BioProcess Lifecycle R&D to Commercialization Eileen Cortes - - PowerPoint PPT Presentation

Quality Application within BioProcess Lifecycle

R&D to Commercialization

Eileen Cortes February 5, 2018

Agenda

• Take Away
• Background: Baseline Concepts
• Process Development Lifecycle
• Application of Quality Practices by Phase of Development
• Quality by Design (QbD)
• Quality Risk Management (QRM)
• Process Validation
• CMOs
• Open Discussion

Take Away…

• How to live QUALITY throughout a BioProduct Lifecycle,

from its Introduction to its Commercialization.

• Identification of “how much Quality” within PD stages
• Identification of “Quality Risks” – Cumulative Risk Awareness
• Quality Control & Maintenance

Background

Internal Quality Program

Industry Guidelines & Standards

Law

Baseline Concepts

GxP Across the Organization

• GxP’s Building Blocks
• Basic Fixed Principles
• Record and Documentation requirements for the materials being

produced or processed

• Establishment of appropriate Quality Systems
• Variable Principles
• Contamination requirements and controls
• Facility Requirements
• Design Requirements
• Defect detection programs
• Monitoring of Process and Suppliers
• Material controls
• Validation and Qualification Practices

Baseline Concepts

Baseline Concepts

• Product Development Lifecycle
• During Clinical Phases of PD, supplies of a new drug are

manufactured.

• These IND’s (investigational new drugs) shall be safe for use in

humans and have the quality attributes necessary for an appropriate clinical product evaluation.

Product Development Process Development

In In pa parall llel What How

Commercially Feasible Process that is fully in compliance with cGMPs

• International quality

standard provided by ICH

• Reference: E6 Good Clinical

Practice

• Enforces tight guidelines on

ethical aspects of a clinical study.

• Comprehensive

documentation for the clinical protocol, record keeping, training and facilities including computer and software.

• Quality Assurance ensure

that these standards are met.

• GMP is a system for ensuring

that products are consistently produce and controlled according to Quality Standards.

• Enforce by the FDA to assure

safety and efficacy of drug products.

Baseline Concepts

GMP GCP

Process Development Lifecycle

Goal of Process Development

• Main Goal
• DESIGN, DEVELOP and CHARACTERIZE a PROCESS that can be

TRANSFERRED to a COMMERCIAL ENVIRONMENT

• SUPPORT a Manufacturing Process that will yield a Quality

Product on a CONSISTENT basis

• CONTINUE after approval to INCREASE PROCESS

UNDERSTANDING, IMPROVE Process throughout product life- time, MITIGATE risk of potential product defects and Disruption to Supply

How? Partnership -Integration of CMC and cGMP’s

*Figure for PDA Technical Report No. 56 “Application of Phase Appropriate Quality Systems and cGMP to the Development of Therapeutic Protein Drug Substance

Integration of CMC & cGMP Quality Systems

• Quality Systems in place to ensure that:
• CMC requirements are described in proper documentation submitted to

authorities to gain approval of clinical study start.

• cGMP requirements have to take the CMC requirements into account,

derived from regulations/guidelines that allows consistent production and testing of a quality product (purity, safety, potency). Product cGMP CMC

ICH Q8, Q9, Q10 & Q11

How CMC and cGMP can work together?

Focus Submission/Dossier Facility/Manufacturing/ Testing Industry Role Setting criteria and controls for manufacturing and quality Implementing manufacturing and testing practices designed to meet manufacturing and quality standards Guidance ICH Q1 to Q6 ICH Q7 Agency Role Assessment and approval of manufacturing and quality standards and controls Verification of conformance to cGMP and to regulatory submission/dossier standards through facility inspections; evaluation of quality system

Note: Validation summary data is included in regulatory application.

