Pharmaceutical Industry Trends

Approaches to Process Validation and Risk

Management
(Quality Systems and cGMPs)

Anita R. Michael, Pharmaceutical Specialist FDA Office

of Regulatory Affairs

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 Process Validation
Guidance for Industry Process Validation:
General Principles and Practices

January 2011 (CGMP) Revision 1

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 Statutory and Regulatory Requirements for Process Validation

Process validation for drugs (finished pharmaceuticals and components) is a

legally enforceable requirement under section 501(a)(2)(B) of the Act (21
U.S.C. 351(a)(2)(B))

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 Validation General Principal and Practices
Process Validation General Stages 1, 2 and 3:

• Stage1 Process Design development and scale up activities

• Stage2 Process Qualification process design is confirmed capable

of reproducible commercial manufacturing

• Stage3 Continued Process Verification ongoing assurance assuring

that your process remains in a state of control

Gain information during R&D and continue throughout the

lifecycle of the product gaining additional knowledge and driving
process improvement and better product

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 Stage 1,2,3 (Validation Protocols and Final Reports)

• Description of the process

• Prospective Validation Study

• Risk Assessment for the Process

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 Stage 1,2,3 (Validation Protocols and Final Reports)

• Risk assessment for DQ, IQ, OQ and PQ and risk assessment for
testing

• List of Critical Equipment and Critical Utilities (WFI, Compressed Air,

Steam)

• Process Flow Diagrams

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 Stage 1,2,3 (Validation Protocols and Final Reports)

• Number of Batches and Size of Each Batch

• Predetermined Process Parameters

• Qualification Study for Homogeneity and Reproducibility

• Risk assessment when revalidation is needed

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 Stage 1,2,3 (Validation Protocols and Final Reports)

• Define the Critical Process Parameters (Risk analysis, tools Fish

Bone diagrams, Failure Mode and Effects Analysis-FMEA)

• Some examples of CPP (sterile filtering, mixing, wet granulation,

tablet compression, coating etc.)

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 Stage 1,2,3 (Validation Protocols and Final Reports)

• Define the In-process Critical Quality Attribute and finished

product Critical Quality Attribute (in-process and finished testing)

• Cleaning Validation Study and Cleaning SOPs: Swab testing,

residual solvents, rinse studies, toxicity studies, recovery studies.

• Analytical Method Validation Studies (completed) and Tech Transfer

Reports Completed

• Statically Sound Sampling plan (RSD), blend studies and hold

studies

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 cGMP’s 211 Trends for Process Validation

CGMP regulations require that manufacturing processes be

designed and controlled assuring in-process materials and
the finished product meet predetermined quality,
consistently and reliably.

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 cGMP’s 211 Trends for Process Validation

• § 211.100(a), which states that “[t]here shall be written procedures

for production and process control designed to assure that the drug
products have the identity, strength, quality, and purity they purport
or are represented to possess...”

• § 211.110(a) Sampling and testing of in-process materials and drug

products, requires that control procedures “. . . be established to
monitor the output and to validate the performance of those
manufacturing processes that may be responsible for causing
variability in the characteristics of in-process material and the drug
product” (in-process controls) for final product quality.”
•
• § 211.160(b)(3) the CGMP regulations regarding sampling set forth
a number of requirements for validation.
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 cGMP’s 211 Trends for Process Validation

• § 211.165(c) and (d) samples must represent the batch under

analysis the sampling plan must result in statistical confidence.

• § 211.165(a) the batch must meet its predetermined specifications

and control batch-to-batch variability.

• §211.180(e) requires that information and data about product quality

and manufacturing experience be periodically reviewed to determine
whether any changes to the established process are warranted.
Ongoing feedback about product quality and process performance is
an essential feature of process maintenance. (life cycle
approaches)

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 cGMP’s 211 trends for Process Validation

• § 211.42 CGMP regulations require that facilities in which drugs are

manufactured be of suitable size, construction, and location to
facilitate proper operations.

• § 211.63 Equipment must be of appropriate design, adequate size,

and suitably located to facilitate operations for its intended use.

