quality risk bvr

8/8/2019 Quality Risk Bvr

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Quality Risk ManagementQuality Risk Management

SeminarSeminar


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ScopeScope

Provides principles and examples of tools for Quality Risk

Management that can be applied to different aspects of

pharmaceutical quality. These aspects include development,

manufacturing, distribution and the inspection submission/review

processes throughout the lifecycle of drug substances and drugproducts, biological and biotechnological products (including the use

of raw materials, solvents, excipients, packaging and labeling

materials in drug products, biological and biotechnological products.


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DefinitionsDefinitions

Quality: The degree to which a set of inherent properties of the

product, system or process fulfils the requirements.

Risk: The combination of the probability of occurrence of harm and

the severity of that harm.

Harm: Damage to health, including the damage that can occur fromloss of product quality or availability.

Risk Management: The systematic application of Quality

management policies, procedures and practices to the tasks of

assessing, controlling, communicating and reviewing risk.

Quality Risk Management:A systematic process for theassessment, control, communication and review of risks to the

quality of the drug (medicinal) product across the product lifecycle


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Principles of Quality RiskPrinciples of Quality Risk

ManagementManagement

The evaluation of the risk to quality should be based on

scientific knowledge and ultimately link to the protection of

the patient; and

The level of effort, formality, and documentation of the

quality risk management process should be commensuratewith the level of risk.


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General Quality RiskGeneral Quality Risk

Management ProcessManagement Process

Responsibilities:Quality risk management activities are usually, but not always,

undertaken by interdisciplinary teams. When teams are formed, they

should include experts from the appropriate areas (e.g., Quality Unit,

Business Development, Engineering, Regulatory Affairs, Production

Operations, Sales and Marketing, Legal, Statistics, and Clinical) in

addition to individuals who are knowledgeable about the quality risk

management process.

Decision makers should

Take responsibility for coordinating quality risk management acrossvarious functions and departments of their organization and

Ensure that a quality risk management process is defined, deployed,

and reviewed and that adequate resources are available.


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1. Initiating a Quality Risk ManagementProcess:Quality risk management should include systematic processesdesigned to coordinate, facilitate and improve science-based

decision making with respect to risk. Possible steps used to initiateand plan a quality risk management process might include thefollowing:

1.Identification of risk in a selected domain of interest

2.Planning the remainder of the process.

3.Mapping out the following:

a. The social scope of risk managementb. The identity and objectives of stakeholders

c. The basis upon which risks will be evaluated andtheir constraints.


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1. Initiating a Quality Risk Management

Process (Cont.):4. Defining a framework for the activity and an agenda for

identification.5. Developing an analysis of risks involved in the process.

6. Mitigation of risks using available technological, human and

organizational resources.


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2. Risk assessment:It is considered as the initial and periodical step in a riskmanagement process. Risk assessment is the determination ofquantitative orqualitative value of risk related to a concrete situation

and a recognized threat.

3. Risk Identification:It is a systematic use of information to identify hazards referring tothe risk question or problem description. Information can includehistorical data, theoretical analysis, informed opinions, Risk

identification addresses the "What might go wrong?" question,including identifying the possible consequences. This provides thebasis for further steps in the quality risk management process.


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4. Risk analysis:

It is the estimation of the risk associated with the identified hazards.

It is the qualitative or quantitative process of linking the likelihood of

occurrence and severity of harms.

5. Risk Evaluation:It compares the identified and analyzed risk against given risk

criteria.


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6. Risk Control:

Risk control includes decision making to reduce and/or accept risks.

The purpose of risk control is to reduce the risk to an acceptable

level. The amount of effort used for risk control should beproportional to the significance of the risk. Decision makers might

use different processes, including benefit-cost analysis, for

understanding the optimal level of risk control.


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6. Risk Control (Cont.):

Typical questions in a risk control process include:

y a. Does the risk exceed an acceptable level (e.g. Regulatorystandards), action levels?

b. What steps might be taken to reduce or eliminate remainingrisks?

c. What is an appropriate balance among risks, benefits, andresources to manage risks?

d. These questions address the immediate risks identified in a riskmanagement program. Most risk management scholars add (atleast) a fourth consideration:

d. Are new risks introduced as a result of risk management stepsto control the identified risks?