Quality Practices by Phase of Development

• Phase-Approach – 5 Stages

1. Research and Development – At Laboratory Environment 2. Toxicity Studies

• Effective documentation and characterization
• Similar/representative material

3. Phase 1 trials

• Goal: Start to show that quality has / is designed into the process

4. Phase 2 trials

• Goal: Increase Quality and cGMP expectations

5. Phase 3 trials

• Goal: Validated Processes, Methods and Controls

Application of Quality Practices by Phase

• f Development

cGMP & Quality per Phases

cGMP by Stage of Development

• Recommendations for the implementation of cGMP and

quality system for products under development through Phase 3 reflect a graded phase approach in where cGMP expectations increases as development approaches later phases.

• Recommendations are per FDA defined Systems:
• Facilities
• Equipment
• Materials
• Production
• Laboratory
• Packaging / Labeling
• Quality

cGMP by Stage of Development

System R&D Phase 1 Phase 2 & 3 Quality

• Quality

Management

• Documentation
• Product Release
• Change

Management

• Deviations/CAPA
• Auditing
• Quality

Agreements

• Personnel with

science background and trained in GLPs.

• Awareness of

GMPs.

• Failures should be

investigated to increase process knowledge.

• Quality Unit must be in place.

Product is release by QA/QP after satisfactory review of batch records and data, analytical results, COA, environmental and water results and compliance with IND registration.

• Responsibilities are governed by

cGMP.

• QA/QP ensures proper approval of

deviations and CAPAs.

• Quality standards in place.

Facilities

• Critical Utilities
• Non critical

utilities

• Water
• Process Gases
• Segregation/contai

nment

• Maintenance/Sani

tization

• Appropriate for

laboratory

• Use of high

quality water (WFI

• r RO), bioburden

reduction filtration with testing for endotoxin

• Facilities suitable for

intended use

• Critical utilities should be

qualified

• Facility cleaning and

sanitization program in place

• Facilities suitable for intended use.
• Includes:
• Controlled of

manufacturing areas, segregation, pressure differentials

• Critical utilities

should be commissioned and qualified

• PMs in place
• Alarm strategy in

place

cGMP by Stage of Development

System R&D Phase 1 Phase 2 & 3 Equipment

• Qualification
• Maintenance
• Cleaning
• Calibration
• Computerized

Systems

• Equipment

maintained, cleaned, and calibrated as per vendor recommendations

• Equipment should be

commissioned, calibrated, and monitored to ensure fit for use.

• Equipment used for process

should be sterilized by a validated process or sterile disposable equipment.

• Records of equipment

cleaning should be generated and maintained. Computer systems should be qualified for the intended use.

• Critical equipment should be fully

qualified prior to PPQ or process validation runs.

• Preventive maintenance,

cleaning/sanitization/sterilization process and calibration program should be in place and fully documented per ICH Q7.

• Cleaning/sanitization/sterilization

should be validated prior conformance lots.

• Computer systems for critical GMP

equipment should be validated.

• Alert and action alarm limits for

deviations from set points and process parameters should be defined based on risk assessment.

cGMP by Stage of Development

System R&D Phase 1 Phase 2 & 3 Materials

• General controls
• Receipt &

Quarantine

• Sampling and

Testing

• Storage and

expiry

• Warehouse

procedures

• Supplier

Qualification

• CoA and expiry
• Incoming items and

documentation (logbooks)

• Equipment/Units

used with regular calibration/mainten ance

• Good controls over

materials is required to ensure proper receipt, storage, release and integrity.

• Release of materials based
• n CoA
• Same controls from phase 1
• Suppliers should be fully qualified

cGMP by Stage of Development

System R&D Phase 1 Phase 2 & 3 Production

• Production
• perations
• Hold Times
• In process

sampling and controls

• Pooling criteria
• Contamination

controls

• Cross-

contamination controls

• Quality by Design
• Routine

documentation and quality practices

• Procedures and

Equipment logs

• Area Clearance and

segregation

• Reliability of

suppliers

• Process and equipment

scaled based on size of projected clinical batch.

