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1/26
Product Control Strategy and
Risk Management
Presented by: Karen S. Ginsbury
October 31, November 02, 2017
For IFF
2/26PCI Pharmaceutical Consulting Israel Ltd.
Product Control Strategy and Risk
Management
• Developing a Target Product Profile
• Product Specification File
• Initial risk assessment = Preliminary Hazard Analysis
• Company Strategy for controlling material to be used to generate data for use in regulatory submissions: pre-clinical toxicology, phase 1 – 3
• Product specific control strategy
3/26PCI Pharmaceutical Consulting Israel Ltd. 3/98
Product Design and GMP
“The system of QA appropriate for the
manufacture of medicinal products should
ensure that:
– medicinal products are designed and
DEVELOPED in a way that takes into
account the requirements of GMP..”
From the “Orange Guide” / EU cGMPs
Chapter 1, page 1 Quality Management
4/26PCI Pharmaceutical
Consulting Israel Ltd
GMP
ICH Q10 Pharmaceutical Quality System
Pharmaceutical
Development
Commercial
Manufacturing
Product
Discontinuation
Technology
Transfer
Investigational products
Management Responsibilities
Process Performance & Product Quality Monitoring System
Corrective Action / Preventive Action (CAPA) System
Change Management System
Management Review
PQS
elements
Knowledge Management
Quality Risk ManagementEnablers
Annex 2
Diagram of the ICH Q10 Pharmaceutical Quality System Model
ICH Q10 PQS model
5/26PCI Pharmaceutical Consulting Israel Ltd. 5/98
The Goal and Characteristics of
Pharmaceutical Quality Decision
System
“The quality of drug substances and
drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specificationsapplied to them throughout development and manufacture.”
Characteristics
Goal
Life-cycle
ICH Q6A
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ICH Quality Vision (July 2003)Q8, Q9, Q10 – The Trilogy
“Develop a harmonized pharmaceutical
quality system applicable across the life
cycle of the product emphasizing an
integrated approach to quality risk
management and science.”
PCI Pharmaceutical Consulting Israel Ltd
7/26PCI Pharmaceutical Consulting Israel Ltd. 7/ 108
LIFECYCLE QUALITY SYSTEMS MODEL
Patient
NeedsPatient
Satisfaction
Quality by
Design
Knowledge &
Technology
Transfer
Qualification
& Validation
Change
Mgmt
Measurement
Analysis
CA/PA
Innovation
Products
Processes
Facilities
Systems
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QbD Definition
• Quality by Design: A systematic approach
to development that begins with
predefined objectives and emphasizes
product and process understanding and
process control, based on sound science
and quality risk management
PCI Pharmaceutical Consulting Israel Ltd
9/26PCI Pharmaceutical Consulting Israel Ltd80/9
Definitions: Quality Target Product
Profile• A target product profile is a prospective
and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realised
• The target product profile forms the basis of design for the development of the product
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Quality Attribute Target
Route of
administration
Oral
Dosage form Capsule, size 2, maximum fill weight 280mg
Strength 0.6mg
Packaging Securitainer, plastic cap and alu overseal, dessicant
Stability 3 yrs at room temperature
Pharmacokinetics Immediate release enabling tmax in 2 hours or less
Appearance White opaque cap and body, hard gelatin capsule
filled with white to off-white granulate
Assay 90-110%
Impurities Impurity A: NMT 0.5%, Impurity B: NMT 0.5%
Total Impurities: NMT 2%
Content Uniformity Meets USP
Dissolution NLT 70% of labeled amount is dissolved in 30 min :
(500 ml water; USP apparatus II {paddles}; 50 rpm)
Microbiology Meets USP criteria (NMT 1000cfu /g; 100cfu fungi)
11/26PCI Pharmaceutical Consulting Israel Ltd80/11
Control Strategy: Definition
• A planned set of controls, derived from current product and process understanding, that assures process performance and product quality
• The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control (ICH Q10)
12/26PCI Pharmaceutical Consulting Israel Ltd80/12
Definitions
Critical Quality Attribute (CQA):
• A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
Critical Process Parameter:
• A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality
13/26
Definitions: PAR
• Proven Acceptable Range:
A characterised range of a process
parameter for which operation within this
range, while keeping other parameters
constant, will result in producing a material
meeting relevant quality criteria
• A process should perform consistently and
as intended when all critical parameters
are held within the established PARs
PCI Pharmaceutical Consulting Israel Ltd
14/26PCI Pharmaceutical Consulting Israel Ltd
Control Parameters vs CQAs
Process Control Parameters– Risk assessment can be used
to identify material attributes and process parameters that can affect CQAs
– Risk assessment tools can be used to identify and rank parameters (e.g., operational, equipment, input material) with potential to have an impact on product quality based on prior knowledge and initial experimental data
– Batch production records are developed with paramter ranges designed to ensure the CQAs are achieved
Critical Quality Attributes– physical, chemical, biological,
or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
– CQAs are generally associated with the drug substance, excipients, intermediates, and drug product
– Drug product CQAs include the properties that impart the desired quality, safety, and efficacy
