1. Ms. PAVITHRA .S
M.Pharm(SEM-I)
Dept. of Pharmaceutics
PRESENTED BY… GUIDED BY…
Prf. K.KARTHICK
Asso.Professor,
Dept. of Pharmaceutics.
Subject: Modern
Pharmaceutics
2. Validation is the action of proving that any procedure,
process, equipment, method, material or activities
actually leads to the expected results which produce a
quality product.
Validation is “Establishing document evidence that
provides a high degree of assurance that a specific
process will consistently produce a product meeting its
pre-determined specifications and quality attributes”.
3. Need for Validation:
◦ To obtain consistent, reliable and accurate data.
◦ To get assurance of quality product.
◦ To improve customer satisfaction.
◦ Customer mandated.
◦ Product liability.
◦ To control production cost.
◦ For the development of the next generation.
◦ Safety.
◦ Act as a proof in decision making.
4. Changes in the established methods
New method developed for a particular problem.
Established method used in different laboratories, different
equipment or different staff.
Out of control situations within internal quality assurance.
Demonstration of equivalence between two methods (eg: A rapid
new test against a standard method).
5. It is an integral part of quality assurance.
It involves controlling the critical steps of a system,
which results in output of repeatable attributes eg: a
validated tablet manufacturing process assures
attributes of product consistency from batch to batch
and a validated sterilization cycle assures the sterility of
the product.
Validation of a system indicates that system has been
subject to such a scrutiny, that results of a system can
be guaranteed.
Validation itself does not improve processes but
confirms consistent output.
6. Validation increases the knowledge of the process which is being
performed.
Assures the repeatability or reproducibility of the process.
Assures the fluency of the production
Reduces the risk of manufacturing problems such as rejection
and reworking.
Reduces the expenses caused in the failures in production.
Decreases the risk of failing in GMP or regulatory non-
compliance
Decreases the expenses of everyday production even though
validation itself will create expenses.
7. Reduces down time
Improves efficiency and productivity be optimization.
Improved employee awareness of processes.
Reduces testing of in-process or finished goods
Provides a source to meet regulatory requirements.
Reduces the chances of product recall from market.
8. The validation work requires considerable resources
such as:
• Time
• Finance
• Human(experts)
9. Qualification and Validation are essentially the same
The term qualification is normally used for equipment
and utensils, and validation is used for systems and
processes.
10. Manufacturers should organise and plan validation in a
manner that will ensure product quality, safety and efficacy
throughout its life cycle.
The scope and extent of qualification and validation should
be based on risk management principles.
Statistical calculations should be applied in order to provide
scientific evidence that the process is appropriately
validated.
It should be done in accordance with predetermined
protocols and the results should be documented.
It should be an appropriate and effective quality system
ensuring the organisation and management of validation.
11. Senior management should ensure that there are
sufficient resources to perform validation in a timely
manner. Management and persons responsible for
quality assurance should be actively involved in the
process and authorization of protocols and reports.
Personnel with appropriate qualification and experience
should be responsible for validation.
There should be a specific programme or schedule to
support planning and execution of validation activities.
Validation should be performed in a structured way
according to the documented protocols and procedures.
16. Documents associated with qualification and validation
include:
◦ Validation master plan(VMP)
◦ Standard operating procedures(SOP)
◦ Specification
◦ Protocols and reports
◦ Risk assessment outcomes
◦ Process flow charts
◦ Operator manuals
◦ Training records
◦ Calibration procedures and records
◦ Sampling plans
◦ Testing plans and methods
◦ Statistical methods and results
◦ History of qualification and validation
◦ Plan for ensuring review of validation status
◦ Plan for ensuring maintaining a validated state.
17.
18.
19. Validation documents always requested in regulatory
audits
Documentation is retained forever.
Documents reviewed long after people are gone
(it should stand alone).
FDA auditors often focus on documentation- validation
documents often requested ahead of audit.
20. Written for the reader- US vs Europe
Objective: understanding
Clarity – much more important than brevity
Stand- alone document
Potential for review in 10+ years
Author/ Managemnt not available for explanation.
Spelling and grammar should be correct
◦ Need good writers
◦ Simple sentences
◦ Simple words
21. VMP is a document , which presents overview of the entire
validation operational structure, content and planning.
