The document discusses the concept of validation in the pharmaceutical industry, emphasizing its importance in ensuring product quality and compliance with regulations. It outlines various types of validation, key validation processes and phases, and the creation of validation master plans to guide activities. Additionally, it details the necessity of planning, documentation, and change control in maintaining consistent and reliable manufacturing practices.

1. PHARMACEUTICAL VALIDATION
Introduction
The concept of validation was first proposed by two Food and
Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid
1970’s in order to improve the quality of pharmaceuticals. The first
validation activities were focused on the processes involved in making these
products, but quickly spread to associated processes including environmental
control, media fill, equipment sanitization and purified water production.
In a guideline, validation is act of demonstrating and documenting
that any procedure, process, and activity will consistently lead to the
expected results. It includes the qualification of systems and equipment.
The goal of the validation is to ensure that quality is built into the
system at every step, and not just tested for at the end, as such validation
activities will commonly include training on production material and
operating procedures, training of people involved and monitoring of the
system whilst in production. In general, an entire process is validated and a
particular object within that process is verified.
The regulations also set out an expectation that the different parts of
the production process are well defined and controlled, such that the results
of that production will not substantially change over time.
Why Is Validation Required?
will producethe productwe wanted or not.

2. pharmaceutical industry uses expensive materials, sophisticated
facilities & equipments and highly qualified personnel.
of the industry.
The costof productfailures, rejects, reworks, and recalls, complaints are
the significant parts of the total productioncost.
-validation is
necessary if failure to be reduced and productivity improved.
The pharmaceutical industries are concerned about validation because of the
following reasons.
Department Responsible
Prepare/execute/approve validation Studies
batch
documentations/procedures are in place, approves protocols and reports
Responsible Authorities For Validation
and ultimately, approve the entire effort, including all of the documentation
generated. The working party would usually include the following staff
members, preferably those with a good insight into the company's operation.

3. Importance of Validation
 Assurance of quality
 Time bound
 Process optimisation
 Reduction of quality cost.
 Nominal mix-ups, and bottle necks
 Minimal batch failures, improved
 efficiently and productivity.
 Reduction in rejections.
 Increased output.
 Avoidance of capital expenditures
 Fewer complaints about process related
 failures.
 Reduced testing in process and in
 finished goods.
 More rapid and reliable start-up of
 new equipments
 Easier scale-up form development
 work.
 Easier maintenance of equipment.

4.  Improved employee awareness of
 processes.
 More rapid automation.
 Government regulation (Compliance
 with validation requirements is
 necessary for obtaining approval to
 manufacture and to introduce new
 products)
Scope of validation
 To make that tha readings of equipment or instruments are consistent with
other measurements and display the correct readings every single time
 To determine tha accuracy, precision ,reliability and deviation of tha
measurements produced by all tha instruments
 To establish tha reliability of tha instrument being used and whether it can be
trusted to deliver repeatable results each time
 To map tha ‘drift’ as document instrument have a tendency to produce
inaccurate measurements over a period of time following repeated use
 Ensuring that tha industry standards, quality assurance benchmarks such as
current good manufacturing practice (c GMP) government regulations are
adhered to.

5. Planning for Validation
All validation activities should be planned. The key elements of a validation
programme should be clearly defined and documented in a validation master
plan (VMP) or equivalent documents. The VMP should be a summary
document, which is brief, concise and clear
The VMP should contain data on at least the following:
Validation policy, Organisational structure of validation
activities.
Summary of facilities, systems, equipment and processes to be validated.
Documentation format:
The format to be used for protocols and reports Planning
and scheduling. Change control. Reference to existing document.
In case of large projects, it may be necessary to create separate validation
master plans.

6. MasterProduct Document
An extensive quantity of documents is generated at each stage of the develop
mentand validation of the final production process.Someof these documents
will be directly related to the manufacture of the final products. Others may
provide the basis for decisions that ultimately result in the final process.
The documents that are required for manufacturing the productthen become
the master productdocument. This document must be capable of providing
all of the information necessary to set up the process to producea product
consistently and one that meets specifications in any location.
Items that will normally be included in the master productdocument are
 Batch manufacturing record
 Master formulation
 Process flow diagram
 Master manufacturing instructions
 Master packaging instructions
 Specifications
 Sampling (location and frequency)
 Test methods
 Process validation data
Each of the above items must contain sufficient detailed information to permit
the complete master productdocument to become an independent, single
package that will provide all information necessary to set up and producea
product.

