Chapter 3.1 3.4-quality and innovation in product and process design

BNN20303Quality Assurance and Quality Control in Biotechnology

By: Dr. Nadirul Hasraf Mat Nayan

CHAPTER 3QUALITY AND

INNOVATION IN PRODUCT AND PROCESS DESIGN

Chapter Overview• CHAPTER 3: QUALITY AND INNOVATION IN

PRODUCT AND PROCESS DESIGNCHAPTER 3.1: Introduction to Quality and Innovation in

Product and Process Design

CHAPTER 3.2: Quality by Design (QBD)

CHAPTER 3.3: The Design Process

CHAPTER 3.4: Quality Function Deployment (QFD)

CHAPTER 3.5: Technology in Design

Chapter Overview• CHAPTER 3: QUALITY AND INNOVATION IN

PRODUCT AND PROCESS DESIGNCHAPTER 3.6: Prototyping Methodologies

CHAPTER 3.7: Designing for Reliability

CHAPTER 3.8: Environmental Considerations in Design

CHAPTER 3.9: Summary

Chapter 3.1

Introduction to Quality and Innovation in Product and

Process Design

3.1: Introduction Have you ever needed a copy quickly, but the copy

machine was jammed?

Have you ever worked against and impending deadline only to have the computer or printer go haywire?

Have you ever gotten into your car on a hot day to find it would not start?

These annoyances displayed above are relatively minor.

However, others examples of product failures can be catastrophic.

3.1: Introduction If a lumberjack uses a defective chainsaw, he or she might lose

an arm.

If a heart monitor malfunctions, the results might be fatal to a patient.

An F1 race car driver’s tires blow at 250 miles per hour, and a spinout results.

A faulty fire alarm fails to alert the home’s occupant until it is too late.

These are major product failures that can result in severe injury or death.

3.1: Introduction Great quality products begin and end with

great design.

Design should influence all product decisions.

Even fundamental business questions like what to build, or how to sell it, should be treated as design decisions.

3.1: Introduction Take Apple’s product for instance.

Apple's success has given the world permission to take design seriously.

That doesn't mean treating design as important.

It's much more than that.

Design is everything.

3.1: IntroductionTherefore, it is the attention of this chapter to

focus on quality assurance.

It have been learned in the previous chapter that quality cannot be ensure at the final stages of inspection.

Hence, quality assurance is best achieved at the design stage.

Chapter 3.2

Quality by Design (QbD)

3.2: Quality By Design (QbD) INTRODUCTION

‘Quality by Design' (QbD) is a methodology initiated by the US Food and Drug Administration’s (FDA).

QbD requires a thorough understanding of a product and its process of manufacture, necessitating an investment in time and resources upfront in the discovery and development of a product.

For QbD, the product and process knowledge base must include an understanding of variability in raw materials, the relationship between a process and product's critical quality attributes (CQAs), and the association between CQAs and a product's clinical properties.


Critical Quality Attributes (CQA) are chemical, physical, biological and microbiological attributes that can be defined, measured, and continually monitored to ensure final product outputs remain within acceptable quality limits

What is Critical Quality Attributes (CQA) ?


Successful implementation of QbD concepts requires cooperation across a multitude of company teams, from R&D to manufacturing to quality control and regulatory affairs.

This is necessary to ensure that QbD concepts are incorporated not only when the first activities are initiated around a product's design but also during the design of the process that is used to make the product and other activities associated with a product's life cycle.

3.2: Quality By Design (QbD) WHAT IS QbD?

QbD became the answer to assisting both the industry and FDA to move toward a more scientific, risk-based, holistic and proactive approach to pharmaceutical development.

The concept promotes industry's understanding of the product and manufacturing process starting with product development, basically building quality in, not testing it.

Under the concept of QbD, when designing and developing a product, a company needs to define desired product performance and identify CQAs.


On the basis of this information, the company then designs the product formulation and process to meet those product attributes.

This leads to understanding the impact of raw material attributes and process parameters on the CQAs and identification and control of sources of variability.


As a result of all this knowledge, a company can continually monitor and update its manufacturing process to assure consistent product quality.

This systematic approach to product development and manufacturing varies a great deal from the traditional approach, which was extremely empirical.

3.2: Quality By Design (QbD) QbD IMPLEMENTATION

In the QbD paradigm, a product is designed so that it will meet its desired clinical performance, and the process is designed to consistently deliver a product that meets the quality attributes necessary for this clinical performance.

This requires that one understands the impact of raw materials and process parameters on product quality, and that the process be continually monitored and updated to assure consistent quality over time.


