Unit 3: Validation

3.1: Introduction to validation / Scope of validation:

1. The concept of validation was first proposed by two Food and Drug Administration (FDA) officials,
Ted Byers and Bud Loftus in 1979 in USA, to improve the quality of pharmaceuticals. Now,
validation is an important part of current good manufacturing practices (cGMP).
2. Definition: Validation is a systematic study of systems, facilities and processes to determine
whether they are performing as per requirements or not.
3. If a process is validated, it indicates that the process has been properly developed and is under
control.
4. Validation should be considered in the following situations:
a) Totally new process
b) New equipment
c) Process and equipment which have been altered
d) Process where the end-product is of poor quality
5. Classification of validation:
a) Equipment validation e) Process validation
b) Facilities validation f) Analytical method validation
c) HVAC System validation g) Computer system validation (CSV)
d) Cleaning validation h) Packaging validation
i) Cold chain validation
6. Functions of validation team in different departments:
1 ENGINEERING Install, and certify plant facility, equipment and support
systems.
2 MANUFACTURING Operate, maintain and optimize - plant facilities, equipment
support systems and process within limits & specifications.
3 QA Establish approvable validation protocols & conduct process
validation by monitoring, sampling and challenging the process
and equipment’s.
4 QC Follow the validation protocol developed by QA & validate the
incoming stock and final product.

3.2: Advantages / Merits of validation:

1. During the validation process the knowledge of the entire process increases.
2. Assures the repeatability of the process.
3. Validation ensures that the pharmaceutical product meet the required standards of quality,
safety, and efficacy.
4. Decreases the risk of manufacturing problems.
 5. Decreases the expenses caused by the failure in production.
6. Decreases the risk of failing in GMP.
7. Cleaning Validation: Ensures that equipment is effectively cleaned to prevent contamination.
8. Risk Management: Identifies and reduces risks and accidents in manufacturing processes.
9. Validation increases consumer confidence by guaranteeing quality of pharmaceutical products.
3.3: Validation master plan:
1. VMP is a document that defines the different areas and systems to be validated.
2. It gives a written plan for achieving and maintain a qualified facility.
3. It identifies the systems and controls to be validated and the level of testing required.
4. The VMP assists in monitoring and tracking the progress of the project by performing periodic
audit reviews.
5. A VMP is created when the project is complex and when more extensive and thorough
verification is required.
6. The Contents of a VMP include, Introduction, Purpose, Scope, Overview / Description of
system to be validated, Responsibilities, Validation methodology, list of protocols and
procedures, list of required SOP’s, Acceptance criteria, Validation report, Change control,
Validation project milestone, Deliverables.
7. The benefits of VMP includes
It provides the total picture of the project.
It is a management tool for tracking progress.
Assignment of responsibility, which promote team work.
It identifies acceptance criteria before the start of validation.
3.4: Calibration master plan: The Calibration Master Plan (CMP) is a written document of
company’s strategies for calibrating instruments within the plant. The CMP has general guidelines,
for calibration, and recalibration frequencies. It is an important document to maintain the accuracy
of instruments used in the manufacturing process.
1. Objectives and Scope: The primary objective of the Calibration Master Plan is to ensure
instruments are properly calibrated during installation and periodically recalibrated to maintain
their performance over time. The CMP applies to all instruments within the facility and focuses
on calibration management.
2. Roles, Responsibilities, and Instrument Categorization: The CMP defines the roles and
responsibilities of various functional groups, such as engineers, Quality Assurance (QA)
personnel, and calibration management staff. Instruments are categorized as either critical or
non-critical based on their impact on product quality. Critical instruments directly affect the quality
of the product, while non-critical instruments have an indirect or no impact. Each instrument is
assigned a unique identification number and tagged for classification. Calibration can be
 performed in-house using Standard Operating Procedures or outsourced to external agencies,
depending on the facility's resources.
3. Calibration Requirements and Procedures: The Calibration Master Plan clearly defines
calibration accuracy, ranges, and failure limits based on the manufacturer’s specifications and
process requirements. An annual calibration calendar is prepared, listing all instruments, their
measurement ranges, locations, and other relevant details. Calibration for critical instruments is
verified during Installation Qualification (IQ).