• §211.68 Automated, mechanical, and electronic equipment must be

calibrated, inspected, or checked according to a written program
designed to assure proper performance.

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 What is Quality Risk Management?

Quality Risk Management System Should Be Patient

Focused?
Quality risk management builds a strong foundation for
regulatory operations, management of facilities and quality
products.

Linking patient, process and validation

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 Quality Risk Management

• Principle One: Evaluation of risk should be based on science and

link to patient safety

• Principle Two: Effort and documentation should commensurate

with the level of risk

• Core: QRM should work in teams. Diverse team of leaders from

various departments (QCU, Production, R&D, Statistics, clinical and
Regulatory Affairs)

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 Quality Risk Management (Risk
Assessment)
Risk Assessment (4 fundamental questions)
Q1. What might go wrong (identification of the hazard)?

Q2. What is the likelihood (probability) it will go wrong? Probability of

Recurrence matrix score

Q3. What are the consequences (severity)? Impact on Quality (patient

safety) matrix score

Q4. What is the probability the hazard be detected? Probability of

detectability matrix score
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 Quality Risk Management Risk
Assessment
• Risk Identification : What might go wrong and identify the possible
consequences

• Risk Analysis: Estimation of the risk associated with the hazard.

Qualitative (particles, smells, cloudy injectable, fungus) and
quantitative (failed assay, dissolution failure, stability failure) links
the likelihood of the occurrence (will it occur a lot) and severity of
harm (can it cause death or grave illness to patient). Also the
detectability of the harm also factors into the estimation of risk (is it
easy to detect for example a contaminated bioreactor).

• Risk evaluation: Risk evaluations look at the strength of the

evidence of all four fundamental questions.
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 Quality Risk Management
Risk Control
• Risk control: Includes the decision making to reduce and or accept
risks. Is risk above acceptable level? How can you eliminate the
risks? Do you have enough resources? Are new risks introduced
from your controls?

• Risk reduction: Company actions taken to lessen the probability of

occurrence of harm and the severity of that harm.

• Risk Acceptance: The decision to accept risk, what is acceptable

and what is not.

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 Quality Risk Management
(communication and review)
• Risk Communication Sharing information about risk
and risk management between decision makers this
committee should be defined.

• Risk Review An ongoing part of Risk Management

process. Results of internal audits, change controls,
CAPA and failure investigations. Reviewing and
evaluating of the outputs and results.

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 Industry Trends Applying Quality Risk Management
for Day to Day Operations (Quality Systems)

Quality Risk Management and Quality Systems

• Quality Defects suspected quality defect, complaint, trend,
deviation, investigation, out of specification result (e.g., recall).

• Auditing/Inspection to define the frequency and scope of audits,

both internal and external. What needs to be addressed Risk
Assessments.

• Periodic review to select, evaluate, and interpret trend results of

data within the product quality review. To interpret monitoring data
(e.g., revalidation or changes in sampling).

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 Industry Trends Applying Quality Risk Management
for Day to Day Operations (Quality Systems)

• Change management and change control evaluate the impact of

the changes on the product quality and availability of the final
product and need for revalidation.

• Continual improvement to facilitate continual improvement in

processes throughout the product lifecycle.

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 Industry Trends Applying Quality Risk Management
for Day to Day Operations (Regulatory)

• Quality Risk Management as Part of

Regulatory evaluate the significance of, for
example, quality defects, potential recalls, and
inspectional findings.

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 How to Apply Quality Risk Management for
Day to Day Operations (Development)

Quality Risk Management as Part of Development

• To design a quality product and its manufacturing process.

• Can your process perform over a wide range of material attributes

(e.g.,particle size distribution, moisture content, flow properties,
processing options, and process parameters).

• Assess the critical attributes of raw materials, solvents, active

pharmaceutical ingredient (API) starting materials, APIs, excipients,
or packaging materials.

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 Quality Risk Management as Part of
Development
• Establish appropriate specifications, identify critical process
parameters, and establish manufacturing controls (e.g., using
information from pharmaceutical development studies and the ability
to control variations during processing).

• Can you link to patient safety? For example content uniformity,

dissolution and bioavailability.