According to FDA:

This is seen in Figure 1, which illustrates the different phases during the life cycle of a pharmaceutical process:

“Quality by design means designing and developing manufacturing processes during the product development stage to consistently ensure a predefined quality at the end of the manufacturing process”

Define, design, characterize, validate, and monitor and control.

3.2: Quality By Design (QbD)

Figure 1- Illustration of the different steps in development of a pharmaceutical product


The final link between ‘monitor and control’ and ‘define’ represents process changes that are initiated based on process-improvement opportunities identified during process monitoring or introduced otherwise to improve process performance or robustness.

Changes originating in this manner would again go through the cycle illustrated in Figure 1.

3.2: Quality By Design (QbD) TOOLS OF QbD

The concept of 'design space' is gaining popularity as a tool for implementation of QbD for pharmaceutical products.

Though design space has primarily been used in the context of pharmaceutical processes, it can also be applied to represent the clinical and product-quality aspects of a product.


What is ‘Design Space’

The relationship between the process inputs (material properties and process parameters) and the critical quality attributes.


FDA interpret design space as:

“the multidimensional combination and interaction of input variables (e.g., material

attributes) and process parameters that have been demonstrated to provide assurance of

quality.”


Defining clinical design space. The concept of clinical design space can be used to quantify

the clinical experience with a product.

The size of the clinical design space for a given product will depend on the (i) number of manufactured lots put in the clinic, (ii) process capability, (iii) availability of applicable data from other similar products and finally (iv) the extent of product heterogeneity that has been introduced during the clinical trials.


Defining clinical design space. The last point is noteworthy because although purposely

introducing product heterogeneity to broaden clinical design space should be given consideration, patient safety should not be jeopardized.

Process capability will determine the variability observed in the manufactured lots, which will then directly affect the clinical design space.


Defining product design space. The concept of design space can also be extended to

quantify product quality.

Similar to the clinical design space, the product design space could be represented as a multidimensional design space with each critical quality attributes (CQA) serving as a dimension.


Defining product design space.

It will be documented in the regulatory filing in the form of in-process, drug substance and drug product specifications and would define the acceptable variability in critical quality attributes (CQA).


Defining process design space. The concept of process design space is perhaps the most

well understood of all three in the pharmaceutical and biotech industry.

Once the acceptable variability in CQAs has been established in the form of the product design space, process characterization studies can be used to define the acceptable variability in process parameters, as shown in Figure 1.


Figure 1 - The creation of process design space from process characterization studies and its relationship with the characterized and

operating space.


Defining process design space. Operating within these acceptable ranges, the combination of which will

ultimately define the process design space, provides the 'assurance of quality'.

The operating range constitutes the operating ranges defined in the manufacturing procedures.

The characterization range is the range examined during process characterization.

The acceptable range is the output of the characterization studies and defines the process design space.

3.2: Quality By Design (QbD) Key steps in implementation of QbD for a biotech product:

The implementation of QbD requires eight key steps, which are:

1. Identifying Target Product Profile (TPP) 2. Identifying Critical Quality Attributes (CQAs)3. Defining Product Design Space4. Defining Process Design Space5. Defining Control Strategy6. Process Validation7. Regulatory Filings8. Process Monitoring, Life-Cycle Management and Continuous

Improvement


1. Identifying Target Product Profile (TPP)

TPP can defined as a:

“prospective and dynamic summary of the quality characteristics of a drug product that ideally will be

achieved to ensure that the desired quality, and thus the safety and efficacy, of a drug product is realized”


1. Identifying Target Product Profile (TPP)

TPP includes:

a. Dosage form and route of administrationb. Dosage form strength(s) c. Therapeutic moiety release or deliveryd. Pharmacokinetic characteristics (e.g., dissolution

performance)

- appropriate to the drug product dosage form being developed and drug product-quality criteria (e.g., sterility and purity) appropriate for the intended marketed product.


2. Identifying Critical Quality Attributes (CQAs)

Once TPP has been identified, the next step is to identify the relevant CQAs.

A CQA can be defined as:

“a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”


2. Identifying Critical Quality Attributes (CQAs)

Identification of CQAs is done through risk assessment.

Prior product knowledge, such as the accumulated laboratory, nonclinical and clinical experience with a specific product-quality attribute, is key in making these risk assessments.

Taken together, this information provides a rationale for relating the CQA to product safety and efficacy.


3. Defining Product Design Space

After CQAs for a product have been identified, the next step is to define the product design space (that is, specifications for in-process, drug substance and drug product attributes).