7. Elements Of Validation
DesignQualification(DQ): -
It is documented review of the design, at an appropriate stage of stages in the
project, for conformance to operational and regulatory expectations. DQ
Check Items:









8. Installation Qualification(IQ): -

equipment that can affect productquality adhere to approved
specifications and are correctly installed.
 ns are:
 utilities, and functionality)





and humidity)
OperationalQualification (OQ): -
It is documented verification that all aspects of a facility, utility or
equipment that can affect productquality operate to Intend throughout all
anticipated ranges. OQ considerations include:
 speed and
setup conditions)







9.  es
or control charts)
 -caseconditions
(Failure Mode and effects

Performance Qualification(PQ): -
It is documented verification that all aspects of a facility, utility or equipment
perform as intended in meeting predetermined acceptancecriteria. PQ
considerations include:

OQ

 ed in OQ

validation activities can be described in three stages.
Stage 1 – ProcessDesign:The commercial process is defined during this
stage based on 100 knowledge gained through development and scale-up
activities.
Stage 2 – ProcessQualification:During this stage, the process design is
confirmed as 103 being capable of reproducible commercial manufacturing.
Stage 3 – Continued ProcessVerification:Ongoing assurance is gained
during routine production that the process remains in a state of control.

10. Types of Validation
The guidelines on general principles of process validation mentions four
types of validation:
1. Prospective validation (or premarket validation)
2. Retrospective validation
3. Concurrent validation
4. Revalidation
1. Prospective validation:
Establishing documented evidence prior to process
implementation that a system does what it proposed to do based on
preplanned protocols.
This approach to validation is normally undertaken whenever the process for
a new formula (or within a new facility) must be validated before routine
pharmaceutical production commences. In fact, validation of a process by
this approach often leads to transfer of the manufacturing process from the
development function to production.
Prospective validation should include, but not be limited to the following:
 Short description of the process.Summary of the critical processing
steps to be investigated.
 List of the equipment/facilities to be used (including measuring,
monitoring/recording equipment) together with its calibration status.
 Finished productspecifications for release.

11.  List of analytical methods, as appropriate.
 Proposed in-process controls with acceptance criteria.
 Additional testing to be carried out, with acceptance criteria and
analytical validation, as appropriate.
 Sampling plan.
 Methods for recording and evaluating results.
 Functions and responsibilities.
 Proposed timetable.
2.Retrospective validation:
Retrospective validation is used for facilities, processes, and
process controls in operation use that have not undergone a formally
documented validation process. Validation of these facilities, processes, and
process controls is possible using historical data to provide the necessary
documentary evidence that the process is doing what it is believed to do.
Therefore, this type of validation is only acceptable for well-
established processes and will be inappropriate where there have been recent
changes in the composition of product, operating processes, or equipment. This
approach is rarely been used today because it’s very unlikely that any existing
product hasn’t been subjected to the Prospective validation process. It is used
only for the audit of a validated process.

12. 3.Concurrentvalidation:
Concurrent validation is used for establishing documented
evidence that a facility and processes do what they purport to do, based on
information generated during actual imputation of the process.
This approach involves monitoring of critical processing steps
and end product testing of current production, to show that the
manufacturing process is in a state of control.
4.Revalidation:
Revalidation means repeating the original validation effort or any
part of it, and includes investigative review of existing performance data.
This approachis essential to maintain the validated status of the plant,
equipment, manufacturing processesand computer systems. Possible reasons
for starting the revalidation process include:


cleaning process, orother changes that could affect productquality


batch size.

specifications.
 es depends on the extent of the
changes and the effect upon the product.