It should contain data on following chapters:
◦ Validation policy of the company, general description of the scope of
those operations covered by VMP, location and schedule.
◦ Organisation and structure of validation activities, personnel
responsibility for each activity such as protocols of individual projects,
validation work, report and document preparation and their control,
approval of validation protocols and reports in all stages of validation
process, tracking system for review, training needs in support of
validation.
◦ Rationale behind any challenge or ‘worst case’ situation.
◦ Specific requirement of the plant/ processes that need extra attention
may be briefly outlined.
◦ List of products, processes and systems to be validated.
◦ Installation and qualification requirement for new equipment.
22. ◦ Planning and scheduling i.e. estimate of staffing, equipment
and specific requirements to complete the validation, time plan
of project with detailed planning of subprojects.
◦ Change control- a statement of company’s commitment to
controlling critical changes to materials, facilities, equipment
or processes, analytical method.
The VMP should be a summary document and should therefore
be brief, concise.
A VMP helps :
• Management to know what validation programme involves with
respect to time, people and money and to understand the necessity
for the programme.
• Members of validation team to know their tasks and
responsibilities.
• GMP inspectors- to understand company’s approaches to
validation and the setup an organisation of all validation activities
23.
24.
25.
26.
27. It should be prepared and the conclusion drawn at each stage
stated.
The final conclusion should reflect whether protocol
requirements were met.
The evaluation should include an assessment of the planned
calibration and maintenance programs for the equipment and
instrument to maintain the validated conditions.
All process monitoring and control procedures, required to
routinely ensure the validated conditions are maintained, should
be reported.
The analysis should be signed by the authorised officer of
organisation who were members of team establishing the
protocol and who have appropriate expertise in the area assigned
to them.
The overall approval of the study should be authorised by the
head of quality control department and head of validation team.
28. Aim and purpose of the study
References to protocols
List of raw materials used
List of equipment used
Critical process steps studied
Results of data collected
Acceptance criteria evaluation
Analysis of result
Validation recommendation
Attachments (Batch records.)
29.
30. Technical areas must be aware that their documents are
critical to validation throughout the product lifecycle.
Process capability design is done to determine:
◦ The number and relative importance of critical process
parameters that influence process outputs.
◦ The numerical values or ranges for each of the critical process
parameters that result in acceptable process output.
If the process capability is properly defined, the process
should result into output of consistent attributes when
operated within the defined limits of critical process
parameters.
31. Critical quality attributes are :
◦ Chemical purity
◦ Impurity profile
◦ Polymorphic forms
◦ Physical characterization(particle size, bulk density, etc)
◦ Moisture content
◦ Microbial quality
32.
33. It is designed to verify that all established limits of the
critical process parameters are valid and that satisfactory
products can be produced even under the ‘worst case’
conditions.
It represents the actual studies or trials conducted to show:
◦ That all systems, subsystems or unit operations of a manufacturing
process perform as intended
◦ That all critical parameters operate within their assigned control
limits.
◦ That such studies and trials which form the basis of the process
capability design and testing are verifiable and certifiable through
proper documentation.
34. It requires frequent review of all process-related
documents, including validation audit reports to ensure
that there has been no changes, deviations, failures,
modifications to the production process and that all the
SOPs have been followed, including change control
procedures.
35. START
DEFINE THE PROCESS OR
THE SYSTEM
System meets
the needs of
the process?
Qualify the system
System meets
requirements?
Qualify process
Continued Validation
Redesign
NO
NO
YES
YES
36. The major types of validation are:
PROCESS VALIDATION
CLEANING VALIDATION
EQUIPMENT VALIDATION
VALIDATION OF ANALYTICAL METHODS
37. As per FDA Nov 2008 “the collection of data from the
process design stage throughout production, which
establish scientific evidence that the product is capable
of consistently delivering quality products”.
Process validation life cycle
Stage 1: process
design
Stage 2:
process qualification
Stage 3:continued
process verification
38. Each type represent a different pathway to concluding
that a manufacture process is in state of control.
◦ PROSPECTIVE VALIDATION: Validation is completed prior
to the manufacture of finished product that is intended for sale.
