Leveraging Technology to Ensure Raw Material Supply Chain Security in the Pharmaceutical Industry

Vinny Browning, Jared Byrne, Kim Colson, Steven Wolfgang

Agenda

• FDA Perspective on Assuring Quality of Pharmaceutical Ingredients and Deterring Adulteration

• Adulteration Screening – Drivers for Choosing Advanced Analytical Technologies

• NMR Science and Capabilities

• Moving NMR into QC

• Panel Discussion

IFPAC January 20,2011

Leveraging Technology to Ensure Raw Material Supply Chain Security

in the Pharmaceutical Industry

INTERPHEX 2011March 29, 2011

Steven Wolfgang, Ph.D.FDA/CDER/Office of Compliance/

Division of Manufacturing and Product Quality

Ingredient Contamination – Are We Only Seeing the Tip of the Iceberg?

Presentation Outline• Globalization of Drug Manufacturing

– Greater uncertainty about supply chains– Events signaling a changing risk profile

• What is Being Done to Protect Consumers from Exposure to Unsafe Poor Quality Drugs?– Legislation and regulation– Manufacturers seek to prevent and detect breaches in

supply chain

Globalization and Greater Drug Complexity Has Changed the Risk Landscape

• Potential for fraud and illicit activity– Economically-motivated acts of deception by suppliers

• Slow adoption of modern standards– emerging economies – chemical industry

• More expansive supply network increases the potential number of ‘weak links’

• More difficult to acquire detailed knowledge needed to manage risk

Bad Actors Can Potentially Infiltrate a Drug Ingredient Supply Chain

• Substitution, dilution of ingredients– OSCS in heparin; melamine in protein; DEG in

polyols• Show and shadow factories

– Ingredient distributor poses as manufacturing site in regulatory submission or to end user

• Falsification of data and information – Fabrication of test results– Purporting to comply with standard

Management Support Can Make it More Difficult for Bad Actors to Infiltrate Drug Supply Chain

• Support from business enterprise and quality unit– Promote increased knowledge about suppliers and

how ingredients are derived– Provide resources to identify and manage risks in

ingredient supply chains• Support from management for development of

advanced, complementary test methods– Reduce excessive reliance on USP methods

• Foster use of modern technology– Reduce excessive reliance on CoA

Prevention and Detection in Control Strategy

• Risk Management– Prevention

• Building Quality Into Drug Products– Qualification of drug ingredients and their suppliers

» Pharmaceutical development» Supplier audits

– Detection • Sampling and testing approaches

– ID testing and CoA will usually only provide limited amount of quality assurance

– Sampling and testing strategy is an often overlooked but important aspect of control strategy once a supplier has been qualified

How are Legislators Reacting?• Drug safety/globalization bills pertaining to drug

ingredients– Impose greater accountability on ingredient supply

chain• Quality Management Systems far upstream• Increased visibility and traceability of ingredients

throughout supply chain• Site registration requirements broadened

– Excipient manufacturers– Intermediaries

– Grant heightened authorities to FDA• Can revoke a site registration

How is FDA Reacting?• Revision to 21 CFR Part 211 – Control of Components

– Drug manufacturer is ultimately responsible for managing and assuring incoming ingredient quality

• Would require finished drug manufacturer to take risk-based supplier quality management approach

– supplier qualification– full supply chain traceability – mandatory periodic audits– certificate of analysis traceable to original

manufacturing site

FDA Has Issued Guidance• Recommends that manufacturers address economically

motivated adulteration (EMA) through testing and adoption of principles of quality risk management– Known risks of EMA

• Testing of Glycerin for DEG http://www.fda.gov/downloads/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/ucm070347.pdf

• Testing of Ingredients At Risk to Melamine Contamination http://www.fda.gov/downloads/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/UCM175984.pdf and http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInf ormation/Guidances/ucm124780.htm#5

Strategic Approach Improved Prevention and Detection

• Workshops such as IFPAC can promote awareness and collaboration– Prevention as the basis for quality and security

• Knowledge• Communication• Quality management systems

– Better analytical methods are desired• To screen for aberrations in quality• Toward replacement of archaic technology

Sharing of Knowledge and Responsibility for Quality

Qualified (3rd) parties

Drug ProductManufacturers

API andExcipient Manufacturers

FDA

Collaboration on Analytical Technology Platform Advancement Through Sharing of Knowledge