• Batch records most capture

process steps and main data.

• IPC should be recorded (note:

acceptance criteria for in- process controls and results are not yet set).

• Initial acceptance ranges

defined for CPPs.

• Process flow charts.
• Same as Phase 1
• Acceptance ranges for CPPs should

be established

• Batch records should be

implemented

• Acceptance ranges for IPC should

be defined

cGMP by Stage of Development

System R&D Phase 1 Phase 2 & 3 Laboratory

• General

Controls

• Testing

intermediates and bulk

• Validation of

analytical methods

• Expiry and

retest dating

• Reserve and

retention samples

• Quality by Design principles

should be applied to the selection, development and qualification of appropriate assays

• Expiry and storage of assay

reagents can be set per vendor recommendations

• Reserve samples should be

sufficient to bridge equivalency to subsequent batches

• Lot in process and

stability testing as per regulatory dossier

• OOS results are

investigated with QA/QP focusing on root cause

• Analytical instruments

calibrated and on PM

• System suitability tests to

be part of the testing methods

• Method qualification

should be initiated

• Safety / critical assays

should be validated

• Assays procedures and

results are recorded (i.e. LIMS)

• Analytical results, CoA are

review/approved by QA/QP

• Phase 2:
• Same as Phase 1 plus

Method Qualification

• Phase 3:
• Same as Phase 1 and 2

plus:

• In process and stability

data is implemented

• OOS investigation should

comply with regulatory requirements

• Analytical validation should

be at an advance stage or completed

• Reserves samples are

sufficient

cGMP by Stage of Development

System R&D Phase 1 Phase 2 & 3 Packaging/ Labeling

• General

Controls

• Packaging

materials

• Label

issuance and control

• Packaging

and labeling

• perations
• Considerations to

appropriate packaging for shipping

• Assessment of proper

containers and labels

• Containers are labeled

with lot number, ID, dates.

• Storage conditions should

be in place as applicable.

• Labeling operation should

be controlled.

• Packaging components be

demonstrated to be suitable for their intended use

• Components have an approved

specification

• Labeling operations

controlled/qualified.

Quality by Design

QbD

• Definition:
• ICHQ8: A systematic approach to development that begins with

predefined objectives and emphasizes product and process understanding, based on sound science and quality risk management.

• FDA: Quality by design means designing and developing

manufacturing processes during the product development stage to consistently ensure a predefined quality at the end of the manufacturing process.

• Take Away:
• Central to the implementation of QbD is a structured and

rigorous approach to product and process development that results in a detailed understanding of the factors that influence clinical efficacy, and a manufacturing control strategy based on the mitigation of risk.

QbD

• That means:
• A Solid Process Development Program
• A Solid Risk Management Program
• Applicability
• Abbreviated New Drug Applications (ANDA)
• Starting Point
• QTPP – Quality Target Product Profile
• Specifications relating to quality, safety, and efficacy
• Questions to Ask:
• How will the drug be delivered -- in what form and at what concentration?
• What is the required bioavailability of the drug and how will this be

controlled?

• How will stability be maintained, both during manufacture and in the

finished product?

QbD

• CQAs
• Variables that directly influence clinical efficacy and quality
• i.e. post-translational modifications, microbiological properties, and

product purity

• Assessment of Risk Associated with each CQA
• What to Ask:
• What is the magnitude of risk associated with a given CQA – is there a

broad or a narrow window of acceptability that will result in the QTPP being met?

• What analytical techniques can be used to provide timely, sufficiently

accurate data to monitor CQAs?

• What controls need to be put in place to ensure that defined

specifications for the CQAs are adhered to?