These specifications are established based on several sources of information that link the attributes to the safety and efficacy of the product.


3. Defining Product Design Space

The specifications for in-process, drug substance and drug product attributes are established based on several sources of information, which include:

i. Clinical design space.ii. Nonclinical studies with the product, such as binding

assays, in vivo assays and in vitro cell-based assays.iii. Clinical and nonclinical studies with similar platform

products.iv. Published literature on other similar products.


4. Defining Process Design Space

The overall approach toward process characterization involves three key steps:

FIRST STEP

Risk analysis is performed to identify parameters for process characterization.



SECOND STEP Studies are designed using design of experiments

(DOE), such that the data are amenable for use in understanding and defining the design space.

THIRD STEP the studies are executed and the results analyzed to

determine the importance of the parameters as well as their role in establishing design space.



In defining process design space, failure mode and effects analysis (FMEA) is commonly used to assess the potential degree of risk for every operating parameter in a systematic manner and to prioritize the activities, such as experiments necessary to understand the impact of these parameters on overall process performance.

A team consisting of representatives from process development, manufacturing and other relevant disciplines will performs an assessment to determine severity, occurrence and detection.


5. Defining Control Strategy

Control strategy is defined as:

“a planned set of controls, derived from current product and process understanding that assures

process performance and product quality.”


5. Defining Control Strategy

The control strategy in the QbD paradigm is established via risk assessment that takes into account the criticality of the CQA and process capability.

The control strategy can include the following elements:

procedural controls, in-process controls, lot release testing, process monitoring, characterization testing, comparability testing and stability testing.


6. Process Validation

Once the process design space has been created, process validation becomes an exercise to demonstrate:

(i) that the process will deliver a product of acceptable quality if operated within the design space.

(ii) that the small and/or pilot scale systems used to establish the design space accurately model the performance of the manufacturing scale process.


7. Regulatory Filings

After the process design space has been established and validated, the regulatory filing would include the acceptable ranges for all key and critical operating parameters that define the process design space in addition to a more restricted operating space typically described for drug products.

The filing would also include the refined product design space, description of the control strategy, outcome of the validation exercise and plan for process monitoring


8. Process Monitoring, Life-Cycle Management and Continuous Improvement

Robustness of the quality system would need to be demonstrated with respect to the following four elements:

i. process performance/product-quality monitoringii. preventative/corrective actioniii. change management iv. management review of process performance and product

quality

3.2: Quality By Design (QbD) Benefits of implementing QbD :

i. ensures better design of products with fewer problems in manufacturing.

ii. allows implementation of new technology to improve manufacturing without regulatory scrutiny.

iii. enables possible reduction in overall costs of manufacturing resulting in less waste.

iv. enables continuous improvements in products and manufacturing.


Figure 1 - Key steps in implementation of QbD for a biotech product

Chapter 3.3

The Design Process

3.3: The Design Process There are many approaches to designing a

products.

Even within the same industries, the approaches will vary in some important ways.

Yet, there are some similarities across the board.

3.3: The Design Process For example:

Design projects are likely to involve a project team rather than a single designer working independently. Preferably, these teams will work closely with customers to ensure that customer needs are met.

Product Idea Generation

Customer future needs

projection

Technology selection for

product development (technology

feasibility statement)

Technology development

for process selection

Final Product

Definition

Product marketing

and distribution preparation

Product design and evaluation

Manufacturing system design

Product manufacture, delivery, and

use

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GENERIC APPROACH TO DESIGNING PRODUCTS

3.3: The Design Process Figure 1 shows a generic approach to designing

products.

The design process includes nine phases that are interrelated.

These stage begin with product idea generation and end with manufacture delivery and use.

Project managers monitor design projects at each stage for cost and adherence to schedules.

3.3: The Design Process STEP 1: Product Idea Generation

During this stage, external and internal sources brainstorm new concepts.

Internal sources include marketing, management, research and development (R&D), and employees suggestion.

The primary source for external product ideas is the customer.

Original equipment manufacturers (OEMs) and contract manufacturers work closely with customers to develop new products.


In other circumstances, customers needs are identified to generate product ideas.

Other external sources for product ideas can be market-related sources such as industry experts, consultants, competitors, suppliers, and inventors.

There are fundamental differences between R&D-generated ideas (known as R&D push) and marketing-generated ideas (known as marketing pull).


a. R&D-Generated Ideas: R&D-generated ideas tend to be ground-breaking, risky, and

technologically innovative.

An example of R&D based development was the Altair microcomputer, in the mid-1970s, which have inspired two computer whizzes named Paul Allen and Bill Gates to develop BASIC Interpreter for the Altair. The rest is history.

