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

Discovery

Screening

Select leads

optimise

Pre-IND

Phase I

Phase II

Phase III

market

Years 1 through 7
In vitro and in vivo biology Molecule synthesis/expression Formulation PK and drug metabolism Safety assessment Process Development Clinical Manufacturing

Years 8 through 15
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

Up to 10 years

Commercialization
ProcessValidation Process Control Strategy Regulatory Approvals

Up to 2 years

Market Supply
Return on Investment Capacity Expansions Tech Transfers Process Improvements

Up to 20 years

Product termination

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 Process Qualification

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 checking

that a product, service, or system meets requirements and specifications and that it fulfils its intended purpose.These are critical components of a quality management system such as ISO 9000.The words "verification" and "validation" are sometimes preceded with "Independent" (or IV&V), indicating that the verification and validation is to be performed by a disinterested third-party.
It is sometimes said that validation can be expressed by the query "Are you building the

right 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 the

customer and other identified stakeholders. It often involves acceptance and suitability with 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 system

complies with a regulation, requirement, specification, or imposed condition. It is often 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 degree

of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria
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 is

the Process It is fair to state that for biological and biopharmaceutical products then process defines the product Which means that if the process is changed the product is changed In order to manufacture a consistent product then the foundation is in-depth understanding and knowledge of the process In order to measure the success of the process then the foundation is in-depth understanding and knowledge of the product 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 basis

early in the product lifecycle

To often the detailed product characterisation and process mapping

studies 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 is

often locked before phase III

In reality it is a pathway to failure of the commercial process due to

a lack of knowledge and understanding

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

purification process Developed using QbD approach at small 1 5 mL packed bed column volumes Data generated supported the deal First program milestone, successful running of the scale up of the purification process From 5mL to 500L packed bed volumes The process performed as predicted by the small scale models Facilitated payment of a 10 million for demonstration of the scaled process operation

What happens without process knowledge and Quality Risk Management?

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

Allston facility

Under the terms of Genzymes consent decree, Genzyme paid an upfront disgorgement of

past profits of $175.0 million. Conditioned upon Genzymes compliance with the terms of the consent decree, Genzyme is permitted to continue manufacturing at the site during the remediation process. plan includes a timetable of specified remediation compliance milestones. compliance milestones are met.

The work plan is expected to take approximately four more years to complete.The work

FDA can Genzyme to pay $15,000 per day, per affected drug (x 4), until the agreed

Estimated cost to date > $ 250 million fines but with the remediation costs most

likely 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 quality

product and its manufacturing process to consistently deliver the intended performance of the product.The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing 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 integral

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

ICH Q8 (r2): statement

In addition, the applicant can choose to conduct pharmaceutical development studies

that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Inclusion of this additional information in this section provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes and their controls.This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate:
risk-based regulatory decisions (reviews and inspections); manufacturing process improvements, within the approved design space described in the

dossier, 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 process

development

QbD "Cycle of Life" Product Knowledge

Process Knowledge
Dr. Moheb Nasr, FDAs View of QbD, 2006

QbD Key Concepts

Define Quality Target Product Profile (QTPP) Research CQAs

pCQAs

Product Understanding

Analytical Methods for Characterisation Degradation Release Stability

Expanded Change Protocols

Clinical & Process Development Design Space

Commercial

Candidate molecule to meet QTPP

Platform Process

Process Parameters Defined

Process Understanding

Process Control Strategy Implemented

Changes Managed via Quality System

Risk Assessments & Risk Management

Key QbD Concepts

Define Quality Target Product Profile (QTPP) Research

Process Performance Qualification Phase

CQAs Comparability Change Protocols Product Understanding

pCQAs

Clinical & Process Development Design Space

Commercial

Design molecule to meet QTPP

Continuous Process Improvements Platform Process

Process Understanding

Technology Transfers

Risk Assessments & Risk Management

Product / Process Life Cycle

Process Understanding mitigates Risk

Based on A. Hussain, FDA, September 2004

Integration of Validation and understanding

ICH Q7, Q9, Q10 & Q11
ICH Q2, Q3A, Q5A, Q5B, Q5C, Q5D, Q6B, Q8 (r2) & ICH Q6B
Increasing Process / Product / CMC knowledge and understanding and increasing Validation requirement

