PQRI%20Survey%20of%20Pharmaceutical%20Excipient%20Testing%20and%20Control%20Strategies%20Used%20by%20Excipient%20Manufacturers,%20Excipient%20Distributors%20and%20Drug-Product%20Manufacturers

1
PQRI Survey of Pharmaceutical Excipient Testing
and Control Strategies Used by Excipient
Manufacturers, Excipient Distributors
andDrug-Product Manufacturers

2
Welcome

• When? The time is NOW!
• The next 2 days provide the opportunity for you
  to participate!
• Please be respectful of time limits.
• Where? The place is HERE!
• This hotel wing will break down to 5 discussion
  areas.
• Your individualized, randomized topic sequence
  ensures you will discuss each topic. See your
  personal packet.
• You will hear the thoughts of all other
  participants at least once.

3
Support

• The Workshop Booklet
• PQRI assistance Sylvia Gantt
• Hotel maps
• Phones
• Facilities

4
PQRI Working Group Members

• Pharmaceutical Quality Research Institute's
  Excipient Working Group has organized the survey
  and workshop.
• Gregory Larner, Statistics Manager with Pfizer
  (Kalamazoo, MI)
• David Schoneker, Chair-elect, IPEC-Americas and
  Director of Global Regulatory Affairs at Colorcon
  (West Point, PA).
• Catherine Sheehan, Director for Excipients Group
  at USP, (Rockville, MD)
• Rajendra Uppoor, Pharmacist, Office of
  Pharmaceutical Science, CDER/FDA (Silver Spring,
  MD).
• Phyllis Walsh, Senior Compendial Manager with
  Schering-Plough (Kenilworth, NJ).
• Robert Wiens, Compendial Affairs/Global Method
  Management, Eli Lilly (Indianapolis, IN).

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The Workshop

• PQRI Excipient Working Group welcomes you to a
  Workshop on Excipient Control Strategies.
• Safe and Effective Excipients is our Goal
• Component Regulations and Control is critical
• Global economy increases complexity
• Need effective and efficient control strategies

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Objectives PQRI Working Group

• Provide a report on the Survey of Excipient
  Testing and Control Strategies
• Determine the impact of those findings on
  stakeholders.
• Hold discussions on the impact of FDA regulation
  and guidance on excipient control strategies and
  how to use them correctly and effectively.

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Objectives - Participants

• Based on the survey information and conference
  discussions the participants will
• Identify concerns of stakeholders - including
  excipient manufacturers, drug product
  manufacturers, regulators, and USP.
• Communicate and clarify regulations.
• Develop stakeholder recommendations and ideas for
  potential changes in compendia, guidances and
  regulations to minimize regulatory burden.

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Deliverables

• Summaries of workshop discussions
• A Joint Position Paper from excipient
  manufacturers, drug-product manufacturers and USP
  on key excipient issues.
• Possible solutions to issues currently faced by
  the stakeholders.

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How the Survey was Conducted

• PQRI conducted an open, publicly available,
  electronic survey
• Current excipient-control strategies were
  studied.
• 3 surveys were available
• pharmaceutical excipient manufacturers,
• excipient distributors and
• drug-product manufacturers (excipient users)

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Survey Highlights - I

• Nearly all respondents (99) stated that their
  excipient specifications comply with USP-NF
  monograph requirements.
• Almost all drug product manufacturers (97) test
  excipients according to USP-NF monograph/general
  chapter methods
• Approximately 1 in 6 excipient manufacturers and
  excipient distributors do not test according to
  USP-NF.

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Survey Highlights - II

• Most (79) respondents (excipient manufacturers,
  excipient distributors, and excipient users) have
  been inspected by the Food and Drug
  Administration (FDA) and most distributors have
  been inspected by their State or Local
  Authorities.
• Most excipient specifications are both national
  (USP-NF) and global, versus up to 15 just
  national (USP-NF).

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Survey Highlights - III

• Most excipients obtained from new vendor sources
  are qualified
• by vendor audit (91) and
• complete testing according to compendial
  monograph (96) for the article.
• An excipient from a new supplier (or vendor), is
  qualified
• approximately 35 of the time by suppliers
  analytical method,
• about 50 by an in-house method,
• 63 of the time by process validation in the
  dosage form, but
• rarely (15) accepted on Certificate of Analysis
  (C of A) with identity test alone.

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Survey Highlights - IV

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

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Survey Highlights - V

• 85 of drug product manufacturers, and all
  distributors have a vendor certification program.
  
• 87 of drug product manufacturers audit
• excipient manufacturing sites, and
• testing sites.
• Greater than 90 of drug product manufacturers
  audits are done on-site of the vendor by their
  own company auditors
• less than 20 by third party,
• 53 of the audits include a questionnaire.

