QM: 7.3 Design and Development (7.3.1, 7.3.2, 7.3.3, 7.3.4, 7.3.5, 7.3.6 & 7.3.7)

7.3	DESIGN & DEVELOPMENT
7.3.1	Planning
7.3.2	Input
7.3.3	Output
7.3.4	Review
7.3.5	Verification
7.3.6	Validation
7.3.7	Change Control

7.3.1 Design and development planning:

Design and Development planning is done by the Developmental Project Lead. Detailed planning for complex processes may require inputs from other areas such as consultant, subject expert, regulatory affairs, engineering etc. Project Lead is also responsible for establishing stage wise tentative timeline for the project.

The process of design and development include:

– Defining an objective

– Determination of critical quality attributes (CQA)

– Risk assessment

– Development of experimental design (Design of Experiment)

– Designing and implementing control strategy

– Continuous improvement

Review, verification and validation (wherever applicable) is performed for each design and development stage. This ensures the availability of the resources, capabilities, suggested timeframe for execution of each stage with deliverables and further improves the plan during the course. This is a continuous process and can be performed under project monitoring plan.

The Project Lead ensures that the project plan is executed only after responsibilities and authorities for each stage are assigned and understood.

Modes for communication for proper flow of information between different groups are defined in communication plan.

The project plan evolves during entire developmental process and it is the responsibility of the project lead to update and communicate any modifications and changes in the plan.

7.3.2 Design and development inputs

Inputs relating to product requirements are determined and records of such requirements are either attached to or referred in the project development plan.

The inputs for product requirements considered (but not limited to) are:

functional and performance requirements,

applicable statutory and regulatory requirements,

where applicable, information derived from previous similar designs, and

other requirements essential for design and development.

These inputs are reviewed for adequacy.

The project lead ensures that the requirements of the product defined above are complete, unambiguous and not in conflict with each other.

7.3.3 Design and development outputs:

The outputs of design and development shall

a) meet the input requirements for design and development,

b) provide appropriate information for purchasing, production and service provision,

c) contain or reference product acceptance criteria, and

d) specify the characteristics of the product that are essential for its safe and proper use.

The above outputs of design and development plan are suitability for verification against the design and development input and are approved prior to release.

7.3.4 Design and development review:

Design and development plan and project progress are reviewed as per design and development review/verification plan. The review is targeted to

a) to evaluate the ability of the results of design and development to meet requirements, and

b) to identify any problems and propose necessary actions.

The review is performed by review committee which comprises of different disciplines/ functions concerned with design and development stage being reviewed. The meeting is coordinated by design and development lead. The committee also includes member form safety department (biological/ chemical/ occupational) if deemed necessary by the developmental stage under review.

The records of the review and necessary actions are maintained. Any modification, change/update are conveyed to all the interested parties.

7.3.5 Design and development verification:

The design and development output is verified against design and development input to verify that the requirements of input are met in the output. This verification is performed as per design and development review and verification plan. The records of these verifications are maintained.

7.3.6 Design and development validation:

The resulting product form design and development stage is validated to ensure that the resulting product is capable of meeting the requirements for the specified application or intended use. The validation proves that the product developed form design and development meet the specifications. The results of design and development validation and necessary actions are maintained.

7.3.7 Design and development changes:

Design and development changes as proposed during design and development review, verification, validation, gained knowledge (better understanding) of process and product are updated regularly. These changes are regularly reviewed as per design and development review and verification plan. The review of design and development changes includes evaluation of the effect of the changes on constituent parts and product already delivered. The product from the modified/changed process is validated. Records of the results of the review of changes and any necessary actions are maintained.

Design and Development

Image Source- http://ranksol.com/blog/required-elements-of-a-web-design-and-development-process-by-ranking-solutions/

Introduction

Design is a process of originating a conceptual solution to a requirement and expressing it in a form from which a product may be produced or a service delivered.

Development is realization of design in the form of prototype and subsequent improvements in the prototype to make product and further innovations in the product. So development is creation and improvement.

In pharmaceutical development (product and process) this clause has huge implications. The entire process of pharmaceutical development is lengthy and complex and the end product/process must comply with all the regulatory and statutory requirements, requirements of the product and customers’ requirements.

Though it is difficult to justify the exclusion from this clause the clause may be excluded if no developmental work is undertaken and product has been received through technology transfer from other source or product manufactured for quite a long time (i.e., initial consistency proved and approval from national regulatory authority) with no process improvements. This clause may also be excluded by the contract manufacturing firms. However, it is applicable for new projects whether they are technology transfer or new facility setup.

