Pharmaceutical Process Validation

Validation

Definition: • Validation is the action of

proving that any procedure, process, equipment,, method, material or activities actually leads to the expected results and produce a quality products.

Why Validation?

Need of Validation: • To obtain consistent, reliable

and accurate data• Act as a proof in decision

making• To get assurance of Quality

product

Validation is the scientific study of a process:• To prove that the process is consistently doing what it is

supposed to do (i.e., that the process is under control)• To determine the process variables and acceptable limits

for these variables, and to set up appropriate in- process controls.

Validation in Pharmaceutical Industry:• Assurance of Quality• Cost Reduction• Government Regulation

Documentation associated with validation includes:• Standard Operating Procedures (SOPs):• Specifications • Validation Master Plan (VMP) • Qualification Protocols and Reports • Validation Protocols and Reports.

Standard Operating Procedures (SOPs):• An authorized written procedure giving instructions for

performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection)

Validation protocol (or plan) (VP): • A document describing the activities to be performed in a

validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use.

Validation report (VR):• A document in which the records, results and evaluation

of a completed validation programme are assembled and summarized. • It may also contain proposals for the improvement of

processes and/or equipment.

Resources required to implement validation: • Time: • rigorous time schedules.

• Financial:• time of specialized personnel and • expensive technology.

• Human: • collaboration of experts from various disciplines • e.g. a multidisciplinary team, comprising quality

assurance, engineering, manufacturing and other disciplines, depending on the product and process to be validated.

Scope of Validation• Appropriate and sufficient system – to perform validation

tasks in a timely manner. • organizational structure and • documentation • infrastructure, • sufficient personnel – with specific qualification and • financial resources

• Proper preparation and planning before performing validation activities• Validation performed in a structured way according to

protocols and documented procedures.

Scope of Validation• A written report on outcome of validation should be

produced for documentation.• Validation should be performed: • for new premises, equipment, utilities and systems, and processes

and procedures; • at periodic intervals; and• when major changes have been made.

• Validation should be done over a period of time. • e.g. at least three consecutive batches should be validated, to

demonstrate consistency.

Scope of Validation• In-process controls and validation: • In-process tests are performed during the manufacture of each

batch according to specifications and methods devised during the development phase.

• Objective of in-process controls - to monitor the process continuously.

• Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. • A risk assessment approach should be used to

determine the scope and extent of validation required.

Validation Master Plan (VMP)

• Definition: It is a high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. • It provides information • on the manufacturer’s validation work programme and • defines details of and timescales for the validation

work to be performed• It should reflect the key elements of the validation

programme.

Validation Master Plan• It should be concise and clear and contain at least the

following:• a validation policy • organizational structure of validation activities • summary of facilities, systems, equipment and

processes validated and to be validated • documentation format (e.g. protocol and report format)• planning and scheduling• change control • references to existing documents.

Validation Protocol• Definition: A document describing the activities to be

performed in a validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use. • A protocols should include• the objectives of the study• the site of the study • the responsible personnel • description of SOPs to be followed • equipment to be used; standards and criteria for the relevant

products and processes • the type of validation • the processes and/or parameters • sampling, testing and monitoring requirements • predetermined acceptance criteria for drawing conclusions

Validation and Qualification

• Validation: Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results.

• Qualification: Action of proving and documenting that any equipment, utilities and systems actually and consistently leads to the expected results

• Validation and qualification are essential components of the same concept.• Qualification is part of validation

Qualification• Qualification: Action of proving and documenting that any

equipment, utilities and systems actually and consistently leads to the expected results

• Qualification should be completed before process validation is performed.

• The process of qualification – • logical, • systematic process • should start from the design phase of the premises,

equipment, utilities and equipment.

Qualification

• There are four stages of qualification:• design qualification (DQ)• installation qualification (IQ)• operational qualification (OQ)• performance qualification (PQ).

• All SOPs for operation, maintenance and calibration should be prepared during qualification.

• Training should be provided to operators and training records should be maintained.

Design Qualification:• Documented evidence that the premises, supporting

systems, utilities, equipment and processes have been designed in accordance with the requirements of GMP

Installation qualification (IQ):• Installation qualification should provide documented

evidence that the installation was complete, satisfactory and operate in accordance with established specifications.• Installation qualification verified – • The purchase specifications, • drawings, manuals, • spare parts lists and • vendor details

Operational qualification (OQ):• Operational qualification should provide documented

evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications.• Operation controls, alarms, switches, displays and other

operational components should be tested.

Performance qualification (PQ):• Performance qualification should provide documented

evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use.• Test results should be collected over a suitable period of

time to prove consistency.

Requalification

• Requalification should be done in accordance with a defined schedule.• The frequency of requalification may be determined on

the basis of factors such as the analysis of results relating to calibration, verification and maintenance.• There should be periodic requalification, as well as

requalification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement).• Requalification should be considered as part of the

change control procedure.