First stage Process

Verified and proven Process

Validated Process

Qualified Analytical Methods

Calibrated Equipment

Process Comparability ProcessValidation Validated Analytical Methods

Calibrated and Qualified Equipment

Increasing cGMP requirements

R&D Pre Clinical Toxicology studies Clinical Phase 1 Clinical Phase 2 Clinical Phase 3

Maintenance of the Validated State

Commercial Manufacturing

Life Cycle Management

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 and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10)

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 approval change 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 products 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.

Quality Target 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 of

production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented. [source ICH Q7]
Typically a company would have a Validation Master Plan (VMP) this document would cover the

validation strategies and requirements for stage of a product development and/or manufacturing

Process definition and the critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should 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 routine manufacturing and process control

The VMP would also specify the need for equipment and facilities qualification and the required

documentation (format / content) needed to support the validation studies

Validation Areas of consideration

Validation covers all aspects relating to Biopharmaceutical product manufacture
Subject forValidation Study Process Process Supporting Focus
Demonstration of consistent qualified process performance

Output
Process Control Strategy Delivery of required product quality

Product Shipping studies Virus removal studies Column and Ultrafiltration usage and lifetime studies Extractables and leachables Raw Materials identification and qualification Demonstration of removal of deposited process residues (product and non-product derived) from process contact surfaces

Process Control Delivery of required product quality

Equipment Cleaning

Elimination of carry over from one process to the next Microbial and sanitary control Process Control Protection of product quality Trusted Analytical methods Demonstration of achievement of required quality attributes Ensuring all process and related (analytical / utilities) equipment is qualified

Analytical Methods

Demonstration that analytical method is fit for purpose and qualified for Accuracy, Precision, Repeatability, Intermediate Precision, Specificity, Detection Limit, Quantitation Limit, Linearity and Range [source ICH Q2] User requirement specification and Qualification phases (Design [D], Insulation [I], Operational [O] and Performance [P]) Water systems, steam, Clean In Place, air handling and environmental controls

Equipment Utilities

Maintaining appropriate microbial and sanity control Control in critical process inputs

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

Equipment, system, and process requirements (e.g., Critical Aspects (CAs), User

Requirements (UR), Functional Specification (FS), PCS, Basis of Design(BOD)) will be identified and documented and must provide the basis for design, commissioning, and qualification of the manufacturing system
Before starting process validation activities, appropriate qualification of critical

equipment and ancillary systems should be completed. Qualification is usually carried out 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 or modified, comply with the approved design, the manufacturers recommendations and/or user requirements. Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and 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 procedures where 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 and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility 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 and controlled, 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. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, 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 be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The methods 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 known pharmacological, 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 total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products) Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination 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 on

equipment surfaces to be followed by a known minimum batch size.This is known as the Maximum Allowable 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 use

1/100. LD50, as applicable, of the cleaning agent (lowest value of the known ingredients) or active of the product being removed.

For chromatography columns, a blank run approach is used.This approach mimics the

chromatography purification process, however, there is no protein loaded onto the column the level of protein eluted were the product would be collected is then measured
Limits may be tiered, based upon the column location in the purification schemeearly (capture

column) versus the final (purification column) in the processwith 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 stage columns.

