Validation and Quality by Design

Richard Francis

Francis Biopharma Ltd

Validation and Quality by Design - Overview

Week 01 (Slides 1 – 85)

Validation and QbD introduction

Validation in depth

Week 02 (Slides 86 – 157)

QbD and scale down process models

Week 03 (Slides 158 – 245)

Risk and Process Control

The long Path of product development

In vitro and in vivo biology

Molecule synthesis/expression

Formulation

PK and drug metabolism

Safety assessment

Process Development

Clinical Manufacturing

Years 1 through 7 Years 8 through 15

ScreeningSelectleads

optimise Pre-IND Phase I Phase II Phase III marketDiscovery

Clinical Development

Medical Affairs

Sales and Marketing

Formulation development

PK and drug metabolism

Safety assessment

Clinical and commercial manufacture

Process development – The old paradigm

Rapid generic platform

Non optimised process

Process experience < 10 batches total, no multivariate

linkage

Product Characterisation limited typically to three PQ

batches

Not a solid foundation for a commercial manufacturing

operation

Limited if no opportunity for process change and

improvements

Not “Rubbish by Accident” more constraint by delaying in-

depth development till phase III clinical studies

The Quality by Design method allows for systematic

approach and facilitates product and process understanding

Product Life Cycle – Industry perspective

Target Product Profile

• Clinical Development• Process / Product Characterisation• Phase I – III clinical manufacture

Commercialization

• ProcessValidation• Process Control Strategy• Regulatory Approvals

Market Supply• Return on Investment• Capacity Expansions• TechTransfers• Process Improvements

Product termination

Up to 10 years

Up to 20 years

Up to 2 years

QbD – High level concept

The core of QbD is essentially map making

Development of the information pool

This is all about generation of product and process

knowledge using sound scientific principles

Process and product characteristics to be mapped

out

Definition of controllable, safe, robust and profitable

areas of operation for routine manufacture

This is an activity set also known as “Process

Development”

The path of Process Development

Process Development• Establish QTTP• Identify CQAs• Define manufacturing process shape /

steps• Define analytical methods• Identify knowledge gaps• Initiate preliminary product degradation

studies

Process Characterisation• Clinical batches and Scale up• Technology transfer• Quality risk assessment of primary

process parameters• Process characterisation studies

(DOE)• Final Process parameter's definition• Operational Space defined in Design

Space• Preliminary Process Control Strategy

approved

Commercial ProcessQualification

• Implement process control strategy• Facilities, Utilities and Equipment

Qualification• Process Performance Qualification• Reference standard characterisation• Definitive product shelf life studies• Product characterisation studies

Process Development - The new paradigm

Validation – Fundamental definition

What is meant by the termValidation, in a broadWikipedia sense it is defined as:

Verification andValidation are independent procedures that are used together for checkingthat a product, service, or system meets requirements and specifications and that it fulfilsits intended purpose.These are critical components of a quality management system suchas ISO 9000.The words "verification" and "validation" are sometimes preceded with"Independent" (or IV&V), indicating that the verification and validation is to beperformed by a disinterested third-party.

It is sometimes said that validation can be expressed by the query "Are you building theright thing?" and verification by "Are you building it right?“

In practice, the usage of these terms varies. Sometimes they are even used interchangeably

Validation compared to Verification (Wikipedia definitions)

"Validation. The assurance that a product, service, or system meets the needs of thecustomer and other identified stakeholders. It often involves acceptance and suitabilitywith external customers. Contrast with verification.“

So in terms of a Biopharmaceutical product consider what is the:

The Product?

The Service?

The system?

What criteria could be used to demonstrate acceptance and suitability?

Who are the external customers?

"Verification. The evaluation of whether or not a product, service, or systemcomplies with a regulation, requirement, specification, or imposed condition. It isoften an internal process. Contrast with validation."

So in terms of a Biopharmaceutical product consider what is the: Difference between a validated and non-validated process, could a verified process still deliver acceptable material

for clinical studies?

Biopharmaceutical definition of validation

Validation: A documented program that provides a high degreeof assurance that a specific process, method, or system willconsistently produce a result meeting pre-determined acceptancecriteria

So consider: What documents are required?

What is meant by “high degree of assurance”

What is meant by “consistently”

How are acceptance criteria determined and how are they developed?

The key question is then: “how do we monitor or measure the success of a process”

“how do we monitor or measure the success of a process”

To answer this question we need to ask another which is “What isthe Process”

It is fair to state that for biological and biopharmaceuticalproducts then process defines the product

Which means that if the process is changed the product ischanged

In order to manufacture a consistent product then the foundationis in-depth understanding and knowledge of the process

In order to measure the success of the process then thefoundation is in-depth understanding and knowledge of theproduct and its potential variants

The key word is “Knowledge”

The Key element is…

Knowledge of process and product

It is imperative to develop the product and process knowledge basisearly in the product lifecycle

To often the detailed product characterisation and process mappingstudies are left to run in parallel to the phase III clinical product

This is the old pre QbD / pre ICH Quality Management approach

It limits the opportunity to modify the process as the process isoften “locked” before phase III

In reality it is a pathway to failure of the commercial process due toa lack of knowledge and understanding

Value of Process Understanding derived from Small scaleprocess models Due Diligence performed on a new

purification process

Developed using QbD approach atsmall 1 – 5 mL packed bed columnvolumes

Data generated supported the deal

First program milestone, successfulrunning of the scale up of thepurification process

From 5mL to 500L packed bedvolumes

The process performed as predictedby the small scale models

Facilitated payment of a £ 10million for demonstration of thescaled process operation

What happens without process knowledge and Quality RiskManagement?

On May 24, 2010, Genzyme entered into a consent decree with the FDA relating to theAllston facility

Under the terms of Genzyme’s consent decree, Genzyme paid an upfront disgorgement ofpast profits of $175.0 million. Conditioned upon Genzyme’s compliance with the terms ofthe consent decree, Genzyme is permitted to continue manufacturing at the site during theremediation process.

The work plan is expected to take approximately four more years to complete.The workplan includes a timetable of specified remediation compliance milestones.

FDA can Genzyme to pay $15,000 per day, per affected drug (x 4), until the agreedcompliance milestones are met.