Although there was not a large established market for personal computers, Paul Allen and Bill Gates have radically affected business and home life since their introduction.


b. Marketing-Generated Ideas: Marketing-generated ideas tend to be more incremental, that

is, they build on existing designs, and better aligned with customer needs.

For example, at the product idea-generation stage, a gap in the market or a customer need should be identified.

Preliminary assessment of the marketability of the product is performed and funding provided for beginning development of a prototype of the product.


b. Marketing-Generated Ideas:

Recent development in computers have included technological development such as improved multimedia capabilities and faster speeds as well as cosmetic changes in casings such as tablet designs and the use of clear plastics.

These are marketing-oriented changes.

3.3: The Design Process STEP 2: Customer Future Needs Projection

This uses data to predict future customer needs.

Designer for Intel, the maker of the microprocessors for personal computers, have been masters at this.

They have been able to project and introduce new products that are well times to fit with changes in the technology requiring them.

At the same time, the company have been able to outpace competing microprocessor developers by staying slightly ahead of the technological curve.

3.3: The Design Process STEP 2: Customer Future Needs Projection

Thus, the task of the product designer is to offer products with value that exceed customer needs at any point in time by careful planning and thought as to what future customer needs will be.

There is no single approach to gathering information about future customer needs.

Surveys might give insights, but they are usually insufficient to uncover emerging customer needs.

3.3: The Design Process STEP 3: Technology Selection For Product Development

During, technology selection for product development, designers choose the materials and technologies that will provide the best performance for the customer at an acceptable cost.

A technology feasibility statement is used in the design process to asses a variety of issues such as necessary parameters for performance, manufacturing, imperatives, limitations in the physics of materials, special considerations, changes in manufacturing technologies, and conditions for quality testing the product.

3.3: The Design Process STEP 3: Technology Selection For Product Development

At this stage, preliminary work can be performed to identify key quality characteristics and potential for variability with each of the different materials.

3.3: The Design Process STEP 4: Technology Development For Process Selection

Technology development for process selection means choosing those processes used to transform the materials picked in the prior step into final products.

Careful technology selection of both automated and manual processes is key from a quality perspective because machinery, processes, and flows need to be developed that will result in a process insensitive to variations in ambient and material-related conditions.

3.3: The Design Process STEP 5: Final Product Definition

Final product definition results in final drawings and specifications for the product with product families by identifying base products and derivative products.

3.3: The Design Process STEP 6: Product Marketing and Distribution Preparation

Product marketing and distribution preparation are marketing-related activities such as developing marketing plan.

The marketing plan should define customers and distribution streams.

The production-related activities are identifying supply-chain activities and defining distribution networks.

3.3: The Design Process STEP 6: Product Marketing and Distribution Preparation

Nowadays, this step often requires the design of after-sales processes such as maintenance, warrantees, and repair processes that occur after the customer own the product.

3.3: The Design Process STEP 7: Product Design and Evaluation

Product design and evaluation requires definition of the product architecture, the design, production, testing of subassemblies, and testing of the system production.

A product design specification (PDS) demonstrates the design to be implemented with its major features, uses, and conditions for use of the product.

3.3: The Design Process STEP 7: Product Design and Evaluation

The PDS contains product characteristics, the expected life of the product, intended customer use, product development special needs, production infrastructure, packaging, and marketing plans.

3.3: The Design Process STEP 8: Manufacturing System Design

Manufacturing system design is the selection of the process technologies that will result in a low-cost, high quality product.

The selection of the process technology is a result of projected demand and the finances of the firm.

Processes must be stable and capable of producing products that meet specification.

One of the major developments in this area is that firms now desire the ability to change over to new products with a minimum cost associated with defects.

3.3: The Design Process STEP 8: Manufacturing System Design

In the past, it was considered standard operating procedure to produce a certain amount of bad product to prove that the system works.

For example, a producer of stove pipe would process a small batch of pipe, inspect the pipe, and then adjust the line, produce another small batch and reinspect, and so forth until they proved the process.

This is no longer considered a cost-effective means of introducing new products.

3.3: The Design Process STEP 9:Product Manufacture, Delivery, and Use

Finally, product manufacture, delivery, and use finish this process.

The consumer then enjoys the result of the design process.

Chapter 3.4

Quality Function Deployment (QFD)

3.4: Quality Function Deployment (QFD)

Introduction:

When customer needs have been determined, those needs must be translates into functional product design.

Quality function deployment (QFD) describes a method for translating customer requirements into functional design.