Analytical Validation (ICH Q7 and Q2)

Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented Methods should be validated to include consideration of characteristics included within the ICH guidelines on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API 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 the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as 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 IntraVenous 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 whole batch! Sterility assurance is provided through rigorous manufacturing controls such as active environmental and personnel monitoring, validated component preparation procedures, 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 process that 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 m filtration (including all process equipment, product contact surfaces, and associated activities, including transfers) to the point where container closure integrity is achieved. The process simulation test must simulate all the specific manufacturing conditions, such as open vs. closed systems, and processing steps, such as product transfer, sterile filtration, 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 a challenge to aseptic operations. Specific worst-case challenges must be defined in each aseptic process simulation protocol. Such worst-case challenges include, but are not 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 Vapour Hydrogen Peroxide decontamination

Process Validation ICH Q7

The number of process runs for validation should depend on the complexity of the process or the

magnitude 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 be situations 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 retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified
Critical process parameters should be controlled and monitored during process validation

studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption 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 limits

specified. The impurity profile should be comparable to or better than historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical 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 an

alternative approach to process validation based on a continuous monitoring of manufacturing performance Approach is based on the knowledge from product and process development studies and / or previous manufacturing experience If a design space has been implemented, then the full scale validation strategy should confirm that the models used during process development phase 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 the dossier clearly specifying which approach to validation has been taken for which part of the manufacturing process

General Considerations for Process Validation FDA 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 Design

approaches it is important to get a good understanding and grounding in the requirements for Validation
Validation practices as applied to facilities, utilities (water, stream

and air), equipment, control systems and processes are a foundation for process development, analytical testing, clinical trial material manufacture and all commercial manufacturing operations
The following of validation practices delivers documented program

that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria

The changing FDA view on Process Validation

For years, many in the industry have been able to recite the FDAs 1987 definition of process validation.The 2008 draft guidance has updated 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 process will 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 establishes scientific 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 a perception 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 it supports 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 publishes guidelines 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 a more collective process validation effort that takes a more holistic view of process, highlights the GxP critical parts of the process and 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 new guidance 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

Process Design Stage Process Validation Stage

Continuous Process Verification Stage

Process Lifecycle Validation (US FDA Guidance for Industry Process Validation: 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 routine commercial 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 in accordance with sound scientific methods and principles, including good documentation practices. 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) performance qualification (PQ). During this stage, CGMP-compliant procedures must be followed and successful completion of this stage is necessary before commercial distribution. Products manufactured during this stage, if acceptable, can be released. a. Design of a Facility and Qualification of Utilities and Equipment Proper design of a manufacturing facility is required under CFR part, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PQ. Activities undertaken to demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly is referred to in this guidance as qualification. 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 accomplish this goal. Adherence to the CGMP requirements, specifically including the collection and evaluation of information and data about the performance of the process, will allow detection of process drift. The evaluation should determine whether action must be taken to prevent the 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 collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the critical quality attributes are being controlled throughout the process.

Process Performance Qualification (Stage 2)

Continued ProcessVerification (Stage 3)

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 other approaches (Concurrent and Retrospective) can be used. (ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients) Note: While the regulations allow for retrospective validation in unusual circumstances (usually only when dealing with legacy products), in practice, most companies today do not use retrospective validation. For legacy products, with a long history of manufacturing but little development data upon which to base a process validation study, it is more accepted to perform a retrospective analysis of the manufacturing batches, and use the information from this analysis to develop the set-points and process 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 be completed before the commercial distribution of the final drug product manufactured from that API. (ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients) Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product 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 change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations 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 retrospective validation, generally data from 10 to 30 consecutive 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 the starting 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 product licensure 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, failure is not well received by senior management! The main activity during PV batches is sampling all process intermediate inputs and outputs to map process performance. 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 in parallel 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 dossier submissions

The changing FDA view on Process Validation

Stage Stage 1: Process Design The outcome is the design of a process suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes parameters, variability and necessary controls Risk assessments Other activities required to define the commercial process Design of Experiment testing Intent To define the commercial process on knowledge gained through development and scale up activities Typical Activities A combination of product and process design (Quality by Design) Product development activities Experiments to determine process

Stage 2: Process Qualification (Process Performance Qualification or Process Validation)

To define the commercial process on knowledge gained through development and scale up activities The outcome is the design of a process suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes

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

Stage 3: Continued Process Verification

To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives

Proceduralised data collection from every batch. Data trending and statistical analysis Product review Equipment and facility maintenance Calibration Management review and production staff feedback Improvement initiatives through process experience

Three Stages of Process Validation (humanized IgG1) Stage 1

Category Activities Outputs / Deliverables
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 2-8C. 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

Rationale examples

EstablishTPP and QTPP

Deamination,Aggregation, Host Cell Protein, Residual DNA, leachables etc.