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Background

• 2003 European Agency for the Evaluation of
  Medicinal Products issued guidance for excipients
  and US Food and Drug Administration issued
  guidance for CMC.
• Industry believed that generally accepted
  excipient control strategies were eliminated by
  the guidance.

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Background, continued

• Control strategies of concern
• Drug Product Manufacturer (DPM) may apply
  internal method, equivalent to Pharmacopeia.
• Select single method capable of ensuring
  compliance with multiple Pharmacopeia.
• 2006 FDA strategically focuses on CGMPs for
  21st Century, including an announcement that the
  2003 guidance is withdrawn.

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Surprises

• About 25 of the time drug product manufacturers
  test excipient suitability for processing, using
  experimental (laboratory) scale batches, or pilot
  scale manufacturing batches.
• This was higher than expected.
• Batches were rarely (15) accepted on CofA with
  identity test alone.
• This is an accepted approach in the CFR, and was
  lower than expected.

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Surprises, continued

• Most excipient manufacturers and distributors
  that replied to the survey do label their
  excipients as compendial grade.
• Excipient GMP requirements perceived as being too
  restrictive generally do not impact their
  decision
• Low demand for compendial grade generally does
  not impact their decision
• Can not meet the compendial monograph criteria
  generally does not impact their decision.
• This may not be reflective of the entire
  excipient manufacturers industry since the
  pharmaceutical industry is often a small fraction
  of their business.

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Summary of Key Survey Findings

• The majority of excipient manufacturers
  excipient distributors and drug product
  manufacturers
• Manufacture their products for global
  distribution.
• Test their excipients according to USP-NF
  monograph and general chapter methods.
• 97 of drug product manufacturers perform more
  than an identification test when receiving
  excipients from their vendors along with
  Certificate of Analysis.

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Summary of Key Survey Findings

• New sources of excipients used by drug product
  manufacturers are qualified by
• vendor audits, and
• complete compendial testing.
• Nearly half (40) of drug product manufacturers
  had difficulty in finding a manufacturer of
  USP-NF grade excipient.
• In such a situation, they would use the best
  grade available,
• test the excipient according to compendial
  monograph and
• conduct the excipient manufacturers assessment.
  

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Summary of Key Survey Findings

• 75 of drug product manufacturers indicated they
  ensure few to all excipients they use conform to
  compendial grade by testing, along with
  manufacturers site audits.
• In 80 of the cases, validated test procedures
  are used to show
• a noncompendial grade excipient conforms to a
  compendial grade, or
• a compendial grade conforms to a multi-compendia
  grade.

22
Summary of Key Survey Findings

• Majority of excipient manufacturers and
  distributors are not concerned about such factors
  as
• Excipient GMP requirements being restrictive or
• low demand for compendial grade, or
• inability to meet compendial monograph
  requirement, or
• potential to be inspected by FDA, or
• audits by drug product manufacturers.
• Nearly 80 of excipient manufacturers,
  distributors and drug product manufacturers have
  been inspected or visited by the FDA or State or
  local authorities.

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Summary of Key Survey Findings

• 89 of drug product manufacturers stated that at
  least 5 of their excipients are in a reduced
  testing program. They do not perform complete
  monograph testing after vendor qualification and
  receipt of Certificate of Analysis.
• Excipient manufacturers, distributors and drug
  product manufacturers responded to be adequately
  familiar with
• FDA and compendial requirements and
• recommendations for excipients testing.

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Summary of Key Survey Findings

• gt70 excipient manufacturers, distributors, and
  drug product manufacturers perform additional
  functionality or processability testing that is
  not part of any compendial monograph
• 87 due to processing concerns
• 87 for solid oral dosage forms
• 24 of drug product manufacturers have products
  for which excipient variability is a problem in
  spite of such extra-compendial testing.

25
Summary of Key Survey Findings

• Alternate international compendial methods are
  used by half or more of excipient manufacturers,
  distributors and drug product manufacturers to
  test some, most or all of their excipients
  instead of USP-NF.
• Nearly 60 of excipient manufacturers and drug
  product manufacturers
• conduct excipient testing per harmonized
  monographs and
• reduce redundant testing by demonstrating
  multiple compendial specification equivalence, or
  
• by using the most stringent method or
  specification.

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Summary of Key Survey Findings

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

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Workshop Topics A and B

• Clarify continuous-flow manufacturing and
  skip-lot testing used for excipients in the
  context of 21 CFR Part 211.84 regulations.
• Discuss how characterization of excipient
  physical and chemical properties helps build
  quality into the drug product.

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Workshop Topics C, D and E

1. Highlight advantages of increased use of
   third-party audits.
2. Discuss strategies to increase the number of
   excipients labeled USPNF.
3. Discuss when reduced testing is appropriate.

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Round Table Discussions

• Attendees will rotate through each topic.
• The topics will stay in the same room.
• Attendees will be randomized so you will meet all
  attendees and attend all topics.