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Audio Script PVF 830-02 Fundamentals of Fundamentals of Process Validation

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Audio Script

Module Title: Fundamentals of Process Validation

Module Code: PVF 830-02

Screen 1 Learning Objectives and Keywords

Welcome. Please carefully review the learning objectives and keywords before proceeding.

Objectives:

1. Explain the term ‘validation’ and why it must be performed in regulated industries 2. List the five established validation categories 3. Explain the risk assessment approach to validation 4. Explain the purpose of a Validation Master Plan and describe its contents 5. Explain the concept of the Validation Life Cycle 6. Describe the different stages of the Validation Life Cycle 7. Explain ‘traceability matrix’ and describe its use in validation 8. Explain the terms DS, FS, and URS 9. Explain the purpose of process validation 10. Describe each of the four qualification stages DQ, IQ, OQ and PQ 11. Explain how the qualification stages relate to the equipment specifications 12. Explain the concepts of change control, revalidation and decommissioning Keywords: Change Control Performance Qualification Commissioning Process Validation Decommissioning Revalidation Design Qualification Risk Assessment Design Specification Specifications Documentation Tolerance Equipment Qualification Traceability Matrix Functional Specification User Requirement Specification Installation Qualification Validation Life Cycle Operational Qualification Validation Master Plan (VMP)



Screen 2 What Will I Learn?

In this lesson you’ll be introduced to the concept of validation. Validation is practiced right across

regulated industries such as

Finished dose pharmaceuticals

Active pharmaceutical ingredients

Biopharmaceuticals

And medical devices

After taking this lesson you’ll be able to recognize, understand, and, if necessary, apply the principles

and techniques of validation to your own work situation.

Screen 3 GMP

This is CureIT Inc, a manufacturer of solid dose pharmaceutical products.

CureIT manufactures products for the US market and so it is regulated by FDA, the US Food and Drug

Administration.

CureIT must operate according to Good Manufacturing Practice or GMP regulations. These are

regulations enforced by FDA and are designed to ensure that drug products are safe for human use.

GMPs also ensure that quality standards are maintained throughout the drug manufacturing

process.

CureIT has developed a new product called Cholgonex, an anti-cholesterol drug in tablet form.

FDA has given initial approval for Cholgonex and now CureIT is planning a new purpose built facility

to manufacture the drug on a commercial scale.

Screen 4 The Three Essential Characteristics

Cholgonex, like all GMP drugs, must have three essential characteristics. These are:

Quality

Safety

Effectiveness

If Cholgonex doesn’t have these characteristics then it shouldn’t be in the marketplace.



To comply with GMP regulations, CureIT must manufacture a Cholgonex product with all of these

characteristics, batch after batch. But how can it be sure of doing this? How can FDA be sure?

A critical quality tool in providing assurance is validation.

As part of GMP, validation is a legal requirement for receiving and maintaining a product

manufacturing license in the United States, European Union, and other regions.

In this lesson we’ll use CureIT’s new tablet manufacturing facility to explain the concept and

application of validation in regulated industries.

Screen 5 Why Validation

To help us understand why validation is necessary, let’s consider end of batch quality control testing.

For a product like Cholgonex, CureIT can do a certain number of quality control tests after the

product is made to assess its quality.

Tablet samples can be inspected and tested for parameters such as strength, content uniformity,

thickness, and so on.

But routine end-product testing alone isn’t enough to ensure we have a quality product time after

time.

Some laboratory tests have limited sensitivity and may not reveal all of the variations that could

occur in the product – variations that could impact on quality, safety and effectiveness.

In other words, CureIT can’t test quality into the product. To give CureIT and FDA confidence in the

quality of Cholgonex, there must be confidence in everything that has a direct impact on its quality –

for example,

Manufacturing equipment

The manufacturing environment

Raw materials.

The manufacturing process itself, and so on.

Providing this confidence is the purpose of validation.

Screen 6 Defining Validation

You can think of validation as a quality system to ensure that quality is designed into a product.

A validated manufacturing process is basically one which has been proven to do what it claims to do.



The validation of the Cholgonex manufacturing process involves collecting and evaluating data,

beginning in the process development phase and continuing through the production phase over the

entire useful life of the product.

Validation involves qualification of all of the critical components of a process.

By process we mean the controlled interaction of

Materials,

Equipment,

Systems,

Buildings,

And personnel

By qualifying something you are proving that it is fit to be used for its intended purpose.

