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Validation and Calibration

History

Drug product quality was seen as the function of the status of the product itself.

Flawed approach- destructive tests-individual products can not be tested.

No statistical method was available to ensure quality of a batch of drug.

US FDA included some form of validation around mid 1970s (Process validation 21 CFR parts 210 and 211)

Initially limited to sterile products and later extended to other dosage forms

This was out of a concern to develop a verification mechanism that would need to be applied to the process to be meaningfully extrapolated to an entire batch

In the Indian scene this emerged as a requirement for those firms who wished to register with foreign agencies.

Followed by those requiring WHO GMP Certification for COPP.

Now included in the revised schedule M

Calibration

A set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring, recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. limits of acceptance of the results of measuring should be established.

The key requirements for critical instruments are as follows: each instrument should have a record in a permanent file all instruments should be assigned a unique number and tagged with that number the calibration method should be defined and approved calibration frequency and process limits should be be defined for each instrument

all records shall be maintained each standard should be traceable to a recognized standard The calibration standards must be more accurate to a closer tolerance that the instrument being tested calibration status should be identified on each instrument

all instruments shall be fit for the purpose training records for all personnel involved in the calibration must be maintained a change control system must be in place the instruments must meet all GMP requirements

Frequency of calibration shall be determined by the following: manufacturer recommendations duty of the instrument relevant standards and regulations historical information consequence of calibration failure experience

Calibration Documentation

Key documents:

Schedule date for calibration and frequency

Instrument ID

Calibration range

others

all records must be clear and unambiguous
unique number must identify the instrument
any instrument removal must be documented
replacement instrument must have documented history
removed instrument should be calibrated immediately to ascertain the cause or impact of failure

Validation And Process Validation

– Validation studies shall be an essential part of Good manufacturing Practices and shall be conducted as per the pre-defines protocols. These shall include validation of processing testing and cleaning procedures.

– A written report summarizing recorded results and conclusions shall be prepared, documented and maintained.

Processes and procedures shall be established on he basis of validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results.

Critical processes shall be validated, prospectively or retrospectively.

When any new master formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing.

The defined process, using the materials and equipment specified shall be demonstrated to yield a product consistently of the required quality.

Significant changes to the manufacturing process, including any change in equipment or material that may affect product quality and the reproducibility of the process, shall be validated.

What is Validation ?

Documented proof that everything, within reasonable certainty, that is involved in the manufacture of a product is under control.

This includes the facility, the environment, the materials, the equipment and the processes including manufacture and cleaning procedures.

WHY VALIDATION

To Establish by documented Evidence to provide a high degree of assurance that a planned process will consistently perform according to the intended specified outcomes

MASTER VALIDATION PLAN

It is a document pertaining to the â€œwhole facilityâ€ that describes which Equipment. Systems. Methods and Processes will be validated and when they will be validated.

It also includes Re-Validation- why and when

VALIDATION CONSISTS OF

Design Qualification – DQ

Installation Qualification – IQ

Operational Qualification – OQ

Performance Qualification – PQ

DESIGN QUALIFICATION

Necessary when planning and choosing equipment or systems to ensure that components selected will have adequate capacity to function for the intended purpose.

Example- selection of steam generator.

Master Validation Plan must address sequence of DQ.

INSTALLATION QUALIFICATION

Qualification of a piece of equipment should check for the requirements that are mentioned in the DQ
Compare with the purchasing information and invoice data

Requirements- Name, description, model, identification numbers, location, utility requirements, connections, safety measures 0f the system

During Installation Qualification it should be verified that the following matches the purchase specification:

Drawings,
manuals,
spare parts list,
vendor address and contact number,
Other pertinent documentation.