Pharmaceutical Development:

Quality cannot be tested into product; it should be built in or should be by design.

The above statement reflects the present regulatory expectation with pharmaceutical products. ICH Q8 states, ‘The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.’

Different elements of pharmaceutical development include,

– Defining an objective

– Determination of critical quality attributes (CQA)

– Risk assessment

– Development of experimental design (Design of Experiment)

– Designing and implementing control strategy

– Continuous improvement.

The process of pharmaceutical development and regulatory expectation are emphasized in different regulatory guidance documents for clear interpretation and harmonized approach. The major work in the field has been done by International Conference on Harmonization (ICH).

FDA’s Guidance on Process Validation has stressed scientific approach for entire pharmaceutical development and process validation.

FDA’s PAT (Process Analytical Technology) initiative also emphasizes on Quality to be designed in the process than tested into product.

The following documents shall be considered for successful pharmaceutical development:

FDA’s Guidance Document on Process Validation: The document encourages the use of modern pharmaceutical development concepts, quality risk management and quality system at all stages of manufacturing process lifecycle. The lifecycle concept links product and process development, qualification and commercial manufacturing processes, and maintenance of the process in a state of control during routine commercial production.

The guide describes process validation activities in three stages:

          Stage 1: Process Design

          Stage 2: Process Qualification

          Stage 3: Continued process verification

The guidance emphasizes, ‘Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial-scale studies. Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions’. 

ICH Q10: This guideline applies to the systems supporting the development and manufacture of pharmaceutical drug substances (i.e., API) and drug products, including biotechnology and biological products, throughout the product lifecycle.

The product lifecycle is divided into following stages:

• Pharmaceutical Development
• Technology Transfer 
• Commercial Manufacturing 
• Product Discontinuation 

The enablers of QMS (Knowledge Management and Quality Risk Management) are applicable for all the stages of product lifecycle, including pharmaceutical development. 

The document describes four elements to promote the lifecycle approach to product quality. the four elements are: 

• Process performance and product quality monitoring system; 
• Corrective action and preventive action (CAPA) System; 
• Change Management system; 
• Management review of process performance and product quality. 

ICH Q9: This document offers a systematic approach to quality risk management. The document proposes integration of quality risk management into industry and regulatory operations which included pharmaceutical development. Annexure II of the document gives examples of situations in which QMS can be useful.

     

ICH Q8: This document entirely focuses on pharmaceutical development and provides insight to regulatory expectations. The guide states that, ‘It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design’.

The guide also emphasizes on the concept of design space.

The guide states, ‘The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation’.

The annexure Pharmaceutical Development provides further clarification of key concepts along with the principles of quality by design. 

ICH Q6: The document assists in the establishment of a single set of global specifications for new drug substance and new drug product. It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures for new drug substance.

FDA’s Guidance Document on PAT: The document provides insight and emphasizes on improving pharmaceutical development, manufacturing and quality assurance through innovation in product and process development, process analysis and process control.

The goal of PAT is to enhance understanding and control the manufacturing process. PAT proposes different tools which have to be considered during process/product development.

The table below simplifies the requirements of Clause 7.3

Design and development planning	Defining an objective of development project Determination of critical quality attributes (CQA) Risk assessment Development of experimental design (Design of Experiment) Designing and implementing control strategy (Method validation)
Design and development inputs	Pharmacopeia/ Regulatory Requirements Requirements of the product (quality, safety and efficacy requirements, container closure system, delivery system, stability etc). Previous experience with similar processes and products Published literature and current status Market viability
Design and development outputs	Critical Quality Attributes and specifications Resources and capabilities Design and Development stages Timelines Experimental Design and statistical tools Study Protocols/ Drawings Responsibilities and Authorities
Design and development review	Review to see outputs are rational and unambiguous. Progress of the project Managing changes in project
Design and development verification	Paper based review to check that the output of design and development planning such as specifications, layouts, drawings, test protocol and study design, test methods and procedures are meeting the input requirements. Exercise which ensures that each requirement in the inputs is accounted for in the outputs.
Design and development validation	Physical, chemical, biological verification of the product. Product of design and development exercise (prototype) is tested for all the specifications and parameters such as safety, efficacy, purity, stability etc.
Design and development changes	Changes in design and development plan arising due to review, verification, validation and better understanding of process/product. These changes are identified, captured, reviewed, verified and validated. The records are maintained in project plan.

Verification and validation has important role to play in software development. For better understanding of the concept in software development refer General Principles of Software Validation; Final Guidance for Industry and FDA Staff.

