Capacity testing
Power failure testing

27. Operational Qualification (Protocol)
Sequence testing
Test data sheets
SOP’s
Conclusions
Modification / change control
Discrepancy/Justification and corrective action
Operational Qualification Summary
References
Attachments/Appendices
- Verification of test instruments
- Chart recordings
- P&I diagrams
- Printouts

28. OQ – Mfg. vessel
Parameters
Have all Installation Qualification been completed for this system?
Is the system clean and free from dirt?
Is the direction of the rotation of agitator correct?
Check the operation of the agitator emergency stop?
Check the operation of all agitator controls, both on the main and local panels?
Check that the agitator in the vessel free to turn?
Pressurize the vessel and record the pressure drop for 10 min.
Perform a vacuum test and record the vacuum drop.

29. Performance Qualification (Definition)
Documented verification that all aspects of a facility, utility or equipment that can affect the product quality perform as intended in meeting the predetermined acceptance criteria.

30. Performance Qualification (Purpose)
To integrate procedures, personnel, systems and materials to verify that the utility / environment / equipment / support systems produces the required output. This output may be a product contact utility, sterilization condition or environment.

31. Performance Qualification (Protocol)
Approval page
Pre-requisites
Objectives
System Description
Responsibilities
Acceptance Criteria
PQ test plan
Challenge test plan
Records of signatures
Test equipment/Instrument list
Test data sheets
SOP’s
References
Conclusions
Attachments

32. Validation Terminology
Process Validation
The documented verification providing a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.
The new guidelines aligns process validation activities with a product life cycle concept.

33. US FDA (21 cfr)– Process Validation
211.42, , ,
(a) , (a), (b)
(b), (c), (d), (e)

34. Process Validation Life Cycle of the product & the process
Stage 1 – Process Design
Stage 2 – Process qualification
Stage 3 - Continuous process verification

35. Stage 1 - ProcesS dESIGN
It is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records.
The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
It is based on the knowledge gained through development & scale-up activities.

36. Stage 2 – Process qualification
During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. The products manufactured during this stage, if acceptable , can be released for distribution.
Two Aspects
Design of facility and qualification of equipment and utilities.
Process Performance Qualification ( PPQ).

37. Concurrent rELEASE
Def.: “Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the standards established in the protocol, but before the entire study has been executed”.
Orphan Drugs
Specific drug for specific use
Short Shelf-life radio pharmaceuticals

38. SATGE 3 – Continued process verification
The goal of this stage is continual assurance that the process remains in a state of control ( the validated state) during commercial manufacture.
The cGMP requirements, specifically the collection & evaluation of information & data about the performance of the process will allow detection of undesired process variability.
This stage is also applicable for legacy products.

39. Validation Terminology
Change Control
Formal evaluation of the potential impact of planned modifications on the validated status of a product, process or facility.

40. Training Training personnel for IQ/OQ execution.
The purpose of the equipment/ system.
Use of test equipment
Applicable SOP’s
cGMP documentation of training
Document all training
Periodically review training requirements

41. Final Summary Report
A document that summarizes and analyses the test results at the end of PQ.
Provides a conclusion about the ability of the system to consistently meet acceptance criteria.
May be a stand alone document at each stage of IQ/OQ and PQ to summarize results.

42. Basic IQ/OQ/PQ
Commissioning and Qualification Project Phases Validation Phases Technology Transfer Collecting data Conceptual Design Basic Design Preliminary VMP Detailed Design Detailed VMP Procurement Detailed planning,DQ Construction IQ Pre commissioning Commissioning OQ Process operation / Validation

43. Validation Master Plan
Introduction
Qualification
Personnel
Schedule
Preventive
Maintenance
Installation
Responsibilities
Change
Control
Operation
Training
Procedures
Documents
Appendices
Process

44. Validation Policy
The company’s overall policy, intentions and approach to validation, including :
Validation of production processes
Cleaning procedures
Analytical methods
In-process control test procedures
Computerized systems
Persons responsible for design, review, approval
Documentation of each validation phase

45. Product Validation Product validation is NOT ……
- just 3 batches that meet specifications
Product validation is ……
- an ongoing process to build confidence into
the manufacturing activities
- an ability to demonstrate consistency at any
time.

46. Cleaning Validation
Cleaning validation is establishing documented evidence that the equipment is consistently cleaned from product, microbial and cleaning agent residues to predetermined acceptable levels.

47. FDA Expectations A written procedure for cleaning validation
which includes :
Responsibility for development, performance and approval of the validation study.
Establishment of SOP’s
Acceptance criteria
- defined to prevent cross contamination
- definition of residue limits

48. Prior to Cleaning Validation Establish specific SOP’s
Cleaning procedure for each piece of equipment
- Flow charts and diagrams
- Cleaning agents, concentration, volume
- Frequency
- time left ‘dirty’

49. Cleaning Validation Sampling procedures - swabs, rinse, location
Residue limits
Analytical methods

50. Cleaning Validation Validation report
- Results Vs. acceptance criteria
- Deviations and how handled
- Conclusion that cleaning process is
validated

51. Revalidation Major change in cleaning procedure
Change in cleaning agent
New equipment

52. Establishment of limits
Knowledge of the materials
- Potency of the drug
- Pharmacological and toxic properties
- Degradation products
- Cleaning agents
- Micro residues

53. Establishment of Limits
Residual Limits must be………….
Practical
Achievable
Verifiable
Safe
FDA does not set acceptance specifications (limits).

54. Setting of Limits MAC = TD x BS x SF / LDD
MAC = Maximum Allowable Carryover
TD = Single Therapeutic Dose
BS = Batch size of next product to be
manufactured on the same equipment.
SF = Safety Factor
LDD = Largest Daily Dose of the next product
in the same equipment.

55. Example
Ranitidine Tablets - Ibuprofen Tablets TD = Single Therapeutic Dose = 150 mg Ranitidine-Tab BS = Batch Size = 100 kg of Ibuprofen SF = Safety Factor = 1/1000 LDD = Largest Daily Dose of the next product in the same equipment = 200 mg X 5 tablets of Ibuprofen MAC = Max Allowable Carryover = 150 X 100 X 1000 x 1000 X 1/1000 X 1/1000 i.e mg in 100 kg Batch size i.e 150 mg in 1 kg = 150 ppm

56. Thank you