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7. Risk Reduction:

It focuses on processes for mitigation or avoidance of quality risk

when it exceeds a specified (acceptable) level (see Figure. 1). Risk

reduction might include actions taken to mitigate the severity andprobability of harm. Processes that improve the detectability of

hazards and quality risks might also be used as part of a risk control

strategy. The implementation of risk reduction measures can

introduce new risks into the system or increase the significance of

other existing risks. Hence, it might be appropriate to revisit the risk

assessment to identify and evaluate any possible change in riskafter implementing a risk reduction process.


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8. Risk Acceptance:

It is a decision to accept risk. Risk acceptance can be a formal

decision to accept the residual risk or it can be a passive decision in

which residual risks are not specified. For some types of harms,even the best quality risk management practices might not entirely

eliminate risk. In these circumstances, it might be agreed that an

appropriate quality risk management strategy has been applied and

that quality risk is reduced to a specified (acceptable) level. This

(specified) acceptable level will depend on many parameters andshould be decided on a case-by-case basis.


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9. Risk Communication:

It is the sharing of information about risk and risk managementbetween the decision makers and others. Parties can communicateat any stage of the risk management process (see Fig. 1: dashedarrows). The output/result of the quality risk management processshould be appropriately communicated and documented (see Fig. 1:solid arrows). Communications might include those amonginterested parties (e.g., regulators and industry; industry and thepatient; within a company, industry, or regulatory authority). Theincluded information might relate to the existence, nature, form,probability, severity, acceptability, control, treatment, detectability, orother aspects of risks to quality. Communication need not be carriedout for each and every risk acceptance. Between the industry andregulatory authorities, communication concerning quality riskmanagement decisions might be effected through existing channelsas specified in regulations and guidance.


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10. Risk Review:

Risk management should be an ongoing part of the qualitymanagement process. A mechanism to review or monitor events

should be implemented.

The output/results of the risk management process should bereviewed to take into account new knowledge and experience. Oncea quality risk management process has been initiated, that processshould continue to be utilized for events that might impact theoriginal quality risk management decision, whether these events areplanned (e.g., results of product review, inspections, audits, changecontrol) or unplanned (e.g., root cause from failure investigations,recall). The frequency of any review should be based upon the levelof risk. Risk review might include reconsideration of risk acceptancedecisions.


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Risk Assessment TechniquesRisk Assessment Techniques

FMEA: Failure Mode Effects Analysis

FMECA: Failure Mode Effects and Criticality Analysis

HACCP: Hazard Analysis and Critical Control Points

HAZOP: Hazard Operability Analysis

FTA: Fault tree Analysis

PHA: Preliminary Hazard Analysis

PDPC: Process Decision Programme Chart


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Failure Mode Effect AnalysisFailure Mode Effect Analysis

(FMEA)(FMEA)


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ScopeScope

Applicable for all equipment/facilities and

operations which are likely to affect the

product/process and for investigation of root

cause of Complaints/OOS/Deviations.


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DefinitionsDefinitions

Cause : The under lying factor behind the failure.

Effect : The result of an action / inaction (that which /could resultfrom a cause)

Failure : Different ways that a process or sub-process can fail toprovide the anticipated result.

FMEA : A systematic method of identifying and preventing productand process problems (Failure modes) before they occur. FMEAused primarily to evaluate the process prior to its implementation.

Risk : Combination of the probability of occurrence of harm andseverity of the harm.

Risk Priority Number (RPN) :It is a numeric assessment of risk

assigned to a process, or steps in a process, as part of failure modeand effect analysis (FMEA). Each failure mode gets a numeric scorethat quantifies likelihood of occurrence, likelihood of detection andseverity of impact.


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FMEA Basic StepsFMEA Basic Steps

Identifying the process to be examined

Providing justification for selecting the item / process / product /system for FMEA.

Assigning FMEA team members and team leader.

