09-10-14 Blackwell For QbD What should a small … QbD, What Should a Small Company Do and Why?...

For QbD, What Should a Small Company Do and Why?

James Blackwell, Ph.D. MBASenior Consultant

BioProcess Technology Consultants, Inc.BioProcess International Conference

Raleigh, NCOctober 12-16th, 2009

From Clone to Commercial®

OverviewSmall company example‐ a CMC view

QbD versus the minimalist approach

Does QbD have a value proposition for small companies?

• Regulatory and quality

• Development and business

Considerations for implementation

Summary and concluding thoughts

Key references

Talk focuses on development (Design) through the Phase 3 process

Small Company Example-A CMC View


A small company definition and perspectiveSmall company definition for discussion purposes

• One whose resources are almost entirely devoted to development of new therapeutics and has not commercialized a product

• Capabilities (some may be out‐sourced) include filing an IND; involvement with Phase 1 and 2 manufacturing; development of a Phase 3 process

Company is resource limited and very eager to meet POC and clinical milestones ASAP

Hard to see “down the road” beyond 2 years


QbD view for many:

• An unnecessary burden

• A “big company” initiative that gives larger companies a competitive advantage

• Design Space will require resources beyond company’s capabilities

• It’s greatest value is “pleasing” regulatory authorities


Main thesis

For small companies, the pros and net benefits to implementing QbD outweighs the cons

The key is to keep it simple and appropriate to needs

QbD versus the Minimalist Approach


ICH Q8 compares QbD with the minimalist approach

The minimalist approach described in ICH Q8(R1) Pharmaceutical Development is typical of small companies and provides a good contrast with QbD

• ICH Q11 Development and Manufacture of Drug Substancesconsensus document not expected earlier than Q1 2010

Should have many commonalities and have no inconsistencies with ICH Q8


Desired QbD State*

preventative; continual improvementreactive; post-approval changes needed

Lifecycle management

risk-based; controls shifted upstreammainly by intermediate and end product testing

Control strategy

part of overall quality control strategy; based on desired performance and supportive data

primary means of quality control; based on batch data

Product specification

PAT utilized for feedback and feed forward in real time

in-process testing for go/no-go; offline analysis

Process control

Design Space flexibility; continuous verification within design space; focus on control strategy and SPC

locked down; validation on 3 batches; focus on reproducibility

Manufacturing process

more science based; systematic; multivariate experiments; focus on unit operation outputs; Design Space; PAT

empirical; typically univariate experiments

Development/Design

Desired QbD StateCurrent StateAspect

**Adapted from ICH Q8(R1)Adapted from ICH Q8(R1)

Does QbD have a Value Proposition for Small Companies?


Our industry needs to change

"The pharmaceutical industry has a little secret: Even as it invents futuristic new drugs,

its manufacturing techniques (still) lag(s) far behind those of potato‐chip and laundry‐soap makers." WSJ Sept. 3, 2003

[emphasis mine]

And I would also add development techniques


QFD- A precursor to QbDQuality Function Deployment (QFD)

A “method to transform user demands into design quality, to deploy the functions forming quality, and to deploy methods for achieving the design quality into subsystems…, and ultimately to specific elements of the manufacturing process.” *

• Core principles of QbD are seen in this definition and most of its methods and techniques can be used for QbD

• QFD (QbD) is the only comprehensive quality system aimed specifically at satisfying the customer (i.e., patient) throughout the development and business process

Dr. Yoji Akao originally developed QFD in Japan in 1966 and it has been used very successfully for decades to improve product quality, cuts costs, and speed development*Akao, Y. "Development History of Quality Function Deployment“. The Customer Driven Approach to Quality Planning and Deployment. Minato, Tokyo 107 Japan: Asian Productivity Organization. pp. 339.


Proven success in other industriesSemi‐conductor, software, and medical device industries offer the best lessons and case studies for our industry

• QFD techniques have been used to increase agility, cost control, speed to market, and quality (LEAN)

• All things important to a small company developing biologics

Our industry can learn much from them

• E.g., FDA’s Draft Guidance for Industry: Process Validation General Principles and Practices references Quality Management Systems – Process Validation, edition 2* for medical devices

*http://www.ghtf.org/documents/sg3/sg3‐final.html


Overall, modern QFD can provide insights into how QbD can provide a framework for integration of various innovative quality methods into the development process

I believe there are significant opportunities for modern qualitytechniques to be used in conjunction with QbD to greatly enhance development efficiencies

