GMP and Inspections

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GMP and Inspections

• Malcolm Holmes

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Points to cover

• How multinational industry assures global
  standards of manufacture
• Use of ICH Q8, 9 10 for robust product quality
• Patient focused use of inspection resource
• Desktop inspections potential problems

facilitating better / more effective decision
making
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Typical global supply chain
2nd API site proposed
Granulate
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Uses of ICH Q8,9 10
Industrial Process 2.5 -3 sigma
5-10 waste
90-95
6 sigma product to patient
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What is Quality Risk Management?
ICH Q9 identifies QRM as risk of harm to patient
Two key ICH Q9 principles
Level of effort proportionate to risk
Level of recording proportionate to risk
Effective QRM facilitates better / more
effective decision making
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Two (wrong) approaches to risk
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Maintaining GMP standards in our global industry

• Core standards from the regulators with
  industry input
• PIC/S EU GMP- USA CFR WHO guidelines
• Harmonisation efforts such as ICH
• Local regulations often based on WHO / PIC/S /
  ICH
• Regulator confirms that GMP applied

• Industry
• Company Quality Management Systems
• Local QMS based company QMS plus local
  requirements
• SOPs to give more detail and transfer into
  practice
• Management responsibility to see that GMP in
  place and in use via QMS

But why arent they all harmonised?
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The GSK QMS as an example
The QMS is

• A comprehensive, living system of policies,
  guidelines and processes aligned to international
  regulatory requirements, performance standards
  and benchmarking activities

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Where we are now - regulators

• Regulators
• Pressure to do more with less
• Mutual Recognition Agreements, confidentiality
  agreements Pharmaceutical Inspection Cooperation
  Scheme (PIC/S)
• GMPs and guidance highly developed / under
  continual revision
• ICH Q8, 9 10
• In the public eye
• Local manufacture wants level playing field
• Public wants assurance of a job well done

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2006 Regulatory inspection Data
(Regulatory Inspections Conducted Outside and
Within The Regulators Own Borders)
Source data - Survey of EFPIA member companies
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22 Companies Provided Data

• Abbott, Altana, Amgen, AZ
• Bayer, Boehringer
• Chiesi
• Eli Lilly
• Gruenenthal, GSK
• Hoffmann La Roche
• JJ
• Merck Co inc

• Novartis, Novo Nordisk
• Organon, Orion
• Pfizer
• Sanofi Aventis, Schering AG, Schering Plough,
  Serono

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Typical Time To Host An Inspection

• Preparation
• 80 - 100 person days
• 5 QC, 5 QA , 5 Pharm. Dev., 5 from other areas
  for 4 5 days. Tasks reviewing, compiling,
  summarising, preparing presentations
• Inspection Management
• 17 person days per inspection day
• 1 host, 1 scribe, 15 people in background roles
• Follow up
• 20 person days
• compile / agree responses reports

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Issue

• More inspectorates routinely conducting
  inspections outside own borders
• At least 37 inspectorates (EU 1 inspectorate)
  active in this field
• From 1999 to 2005 the number increased by about
  20 p.a.
• in 2006 it increased by 11
• The quality of the conducted inspections varies
  significantly
• A single manufacturing site may supply 80
  markets
• Strategic sites currently inspected by up to 15
  times in one year
• Different inspectorates looking at the same
  processes / systems / products

In 2006, responses from 22 companies indicate
that regulators spent 2,023 industry up to
74,831 man days on such foreign inspections
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Statistics

• Number of companies in survey 22
• Number of sites in survey 663
• Total number of inspections 939
• Total number of Foreign Inspections 337
• Total Inspector days Foreign Inspections 2023
• Max inspection per site 15
• Sites with 10 inspections 8
• Sites with 5 -9 inspections 40
• Sites with 4 inspections 17
• Sites with 3 inspections 43
• Sites with 2 inspections 90

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Foreign Inspections 2003 - 2006
25 companies
22 companies
16 companies
25 companies
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Inspector Days Foreign Inspections
22 companies
25 companies
16 companies
25 companies
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New Foreign Inspection Activity
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Inspectorates Most Active Outside own Borders in
2006
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Inspectorates Most Active Outside own Borders
2003-6
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Typical Respondee 2006
Number of sites

• 46 inspections
• 10 inspectorates (all EU1)
• on 12 sites in one year

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Activity analysis foreign inspections
56 increase since 2003
75 increase since 2003
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Sharing of inspection reports

• Have You Shared inspection reports from one
  competent authority with another?
• Yes 8
• No 11
• No response 3
• Would you be prepared to share such reports in
  the future?
• Yes 14
• No 5
• No response 3
• (4 companies may redact reports first, 1 might
  share conclusions only, 3 if a clear benefit in
  doing so and 1 if also agreed by the issuing
  authority.)

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Desktop Inspections
Can be a useful tool but have pitfalls

• Dont try to review everything
• Sample systems and data to demonstrate they are
  in place and in use

• Sometimes we are asked to supply full validation
  documents DQ/IQ/OQ/PQ for all sites and all
  products
• This can be container loads of documents
• Product and cleaning /area / utility are inter
  related
• Area / utility not re-validated with each product
  but impact of new product will be scientifically
  considered to see if re-validation needed

Validation is living / lifecycle / linked to QMS.
Some of what is submitted will be out of date
before it is even received
Gives the impression that a thorough review of
validation is undertaken
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Outcome

• Considerable scope for better focus of both
  Regulatory Industry resources without adverse
  effect on patient safety

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Proposal inspections

• Move inspections approach towards
• risk-based scheduling (need / frequency)
• risk-based conducting (focus and depth)
• system and process orientation

• Perform more inspections locally with focus on
• supply chain
• Cold chain
• Counterfeit potential
• this could bring about patient benefit without
  using more resource

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Proposal sharing of GMP information

• Promote sharing of inspection conclusions /
  reports
• Observe and extend multi / bilateral agreements
  e.g. PIC/S membership / MRAs / Confidentiality
  Agreements