13. Change Control:
Written procedures should be in place to describe the
actions to be taken if a change is proposed to a product component, process
equipment, process environment, processing site, method of production or
testing or any other change that may affect product quality or support system
operations. All changes must be formally requested, documented and
accepted by the validation team.
The likely impact / risk of the change on the product must
be assessed and the need for the extent of re-validation should be
determined. Commitment of the company to control all changes to premises,
supporting utilities, systems, materials, equipment and processes used in the
fabrication/packaging of pharmaceutical dosage forms is essential to ensure
a continued validation status of the systems concerned.
The change control system should ensure that all notified
or requested changes are satisfactorily investigated, documented and
authorized. Products made by processes subjected to changes should not be
released for sale without full awareness and consideration of the change by
the validation team. The team should decide if a re-validation must be
conducted prior to implementing the proposed change.

14. Phases Of Process Validation
The activities relating to validation studies may be classified into three phases:
Phase 1:
Pre-Validation Phase or the Qualification Phase, which covers all activities
relating to productresearch and development, formulation, pilot batch studies,
scale-up studies, transfer of technology to commercial scale batches,
establishing stability conditions, storage and handling of in-process and finished
dosage forms, equipment qualification, installation qualification, master
production documents, operational qualification, process capability.
Phase 2:
ProcessValidation Phase (ProcessQualificationphase) designed to verify
that all established limits of the critical process parameters are valid and that
satisfactory products canbe produced even under the “worst case” conditions.
Phase 3:
Validation Maintenance Phase requiring frequent review of all process related
documents, including validation audit reports to assure that there have been no
changes, deviations, failures, modifications to the production process,and that
all SOPs have been followed, including Change Control procedures. At this
stage the validation team also assures that there have been no changes/
deviations that should have resulted in requalification and revalidation.

15. Validation Protocol :
A written plan stating how validation will be conducted,
including test parameters, product characteristics, production and packaging
equipment, and decision points on what constitutes acceptable test results.
This document should give details of critical steps of the
manufacturing process that should be measured, the allowable range of
variability and the manner in which the system will be tested. The validation
protocol provides a synopsis of what is hoped to be accomplished.
The protocolshould list the selected process and control parameters,
state the number of batches to be included in the study, and specify how the
data, once assembled, will be treated for relevance. The date of approval by
the validation team should also be noted.
In the case where a protocol is altered or modified after its approval,
appropriate reasoning for such a change must be documented.
The validation protocolshould be numbered, signed and dated, and should
contain as a minimum the following information:
1. Title
2. Objective & Scope
3. Responsibility
4. ProtocolApproval
5. Validation Team
6. ProductComposition
7. Process FlowChart
8. Manufacturing Process
9. Review of Equipments / Utilities

16. 10. Review of Raw Materials and Packing Materials
11. Review of Analytical and Batch Manufacturing Records
12. Review of Batch Quantities for Validation (Raw Materials)
13. Review of Batch Quantities for Validation (Packing Materials)
14. HSE Requirements
15. Review of Process Parameters
16. Validation Procedure
17. Sampling Location
18. Documentation
19. Acceptance Criteria
20. Summary
21. Conclusion

17. Validation MasterPlan
A validation master plan is a document that summarizes the company’s
overall philosophy, intentions and approaches to be used for establishing
performance adequacy.
The validation master plan should be agreed upon by
management. Validation in general requires meticulous preparation and careful
planning of the various steps in the process. In addition, all work should be

18. carried out in a structured way according to formally authorized standard
operating procedures.
All observations must be documented and where possible must
be recorded as actual numerical results. The validation master plan should
provide an overview of the entire validation operation, its organizational
structure, its content and planning.
The main elements include the list/inventory of the items to be
validated and planning schedule. All validation activities relating to critical
technical operations, relevant to product and process controls within a firm
should be included in the validation master plan.
It should comprise all prospective, concurrent and retrospective
validations as well as re-validation. The validation master plan should be a
summary document and should therefore be brief, concise and clear.
It should not repeat information documented elsewhere but should
refer to existing documents such as policy documents, SOP’s and validation
protocols and reports.
The format and content should include:
introduction: validation policy, scope, location and schedule
organizational structure: personnel responsibilities
plant/ process /productdescription: rational for inclusions or exclusions and
extent of validation
specific process considerations that are critical and those requiring extra
attention
list of products/processes/systems to be validated, summarized in a matrix
format, validation approach
re-validation activities, actual status and future planning
key acceptance criteria
documentation format
reference to the required SOP’s

