3/10/2018

Process Validation
PV for Tech Transfer and
Contract Manufacturing.

Maurice Parlane
ISPE PV Team
CBE Pty Ltd

ISPE Indonesia/ISPE Singapore 2018

Agenda
• PV with Tech Transfer and CMOs
• Quality Agreements and change management
• PV Considerations in Tech Transfer
• Phase specific PV considerations for CMOs

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PV Deliverables
• Process Design/Stage 1 = define the process, plan knowledge
transfer and communication
Deliverables = patient/product knowledge; Development report
including initial Control Strategy
• Process Qualification/Stage 2 = evaluation of process,
equipment selection and qualification and agreeing PV/PPQ
approach.
Deliverable = Product specification and Control Strategy;
Process Validation report demonstrating process control
• CPV/OPV/Stage 3 = agree reporting and data flows
Deliverable = product and data; Evidence of robustness

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Tech Transfers and CMOs

Common issues to Tech Transfers and CMOs

• Differentiating responsibility for each stages between
receiving party and giving party
• Process knowledge transfer mechanisms
Particular to CMOs
• Implementing quality systems that allow
flexibility for CMO approaches
• Generating a quality agreement that
captures the elements of validation

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Quality Agreement structure

• FDA guidance on quality agreements (2017)

• EU (PIC/S) Chapter 6 (methods) and Chapter 7
• Suggest detailed RACI matrix
• Roles may differ for CMO and Tech transfer
• Responsibilities for generating and approving plan
• Responsibilities for generating and approving validation
protocols and reports should be defined
• Both parties to agree key roles
• Man in the plant?
• Right of access
• SMEs identified
• Change management

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Change Management

Clearly define
• What is a change?
• How will it be evaluated if knowledge is shared.
• How will significant changes will be evaluated
• What is the baseline
(control specifications)
• Responsibility for raw
materials/samples?

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Tech Transfer Plan

Key considerations for a successful tech transfer
• Develop early Agreement between sending and receiving unit
• Sending unit and receiving unit work closely
• Clear understanding of roles and responsibility of both sending
unit and receiving unit team members
• Effective knowledge transfer/training
- Scientific
- Regulatory
- Operational
- Business
- Cultural
• Information Package
• Quality Risk Management
• Stage Gate approach

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Tech Transfer PV Strategy

• Based on process development history, prior experience and
quality risk assessment
• Development and approval of receiving unit manufacturing
instructions (batch records, SOPs, automation recipes etc)
• Implementation of small scale models at receiving unit
• Process training
• Creation of processing models and data trending template
• Identification of in-process controls for monitoring
• Generation of sampling plans
• Justify number of lots (may be <3 for comparability and stability)
• Control strategy finalized prior to PPQ or verified during PPQ
• Materials from qualified vendors to challenge robustness

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Tech Transfer Plan

Initial knowledge transfer (for validation)
• Flow charts
• Define CQAs and include QdD data and historical information
• Detailed manufacturing process, CQA/CPP matrix
• Risk evaluation
• Initial Control Strategy or plan
• Statistical detail and initial variation predictions/limits
• Review to ensure information is clear
Also consider/define
• Define responsibilities for document collection supporting PV
• Analytical method comparability
• Process design summary report and raw data samples
• Process comparability and review methodology

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CMO specific considerations for Stage 1

• Agree the process design approach (CMO

may differ)
• Contract giver should not impose their
systems just because CMO is different –
show equivalence
• Review CMO procedures for risk, model
qualification and process characterisation
• Agree QbD tools
• Control Strategy is required as a
deliverable

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Stage 2 Considerations

• Assessing risks in capabilities

and process controls
(consider engaging CMO/Site SME)
• Alignment of qualification
standards/techniques. (likely to be more
significant with CMO)
• Commit to a control strategy
• Statistical models/tools and acceptance
criteria
• Specific validation considerations relating
to scaling or transfer process.