Estimated cost to date > $ 250 million fines but with the remediation costs mostlikely reaching close to S 1 billion at the end of the work plan

Source: UNITED STATES SECURITIES AND EXCHANGE COMMISSION, Washington, D.C. 20549, FORM 20-F, for Sanofi

Product and Process Knowledge

The aim of pharmaceutical development is to design a qualityproduct and its manufacturing process to consistently deliver theintended performance of the product.The information andknowledge gained from pharmaceutical development studies andmanufacturing experience provide scientific understanding tosupport the establishment of the design space, specifications, andmanufacturing controls. [Source ICH Q8(R2)]

Points to consider: How is a product quality defined – what are the attributes?

Remember quality cannot be tested in to a product it has to be an integralattribute

How is this all captured and documented? How does the knowledge and scientificunderstanding get translated into process definition and controls?

ICH Q8 (r2): statement

In addition, the applicant can choose to conduct pharmaceutical development studiesthat can lead to an enhanced knowledge of product performance over a wider range ofmaterial attributes, processing options and process parameters. Inclusion of thisadditional information in this section provides an opportunity to demonstrate a higherdegree of understanding of material attributes, manufacturing processes and theircontrols.This scientific understanding facilitates establishment of an expanded designspace. In these situations, opportunities exist to develop more flexible regulatoryapproaches, for example, to facilitate:

risk-based regulatory decisions (reviews and inspections);

manufacturing process improvements, within the approved design space described in thedossier, without further regulatory review;

reduction of post-approval submissions;

real-time quality control, leading to a reduction of end-product release testing.

This is a fundamental element of the “Quality by Design” approach to processdevelopment

QbD – "Cycle of Life"

ProcessKnowledge

ProductKnowledge

Dr. Moheb Nasr,FDA’s View of QbD, 2006

QbD – Key Concepts

Research

Candidatemolecule tomeet QTPP

Clinical & Process Development Commercial

Process Understanding

PlatformProcess

Design Space

Product UnderstandingpCQAs

CQAs

ExpandedChangeProtocols

DefineQualityTargetProductProfile(QTPP)

ChangesManagedviaQualitySystem

Risk Assessments & Risk Management

ProcessParametersDefined

Process ControlStrategyImplemented

AnalyticalMethods forCharacterisationDegradationReleaseStability

Key QbD Concepts

Research

Designmoleculeto meetQTPP

Clinical & Process Development Commercial

Process Understanding

PlatformProcess

Design Space

Product UnderstandingpCQAs

CQAs

ComparabilityChangeProtocols

DefineQualityTargetProductProfile(QTPP)

ContinuousProcessImprovements

TechnologyTransfers

Risk Assessments & Risk Management

Process Performance QualificationPhase

Product / Process Life Cycle

Based on A. Hussain, FDA, September 2004

Process Understanding mitigates Risk

Integration of Validation and understanding

R & D Pre ClinicalToxicology studies

ClinicalPhase 1

ClinicalPhase 2

ClinicalPhase 3

CommercialManufacturing

Life CycleManagement

IncreasingcGMP requirements

Maintenance of theValidated State

Calibrated Equipment Calibrated and Qualified Equipment

Qualified Analytical Methods Validated Analytical Methods

ProcessValidation Process Comparability

First stageProcess

VerifiedandprovenProcess

ValidatedProcess

IncreasingProcess / Product/ CMC knowledgeand understandingand increasingValidationrequirement

ICH Q2, Q3A, Q5A, Q5B, Q5C, Q5D, Q6B, Q8 (r2) &ICH Q6B

ICH Q7, Q9, Q10 & Q11

ICH Q8, 9, 10 and 11: Definitions

Control Strategy: A planned set of controls, derived from current product and process understanding that ensures process performance and

product quality. The controls can include parameters and attributes related to drug substance and drug product materials andcomponents, facility and equipment operating conditions, in-process controls, finished product specifications, and theassociated methods and frequency of monitoring and control. (ICH Q10)

Critical Process Parameter (CPP): 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.

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.

Design Space: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that

have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change.Movement out of the design space is considered to be a change and would normally initiate a regulatory post approvalchange process. Design space is proposed by the applicant and is subject to regulatory assessment and approval

ICH Q8, 9, 10 and 11: Definitions

Lifecycle: All phases in the life of a product from the initial development through marketing until the product’s discontinuation.

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.

Quality: The suitability of either a drug substance or a drug product for its intended use.This term includes such attributes as the

identity, strength, and purity (ref ICH Q6B).

Quality by Design (QbD): 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.

QualityTarget Product Profile (QTPP): A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired

quality, taking into account safety and efficacy of the drug product.

Validation - Lifecycle

The company's overall policy, intentions, and approach to validation, including the validation ofproduction processes, cleaning procedures, analytical methods, in-process control test procedures,computerized systems, and persons responsible for design, review, approval and documentation ofeach validation phase, should be documented. [source ICH Q7]

Typically a company would have a Validation Master Plan (VMP) this document would cover thevalidation strategies and requirements for stage of a product development and/or manufacturing

Process definition and the critical parameters/attributes should normally be identified during thedevelopment stage or from historical data, and the ranges necessary for the reproducible operationshould be defined.This should include:

Defining the Active Pharmaceutical Ingredient (API) in terms of its critical product attributes

Identifying process parameters that could affect the critical quality attributes of the API

Determining the range for each critical process parameter expected to be used during routinemanufacturing and process control

The VMP would also specify the need for equipment and facilities qualification and the requireddocumentation (format / content) needed to support the validation studies

Validation – Areas of consideration

Validation covers all aspects relating to Biopharmaceutical product manufacture

Subject forValidation Study Focus Output

Process Demonstration of consistent qualified processperformance

Process Control Strategy

Delivery of required product quality

Process Supporting Product Shipping studiesVirus removal studiesColumn and Ultrafiltration usage and lifetime studiesExtractables and leachablesRaw Materials identification and qualification

Process Control

Delivery of required product quality

Equipment Cleaning Demonstration of removal of deposited process residues(product and non-product derived) from process contactsurfaces

Elimination of carry over from one process to the nextMicrobial and sanitary controlProcess ControlProtection of product quality

Analytical Methods Demonstration that analytical method is fit for purposeand qualified for Accuracy, Precision, Repeatability,Intermediate Precision, Specificity, Detection Limit,Quantitation Limit, Linearity and Range [source ICHQ2]

Trusted Analytical methods

Demonstration of achievement of required qualityattributes

Equipment User requirement specification and Qualification phases(Design [D], Insulation [I], Operational [O] andPerformance [P])

Ensuring all process and related (analytical / utilities)equipment is qualified

Utilities Water systems, steam, Clean In Place, air handling andenvironmental controls

Maintaining appropriate microbial and sanity controlControl in critical process inputs

Qualification phases for equipment, facilities and utilities (ICH Q7)

Equipment, system, and process requirements (e.g., Critical Aspects (CAs), UserRequirements (UR), Functional Specification (FS), PCS, Basis of Design(BOD)) will beidentified and documented and must provide the basis for design, commissioning, andqualification of the manufacturing system

Before starting process validation activities, appropriate qualification of criticalequipment and ancillary systems should be completed. Qualification is usually carriedout by conducting the following activities, individually or combined:

Design Qualification (DQ): documented verification that the proposed design of the facilities,equipment, or systems is suitable for the intended purpose.