QbD

• Challenges
• Silo Departmentalization
• Little experience of QbD application
• Complexity and heterogeneity of Bio Products
• Successful development and application of biologics is evolving
• Making difficult to have robust CQAs that are linked to CMAs and

CPPs to support scale up and Tech Transfer

• Others:
• Ease of product characterization
• Process variability
• Stability
• Analytical Instruments

QbD

• QbD Implementation
• Following PD lifecycle
• Define Space
• Clinical
• quantify the clinical experience with a product
• multidimensional design space, with each CQA serving as a dimension
• Outcome: product and process knowledge as clinical data become available
• Product
• quantify product quality
• multidimensional design space with each CQA serving as a dimension
• Outcome: Regulatory filing – in process, DS and DP specifications that would

define the acceptable variability in CQAs

• Process
• process characterization studies can be used to define the acceptable variability

in process parameters

• provides the 'assurance of quality‘
• Outcome: Acceptable ranges are identified and documented in Regulatory

Filing

QbD

• Process Flow Example

Quality Risk Management

QRM

• QRM at Initial Stage
• acquire sufficient product and process knowledge to assess risks

associated with formulation development of the finished pharmaceutical product (FPP) according to the QTPP

• QRM at Development Stage
• determine and manage risks to bioavailability, safety, efficacy and

product quality

• QRM in development should differentiate process parameters

and quality attributes from critical process parameters (CPPs) and critical quality attributes (CQAs), thereby contributing to defining and refining the control strategy

QRM Process

• Initiation
• define the problem and/or risk question, including pertinent

assumptions identifying the potential for risk;

• assemble background information and/or data on the potential

hazard, harm or human health impact relevant to the risk assessment;

• identify a leader and the necessary resources;
• specify a timeline, the deliverables, and an appropriate level of

decision-making for the risk management process.

• Quality Aspect: Internal SOPs should define steps,

stakeholders, roles and responsibilities (governance and management responsibilities)

QRM Process

• WHO?
• Multidisciplinary team is highly recommended to perform the

following:

• conduct a risk analysis;
• identify and analyze potential risks;
• evaluate risks and determine which ones should be controlled and

which ones can be accepted;

• recommend and implement adequate risk control measures;
• devise procedures for risk review, monitoring and verification;
• consider the impact of risk findings on related or similar products

and/or processes.

• Quality Aspect: QRM activities should be defined and

documented.

QRM Application

• QRM during Product Development
• The first QRM exercise should be performed once the QTPP is

defined and pre-formulation work on the product is complete.

Note: At this stage of a project there may be significant gaps in

• knowledge. Therefore, it will be important to apply risk tools that are

appropriate for such a situation.

• Risk Tools:
• cause and effect diagrams (also known as Ishikawa or Fishbone

diagrams);

• flowcharts (e.g. input-process-output (IPO));
• decision-trees;
• fault-tree analysis;
• relationship matrices.

• Product Development Advances
• More detailed analysis of the risks associated with both the active

pharmaceutical ingredient (API) and the FPP should be considered.

• Risks would cover concerns associated with stability, bioavailability

and patient safety including any challenges to these areas resulting from the manufacturing process (including, for example, API form conversion under certain conditions of processing).

• Product Knowledge Advances
• Detailed QRM exercises
• concentrating on areas considered to present higher priority risk.
• Developed Product
• Comprehensive risk assessment will support a thorough

understanding of the product and will enable all key variables to be identified, understood and controlled.

• Validation & Qualification
• QRM methodology based on process/product knowledge through

the Lifecycle

QRM Application

• Commercial Manufacturing
• Risk assessment and risk control during the life-cycle of a product:
• product quality risks;
• adverse impact on patient health resulting from product quality defects;
• interruption of product supply to patients;
• GMP and regulatory compliance risks;
• multisite risks;
• multiproduct risks;
• new facility and changes to existing facility, e.g. start-ups, new commercial

manufacturing processes, technology transfers and product discontinuation.