Simple Example of Installation Qualification

Equipment: _________________
Model: _________________
Manufacturer: _______________
Date of Purchase: ____________

1.	Manual	Provided/Not Provided	Remarks
2.	Physical Damage	OK/Damage found
3.	Dimensions	Not / As per requirement
4.	Switches	OK/Damage/Inadequate
5.	Covers Working	OK/Damage/Inadequate
6.	Limit Switches	OK/Damage/Inadequate
7.	Electrical Fittings	OK/Damage/Inadequate
8.	All fastenings	OK/Damage/Inadequate

The details of the equipment should be critically tallied with the order placed with the vendor. Needless to add the order placed should be as per the Design Qualification (DQ).

All critical components of the equipment should be tabulated and only after successful verification should the equipment verified as conforming to IQ

OPERATIONAL QUALIFICATIONS

Outlines the information required to provide evidence that all the components of a system or equipment operate as specified.

This involves testing of all:

normal operation controls,
all alarm points,
all switches,
all displays,
interacting controls,
any other indications of operation & functions

Specifications and acceptance criteria must be defined for all operation

Should provide a listing of SOPs, reference to specific manual instructions for operation, maintenance and calibration

Performance Qualification

To be carried out after both IQ and OQ have been successfully completed

Describes the procedures for demonstrating that a system or piece of equipment can consistently perform and meet required specifications under routine operation, and where appropriate, under worst case situations.

Describe the preliminary procedure required
Detailed performance test
acceptance criteria for each test
all supporting systems and procedures should have been validated (e.g.. Steam system should be validated before autoclave validation)

Process Validation Performance (How to do it)

Process: Run the process according to SOP three times and record all required data.

Deviations to the procedures must be recorded on the data record forms.

Analytical tests: Perform the routine tests associated with the process according to SOP, Test results must be approved by the QC.

Evaluation

Attach all data record forms and charts.

Perform all calculations and analyses which are predetermined and approved.

Compare with the accepted criteria.

Prepare Deviation Report

Deviation if any must be recorded and justification for acceptance, if any, mentioned.

Prepare Process Validation Report

This must mention the start date, completion date, observations, problems encountered, completeness of information, a summary of the deviation report, results of test, comparison with the accepted criteria, other relevant data.

A conclusion should take into account individual as well as the results of three consecutive validation runs.

Approval and Acceptance

QA should review and approve the report.
The Process must meet all specifications
For three consecutive runs

Process validation

Experimental
Prospective validation
Concurrent validation
Analysis of historical data
Retrospective validation
Revalidation
After change
periodic

Process Validation Requirements

Type of process Validation

Requirements

New

Every new process must be validated before approval for routine production

Existing

1. Process designed to render a product sterile

2. Non- sterile production

All processes affecting sterility and manufacturing environment must be validated; the most important is the sterilization stage.

Low-dose tablets and capsules containing highly active substances: validation of mixing and granulation in relation to content uniformity.

Other tablets and capsules: Validation of tablet compressing and capsule filling in relation to uniformity of mass.

Example of Process Validation Manufacture of Paracetamol tablets

Procedure of receipt of RM to the plant

Procedure of storage and testing

Procedure of issue of material to Prod.

Actual manufacturing:

Weighing
Sieving
mixing
Granulation
Drying
Lubrication
Compression

Release & Packing

Each of the above operations have to be validated against the requirements of the procedure and documented!!!!

FAQs

1. What is the primary difference between validation and calibration?

Validation focuses on confirming that a process or system meets its intended function, while calibration ensures the accuracy of measurement instruments.

2. Why is calibration crucial in the manufacturing sector?

Calibration is essential in manufacturing to maintain quality standards, reduce variability, and optimize equipment performance.

3. How do validation and calibration contribute to patient safety in healthcare?

In healthcare, validation and calibration ensure the precision of medical devices, compliance with regulatory standards, and, ultimately, patient safety.

4. What challenges do industries face when implementing validation and calibration?

Challenges include compliance issues, cost factors, and keeping up with technological advancements.

5. Why is the role of professionals, such as calibration technicians and validation engineers, so vital in these processes?

Professionals ensure the accurate implementation of validation and calibration, contributing to the reliability and consistency of equipment and processes.