Installation Qualification (IQ): documented verification that the equipment or systems, as installed ormodified, comply with the approved design, the manufacturer’s recommendations and/or userrequirements.

Operational Qualification (OQ): documented verification that the equipment or systems, as installedor modified, perform as intended throughout the anticipated operating ranges.

Performance Qualification (PQ): documented verification that the equipment and ancillary systems, asconnected together, can perform effectively and reproducibly based on the approved process methodand specifications

Cleaning Validation – considerations (ICH Q7) Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or

carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedureswhere residues are removed by subsequent purification steps

Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment andthe equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on thesolubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability

The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored andcontrolled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled

Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. Thesampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may beimpractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transferpipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment)

Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should besufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established.Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum knownpharmacological, toxicological, or physiological activity of the API or its most deleterious component

Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce totalmicrobiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacturesterile products)

Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routineproduction. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of grosscontamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis

Cleaning Validation – Carry Over

Calculation of acceptance criteria is based on the specific amount of residue that can exist onequipment surfaces to be followed by a known minimum batch size.This is known as the MaximumAllowable Carryover (MACO), this is a critical need in Multiproduct facilities

The following information is required to perform MACO calculations: all follow-up product batch sizes are required to determine the

minimum batch size

equipment product contact surface area calculations

minimum therapeutic daily dose of the active of the product being removed

maximum daily dosage of next drug active made in same equipment

safety factor (SF) for oral dose, fill/finish, and downstream biologics use will be 1/1000. Upstream biologics will use1/100.

LD50, as applicable, of the cleaning agent (lowest value of the known ingredients) or active of the product beingremoved.

For chromatography columns, a blank run approach is used.This approach mimics thechromatography purification process, however, there is no protein loaded onto the column the levelof protein eluted were the product would be collected is then measured

Limits may be tiered, based upon the column location in the purification scheme—early (capturecolumn) versus the final (purification column) in the process—with a less-stringent carryover limit(e.g., 1%, 0.5%) for early stage columns and a tighter carryover limit (e.g., 0.1%) for later stagecolumns.

Analytical Validation (ICH Q7 and Q2)

Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or otherrecognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditionsof use and documented

Methods should be validated to include consideration of characteristics included within the ICH guidelines on validation ofanalytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of theAPI production process

Appropriate qualification of analytical equipment should be considered before starting validation of analytical methods

Complete records should be maintained of any modification of a validated analytical method. Such records should include thereason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliableas the established method

Analytical Validation – Regulatory requirements

[ICH Q2] – International Conference on Harmonization Q2(R1) 2005 -Validation of

Analytical Procedures:Text and Methodology

[FDA Guidance for Industry] - Bioanalytical MethodValidation

[Ph.Eur.] - European Pharmacopoeia

[USP] - United States Pharmacopoeia

[Ph.Jap.] - Japanese Pharmacopoeia

[Ph.Int.] - International Pharmacopoeia

Analytical Method selection process

Aseptic Process Validation Typically most Biopharmaceutical products are administered to the patients (the key customer!) as a sterile product via lyophilised / reconstituted injection of Intra-

Venous route, or pre-filled syringe / cartridge or as a sterile liquid preparation

The critical requirement for all these products types is assurance of sterility. Remember the only was of testing to demonstrate sterility would be to test the wholebatch!

Sterility assurance is provided through rigorous manufacturing controls such as active environmental and personnel monitoring, validated component preparationprocedures, and sterility testing in accordance with compendia standards, which is performed as a release test on every batch of Drug Product. Each step of the processthat contributes to sterility assurance level of the product is fully qualified

Growth promoting media is used in Aseptic process simulation studies (media fills) that cover the point of final sterilization of the product, typically 0.2 µm filtration(including all process equipment, product contact surfaces, and associated activities, including transfers) to the point where container closure integrity is achieved. Theprocess simulation test must simulate all the specific manufacturing conditions, such as open vs. closed systems, and processing steps, such as product transfer, sterilefiltration, filling, transfer of semi-stoppered vials to the lyophiliser, the lyophilisation process, stoppering and crimping of vials, and final assembly of syringes

Aseptic process simulation studies must closely simulate aseptic manufacturing operations and incorporate justified worst-case activities and conditions that provide achallenge to aseptic operations. Specific worst-case challenges must be defined in each aseptic process simulation protocol. Such worst-case challenges include, but arenot limited to:

maximum personnel participation (maximum activity level)

slow and fast filling speeds

filling duration

use of components/equipment at the maximum sterile holding

time duration

maximum number of additions to the sterile bulk vessel

maximum number of extractions from the sterile bulk vessel (e.g., sampling)

factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator

fatigue)

lyophilisation simulation, when applicable

line configuration

As well as filter integrity testing, smoke test for air flow and biological indicators to demonstrate acceptable overkill during sterilisation procedures such as VapourHydrogen Peroxide decontamination

Process Validation – ICH Q7

The number of process runs for validation should depend on the complexity of the process or themagnitude of the process change being considered. For prospective and concurrent validation,three consecutive successful production batches should be used as a guide, but there may besituations where additional process runs are warranted to prove consistency of the process (e.g.,complex API processes or API processes with prolonged completion times). For retrospectivevalidation, generally data from ten to thirty consecutive batches should be examined to assessprocess consistency, but fewer batches can be examined if justified

Critical process parameters should be controlled and monitored during process validationstudies. Process parameters unrelated to quality, such as variables controlled to minimize energyconsumption or equipment use, need not be included in the process validation

Process validation should confirm that the impurity profile for each API is within the limitsspecified. The impurity profile should be comparable to or better than historical data and, whereapplicable, the profile determined during process development or for batches used for pivotalclinical and toxicological studies