• Quality Aspect: outcomes should be summarized, documented and

appropriately communicated (approved)

• Risk Review
• effectiveness of risk control activities and actions;
• changes in observed risk levels or existing controls
• Areas of Focus
• system focus
• process focus
• product focus

QRM Application

• Integration with Quality Systems
• Integrated quality management:
• documentation
• training and education
• quality defects
• auditing and inspection
• change management and change control (includes equipment, facilities, utilities, control and IT systems)
• continual improvement and corrective and preventive actions (CAPA);
• Facilities, equipment and utilities:
• design
• qualification
• maintenance and decommissioning of facility or equipment
• hygiene aspects
• cleaning of equipment and environmental control
• calibration and preventive maintenance
• computer systems and computer-controlled equipment;
• Supplier, materials and contract service management:
• assessment and evaluation of suppliers and contract manufacturers
• starting material
• use of materials
• storage
• logistics and distribution conditions;
• Technology transfer:
• from development to manufacturing
• during commercial manufacturing between sites
• from commercial manufacturing to product discontinuation.

QRM Application

• Product Manufacturing Operations
• Production:
• manufacturing process risks
• Validation
• in-process sampling and testing controls
• production planning
• deviation and investigation management
• change management;
• laboratory control and stability studies:
• ut-of-specification results
• retest period and expiry date
• method transfers;
• packaging and labelling:
• design of packages
• selection of container-closure system
• label controls;
• storage, transport and distribution:
• cold chain.

QRM Application

Process Validation

Process Development and Validation

• Process Development

and Validation

• per FDA’s 2011 guidance

Validation includes…

• “the collection and

evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product”

Clinical Phases & Validation

Process Validation Stages

STAGE 1: PROCESS DESIGN

• The following deliverables are prepared based on historical data, process

development, and characterization studies

• Critical Quality attributes (CQA)
• Process Description
• Parameter Justification Report (PJR)
• The following exercises are performed to evaluate process parameters and

material attributes that have potential impact on CQAs and to identify any validation gaps

• Detailed Process Risk Assessment (FMEA)
• Validation Gap Assessment
• Identified risks and validation gaps are mitigated as described in Process Risk

Mitigation Plan (PRMP) and subsequent Report (PRMR)

• The Criticality Assessment (CA) is the summary of the cumulative knowledge

for the manufacturing process through the process design stage

Process Validation Stages

STAGE 2: PROCESS PERFORMANCE QUALIFICATION

• Validation protocols are created in order to evaluate process acceptance

criteria, critical process parameters, and parameters identified in the criticality assessment document

• Sampling plans are detailed in each validation protocol including sampling

points, number of samples, and frequency of the sampling

• Before starting PPQ activities, an evaluation of pre-requisites is required

following the Stage 2 Checklist (recommendation: per SOP)

• Process validation reports are written to summarize the following
• Activities performed
• List of deviations or non-conformances
• Sample results, CPPs and KOPs
• Any recommended monitoring or corrective actions

Process Validation Stages

STAGE 3: CONTINUED PROCESS VERIFICATION

• Monthly review of products produced to provide continued assurance that

manufacturing process remain in control during commercial manufacturing

• Attributes and parameters are defined in the respective Criticality

Assessment

• Critical quality attributes (CQAs)
• Critical process parameters (CPPs)
• Key operational parameters (KOPs)
• Critical material attributes (CMAs)
• Packaging parameters (if applicable)
• Routine data analysis includes control charts and capability analysis
• Statistical analysis include Pareto, Multivariate, Change Point, Control Charts, etc.

Process Validation Flow

Guidelines for Drug Substance PPQ

Guidance documents provided by FDA, EMA, & ICH are clear on drug substance PPQ/PV. It is a mandatory requirement for the marketing application (BLA, MAA). The following guidelines address this:

47

Guidance Document Reviewed Regulatory Body Level of Detail in Guidance Output/ Recommendation Info Provided On Pg(s).