◦ CONCURRENT VALIDATION: When prospective validation
is not possible, it may be necessary to validate process during
the routine production.
◦ RETROSPECTIVE VALIDATION: Processes that have been
in use for sometime without any significant changes may be
also be validated according to an approved protocol.
◦ REVALIDATION: It is performed when some changes are
introduced in a system.
39. It is usually undertaken whenever a new formula, process
and facility need to be validated before routine
pharmaceutical production starts. Eg: switching to new
filter medium, leak testing of lyophiliser.
It is also usually employed when sufficient historical data
is either unavailaible or insufficient and, inprocess and
final product testing is inadequate to ensure high degree of
confidence for product quality characteristics and
reproducibility. Eg: a sterile solution filled on new
equipment should only be released after a media fill
validation.
FDA guidelines on pre-approval inspection, associated with
NDA/ ANDA submission, added a new dimension to this
type of validation.
40. FDA is seeking evidence that the manufacturing
process is validated before it allows a product to enter
the market for sale.
FDA favours prospective validation for high degree of
confidence and minimal risk, as it ensures process to be
under control and effective prior to manufacture or
release of the product.
Higher degree of confidence is associated with higher
cost of production, therefore a due consideration must b
given to FDA preference and cost to benefit analysis.
41. Concurrent validation is appropriate when:
◦ It is not possible to complete a validation programme before routine
manufacturing starts and it is known in advance that finished product
will be for sale. Eg: during the transference ot process to contract
manufacturer.
◦ It is more appropriate to validation a process during routine production
due to well understanding of process. Eg:change in tablet shape or
strength.
◦ Extensive testing and monitoring ensures the desired quality
characteristics of product with high degree of confidence but doesnot
provide a degree of assurance that subsequent batches processed under
the same condition and parameter will attain same quality attributes.
◦ Due to the limited acceptability of prospective and retrospective
validation, the concept of concurrent validation under the paragraph
“Acceptability of product testing” in validation process guidelines have
been included by FDA.
42. There are so many processes in use in many companies that have not
undergone a formally documented validation process.
Validation of these processes is possible, provided sufficient historical data is
available to provide documentary evidence that various processes are
considerably stable.
This type of validation is preferred because of cost effectiveness
It is acceptable only for well established processes and where critical quality
attributes and critical process parameters have been identified and documented.
In general. Datas from 10 to 30 consecutive batches should be examined to
assess process consistency, the review should include any batches that failed to
meet specifcations.
Any discripancies in the historical data may be excluded provide there is
sufficient evidence that the failure was caued by isolated occurences. Eg:
employee error.
Sources: batch documents, control charts, maintainance logbooks, records of
personnel changes, process capability studies, finished product data, trend
cards and storage stability results.
43. It is a repetition of the validation process or a specific part
of it.
It is either performed periodically to ascertain the process
or to incorporate some changes in the procedure.
1.Changes to validated system: A system once validated,
continues to remain validated as long as all conditions and
control parameters are not changed. Therefore a change
control quality assurance system must be established which
requires revalidation whenever there are conditions which
impact changes in product characteristics . Eg: changes in
the test procedure, raw materials, packaging system, plant
site, facilities, equipments, processing steps, batch size, etc.
44. 2.Periodic Revalidation: some manufacturers revalidate
certain systems at pre-established periodic intervals, even
when no change is believed to occur.
The need for revalidation is very useful in case of sterile
processes when compared to non-sterile processes.
3.Change control classification: The change-control
program should provide a classification scheme to evaluate
changes in raw/packaging materials, manufacturing
site/location, batch size, manufacturing equipments and
production process, product attributes (changes in
formulation, strength).
The classification procedure should be used in determining
the level of testing, validation and documentation is needed
to justify changes to a validated process.
Changes should be categorised as minor and major changes
(depending upon the nature an extent of the changes)
45. A minor change is defined as the one that is unlikely to
have a detectable impact on the critical attributes of the
product.
A major change is the one that would likely, significantly
affect the critical quality attributes of the product.
FDA in its scale up and post approval changes
(SUPAC) guidelines classifies the various levels of changes
depending upon the impact of changes on quality and
performance of product
Level 1 changes: changes that are unlikely to have any
detectable impact on formulation quality and performance.