EMEA Guideline on Process Validation

Open consultation ended October 2012, under going final approval stages

Continuous process verification (CPV) has been introduced to cover analternative approach to process validation based on a continuousmonitoring of manufacturing performance

Approach is based on the knowledge from product and processdevelopment studies and / or previous manufacturing experience

If a design space has been implemented, then the full scale validationstrategy should confirm that the models used during process developmentphase to define the design space are still valid

A hybrid approach of traditional (5 consecutive batches) and CPV

A justification for using this hybrid approach must be presented in thedossier clearly specifying which approach to validation has been taken forwhich part of the manufacturing process

General Considerations for Process ValidationFDA Guidance Jan 2011

In all stages of the product lifecycle, good project management and good archiving that capture scientific

knowledge will make the process validation program more effective and efficient. The following practices

should ensure uniform collection and assessment of information about the process and enhance the

accessibility of such information later in the product lifecycle.

Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or

confirm information about the product and process. All studies should be planned and conducted

according to sound scientific principles, appropriately documented, and approved in accordance with

the established procedure appropriate for the stage of the lifecycle.

Many products are single-source or involve complicated manufacturing processes. Homogeneity within

a batch and consistency between batches are goals of process validation activities. Validation offers

assurance that a process is reasonably protected against sources of variability that could affect

production output, cause supply problems, and negatively affect public health.

Validation Considerations

Before further study of the ICH guidance's and Quality by Designapproaches it is important to get a good understanding andgrounding in the requirements forValidation

Validation practices as applied to facilities, utilities (water, streamand air), equipment, control systems and processes are a foundationfor process development, analytical testing, clinical trial materialmanufacture and all commercial manufacturing operations

The following of validation practices delivers documented programthat provides a high degree of assurance that a specific process,method, or system will consistently produce a result meeting pre-determined acceptance criteria

The changing FDA view on Process Validation

For years, many in the industry have been able to recite the FDA’s 1987 definition of process validation.The 2008 draft guidance hasupdated the definition and shifted the focus from documentation to “scientific evidence” throughout the product life cycle

For example 1987 Definition “establishing documented evidence which provides a high degree of assurance that a specific processwill consistently produce a product meeting its pre-determined specifications and quality characteristics”

2008 Definition “the collection and evaluation of data, from the process design stage throughout production, which establishesscientific evidence that a process is capable of consistently delivering quality products”

In the past, process validation emphasis has been on collecting large quantities of data from validation batches, leading to aperception of process validation as largely a documentation exercise

The updated approach requires the manufacturer to collect data throughout the product life cycle and evaluate it for evidence that itsupports a quality process

Focus on alignment with ‘product lifecycle’

The FDA is a party to the International Conference on Harmonisation (ICH) for human pharmaceuticals.The ICH publishesguidelines on quality, safety, efficacy and multidisciplinary topics. Quality guidelines Q8 (Pharmaceutical Development), Q9(Quality Risk Management) and Q10 (Pharmaceutical Quality System) are directly referenced in the new FDA guideline

The FDA has also referenced the ASTM E25001, where the focus has shifted from validation of individual parts of a process, to amore collective ‘process validation’ effort that takes a more holistic view of process, highlights the GxP critical parts of the processand focuses efforts and resources on the most critical aspects

Of specific importance to the validation guidance is the concept, detailed in these quality guidelines, of “product lifecycle”.The newguidance has been aligned with this concept, giving the following three-stage approach to process validation:

Stage 1 – Process Design

Stage 2 – Process Qualification

Stage 3 – Continued Process Verification

Changing view of Process Validation - FDA

ProcessDesignStage

ProcessValidation

Stage

ContinuousProcess

VerificationStage

Process Lifecycle Validation (US FDA Guidance for Industry ProcessValidation: General Principles and Practices, DRAFT GUIDANCE)

Process Design (Stage 1) Building and Capturing Process Knowledge and Understanding Process design is the activity of defining the commercial manufacturing

process that will be reflected in the master production and control records. The goal of this stage is to design a process suitable for routinecommercial manufacturing that can consistently deliver a product that meets its critical quality attributes.

Generally, early process design experiments do not need to be performed under CGMP conditions. They should, however, be conducted inaccordance with sound scientific methods and principles, including good documentation practices.

Process Performance Qualification (Stage 2) During the process qualification stage of process validation, the process design is confirmed as being capable of reproducible commercial

manufacture. This stage has two elements: 1) design of the facility and qualification of the equipment and utilities, and 2) performancequalification (PQ).

During this stage, CGMP-compliant procedures must be followed and successful completion of this stage is necessary before commercialdistribution.Products manufactured during this stage, if acceptable, can be released. a. Design of a Facility and Qualification of Utilitiesand Equipment Proper design of a manufacturing facility is required under CFR part, subpart C, of the CGMP regulations on Buildingsand Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PQ. Activities undertakento demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly is referred to in thisguidance as qualification.

Continued ProcessVerification (Stage 3) The goal of the third validation stage is to continually assure that the process remains in a state of control (the validated state) during

commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplishthis goal. Adherence to the CGMP requirements, specifically including the collection and evaluation of information and data about theperformance of the process, will allow detection of process drift. The evaluation should determine whether action must be taken to preventthe process from drifting out of control.

An ongoing program to collect and analyze product and process data that relate to product quality must be established. The data collectedshould include relevant process trends and quality of incoming materials or components, in-process material, and finished products. Thedata should be statistically trended and reviewed by trained personnel. The information collected should verify that the critical qualityattributes are being controlled throughout the process.

Types of Process Validation/ Approaches to Process Validation Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform

effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the otherapproaches (Concurrent and Retrospective) can be used. (ICH Q7 Good Manufacturing Practice Guide for Active PharmaceuticalIngredients) Note: While the regulations allow for retrospective validation in unusual circumstances (usually only when dealingwith legacy products), in practice, most companies today do not use retrospective validation. For legacy products, with a longhistory of manufacturing but little development data upon which to base a process validation study, it is more accepted to performa retrospective analysis of the manufacturing batches, and use the information from this analysis to develop the set-points andprocess ranges that are used in either a concurrent or prospective validation study.