Submission of CMC Info for a MAb for In Vivo Use (1996) FDA (CBER & CDER) High-level assessment Provide description & documentation of the validation studies of cell growth & harvest, purification, microbiology, & steps to remove/inactivate viruses. 14 Guideline on PV for the Manufacture of Biotech- Derived Active Substances & Data to be Provided in Regulatory Submissions (2014, Draft) EMA (CHMP) Detailed assessment Prospective PV is expected. Validation data should be generated and provided in MAA for production (commercial) scale batches. All Q11: Development & Manufacture of Drug Substances (2012) ICH High-level assessment PV results on both commercial-scale and small scale studies typically performed for biologics. 12-13

Guidelines for Drug Product PPQ

Guidance documents provided by FDA & EMA are clear on drug product PPQ/PV. Certain aspects of drug product manufacturing are required at time of marketing application submission (BLA, MAA), while remaining aspects should be available no later than PAI. The following guidelines address this:

48

Guidance Document Reviewed Regulatory Body Level of Detail in Guidance Output/ Recommendation Info Provided On Pg(s).

Submission of CMC Info for a MAb for In Vivo Use (1996) FDA (CBER & CDER) High-level assessment C of As & analytical results for at least 3 consecutive lots should be included. 19 Submission of Documentation for Sterilization Process Validation in Applications for DPs (1994) FDA (CDER & CVM) High-level assessment Focus is on drug product aseptic processes including: DP solution filter validation, DP solution hold times, critical operations that expose DP to environment, media fills, etc. 11-17

• Guideline on PV for

Finished Products – Info & Data to be Provided in Regulatory Submissions (2014)

• EudraLex, Vol. 4,

Annex 15 EMA (CHMP & CVMP) European Commission Detailed assessment Detailed assessment Validation data should be generated and provided in MAA for production (commercial) scale lots for at least 3 lots, unless otherwise justified. One or 2 full-scale runs may suffice w/ pilot scale runs and justification for not needing 3 full-scale runs. 4-7 6-10

Guidelines for Stability to be Included in Marketing Application

49

Guidance Document Reviewed Assessment Output/ Recommendation Detailed Summary of Info Provided In

Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product of a Monoclonal Antibody Product for In Vivo Use (CBER & CDER, Aug. 1996) Cross-references ICH quality guideline for specific requirements 3 consecutive batches, preferably at commercial scale and in final container closures

• Pgs. 25, 28 of PDF

ICH Q5C DRUG SUBSTANCE and DRUG PRODUCT A minimum of 6 months stability data at the time

• f submission should be

submitted in cases where storage periods greater than 6 months are requested. Note: Our primary stability should suffice to establish our shelf-life DP batches should be made with different BDS “where possible”

• Pgs. 2-3 of PDF

Guidelines for Stability to be Included in Marketing Application

50

Guidance Document Reviewed Assessment Output/ Recommendation Detailed Summary of Info Provided In

ICH Q5C DRUG SUBSTANCE and DRUG PRODUCT Data from pilot-plant scale batches produced at a reduced scale may be provided at the time the dossier is submitted to the regulatory agencies with a commitment to place the first 3 manufacturing scale batches into the long-term stability program after approval. DRUG PRODUCT Product expiration dating will be based upon the actual data submitted in support of the application. Since dating is based upon the real-time/real- temperature data submitted for review, continuing updates of initial stability data should occur during the review and evaluation process. Stability information should be provided on at least 3 batches of final container product representative of that which will be used at manufacturing scale. Note: Our primary stability should suffice to establish our shelf-life DP batches should be made with different BDS “where possible”

• Pgs. 2-3 of PDF

External / CMO

CMO: Contract Manufacturing Organization

• Choice of a good CMO is extremely important. CMO shall be

selected and managed with care and attention.

• Examples of variables to take into consideration:
• Strength of scientific teams
• Available technologies
• Available capacity
• Ability to manage multiple clients
• Typical lead times for production, including time to supply

relevant data to agencies or clinical trial application

• Strength in Project Management
• Regulatory Agency inspection status and results
• Strength of Quality Systems

Q&A Open Discussion

Thank You!