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 Industry Trends Applying Quality Risk
Management as Part of Development
• To decrease variability of quality attributes

• To reduce product and material defects

• To reduce manufacturing defects

• To make use of the design space concept

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 Industry Trends Applying Quality Risk Management
as Part of Production Systems

• Validation approaches to verification, qualification, and validation

activities (e.g. analytical methods, processes, equipment, and
cleaning methods). Distinguish between critical and noncritical
process steps to facilitate design of a validation study.

• In-process sampling & testing well defined in-process control

testing and justify the use of process analytical technologies (PAT)
in conjunction with parametric and real time release.

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 Industry Trends Quality Risk Management as Part of
Laboratory System and Stability Studies

• Out of specification results identify potential root

causes and corrective actions during the investigation of
out of specification results.

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 Industry Trends Life Cycle Approach

Applying Product Lifecycle

• All phases of the life of the products, from
development, marketing and
discontinuation.

• Continual Improvement of Process

Performance and Product Quality.

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 Life Cycle Approach (4 elements)

Four specific pharmaceutical quality system elements for Life

Cycle Approaches
1. Process performance and product quality monitoring system

2. Corrective action and preventive action (CAPA) system; deviations

risks assessment (level1, level 2 or level 3)

3. Change management system; (risk assessment level 1, 2, and 3)

4. Management review of process performance and product quality

(critical failures, recalls, adverse events and medical complaints, low
sales and legal)
These 4 elements support product lifecycle stages 29
 Life Cycle Approach (Lifecycle Stage
Goals)
i) Pharmaceutical Development is designing a product and its manufacturing
process to consistently deliver a safe drug that works.

ii) Technology Transfer is transfer product and process knowledge between

development and manufacturing, and within or between manufacturing sites to
make a safe drug that works.

iii) Manufacturing is maintaining a state of control and facilitating continual

improvement. With a robust pharmaceutical quality system and exceeding the
cGMPs.

iv) Product Discontinuation The goal of product discontinuation activities is to

effectively manage the terminal stage of the product lifecycle.

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 Process Validation
and Product Life Cycle
•Process validation activities should align with Product Life Cycle
concepts

•Lifecycle concepts links the product with the process development,

qualification of the commercial manufacturing process and maintains
the process in a State Of Control

•Lifecycle concepts include using modern manufacturing principals,

driving process improvement, innovation and Sound Science

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FDA 21st Century Initiative Risk
Objectives:
 Encourage the early adoption of new

technological advances by the pharmaceutical
industry
 Facilitate industry application of modern quality

management techniques, including implementation
of quality systems approaches
 Encourage implementation of risk-based

approaches
 Ensure that regulatory review, compliance, and

inspection policies are based on state-of-the-art
pharmaceutical science
 Enhance the consistency and coordination of

September 2004 FDA's drug quality regulatory programs

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Quality Related Guidance and Initiatives

2004 2005 2006 2007 2008 2009 2010

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Linking Patient - Product - Process
Clinical
Patient Outcome

Critical Quality
Product Attributes

Material Attributes &

Process Process Parameters

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Integration of Pharmaceutical Quality

Pharmaceutical
Quality

Q8(R) Q9 Q10

Pharm.
Pharm. Quality Risk Quality
Development Management Systems

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 Quality Target Product Profile
“Begin with the end in mind”
Product
profile • Summary of the quality characteristics of a
drug product to ensure safety and efficacy
CQAs
• Includes, but not limited to:
– Dosage form
Risk
assessment – Route of administration
– Pharmacokinetic characteristics
• e.g., dissolution, aerodynamic performance
Design
space
– Quality characteristics for intended use
• e.g., sterility, purity
Control – Patient needs – elderly, children
strategy – Amount of drug per dose
– Desired dosing schedule
Continual
Improvement
– Route of administration
– Safety requirements 36
 Critical Quality Attributes (CQAs)
Product
profile A measurable property of the drug substance or
drug product that is critical to ensuring patient
CQAs safety and efficacy
Risk
assessment

Design
space

Control
strategy

Continual
Improvement

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 Defining CQAs Example:
In Vitro – In Vivo Correlations
In Vivo Response In Vitro/In Vivo Correlation
(Plasma Conc. Profile)