Level 2 changes: changes that could have a significant
impact on formulation quality and performance.
Level 3 changes: changes that are likely to have significant
impact on formulation quality and performance.
46. Equipment validation starts from the decision to bring a
piece of new equipment to the organisation and
continues till the decommissioning of equipment at the
end of useful life.
It goes through the three following phases:
◦ Pre-purchase or Pre-qualification phase – vendor specification,
design qualification.
◦ Post-purchase or Qualification phase- installation, operational
& performance qualification.
◦ Routine operation or Ongoing evaluation phase.
48. Usually an operating department will require the purchase of a piece
of equipment.
The rationale to bring a new piece of equipment should be well
founded.
The benefits of acquiring the equipment, such as increasing
productivity, meeting a specific need, or enhancing the capability
should outweigh the expenditure of valuable and limited resources
required to acquire the equipment and support its operation.
The operating department should establish the requirements in
order to start a project.
The user should first decide on the basic functional requirement to
define a type of equipment required to fulfil their needs.
A more detailed operational requirement can then be defined based
on the functional requirements.
All these should be recorded in the user requirement document.
49. Initially various units available in the market should be
taken at a glance.
The extent of resources and funds to accomplish the task
should also be given due consideration .
The least expensive equipment may not be the best
investment.
The most expensive may not be the appropriate instrument
for operation.
Many of the functionality of the equipment system may not
be required at all for the organization.
A consideration must also be given to the general
background of the final user.
Simplicity is beauty and not all users are ready to tackle the
complicated operations due to time constraints and training.
50. Although technical and economic factors have a major
bearing on the selection of the vendor, no final decision
should be made before analysing each prospective vendor’s
capabilities in each of these areas.
vendor’s specifications are:
◦ The vendors previous experience in implemeting similar
projects.
◦ The vendor’s financial stability
◦ The vendor’s guarantee of installation, training, start up
support and after sales support,
◦ The level of training offered by the vendor
◦ Delivery times
◦ The vendor’s familiarity with regulatory requirements of the
equipment.
◦ The vendor’s documentation and support of testing
◦ Experience of current users.
◦ Acceptance criteria and operational limit should be clearly
understood by the vendor.
51. It outlines the key feature of the system designed to address
the user requirements, regulatory complaince and selection
rationale of the particular supplier.
Caution should be taken when putting together a design
qualification since it will have major impact on installation,
operation and performance qualifications.
The more functions thhat are specified in the DQ, the more
work have to included in the installation, operation and
performance qualification process.
The compliance of the basic design with the user
requirement and regulatory requirement should be
demonstrated and documented.
52. SITE PREPARATION:
Careful planning is required to ensure that the necessary
preparations to house the new equipment in the organization
are completed.
Insufficient site preparations can cause major
inconvenience and long delays in the installation process.
It is the wastage of money and time to have engineer show
up in premises but not able to do anything due to lack of
site preparation.
It is a common mistake to under estimate the effort and time
required for site preparation.
53. Physical dimension of the equipment and accessories:
It must be made sure that there is enough space to
accommodate the equipment and accessories and the
bench is strong enough to support the instrument.
Suitable operating environment for the equipment
Utilities
Health and Safety requirements
54. Instrument qualification is required to establish the
functional capabilities and reliability of the system for
its intended use.
The instrument post purchase qualification can be
divided into three stages:
◦ Installation qualification
◦ Operation qualification
◦ Performance qualification.
55. IQ simple means, “is it correctly installed?’’
This is ensured through appropriate tests, related documents and
records that equipment and ancillary system have been correctly
commissioned, and are in confirmity with installation
specification, equipment manuals schematics and engineering
drawing.
It further consists of documented verifications that all key
aspects of equipment are in working condition and have been
properly installed in accordance with the manufacturer’s
specification and placed in an environment suitable for its
intended use.
IQ means the documentary evidence to prove that the premises,
supporting utilities and the equipment have been built and
installed in compliance with their design specifications.
56. 1.PREVENTATIVE MAINTENANCE: The IQ should
document that the equipment is enrolled in a preventive
maintenance program to assure that the system
continues to operate properly and no component of
the system becomes inoperable due to wear and tear.
