validation overview.

1. Validation
Modern pharmaceutics
Jitul Adhikary
1st sem Mpharm-pharamaceutics

2. Validation definition
A case was the 1971 Devonport incident, in which a batch of 5% dextrose IV bottles that were not correctly
sterilized reached the market and were administered to patients. Sadly, five patients at a Devonport, England,
hospital died after receiving the contaminated solution.
The outcome of this was the introduction by the regulators of the concept of “Validation”:
• Documented evidence which provides a high degree of assurance that a specific process will consistently
produce a product meeting its predetermined specifications and quality attributes
• Validation is a defined program which, in combination with routine production methods and quality control
techniques, provides documented assurance that a system is performing as intended and/or that a product
conforms to its predetermined specifications

3. Merits of validation
1. Regulatory compliance
2. Increased throughput
3. Reduction in rejections and reworks
4. Reduction in utility costs
5. Avoidance of capital expenditures
6. Fewer complaints about process related failures
7. Reduced testingin process and finished goods

4. Merits of validation
8. More rapid and accurate investigations into process deviations
9. More rapid and reliable startup of new equipment
10. Easier scale-up from development work
11. Easier maintenance of the equipment
12. Improved employee awareness of processes
13. More rapid automation

5. Scope of validation:
1. Selection of raw materials ie raw materials of desired qualiy attributes.
2. Product design based on expected performance
3. Process design to built the desired quality attributes in the product.
4. Design of control parameters, such as change control, acceptance criteris, tolerance limits etc.
5. In process quality control parameter and sampling plans
6. Finished product testing or evaluation criteria.
7. Validation of related analytical process.
8. Validation of related system, facility and equipment.
9. Personnel training.
10. Validation also involves careful determination of criteria variables of process, such as moisture content of granules,
drying temperature & time and then establishing of acceptable range and tolerance limits for the same. A careful
and continuous control of these variables will ensure product quality.

6. Stakeholder in validation process
• Implementation requires the validation organization to interact with many peer groups. Within the
company, those other departments include the following:
1. R&D: involved with new product development and new process improvement.
2. Engineering: involved with new or modified equipment or facilities.
3. Production: concerned with processes that require validation.
4. Maintenance: concerned change control, calibration, and preventative maintenance.
5. Quality Control: involved with the testing laboratories.
6. Quality Assurance: concerned with GMP compliance.
Additionally, for those companies that outsource the manufacturing or packaging of their products, these
interactions occur with the contracting firm’s Validation department.

7. Validation master plan
• A Document providing information on the company’s validation work. It should provide detail and of
timescales for validation work to be performed. It also contains details of responsibilities relating to the plan
that is to be stated.
• Validation masterplan
• A manufacturer should have a validation master plan that reflects the key elements of validation. It should
be concise and clear and at least contain reference to/have a short description of the following:
• ■ title page and authorization (approval signatures and dates);
• ■ table of contents; ■ abbreviations and glossary;
• ■ validation policy; ■ philosophy, intention and approach to validation;
• ■ roles and responsibilities of relevantpersonnel;
• ■ resources to ensure that qualification and validation are done;
• ■ outsourced services (selection, qualification, management through the life-cycle);
• ■ scope of qualification and validation;
• ■ documentation required in qualification and validation, such as procedures, certificates, protocols and
reports;
• ■ premises qualification, such as room verification where appropriate;
• ■ qualification of utilities;

8. • ■ equipment and instrumentqualification; ■ process validation; ■ cleaning
validation; ■ personnel qualification (such as analystqualification); ■
analytical method validation; ■ computerized system validation; ■
establishment of acceptance criteria; ■ life-cycle management, including
retirement policy; ■ requalification and revalidation; ■ relationship with
other quality management elements; ■ validation matrix (such as a table
indicating the history and status of qualification and validation on-site); ■
retention of qualification and validation documentation; ■ deviation
management; ■ change control; ■ risk management principles; WH O
Technical Report Series, No. 1019, 2019 Annex 3 127 ■ training; ■
references. 7.2 The validation master plan should be reviewed at regular
intervals and kept up to date, according to currentGMP.

