1. Pharmaceutical Validation
Introduction to
Pharmaceutical Validation

2. Contents What is Validation? When is validation needed?
Some Purposes of Validation
Approaches to validation
Scope of validation
Advantages of validation
Organization for validation

3. Concurrent validation Retrospective validation Revalidation
Types of Documentation
Validation Master Plan
Types of Process Validation
Prospective validation
Concurrent validation
Retrospective validation
Revalidation

4. Prerequisites for process validation
Qualification
Design qualification
Installation qualification
Operational qualification
Performance qualification
References

5. What is Validation? Definition :
Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result.
ISO definition :
Validation is the confirmation by examination and the provision of objective evidence that the particular requirements for a specific intended use are fulfilled.

6. What is Validation?
According to the Food and Drug Administration (FDA), the goal of validation is to:
“establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.”

7. Method Validation :
Method validation is the process of establishing the performance characteristics and limitations of a method and the identification of the influences which may change these characteristics and to what extent. It is also the process of verifying that a method is fit for purpose.

8. When is validation needed?
Before introduction of a new method into routine use.
Whenever the conditions change for which a method has been validated, e.g., instrument with different characteristics
Whenever the method is changed, and the change is outside the original scope of the method.

9. Some Purposes of Validation
To accept an individual sample as a member of a population under study.
To admit samples to the measurement process.
To minimize later questions on sample authenticity.
To provide an opportunity for resampling when needed.

10. Approaches to validation
Two basic approaches:
Evidence obtained through testing (prospective and concurrent validation), and
Analysis of accumulated (historical) data (retrospective validation)
Whenever possible, prospective validation is preferred.
Retrospective validation is not applicable to sterile products

11. Both prospective and concurrent validation, may include:
extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity;
simulation process trials;
challenge/worst case tests, which determine the robustness of the process; and
control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.

12. Scope of validation
Validation requires an appropriate and sufficient infrastructure including:
organization, documentation, personnel and finances
Involvement of management and quality assurance personnel
Personnel with appropriate qualifications and experience
Extensive preparation and planning before validation is performed
A specific programme for validation activities in place

13. Validation done in a structured way according to documentation including procedures and protocols.
Validation should be performed:
for new premises, equipment, utilities and systems, and processes and procedures;
at periodic intervals; and
when major changes have been made.
Validation in accordance with written protocols.

14. Demonstrate suitability for new manufacturing formula or method
A written report on the outcome to be produced.
Validation over a period of time, e.g.
at least three consecutive batches (full production scale) to demonstrate consistency. (Worst case situations should be considered.)
Demonstrate suitability for new manufacturing formula or method

15. Process, materials and equipment to prove consistent yield of a product of the required quality
Manufacturers to identify what validation work is needed
Significant changes (facilities, equipment, processes) - should be validated
Risk assessment approach used to determine the scope and extent of validation needed

16. Advantages of validation:
During the process the knowledge of process increases
Assures the repeatability of the process
Assures the fluency of production
Assures that the product is continuously according to the marketing authorisation
Decreases the risk of the manufacturing problems
Decreases the expenses caused by the failures in production
Decreases the risks of failing in GMP
Decreases the expenses of the every day production even though the validation itself will create expenses

17. Organization for Validation
The qualification and validation work can be organized by employing one or more of the following structures :
The consultant
The task force
The dedicated group.
Ideally there should be a department in the organization. But if it is not possible then, these alternative approaches are used for the work.

18. The Consultants :
On the commercial basis several consultants undertake the work.
Consultants can apply the experience gained in the other companies.
The persons with consultants may not be permanent employees, they may be on contractual basis.
There is a risk of incomplete job and extra expenses, if the validation job is not completed by the consultants within the bounds of time and cost.

19. The task force :
The task force concepts refers to organisation structure with in the company in which persons proficient in different fields are drawn from different departments.
Usually, persons are drawn from different departments.
The departments are production, engineering , quality assurance, research and developments.
The head of the committee is resposible for validation work.

20. The dedicated group :
In the dedicated group members from the following departments are selected :
Production
Engineering
Calibration laboratory
Quality control laboratory
Maintenance
HVAC
Product development

21. Department interaction :
Once the validation team has been constituted and mission have been formalized, the team will interact with different departments which are :
Research and development department
Engineering department,
Production department,
Maintenance department,
Quality control department,
Quality assurance department.