4. Review, Updates, and Compliance: The CMP is reviewed annually, to make necessary
changes in calibration approaches. Any updates to calibration schedules, SOPs, or frequencies
must be documented with supporting evidence.

3.5: ICH and WHO guidelines for calibration and validation of equipment’s:
I. Design and Construction:
1. Equipment used in the manufacture of API’s and pharmaceutical products should be of
appropriate design and size.
2. They should be suitably located for use, cleaning, sanitization and maintenance.
3. Equipment should be constructed so that the surfaces that contact raw materials / APIs /
formulation do not alter the quality of the product.
4. Production equipment should be used within its qualified operating range.
5. Major equipment (e.g., reactors, storage containers) and permanently installed processing lines
used during the production should be properly identified.
6. Any substances used in the operation of equipment, such as lubricants, heating fluids or
coolants, should not contact the API / formulation and should not alter their quality. If possible,
food grade lubricants and oils should be used.
7. Closed equipment should be used whenever possible. If open equipment is used, precautions
should be taken to minimize the risk of contamination.
8. A set of current drawings should be maintained for equipment and critical installations (e.g.,
instrumentation and utility systems).
II. Equipment Maintenance and Cleaning:
1. Schedules and procedures (including assignment of responsibility) should be established for
maintenance and cleaning of equipment.
2. Written procedures should be there for cleaning of equipment used in the manufacture of APIs
/ formulations. Cleaning procedures should contain all details for cleaning in a reproducible and
effective manner.
3. These procedures should include:
a. Assignment of responsibility for cleaning of equipment;
b. Cleaning schedules
 c. Methods and materials for cleaning, including dilution of cleaning agents.
d. If necessary, instructions for disassembling and reassembling each article of equipment
for proper cleaning;
e. Instructions for the removal of previous batch identification labels.
f. Instructions for the protection of clean equipment from contamination before use.
g. Inspection of equipment for cleanliness immediately before use.
4. If equipment is used for continuous production of successive batches of the same APIs /
formulations, equipment should be cleaned at appropriate intervals.
5. Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents
should be defined and justified.
6. Equipment should be identified with its cleanliness status by appropriate means.
III. Calibration:
1. All equipment’s that are critical for assuring the quality of APIs / formulations should be calibrated
according to written procedures and an established schedule.
2. Equipment calibrations should be performed using standards and records of these calibrations
should be maintained.
3. The current calibration status of critical equipment should be known. Instruments that do not
meet calibration criteria should not be used.
3.6: Validation of specific dosage forms:
1. Validation is necessary for producing a dosage form repeatedly with the desired quality.
2. Validation establishes the controls, flexibility and limitations for the manufacturing process.
Validation of a tablet dosage form is discussed below.
3. Validation should be done with three successive batches of dosage form. The QA department
collects the samples, carries out the tests and create the validation report.
4. Example: Mixing, granulation, drying, lubrication, and compression steps have to be validated
for a tablet dosage form.
5. Example: Mixing technique, speed of mixing, time of mixing, mixing load are important
parameters in validation of the mixing and granulation process.
6. Similarly, drying air temperature, drier selection, drying time and load are important parameters
in validation of the drying step to produce granules with optimum moisture content and flow
properties for compression.
7. The tablet compression process is validated by optimizing critical parameters such as
compression force, speed, and tablet weight. The tablets are tested for uniformity, hardness,
disintegration, and dissolution to ensure consistent tablet quality.
3.7: Types of validation: Validation is a systematic study of systems, facilities and processes to
determine whether they perform their functions adequately and consistently as specified to obtain
desired quality product in desired quantity. The different types of validation are discussed below.
1. Process Validation: Ensures the manufacturing process consistently produces products having
the desired quality standards. The process is developed through small-scale trials, and
parameters like mixing time and compression force are validated during process qualification,
and these parameters are monitored during commercial production to ensure consistency.
Example: Validation of the tablet compression process for a sustained-release dosage form like
metformin.