In Vitro Release
(Dissolution Profile) Predictive Model

Formulation and
Manufacturing Process

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Reference: Medscape, 2002
 Risk Management (ICH Q9)
Product
profile
• A systematic process for the assessment,
CQAs control, communication and review of risks to
the quality of the drug product
Risk
assessment
• Evaluation of risk to quality should:
– be based on scientific knowledge
Design
space – link to the protection of the patient
– Extend over the lifecycle of the product
Control
strategy
• Typically conducted with an integrated group of
Continual experts, including development and
Improvement
manufacturing
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 Risk Assessment Example #1
Ishikawa Diagram
Tablet Compression

Machines Methods Measurements

Precompression Force
Weight
Press Speed
SOPs Thickness Main Compression Force
Pre and Main Compression Batch records
Feeder Speed
Metal Check
Material Addition Method
Cam Size/Tooling Cylindrical fill height
Machine set-up Tablet Quality
Drop Height Turret RPM
Dissolution,
Hardness,
Manufacturing Suite Drug Substance Appearance
Operators
Internal Temp
Age P.S. LOD ID
Experience Humidity Diluent

Other Excipients
Training External Temp P.S. LOD
Batch Size
Quantity Properties
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Personnel Environment Materials
 Risk Assessment Example #2
Failure Mode and Effects Analysis
Humidity Sensitive Crystalline Product
Risk
Severity Occurrence Detection priority Criticality
Category Process Parameter
S (1-5) O (1-5) D (1-5) number rank
S*O*D
Residual solvent 5 4 3 60 1
Induction time 4 3 2 24 6
Crystalliztn
Anti-solvent
5 3 2 30 4
addition time
Mixing 2 2 1 4 11
Temperature during
4 4 2 32 3
Isolation/ crystal drying
drying
Solids transfers 3 1 1 3 13
Washing effectiveness 2 1 1 2 15
Handling/ Relative humidity 5 3 3 45 2
storage 41
Inerting 4 2 3 24 6
 Mapping the Linkage
Inputs: Outputs:

M1 CQA1
Critical
M2
CQA2 Quality
Material Attributes Attributes

CQA3
P1

P2
Relationships:
P3 CQA1 = function (M1)
CQA2 = function (P1, P3)
Process CQA3 = function (M1, M2, P1)
Parameters 42
 Control Strategy
Product
profile
• A planned set of controls, derived from current
CQAs
product and process understanding, that
assures process performance and product
Risk
quality (ICH Q10)
assessment

• Control strategy can include

Design
– parameters and attributes related to drug substance
space and drug product materials and components
– facility and equipment operating conditions
Control – in-process controls
strategy
– finished product specifications
Continual
– associated methods and frequency of monitoring
Improvement and control

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 Control Strategy Example –
Real Time Release
NIR MV
Laser Model
NIR Monitoring Spectroscopy
Diffraction Predicts
Blend Uniformity (At-Line)
Particle Size Dissolution
• Identity
• Assay (a CQA)
Raw materials &
-Function of
API dispensing
input
• Specifications
parameters
based on product
and in-process
measurements

Roller Tablet Pan

Dispensing Blending Sifting
compaction Compression Coating
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 Continual Improvement
Product • Lifecycle risk management
profile
– Use development information as starting point
CQAs
– Update as experience gained
Risk
assessment
• Process tracking and trending
– Statistical process control
Design – Adjust trends before they become problems
space
• Knowledge management
Control
strategy
• Model maintenance and updating
Continual
Improvement

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 Modern Control Strategies
• Translating process understanding into
effective controls
– On-line and in-line measurement instruments
– Effective sampling strategies
– Feed-back and feed-forward control systems
• Modern manufacturing approaches
– Lean manufacturing and real-time release testing
– Continuous manufacturing
• Continual Improvement
– Maintenance and update of process and analytical models
– Utilization of process data to update control models
(e.g., Multivariate statistical process control)
– Knowledge retention and risk management updates
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International Warning Letter GMPs

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 Quality System
Top Three International W/L GMP Citations FY’14 & FY’15
Cite Details
#1 211.192 There is a failure to thoroughly review [any unexplained
discrepancy] [the failure of a batch or any of its components
to meet any of its specifications] whether or not the batch
has been already distributed.