22. Types of Documentation
Validation Master Plan (VMP)
Validation protocols (VP)
Validation reports (VR)
Standard Operating Procedures (SOPs)

23. Approval page and table of contents Introduction and objectives
The Validation Master Plan could consist of:
Approval page and table of contents
Introduction and objectives
Facility and process description
Personnel, planning and scheduling
Responsibilities of committee members

24. Process control aspects
Equipment, apparatus, processes and systems to be validated
Acceptance criteria
Documentation e.g. validation protocols and reports
SOPs
Training requirements

25. Protocol Protocol consists of :
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

26. Report Report consists of : Title Objective of the study
Refer to the protocol
Details of material
Equipment
Programmes and cycles use
Details of procedure and test methods

27. Validation Master Plan
Principle Validation in general requires a meticulous preparation and careful planning of the various steps in the process. In addition, all work involved should be carried out in a structured way according to formally authorized standardized working and administrative procedures.

28. In addition validation is characterized by:
Multidisciplinary approach:
A specific characteristic of validation work is that it requires the collaboration of experts of various disciplines such as pharmacists, technologists, metrologists, chemical analysts, microbiologists, engineers, experts on Q.A. validation etc..
Time constraint:
Generally validation work is submitted to rigorous time schedules. These studies are always the last stage prior to taking new processes, facilities into routine operation.
Costs:
Validation studies are costly as they require time of highly specialized personnel and expensive technology.

29. Purpose
The VMP should present an overview of the entire validation operation, its organizational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule.
A VMP helps management:
to know what the validation programme involves with respect to time, people and money, and to understand the necessity for the programme;

30. A VMP helps all members of the validation team:
to know their tasks and responsibilities.
A VMP helps GMP inspectors:
to understand the firm's approach to validation and the set up an organisation of all validation activities.

31. Definition
A Validation Master Plan is a document that summarises the firm's overall philosophy, intentions and approach to be used for establishing performance adequacy.

32. Scope
All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in a VMP. This includes qualification of critical manufacturing and control equipment.
It should comprise all Prospective, Concurrent, Retrospective Validations as well as Re-validations.
In case of large projects like the construction of a new facility, often the best approach is to create a separate VMP. (In such situations the VMP should be part of the total project management.)

33. Format and Content
The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents, SOP's and Validation Protocols/Reports.
The VMP should be agreed by management.

34. A VMP should contain data on the following subjects/proposed chapters.
Introduction
Firm's validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities).
Plant / Process / Product Description
Provides a cross reference to other documents. A rationale for the inclusion or exclusion of validations, for the validation approach and the extent of validation should be included.

35. Organizational Structure of All Validation Activities
Personnel responsibility for the VMP, protocols of individual validation projects, validation work, report and document preparation and control, approval / authorization of validation protocols and reports in all stages of validation processes, tracking system for reference and review, training needs in support of validation.
Specific Process Considerations
Under this heading specific characteristics / requirements of the plant / process etc. that are critical for yielding a quality product and need extra attention may be briefly outlined here.

36. List of Products / Processes / Systems to be Validated
All validation activities comprised in the VMP should be summarized and compiled in a matrix format. Such matrix should provide an overview and contain:
All items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ]. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems,
The validation approach, i.e. Prospective, Retrospective or Concurrent, the Re-validation activities, actual status and future planning.

37. Key Acceptance Criteria
statement on key acceptance criteria for the items listed under above.
Documentation Format
The format to be used for protocols and reports should be described or referred to.
Required SOP's
List of relevant SOP’s should be presented.

38. Planning & Scheduling
An estimate of staffing (including training needs), equipment and other specific requirements to complete the validation effort should be described in the VMP. A time plan of the project with detailed planning of subprojects. This time plan could be included in the above mentioned matrix A VMP requires regular updating.
Change Control
A statement of the company's commitment to controlling critical changes to materials, facilities, equipment or processes (including analytical techniques), should be included.

39. Types of Process Validation
Experimental approach
Prospective validation
Concurrent validation
Analysis of historical data
Retrospective validation
Revalidation
Periodic revalidation
Revalidation after change

40. Prospective validation
carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps.
These are then evaluated on the basis of past experience to determine whether they might lead to critical situations.
Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set.

41. The trials are then performed and evaluated, and an overall assessment is made.
If, at the end, the results are acceptable, the process is satisfactory. Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory.
This form of validation is essential in order to limit the risk of errors occurring on the production scale, e.g. in the preparation of injectable products.

42. Concurrent validation
carried out during normal production
This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process
The first three production-scale batches must be monitored as comprehensively as possible.
The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.
This careful monitoring of the first three production batches is sometimes regarded as prospective validation.
Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product.

43. Retrospective Validation
Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged
such experience and the results of in-process and final control tests are then evaluated.
Recorded difficulties and failures in production are analyzed to determine the limits of process parameters.