19. Validation of Pharmaceutical Ingredients

20. U.S. Food and Drug Administration (FDA) for process validation of
manufacturing pharmaceutical active ingredients(APIs) and inactive ingredients
used in human and veterinary drug products.
Active pharmaceutical ingredients belong essentially to one of the following
four basic chemical classes:
1. Weak acids and their salts (sodium sulfacetamide, potassium
guaiacolsulfonate,
calcium fenoprofen, magnesium salicylate, etc.) approximately
30%
2. Weak bases and their salts (nortriptyline hydrochloride, phenelzine
sulfate, chloroquine phosphate, scopolamine hydrobromide, tamoxifen
citrate, etc.) approximately 45%
3. Organicnonelectrolytes (neutral molecules, chloral hydrate, hydrocortisone,
testosterone, mannitol, etc.) approximately 15%
4. Quaternarycompounds (substituted ammonium salts, methacholine
chloride, mepenzolate bromide, phospholine iodide, etc.) approximately
10%
Pharmaceutical excipients (inactive ingredients) are substances other than
the active drug substanceor the drug productthat have been evaluated for safety
and are included in the pharmaceutical dosage form (drug delivery system) for
one or more of the following functions:
1. Aid in the processing of the drug productduring manufacture (e.g.,
binder, disintegrant, lubricant, suspending agent, filtering aid)
2. Protect, support, or enhance stability, bioavailability, or patient acceptability
(e.g., chelant, surfactant, sweetener)
3. Assist in productidentification (e.g., colorant, flavor, film former)

21. 4. Enhance any other attribute of the overall safety and effectiveness of
the drug during storage or use (e.g., inert gas, preservative, sunscreen)
TransdermalProcess Validation
Good manufacturing practices (CGMPs)are regulations established by the U.S.
Food and Drug Administration (USFDA). These regulations not only serve as
the operating “Bible” for drug manufacturers, but also provide operating
directions in the area of manufacture, processing, packing, and holding of drugs
Product/processcertification.
Transdermal drug delivery systems are self-contained, discrete dosage
forms that, when applied to intact skin, are designed to deliver the drug(s)
through the skin to the systemic circulation. Systems typically comprise an
outer covering (barrier), a drug reservoir, which may have a rate controlling
membrane, a contact adhesive applied to some or all parts of the system
and the system/skin interface, and a protective liner that is removed before
applying the system.
The activity of these systems is defined in terms of the release rate of the
drug(s) from the system
 Provide improved systemic bioavailability of the active ingredients
 Permit slow, timed release of the active
 Avoid the affect of a bolus drug dose
 Provide for multiple daily doses with a single application
 Provide a means to quickly terminate dosing
 Provide instantaneous identification of medication in emergency

22. VALIDATION OF SOLID DOSAGE FORMS
VALIDATION OF RAW MATERIALS
The steps involved in the validation of a raw material or excipient follow
those cited in the CGMPs and in the formal written documentation of those
procedures and methods used.
1. Each raw material should be validated by performing checks on several
batches (at least three) from the primary supplier as well as the
alternate supplier. The batches chosenshould be selected to represent
the range of acceptable specifications, both high and low
2. Depending on the susceptibility of the raw material to aging, physical,
chemical, and/or microbiological stability should be assessed. This is
especially true for liquid or semisolid ingredients, in which interaction
with the container or permeability of the container to air and moisture
could have a detrimental effect on the raw material.

