QbD Risk analysis for process evaluation Steve Weitzel

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.

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

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

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

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

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

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%

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?

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,

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,

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

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 http://www.fda.gov/cder/gmp/gmp2004/CGMP%20report%20final04.pdf

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

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)

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

Process Mapping Formulate Fill Package

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

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

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

Example solid dosage form In this group session, (see handout 1-3-23) 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

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

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

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?

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

↓ 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

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

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?"

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?

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

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

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.

Fault Tree Analysis (FTA) History Fault Tree Analysis (FTA) is a technique for reliability and safety analysis. Bell Telephone Laboratories developed the concept in 1962 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.

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.

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)

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.

Tree Diagram Chain of causes

Failure Mode Effects Analysis (FMEA) FMEA was formally introduced in the late 1940’s with the introduction of the military standard 1629. 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.

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)

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

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

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?

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

Example solid dosage form In this group session, (see handout 1-3-23) 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.

Workshop Discussion using Solid Dosage Form example Case Discussion from attendees