Prospective validation should normally be performed for all API processes. Prospective validation of an API process should becompleted before the commercial distribution of the final drug product manufactured from that API. (ICH Q7 GoodManufacturing Practice Guide for Active Pharmaceutical Ingredients)

Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limitednumber of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validatedprocess that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drugproduct for commercial distribution based on thorough monitoring and testing of the API batches.

The number of process runs for validation should depend on the complexity of the process or the magnitude of the process changebeing considered. For prospective and concurrent validation, three consecutive successful production batches should be used as aguide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complexAPI processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

Mechanics of a Process Validation effort

This is not a trivial effort and is viewed as the pinnacle of the process development effort, though in reality is thestarting point of a longer term relationship with the process and product once in commercial manufacturing

Process Validation is the gateway activity run in parallel with pivotal phase clinical studies leading too productlicensure to commercial manufacturing and will be used to verify the commercial process control strategy

PV batches and the associated studies represent a significant investment of man power, facility time and cash, failureis not well received by senior management!

The main activity during PV batches is sampling all process intermediate inputs and outputs to map processperformance. The numbers of samples and tests typically represent a staggering work load for QC and testing labs

Additional studies such as virus clearance, chromatography column storage and reuse are typically performed inparallel to the PV batches

Extensive product characterisation and forced degradation studies are conducted in this phase of the process /product development life cycle as well as extensive stability studies, all data leading to the regulatory agency dossiersubmissions

The changing FDA view on Process ValidationStage Intent Typical Activities

Stage 1:

Process Design

To define the commercial process on knowledge gainedthrough development and scale up activities

The outcome is the design of a process suitable for routinemanufacture that will consistently deliver product thatmeets its critical quality attributes

A combination of product and process design (Quality by Design)Product development activities Experiments to determine process

parameters, variability and necessarycontrols

Risk assessments

Other activities required to define the commercial process

Design of Experiment testing

Stage 2:

Process Qualification

(Process Performance Qualificationor Process Validation)

To define the commercial process on knowledge gainedthrough development and scale up activities

The outcome is the design of a process suitable for routinemanufacture that will consistently deliver product thatmeets its critical quality attributes

Facility design

Equipment & utilities qualification Performance qualification (PQ)*Strong emphasis on the use of statistical analysis of process data tounderstand process consistency and performance

Stage 3:

Continued Process Verification

To provide ongoing assurance that the process remains in astate of control during routine production through qualityprocedures and continuous improvement initiatives

Proceduralised data collection from every batch.

Data trending and statistical analysis Product reviewEquipment and facility maintenance CalibrationManagement review and production staff feedback

Improvement initiatives through process experience

Three Stages of Process Validation (humanized IgG1) Stage 1Category Activities Outputs / Deliverables Rationale examples

Process Development

EstablishTPP and

QTPP

Identify Critical

Quality Attributes

Define

Manufacturing

Process

Immunological indication; MOA (mechanism of action) requires both

CDC (complement depended cytotoxicity) and ADCC (antibody

dependent cell-mediated cytotox) activity; IV administration at a

fixed dosage; Liquid formulation with concentration at 20 mglml,

Iso-osmolar solution; material provided in a single use vial with a shelf

life of at least 24 months at 2-8°C.

Presumptive CQAs (inherent attributes from the molecule that

provide desired activity, purity, and safety) were identified based on

prior knowledge. Potential process parameters that impact the CQAs

were identified for each unit operation based on platform information

Prior knowledge, existing risk assessments for similar molecules, and

early development data were used to define, unit operations: Seed

train, bioreactor, harvest, Protein A, viral inactivation, column

purification 2, column purification 3, viral filtration, UFOF. In

addition:

Normal Operating Ranges identified

Raw materials identified

Cell line characterized to show free from adventitious agents. Master

and working cell banks prepared and characterized. Analytical

method development was started.

Initial formulation development (liquid or frozen) was initiated. Due

to ease of control, frozen was initially selected while the liquid

formulation was being developed in parallel

Deamination,Aggregation,

Host Cell Protein, Residual

DNA, leachables etc.

A Process Design Summary Report created containing preliminary product / process information

Source PDA Technical Report 60: Process Validation – A lifecycle approach

Three Stages of Process Validation (humanized IgG1) Stage 1Category Activities Outputs / Deliverables Rationale examples

Process

Development

Finalize CQAs and CPPs

Documenting Process

Design

Material was produced for First-in-Human studies, in a GMP facility in a 2000L bioreactor

facility, using a scaled-down version of the intended commercial process.

Samples were put on stability to establish expiration times.

Material was produced for Phase 2 in a 2000L bioreactor process using the same GMP facility.

Samples were taken and used for characterization studies in small-scale equipment (satellite

studies) to define the eventual commercial process

Product was analysed for the following (at a minimum):

Appearance and identity Purity (IEC, SEC, CE SDS, endotoxin, bioburden, impurities Potency

Initial product acceptance criteria based on targets were set from other molecules and early

development studies. Stability studies were initiated using a subset of the

release testing assays

Most of the analytical methods were qualified at this stage.

Clinical Phase 3 manufacturing was performed in a different 2000L bioreactor facility. Prior to

the start of phase 3 material manufacture, some of the following activities were performed

Tech transfer process was conducted to transfer the process from the Phase 2 facility to a Phase

3 facility.

Comparability study (DS & DP) protocols were generated

Batch records were created

Operator Training performed

Primary containers were finalized

After Phase 3 material manufacture, the Process Design Summary Report was updated (e.g.,

COAs and CPPs, unit operations)

Upstream Process Parameters:

Viable cell density

%Viability Temperature pH

Dissolved Oxygen

Downstream Process Parameters:

Protein load

Protein concentration

Elution buffer pH Viral inactivation pH

Diafiltration volumes

A team of scientists led the tech transfer

effort by performing facility fit, generating

Technical reports, training of operators,

and transferring of manufacturing process

and associated scale-down models.

Quality Risk Assessment

(QRA)

A modified FMEA was used to perform Quality Risk Assessment (ClRA). A template created

for similar products was used as a starting material with appropriate modifications.

Using the risk assessment process :

Initial categorization of process parameters was performed Initial framework for control

risks identified in the risk assessment

Downstream process determined that

acidic variants impacted biological activity.

Placed tighter controls on in-process hold

times to control level of acidic variants.