2.EQUIPMENT INFORMATION AND SUPPLIER
INSTRUMENTS: The IQ should document equipment
information including manufacturing agency, model
number, and the serial number and verify that the
information complies with the purchase orders and user
requirements,
57. In addition, verification of equipment compliance with
regulatory requirement should be performed.
Supplier’s working and operating instructions,
maintenance requirements, calibration requirements
and cleaning including sanitation and sterilisation
requirement for the equipment should be collected and
correlated.
3.CALIBRATION: The IQ should document that
specific devices contained with the equipment have
been calibrated to traceable standards.
documentation should include date on which
calibration was performed and when calibration is due.
58. The test required to calibrate the equipment, the
acceptance criteria and frequency of each test should be
included in the calibration section of the SOPs.
INSTRUMENT FEATURES
CALIBRATION RECORD SHEET
DESCRIPTION:
1. IDENTIFICATION NO:
2. MODEL NO:
3. SERIAL NO:
4. CAPACITY:
5. LOCATION:
6. DIMENSIONS:
7. PURPOSE:
CALIBRATION INFORMATION:
1. CALIBRATION FREQUENCY
2. CALIBRATION NO:
3. CALIBRATION SOP NO AND TITLE:
4. CALIBRATION LIMITS:
5. UTILISATION RANGE: MAX:…….. MIN:…………
Compiled by:….. Date……….
59. 4. VERIFICATION OF COMPONENTS AND
EQUIPMENT: Once the equipment reaches the owner’s
plant, a parts list should be reviewed. This is to verify that
all the parts against shipping and purchase order have been
found acceptable.
5.SOPs : The IQ should document all SOPs pertaining to
the approved equipment and its installation place.
Applicable SOPs may include preventative maintenance,
calibration, operation, document archival, and equipment
logbook usage.
6.UTILITIES AND ENVIRONMENTAL CONDTIONS:
The IQ should document the manufacturer’s specification
for required utilities anfd verify that appropriate utilities are
available for the system. Eg: electricity, steam, vaccum,
heating, ventilation and air conditioning(HVAC)
60. OQ is a series of tests that measures the performance
capability of the equipment.
OQ focuses on the equipment, rather than
demonstrating performance capabilities relating to
producing a particular product.
The process should establish that the equipment or
system modules operate as intended, or capable of
consistent operation within established specification.
All testing equipments must be and all the
methodologies used to perform the OQ test must be
validated.
61. All documents to support the testing equipment calibration
should be included in the qualification report .
OQ must be performed via an established and accepted
protocol
The proper operation will be verified by performing the test
functions specified in the protocol.
The OQ testing should describe all aspects of the testing in
detail.
The plans for OQ should identify the studies to be
undertaken on the critical variables, the sequence of those
studies and measuring equipment to be used and acceptance
criteria to met.
SOPs and draft cleaning procedures are issued and
approved after the completion of successful OQ.
62. PQ is defined as the process to verify that the system is
repeatable and consistently producing a quality
product.
PQ should follow an authorised protocol, may include
the following:
◦ Tests using production materials that have been developed
from the specialist knowledge of the process and how the
equipment or system is intended to deliver its performance
characteristics.
◦ Studies utilising production materials to include a condition or
set of conditions encompassing upper and lower operating
limits.
63. After the instrument is qualified and has been
transferred to the operating department , SOPs must be
strictly followed for operation, maintenance and
calibration of equipment.
USAGE AND SERVICE RECORD: Good usage and
service record for the equipment must be maintained
through a logbook. Such a record is required for the
GMP purposes, further it facilities the notification to
the user in case of system failure.
CALIBRATION RECORD: It must be maintained for
each equipment , stating information about date of
calibration test done, name and signature of responsible
person who performed calibration.
64. Each instrument must have calibration sticker with
information related to the status of the syste, when the
calibration was performed, who did the calibration, and the
next calibration date .
CONSIDERATIONS:
◦ Responsibility of personnel involved in the calibration.
◦ Frequency of calibration for each type of instrument.
◦ Review and approval of calibration date
◦ Procedure of issue of calibration sticker
◦ Documentation requirement of the calibration and record keeping.
◦ Remedial action in event of calibration failure
◦ Procedure to notify users and obtain impact assessment in case of
calibration failure.