Process Development

Identify Critical Quality Attributes

Define Manufacturing Process

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 1

Category Activities Outputs / Deliverables
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

Rationale examples
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

Finalize CQAs and CPPs

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)

Documenting Process Design

Process Development

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. 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

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

Three Stages of Process Validation (humanized IgG1) Stage 1

Category Activities Outputs / Deliverables
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

Finalize CQAs and CPPs Process Characterisation

Documenting Process Design

Three Stages of Process Validation (humanized IgG1) Stage 2

Category Activities Outputs / Deliverables

Specific validation protocols were identified.The process validation strategy and ancillary studies were described in the plan The facility fit assessment identified the requirement of a larger scale centrifuge. Based on user requirements and design specifications, the new centrifuge was ordered.After FAT and SAT, the equipment was commissioned and qualified.To understand the control required, a risk assessment was performed
ProcessValidation Master Plan Equipment, Utilities, and Facility Qualification Process Characterisation Technology Transfer and Engineering Runs Process Performance Qualifications (PPQ) Readiness Assessment

The transfer process used engineering runs to demonstrate that the process worked and to fine-tune the operation set points. Two engineering runs were performed using GMP materials with draft batch production 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 to start the PPQ process PPQ protocols were drafted and approved A sampling plan that described the sample points, number of samples, statistical justification, and analytical methods was created and approved A Continued ProcessVerification plan was created to identify the parameters and attributes to be tested and monitored during PPQ and Stage 3 (Continued Process Verification). Some of the elements included in the plan were justification of parameters, frequency of, statistical procedures used to determine state of control, and handling of excursions

Three Stages of Process Validation (humanized IgG1) Stage 2

Category Activities Outputs / Deliverables Rationale examples

A qualitative decision tool was used to determine the number of PPQ runs. Some of the factors considered were; Process variability {e.g., novel and difficult scale-up unit operations, raw material variability, age of equipment and facility, level of commercial manufacturing experience of operators, clinical manufacturing experience, robustness of control strategy), The tool suggested a range of 5 to 6 runs for the PPQ campaign
PPQ Campaign Process Performance Qualification (PPQ) Stability

In general, Health Authorities require 6 months of real-time stability data at the time of submission. Any excursions were handled according to the established procedures. Additional sampling is performed for all the runs in the event of an unforeseen inci dent, which would have compromised the initial PPQ runs In addition to real-time testing and the designated storage temperature, stability at Discussions with the Health Authorities are helpful accelerated conditions is performed per and generally a proposal is submitted for the ICH guidelines number of runs The stability program also includes a comprehensive study in which the OS is held at its longest expiry and then used to Three lots of OS and DP from the PPQ campaign prepare DP vials, which will are also held were put into the stability program. Multiple for the entire expiry time freeze and thaw cycles of the OS were also In addition to the primary stability data included in this study. obtained during the PPU runs, supportive stability data acquired during Clinical development is also used in the submission

Three Stages of Process Validation (humanized IgG1) Stage 3

Category Activities Outputs / Deliverables The CPV plan that was developed prior to start of the PPQ was submitted to the Health Authorities Testing and monitoring were performed during Stage 3 according to the CPV plan CPV data review was conducted as described in the CPV plan. The monitoring reports generated supplemented the Annual Product Review The CPV plan was used throughout the product lifecycle and helped to ensure that the process was in a state of control Process Monitoring Continued Process Verification Each commercial product had a Product Technical Team (PTT) that helped to oversee the process for the remainder of the product lifetime Rationale examples Preliminary control limits were established after 15 commercial batches (including PPQ batches) that were manufactured Final control limits were established after 30 commercial batches had been manufactured The PTT is cross-functional, including manufacturing, process development, analytical, quality, and statistics.The team is responsible for reviewing the processing data that accumulates during commercial production. The PTI can recommend process changes and helps to ensure continuous improvement. The file is maintained throughout the product lifetime and is be updated to include in-process and specification changes that might occur