FDA

SDOs

Excipient and API suppliersDrug manufacturersVendors of instrumentation and software Academia

Closing Remarks• Knowledge is a basis toward building

assurance– Basis for sound risk management

• Monitoring (testing, examination, auditing) is a route toward building assurance– Trust but verify

Contact Informationsteven.wolfgang@fda.hhs.gov

• Subject Contacts: http://www.fda.gov/AboutFDA/CentersOffices/C DER/ucm096102.htm

• Questions & Answers on Drug CGMP:http://www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm124740.ht m

Globally Occurring Events Causing us to Evaluate the Supply Chain

• Patient / customer deaths indicate that industry raw material supply chains lack sufficient controls to be secure (Glycerin, Melamine, Heparin)

• Our practices of compendia identification methods do not detect adulteration – for example, Heparin used sodium presence as the ID test

• Globalization continues to push industry supply chains into emerging high risk markets while a struggling world economy provides opportunity for the entrance of criminal elements

IFPAC January 20,2011

1

1. Taixing Glycerin Factory (Hengxiang, China)

Chemical plant not inspected by SFDALabeled Glycerin, USPSymbol means glycerin substituteCofA reads 99.5% pure

2

2. CNSC Fortune Way (Beijing, China)

Removes mfg name from CofA and replaces with ownTranslates to EnglishNo testing

3

3. Rasfer International (Barcelona, Spain)

Removes mfg name from CofA and replaces with ownNo testing

55. Social Security Administration (Panama)

No testingManufactures cough medicine using tainted glycerin

4. Medicom Business Group (Panama)

Changes expiration dateNo testing

4

Complex and Insecure Supply Chains have Consequences: Tainted Glycerin ~ 100 Deaths

IFPAC January 20,2011

Advanced Analytical Technologies is only a component of Supply Chain Security• Tracing the supply chains of our incoming materials

back to their original source

• Extending excipient audits back to original manufacturing locations

• Implementing incoming raw material Photo Library inspections for counterfeit detection

• Melamine screening of at risk materials

• Advanced analytical adulteration screening of materials with high risk supply chains

IFPAC January 20,2011

Amgen Chose Approaches Based on Detection of Economically Motivated Adulteration

• Provide a general screen of all key raw materials that may have been adulterated with an unknown compound for economic gain

• Implement a platform technology with capability of near universal detection

• Adopt a level of 5% (w/w) as a lower limit of what might provide economic gain

IFPAC January 20,2011

Technique Pro Con

NIR • No sample preparation– in situ analysis• Short analysis time

• Easy to use

• Low cost instrument

• Spectral bands are not compound specific

• Lacks compound specificity in analysis of mixtures

• Requires chemometric models based on large

sample library

• Not quantitative

Raman • Portable instrument available – very low

cost

• Minimal sample prep – some in situ analysis

• Short analysis time

• Raman signal is weak

• Fluorescence interference – color samples are

difficult

• Lacks compound specificity in analysis of mixtures

• Requires chemometric models

FT-IR • Strong spectral signals

• Applicable to wide range of samples

• Widely available spectral library

• Sample preparation introduces spectral variability

• Lacks compound specificity in analysis of mixtures

• Not quantitative

NMR • High resolution signals – highly

reproducible

• Simple sample prep – dissolve or dilute

only

• Compound-specific spectral bands,

unambiguous assignments

• High specificity to mixture analysis

• Quantitative

• Automatable

• Low detection limit - < 0.5% is routine

• Unsuitable for inorganics

• Requires trained technicians and access to

experts

• Regular routine maintenance – e.g. He, N2 top-off

• More expensive than other techniques

Multiple Analytical Technologies were Assessed

IFPAC January 20,2011

Our Conclusions from Comparison Study

• NIR identification method does not provide adequate protection from potential economic adulteration

• Raman-microscope provides high resolution spectra that discriminates adulterated and unadulterated samples but requires manual inspection

• FTIR provides high resolution spectra that discriminates adulterated and unadulterated samples but requires manual inspection for adulteration detection

• NMR can unambiguously detect adulteration with absolute structural assignment

IFPAC January 20,2011

There isn’t one right answer

• Amgen choose NMR because it best fit our capability, resource, and material base

• As we discussed, there are other options. In addition to these, LC-MS and GC-MS are options for Melamine or ICP-MS for any inorganics both of which we have deployed