Sometimes this process of translation is referred to as the voice of the customer.


Introduction:

The quality function deployment approach was developed by Dr. S. Mizuno, a former professor of the Tokyo Institute of Technology.

Since then, this approach has been used extensively throughout the world.


Introduction: Designers need a means for implementing

customer requirements into design and the house of quality, illustrated in Figure 1, shows how QFD is used to accomplish this.

The left wall on the house of quality contains a listing of customer requirements.

The roof of the house of quality lists technical requirements.


Following are steps in performing QFD: STEP 1: Develop a list of customer requirements

The list of customer requirements includes the major customer needs as they relate to a particular aspect of a process.

In Figure 2, a part of a QFD house of quality is shown with customer requirements for a restaurant.

Customers want to have a clean restaurant, a comfortable seating arrangement, delicious food, and responsive servers.


STEP 1: Develop a list of customer requirements

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Clean Facilities

Comfortable Seating

Delicious Food

Responsive Severs

Figure 2: QFD Customer Requirements


STEP 2: Develop a listing of technical design elements along the roof of the house

These are the design elements that relate customer needs.

Figure 3 shows the design elements for the restaurant that may affect the customers’ requirements.

These design elements are the building materials such as type of tile, dirt resistance floor tiles, material used in making seats, training for servers, and standardization of menu.

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Figure 3: QFD Technical Requirements


STEP 3: Demonstrate the relationship between the customer requirements and technical design elements

A diagram can be used to demonstrate these relationships.

The symbols shown in Figure 4 are used, and scores are assigned relating to these symbols (i.e., 1, 3, and 9).

Where 9 means strongly associated, 3 is somewhat associated, and 1 is weakly associated.

Notice that tile and dirt resistance are strongly associated to clean facilities.

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Figure 4: QFD Technical Requirements and Customer Requirements Relationship

SYMBOLS:

9 (Strong association)

3 (Somewhat associated)

1 (Weak association)


STEP 4: Identify the correlations between design elements in the roof of the house

Using the symbols identified in Figure 5, show whether different design elements are positively or negatively correlated.

Positive and negative scores are assigned to each symbol as shown.

Notice that seat material and type of tile are negatively related, whereas, type of tile is strongly positively related to dirt resistance.

Server training and menu standardization are strongly positively related.


STEP 5: Perform a competitive assessment of the customer requirements

On both the right side and in the lower middle portion of Figure 6, there is an assessment of how a product compare with those of its key competitors.

These comparisons are on a five-point scale with five being high.

A stands for competitors A, B means competitor B, and US stands for the company in question.

Note that there are two assessment, one for customer requirements and another for technical requirements.


STEP 6: Prioritize customer requirements

On the far right of Figure 7 are customer requirement priorities.

These priorities include importance to customer, target values, sales point, and absolute weight.

A focus group of customers assign ratings for importance.

This is a subjective assessment of how critical a particular customer requirement is on a 10-point scale, with 10 being most important.



Customer requirements with low competitive assessment and high importance are candidates for improvement.

Target values are set on a 5-point scale (where 1 is no change, 3 is improve the product, and 5 make the product better than the competition).

With the target value, the design team decides whether to change the product.

The sales point is established by the QFD team members on a scale of 1 to 2, with 2 meaning high sales effect and 1 being low effect on sales.



The absolute weight is then found by multiplying the customer importance, target factor, and sales point.

This is expressed in the following equation:

Absolute weight = customer importance x target value x sales point


STEP 7: Prioritize technical requirements

As shown in Figure 8, technical requirements are prioritized by determining degree of difficulty, target value, absolute weight, and relative weight.

The degree of difficulty is assigned by design engineers on a scale of 1 to 10, with 1 being least difficult and 10 being most difficult.

The target values for technical requirements is defined the same way the target values for the customer requirements were assigned.


STEP 7: Prioritize technical requirements

The values for absolute and relative weights are now established.

The value for absolute weight is the sum of the products of the relationship between customer and technical requirements and the importance to the customer columns (fourth column from the right).

The value for relative weight is the sum of the products of the relationship between customer requirements and technical requirements and the customer requirements absolute weights (the farthest right column).


STEP 8: Final evaluation

The relative and absolute weights for technical requirements are evaluated to determine what engineering decisions need to be made to improve the design based on customer input.

This is performed by computing a percentage weight factor for each of the absolute weight and relative weight number as in Figure 9.


Summary

As can be seen in this example, the standardized menu has a very high relative importance.

This gives the restaurant a focus for the coming period.

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Chapter 3.1 3.4-quality and innovation in product and process design