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Product Specification File – Annex 13
• A reference file containing, or referring to
files containing, all the information
necessary to draft the detailed written
instructions on processing, packaging,
quality control testing, batch release and
shipping of an investigational medicinal
product
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Product Specification File – Annex 13
• Should be continually updated during development to allow traceability to previous versions (audit trail)
• Includes (but not necessarily limited to):– Specifications and analytical methods for starting materials,
packaging materials
– intermediate, bulk and finished product
– Manufacturing methods
– In-process testing and methods
– Approved label copy
– Relevant clinical trial protocols and randomisation codes
– Relevant technical agreements with contract givers
– Stability data
– Storage and shipment conditions
17/26
Product Specification File – Annex 13
• The contents will vary depending on the product and stage of development
• The information should form the basis for assessment of the suitability for certification and release of a particular batch by the Qualified Person and should therefore be accessible to him/her
• Where different manufacturing steps are carried out at different locations under the responsibility of different
• Qualified Persons, it is acceptable to maintain separate files limited to information of relevance to the activities at the respective locations
18/26PCI Pharmaceutical Consulting Israel Ltd80/18
Risk Assessment in R&D: Control Parameters
Ishikawa (Fishbone) Diagram
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Q8 R1: Risk Management in R&D
• A cross-functional team of experts could work together to develop an Ishikawa (fishbone) diagram that identifies all potential variables which can have an impact on the desired quality attribute
• The team could then rank the variables based on probability, severity, and detectability using failure mode effect analysis
• (FMEA) or similar tools based on prior knowledge and initial experimental data
• Design of experiments or other experimental approaches could then be used to evaluate the impact of the higher ranked variables, to gain greater understanding of the process, and to develop a proper control strategy
20/26PCI Pharmaceutical Consulting Israel Ltd80/20
How Far to Go?
Design Space Versus Proven Acceptable Ranges
• A combination of proven acceptable ranges does not constitute a design space.
• However, proven acceptable ranges based on univariate experimentation can provide some knowledge about the process.
Design Space and Edge of Failure
• It can be helpful to know where edges of failure could be, or to determine potential failure modes
• It is not an essential part of establishing a design space
21/26PCI Pharmaceutical Consulting Israel Ltd80/21
Control Strategy
• A control strategy is designed to consistently
ensure product quality
[get ready for lifecycle process validation]
• describe and justify how in-process controls and
the controls of:
– input materials (drug substance and excipients)
– container closure system
– intermediates and end products
• contribute to the final product quality
22/26PCI Pharmaceutical Consulting Israel Ltd80/22
Control Strategy
• Controls should be based on product, formulation and process understanding and should include, at a minimum, control of the critical parameters and attributes
• A comprehensive pharmaceutical development approach will generate process and formulation understanding that identifies sources of variability
• Critical sources of variability that can lead to product failures should be identified,appropriately understood, managed or controlled
23/26PCI Pharmaceutical Consulting Israel Ltd80/23
Control Strategy
• Understanding sources of variability and their impact on downstream processes or processing, intermediate products and finished product quality can provide flexibility for shifting of controls upstream and
• minimise the need for end product testing
• Control of process parameters allows variability of raw materials to be compensated for in an adaptable process to deliver consistent product quality
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Elements of a Control Strategy
• Control of input material attributes (e.g. drug substance, excipients, primary packaging materials) based on an understanding of their impact on processability or product quality
• Product specification(s)
• Controls for unit operations that have an impact on downstream processing or end-product quality (e.g., the impact of drying on degradation, particle size distribution of the granulate on dissolution);
• In-process or real-time release in lieu of end-product testing;
• A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models
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Q8, Q9 and Q10
PCI Pharmaceutical Consulting Israel Ltd 25/115
Knowledge Space
Knowledge Space
Input variables or
process parameters
with no effect on
CQAs
All that is
known to fail to
meet the CQAs
Normal
Operating
Range
Design Space
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Using Q1 – 10 in developing a
Control Strategy• Incremental GMPs
• Updated risk assessment as knowledge grows
• MUSTS = safety e.g. packaging controls, equipment qualification, other?
• Negotiable:
– amount of methods validation
– Characterisation of reference material
– Cleaning (verification)
– Supplier qualification ?
– Microbiology (Q6)
– Other?
PCI Pharmaceutical Consulting Israel Ltd