PQRI Opening Session 1 PQRI Survey of Pharmaceutical Excipient Testing and Control Strategies Used by Excipient Manufacturers, Excipient Distributors and

PQRI Opening Session1

PQRI Survey ofPQRI Survey of Pharmaceutical Excipient Pharmaceutical Excipient

Testing and Control StrategiesTesting and Control Strategies

Used by Excipient Manufacturers, Used by Excipient Manufacturers, Excipient Distributors andExcipient Distributors and

Drug-Product ManufacturersDrug-Product Manufacturers


WelcomeWelcome

When? The time is When? The time is NOW!NOW! The next 2 days provide the opportunity for The next 2 days provide the opportunity for

you to participate!you to participate! Please be respectful of time limits.Please be respectful of time limits.

Where? The place is Where? The place is HERE!HERE! This hotel wing will break down to 5 discussion This hotel wing will break down to 5 discussion

areas.areas. Your individualized, randomized topic sequence Your individualized, randomized topic sequence

ensures you will discuss each topic. See your ensures you will discuss each topic. See your personal packet.personal packet.

You will hear the thoughts of all other You will hear the thoughts of all other participants at least once. participants at least once.


SupportSupport

The Workshop BookletThe Workshop Booklet PQRI assistance – Sylvia GanttPQRI assistance – Sylvia Gantt Hotel mapsHotel maps PhonesPhones FacilitiesFacilities


PQRI Working Group MembersPQRI Working Group Members

Pharmaceutical Quality Research Institute's Pharmaceutical Quality Research Institute's Excipient Working Group has organized the Excipient Working Group has organized the survey and workshop. survey and workshop. Gregory LarnerGregory Larner, Statistics Manager with Pfizer , Statistics Manager with Pfizer

(Kalamazoo, MI) (Kalamazoo, MI) David SchonekerDavid Schoneker, Chair-elect, IPEC-Americas and , Chair-elect, IPEC-Americas and

Director of Global Regulatory Affairs at Colorcon (West Director of Global Regulatory Affairs at Colorcon (West Point, PA). Point, PA).

Catherine SheehanCatherine Sheehan, Director for Excipients Group at , Director for Excipients Group at USP, (Rockville, MD) USP, (Rockville, MD)

Rajendra UppoorRajendra Uppoor, Pharmacist, Office of Pharmaceutical , Pharmacist, Office of Pharmaceutical Science, CDER/FDA (Silver Spring, MD). Science, CDER/FDA (Silver Spring, MD).

Phyllis WalshPhyllis Walsh, Senior Compendial Manager with , Senior Compendial Manager with Schering-Plough (Kenilworth, NJ). Schering-Plough (Kenilworth, NJ).

Robert WiensRobert Wiens, Compendial Affairs/Global Method , Compendial Affairs/Global Method Management, Eli Lilly (Indianapolis, IN).Management, Eli Lilly (Indianapolis, IN).


The WorkshopThe Workshop

PQRI Excipient Working Group welcomes PQRI Excipient Working Group welcomes you to a Workshop on Excipient Control you to a Workshop on Excipient Control Strategies.Strategies.

Safe and Effective Excipients is our Goal Safe and Effective Excipients is our Goal Component Regulations and Control is criticalComponent Regulations and Control is critical Global economy increases complexityGlobal economy increases complexity Need effective and efficient control strategiesNeed effective and efficient control strategies


Objectives – PQRI Working GroupObjectives – PQRI Working Group

Provide a report on the Survey of Provide a report on the Survey of Excipient Testing and Control Excipient Testing and Control StrategiesStrategies

Determine the impact of those Determine the impact of those findings on stakeholders. findings on stakeholders.

Hold discussions on the impact of Hold discussions on the impact of FDA regulation and guidance on FDA regulation and guidance on excipient control strategies and how excipient control strategies and how to use them correctly and effectively.to use them correctly and effectively.


Objectives - ParticipantsObjectives - Participants

Based on the survey information and Based on the survey information and conference discussions the participants conference discussions the participants will: will: Identify concerns of stakeholders - including Identify concerns of stakeholders - including

excipient manufacturers, drug product excipient manufacturers, drug product manufacturers, regulators, and USP. manufacturers, regulators, and USP.