Modern QFD is tailored to identify the

minimum QFD (or QbD) effort required with the

optimum tools and sequence

Development efficiencies can be greatly improved

From Clone to Commercial®Moheb NasrMoheb Nasr


Regulatory and qualityFDA's 1987 "Guideline on General Principles of Process Validation“ was and is “voluntary”, but almost all of its concepts were quickly incorporated into the vast majority of process validations being performed

Likewise, when the FDA’s product lifecycle concept guidance on process validation (based largely on QbD concepts) is finalized (~November 2009), it is also likely to find general applicability and acceptance

Failure to adopt approaches “encouraged” by regulatory authorities will represent increasing regulatory risk with time and for particular development programs

Reducing regulatory risk adds significant program value by speeding time to clinic and market by preventing avoidable regulatory delays


An effective quality risk management is a proactive means to identify and control potential quality issues during development and manufacturing

Quality risk management can facilitate better and more informed decisions; provide regulators with greater assurance and benefit the extent of direct regulatory oversight

KM within the quality system helps produce higher value knowledge and documents that are organized and easier to retrieve years later

KM supports lean development and the product life‐cycle


Development and businessFull value of QbD is realized when business objectives and processes are incorporated and modern quality methods are incorporated

• E.g., Titer must by > 3 g/L and overall yield > 75% for commercial product to be cost competitive

Increased program value (and value to a potential partner) by “porting” into their systems by de‐risking, aiding tech transfer, and easing regulatory concerns


Patient focus and long term view driven by Target Product and Process Profile, risk analysis, and DOE: 1) sharpen near term thinking and helps prioritize efforts; 2) limit unnecessary changes; and 3) help focus the team and reduces sub‐optimization

Change control makes for better decision making as a result of cross functional input

Better understanding of risks aligns resources and helps avoid costly mistakes later

Considerations for Implementation


Quality systemsFrom a product lifecycle viewpoint, biggest impact of QbD will be to development‐ (Design phase)

Process Qualification (previously know as validation) becomes almost an afterthought

Pillars to QbD implementation

• Change control

• Knowledge management

• Risk management


Implementation priorities

Implementation

1. First priority‐ QbD implementation with focus on regulatory requirements

• Update quality system with the essential QbD elements of ICH and new guidance from FDA on process validation

2. In order to gain full benefit, a longer term priority‐ integrate QbD system and approach with other quality and business methods as time and resources allow, e.g., QFD processes and methods


Implementing QbDIndustry consensus on application of QbD doe not exist for all aspects of process development

• This should not be an excuse for not starting down that path now

• The majority of the requirements and basis for implementation have been worked out since the FDA’s “21st

Century Initiative” was launched in 2004 and are covered in ICH guidances other publications


Science and Technological Innovation

ICH Q8(R1)

“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. “[emphasis mine]


Implementation considerationsImplementation of QbD does not mean experimentalexploration of all potential process variables, and their interactions and impact, on all potential critical quality attributes and product variants in order to establish a Design Space

• In fact, you don’t need a Design Space at all*

A number of things can be done to focus efforts and use development efforts efficiently

1. Development effort should be proportional to stage of clinical development and business need

• E.g., FIH study may not need the most productive clone possible. All CQA will not be known at this stage but many important ones will (e.g., DP sterility)

*ICH Quality Implementation Working Group on Q8, Q9 and Q10 Questions & Answers

June 10, 2009


2. Fully exploit previous literature and scientific rationale

3. Judicious use of screening experiments, fractional factorial design, risk analysis to set stage for full multivariate experimentation based on desired operational flexibility and fundamental process characterization

4. Exploit scale‐down and HTS experimental techniques

• E.g., minibioreactors; PreDictor™ (GE Healthcare) 64 well plates for chromatography studies


5. Selective development of the Design Space‐ it may not be necessary or prudent to have a Design Space for every unit operation

• A combination of proven acceptable ranges (PARs) developed from univariate experimentation is not a design space

6. Use of platform (or very well characterized and robust) technologies (e.g., Protein A for monoclonal antibody capture)

7. Use of modern quality and lean practices to drive efficiencies and manage the development process


Very Good Very Good Quality Quality SystemSystem

≠≠ Large and Large and Complex Complex

OneOne!!