• The key is acting aggressively – for security we should all bias our organizations towards action and choose the technologies that best fit our company and situation

IFPAC January 20,2011

Acknowledgement

24. März 2011 1

Thank you to Amgen for engaging us in this application

2

Quality Control of Raw Materials

NMR Test Results

Pass

Main Component 98%Solvents OKAdulterants 0%Known Impurities 2%Unknowns 0%

• Identify Main Component and Impurities

• Identify Presence of Unexpected Materials

• Quantify Amount of Each Component

• Designed for Use in Both GMP/GLP and non-GMP/GLP Labs

In full Automation

Plausible Application for NMR?

24. März 2011 3

NMR: Simultaneous Targeted AND Non-Targeted Analysis

NMR is fully quantitative so we can see materials that have overlapping signals.

We can see everything that has an NMR active nuclei and is soluble.

Calibrated Instrument (ERETIC II/PULCON)

Total integral analysis

4

NMR Technology Now – Production lab compatible

Safety

• Fringe Field Reduced to within Dewar

Siting Requirements

• Less space

• Less demanding (vibrations)

Ease-of-use

• Automation (NMR expert not req.)

• Liq. Helium fill time (1 year)

• N2 (liq.) Fill service contracts

• Remote access

Additional Criteria

• Daily use by non-technical NMR Users ‘QC User’

• Customizable by NMR Technical User

NMR Tech User

Site 1Site 2

Site

3

6

Necessary Features for Automated QC NMR

• Automated

• Data Acquisition

• Data Processing

• Quantitative and Qualitative Analysis

• Report Generation

• System Suitability Test for GMP & GLP Labs

• Convenience Features (system maintains itself?)

• Lock-out mode for access-limited users

7

Automatic Data Acquisition and Processing for QC

Requirements• Stable, reproducible instrumentation• Robust parameters

• Must be Fit for quantitative use• Must be Fit for desired discrimination

but generally applied• Auto-phase consistency• Flat baselines

Blue:noesy1d

8

Customizable for Site Specific Materials

9

Simple Submission Interface

Not accessible to QC User in Lockdown mode

10

Simple Submission Interface

Calls Parameter Sets, nuclei and conditions. Data analysis for 1H and 13C is implemented.Filename for dataset.

11

Simple Submission Interface

12

Automated Analysis - Qualitative

• Qualitative Analysis

SBASE

Automated Analysis - Quantitative

• Quantitative Analysis

Integration by: • Integral (pure)• Peak fit (overlap)

14

Supplied Analysis Methods

Quantifications methods used in Assure-RMS.Based on the relative concentration to the main component as exemplified with lysine as the adulterant and arginine as the main component. Custom

analysis equations are possible.

Internal Composition

Absolute Relative to Main Component

% Molar

% Gram

Internal Composition

Absolute Relative to Main Component

% Molar

% Gram

Protons of#

MW * Arginine

Protons of#

MW * Lysine

Protons of#

MW * Lysine

Protons of#

Arginine

Protons of#

ineLys

Protons of#

Lysine

Protons of#

Arginine

Protons of#

Lysine

Protons of#

MW * Arginine

Protons of#

MW * Lysine

15

Customization is possible

EU Directive ISO 21461 Analyze rubber for polyaromatic hydrocarbons(PAH) content.

Amount of bay region hydrogen according to must be < 0.35% for tires.

100%

8.52.035.90.6

5.93.8

ppmCHClppm

ppm

BayIII

IH

Automated Report Generation for QC

• Report Generation

• QCReport - a ‘pass’ or ‘fail’ report

• Define Qualifiers (SBASE match, quantity, type of material)

• New spectrum tested against qualifiers

• Detailed ExpertReport - total analysis

17

Automatic Report Generation - QCReport

18

Automatic Report Generation -ExpertReport

Automatic Report Generation - ExpertReport

Concentration calculation based on molar % of reference taken from Assure-RMS

Potato Analysis

Compound Amount Status

sucrose 100 quantified

fructose 13.6 quantified

alpha-D-glucose 24.1 quantified

beta –D-glucose 30.8 quantified

asparagine 134 quantified

20

Necessary Features for GMP & GLP

• System Suitability Tests for GMP/GLP Labs

• 1H lineshape

• 1H sensitivity

• 13C sensitivity

• Temperature calibration and adjustment

Validates that the instrument is performing to specifications

Optimizes the instrument performance

Helps instrument maintain itself

21

System Suitability Tests Management Window

22

System Suitability Tests Management

Allows use with any NMR

probe

23

System Suitability Tests Management

Assists SBASE MATCH Function

24

Summary: Automated QC Screening by NMR

User Involvement

24. März 2011 25

Thank You!

