Global API Manufacture and Post Approval Changes Regulatory Constraints Chris Dafforn AstraZeneca ch

1
Global API Manufacture and Post Approval Changes
Regulatory Constraints Chris Dafforn
AstraZeneca chris.dafforn_at_astrazeneca.com
Clinical Trials Phase
II
III
NDA MAA
I
Formulation Line Extensions
Late Life Cycle Patent
Expiry
Key Events
Development for launch
Product Maintenance and life cycle support
including Generics
CD prenomination
Principle Testing
Concept Testing
Launch Phase
Typical Number of Registrations
150
300
1500

• Optimisation
• Scale
• Specification
• Starting Materials
• Retest dates

• IPCS
• Scale,
• Yield
• Telescoping
• Site changes
• Specification

• IPCs
• Yield
• Optimisation
• Scale
• Operating conditions

• Equipment
• Starting material sources
• Alternate routes
• Impurity profile (Quantitative)
• Analytical methods
• Outsourcing

• Synthetic route
• Impurity profile (Qualitative)
• Pharmacopoeial monograph

Typical Changes in API
150,000
500,000
750,000
Typical global fees cost per change
Change Inhibited
Drug Master FilesExisting
GMP Certification InspectionExisting
Submission Detail Existing
Proposal
Proposal
Proposal
Active Pharmaceutical Ingredients (APIs) are
produced for global supply there are a number of
interlinked constraints that prevent the
facilitation of continuous improvement due to the
Regulatory environment, which is shaped by
National or Regional requirements. These include
the application of GMP, the content of submitted
information, and the handling of changes through
the EU Variations system, the US Post-Approval
Changes supplements or the Japanese
notification/partial change system. Where prior
approval is necessary the delays can impact the
cost/benefit of implementation, divert management
time and act as an inhibitor of improvement.
  Suggestions for modest changes to the
Regulatory environment are made through the
medium of multiple cause and effect diagrams.
These are examples not an exhaustive list of
what could be changed and are believed to be
practicable in the context of the
responsibilities of Regulatory Authorities.
Encouragement of continuous improvement should
lead to benefits to the consumer through more
rapid introduction of beneficial changes, and to
the producers through operating efficiencies.
Objective Refocus the description of synthesis
and control to describe what needs to be
achieved and why. Use the description as an
example not an absolute recipe
Objective Eliminate multiple submission and
review of the same change through approval of the
master File, and eliminate the need for users of
the Master File to submit variation
Objective Eliminate multiple Authority
Inspections of the same site. Reduce variability
in actionable Inspection observations
2
Global API Manufacture and Post Approval Changes
Regulatory Constraints Chris Dafforn
AstraZeneca chris.dafforn_at_astrazeneca.com
Clinical Trials Phase
II
III
NDA MAA
I
Formulation Line Extensions
Late Life Cycle Patent
Expiry
Key Events
Development for launch
Product Maintenance and life cycle support
including Generics
CD prenomination
Principle Testing
Concept Testing
Launch Phase
Typical Number of Registrations
150
300
1500

• Optimisation
• Scale
• Specification
• Starting Materials
• Retest dates

• IPCS
• Scale,
• Yield
• Telescoping
• Site changes
• Specification

• IPCs
• Yield
• Optimisation
• Scale
• Operating conditions

• Equipment
• Starting material sources
• Alternate routes
• Impurity profile (Quantitative)
• Analytical methods
• Outsourcing

• Synthetic route
• Impurity profile (Qualitative)
• Pharmacopoeial monograph

Typical Changes in API
150,000
500,000
750,000
Typical global fees cost per change
Change Inhibited
Drug Master Files
GMP Certification Inspection
Submission Detail
API Regulatory approval DMFs
Objective Eliminate multiple Authority
Inspections of the same site. Reduce variability
in actionable Inspection observations
Active Pharmaceutical Ingredients (APIs) are
produced for global supply there are a number of
interlinked constraints that prevent the
facilitation of continuous improvement due to the
Regulatory environment, which is shaped by
National or Regional requirements. These include
the application of GMP, the content of submitted
information, and the handling of changes through
the EU Variations system, the US Post-Approval
Changes supplements or the Japanese
notification/partial change system. Where prior
approval is necessary the delays can impact the
cost/benefit of implementation, divert management
time and act as an inhibitor of improvement.
  Suggestions for modest changes to the
Regulatory environment are made through the
medium of multiple cause and effect diagrams.
These are examples not an exhaustive list of
what could be changed and are believed to be
practicable in the context of the
responsibilities of Regulatory Authorities.
Encouragement of continuous improvement should
lead to benefits to the consumer through more
rapid introduction of beneficial changes, and to
the producers through operating efficiencies.
Objective Refocus the description of synthesis
and control to describe what needs to be
achieved and why. Use the description as an
example not an absolute recipe