Explaining the methodology to the team

Preparing a flowchart or detailed process flow of the processunder analysis. All steps in the process should be included.

Designating which of the steps in the process constituteFunctions and identify elements of variations in equipment,methods, materials, control and measurement.

Determination which functions represents potential Failure

modes or points of potential failure and record.Determining the worst potential Effect or consequences of eachof the failure modes.


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Determining the contributory factors for each failure mode (Use of

term contributory factor rather than cause).

Identifying any controls in the process. controls are components

of the process which

reduce the likelihood of a contributory factor or a failure mode, reduce the severity of an effect

Detect the occurrence of a failure mode or contributory factor

before it leads to the adverse outcome. Example of control

measures: SOP, BMR, BPR, Validation, in process controls

and alarm systems


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Rate the severity of each effect on a scale of 1-5,

Scale Severity Rating

1 No Effect on output

2 Minor Effect

3 Moderate Effect

4 Serious Effect

5 Hazardous Effect

The impact of controls that improve the severity of an effect are

reflected in this rating as well.


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Rate the occurrence (likelihood) of each contributory factor on a

scale of 1-5.

Scale Occurrence Rating

1 Failure unlikely

2 Remote Failure

3 Occasional Failure

4 High Failure

5 Failure Certain

The impact of controls that reduce the likelihood of occurrence of a

failure mode or contributory factor are reflected in this rating as well.


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Based on the control measures; rate the effectiveness of each

Detection control on a scale of 1-5.

Scale Detection Rating

1 Flawless detection system

2 Will detect Failure

3 Might detect Failure

4 Almost Certain not to detect Failure

5 Lack of Detection Control


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Multiply the three ratings by one another for each factor. Theresultant number in the risk priority number (RPN) for thatcontributory factor. For example: if severity rating is 3, occurrencerating is 2 and detection level is 1, then RPN = 3 x 2 x 1 = 6

Rank order the contributory factor according to the RPN.

The RPN determines the criticality of the failure mode and helpsdetermine whether the risk of failure should be accepted (No actionmay be required for the potential failure), controlled (take action toenhance detection or reduce the risk of the potential failure) oreliminated (prevent the potential failure.

FMEA is used to analyze the current process and evaluate thepotential impact of change under consideration. Calculate estimated

RPN each time we consider, a change to the process, to evaluatethe impact of the change. If RPN is high, then priority should begiven to such items and based on the current control measures,action plan for additional measures required should be made.Priority should also given to items with high severity rate.


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Acceptance criteria: The FMEA should be considered as

acceptable if the estimated RPN is less than or equal to 10, along

with minimum rating for factors of occurrence and severity.

Example of FMEA table:

Item orProcessStep

PotentialFailureMode

PotentialEffect(s)of Failure

Severity

PotentialCause(s)

Occurren

ce

Currentcontrols

Detection

RPN

Recommended action

ResponsibilityandTargetDate

Afteractiontaken

Severity

Occurrence

Detection

RPN


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Case StudyCase Study -- 11

Item orProcess Step

Potential Failuremode

PotentialEffect(s) of

FailureS

Potential causes

OCurrent control

measuresD

RPN(SXOX D)

Recomm-

endedAction

Responsibility

andTargetDate

Afteractiontaken

S O DRPN

(SXOX D)

Sifting/Milling

Loss ofintegrity ofsifter /multimillsieves /screen.

Sifting operationwill not be as per process

specifications.Improper particledistribution.Pr oblem dur ingcompression.Content uniformitymay be affected.Flow of granulesmay not be goodenough for compression.Bulk density maybe out of specification.Metal particles

can enter into theproduct

5

Sieve /screenmaydamageduringoperation,cleaning orimproperhandling.

2

Sieve / screenintegrity is checkedbefore and afterevery sifting /screening operation.If sieve integrity isfound to be lost aftersifting whole batch isresifted using intactsieve.All tablets arepassed throughmetal detectors.

2 5x2x2=20

Magneticgrills to beused topass siftedmaterialscomingfrom sifterandmultimill.