Updated Quality Risk Assessment and the

Control Strategy. Increased the

concentration of final bulk to save on

storage capacity

Three Stages of Process Validation (humanized IgG1) Stage 1

Category Activities Outputs / Deliverables

Process

Characterisation

Finalize CQAs and CPPs

Documenting Process

Design

Process characterization studies were designed based on prioritization developed from risks identified in the QRA

Statistical methods involving DoEs (screening designs to full factorial) were used to understand interactions of high risk

parameters and a design space developed wherever possible

Scale-down models were created and tested; some required qualification (e.g., virus clearance)

In these cases, protocols were created and approved by Quality, Based on characterization and small scale model

studies, operating ranges for process parameters were finalized.

Acceptance ranges for performance parameters were established

Based on process characterization and scale-down model studies, the ORA was updated, which in several cases

required re scoring.

In a cross-functional team, the CGAs and CPPs were reviewed and finalized. The final CGAs and CPPs were subject to

approval by the Health Authorities wherever applicable.

The control strategy was updated based on the understanding of CQAs, CPPs, process controls, and detection

capabilities

The Process Design Summary Report was updated {CQAs, CPPs, unit operations, operating ranges, specifications,

and acceptance criteria and controls)

A commercial manufacturing was site was identified ( 12K bioreactor capacity), and a team of scientist and process

engineers performed a facility fit analysis to identify any gaps in equipment capabilities

Tech transfer process was initiated to the commercial site. A tech transfer risk assessment was performed to

understand the high risks. Scale down model process transfer was also started in parallel

Around this time, the analytical method validation was completed

Three Stages of Process Validation (humanized IgG1) Stage 2Category Activities Outputs / Deliverables

Process

Characterisation

ProcessValidation MasterPlanEquipment, Utilities, andFacility Qualification

TechnologyTransfer andEngineering Runs

Process PerformanceQualifications (PPQ)Readiness Assessment

Specific validation protocols were identified.The process validation strategy andancillary studies were described in the plan

The facility fit assessment identified the requirement of a larger scale centrifuge. Basedon user requirements and design specifications, the new centrifuge was ordered.AfterFAT and SAT, the equipment was commissioned and qualified.To understand the controlrequired, a risk assessment was performed

The transfer process used engineering runs to demonstrate that the process worked andto fine-tune the operation set points.Two engineering runs were performed using GMP materials with draft batchproduction records.These runs enabled training on the new process for the operators

A checklist was used to ensure that all the processes and procedures were in place tostart the PPQ process

PPQ protocols were drafted and approved

A sampling plan that described the sample points, number of samples, statisticaljustification, and analytical methods was created and approved

A Continued ProcessVerification plan was created to identify the parameters andattributes to be tested and monitored during PPQ and Stage 3 (Continued ProcessVerification). Some of the elements included in the plan were justification ofparameters, frequency of, statistical procedures used to determine state of control, andhandling of excursions

Three Stages of Process Validation (humanized IgG1) Stage 2Category Activities Outputs / Deliverables Rationale examples

Process Performance

Qualification (PPQ)

PPQ Campaign

Stability

A qualitative decision tool was used to determinethe number of PPQ runs. Some of the factorsconsidered were; Process variability {e.g., noveland difficult scale-up unit operations, raw materialvariability, age of equipment and facility, level ofcommercial manufacturing experience ofoperators, clinical manufacturing experience,robustness of control strategy),The tool suggested a range of 5 to 6 runs for thePPQ campaign

Discussions with the Health Authorities are helpfuland generally a proposal is submitted for thenumber of runs

Three lots of OS and DP from the PPQ campaignwere put into the stability program. Multiplefreeze and thaw cycles of the OS were alsoincluded in this study.

In general, Health Authorities require 6months of real-time stability data at thetime of submission.Any excursions were handled according tothe established procedures.Additional sampling is performed for allthe runs in the event of an unforeseen incident, which would have compromised theinitial PPQ runsIn addition to real-time testing and thedesignated storage temperature, stability ataccelerated conditions is performed perICH guidelines

The stability program also includes acomprehensive study in which the OS isheld at its longest expiry and then used toprepare DP vials, which will are also heldfor the entire expiry time

In addition to the primary stability dataobtained during the PPU runs, supportivestability data acquired during Clinicaldevelopment is also used in thesubmission

Three Stages of Process Validation (humanized IgG1) Stage 3Category Activities Outputs / Deliverables Rationale examples

Continued Process

Verification

ProcessMonitoring

Product TechnicalTeams

Specification File

The CPV plan that was developed prior to start of the PPQwas submitted to the Health AuthoritiesTesting and monitoring were performed during Stage 3according to the CPV planCPV data review was conducted as described in the CPVplan.The monitoring reports generated supplemented theAnnual Product ReviewThe CPV plan was used throughout the product lifecycleand helped to ensure that the process was in a state ofcontrol

Each commercial product had a Product TechnicalTeam(PTT) that helped to oversee the process for the remainderof the product lifetime

The PTT was also responsible for reviewing data frommultiple production sites to ensure consistent processperformance and product quality

A manufacturing process specifications file was generatedat the time of the license submission

The file was updated upon approval and contained thelicensed

Preliminary control limits were established after15 commercial batches (including PPQ batches)that were manufactured

Final control limits were established after 30commercial batches had been manufacturedThe PTT is cross-functional, includingmanufacturing, process development, analytical,quality, and statistics.The team is responsible forreviewing the processing data that accumulatesduring commercial production.The PTI can recommend process changes andhelps to ensure continuous improvement.

The file is maintained throughout the productlifetime and is be updated to include in-processand specification changes that might occur

Process Performance Qualification (PPQ)

Number of Qualification Batches:

Not clearly defined in current drafts of regulations – typical expectation is for 3 to 5 consecutive batches

A draft Process Control Strategy (PCS) should be in place prior to initiating PPQ batches

This demonstrated an acceptable level of process characterisation and product knowledge

This gives a greater degree of assurance that the PPQ batches will be successful and achieve pre-definedacceptance criteria

Engineering batches performed pre PPQ batches can be used to verify the PCS to support PPQ batchoperation

PPQ batches are typically conducted in a manner that demonstrates a state of control under normal operatingconditions in order to assess and demonstrate normal / acceptable process variability

PPQ acceptance Criteria:

