1. QbD Risk analysis for process evaluation
Steve Weitzel

2. Development Data yields Product data which leads to….
Product Profile with CQAs and specifications will meet clinical and medical objectives
Process Development- results in sufficient understanding of sources of variation and required controls of variation to achieve profile
Process Validation is intended to demonstrate that the equipment and procedures are capable of consistently producing a product within the required profile.

3. Process and parameters
Parameters and variables in each unit operation
Process Steps(unit operations) and Relationship to a given CQA define Critical Process Parameters
Process capability designed to fall within required operating range to achieve output/attribute range
Excessive or unpredictable variation leads to increased risk of defect in attribute
Control scheme reduces variation or detects variation

4. In-Process Attributes BLEND & GRANULATE
System B
Output
In-Process Attributes
Quality, strength, Composition,
Methods, Tools
& Equipment
Procedure-
Media, agents,
Conditions,CPPs
BLEND & GRANULATE
Starting
Materials
Quality,
Composition
System D
Output
In-Process Attributes
Quality, strength, Composition,
Methods, Tools
& Equipment
Procedure-
Media, agents,
Conditions, CPPs
DRY
Starting
Materials
Quality,
Composition
System T
Output
In-Process Attributes
Quality, strength, Composition,
Methods, Tools
& Equipment
Procedure-
Media, agents,
Conditions,CPPs
COMPRESS
Starting
Materials
Quality,
Composition
Output
Product Attributes
Quality, strength, Composition,
COAT
PACK

5. Control Scheme/ Strategy?
CQA/ Attribute:
Process/ parameter
Blend and Wet Granulate
Fluid Bed Dry
Sieve
Particle size distribution of the active(s)
Blending time of the powder;
Granulating time and speed
granule particle size distribution
Amount of granulating fluid-binder concentration; Granulating time and speed
Drying Time
10 mesh
Granule active content and homogeneity
blending time of external phase
Moisture Content
Starting material %; Weights
Drying Time, temperature

6. Risk Analysis and Process Evaluation Tools
Risk To End-User: Risk from using product or device
Loss of Efficacy/benefit
Loss of safety
Adverse drug reaction/effect
Infection
Toxicity- acute, chronic
Biocompatibility
Risk To Product: Risk of defect to design or quality attribute
Risk In Process: Risk of deviation that leads to defect

7. Start with Qualitative Risk Analysis
End-User Type
Child/Adult/Geriatric
Healthy/Immunocompromised/Terminal
Product type
Drug: sterile/non-sterile; route of delivery; therapeutic category
Device: invasive/non-invasive;
Diagnostic: in-vivo/in-vitro
Type of Process
Aseptic/non-aseptic; manual/automated

8. Product Profile/Attributes Potential Defects
Attribute/Defect type
Theraputic Efficacy/benefits
Safety/Adverse effects
Significant
Noticeable, moderate
zero to minor
Minor
Irriatation
Severe reaction
No Defects, In-spec
70%
20%
10%
95%
4.95%
0.05%
API impurity, degradent
60%
90% 5%
Formulation Composition, low strength
50%
30%
97%
2.99%
0.01%
granule size, poor dissolution
High Moisture%
Bacterial contamination
35%
Wrong color shade
4.5%

9. General Risk Model Risk=P x S
P=Probability of occurrence of defect
S=Severity of impact on end-user if there is an occurrence
For a given end-user and product type the severity of an adverse affect resulting from a defect varies greatly
Frequency that defect occurs?
Likelihood defect will be detected?
Likelihood process deviation will result in product defect?
Likelihood process deviation will be detected?