Product Technical The PTT was also responsible for reviewing data from Teams multiple production sites to ensure consistent process Specification File performance and product quality A manufacturing process specifications file was generated at the time of the license submission The file was updated upon approval and contained the licensed

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-defined

acceptance criteria Engineering batches performed pre PPQ batches can be used to verify the PCS to support PPQ batch operation PPQ batches are typically conducted in a manner that demonstrates a state of control under normal operating conditions 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

Introduction Methods and Materials Deviations

Protocol Excursions Discussion of PPQ results Recommendations for continuous verification Conclusions

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

Development of a Continuous Process Verification Plan

Stage 3 Formalise CPV plan prior to start of commercial manufacturing STAGE 2 Adjust CPV plan based on PPQ learning's -revise commitment to number of batches under CPV prior to reassessing acceptance criteria

STAGE 1 Draft initial CPV plan - Use statistical methods - Identify data to be trended with rationale -Establish confidence in process based small-scale models -Specify frequency of reporting

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 to the FDA. The guidance also describes the basic elements of a comparability protocol and specific issues to consider when developing comparability 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, then

a Change-Being-Effected Supplement (CBE) for changes assessed to have moderate potential to impact product attributes, then a CBE-30 having moderate potential but were the FDA require the change to be approved at least 30 days before product is released and finally a Prior Approval Supplement (PAS) were the change has substantial potential to adversely affect product attributes 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 be used, 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 assess the effect of the CMC changes on the product or other material and/or demonstrate equivalence between pre- and post-change material

ProcessValidation Virus clearance

Process Control Strategy Workshop

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 or

clearance steps
Typically these include:
Virus inactivation by low pH (< 4.0), filtration (< 20 nm pore) and Solvent / Detergent treatment (Tri

Nitrile 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

Particle count (log10/ml) 5.7 +/- 0.5 RT Activity (log10nU/ml) 6.7 +/- 0.3

Product

MAb1

17

MAb2

8.4 +/- 0.3

8.4 +/- 0.2

MAb3

16

8.9 +/- 0.4

7.4 +/- 0.5

MAb4

6.8 +/- 0.2

6.5 +/- 0.2

RP1

7.4 +/- 0.5

6.6 +/- 0.4

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

Viral Clearance The Technical Concept Test Raw Materials & Cell Lines

Valid Risk Asessment

Virus Clearance Strategy

Validate min 2 Orthogonal Virus Clearance Technologies

Min 1 robust Technology for small non enveloped viruses

Test final product

Integrated & Orthogonal Virus Clearance Technology

Process Intermediate
Nanofilter Virus Removal Targets all viruses

Filtration

Inactivation

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

Chromatography

Resin and Membrane Chromatography Virus Adsorption or partition Targets all viruses dependent on 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 (0.5g/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 and the product passes through the filter

The causative agents of all five major viral contaminations

In full scale CHO cell culture operations

bulk harvests reported during the last 2 decades, murine minute virus (MMV) REO virus (REO) CacheValley virus (CVV) Epizootic hemorrhagic disease virus (family Reoviridae, genus Orbivirus) Vesivirus No confirmed cases of transmission to a patient, but represent a clear and present danger

RT-PCR method for detection of Vesivirus contamination of a bioreactor

Virus Like Particles in CHO cells

ICH Q5A Examples of Viruses used in clearance and inactivation studies

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

Validation of model virus removal and inactivation capacity of an erythropoietin purification process Mayt Preza, et al, Biologicals 39 (2011) 430e437