Should be established using historical data and prior knowledge

Using data from pre-clinical, development , clinical and pre-commercial batches

The rationale should be clearly defined and documented

Analytical methods should be well developed and validated

Process sampling methods and sample handling should be well established

PPQ documentation

PPQ Protocol PPQ Report Introduction

Purpose and Scope

References

Process Design report

Process validation master plan

Commercial manufacturing batch records

Related qualification documents

Analytical methods

Supporting Technical reports

Equipment / Materials

Responsibilities

Description of unit operations / Process

Methodology

Data Collection

Sampling Plan

AnalyticalTesting

Deviations

Definitions of acceptable performance

Acceptance Criteria for PPQ

Introduction

Methods and Materials

Deviations

Protocol Excursions

Discussion of PPQ results

Recommendations for continuous verification

Conclusions

Development of a Continuous Process Verification Plan

STAGE 1

Draft initial CPV plan

- Use statistical methods

- Identify data to be trended withrationale

-Establish confidence in processbased small-scale models

-Specify frequency of reporting

STAGE 2

Adjust CPV plan based onPPQ learning's

-revise commitment to numberof batches under CPV prior toreassessing acceptance criteria

-

Stage 3

Formalise CPV plan priorto start of commercialmanufacturing

Comparability Protocols (Post initial Process Validation)Chemistry, Manufacturing, and Controls Information, FDA guidance, February 2003

This guidance describes the general principles and procedures associated with developing and submitting a comparability protocol tothe FDA. The guidance also describes the basic elements of a comparability protocol and specific issues to consider when developingcomparability protocols for changes in:

The manufacturing process

Analytical procedures

Manufacturing equipment

Manufacturing facilities

Container closure systems

Process analytical technology (PAT)

The changes can be defined as Annual Report (AR) for those with minimal potential to adversely affect product attributes, thena Change-Being-Effected Supplement (CBE) for changes assessed to have moderate potential to impact product attributes, thena CBE-30 having moderate potential but were the FDA require the change to be approved at least 30 days before product isreleased and finally a Prior Approval Supplement (PAS) were the change has substantial potential to adversely affect productattributes for this type the FDA must approve before progression and might require a manufacturing site inspection

A comparability protocol prospectively specifies the tests and studies that will be performed, analytical procedures that will beused, and acceptance criteria that will be achieved to assess the effect of CMC changes

A comparability protocol must have description and details of the planned change, specify the tests and studies to be performed,details of the analytical procedures and most important pre defined acceptance criteria

The acceptance criteria (numerical limits, ranges or other criteria) for each specified test and study that will be used to assessthe effect of the CMC changes on the product or other material and/or demonstrate equivalence between pre- and post-changematerial

Process Control Strategy Workshop

ProcessValidation –Virus clearance

Virus Removal All Mammalian Cell Lines have the potential to product virus

typically an enveloped retrovirus or virus like particles

Equally any virus gaining access to the cell culture will potentially grow multiply

Pose a serious risk of patient infection so must be removed or inactivated

Most mammalian cell culture processes will have at least two orthogonal viral inactivation and orclearance steps

Typically these include:

Virus inactivation by low pH (< 4.0), filtration (< 20 nm pore) and Solvent / Detergent treatment (TriNitrile Butyl Phosphate /Polysorbate combination)

The can be supported by clearance data from Chromatography and Membrane purification platforms –using scaled down process models and spiking different virus types to assess removal from product

A viable viral removal / inactivation step yields ≥ 3 Log10 reduction

Steps using different mechanisms can be added together to give a total process clearance factor

Expression of Retrovirus Like Particles in CHO Cells

Adapted from: (Brorson K et al. Biotechnology and Bioengineering 2002, 80, 257 – 267)

Product nParticle count

(log10/ml)RT Activity

(log10nU/ml)

MAb1 17 5.7 +/- 0.5 6.7 +/- 0.3

MAb2 2 8.4 +/- 0.3 8.4 +/- 0.2

MAb3 16 8.9 +/- 0.4 7.4 +/- 0.5

MAb4 1 6.8 +/- 0.2 6.5 +/- 0.2

RP1 3 7.4 +/- 0.5 6.6 +/- 0.4

Viral Clearance – The Technical Concept -

Virus ClearanceStrategyVirus ClearanceStrategy

Validate min 2 OrthogonalVirus Clearance TechnologiesValidate min 2 OrthogonalVirus Clearance Technologies

TestRaw Materials & Cell LinesTestRaw Materials & Cell Lines

Min 1 robust Technology forsmall non enveloped virusesMin 1 robust Technology forsmall non enveloped viruses

ValidRisk AsessmentValidRisk Asessment

Testfinal productTestfinal product

Integrated & Orthogonal Virus Clearance Technology

Process Intermediate

FiltrationFiltrationNanofilter Virus Removal Targets all viruses

InactivationInactivationChemical and Physical Low pH Virus Inactivation S/D Targets Enveloped viruses

ChromatographyChromatographyResin and MembraneChromatography Virus Adsorption or partition Targets all viruses dependenton surface chemistry

Virus Filtration – location in process flow

Biomolecules that can plug virus filters

Protein aggregates (HCP)

Host cell DNA

Dimers, Trimers or even higher protein

polymers

Denaturated proteins, Lipids & triglycerides

Target molecule concentration (0.5µg/ml to

30mg/ml)

Positioning of virus filter earliest after

1st chromatography step

Virus Removal Filtration

SEM Cross Section of a Virus Retentive Membrane

Virus is retained andthe product passesthrough the filter

The causative agents of all five major viral contaminations

In full scale CHO cell culture operationsbulk harvests reported during the last 2decades,

murine minute virus (MMV)

REO virus (REO)

CacheValley virus (CVV)

Epizootic hemorrhagic disease virus (familyReoviridae, genus Orbivirus)

Vesivirus

No confirmed cases of transmission to apatient, but represent a clear and presentdanger

RT-PCR method fordetection ofVesiviruscontamination of abioreactor

Virus LikeParticles in CHOcells

ICH Q5A – Examples of Viruses used in clearance andinactivation studies

Verification of small scale with full scale process stages foruse in Virus clearance studies

Validation of model virus removal and inactivation capacity of an erythropoietinpurification processMayté Péreza, et al, Biologicals 39 (2011) 430e437

Process Control Strategy Workshop

ProcessValidation – Impurity clearance

Impurities Removal – Host Cell Protein and DNA

1. Host Cell Proteins 2. Host Cell DNA

Critical Due to impact onsafety and clinicalperformance of products

Host Cell Proteins (HCP)– Risk factors

HCP’s are considered highrisk due to potential safetyand clinical risks

The average E.Coli cellexpresses approximately3,000 proteins

The average Chinese HamsterOvary (CHO) cell expressesapproximately 30,000proteins