10. Quality Risk Classification (based on SUPAC and GAMP-4)
Quality by design +
Systems approach
Risk Likelihood
High
Medium
Low
Level 3
Level 2
Impact on Quality
Level 1
Reference: ACPS Subcommittee:Ajaz S. Hussain, Office of Pharmaceutical Science, CDER,

11. Quality Risk Priority Probability of Detection Medium Low High 3
Quality by design +
Systems approach
Probability of Detection
Low
Medium
High
High 3
Medium
Risk Classification 2 1
Low
Reference: ACPS Subcommittee:Ajaz S. Hussain, Office of Pharmaceutical Science, CDER,

12. Supply Chain stability
Process Evaluation
Defect type
Possible Cause-Process Deviations
No Defects In-spec
API impurity, degradent
Supplier quality
R/M Storage
stability
Process conditions
Supply Chain stability
Formulation Composition, Strength
Low strength API
Formulation error
High Moisture%
packaging
Bacterial contamination
Water System
Raw materials
Cleaning failure
Personnel Practice
Wrong color shade
Off-Spec
Material

13. Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach
Final Report - Fall 2004
Department of Health and Human Services U.S. Food and Drug Administration
September 2004

14. Process Deviation Process Change Unintended, undected
Unintended, detected
Process Change
Intentional, necessity
Intentional, beneficial

16. Risk Analysis and Process Evaluation Tools
Process Mapping
Hazard Analysis and Critical Control Points (HACCP)
Hazard Operability Analysis (HAZOP)
Fault Tree Analysis (FTA)
Cause and Effect Analysis
Failure Mode Effects Analysis (FMEA)

17. Organizing and Planning Equipment and process evaluation
List systems, subsystems, equipment
Intended purpose
Operating range>control systems
Process Flow Charts
Risk assessment
Sources of process variation>control points
Sources of contamination> control points

18. Process Mapping
Formulate
Fill
Package

19. Systems Formulate Mixing Tank Filling Sterilize Autoclave Fill line
Package
Labeler,
Cartoner

20. Subsystems Formulate Container Pre-mix Prep Filter Filling In feed
Sterilize
Dilution
Tank
Filler
Capper
Autoclave
Package
Closure Prep
Personnel
Pkg
Agents,
supplies

21. C. Method of Manufacture- Drug Substance 1. Raw Materials
2. Flow Charts
3. Detailed Description
a. Animal Sources (including fertilized avian eggs)
b. Virus Sources
c. Cellular Sources
i. Microbial Cells
ii. Animal Cells
iii. Genetic Constructs and Recombinant Cell Lines
iv. Cell Bank System
v. Cell Growth and Harvesting
d. Purification and Downstream Processing
i. Inactivation
ii. Purification
iii. Stability Processing
iv. Detoxification
FDA Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product

22. Example solid dosage form
In this group session, (see handout ) you should list the aspects that you will evaluate when assessing the validation for the project that your group had been given.
Identify the critical parameters that should have been evaluated by the manufacturer.
List the tests to be carried out and comment on the acceptance criteria to be set.
Supplementary Training Modules on Good Manufacturing Practices, WHO - EDM

23. Determining critical control point example of a tablet granulation process
Particle size distribution of the active(s)
Blending time for the powder
Granulating time and speed,
Amount of granulating fluid-binder concentration
Drying time - final moisture content, granule particle size distribution
Granule active content and homogeneity, blending time of external phase
Determination of critical control points is a way of ensuring validation effort is not wasted and to identify quality control points.
For tablets manufactured by granulation and compression, the critical mixing parameters may include:
particle size distribution of the active pharmaceutical ingredient(s)
blending time for the powder
granulating time and speed
amount of granulating fluid-binder concentration
drying time - final moisture content, granule particle size distribution
granule active content and homogeneity, blending time of external phase
In the production of higher risk prescription tablets, especially those containing low dose of active(s), compressed tablet uniformity should be checked more intensively than uniformity of bulk blend study.
The next slide shows how to “flow chart” a process to determine critical control points.
Supplementary Training Modules on Good Manufacturing Practices, WHO - EDM

24. Determining critical control points
A useful strategy to determine which steps to study intensively, is to “flow chart” the process and conduct a hazard analysis of critical control points. Critical control points indicate critical processing steps. It is necessary to note how often critical control points come at the end stages as the value-adding process proceeds.
The flow chart above shows a tablet granulation process where Step XVI and XVIII have been identified as a critical control point. Blend uniformity and cleaning validation has to be performed at step XVI, and during actual manufacture, a reconciliation of the actual yield against the expected yield must be performed before the tablet compression step.
(The trainer should explain that this diagram is incomplete, as there are other IQ, OQ, PQ requirements, steps, etc. to be included The slide provides an example only.)
Supplementary Training Modules on Good Manufacturing Practices, WHO - EDM

25. Hazard Analysis and Critical Control Points (HACCP)
Required by FDA for food safety assessment
Commonly used for infection control or biosecurity evaluation and control
Approach also used for Medical devices
Analogies for drug manufacture?