2. Equipment Validation: Verifies that equipment used in production operates as intended.
Installation Qualification (IQ) confirms proper installation, Operational Qualification (OQ) tests
functionality, and Performance Qualification (PQ) evaluates real-time performance using the
actual process.
Example: Validation of a tablet press used in the production of aspirin tablets to ensure it meets
the required specifications for weight, hardness, and uniformity.
3. Cleaning Validation: Confirms that cleaning procedures effectively remove residues and
prevent cross-contamination. Cleaning procedures are tested by analyzing swab or rinse
samples for residue levels of active ingredients, cleaning agents, or microbial contaminants.
Example: Cleaning validation of equipment used in the production of amoxicillin capsules to
ensure no residual antibiotic contaminates the subsequent batch.
4. Analytical Method Validation: Ensures analytical methods used for quality testing are accurate,
precise, and reliable. Parameters such as specificity, linearity, accuracy, precision, and
robustness are validated using standard guidelines (e.g., ICH Q2). Example: Validation of a high-
performance liquid chromatography (HPLC) method for the quantification of paracetamol in a
syrup formulation.
5. Sterilization Validation: Demonstrates that sterilization processes effectively eliminate
microbial contaminants. Microbial challenge tests are performed using biological indicators to
ensure sterilization methods like autoclaving, filtration, or radiation achieve sterility assurance
levels.
Example: Validation of an autoclaving process used for sterilizing injectable vitamin B12 vials.
6. Computer System Validation (CSV): Verifies that computerized systems used in manufacturing
and quality control comply with regulatory requirements. System requirements are documented,
software is tested for intended use, data integrity is verified, and checked for regulatory
compliance. Example: Validation of the computerized system used for tracking temperature and
humidity levels in a cold chain for the distribution of insulin.
7. HVAC System Validation: Ensures heating, ventilation, and air conditioning systems maintain
a controlled environment for production. Parameters like temperature, humidity, air changes, and
particulate counts are measured under dynamic and static conditions to ensure compliance with
cleanroom standards. Example: Validation of the HVAC system in a cleanroom environment
used for the production of sterile injectable vaccines.
8. Packaging Validation: Confirms that packaging materials maintain product integrity and stability
throughout the shelf life. Tests such as stability studies, leakage tests, and transport simulation
tests are conducted to evaluate the suitability of the packaging materials.
Example: Validation of blister packaging for a chewable vitamin C tablet to ensure moisture
protection and prevent degradation.
9. Media Fill Validation: Simulates aseptic processing by filling sterile media to test the sterility of
production operations. Aseptic media fills are conducted under normal operating conditions, and
the filled containers are monitored for microbial contamination, with results analyzed.
Example: Media fill validation for the aseptic filling of an intravenous (IV) chemotherapy drug like
cyclophosphamide.
10. Performance Validation: Confirms that a system or process performs as expected under real-
world conditions. The system or process is tested using production-scale operations, and outputs
are monitored for compliance with specifications. Example: Performance validation of a blister
packaging machine used to pack over-the-counter drugs like ibuprofen tablets.
11. Prospective Validation: Is conducted before commercial production to establish documented
evidence that a process works as intended. Validation protocols are created, test batches are
run under controlled conditions, and critical quality attributes are analyzed for compliance.
Example: Prospective validation of the tablet compression process for a new formulation of
atorvastatin tablets.
12. Concurrent Validation: It is performed during actual production to validate the process in real-
time. Data from commercial-scale batches are collected, and process parameters and quality
attributes are evaluated simultaneously. Example: Concurrent validation of the manufacturing
process for a new lot of loratadine tablets during routine production.
13. Retrospective Validation: It is conducted for processes that are already in use based on
historical data and records. Past batch records, deviations, and quality control results are
analyzed to ensure the process consistently meets quality standards. Example: Retrospective
validation of the capsule filling process for metoprolol succinate after several years of commercial
production.
14. Revalidation: Periodic or as-needed validation ensures processes, systems, or equipment
remain compliant. Validated parameters are reassessed, tests are performed, and validation
documentation is updated after changes in processes, equipment, or raw materials.