44. A trend analysis may be conducted to determine the extent to which the process parameters are within the permissible range.
Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company.

45. Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule.
For tablets which have been compressed under individual pressure-sensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. On the other hand, it should not be applied in the manufacture of sterile products.

46. Revalidation
Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.
Revalidation may be divided into two broad categories:
• Revalidation after any change having a bearing on product quality • Periodic revalidation carried out at scheduled intervals.

47. Revalidation after changes :
Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics.
Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent.

48. Revalidation after changes may be based on the performance of the same tests and activities as those used during the original validation, including tests on sub processes and on the equipment concerned. Some typical changes which require revalidation include the following:
• Changes in the starting material(s) :
Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product.

49. • Changes in the packaging material :
e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability.
• Changes in the process :
e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality.

50. Changes in equipment :
e.g. measuring instruments, may affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process.
• Changes in the production area and support system :
e.g. the rearrangement of manufacturing areas and/or support systems, may result in changes in the process. The repair and maintenance of support systems, such as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the manufacture of sterile products.
• Unexpected changes and deviations may be observed during self-inspection or audit, or during the continuous trend analysis of process data.

51. Periodic revalidation
It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made.
The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during in-process and finished product testing after the latest validation, aimed at verifying that the process is under control. During the review of such historical data, any trend in the data collected should be evaluated.

52. In some processes, such as sterilization, additional process testing is required to complement the historical data. The degree of testing required will be apparent from the original validation.
Additionally, the following points should be checked at the time of a scheduled revalidation:
• Have any changes in master formula and methods, batch size, etc., occurred? If so, has their impact on the product been assessed?
• Have calibrations been made in accordance with the established programme and time schedule?

53. Has preventive maintenance been performed in accordance with the programme and time schedule?
• Have the standard operating procedures (SOPs) been properly updated?
• Have the SOPs been implemented?
• Have the cleaning and hygiene programmes been carried out?
• Have any changes been made in the analytical control methods?

54. Prerequisites for process validation
Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. Thus qualification is the prerequisites for validation.
The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e. before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc.

55. Other aspects of manufacture must be validated, including critical services (water, air, nitrogen, power supply, etc.), and supporting operations, such as equipment cleaning and sanitation of premises. Proper training and motivation of personnel are prerequisites to successful validation.

56. Qualification
Qualification should be completed before process validation is performed
A logical, systematic process followed
Start from the design phase of the premises, equipment, utilities and equipment
Major equipment and critical utilities and systems normally require IQ, OQ and PQ

57. Some equipment, utilities and systems require only IQ and OQ as the correct operation could be considered to be a sufficient indicator of its performance
The equipment, utility and system should then be maintained, monitored and calibrated according to a regular schedule

58. Qualification Vs Validation
Qualification and validation are essentially components of the same concept
The term qualification is normally used for equipment, utilities and systems
The term validation is normally used for processes
In this sense, qualification is part of validation

59. Qualification stages There are four stages of qualification:
design qualification (DQ);
installation qualification (IQ);
operational qualification (OQ); and
performance qualification (PQ).
All SOPs for operation, maintenance and calibration should be prepared during qualification
Training provided and records maintained

60. Design qualification: Provides documented evidence that the design specifications were met
Installation qualification: Provides documented evidence that the installation was complete and satisfactory
During IQ:
Purchase specifications, drawings, manuals, spare parts lists and vendor details should be verified
Control and measuring devices should be calibrated

61. Operational qualification:
Provides documented evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications
Demonstrate satisfactory operation over the normal operating range as well as at the limits of its operating conditions (including worst case conditions)
Operation controls, alarms, switches, displays and other operational components should be tested

62. Performance qualification:
Provides documented evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use
Test results collected over a suitable period of time to prove consistency

63. Requalification
In accordance with a defined schedule
Frequency to be determined (e.g. on the basis of factors such as the analysis of results relating to calibration, verification and maintenance)
Periodic and after changes
e.g. changes to utilities, systems, equipment; maintenance work; and movement
Part of change control procedure

64. References
P. P. Sharma, “Validation in Pharmaceutical Industry-concepts, approaches & guidelines”, 1st edition, 2007 Vandana Publication House.
B. T. Loftus & R. A. Nash, "Pharmaceutical Process Validation", Drugs and Pharm Sci. Series, Vol. 129, 3rd Ed., Marcel Dekker Inc., N.Y.

65. Probable questions : Describe Validation Master Plan.
Explain the types of Process Validation
What is qualification? Explain the stages of qualification.
Which types of documentation is carried out in the validation?

66.
Thank you