KISS


QbD adjustments to the quality system

Overall lifecycle approach to process validation and QbD needs to be described in the Quality Manual

Key aspects of quality system affected in development phase

• Management review and responsibilities

• Change control

• Quality system enablers: knowledge management and quality risk management

Key documents: ICH Q8(R1), Q9, Q10, and forthcoming Q11 and new FDA guidance on process validation


Change control system

Focus on change control management directed on areas of QbD that can affect product quality

• Justification for and changes to CQA, CMA, CPP, and TPP and their risk analyses

• Quality and technical documents

• Movement within or changes to the Design Space


Knowledge managementProcess validation definition: “Establishing documented evidencewhich provides a high degree of assurance that a specific process will consistently produce a product meeting its pre‐determined specifications and quality attributes” ‐ FDA Guideline, 1987

Given a lifecycle view of process validation and QbD, KM during development is vitally important

Development knowledge supports filings and is discoverable during audits

• It will be used by regulators to understand the basis for the manufacturing process and control strategy, including the rationale for selection of critical process parameters and critical quality attributes; and for the Design Space


Needs linkage to management review

Single most important aspect for small companies is to write andarchive technical reports that document experiments and conclusions

• Incorporate risk analyses and rationale for CQA, CMA, and CPP, and appropriate attributes of TPP

• Needs QA data review and sign‐off, document control, and safe archiving

• Lab notebooks need appropriate controls and archiving


Quality risk managementICH Q9 suggests tools and methodology, it does not dictate a specific approach

One possible approach is to reference ICH Q9 and state that QRM will be used to support selection of CQA, CMA, CPP, TPP and thecontrol strategy; and state that this will be documented in appropriate technical reports and other QA documentation

• The quality system should describe how to document the quality risk management process that is defined, deployed and reviewed for these purposes, and could include:

Problem and/or risk question, including pertinent assumptions identifying the potential for risk

Background information and/ or data on the potential hazard harm or human health impact relevant to the risk assessment

Risk analysis leader and other involved resources


Barriers to QbD implementationLack of understanding of present and future value of QbD

For a small company, adapting the company culture is not a huge barrier, but

• Upper management buy‐in and support is needed for success

Lack of understanding of cost and resources needed for implementation and fear that cost and resources needed is prohibitive

Summary and Concluding Thoughts


Cost and Benefit of QbD (Small Company)

Initiate QbDEfforts

QbD FullyRealized

QbD Implementation Progress

Dev

elop

men

t and

Man

ufac

turin

g C

osts

Current State

Desired State

•Quality by testing & inspection•Empirical•Reactive•Not lean

•Quality by design development•Efficient development efforts

•Faster to clinic and commercial•Proactive

•Lean

Increased Resources(e.g., development costs, organizational planning) Decreased Resources

(e.g., development costs, organizational planning)


QbD and improved business processes are not out of reach for small companies

QbD can add value to a small company if the will power exists

• The key is to implement it efficiently and cost effectively

• KISS

QbD has significant value, even if a Design Space is not developed and filed

• At a minimum, use a science and risk based development approach

• If a Design Space is desired, keep the resource requirements focused and limited, as appropriate

Don’t worry that “all the details haven’t been worked out”‐rather, get started


Change control, KM, and QRM should focus on CQA, CMA, and CPP, and appropriate attributes of TPP

Adopt and drive modern quality and business methods to speed time to market; improve quality; and lower costs

• Study precedents set in other industries

• These methods and tools are not difficult to use and everyone does not need to be “Black” and “Green” belts

• Swarm around and focus on the CQA, CMA, CPP, and TPP

Keep quality system flexible and allow for both minimal and QbD approaches

If using a CMO, make sure they are capable and willing to support your needs and quality system


Key referencesICH, Q8(R1), Q9, Q10 and Q11 (soon)

FDA’s Draft Guidance for Industry Process Validation: General Principles and Practices

FDA’s Draft Guidance for Industry: Process Validation General Principles and Practices references Quality Management Systems – Process Validation, edition 2

Rathore A, Winkle H. Quality by Design for Biopharmaceuticals. Nat Biotechnol. 2009 Jan;27(1):26‐34.

ReVelle Jack, et al. The QFD Handbook

Driscoll C. Building Agility into Pharma and Biopharma‐ Learning lessons from other industries. Contract Pharma. 2009 Sep.

QFD case studies and lessons: http://www.qfdi.org/books/proceedings.htm


Thanks

Sheila Magil, Senior Consultant, BioProcess Technology Consultants


My contact information

James Blackwell, Ph.D., M.B.A

BioProcess Technology Consultants, Inc.

289 Great Road, Acton, MA

[email protected]

Ph: 978‐266‐9112

09-10-14 Blackwell For QbD What should a small … QbD, What Should a Small Company Do and Why?...

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