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Stage 2a Planning

• Revisit risk assessment following clarification on process

• Qualification strategy/plan. Need to ensure alignment to
control strategy and risk assessment.
• Do not impose your own standards unless the program is deficient
• Ensure responsibilities for review/approval cover all parties in the
qualification project
• Higher emphasis on traceability to Critical Aspects
• Alarm strategy, deviation and intervention procedures
• Cleaning validation – other products at receiving site
• Pass all relevant technical information to CMO/transfer site

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Stage 2b Planning
• Agree on PPQ/PV strategy (# batches) and criteria for
entering Stage 3
• Many stakeholders; particularly if concurrent. Identify team
• Agree roles and acceptance criteria
• Large teams – use RACI
• Failure avoidance… consider assessment of gaps/history
from Stage 1 to Stage 2
• What has changed?
• Do we demonstrate control?
• Can stage 1 data support stage 2 validation/control
• Agree confidence and coverage levels
• Responsibilities for joint validation summary report
• Stability and transport requirements for materials

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Stage 3 Considerations

• Monitoring strategy based on PPQ/PV

summary report
• Sampling plans and reporting alignment
• GMP dataflows for Primary Records
• Responsibilities for trend identification
and response
• Management of continual improvements
(do you reward improvement?)
• IP considerations in technology
improvements

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Stage 3 Planning

• CQA Monitoring Plan is a shared document

• Review history and issues reported at MAH
• Review CMOs process steps and any issues/root cause
• Agree triggers
• Identify responsibility for identifying trends
• Tools and reporting format
• Reporting schedule
• Continuous improvement goals
• Reports for batch disposition

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Stage 3 business considerations

• Responsibilities for investment (incentives)

• Continual improvement measurement criteria if
performance targets are to be set
• Ownership of IP
for improvements

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SUMMARY
• Manufacturing operations which are outsourced are
expected to comply with PV requirements
• Lifecycle PV places increased emphasis on knowledge
management and planning for
tech transfer or CMOs
• Additional risk assessment steps
are warranted when responsibility
for manufacture is external

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Process Validation

Future trends in PV

Maurice Parlane
ISPE PV Team
CBE Pty Ltd

ISPE Indonesia/ISPE Singapore 2018

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Industry Trends

PV Landscape
• Innovator companies rapidly accelerating methods and
techniques in this area
• Legacy products slow to adopt, low capability processes
• CY 2017 US FDA commonly citing companies for lack of
OPV program
• Tendency to develop Design Space, but only register
PAR or PAR and NOR.
• 1-2-3 approach vs 3-1-2 approach
• Differentiation of Clinically Relevant CQAs

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ICH Developments

ICH Q12 – Under Industry Review

• The “Robust PQS” model.
• Link PQS to Established Conditions, so change can
occur within PQS (reduced regulatory oversight)
• Recognizes regional differences between assessment
of submissions
• Assumes sponsor will register PAR or Design Space
• Industry caution = may bring GMP type oversight to
parts of Stage 1

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FDA Developments
Quality Metrics
• July 2012 US FDA Safety and Innovation Act (FDASIA)
required a risk-based inspection program.
• Sections 704, 705 & 706 relate to provision of information
(quality metrics) to enable this
Section 704 – “any field of information submitted in a registration”
Section 705 – “risk-based schedule” including the following “risk factors”
A. Compliance history
B. Record, history and nature of recalls
C. Inherent risk of the drug
Process Capability suggested as a future metric but no
definition given for its derivation

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New ISPE PV discussion papers

Further PV Discussion Papers

• Detailed Packaging Validation – Techniques specific to
packing of drug products
• PV for Continuous Manufacturing – specific PV
techniques for scale and accounting for “batches”
• PV for Breakthrough Therapies – expedited data
submissions

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ISPE Process Capability Team

1. Performance and compliance

applications

ISPE Process
Capability 2. Statistical considerations
Team

3. Maturity model development

Develop a position on process capability as a performance indicator

and/or compliance metric reportable to FDA
Consider implementation challenges in use of statistics
Develop maturity model to allow comparability and self assessment

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ISPE Process Capability Team

Process Capability Maturity
Highlight areas for improvement starting from a current level
and moving to a target level. Nine categories
• Policy – SOPs are established
• Data Management – systems for collection and accessing data
• Frequency – how often capability
• Basis for Specification – manner in which specs are developed
• Calculation consistency
• Response – thresholds for action
• Organization skill set and execution
• Risk-based context – part of the overall QRM framework
• Commercialization – data used at launch

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ISPE Process Capability Maturity Model

• For each of the 9 maturity categories, five levels of

maturity are established
• Calculate current value (Cv) and future value (Fv) for each
element
• Prioritisation (delta)
= Fv - Cv

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QUESTIONS?

Maurice Parlane,
Director, CBE Pty Ltd
www.cbe-ap.com.au
 +64 21 650 692
 maurice.parlane@cbe-ap.com.au

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