References:

ICH: Pharmaceutical quality system Q10

ICH: Quality Risk Management Q9

ICH: Pharmaceutical Development Q8

ICH: Specifications: Test procedures and acceptance criteria for new drug substances and new drug products Q6

FDA: Guidance for Industry- Process Validation: General Principles and Practices

FDA: Guidance for Industry PTA- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

FDA: General Principles of Software Validation; Final Guidance for Industry and FDA Staff 

QM: 7.2 Customer Related Processes (7.2.1, 7.2.2 & 7.2.3)

Customer-related processes

Introduction

ISO 9000 defines customer as an organization or person that receives a product or service and includes purchaser, consumer, client, end user, retailer, beneficiary and purchaser.

A customer can be internal or external to the organization.

Customers are stakeholders: they have entered into a commitment in return for some benefits that possession of a product or experience of a service may bring. Customers demand, request or otherwise place an organization under a commitment, implying that there is no such thing as an internal customer.

The customer is often thought of as the person who buys a product or service but, in the above definition, this is a customer who is a purchaser. The end user may not buy the product but is the person for whom the product or service is produced.

To understand the requirements of the clause it is important to identify the customers to the product.

The customer of the pharma/biopharma product are end user (consumer), regulatory agencies (for end user and for benefit of end user), stockiest, distributor, retailer, pharmacist, health care staff etc.

7.2	CUSTOMER RELATED PROCESSES
7.2.1	Determination of Requirements Related to Product
7.2.2	Review of Requirements Related to Product
7.2.3	Customer Communication

7.2 Customer-related processes

7.2.1  Determination of requirements related to product

The company’s prime focus is to reach out for the customers, understanding their environment and identifying solutions suitable to their needs and applications, which will both meet and exceed their expectations. The company focuses on innovations to provide quality product at competitive price thus providing health to all.

Requirements related to the product have been determined by the organization during the developmental stage and reviewed at regular interval for compliance with customer and regulatory requirements. Other requirements related to product which are determined, include:

• Requirements specified by customers (distribution companies, retailers, health care staff), including the requirements for products type and quantity and delivery time, transportation and storage control. All inquiries / tenders are carefully studied, before quoting, to identify that all requirements are adequately defined and there is no requirement which is beyond organization’s capability in terms of capability, specifications, delivery schedule etc. The orders are accepted only if the organization can meet the commitments and customer’s requirement. Any post delivery activity not identified during product realization are clarified and addressed before commitment to supply.

• Requirements not stated by the customer but necessary for intended use of the products such as requirements for unit pack configuration/packaging and instructions for safe use/administration, instruction for disposal. Such requirements once identified are clarified and agreed with before delivery.

• Statutory and regulatory requirements related to the product including the requirement stated in pharmacopeias or determined by National Regulatory Authority. These requirements are stated in manufacturing and testing plans.

• Organizational requirements and requirements stated by commercial partners. These requirements are clarified and incorporated prior to execution of the order and delivery of the products.

7.2.2 Review of Requirements Related to the Product

After the requirements related to product are determined and defined a formal review of all the requirements related to product is performed together with additional requirements that are not specified but are necessary for fitness for use and governed by laws and regulations, and requirements for availability, delivery, and support. The review is conducted to establish and maintain customer satisfaction before commitment to supply a product to the customer. The review ensures that: 

• Product requirements (including requirements related to delivery and post-delivery activities) are defined
• Special requirements of the product are determined
• Contract or order requirements differing from those previously expressed are resolved
• The organization has the resources, ability, capability and capacity to meet the requirements of the order / contract.
• Risks (e.g., short delivery time) have been identified

Records of the results of review and actions arising from this review are maintained.

When product requirements are changed, relevant documents are amended and the relevant personnel are made aware of the changed requirements. Documents for such changes are updated.

7.2.3 Customer Communication

Communications may address information related to product, inquiries, contracts, contract amendments, order handling, complaints, and advisory notices / recalls. Required arrangements for communication with customers relating to the followings are determined and implemented: 

·      Product information according to the customer communication procedure

·      Customers can contact the organization via phone, e-mail, fax and mail.

·      Enquiries, contracts or order handling, according to the sales procedure

·      Customer feedback, according to the customer communication procedure.

·      Enquiries, contracts and order handling, including amendments etc. are handled effectively.

      

Customer complaints are handled by Quality Department through the Sales Department. Customer feedback and complaints are classified into categories to allow for better tracking of trends and evaluating improvement in specific aspects (complaints follow-up procedure). Every complaint is communicated to relevant functions within and outside the organization. When appropriate, Quality Assurance may be requested to initiate corrective or preventive actions. When product recall is necessary, this process will be handled according to the product recall procedure.