Production,Engineering and QA

5 2 1 5x2x1=10


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Item orProcess

Step

PotentialFailuremode


FailureS

Potential causes

OCurrent control

measuresD

RPN(SXOX D)

Recomm-

endedAction

Responsibility

andTargetDate

Afteractiontaken

S O DRPN(SXOX D)

ranulationFBD/FBEfinger bagruptures.

Loss of product. 5

The baggotdamagedduringdrying,handlingorWashing.

1

Solid flow monitor isinstalled after fingerbag, which trips theFBD whenever itdetects flow of powder.The funct ioning of solid flow monitor ischecked periodically.The bags arec ritically checkedvisual ly before andafter usage andcleaning

1 5x1x1=5

Currentcontrolmeasuresareadequate

- - - - -


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Item orProcess

Step



FailureS

Potential causes

OCurrent control

measuresD

RPN(SXOX D)

Recomm-

endedAction

Responsibility

andTargetDate

Afteractiontaken

S O DRPN(SXOX D)

CompressionHopper leveldecreasedbelow limit.

Flow ofgranules notproper.Soft / underweight tablets.May result inmarketcomplaint.

4

Lack of granules inhopper.

2

Height adjustablehoppers areprovided to controlthe flow of granules

over turret.Detachable powderlevel sensor on bothhoppers is availableat hopper viewwindow.Machine inter lockingwith hopper levelsensor is provided.If level of granules is

below the viewwindow the greenlamp flashes &displayed on PLC as low hopper level.

and machine stops ifthe granules levelfurther falls below.

1 4x2x1=8

Currentcontrolmeasuresareadequate

- - - - -


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Item orProcess

Step



FailureS

Potential causes

OCurrent control

measuresD

RPN(SXOX D)

Recomm-

endedAction

Responsibility

andTargetDate

Afteractiontaken

S O DRPN(SXOX D)

CoatingPeeling offilm fromtablets.

Tablets failingin appearance.Marketcomplaint.

4

Low

mechanicalstrength ofcoating.Inadequateplasticizerin coatingsuspension.Pooradhesionofcoating totablets.

2

Coating liquidformulation isvalidated duringprocess validation.Coated tablets aresubject to 100%inspection.Immediate andcontinuous Drying oftablets is facilitatedby proper exhaust.

1 4x2x1=8

CurrentcontrolMeasuresareadequate.

- - - - -


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Item orProcess

Step



FailureS

Potential causes

OCurrent control

measuresD

RPN(SXOX D)

Recomm-

endedAction

Responsibility

andTargetDate

Afteractiontaken

S O DRPN(SXOX D)

Bottle Packing

Bottle withImproperinductionsealing

Product qualityaffectedMarketcomplaint

5

Sealinghead notset atrequiredheight.TiltedCapsConveyorspeed notset as perrequirement.Electricalpower tosealinghead is notset as perrequirement.Cap

withoutinductionsealingwad.

1

Machine is set asper SOP andchecked byproduction officerinitially Leak test ofsealed bottle isperformed after initialsetting of machine.Conveyor speed isset as perrequirement initiallyand certified.Power setting isdone as perrequirement duringinitial setting.Bottles are checked

for f requently.

1 5x1x1=5

Currentcontrolmeasuresareadequate.

- - - - -


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Applications of FMEAApplications of FMEA

Some applications for FMEA analysis:

Used to evaluate the design of products and processes(manufacturing line, service procedures, etc.) to anticipate andaddress potential failure modes early in the process when they are

less expensive to correct.Contributes to the development of effective maintenanceprocedures.

Used to evaluate plans to modify an existing process.

Used to investigate the reliability of existing systems/processes.

Provides a central location for reliability-related information for the

system/process.Provides a knowledge base for future troubleshooting efforts.

Provides a learning tool for new professionals.


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Applications of FMEAApplications of FMEA

Contributes to the identification of requirements for built-in testequipment.

Performed to meet a customer requirement and/or to comply withSafety and Quality requirements, such as:

ISO 9001, QS 9000

ISO/TS 16949

Six Sigma

FDA Good Manufacturing Practices (GMPs)

Process Safety Management Act (PSM).


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