These proteins are alsoextensively modified duringthe cell culture process,resulting in multiples forms

E.Coli HCP CHO HCP

MonoclonalAntibody Protein

Impurity removal – CHO cell Host Cell Proteins

Region in which mostMonoclonal Antibodieswould fit in terms of sizeand overall charge

Typically good opportunityfor high clearance of CHOcell Host Cell Proteinsfrom target molecule

A productlocated in thisregion would bedifficult to purifyfrom CHO cellHost CellProteins

Example of Bioprocess Affinity Chromatography Step

F FT E

Legend:F = FeedstockFT = Flow ThroughE = Eluate (Product Containing)

Complexity of capture purification step feedstock

2 dimensional electrophoresis

Separation based on molecular size andcharge

A,B,C and D same monoclonal antibodymanufactured under different cell cultureconditions

Undesirable free heavy and light chainvariants indicated in B and C gels

The shaded region indicates the targetedarea for a capture step to bind the targetantibody

In addition DNA, RNA and mediacomponents are also present that shouldnot be co-purified and do impact onproduct quality

Process Control Strategy Workshop

ProcessValidation – Resin and Filter Re-Use Studies

Chromatographic Resin and Ultra filter reuse studies

Require qualified scale down models as tools for re-use studies

The process step is then repeated multiple times tomimic operational requirements

This should also incorporate hold and storage steps aswell

For Chromatographic separations the elution profilesand characteristics such as HETP and peak asymmetryshould be monitored in addition to defined attributessuch as purity, yield and leachates (were applicable)

Viral and impurity clearance studies should beperformed on new and reused materials to qualify therequired operational requirements

Validation of the Reuse of Protein A Sepharose

Protein A reuse study• Initially performed for 25

Cycles• No change in yield or purity• Protein A leakage declined

with reuse• Subsequently run to 550 cycle

with no significant impact oneluted IgG CQA’s

• Viral clearance performed onnew and old (reused resin)

• Mock product runs performedevery 10th cycle (no productloaded but eluate peakmeasured for protein), nocarry over detected

Validation of the Re-Use of Protein A Sepharose for the purification ofMonoclonal antibodies. Richard Francis, et al, Separations forBiotechnology, Elsevier Applied Science, volume 2, p491, 1989

Reuse of a mix mode resin for a Polyclonal IgG purification

Reuse of an anion exchange membrane absorber

Lifetime performance for membrane adsorber capsules operated at either 400 or 800MV loading withoptimized cleaning/regeneration procedure (operating pressure at start and end of each cycleshown).

A New Large-Scale Manufacturing Platform forComplex BiopharmaceuticalsJens H.Vogel et al, Biotechnology and Bioengineering,Vol. 109, No. 12, December, 2012

Process Control Strategy Workshop

ProcessValidation – Extractables and Leachables

Extractables and Leachables

Extractables: Extractables are chemical compounds that can be extracted from polymeric materials in the presence ofan appropriate solvent under exacerbated conditions such as increased time, temperature and surface area

Leachables: Leachables are the subset of extractables that actually can migrate into a pharmaceutical formulation underas-used conditions

Extractable studies:Testing that specifically involves exposing a sample of the polymeric material to an appropriatesolvent system under exacerbated conditions in order to maximize the amount of extractables

Leachable studies:Testing that mimics the manufacturing process and exposes the polymeric material to the formulateddrug substance, final drug product, or final formulation buffer under normal conditions in order to evaluate the amountof leachables

Migration: Release of substances (leachables) from the polymeric product contact materials into the content of thecontainer under conditions which reproduce those of the intended use

Polymeric Material: Bulk long chain molecules of rubber (elastomers), rigid or flexible plastics, or any other relevantsynthetic materials, used as a product contact material for process material transfer, storage, or primary packaging.Manufactured to have specific properties such as tensile strength, elongation and hardness

Extractables and Leachables - Issues

Can impact product Attributes

Can impact product stability profile

Can represent a significant risk to patient safety

Leachables must be determined and risk assessed

Regulatory Guidance for Evaluation of Product ContactMaterials

An overview of the cGMP requirements outlined in the regulatory guidance documents that are applicable to theproduct contact materials used in the production of FDS and FP is provided below:

Equipment is designed to suit its intended purpose.

(EUVol. 4, Section 3.34; EUVol. 4, Annex 18, Section 5.10; 21CFR211.63)

Equipment design should present no hazard to products, such that product-contact parts are not reactive, additive orabsorptive to the extent that it would affect the quality of product.

(EU Vol. 4, Sec. 3.39; EU Vol. 4, Annex 18, Sec. 5.11; 21CFR211.65; 21CFR600.11)

Equipment should be constructed so that surfaces that contact raw materials, intermediates, or Drug Substance do notalter the quality of the intermediates and Drug substance beyond the official or other established specifications.

(ICH API GMPs section 5.11)

USP <661>, Containers, Physicochemical Tests – Plastics, USP <87>, Biological ReactivityTests, InVitro,USP<88>, Biological ReactivityTests, InVivo, USP<381>, Elastomeric Closures for Injections

EP 3.2.9, Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for Freeze-Dried Powders

Possible physical degradation pathways of proteins causedby interfaces, foreign particles and leachables

Effects of Surfaces and Leachables on the Stability of Biopharmaceuticals, JARED S. BEE, et al,Wiley OnlineLibrary (wileyonlinelibrary.com). DOI 10.1002/jps.22597

ICH Q 8, 9 & 10: working together

QbD as an essential tool for Process Validation andContinuous Verification

The old process validation paradigm of three consecutive batches is no longer acceptable

At last I might add, having lived in a perpetual realm of process validation for the last 27years

I’ve seen to many failures

Due to much haste and a lack of knowledge –The cost is extremely significant in termsof time, reputation and loss of market potential

The new vision and regulatory expectation is continuous process verification

Based upon scientific knowledge and understanding relating to the product and process

QbD is the key methodology for development of the knowledge space for processparameters and product critical quality attributes

Back to the beginning…

Validation: A documented program that provides a high degree ofassurance that a specific process, method, or system willconsistently produce a result meeting pre-determined acceptancecriteria

Questions?

Back to the beginning…

Validation: A documented program that provides a high degree ofassurance that a specific process, method, or system willconsistently produce a result meeting pre-determined acceptancecriteria

Questions?