Validation also involves demonstrating consistent control of the entire process for repeated

manufacturing runs or batches.

Screen 7 What to Validate

The production of tablets involves several different ‘unit operations’ including

Blending

Granulation

Milling

And compression

Each of these operations has its own specialized equipment, process, control systems,

environmental controls and so on.

All of these will be part of the new Cholgonex facility so you can see that validation is very far

reaching in its scope.

Essentially, there are five main areas of validation in a regulated facility. These are...

Process Validation

Equipment and Utilities Validation

Computer Validation

Analytical Validation



Cleaning Validation

With its new Cholgonex facility, CureIT will need to validate in all of these areas to varying degrees.

Deciding exactly what to validate involves using a technique called Risk Analysis.

Screen 8 Risk Assessment

Validation can be an expensive and time consuming activity so it makes sense to carefully define the

scope and extent of validation required and maximize use of resources.

One way of doing this is to use Risk Assessment.

Risk Assessment involves identifying critical and non-critical components of the drug manufacturing

process.

It then separates these components into those which have direct or indirect product contact…others

which have product quality impact… and those which do not affect the product in any way.

Validation is done for the first two cases but not for the last.

Risk Assessment also identifies the activities necessary for validation, maintenance and calibration.

Risk Assessment tools include Failure Modes and Effects Analysis or FMEA. FMEA is designed to

answer the question: “what would happen if this failure occurred?”

It evaluates the impact of potential failures and the likelihood of their occurrence for each

component of the process.

Screen 9 Planning and the Validation Master Plan

In validation careful planning and preparation is everything! A key planning tool is the Validation

Master Plan or VMP.

The VMP has three main functions…

1. It helps CureIT’s management understand why the validation program is necessary and what

it involves in terms of time, personnel and cost.

2. It defines the responsibilities of all the validation team members.

3. It gives inspectors an insight into CureIT’s approach to validation and how validation

activities are organised.

The VMP is developed early on in the validation activities and is updated as needed if the plan

changes.



From a regulatory viewpoint, a VMP is essential because it describes how the reliability and

consistency of the equipment, systems and processes associated with the manufacture of Cholgonex

will be established. It also describes how the validated state will be maintained.

Screen 10 Validation Life Cycle

The standard industry approach to validation is to consider it as part of the Life Cycle of a

manufacturing process.

For the Cholgonex manufacturing process, the Life Cycle starts at the design stage and finishes when

the process is retired or decommissioned. Here are the main phases of the Life Cycle:

Design

Construction

Commissioning

Qualification

Validation

Decommissioning

The relationship between these phases can be shown using the widely used ‘V’ model of

specification and qualification. Here’s what the V model looks like:



The left side of the V depicts the design development process.

The bottom of the V is the construction of the facility.

The right side depicts the qualification activities that are used to prove or verify that the

implemented design successfully achieves the original design requirements.

From the V model you can see how the qualification activities and design specifications are linked.

To understand how this works in practice, we’ll use the new Cholgonex facility as an example.

Screen 11 User requirements Specification

The design stage of the Cholgonex project begins with the User Requirement Specification...

…or URS

This is prepared by CureIT and describes what it wants the new facility to do – in this case,

manufacture the Cholgonex product to meet GMP requirements.

The URS requires input from many different functions within CureIT, including

Quality assurance

Engineering

Manufacturing



And compliance

The URS doesn’t specify any materials, equipment, software or other components. It only specifies

needs from a process perspective.

The URS is normally sent out to prospective equipment and service providers such as consulting

engineering firms, equipment providers, architects and so on, so that tenders for the work can be

made.

Having the URS ensures that both the user and contractor are clear about the facility’s requirements.

The URS is carefully documented so that any subsequent changes can be tracked throughout the life

of the project. A common way to track changes is to use a traceability matrix (TM).

A TM connects the ‘deliverables’ at the end of the project with the requirements stated at the

beginning of the project – in other words, it compares what is delivered with what was required.

Here’s an example of what a traceability matrix looks like.

Screen 12 Functional Specification and Design Specification

Based on the needs specified in the URS, potential suppliers will suggest systems or equipment to

meet these needs. As the potential suppliers are normally the experts, they can recommend

technical solutions and alternatives to meet the requirements listed in the URS.



The potential supplier should be able to provide evidence that it can provide systems or equipment

suitable for a GMP-regulated environment. This is the Functional Specification or FS. The FS is the

basis for the design of the entire system.

