PROCESS CHANGES AS PART OF THE LIFECYCLE OF A PROCESS

Dagmar MeissnerJanuary 2011

2

Outline

• Defining process change• Assessing and implementing proposed

process changes• Reducing the frequency of process

changes• What went wrong? (Case studies)• Conclusions

3

(Charles Darwin, 1809 – 1882)“It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is the most adaptable to change.”

DEFINING PROCESS CHANGE

Drug Development LifecycleDiscovery

Process Transferand Design Process Scale-Up Process Scale-up #2

and prelim. optimization and Optimization

Preparation for Commercialization

Clinical TrialsPreClinical Studies CommercializationPhase IIIPhase IIPhase I

ResearchProcess Development

Manufacturing

Drug Development

6

Willingness to change a process depends on the stage of the product

COST

PD/preclin. Phase I/II Phase III Commercial Scale

FlexibilityTo Change

7

Changes

• Corrective Action• Out of spec product (OOS) • Scale-up/design issues

• Continuous Improvement• Evolutionary process improvements

• New production platform• Technology transfer from another company• Improved process quality (cost)• New administration method/packaging

• Innovation• New technologies, scientific advances

ASSESSMENT AND IMPLEMENTATION

Typical Protein Manufacturing Process

4

FermentorCapture Column Purification 1 Purification 2

Clarification

UF

Sterile filtration

Bulk Product

Cell Bank

Inocculation Train

Typical Process Changes

10

Cell SystemExpression SystemCell Banking System

Drug ProductExcipientsSpecificationTest methods

Drug SubstanceSpecificationTest methods

Purification/Downstream ProcessingChanges to purification stepsChanges to Scale (increased titers)

Production BioreactorCell Growth and HarvestingScale-up

Production Process Analytical/Formulation/Packaging

PackagingContainer/closure systemAdministration methodFormulation

11

It walks like a duckIt quacks like a duckIt is a duck ……… but is it the same duck???

Did the product change? identity strength quality purity

How did it change and is it relevant?

Effect of Process Changes

9

Process Change (Cell line, fermentation, downstream

processing)

Drug Substance/Drug Product

Chemical/biochemical Properties In vivo properties

13

Product Attributes to Verify• Chemical Biochemical Properties

• Impurities• Clearance (DNA, viral, HCP)• Molecular weight• Folding/disulfide bonds• Glycosylation• Aggregation• Activity/Bioassay• Physical Characterization• Stability• Etc.

• In vivo Properties• Pharmacokinetics• Safety• Efficacy

14

Evaluate Proposed ChangesDecision if the proposed change can/should be implemented

• Teams in place to evaluate proposed changes and impact on product

• Implemented Decision Tree • Risk Management• Communication critical

“That natural selection generally acts with extreme slowness I fully admit.” (Charles Darwin)

Creating a Process for a Drug Substance (DS) is an Interdisciplinary Approach

The same principle applies to the evaluation of a proposed process change

Proc

ess D

evel

opm

ent

Qua

lity

Assu

ranc

e

Faci

lities

/Eng

inee

ring

Anal

ytica

l

Valid

ation

Man

ufac

turin

g

PROCESS

16

Decision Process

17

Implementing Change• Change control in place• Realistic timelines and resource allocation• Know the agency and their expectations• Communication • Good science

“The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided.” (ICH 8 guidelines)

Basis for Success• Crossfunctional team

• Project Management• Alignment of objectives• Effective communication• Early involvement of

critical group members

• Clear process in place for evaluating and implementing a proposed change

PROCESSManufacturing

Analytical

Process Development

Quality Assurance

FacilitiesEngineering

Validation

REDUCING FREQUENCY OF CHANGES

20

How to reduce frequency for changes• Invest time upfront

• Analytical methods early in place• Realistic release specifications • Scientific understanding of process • Proper characterization of product

• Process development and scale-up driven by science and engineering rather than deadlines

• Determine key points where implementation is sensible (e.g. before Phase III start), and combine multiple changes into one submission in order to reduce cost

• Carefully evaluate the necessity for change• Clear PRODUCT specifications

• Dosage form and size• Concentration• Administration method

21

Available Tools

• Analytical Methods• Risk analysis (part of QbD program)• Process Analytical Technology (PAT)