Example: Revalidation of a tablet coating process for a sustained-release formulation of the
antihypertensive drug amlodipine, after switching to a new coating material.
3.8: Government regulations in Validation: The different government regulations in validation
are discussed below.
1. Compliance with cGMP Guidelines: Validation processes must adhere to the current Good
Manufacturing Practices (cGMP) as per regulatory standards like 21 CFR Part 210 and 211
(USA) or Schedule M (India). These ensure product quality and safety.
2. Validation Master Plan (VMP): Regulatory authorities mandate the preparation of a VMP that
outlines the scope, responsibilities, and schedule for validation activities, including equipment,
processes, and systems.
3. Process Validation Requirements: Pharmaceutical manufacturers must conduct process
validation (e.g., prospective, concurrent, and retrospective) to demonstrate that processes
consistently produce products meeting quality specifications.
4. Equipment Qualification (DQ/IQ/OQ/PQ): Validation regulations require Design Qualification
(DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance
Qualification (PQ) for all critical equipment and systems.
5. Analytical Method Validation: Methods used for testing and analysis must be validated as per
guidelines from ICH Q2 (R1) or USP, ensuring accuracy, precision, specificity, and
reproducibility.
6. Computer System Validation (CSV): Validation of computerized systems is mandatory under
21 CFR Part 11 or EU Annex 11 to ensure data integrity, electronic record-keeping, and
compliance with regulatory requirements.
7. Validation of Cleaning Procedures: Regulatory agencies require cleaning validation to confirm
that cleaning procedures effectively remove residues and contaminants, preventing cross-
contamination.
8. Utilities and Environmental Validation: Validation of utilities such as HVAC, water systems,
and compressed gases, as well as environmental monitoring, ensures they meet quality and
operational standards.
9. Change Control and Revalidation: Any changes to equipment, processes, or systems must go
through a formal change control process and may require revalidation to ensure compliance with
quality standards.
10. Documentation and Record Keeping: Validation activities must be thoroughly documented in
protocols and reports, with detailed records of execution, results, deviations, and corrective
actions for regulatory inspections and audits.
These regulations ensure consistent product quality, patient safety, and compliance with global
pharmaceutical standards.
3.9: Manufacturing process validation model in a pharma industry:
1. Lifecycle Approach: The process validation model follows a lifecycle approach given by FDA
and ICH guidelines (ICH Q8, Q9, Q10). This approach ensures that the entire process, from
development to commercial production, is designed, controlled, and monitored. It includes three
key stages: Process Design, Process Qualification, and Continued Process Verification.
2. Stage 1: Process Design: Process design involves the development and definition of a robust
manufacturing process based on product development data. This stage identifies Critical Quality
Attributes (CQAs) such as potency, purity, and stability, and links them to Critical Process
Parameters (CPPs). Tools like Design of Experiments (DoE) are used to understand the impact
of variability and optimize the process.
3. Stage 2: Process Qualification (PQ): In this stage, the process is evaluated at a commercial
scale to confirm that it consistently delivers products meeting predefined quality standards.
Equipment and systems undergo qualification phases, including Design Qualification (DQ),
Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification
(PQ). At least three consecutive successful validation batches are typically required to
demonstrate reproducibility.
4. Pilot-Scale Studies: Before commercial production, pilot-scale studies are conducted to
simulate the manufacturing process. These studies help identify potential issues, fine-tune
process parameters, and demonstrate scalability from the laboratory or bench scale to the full
production scale. They also generate critical data to support process validation protocols.
5. Critical Parameters Monitoring: During validation, Critical Process Parameters (CPPs) such
as temperature, pressure, and mixing speed are carefully monitored and controlled. These
parameters directly impact the product's CQAs. Advanced tools like Process Analytical
Technology (PAT) may be used to enable real-time monitoring and ensure process consistency.
6. Concurrent Validation: Concurrent validation is conducted under real-time production
conditions when immediate product release is required (e.g., for life-saving drugs). Regulatory
authorities closely monitor such validation to ensure compliance. This type of validation is also
useful for demonstrating consistency during routine manufacturing processes.