Communicate and clarify regulations. Communicate and clarify regulations. Develop stakeholder recommendations and Develop stakeholder recommendations and

ideas for potential changes in compendia, ideas for potential changes in compendia, guidances and regulations to minimize guidances and regulations to minimize regulatory burden. regulatory burden.


DeliverablesDeliverables

Summaries of workshop discussions Summaries of workshop discussions A Joint Position Paper from excipient A Joint Position Paper from excipient

manufacturers, drug-product manufacturers, drug-product manufacturers and USP on key manufacturers and USP on key excipient issues. excipient issues.

Possible solutions to issues currently Possible solutions to issues currently faced by the stakeholders.faced by the stakeholders.


How the Survey was ConductedHow the Survey was Conducted

PQRI conducted an open, publicly PQRI conducted an open, publicly available, electronic survey available, electronic survey

Current excipient-control strategies were Current excipient-control strategies were studied.studied.

3 surveys were available:3 surveys were available: pharmaceutical excipient manufacturers, pharmaceutical excipient manufacturers, excipient distributors and excipient distributors and drug-product manufacturers (excipient users) drug-product manufacturers (excipient users)


Survey Highlights - ISurvey Highlights - I

Nearly all respondents (99%) stated that their Nearly all respondents (99%) stated that their excipient specifications comply with excipient specifications comply with USP-NFUSP-NF monograph requirements. monograph requirements.

Almost all drug product manufacturers (97%) test Almost all drug product manufacturers (97%) test excipients according to excipients according to USP-NFUSP-NF monograph/general chapter methods; monograph/general chapter methods;

Approximately 1 in 6 excipient manufacturers and Approximately 1 in 6 excipient manufacturers and excipient distributors excipient distributors do notdo not test according to test according to USP-NFUSP-NF. .


Survey Highlights - IISurvey Highlights - II

Most (79%) respondents (excipient Most (79%) respondents (excipient manufacturers, excipient distributors, and manufacturers, excipient distributors, and excipient users) have been inspected by the Food excipient users) have been inspected by the Food and Drug Administration (FDA); and most and Drug Administration (FDA); and most distributors have been inspected by their State or distributors have been inspected by their State or Local Authorities.Local Authorities.

Most excipient specifications are both national Most excipient specifications are both national ((USP-NFUSP-NF) and global, versus up to 15% just ) and global, versus up to 15% just national (national (USP-NFUSP-NF).).


Survey Highlights - IIISurvey Highlights - III

Most excipients obtained from new vendor Most excipients obtained from new vendor sources are qualified sources are qualified by vendor audit (91%) and by vendor audit (91%) and complete testing according to compendial monograph complete testing according to compendial monograph

(96%) for the article. (96%) for the article. An excipient from a new supplier (or vendor), is An excipient from a new supplier (or vendor), is

qualified qualified approximately 35% of the time by supplier’s analytical approximately 35% of the time by supplier’s analytical

method, method, about 50% by an in-house method, about 50% by an in-house method, 63% of the time by process validation in the dosage 63% of the time by process validation in the dosage

form, but form, but rarely (15%) accepted on Certificate of Analysis (C of A) rarely (15%) accepted on Certificate of Analysis (C of A)

with identity test alone.with identity test alone.


Survey Highlights - IVSurvey Highlights - IV

Greater than 70% of all respondents Greater than 70% of all respondents perform additional functionality or perform additional functionality or processability testing:processability testing: 76% to determine excipient suitability, 76% to determine excipient suitability, 66% always for the excipient, 66% always for the excipient, little over 50% for oral solutions. little over 50% for oral solutions. 87% for solid oral dosage forms. 87% for solid oral dosage forms.


Survey Highlights - VSurvey Highlights - V

85% of drug product manufacturers, and 85% of drug product manufacturers, and all distributors have a vendor certification all distributors have a vendor certification program. program. 87% of drug product manufacturers audit 87% of drug product manufacturers audit

excipient manufacturing sites, andexcipient manufacturing sites, and testing sites.testing sites.

Greater than 90% of drug product Greater than 90% of drug product manufacturers’ audits are done “on-site of the manufacturers’ audits are done “on-site of the vendor” by their own company auditors vendor” by their own company auditors

less than 20% by third party, less than 20% by third party, 53% of the audits include a questionnaire.53% of the audits include a questionnaire.