#2 211.25(a) Employees are not given training in [the particular operations

they perform as part of their function] [current good
manufacturing practices] [written procedures required by
current good manufacturing practice regulations].

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 Quality System
Top Three International W/L GMP Citations FY’14 & FY’15
#3 211.22(a or d) a. There shall be a quality control unit that shall have the
responsibility and authority to approve or reject all
components, drug product containers, closures, in-process
materials, packaging material, labeling, and drug products,
and the authority to review production records to assure that
no errors have occurred or, if errors have occurred, that they
have been fully investigated. The QCI shall be responsible
for approving or rejecting drug products manufactured,
processed, packed, or held under contract by another
company.

d. The responsibilities and procedures applicable to the

quality control unit shall be in writing; such written procedures
shall be followed.

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 Laboratory Controls System
Top Four International W/L GMP Citations in FY’14 & FY’15
Cite Details
#1 211.194(a) Laboratory records shall include complete data derived from all tests
necessary to assure compliance with established specifications and
standards, including examinations and assays.

#2 211.160(b) Laboratory controls do not include the establishment of scientifically

sound and appropriate [specifications] [standards] [sampling plans]
[test procedures] designed to assure that [components] [drug
product containers] [closures] [in-process materials] [labeling] [drug
products] conform to appropriate standards of identity, strength,
quality and purity.

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 Laboratory Controls System
Top Four International W/L GMP Citations in FY’14 & FY’15
#3 211.160(a) Deviations from written [specifications] [standards] [sampling plans]
[test procedures] [laboratory mechanisms] are not [recorded]
[justified]; Established [specifications] [standards] [sampling plans]
[test procedures] [laboratory control mechanisms] are not [followed]
[documented at the time of performance]; The establishment of
[specifications] [standards] [sampling plans] [test procedures]
[laboratory control mechanisms] including any changes thereto, are
not [drafted by the appropriate organizational unit][reviewed and
approved by the quality control unit].

#4 211.165(a or e) a. There shall be appropriate laboratory determination of satisfactory

conformance to final specs of the drug product.
e. The accuracy, sensitivity, specificity, and reproducibility of test
methods shall be established and documentedddd. Such validation
and documentation may be accomplished in accordance with
211.194(a)(2).

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 Production System
Top Two International W/L GMP Citations FY’14 & FY’15
Cite Details
#1 211.100(a) There are no written procedures for production and process
controls designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are
represented to possess.
#2 211.188(b) Batch production and control records shall be prepared for
each batch of drug product produced and shall include
complete information relating to the production and control of
each batch. These records shall include: documentation that
each significant step in the manufacture, processing,
packing, or holding

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 Facilities & Equipment System
Top Two International W/L GMP Citation for FY’14 & FY’15
Cite Details
#1 211.68(b) Appropriate controls shall be exercised over computer or related
systems to assure that changes in master production and control
records or other records are instituted only by authorized personnel.
Input to and output from computer or related system of formulas or
other records or data shall be checked for accuracy…A backup file of
data entered into the computer or related system shall be maintained
except where certain data, such as calculations performed in
connection with laboratory analysis, are eliminated by
computerization or other automated processes. In such instances a
written record of the program shall be maintained along with
appropriate validation data. Hard copy or alternative systems, such
as duplicates, tapes, or microfilm, designed to assure that back data
are exact and complete and that it is secure from alteration,
inadvertent erasures, or loss shall be maintained.
#2 211.67(b) Written procedures shall be established and followed for cleaning
and maintenance of equipment.

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 Material System
International W/L GMP Citation for FY’14 & FY’15
Cite Details

211.84(a) Each lot of components, drug product containers, and

closures shall be withheld from use until the lot has been
sampled, tested, or examined, as appropriate, and released
for use by the quality control unit.

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 My Information

Anita R. Michael, Pharmaceutical

Specialist for FDA Office of Regulatory
Affairs
Email [email protected]

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