Using the FS, CureIT and its suppliers can then develop the detailed facility design called the Design

Specification or DS. The DS is detailed enough to allow the facility, system or equipment to be built.

Screen 13 Design review

Before moving ahead with the construction and fit out of the facility, CureIT must be certain that the

proposed design will meet regulatory requirements. To do this the facility must be qualified.

Qualification is the process of demonstrating that those areas of the facility that come under GMP

regulations operate as intended.

There are a number of qualification categories...

The first is Design Review or DR. During Design Review (DR), the design specified by CureIT is

compared with the actual design of the facility detailed in the Design Specification.

The basis of DR is the DS previously prepared for the facility as shown here in the V model. DR is

done by CureIT’s qualified staff and the facility designers.

This is the only review stage which confirms that the proposed design will work so it is critically

important to the success of the project.

Once the DR is approved, the status of the design specifications is ‘frozen’ and the facility is ready to

be built. Any changes after this point must go through a change control procedure and we’ll look at

this later.

Screen 14 Installation, Commissioning and SAT

The facility is now built and is ready to be fitted out with manufacturing equipment and systems.

It is normally the responsibility of the supplier to deliver and install the equipment, and verify that it

is operational on-site. This is the last step before the responsibility is handed over to CureIT.

Installation involves unpacking, checking for transport damage, and moving the equipment to the

location where it will be used.

The equipment is then connected to utilities such as electricity, water, steam, and compressed air.

The supplier will then verify that it is working correctly. This procedure is called commissioning.

Commissioning can be used to support qualification activities if performed and documented

properly. We’ll look at qualification activities shortly.



During commissioning adjustments and corrections may be necessary.

After the commissioning, CureIT may do a Site Acceptance Test (SAT) to verify that the equipment is

working and that spare parts, manuals, and other documentation are on-site and meet expectations.

Screen 15 Further Qualification

Before validating the Cholgonex manufacturing process, CureIT must ensure that the new facility

with its equipment, utilities, and systems is functioning correctly.

This is done by performing further qualification checks on those items that have a direct impact on

product quality.

Qualification and validation are essentially components of the same concept. The term qualification

is normally used for

Facilities,

Equipment,

Systems

And utilities

The term validation is normally used for processes.

Equipment, utilities and systems must be qualified to operate in a validated process. So in this sense,

we can say that qualification is one of the activities that support validation of production processes.

By doing qualification before process validation, CureIT will ensure that the process validation study

is not affected by a poorly functioning facility, equipment or utilities.

Screen 16 Installation Qualification

We’ve already looked at Design Qualification. The next qualification check is Installation

Qualification or IQ.

IQ involves providing written verification that all equipment is installed correctly and that it matches

what has been approved in the Design Specification.

The testing requirements are contained in a document called the IQ protocol.

While the facility construction, equipment delivery and installation is the responsibility of the

contractor or supplier, CureIT is responsible for the Installation Qualification (IQ) and the remaining

qualification steps.



In the case of equipment, CureIT would do an IQ on each of the equipment items used in the

Cholgonex manufacturing process –

Granulator

Blender,

Tablet press…and so on.

Calibration of major items of equipment, accessory equipment, and utilities is also done at the IQ

stage.

Here’s an example of an IQ checklist for a tablet press.

Screen 17 Operational Qualification

Once the IQ is done, the Operational Qualification or OQ can begin according to the OQ protocol.

The Operational Qualification (OQ) phase verifies that the equipment or system performs

functionally as described in the Functional Specification. In other words, the equipment is actually in



operation and is being checked to ensure that it can perform as intended throughout its operating

range.

In the case of the Cholgonex tablet press, OQ would include items such as these…

Standard Operating Procedures for equipment use, maintenance, calibration, and cleaning are all

developed during the OQ process.

Screen 18 Performance Qualification

Performance Qualification or PQ follows on from successful completion of OQ. PQ is designed to

verify the satisfactory performance of equipment or systems for a specific application – here the

specific application is the manufacture of Cholgonex.

PQ is carried out using real process materials and involves tests to demonstrate satisfactory

performance over the full range of expected operating conditions.

Looking at the V model you can see from the PQ tests that the system meets the requirements set

out in the User Requirements Specification.

Unlike OQ where each item of equipment or plant is qualified separately, PQ qualifies everything

together as part of the entire production process.