BackgroundBackground

2003 – European Agency for the 2003 – European Agency for the Evaluation of Medicinal Products Evaluation of Medicinal Products issued guidance for excipients and issued guidance for excipients and US Food and Drug Administration US Food and Drug Administration issued guidance for CMC.issued guidance for CMC.

Industry believed that generally Industry believed that generally accepted excipient control strategies accepted excipient control strategies were eliminated by the guidance.were eliminated by the guidance.


Background, continuedBackground, continued

Control strategies of concernControl strategies of concern Drug Product Manufacturer (DPM) may apply Drug Product Manufacturer (DPM) may apply

internal method, equivalent to Pharmacopeia.internal method, equivalent to Pharmacopeia. Select single method capable of ensuring Select single method capable of ensuring

compliance with multiple Pharmacopeia.compliance with multiple Pharmacopeia. 2006 – FDA strategically focuses on CGMPs 2006 – FDA strategically focuses on CGMPs

for 21for 21stst Century, including an Century, including an announcement that the 2003 guidance is announcement that the 2003 guidance is withdrawn.withdrawn.


SurprisesSurprises

About 25% of the time drug product About 25% of the time drug product manufacturers test excipient suitability for manufacturers test excipient suitability for processing, using experimental processing, using experimental (laboratory) scale batches, or pilot scale (laboratory) scale batches, or pilot scale manufacturing batches. manufacturing batches. This was higher than expected.This was higher than expected.

Batches were rarely (15%) accepted on Batches were rarely (15%) accepted on CofA with identity test alone. CofA with identity test alone. This is an accepted approach in the CFR, and This is an accepted approach in the CFR, and

was lower than expected.was lower than expected.


Surprises, continuedSurprises, continued

Most excipient manufacturers and distributors Most excipient manufacturers and distributors that replied to the survey do label their excipients that replied to the survey do label their excipients as compendial grade. as compendial grade. Excipient GMP requirements perceived as being too Excipient GMP requirements perceived as being too

restrictive generally do not impact their decision;restrictive generally do not impact their decision; Low demand for compendial grade generally does not Low demand for compendial grade generally does not

impact their decision;impact their decision; ““Can not meet the compendial monograph” criteria Can not meet the compendial monograph” criteria

generally does not impact their decision.generally does not impact their decision. This may not be reflective of the entire excipient This may not be reflective of the entire excipient

manufacturers industry since the pharmaceutical manufacturers industry since the pharmaceutical industry is often a small fraction of their business. industry is often a small fraction of their business.


Summary of Key Survey FindingsSummary of Key Survey Findings

The majority of excipient manufacturers; The majority of excipient manufacturers; excipient distributors and drug product excipient distributors and drug product manufacturers manufacturers Manufacture their products for global Manufacture their products for global

distribution. distribution. Test their excipients according to Test their excipients according to USP-NFUSP-NF

monograph and general chapter methods. monograph and general chapter methods. 97% of drug product manufacturers 97% of drug product manufacturers

perform more than an identification test perform more than an identification test when receiving excipients from their when receiving excipients from their vendors along with Certificate of Analysis. vendors along with Certificate of Analysis.



New sources of excipients used by drug product New sources of excipients used by drug product manufacturers are qualified by manufacturers are qualified by vendor audits, and vendor audits, and complete compendial testing. complete compendial testing.

Nearly half (40%) of drug product manufacturers Nearly half (40%) of drug product manufacturers had difficulty in finding a manufacturer of had difficulty in finding a manufacturer of USP-NFUSP-NF grade excipient. grade excipient. In such a situation, they would use the best grade In such a situation, they would use the best grade

available, available, test the excipient according to compendial monograph test the excipient according to compendial monograph

and and conduct the excipient manufacturer’s assessment. conduct the excipient manufacturer’s assessment.



75% of drug product manufacturers indicated 75% of drug product manufacturers indicated they ensure few to all excipients they use they ensure few to all excipients they use conform to compendial grade by testing, along conform to compendial grade by testing, along with manufacturer’s site audits. with manufacturer’s site audits.

In 80% of the cases, validated test procedures are In 80% of the cases, validated test procedures are used to showused to show:: a noncompendial grade excipient conforms to a a noncompendial grade excipient conforms to a

compendial grade, or compendial grade, or a compendial grade conforms to a multi-compendia a compendial grade conforms to a multi-compendia

grade.grade.



