Product Control Strategy and Risk Management -...

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Product Control Strategy and

Risk Management

Presented by: Karen S. Ginsbury

October 31, November 02, 2017

For IFF

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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

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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

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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

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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.”

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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

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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)

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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?

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