Introduction to Validation

04/08/2023 11:00 AM University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh

Validation


Contents:

A. Definition.B. FDA Guidelines.C. Elements of Validation: 1. Installation Qualification. 2. Operational Qualification. 3. Performance Qualification.D. Process Validation.E. Types of Process Validation: 1. Prospective Validation. 2. Retrospective Validation. 3. Concurrent Validation. 4. Revalidation.F. Total Approach to Process Validation.G. Pilot Scale-up and Process Validation.H. Process Validation: Order of Priority. I. Process Design and Characterization.J. Reference.


What is Validation?

• Documented evidence that the manufacturing process consistently produces product that meets predetermined specifications

Defines product quality

Developed and validated based on a thorough understanding of the critical process parameters

Parameters are carefully controlled within the validated ranges to ensure a consistent manufacturing process.

• Manufacturing process validation consists of successfully manufacturing at least three full-scale batches in succession, which pass all in-process and product quality attributes


FDA Guidelines:

• The U.S. Food and Drug Administration (FDA) has proposed guidelines withthe following definition for process validation:

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.

• According to the FDA’s Current Good Manufacturing Practices (CGMPs)21CFR 211.110 a: Control procedures shall be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to the following, where appropriate:

1. Tablet or capsule weight variation 2. Disintegration time 3. Adequacy of mixing to assure uniformity and homogeneity 4. Dissolution time and rate 5. Clarity, completeness, or pH of solutions


• Conventional quality control procedures for finished product testing encompassthree basic steps:

1. Establishment of specifications and performance characteristics.2. Selection of appropriate methodology, equipment, and instrumentation to ensure that testing of the product meets specifications.3. Testing of the final product, using validated analytical and testing methods to ensure that finished product meets specifications.

• With the emergence of the pharmaceutical process validation concept, the following four additional steps have been added:

4. Qualification of the processing facility and its equipment.5. Qualification and validation of the manufacturing process through appropriateMeans.6. Auditing, monitoring, sampling, or challenging the key steps in the process for conformance to in-process and final product specifications.7. Revalidation when there is a significant change in either the product or its manufacturing process.


ELEMENTS of VALIDATION ELEMENTS of VALIDATION

Equipment validation: Installation Qualification(IQ)

Operational Qualification(OQ)

Process validation: Performance Qualification(PQ)


Installation Qualification (IQ):

• This is the first step in validation.

• This protocol insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications.

• Calibration of major equipment, accessory equipment, and/or utilities should be performed in this step as well.


Operational Qualification (OQ):

• This step proceeds after the IQ has been performed.

• In the OQ, tests are performed on the critical parameters of the system/process. These are usually the independent and/or manipulated variables associated with the system/equipment.

• All tests data and measurements must be documented in order to set a baseline for the system/equipment.


Performance Qualification (PQ):

• This is the third and final phase of validation.

• This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable.

• PQ is performed on the manufacturing process as a whole. Individual components of the system are not tested individually.


FDA Guideline Definition…

“PROCESS VALIDATION” is establishing documented evidence which

provides a high degree of assurance that a specific process consistently

produce a product meeting it’s predetermined specifications and quality

attributes”

PROCESS VALIDATION PROCESS VALIDATION


PROCESS VALIDATION


Types of Process Validation Types of Process Validation

1. Prospective validation

2. Retrospective validation

3. Concurrent validation

4. Revalidation


1. Prospective validation: is defined as the establishment of documented evidence that a system does what it purports to do based on pre-planned protocol. This validation is usually carried out prior to the introduction of new drugs and their manufacturing process. This approach to validation is normally undertaken whenever a new formula, process or facility must be validated before routine pharmaceutical formulation commences.


2. Retrospective validation: is defined as the establishment of documented evidence that a system does what it purports to do based on review and analysis of historical data. This is achieved by the review of the historical manufacturing testing data to prove that the process has always remained in control.


3. Concurrent validation: is similar to prospective, except the operating firm will sell the product during the qualification runs, to the public at its market price. This validation involves in process monitoring of critical processing steps and product testing.


4. Revalidation: It is the repetition of a validation process or a specific part of it. This is carried out when there is any change or replacement in formulation, equipment, plant or site location, batch size and in the case of sequential batches that do not meet product and process specifications.