26. Principle 1: Conduct a hazard analysis.
HACCP PRINCIPLES
HACCP is a systematic approach to the identification, evaluation, and control of food safety hazards based on the following seven principles:
Principle 1: Conduct a hazard analysis.
Principle 2: Determine the critical control points (CCPs).
Principle 3: Establish critical limits.
Principle 4: Establish monitoring procedures.
Principle 5: Establish corrective actions.
Principle 6: Establish verification procedures.
Principle 7: Establish record-keeping and documentation procedures.
Hazard Analysis and Critical Control Point Principles and Application Guidelines;
FDA, Adopted August 14, 1997

27. ↓ Figure 1. Preliminary Tasks in the Development of the HACCP Plan
Assemble the HACCP Team ↓
Describe the Food and its Distribution
Describe the Intended Use and Consumers of the Food
Develop a Flow Diagram Which Describes the Process
Verify the Flow Diagram
Hazard Analysis and Critical Control Point Principles and Application Guidelines;
FDA, Adopted August 14, 1997

28. Hazard to be addressed in plan? Y/N Control Measure(s)
Step
Potential Hazard(s)
Justification
Hazard to be addressed in plan? Y/N
Control Measure(s)
5. Cooking
Enteric pathogens: e.g., Salmonella, verotoxigenic-E. coli
enteric pathogens have been associated with outbreaks of foodborne illness from undercooked ground beef Y
Cooking
Process Step
CCP
Critical Limits
5. Cooking
YES
Oven temperature:___° F Time; rate of heating and cooling (belt speed in ft/min): ____ft/min Patty thickness: ____in. Patty composition: e.g. all beef Oven humidity: ____% RH

30. Hazard Operability Analysis (HAZOP)
A structured and systematic examination of a planned or existing process or operation in order to identify and evaluate problems that may represent risks to personnel or equipment, or prevent efficient operation. The HAZOP technique was initially developed to analyze chemical process systems, but has later been extended to other types of systems and also to complex operations and to software systems. A HAZOP is a qualitative technique based on guide-words and is carried out by a multi- disciplinary team (HAZOP team) during a set of meetings.
Three Hazop Questions:
"What could go wrong?"
"How would we know it?"
"What could we do about it?"

31. Hazard Operability Analysis (HAZOP) Procedure
Define Process Design Intention-
Flow, times, parameters, set points, key words
Potential Deviations
Probable Causes
Likely consequences
Evaluation: Existing controls? Assurance of control?

32. Hazard Operability Analysis (HAZOP).
Hazard Operability Analysis (HAZOP) F
University of Florida, Chemical Engineering Dept.

33. Hazard Operability Analysis (HAZOP).
Hazard Operability Analysis (HAZOP)
University of Florida, Chemical Engineering Dept.

34. Hazard Operability Analysis (HAZOP) Consequences
Employee safety (in plant or neighboring research center)
Loss of plant or equipment
Loss of production (lose competitive edge in market)
Defect/Loss of Quality
Liability
Insurability
Public safety
Environmental impacts.

35. Fault Tree Analysis (FTA)
History
Fault Tree Analysis (FTA) is a technique for reliability and safety analysis. Bell Telephone Laboratories developed the concept in for the U.S. Air Force for use with the Minuteman Missile system. It was later adopted and extensively applied by the Boeing Company. Fault tree analysis is one of many symbolic "analytical logic techniques" found in operations research and in system reliability.

37. External Event (House Event)
Primary Event Block
Classic FTA Symbol
Description
Basic Event
A basic initiating fault (or failure event).  
External Event (House Event)
An event that is normally expected to occur. In general, these events can be set to occur or not occur, i.e. they have a fixed probability of 0 or 1.
Undeveloped Event
An event which is no further developed. It is a basic event that does not need further resolution.
Conditioning Event
A specific condition or restriction that can apply to any gate.