9. Types of validation
• Validation is divided into following subsections which include:[3]
1. Analytical method validation
2. Process validation
3. Cleaning validation
4. Equipment validation
Let’s take an overview of different types of the validation process and discuss in detail about equipment validation and its
phase with their importance in pharmaceutical industries.
1. Analytical method validation: The purpose of analytical validation is to verify that the selected analytical procedure will
give reliable results that are adequate for the intended purpose. There are different parameters which come under
analytical method validation. These are as follows:[2,4]
1. Accuracy
2. Precision
3. Repeatability
4. Reproducibility
5. Specification
6. Linearity
7. Range
8. Detection limit
9. Quantitation limit

10. Types of validation
1. Process validation: This type of validation demonstrates documented proves, which carries a higher degree of surety that the process will consistently produce a
product which meets all the predetermined quality characteristics and specifications. The process validation also assures the repeatability of the process and
decreases the risk of manufacturing problems which lead to an increase in output of predetermined quality.
2. On the bases of the stage of production under process validation, it can be of four types which are as follow:
1. Prospective validation
2. Concurrent validation
3. Retro specific validation
4. Revalidation.
3. Cleaning validation: Cleaning validation provides documented set up with a high degree of surety that particular system/equipment or part of equipment is
consistently clean-up to predetermined quality and acceptable limits. Pharmaceutical products are contaminated by variety of substances such as lubricants,
airborne materials, prepared product residues, and microbes. Hence, an adequate cleaning procedure plays an important role to prevent contamination and cross
contamination.[1,5]
4. Equipment validation: Equipment validation is established documented set up that proves any equipment works correctly and leads to accepted and accurate
results (predetermined result). The process of equipment validation is based on the principle that equipment must be designed, constructed, maintained, and
adapted to perform the operations which are to be carried out. Equipment’s are the basic component of pharma industries; therefore, before performing a process
in pharma industries, it becomes primary important to issue equipment validation (documented evidences of equipment).[5,6]
• Types of equipment validation [Figure 2]: The process of equipment validation is not a single step activity that it has different phases which have further
subsections or steps, these are as follow:[6]
• Design qualification
• Installation qualification
• Operational qualification
• Performance qualification
• Process qualification

11. Validation of Solid dosage form
1. VALIDATION OF RAW MATERIALS
• The validation process of a solid dosage form begins with a validation of the raw materials, both active pharmaceutical ingredients (APIs) and excipients
1. ANALYTICAL METHODS VALIDATION
• The following list of analytical criteria must be assessed prior to beginning
• any validation program:
• 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-day variation: Does the precision and accuracy of the method change when conducted numerous times on the same day and repeated on a subsequent day?
• 5. Between-operator variation: 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-instrument variation: How will different instruments within the same laboratory run by the same analyst affect the accuracy and precision of the method?
• 7. Between-laboratory variation: Will the precision and accuracy of the method be the same between the development and quality control laboratories?

12. Validation of Solid dosage form
• IV. EQUIPMENT/FACILITY VALIDATION
• The product development of a pharmaceutical product has its origins in a systematic approach to formulation, process and manufacture, and the analytical testing that is necessary to monitor quality and reproducibility.
• . DEFINITION AND CONTROL OF PROCESS VARIABLES
• Process validation can be defined as a means of challenging a process during development to determine which variables must be controlled to ensure the consistent production of a product or intermediate.
• A. 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).
• 2. Granulation particle size distribution: 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 proper blend 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/capsule weight: 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., poor granulation flow) is not
optimized and/or that the equipment may need maintenance.
• 5. Tablet hardness: 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. Tablet thickness: 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 proper flow and
compression properties.
• 7. Disintegration: Disintegration is determined during the manufacture as a predictor of tablet performance (e.g., dissolution).
•

13. Validation of Solid dosage form
• B. Finished Product Tests
• 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 product contains the labeled amount of drug.
• 3. Content uniformity: Samples are taken across the batch profile (beginning, middle, and end) and analyzed to ensure that the
dosage forms comply with compendial standards (±15% of the labeled amount) or 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. Tablet hardness: A critical parameter for dosage form handling and performance.
• 5. Tablet friability: 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.

14. Manufacturing process model

15. Calibration of Equipments
Calibration and verification:
• Calibration and verification of equipment, instruments and other devices, as applicable, should be initiated
during installation qualification, to ensure that the system operates according to the described specifications
and because the calibration status could have been affected during transport and installation. Thereafter, it
should be performed at regular intervals in accordance with a calibration programme and SOPs. WH O
Technical Report Series, No. 1019, 2019 Annex 3 133, Personnel who carry out calibration and preventive
maintenance should have appropriate qualification and training. A calibration programme should be available
and should provide information such as calibration standards and limits, responsible persons, calibration
intervals, records and actions to be taken when problems are identified

16. ICH guideline on analytical procedure

17. Equipment qualification

19. Validation life cycle

20. Equipment qualification flow diagram