Conditions requiring revalidation study and documentation are listed as follows:

1. Change in a critical component (usually refers to raw materials).2. Change or replacement in a critical piece of modular (capital) equipment.3. Change in a facility and/or plant (usually location or site).4. Significant (usually order of magnitude) increase or decrease in batch Size.5. Sequential batches that fail to meet product and process specifications.

04/08/2023 11:00 AM


Total Approach to Pharmaceutical Process Validation:


Pilot Scale-up and Process Validation:

• The following operations are normally carried out by the development function prior to the preparation of the first pilot-production batch. The development activities are listed as follows:

1. Formulation design, selection, and optimization 2. Preparation of the first pilot-laboratory batch 3. Conduct initial accelerated stability testing 4. If the formulation is deemed stable, preparation of additional pilot laboratory batches of the drug product for expanded nonclinical and/or clinical use.

• The pilot program is defined as the scale-up operations conducted subsequent to the product and its process leaving the development laboratory and prior to its acceptance by the full scale manufacturing unit.

• Thus, product and process scale-up should proceed in graduated steps with elements of process validation (such as qualifications) incorporated at each stage of the piloting program.



Laboratory Batch Laboratory Pilot Batch Pilot Production

• The first step in the scale-up process is the selection of a suitable preliminary formula for more critical study and testing based on certain agreed-upon initial design criteria, requirements, and/or specifications.

• The size of the (1Χ) laboratory batch is usually 3–10 kg of a solid or semisolid, 3–10 liters of a liquid, or 3000 to 10,000 units of a tablet or capsule.

• Laboratory pilot batch represents the first replicated scale-up of the designated formula.

• The size of the (10Χ) laboratory pilot batch is usually 30–100 kg, 30–100 liters, or 30,000 to 100,000 units.

• It consist of process ranging, process characterization, and process optimization as a prerequisite to the more formal validation program that follows later in the piloting sequence.

• The pilot-production phase may be carried out either as a shared responsibility between the development laboratories and its appropriate manufacturing counterpart or as a process demonstration by a separate, designated pilot-plant or process-development function.

• The object of the pilot-production batch is to scale the product and process by another order of magnitude (100Χ) to, for example, 300–1,000 kg, 300 –1,000 liters, or 300,000–1,000,000 dosage form units (tablets or capsules) in size.


Fig: Main piloting options.

Development Laboratory

Pilot Plant Production

Development Laboratory

Production

Pilot Batch Request

Pilot Batch Completion Request



Process Validation: Order of Priority

A. Sterile Products and Their Processes 1. Large-volume parenterals (LVPs). 2. Small-volume parenterals (SVPs). 3. Ophthalmics, other sterile products, and medical devices.

B. Nonsterile Products and Their Processes 1. Low-dose/high-potency tablets and capsules/transdermal delivery systems (TDDs). 2. Drugs with stability problems. 3. Other tablets and capsules. 4. Oral liquids, topicals, and diagnostic aids.


Process Design and Characterization:

• Process capability is defined as the studies used to determine the critical process parameters or operating variables that influence process output and the range of numerical data for critical process parameters that result in acceptable process output.

• If the capability of a process is properly delineated, the process shouldconsistently stay within the defined limits of its critical process parameters andproduct characteristics.

• Process demonstration formerly called process qualification, 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

process parameters operate within their assigned control limits; and that suchstudies and trials, which form the basis of process capability design and testing,are verifiable and certifiable through appropriate documentation.



• Process characterization represents the methods used to determine the critical unit operations or processing steps and their process variables, that usually affect the quality and consistency of the product outcomes or product attributes.

• Process ranging represents studies that are used to identify critical process or test parameters and their respective control limits, which normally affect the quality and consistency of the product outcomes of their attributes.

Validation is Always Part of the Picture

Ongoing Validation

(DOE, IQ, OQ, PQ, PV)*

Pre-IND Phase I Phase II Phase III Commercial Manufacturing

* DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation

Specification DevelopmentFinal process validation

Re-validation

• The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product

• 6 sigma target


Reference:

1. Robert A. Nash; Alfred H. Wachter; “Pharmaceutical Process Validation”; International Third Edition; pg. 17-40.

2. Guidance for Industry; Process Validation: General Principles and Practices 2008.

3. Rest from Internet.

Thank You

Documents

Introduction to Validation