1. VALIDATION & PERSONNEL
GUIDED BY:
DR.N.P. CHOTAI
PREPARED &PRESENTED BY:
VISHAL B,NAKRANI
M.PHARM(Q.A.,2nd SEM.)
ID.NO:05PH912
DATE:31/05/06

2. Content:
Validation definition
Advantage of validation
Protocol development
GMP Inspector’s check list for validation
Personnel
Validation Working Groups
Reference

3. Validation WHO validation definition
The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results.
As indicated in Part 1 of this module, the WHO validation definition is:
“The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results.”
From: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, (WHO Technical Report Series, No 823). Annex 1.

4. The WHO GMP Guidelines state:
Validation studies are an essential part of good manufacturing practice and should be conducted in accordance with predefined protocols.
written report
process and procedures
processing
testing
cleaning procedures
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

5. Functionality, consistency and
repeatability
is confirmed by
validation
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

6. does not improve the process but it
Validation as such
does not improve the process
but it
confirms and assures that the process
Has been well developed
It is well maintained
It operates as it should
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

7. 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 produce according to the marketing authorisation
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

8. 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

9. Protocol development
Each stage in the validation of the overall process should proceed in accordance with a pre-established and formally approved detailed, written protocol, or series of related protocols.
Protocols should have a Title, Date and a unique Identification or Reference Number. They should be formally authorized/approved by persons with the competence and authority to do so.

10. It should specify the objectives and scope of the study
It should specify the objectives and scope of the study. Like, a clear and precise definition of the process, equipment, system or sub-system which is to be the subject of the study, with details of performance characteristics.

11. DQ IQ OQ PQ relationships and considerations:
DQ (Design Qualification) should relate to Process: what needs to be done? DQ can be user requirements.
IQ (Installation Qualification) considerations include:
Equipment design features (i.e. materials of construction cleanability, etc.)
Installation conditions (functionality, utilities, wiring, etc.)
Calibration, preventative maintenance, cleaning schedules; safety features
Supplier documentation, prints, drawings and manuals, software documentation
Environmental conditions (such as clean room requirements, temperature, humidity)
Spare parts list
OQ (Operational Qualification) considerations include:
Process control limits (e.g. time, temperature, pressure, line speed, setup conditions)
Software parameters; starting material specifications
Process operating procedures; material handling requirements
Process change control; training; short term stability and capability of the process, (latitude studies or control charts)
Risk analysis and potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis)
PQ (Performance Qualification) includes:
Actual product and process parameters and procedures established in OQ
Assurance of process capability as established in OQ
Acceptability of the product
Process repeatability, long term process stability

12. GMP Inspector’s check list for validation (1)
Check that the manufacturer has:
A VMP and multi-functional team for validation
Planned approach , defined requirements
Identified and described processes
Analyse the amount of validation work to perform
Check list for validation:
This is a list of activities which may be used as a checklist to review validation activity. The manufacturer should:
Create a master validation plan: as described in Part 1.
Form a multi-functional team for validation: as described in Part 1.
Plan the approach, and define the validation requirements.
Identify and then describe the processes.
Specify the process parameters and desired output.
Analyse the amount of validation work to perform. It is most important that the inspectorate and the manufacturer agree on the risk involved and the extent of validation. High risk products, such as biologicals derived from human blood must be at one end of the scale (requiring considerable validation effort), while at the other end may be very simple, low risk, over- the-counter medicines requiring less validation.

13. GMP Inspector’s check list for validation (2)
Check that the manufacturer has:
Selected methods and tools for validation
Created protocols
Performed DQ, IQ, OQ, PQ and documented results
Exerted change control, set revalidation time
Check list for validation: (Contd.)
This is a continuation of the list of activities which may be used as a checklist to review validation activity. The manufacturer should:
Select methods and tools for validation
Create validation protocols
Perform DQ, IQ, OQ, PQ and document results
Exert change control and set revalidation time or frequencies