Back to Vinny

24. März 2011 26

Kim.colson@bruker-biospin.com

Case Study: Moving NMR to our QC Lab

• Scope: Develop a automated NMR adulteration detection method in QC

• The next several slides will take us through the challenges, consideration, complexities that we faced as well as lessons learned

IFPAC January 20,2011

Challenges of Moving Analytical Technologies to QC

• Moving an R&D method developed in PD to QC to detect NMR adulteration

• Developing a complex method as a limit test

• Standardizing sample preparation

• Concentration

• Solvent (D2O, DMSO-d6, other if necessary)

• Standardizing data acquisition and processing parameters

• Rely on automated instrument software for tune, match, lock and shim

• Developing 1H and 13C spectral database of raw materials

• Developing custom analytical software

IFPAC January 20,2011

Vendor and Equipment Considerations

• Choosing the most appropriate equipment/Vendor

• Equipment Selection

• Environmental Factors

• Facility Designed

• Instrument Placement

• Vendor experience

• Vendor selection will dictate program success

• Location

• Knowledge

• Culture

• Written agreement of actions

IFPAC January 20,2011

Lesson: Understand vendor recommendations (e.g.

location of instrument to the components to purchase)

Funding Limitations to Consider

• Equipment Capital

• Labor Expenses

• Uncertain timelines

• Consider a gate approach

• Concept

• Design

• Execution

IFPAC January 20,2011

Lesson: Work with your finance teams to clearly

understand your processes and durations

IS Processes Requiring Action

• IS items to consider

• Server location(s) in one site with redundancy

• Allowable down time of the server/application

• Help desk support process

• Software administration

• Auditing of the vendor software prior to purchase and subsequent post audits (performed questionnaires/on site)

• Challenges

• R&D IS structures don’t plug and play into QCs

• Development of internal expertise

• Software (i.e. patches and upgrades)

• Value of COTS

IFPAC January 20,2011

Lesson: IS is a key component to ensure success

GMP Documentation Requirements

• Don’t underestimate the document load

• To implement in the GMP environment multiple GMP documents are required this list included

• Installation

• Developmental/Qualification/Transfer/Validation

• Training

• Operational

• Methods

IFPAC January 20,2011

Lesson: Vendor engagement and support can facilitate

partner, leveraging training or recreating SOP, could

they have supported us more

Complexities of a Global Project

• In our scenario we were working directly with the PD Lab as well as with another QC Lab, each in different time zones

• Leverage meeting via telecons, Web Meetings, Telepresence, and limited face to face meetings

• Leverage proximity to the vendor to assess custom software in the vendor’s shop

• Training at one site and/or at supplier, centralize

• Competing priorities requiring level loading work and rebalancing

• Conflict Resolution with multiple disciplines with different ideas

IFPAC January 20,2011

Lesson: Real or virtual face to face meetings are

essential

Qualification and Validation Activities Required to Proceed

• Qualification

• A pre-defined strategy must be determined and agreed upon by all parties with defined accountability and ownership

• Validation

• As with the qualification, a pre-defined strategy must be determined and agreed upon by all parties with defined accountability and ownership

IFPAC January 20,2011

Lesson: Consider the type of test being deployed (i.e quantitative

vs. qualitative) an align your validation accordingly

Technology Transfer Activities Required Post Validation

• Transfer knowledge to other sites, as required

• The following should be considered:

• Transfer plan

• Transfer protocol

• Transfer report

• On site training and support ensures consistency

IFPAC January 20, 2011

Lesson: Have QC support method qualification to build

experience and limit method transfer requirement

Additional Lessons Learned from Our Implementation

• Ensure clear alignment of expectations with the vendor in writing up front

• Relying on the vendor to recommend equipment location

• Complexities of working on a global project across multiple time zones

• Project manager leveraging day to day duties with the management of project and managing vendor relations

• Need a cohesive and committed team to drive success

• Must have an executive champion

IFPAC January 20,2011