7. Revalidation Requirements: Revalidation is mandatory whenever significant changes are
made to the process, equipment, raw materials, or facility layout. It ensures the modified process
remains capable of producing products that meet quality standards. Periodic revalidation may
also be required based on product-specific regulatory requirements or emerging quality trends.
8. Stage 3: Continued Process Verification: After commercialization, process performance is
continually monitored to detect any deviations or trends. Tools like Statistical Process Control
(SPC) and trend analysis are employed to assess the stability of the process and ensure
consistent product quality. This stage emphasizes a proactive approach to quality assurance
rather than reactive corrections.
9. Use of Quality by Design (QbD): QbD integrates quality into the design and development of
the manufacturing process. By identifying variability sources early and applying robust controls,
QbD minimizes risks. It involves creating a Design Space—a range of acceptable process
parameters—ensuring that any operations within this range result in products meeting quality
standards.
10. Documentation and Reporting: All validation activities must be meticulously documented,
including protocols, results, deviations, and corrective actions. Documentation serves as
evidence of compliance during regulatory inspections and audits. Detailed records not only
ensure transparency but also provide insights for future process optimization and
troubleshooting.
This model is useful for achieving consistent product quality while meeting regulatory expectations.
3.10: User Requirements Specification (URS): The User Requirements Specification (URS) is
a document created at the initial stage of the equipment procurement process. It outlines the
functional, performance, and regulatory requirements the equipment or system must meet. This
document specifies important details such as capacity, compatibility with existing systems,
operational conditions, safety features, and regulatory compliance needs. The URS gives well-
defined requirements to prevent miscommunication between users and suppliers.
Example: For a tablet compression machine, the URS might specify requirements such as a capacity
to compress 100,000 tablets per hour, compatibility with GMP standards.
3.11: Design Qualification (DQ): It checks whether the design of the equipment or system is as
per the requirements of the URS. The equipment's design, components, and materials are checked
with respect to the URS. DQ provides confidence that the equipment will meet both regulatory
requirements and operational needs. It is carried out before equipment installation begins.
Example, DQ involves verifying technical specifications like punch size, hopper capacity, etc.
3.12: Installation Qualification (IQ): It ensures that the equipment or system is installed correctly
as per the approved design. It involves verifying that all components are installed in the designated
location, utility connections are correct, and supporting documentation (e.g., manuals, wiring
diagrams) are available. IQ also checks for compliance with safety and regulatory standards. This
qualification is a crucial step before moving on to operational testing.
Example: During IQ for the tablet compression machine, the proper installation of parts like punches,
dies, and motors are checked. Utility connections, such as compressed air and power supply, are
tested for accuracy. Documentation like equipment manuals, wiring diagrams, and calibration
certificates are reviewed. IQ ensures the machine is physically set up as per design specifications.
3.13: Operational Qualification (OQ): It confirms that the installed equipment operates as intended
under defined conditions. Each function of the equipment is tested to ensure that they are within
acceptable limits. Examples of OQ tests include, verifying temperature controls, pressure settings,
speed, alarms etc. Any deviations or failures during OQ is documented and corrected before
proceeding further. This phase ensures that the equipment performs reliably under normal operating
conditions.
Example: In OQ, the tablet machine is tested for speed control, pressure settings, and weight
uniformity of tablets. Alarms for deviations like low hopper levels or punch failures are verified.
3.14: Performance Qualification (PQ): It is done by running the equipment / machinery with real
materials and if the final product meets the quality specifications, it has met performance
qualification. PQ assesses repeatability, efficiency, and compliance with quality standards. This
phase is the final step in the qualification process and indicates that the machinery is ready for
routine use. PQ documentation is necessary for regulatory approval and quality assurance.
Example: During PQ, the tablet compression machine runs with actual raw materials (e.g., granules)
to produce tablets. The final product is tested for weight variation, hardness, disintegration time, etc.
Multiple batches are processed to confirm consistent performance. Successful PQ ensures that the
machine is ready for routine commercial use.