Advantages of Validation

Main advantages of Validation:Assurance of quality• Validation is an extension of the concepts of quality

assurance since close control of the process is necessary to assure product quality. • It is not possible to control a process properly without

thorough knowledge of the capabilities of that process.• Without validated and controlled processes, it is

impossible to produce quality products consistently

Process optimization• Optimize – to make as effective, perfect or useful as

possible• Validation helps to optimize the process for its maximum

efficiency with maintaining its quality standards. • The optimization of the facility, equipment, systems, and

processes results in a product that meets quality requirements at the lowest cost.

Reduction of quality costs• Any validated and controlled process will result in fewer

internal failures like• Fewer rejects• Reworks• Re-tests• Re-inspection

Process ValidationProcess Validation – Statutory and Regulatory

requirement

• Requirement of cGMPs for finished pharmaceuticals (21

CFR 211)

• Requirement of GMPs for medical devices (21 CFR 810)

• Apply to manufacturing of both drug product and medical

devices

Definition of Process Validation (as per US FDA):

• Process validation is establishing documented evidence

which provides a high degree of assurance that a specific

process will consistently produce a product meeting its

predetermined specifications and quality characteristics.

In short,

• Process validation is defined as the collection and

evaluation of data, from the process design stage through

commercial production, which establishes scientific

evidence that a process is capable of consistently

delivering quality product.

Process Validation Activities

• Process validation involves a series of activities taking

place over the lifecycle of the product and process.

• Process validation activities in three stages

• Stage I: Process Design

• Stage II: Process qualification

• Stage III: Continued process verification

Stage 1 – Process Design:

• The commercial manufacturing process is defined during this

stage based on knowledge gained through development and

scale-up activities.

Stage 2 – Process Qualification:

• During this stage, the process design is evaluated to

determine if the process is capable of reproducible

commercial manufacturing.

Stage 3 – Continued Process Verification:

• On-going assurance is gained during routine production that

the process remains in a state of control.

Types of Process Validation

The guidelines on general principles of Process Validation

mention four types of validation.

• Prospective Validation (Premarket validation)

• Retrospective Validation

• Concurrent Validation

• Revalidation

Prospective Validation• Definition: It is establishing documented evidence prior to

process implementation that a system does what it proposed to

do based on pre-planned protocols.

• An experimental plan called the validation protocol is executed

before the process is put into commercial use.

• It is normally undertaken for a new drug product or new

facilities are introduced into a routine pharmaceutical

production.

• Objective: To prove that the process will work in accordance

with a validation protocol

• During Product development stage• Production process broken down into individual steps • Each steps evaluated on the basis of experience or theoretical

considerations• Critical factors that may affect the quality of the finished product

are determined.

• Personnel involved in Prospective validation are• Representatives from Production • QC/QA, Engineering• Research and Development

• It is a challenge element to determine the robustness of the process. Such a challenge is generally referred to as a "worst case" exercise.

Everything should be planned and documented fully in an authorized protocol. It contains…

a) Objective, scope, responsibilitiesb) Process Flowc) A description of the process,d) A description of the experiment,e) Details of the equipment/facilities to be used together with its calibration status,f) The variables to be monitored,g) The samples to be taken - where, when, how and how many,h) The product performance characteristics/attributes to be monitored, together with the test methods,i) The acceptable limits,j) Time schedules,k) Details of methods for recording and evaluating results, including statistical analysis.l) Summary / Conclusion

Pre-Requisite of process validation

• All equipment to be used should have been qualified (Installation/Operational Qualification),• The production Facility and area should be validated.• Analytical testing methods to be used should have been

fully validated,.• Critical support systems like water system, compressed

air system etc, should be validated.• Raw and packaging material specifications are approved.• Staff taking part in the validation work should have been

appropriately trained.

Retrospective Validation• Definition: It is an establishing documented evidence that a

process does what it is supposed to do based on review and analysis of historic data.

• Many process – routine use – not validated • Validation of these processes - historical data to provide the

necessary documentary evidence that the process is doing what it is supposed to do.

• Steps require for validation• Protocol preparation• Validation reports• Data analysis• Conclusion • Recommendations

Concurrent Validation

• Definition: Concurrent Validation means establishing documented evidence a process does what it is supposed to do based on data generated during actual implementation of the process.

• Validation – during routine production• Validation involves –• In-process monitoring• End product testing

• Personnel – Authorized staff• Documentation – as per Prospective Validation

Revalidation

• Definition: Re-validation provides the evidence that changes in a process and/or the process environment, introduced either intentionally or unintentionally, do not adversely affect process characteristics and product quality.

• There are two basic categories of Re-validation:• Re-validation in cases of known change (including

transfer of processes from one company to another or from one site to another),• Periodic Re-validation carried out at scheduled

intervals

Changes that are likely to require Re-validation are as follows:• Changes of raw materials (physical properties such as

density, viscosity, particle size distribution may affect the process or product),• Change of starting material• Changes of packaging material (e.g. substituting plastic

for glass),• Changes in the process (e.g. mixing times, drying

temperatures),• Changes in the equipment (e.g. addition of automatic

detection systems).• Changes of equipment • Production area and support system changes (e.g.

rearrangement of areas, new water treatment method),• Transfer of processes to another site