Majority of excipient manufacturers and Majority of excipient manufacturers and distributors are not concerned about such factors distributors are not concerned about such factors as: as: Excipient GMP requirements being restrictive or Excipient GMP requirements being restrictive or low demand for compendial grade, or low demand for compendial grade, or inability to meet compendial monograph requirement, or inability to meet compendial monograph requirement, or potential to be inspected by FDA, or potential to be inspected by FDA, or audits by drug product manufacturers. audits by drug product manufacturers.

Nearly 80% of excipient manufacturers, Nearly 80% of excipient manufacturers, distributors and drug product manufacturers have distributors and drug product manufacturers have been inspected or visited by the FDA or State or been inspected or visited by the FDA or State or local authorities. local authorities.



89% of drug product manufacturers stated 89% of drug product manufacturers stated that at least 5 of their excipients are in a that at least 5 of their excipients are in a reduced testing program. They do not reduced testing program. They do not perform complete monograph testing after perform complete monograph testing after vendor qualification and receipt of vendor qualification and receipt of Certificate of Analysis. Certificate of Analysis.

Excipient manufacturers, distributors and Excipient manufacturers, distributors and drug product manufacturers responded to drug product manufacturers responded to be adequately familiar with: be adequately familiar with: FDA and compendial requirements and FDA and compendial requirements and recommendations for excipients testing.recommendations for excipients testing.



>70% excipient manufacturers, >70% excipient manufacturers, distributors, and drug product distributors, and drug product manufacturers perform additional manufacturers perform additional functionality or processability testing that functionality or processability testing that is not part of any compendial monograph: is not part of any compendial monograph: 87% due to processing concerns87% due to processing concerns 87% for solid oral dosage forms 87% for solid oral dosage forms

24% of drug product manufacturers have 24% of drug product manufacturers have products for which excipient variability is a products for which excipient variability is a problem in spite of such extra-compendial problem in spite of such extra-compendial testing. testing.



Alternate international compendial methods are Alternate international compendial methods are used by half or more of excipient manufacturers, used by half or more of excipient manufacturers, distributors and drug product manufacturers to distributors and drug product manufacturers to test some, most or all of their excipients instead test some, most or all of their excipients instead of of USP-NFUSP-NF. .

Nearly 60% of excipient manufacturers and drug Nearly 60% of excipient manufacturers and drug product manufacturers product manufacturers conduct excipient testing per harmonized monographs; conduct excipient testing per harmonized monographs;

and and reduce redundant testing by demonstrating multiple reduce redundant testing by demonstrating multiple

compendial specification equivalence, or compendial specification equivalence, or by using the most stringent method or specification.by using the most stringent method or specification.



About 50% of excipient About 50% of excipient manufacturers and drug product manufacturers and drug product manufacturers have applied manufacturers have applied harmonized excipient monographs harmonized excipient monographs and harmonized general chapters and harmonized general chapters across all their sites. across all their sites.


Workshop Topics A and BWorkshop Topics A and B

A.A. Clarify “continuous-flow Clarify “continuous-flow manufacturing” and “skip-lot manufacturing” and “skip-lot testing” used for excipients in the testing” used for excipients in the context of 21 CFR Part 211.84 context of 21 CFR Part 211.84 regulations. regulations.

B.B. Discuss how characterization of Discuss how characterization of excipient physical and chemical excipient physical and chemical properties helps build quality into properties helps build quality into the drug product. the drug product.


Workshop Topics C, D and EWorkshop Topics C, D and E

C.C. Highlight advantages of increased Highlight advantages of increased use of third-party audits. use of third-party audits.

D.D. Discuss strategies to increase the Discuss strategies to increase the number of excipients labeled number of excipients labeled USP—USP—NFNF. .

E.E. Discuss when reduced testing is Discuss when reduced testing is appropriate.appropriate.


Round Table DiscussionsRound Table Discussions

Attendees will rotate through each Attendees will rotate through each topic.topic.

The topics will stay in the same The topics will stay in the same room.room.

Attendees will be randomized so you Attendees will be randomized so you will meet all attendees and attend all will meet all attendees and attend all topics.topics.

Documents

PQRI Opening Session 1 PQRI Survey of Pharmaceutical Excipient Testing and Control Strategies Used by Excipient Manufacturers, Excipient Distributors and