14. Validation - Logical entity:
protocol +
procedure +
report
Summary
Validation is a quality tool to ensure that quality is designed into a process. Validation is a requirement that has always made sense from both a regulatory and quality perspective.
Validation is regarded as a prevention-based activity: if more effort is placed on development and validation at the beginning, then there will be less chance of failure during the product’s life.
Validation is expensive, a growth industry and in danger of becoming overwhelming for many pharmaceutical manufacturers, particularly those in developing nations. The result may be not to complete any validation work at all. However, the risk-based assessment and determination of critical steps of manufacture should be used to identify what needs to be validated, and what can be simply verified, by testing if needs be.
A key statement is: “The process must be under control”; that is, by quality terms, it must be a capable process. Juran defines process capability as "the measured, inherent reproducibility of the product turned out by a process.” In validation the manufacturer is trying to measure reproducibility and establish that the variability falls within pre-established confidence limits.
Suggested Reading: J. M. Juran and Frank M. Gryna, eds., Juran's Quality Control Handbook, 4th Edition, McGraw-Hill, Inc, 1988.

15. Personnel
Personnel actually performing any validation studies, and in routine operation can have so crucial an effect on the quality of the end-product, it is appropriate and necessary to consider both these aspects of personnel involvement.
Appropriately qualified personnel should ensure that the protocol and the testing methodology are properly evaluated and certified.

16. All personnel conducting tests should be trained and experienced in the use of the instruments, measuring devices and materials used.
Engineering/maintenance personnel should be fully trained and competent in the operation and maintenance of the machines, equipment, and air control systems involved.
Any operators involved in performing a validation study should adopt the same techniques, disciplines, and standards of hygiene, clothing and behavior as in normal routine manufacture.

17. It is therefore vital that all personnel involved in validation are trained, and fully understand, the concepts and principles of GMP, and validation.
They must understand the importance of personal hygiene and cleanliness, and be made fully aware of the possible hazardous consequences of product contamination.
Operators should be provided with suitable Clean Room clothing and trained in appropriate gowning technique.

18. The type of clothing to be worn, and gowning process should be defined in written procedures, available to the operators, and preferably displayed in the changing room.
The same clothing/gowning standards should be observed during validation studies as in routine production, and vice versa.

19. Validation Working Groups
The executive part of the validation work should be delegated to dedicated personnel:
Director of validation
Manager or senior manager of validation
A representative from quality assurance
A representative from technical services
A representative from research & development
A representative from quality control
A representative from production

20. Director of validation
Primary responsibility:
• Directs company-wide process validation program.
• Directs company-wide cleaning validation program.
• Reviews and/or approves Master Batch Records for development and Production, as required.
• support company-wide equipment qualification and validation program.

21. • Supports company-wide computer system validation program.
•Supports company-wide activities associated with development of new technology, improvement of existing technology and utilizing newer, more automated equipment and processes.
•Supports company management in evaluation of new products, technology and equipment.

22. Essential functions:
Designs, implements and oversees company-wide programs for process and cleaning validation.
Ensures that the system is in compliance with federal and industry guidelines, and that each system is documented and tracked in an orderly manner.
Designs, implements and oversees studies aimed to determine whether process or systems meet or exceed the specifications of its design, is suitable for its intended application, conforms to cGMP requirements, satisfies concerns of regulatory agencies and meets company goals established for quality.

23. Reviews and gives final approval for written validation protocols and summaries.
Reviews and approves validation section of change control notices to ensure that each process continues to operate within its designed parameters.
Reviews and approves procedures that have been established to revalidate the process in the event of a process or equipment change.

24. Ensures validation protocols and studies are properly documented, archived and stored for timely retrieval.
Discusses validation studies and plans with customers and regulatory agencies as required during reviews or inspections.
Develop and submit quarterly and monthly reports as defined by Manager
Responsible for Master Validation Plans, SOP’s, and Validation Guidelines. Reviews and approves SOP’s in their related area.
Reviews and approves Master Batch Records.

25. Oversees and approves all documents pertaining to company’s quality development program, such as process development protocols and technology assessment summaries.
Designs and evaluates all documents associated with development and implementation of new technology and improvement of existing technologies, such as master batch records, evaluation protocols, summary reports and change control notices.
Participates in other activities, as may be requested, relative to new products and/or new technology transfers.