Performance Qualification or PQ is the final qualification activity before process validation begins.

PQ is not the same as Process Validation – it is a subset of it.

Here are examples of items that would be looked at for the tablet press as part of performance

qualification for Cholgonex.



Screen 19 Process Validation

Once the qualification activities are successfully completed, the process validation can begin.

Process validation is designed to prove that a specific process will consistently produce a product

meeting predetermined specifications and quality attributes. Process validation is also called Process

Performance Qualification.

The standard industry approach to process validation is to manufacture three batches of product

using the exact procedure that will be used in routine manufacture.

All of the process data and results of quality control tests are then gathered together in a validation

report which is provided to regulatory bodies for examination.

Process validation should never be designed to fail. If there are problems with process validation,

then there are problems with the process itself and it is not ready to be validated.

Screen 20 Validation – Past, Present or Future



When performing process validation there are three possible approaches…

Prospective validation – this is validation that’s done before the process is put to commercial use.

Agencies such as FDA would normally demand that process validation be completed before a

product such as Cholgonex goes on sale for the first time.

Concurrent validation – this is similar to prospective validation except that batches are validated

and released one batch at a time.

The validation procedures and acceptance criteria are similar to what would be used for prospective

validation.

Retrospective validation – this covers situations where a product is already on the market without

documented validation data.

It involves using historical data to provide documented evidence that the process does what it

purports to do. It is not intended as an approach for validating new processes.

Screen 21 Change Control

As we saw earlier, validation is not a once-off event. Once a process is in a validated state it must be

kept that way throughout the useful life of the process.

After a process or system is validated and becomes operational, changes can occur that may affect

its validated status.

For example, there might be changes in materials, product components, process equipment, process

environment and so on. Any such change could affect the product quality or reproducibility of the

process.

A change control system is essential which involves having written procedures in place to describe

what happens if a change is proposed.

The changes must be documented, approved, and tested before use in an operational environment.

If a change is considered to have a potential effect on the validated state of the system, then CureIT

may need to do a requalification or revalidation.

Screen 22 Revalidation

Revalidation is the process of repeating all or part of the validation or qualification process to

provide assurance that the system is still performing in a known way after a change has taken place.

The scope of revalidation is closely tied to the type of change made and it is guided by the change

control procedure.



Examples of where revalidation might be needed are changes in

Packaging

Formulation

Equipment

or processes that could impact on product effectiveness or product characteristics.

Screen 23 Future Developments

Although the ‘v-model’ approach to validation is the one most widely used throughout industry,

other alternative approaches are being developed and in some cases implemented.

One such approach is detailed in the ASTM E2500.

The aim of the ASTM approach is to make validation more efficient and less expensive.

The standard is designed to conform to both US and EU GMP regulations.

Basically, the standard puts forward a ‘risk-based’ and ‘science-based’ approach to the specification,

design, and verification of manufacturing systems and equipment.

The standard defines verification as “confirmation through the provision of objective evidence that

specified requirements have been fulfilled.”

Verification is normally documented in IQ, OQ, and PQ documents but the ASTM approach simply

states that the verification approach must be documented.

It recommends that the extent of verification and the level of detail of documentation should be

based on risk to product quality and patient safety.

It also recommends that verification activities should focus only on those aspects of a manufacturing

system that are necessary to control the manufacturing process to ensure consistent product

quality.

These critical aspects of the system should be derived from a “scientifically sound” understanding of

the process.

The standard aims to eliminate expensive practices such as duplicating verification steps during

qualification and qualifying systems that really only require commissioning.

It also seeks to avoid excessive levels of documentation by allowing use of supplier documentation.

The ASTM approach has not yet been widely implemented throughout GMP-regulated industries

though, and for now the V” model continues to be the standard approach.



Screen 24 …And Finally

In this lesson, we’ve seen how design, engineering, commissioning and validation activities are all

integrated in the setting up of a GMP-compliant manufacturing facility.

Planning and co-ordination of validation activities is generally defined in a Validation Master Plan.

Process validation is a collection of documented studies that demonstrate product and process

consistency.

Essential to process validation are facility and equipment qualification involving

Installation qualification

Operational qualification

And performance qualification

Other essential validation activities include

Analytical validation

Cleaning validation

And computer validation

Validation, combined with quality control release testing and GMP compliance, provides a high level

of assurance that pharmaceutical products will not only be of consistently high quality but will also

be safe and effective for human use.

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