Analytical Method Development• On the critical path for process development• Should be done early, however, is often

neglected• Proper characterization essential for process

optimization, technology transfer, scale-up• Some informal analytical methods may be

developed within PD• Qualified method in terms of accuracy,

reproducibility, linearity important for successful data analysis

A Quick Word on Specifications• Specifications should be as wide as reasonably

possible given the stage of the development• Scaled up process may need wider specifications

than bench scale• Don’t pick best case product for preclinical safety

studies but “realistic case”• Caution to set specifications too early and too

tight• Continue to gather data FIO with the goal of

setting some specifications later in time

24

From the FDA Tool Box: QbD

Quality by Design (QbD) “[…] The demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches “

(from ICH Q8 (R2))

25

Risk Analysis

• Large component of QbD• Goal: identify and prioritize weaknesses of

process in terms of process parameters• Outcome:

• List of process parameters that are considered high risk;

• Ability to improve process robustness;• Reduction of OOS and associated corrective

actions

Risk Analysis

• FMEA (Failure Mode and Effect Analysis)• Team Approach• Performed at every unit operation step • Critical analysis of operating parameters • Evaluation of risk of failure/process upsets and potential

impact• Detection (D)• Occurrence (O)• Severity (S)

• Based on historical data from small and large scale if available (data mining)

Risk Analysis

Occurrence Detection Impact/Severity

Very high Remote Very high

High Unlikely High

Rare Moderate Moderate

Remote Likely Minor

High None

Increased Risk N

umber

Assign qualitative values for each parameter (Scale 1-10):

Risk Analysis (cont’d)Outcome:

A means to prioritize the level of risk associated with a specific step or process/material parameter

Risk Priority Number, RPN

RPN = D x O x S

(Detection x Occurrence x Severity)

FMEA - Example

Item No.

Process Step

Operating Parameter

Potential Failure Modes

Occurrence

Rating

Detection

Rating

Severity

Ranking

Risk Priority Number

Additional Controls and/or

Comments or Risk Remediation

1 Column LoadProduct

concentrationTiter too high in

load 4 4 4 64Expand design space for

load concentration

2 Elution pH

Failed pH probe solution prep

error 6 6 6 216

3 Elution conductivity

Failed probe; solution prep

error 2 5 7 70

Consider in-line conductivity

sensor/alarm; expand design space

4 Elution TemperatureFaulty temp

control

5 EquilibrationEquilibration

volume

Equil stopped too early; operator error, flow cell

error 6

FMEA: Prioritization of Parameters

0

50

100

150

200

250

300R

PN

Outcome of FMEA

• Increased understanding of process• Critical quality attributes• CPP (Critical process parameters)• CMA (Critical material attributes)• Safe operating ranges• Partial understanding of design space

• Prioritized punch list of equipment/process issues• Prioritized list of operating parameters to expand

design space

Process Analytical Technology

“PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.”

www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088828.html

"real time“ quality assurance32

PAT – Example 1In-line buffer dilution with pH and conductivity control for chromatography step (isocratic or gradient)

33

Conc. Acid

Salt solution

Recirc pump

WFI

cond pH

Waste

Chromatography skid

Buffer Composition Control by Mass Flow versus PAT

Courtesy of: Michael Li, Asahi Kasei BioProcess

PAT Example: chromatography Gradient control for the separation of trypsinogen and ribonuclease A using IEX chromatography using mass flow control versus PAT based on pH and conductivity

Courtesy of: Michael Li, Asahi Kasei BioProcess

Chromatogram using Mass Flow

Chromatogram using PAT

PAT – Example 2

• Continuous monitoring system for a protein refolding step

• Goal: Consistency in product quality and process performance across batches

• Protein: Recombinant human endothelial growth factor (rhVEGF)

• Based on understanding of oxygen needs during the reaction and its impact on quality

• Monitoring %DO maintaining constant oxygen transfer KLa across scales 3L, 2,000L, 15,000L

Protein Refolding Using PAT

Courtesy of: Shelly Pizarro, Genentech

Experimental Setup:Control of O2/N2 sparging based on DO profile in reactor at constant kLa :

Protein Refolding Using PAT

Courtesy of: Shelly Pizarro, Genentech

Refold reaction:• Reduction of monomers over time• Creation of main peak (rhVEGF)• After 3-6 hrs oxidized and misfolded

species appear• Process Analytical Tool: DO

Stop reaction at specific point in DO profile rather than just time to minimize misfolds

39

PAT Summary

• PAT increases robustness of process by controlling key parameters directly

• Reduced frequency of OOS• Increased process understanding• It comes at an increased cost

(development time, equipment cost, validation)

WHAT WENT WRONG?Case Studies (n=3)

41

483s – Case Study IAMAG Pharmaceuticals, Inc.