26. Performs employees performance reviews and submits them for approval in a timely fashion.
Takes any corrective actions required up to and including termination as appropriate and in accordance with company policies and procedures.
Builds and maintains a staff of professional, highly motivated and knowledgeable individuals.
Participates in selection of personnel and provides effective training.
Establishes standards of performance in accordance with company guidelines and evaluates performance against those standards for all staff members.

27. Knowledge/Skills/Abilities
Thorough knowledge and understanding of governmental requirements and industry standards, related to current Good Manufacturing Practices and other appropriate government regulations and requirements as related to essential job functions
Thorough knowledge of current validation compliance, standards, requirements for a Pharmaceutical Industry, both domestic (FDA) and international (ICH).
Ability to establish validation standards, SOP’s and audits meeting current and future FDA requirements
Experience working with and/or leading cross-functional groups

28. Excellent written, verbal and interpersonal communication skills, highly organized and detail-oriented.
Ability to effectively and directly interface with FDA and technical company personnel at various levels
Ability to effectively communicate, directing, guiding personnel who are not direct reports.
A strong scientific experience and knowledge of analytical, research, engineering, manufacturing, quality control and quality assurance.

29. Good computer skills with knowledge of Microsoft Office programs (Word, Excel, Power point )
Ability to utilize statistical techniques and approaches to reach scientifically sound decisions regarding validation issues
Thorough knowledge and understanding of product formulations, pharmaceutical technology and equipment performance relative to solid dosage forms, liquids and semi-solids.

30. Education/Experience
B.S., M.S. or PhD in Industrial Pharmacy, Pharmaceutics, Chemical Engineering or related science area

31. Manager/Senior Manager, Validation
Responsibilities:
Responsible for the management of the Validation Department personnel
Responsible for Validation Department budget development and monitoring
Lead and coordinate the qualification and validation efforts for new GMP facilities

32. Ensure that appropriate validation master plans addressing facilities, utilities, equipment, cleaning, and process are established and implemented according to timelines
Manage and coordinate the activities of contractors performing qualification and validation work
Ensure that a validation/re-validation program is established and implemented in the new manufacturing facility and provide program oversight

33. Review, approve, source and/or write validation documents
Provide technical expertise and interpretation on regulations and guidelines as they relate to validation activities
Oversee the development and revision of validation procedures and protocols to ensure that regulatory compliance and company objectives are maintained
Ensure that the Validation Department personnel are appropriately coached, trained and developed for current and anticipated projects
Prepare and assist with the inspections from regulatory agencies

34. Requirements:
Bachelor’s degree in Engineering, Science or related technological field or equivalent combination of education and experience
Seven to ten years experience of validation experience in a cGMP environment with increasing levels of responsibility for a wide range of validation projects
Thorough knowledge of validation principles, manufacturing processes, quality systems, engineering design fundamentals, regulatory agency expectations and industrial trends
In-depth knowledge of validation requirements (GMP, FDA, etc.) for pharmaceutical manufacturing facilities, equipment and systems

35. Proven track record in managing a validation department with multiple direct reports
Demonstrated ability in effectively managing multiple validation projects simultaneously
Excellent leadership and organization skills to effectively directing and managing validation personnel and contractors in ensuring project completion on time
Excellent verbal and written communication skills including the ability to write, revise, and comment on validation protocols and reports

36. Research & development
SPECIFIC RESPONSIBITIES OF EACH PERSONNEL WITH THE SCOPE OF VALIDATION
Engineering
Install; qualify & certify plant, facilities equipment & support system.
Research & development
Design and optimize manufacturing process within design limits specification &/or requirements in other words , the establishment of process capability information
Production
Operate & maintain plant, facilities, equipment support system & the specify manufacturing process within its design limits, specification&/or requirements
Quality-assurance
Establish approach validation protocol & conduct process validation by monitoring, sampling, testing, challenging, &/or auditing the specific manufacturing process for compliance with design limits, specification, &/or requirements

37. Reference:
1.mednet3.who.int/prequal/pq_pres/ workshop_Russia/M08-Validation02-f_U.ppt
2.siop.org/_Principles/principlesdefault.htm - 16k k
4. Pharmabiz, Sunday, april09, 2006
5.Validation standard operating procedure

38. THANK YOU