ProcessValidation Impurity clearance

Process Control Strategy Workshop

Impurities Removal Host Cell Protein and DNA

1. Host Cell Proteins 2. Host Cell DNA

Critical Due to impact on safety and clinical performance of products

Host Cell Proteins (HCP) Risk factors

HCPs are considered high

E.Coli HCP

CHO HCP Monoclonal Antibody Protein

risk due to potential safety and clinical risks The average E.Coli cell expresses approximately 3,000 proteins The average Chinese Hamster Ovary (CHO) cell expresses approximately 30,000 proteins These proteins are also extensively modified during the cell culture process, resulting in multiples forms

Impurity removal CHO cell Host Cell Proteins

A product located in this region would be difficult to purify from CHO cell Host Cell Proteins

Region in which most Monoclonal Antibodies would fit in terms of size and overall charge Typically good opportunity for high clearance of CHO cell Host Cell Proteins from target molecule

Example of Bioprocess Affinity Chromatography Step

FT

Legend: F FT E

= = =

Feedstock Flow Through Eluate (Product Containing)

Complexity of capture purification step feedstock

2 dimensional electrophoresis Separation based on molecular size and

charge A,B,C and D same monoclonal antibody manufactured under different cell culture conditions Undesirable free heavy and light chain variants indicated in B and C gels The shaded region indicates the targeted area for a capture step to bind the target antibody In addition DNA, RNA and media components are also present that should not be co-purified and do impact on product quality

Process Validation Resin and Filter Re-Use Studies

Process Control Strategy Workshop

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 to mimic operational requirements This should also incorporate hold and storage steps as well For Chromatographic separations the elution profiles and characteristics such as HETP and peak asymmetry should be monitored in addition to defined attributes such as purity, yield and leachates (were applicable) Viral and impurity clearance studies should be performed on new and reused materials to qualify the required 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 on eluted IgG CQAs Viral clearance performed on new and old (reused resin) Mock product runs performed every 10th cycle (no product loaded but eluate peak measured for protein), no carry over detected

Validation of the Re-Use of Protein A Sepharose for the purification of Monoclonal antibodies. Richard Francis, et al, Separations for Biotechnology, 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 with optimized cleaning/regeneration procedure (operating pressure at start and end of each cycle shown). A New Large-Scale Manufacturing Platform for Complex Biopharmaceuticals Jens H.Vogel et al, Biotechnology and Bioengineering,Vol. 109, No. 12, December, 2012

Process Validation Extractables and Leachables

Process Control Strategy Workshop

Extractables and Leachables

Extractables: Extractables are chemical compounds that can be extracted from polymeric materials in the presence of an 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 under as-used conditions Extractable studies:Testing that specifically involves exposing a sample of the polymeric material to an appropriate solvent 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 formulated drug substance, final drug product, or final formulation buffer under normal conditions in order to evaluate the amount of leachables Migration: Release of substances (leachables) from the polymeric product contact materials into the content of the container 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 relevant synthetic 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 Contact Materials

An overview of the cGMP requirements outlined in the regulatory guidance documents that are applicable to the product contact materials used in the production of FDS and FP is provided below:
Equipment is designed to suit its intended purpose.

(EU Vol. 4, Section 3.34; EU Vol. 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 or absorptive 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 not alter 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 Reactivity Tests, InVitro, USP<88>, Biological Reactivity Tests, In Vivo, USP<381>, Elastomeric Closures for Injections EP 3.2.9, Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for FreezeDried Powders

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

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

ICH Q 8, 9 & 10: working together

QbD as an essential tool for Process Validation and Continuous 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 27

years Ive seen to many failures Due to much haste and a lack of knowledge The cost is extremely significant in terms of 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 process

parameters and product critical quality attributes

Back to the beginning

Validation: A documented program that provides a high degree of

assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria
Questions?

Back to the beginning

Validation: A documented program that provides a high degree of

assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria
Questions?