39. Cause and Effect Analysis
Known Effect
Problem, Defect, Deviation, Outcome
Systematic listing of possible causes by factors and categories (Ishikawa or fishbone diagram)
people, facilities, equipment, resources, procedures, policies
Chain of causes (tree diagram) To get to root cause
Asking why? Why? Why? (Toyota method)

40. Cause and Effect mapping
Identify the EFFECT (problem):
Work out the major factors involved: identify the factors that may contribute to the problem.
Identify possible causes: For each of the factors you considered in stage 2, brainstorm possible causes of the problem that may be related to the factor..
Analyze your diagram: Investigate the most likely causes further. This may involve setting up investigations, carrying out surveys, etc. These will be designed to test whether your assessments are correct.

43. Tree Diagram
Chain of causes

44. Failure Mode Effects Analysis (FMEA)
FMEA was formally introduced in the late 1940’s with the introduction of the military standard Used for Aerospace / rocket development, the FMEA and the more detailed Failure Mode and Effects Criticality Analysis (FMECA) were helpful in avoiding errors on small sample sizes of costly rocket technology.

45. FMEA Procedure Process Mapping: key steps and operations
Failure Modes of key steps and operations
Effects of failure modes and severity rating(0-10)
List causes and likelihood of occurrence(0-10)
List current controls
Rate likelihood of detection via inspection, instruments, sampling, etc. (0-10)
Calculate weighted Risk Priority Number (RPN)

46. Potential Failure Mode Potential Effects of Failure Severity Class
Core Team :
Process / Function
Potential Failure Mode
Potential Effects of Failure
Severity
Class
Potential Causes / Mechanisms of Failure
Current Design Controls Prevention
Occurrence
Current Design Controls Detection
Detect
R.P.N.
Recommended Actions
Responsibility & Target Completion Date
Action Results
Actions Taken
Occur
Detection
No action required

48. CRIT (critical characteristic RPN (risk priority number)
Function
Failure mode
Effects
S (severity rating)
Cause(s)
O (occurrence rating)
Current controls
D (detection rating)
CRIT (critical characteristic
RPN (risk priority number)
Recommended actions
Responsibility and target completion date
Action taken
Fill tub
High level sensor never trips
Liquid spills on customer floor 8
level sensor failed; 2
Fill timeout based on time to fill to low level sensor 5 N 80
Perform cost analysis of adding additional sensor halfway between low and high level sensors
Jane Doe 10-Oct-2010
level sensor disconnected

49. Summary: Formal risk evaluation tools
Ususally Applies to:
Method
Process Mapping, control
HACCP
HAZOP
FAULT TREE
CAUSE & EFFECT
FMEA
All
Food safety; biosecurity
Chemical/process safety
Defense, aerospace,
Manufacturing, service quality
Aerospace; all
What makes sense for your application?

50. In-Process Attributes BLEND & GRANULATE
System B
Output
In-Process Attributes
Quality, strength, Composition,
Methods, Tools
& Equipment
Procedure-
Media, agents,
Conditions,CPPs
BLEND & GRANULATE
Starting
Materials
Quality,
Composition
System D
Output
In-Process Attributes
Quality, strength, Composition,
Methods, Tools
& Equipment
Procedure-
Media, agents,
Conditions, CPPs
DRY
Starting
Materials
Quality,
Composition
System T
Output
In-Process Attributes
Quality, strength, Composition,
Methods, Tools
& Equipment
Procedure-
Media, agents,
Conditions,CPPs
COMPRESS
Starting
Materials
Quality,
Composition
Output
Product Attributes
Quality, strength, Composition,
COAT
PACK

51. Example solid dosage form
In this group session, (see handout ) you should list the aspects that you will evaluate when assessing the validation for the project that your group had been given.
Identify the critical parameters that should have been evaluated by the manufacturer.
List the tests to be carried out and comment on the acceptance criteria to be set.

52. Workshop Discussion using Solid Dosage Form example
Case Discussion from attendees