• Proposal 3
• Eliminate or reduce Multiple Inspections of API
  manufacturing sites through Regulatory Mutual
  recognition of Inspections and GMP Certification
• What happens now
• Global supplies of API apply a harmonised
  standard (ICH Q7A) for GMP, but are subject to
  inspections for compliance by a number of
  Competent Authorities. When making submissions
  for new Product approvals, manufacturers may need
  to submit evidence of satisfactory GMP standards
  sometimes in the form of an Authority-issued GMP
  certificate.
• This results in
• Diversion of management effort to host multiple
  Inspections of the same manufacturing site
• Confusion as to the appropriate authority to
  issue a GMP Certificate
• Delays in approval of new sites leading to delays
  in approval of Post-Approval Change supplements
  or variations
• The burden of Inspection and Certification
  falling on a small number of Competent
  Authorities
• Variable, potentially conflicting responses by
  manufacturers to Inspectional observations.

Objective Eliminate multiple submission and
review of the same change through approval of the
master File, and eliminate the need for users of
the Master File to submit variation

• Proposal 1
• Refocus the description and Regulatory review of
  the synthesis and control to describe WHAT
  needs to be achieved and WHY. Use descriptions
  as examples and not as an absolute recipe
• What happens now?
• Reviewing chemist requires an increasing level
  of detail to understand the process this
  results in
• More detail that needs to be changed
• Greater chance of discrepancy between approved
  dossier content and actual practice
• Greater need for updating of approved dossier
• More chance of adverse inspectional observations
• Lack of trust that Manufacturer can exercise
  sufficient control over the process
• Deviations and recalls may be increased

• Proposal 2
• Introduce an approval process for the API
  synthesis and control which is separate from
  approval of the pharmaceutical dosage form
• What happens now
• A Drug Master File or Drug Substance Component
  of a submission is only approved as part of a
  Drug Product Approval.
• This results in
• Multiple approvals of the same change applied
  to one API used in many products approved in many
  global markets
• Multiple submissions of the same information over
  different timescales by different clients (Master
  Files)
• Separation of the accountability for compliance
  and the beneficiary of continuous improvement

What could be altered?
What could be altered?
What could be altered?

• Reviewing chemist is given an understanding of
  the extent of the work undertaken by the
  manufacturer to develop knowledge about the
  synthesis, the impact of variability, the
  significance of process controls and the impact
  on the product.
• This is achieved by
• Explaining the logic behind starting material and
  in-process controls
• Describing laboratory work performed to
  understand the consequences of variability of
  inputs in the process
• Defining the critical aspects of control
  methodology
• Improving the control over processes and input
  materials through the application of advanced
  analytical technology
• Performing root cause analysis on failures and
  applying analytical tools such as FMEA/HACCP to
  reduce risks to product quality
• The increased trust that the manufacturer can
  exercise control over the processes may result in
  the reviewing chemist demanding less descriptive
  detail which forms the basis of compliance

• Approve the details of the API synthesis and
  controls as a separate, independent Regulatory
  step
• To do this, it would be necessary to
• Ensure links to API characteristics and dosage
  form critical to quality specification
  parameters are explicit
• Ensure DMF holder and Product Authorisation
  holder (NDA, MAA) agree location of dosage form
  specific review-able information in the dossiers
  (eg particle size, microbial quality)
• Provide a Variation or Post-Approval Change
  system appropriate to Master Files, to include
  fees payable by Master File holder
• Changes and compliance with the Master File
  content become the accountability of the Master
  File holder, and the management of change
  projects including Regulatory approval is
  entirely within the control of one organisation.
• Mutual recognition of approval may become easier
  to implement

Change in Global API Manufacture is inhibited
because

• Harmonise the Inspection standards across
  Regulatory Competent Authorities and encourage
  global Mutual Recognition of Inspections and
  Certification. Reduce variability in corrective
  actions required.
• To do this it would be necessary to
• Educate and train Inspectors in common standards
  (ICH Q7A) with harmonised training courses
• Consider extending PIC(s) to include API
  Inspection
• Encourage Competent Authorities to agree a
  standard certification package
• Encourage competent Authorities to recognise the
  single global standard ICH Q7A and accept
  foreign certification
• This enables Management to focus less on
  correcting Inspection observations and more on
  implementing continuous improvement

• Regulations are National or Regional
• Different dossier content is filed in different
  markets
• Requirements for approval of changes differ from
  market to market
• Timings for approval of changes differ from
  market to market
• Manufacturer of API supplies to many marketed
  products, each of which requires prior approval
  of the same change
• Fees for approval of changes high in relation to
  benefits from small changes
• Definitions of starting materials varies, and
  consequences for GMP controls vary from market
  to market