• Engineering modified wiring connections on the same cooling relay which services the Clean Room complex . This change caused the relative humidity in the Clean Room complex to exceed the established specification […]. Therefore, Production and Quality Control approved the relative humidity specification change to XX %. A change control was not executed to scientifically evaluate how this specification change would affect operations and quality of the Clean Room […].

42

483s – Case Study II

• Applied Laboratories Inc.• Your change control procedure […] was found

to lack provisions for complete documentation of the nature and approval of production and process changes, (FDA-483 #14) as required by 21 CFR 820.70(b).

43

Case Study III

Nature Biotechnology 26, 592 (2008) (by George Mack)

• FDA balks at Myozyme scale-up• Genzyme ran into a snag in April [2008] when the

US Food and Drug Administration (FDA) rejected its application to produce Myozyme (alglucosidase alfa, rhGAA) in its 2,000–liter-scale facility under the same approval authorization given for its 160-liter-scale plant. The FDA says the carbohydrate structure of the products manufactured at each scale differs and thus the 2,000-liter product requires a new biologic license application.

44

Myozyme becomes Lumizyme after biologics scale-up

• In February 2009, Genzyme was scheduled to launch the same biologic under two different names in the US after the FDA decided the drug produced at 2000L was considerably different to the 160L version.

• Approval for Lumizyme was gained in May 2010 (after additional delays due to mfg issues)

15 month delay

45

To Conclude

• Don’t be afraid of change, it is part of evolution• Carefully evaluate and plan a process change• Implement strategies for risk management• Have procedures in place (documentation, validation, additional

preclinical or clinical studies, etc)• Work with FDA • Use scientific knowledge, historical data, experimental design,

and common sense

FDA and Industry have a common objective to ensure that high quality pharmaceutical products continue to be available to the public. (from: PAT workgroup presentation)

Thank you!

Special Thanks to:• ISPE• Michael Li (Asahi Kasei Bioprocess)• Henriette Kuehne (Amylin)• Mayank Patel (PAXVAX)• Jörg Thömmes (Biogen IDEC)• Shelley Pizarro (Genentech)

References• ICH Q8R2 guidelines (2008) - http://www.ich.org/cache/compo/276-254-1.html• ICH Q9 guidelines (2005) - http://www.ich.org/cache/compo/276-254-1.html• Maximizing Uptime for Mission-Critical Manufacturing Units; By Gary

Shamshoian, P.E., Genentech, Inc., and Don Nurisso, P.E., EYP Mission Critical; http://www.pharmamanufacturing.com/articles/2007/008.html;

• Change within design space is not a regulatory change: Genentech official. http://www.thefreelibrary.com/Change+within+design+space+is+not+a+regulatory+change%3a+Genentech+...-a0174973741

• Use PAT to Dilute Buer from Concentrate with a Linear pH Gradient for Downstream Bioprocessing. Michael Li, Hiroyuki Yabe, Shree Jariwala, and Tomo Miyabayashi Asahi Kasei Bioprocess; Poster Presentation at BPI conference 9/2010

• Biomanufacturing process analytical technology (PAT) application for downstream processing: Using dissolved oxygen as an indicator of product quality for a protein refolding reaction. Shelly A. Pizarro, Rachel Dinges, Rachel Adams, Ailen Sanchez, Charles Winter Biotechnology and Bioengineering Volume 104, Issue 2, pages 340–351, 1 October 2009

48

and prioritizand prioritiz

49

Backup slides

Defining Operating RangesFor a Single Operating Parameter

Design Space

51

Experimental Data

Design Space

Approved ProcessModeling used to support Design Space Characterization

Looking at all critical process parameters and material attributes

PAT – Example 1

Courtesy of: Michael Li, Asahi Kasei BioProcess

Interrelation between Quality Attributes and Process & Materials

Critical Quality Attributes

Inputs Outputs

Material Attributes

Process Parameters

MA1

MA2

CPP1

CPP2

CQA1

CQA3

CQA2