23. 3. Once the samples of raw materials have been selected as having fallen
into an established, acceptable range of specifications and stability, it
should be used to manufacture a batch of the final dosageform. It
may be appropriate to manufacture several lots of final productwith
raw material at the low and high ends of the specification limit. Such
testing would be especially useful when it is known that the product
may be sensitive to small changes in the characteristics of the excipients
or active ingredient.
4. The final step of raw material validation should involve an on-site inspection
of the supplier to review the vendor’s manufacturing operations
and controlprocedures. The reliability of each vendor and how well
each conforms to regulatory requirements must also be determined.
ANALYTICAL METHODS VALIDATION
1. Accuracy of method: The ability of a method to measure the true
value of a sample.
2. Precision of method: The ability of a method to estimate reproducibility
of any given value, but not necessarily the true value.
3. Specificity:The ability to accurately measure the analyte in the presence
of other components.
4. In-day/out-of-dayvariation:Does the precision and accuracy of the
method change when conducted numerous times on the same day and
repeated on a subsequent day?

24. 5. Between-operatorvariation:Repeat of the precision and accuracy
studies within the same laboratory using the same instrument but different
analysts to challenge the reproducibility of the method.
6. Between-instrumentvariation:How will different instruments within
the same laboratory run by the same analyst affect the accuracy and
precision of the method?
7. Between-laboratoryvariation:Will the precision and accuracy of the
method be the same between the development and quality control
laboratories?
EQUIPMENT/FACILITYVALIDATION
The productdevelopment of a pharmaceutical producthas its origins in a
systematic approachto formulation, process and manufacture, and the analytical
testing that is necessary to monitor quality and reproducibility. Once
development scale activities (productdevelopment, early toxicology, and
clinical evaluation) provide encouragement that the development compound
could become a commercial product, a multi departmental team is usually
formed with product development, production, and engineering staff to plan a
life-cycle approachrelated to the manufacture of the product.
In-Process Tests
1. Moisture content of “dried granulation”:Loss on drying (LOD) can
be used to determine whether or not the granulation solvent has been
removed to a sufficient level during the drying operation (usually less
than 2% moisture).

25. 2. Granulation particlesizedistribution:An extremely important parameter
that can affect tablet compressibility, hardness, thickness, disintegration,
dissolution, weight variation, and content uniformity. This
parameter, which can be done by sieve analysis, should be monitored
throughout the tablet validation process.
3. Blend uniformity:Samples of the blend are taken and analyzed to
ensure that the drug is uniformly dispersed throughout the tablet/capsule
blend. The properblend time must be established so that the
blend is not under- or overmixed. The sampling technique is critical
for this test to be valid [45].
4. Individual tablet/capsuleweight:The weight of individual tablets or
capsules is determined throughout compression/encapsulation to ensure
that the material is flowing properly and the equipment is working consistently.
The individual weight should be within 5% of the nominal weight. Weight
fluctuations or frequent machine adjustments suggest that the
formulation/process (e.g., poorgranulation flow) is not optimized and/or that
the equipment may need maintenance.
5. Tablethardness:Tablet hardness is determined periodically throughout
the batch to ensure that the tablets are robust enough for coating,
packing, and shipping and not too hard to affect dissolution.
6. Tabletthickness: Tablet thickness is also determined periodically
throughout the batch and is indirectly related to the hardness. It is
another indication of whether or not the formulation has properflow
and compressionproperties.
7. Disintegration:Disintegration is determined during the manufacture
as a predictor of tablet performance (e.g., dissolution).
B. Finished Product Tests

26. 1. Appearance:The tablets should be examined for such problems as
tablet mottling, picking of the monogram, tablet filming, and capping
of the tablets. If the tablets are colored, the color quality needs to be
examined.
2. Assay: This test will determine whether or not the productcontains
the labeled amount of drug.
3. Contentuniformity: Samples are taken across the batch profile (beginning,
middle, and end) and analyzed to ensure that the dosage forms
more stringent internal limits. It will indicate whether there is demixing
during the manufacturing operation (i.e., segregation during flow
of granulation from a storage bin).
4. Tablethardness:A critical parameter for dosageform handling and
performance.
5. Tabletfriability: Friability is an important characteristic on the tablets’
ability to withstand chipping, cracking, or “dusting” during the
packaging operations and shipping.
6. Dissolution: Dissolution is important to ensure proper drug release
characteristics (in vitro availability) and batch-to-batch uniformity.