PHAM 500: Quality Assurance

FOR

KATHMANDU UNIVERSITY (KU) M. PHARMACY FIRST YEAR

BY:

JAYA BIR KARMACHARYA (MBA, MPHARM) CFO, OMNICA 19 NOVEMBER 2011 KUSOM, NEPAL Ref.: WHO TRS 961, 2011; Q9 ICH Guideline on QRM
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Product shelf life Schedule M: 10. Raw Materials 10.9 Only raw materials which have been released by the QC department and which are within their shelf-life shall be used. It shall be ensured that shelf life of formulation product shall not exceed with that of active raw materials used. WHO TRS 961 2011: 14. Materials: Starting Materials 14.15 Only starting materials released by the QC department and within their shelf-life should be used.
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Requirements for QA Systems 12. Regular evaluation of product quality to verify consistency and continued improvement
(Regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement)

13. System for quality risk management (QRM).

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QA Systems
Manufacturer is responsible for the quality of the product  Fit for intended use  Comply with marketing authorization  Safety, efficacy and quality
(The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality, or efficacy).
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QA Systems
 Senior management and commitment of all staff
(The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in many different departments and at all levels within the company, the companys suppliers, and the distributors).

Requires a comprehensively designed and well implemented QA system

(To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of quality assurance incorporating GMP and quality control).

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Quality Risk Management (QRM)

It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. The manufacturing and use of a medicinal product, including its components, necessarily entail some degree of risk. It is important to understand that product
quality should be maintained throughout the product lifecycle such that the attributes that are important to the quality of the medicinal product remain consistent with those used in the clinical studies.

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Quality Risk Management (QRM)

Traditionally risk to quality have been assessed and managed in a variety of informal ways for example compilation of observations, trends and other information. These provide information that support topics
like handling of complaints, quality defects, deviations etc.

Now risk management can be performed with recognized management tools along with support of statistical tools in combination, which make easy for application of quality risk management principles.

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Quality Risk Management (QRM)

Risk Management is a process for identifying hazards associated with a product, estimating and evaluating the associated risks, controlling these risks, and monitoring the effectiveness of the control. An effective QRM ensures the high quality of medicinal product to the patient. In addition QRM improves decision making if a quality problem arises. It should include systemic processes designated to co-ordinate, facilitate and improve science-based decision-making with respect to risk.
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Quality Risk Management (QRM)

Effective QRM facilitates better and more informed decisions and provide medicinal product regulators with greater assurance of a companys ability to deal with potential risk. Risk management principles are effectively utilized in many areas of business and development including finance, insurance, occupational safety, public health, pharmacovigilance and agencies regulating these industries.

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Quality Risk Management (QRM)

It can be applied to different aspect of pharmaceutical quality including development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, medicinal products, biological and biotechnological products (including the use of raw
materials, solvents, excipients, packaging and labeling materials in medicinal products, biological and biotechnological products).

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General QRM Process

 QRM is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product across the product lifecycle. It can be applied both proactively and retrospectively.  QRM should ensure that:  the evaluation of the risk to quality is based on scientic knowledge, experience with the process and ultimately links to the protection of the patient;  the level of effort, formality and documentation of the QRM process is commensurate with the level of risk.
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Quality Risk Management: Process flow

Initiate Quality Risk Management Process
Risk Assessment Risk Identification Risk Analysis

Risk Evaluation Unacceptable Risk Control Risk Mitigation

(incl. elimination and avoidance)

Risk Communication

Risk Management Tools

[Severity]

Risk Reduction
[Probability ]

Risk Acceptance

Output / Results of the Quality Risk Management Process Risk Review Review Events
(e.g. Inspections/Audits, Complaints)

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QRM: Responsibilities QRM 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 QRM across various functions and departments of their organization; and assure that a QRM process is defined, deployed and reviewed and that adequate resources are available.
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Initiating a QRM Process

QRM should include systematic processes designed to coordinate, facilitate and improve science-based decision making with respect to risk. A QRM process might include the following: Define the problem and/or risk question, including pertinent assumptions identifying the potential for risk Assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk assessment Identify a leader and necessary resources Specify a timeline, deliverables and appropriate level of decision making for the risk management process.
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Risk Assessment Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Quality risk assessments begin with a well-defined problem description or risk question. As an aid to clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often helpful: 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong? 3. What are the consequences (severity)?
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Risk Assessment Risk identification is a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders. Risk identification addresses the What might go wrong? question, including identifying the possible consequences. This provides the basis for further steps in the quality risk management process.

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Risk Assessment Risk analysis 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. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk. Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk evaluations consider the strength of evidence for all three of the fundamental questions.

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Risk Assessment In doing an effective risk assessment, the robustness of the data set is important because it determines the quality of the output. Revealing assumptions and reasonable sources of uncertainty will enhance confidence in this output and/or help identify its limitations. Uncertainty is due to combination of incomplete knowledge about a process and its expected or unexpected variability. Typical sources of uncertainty include gaps in knowledge gaps in pharmaceutical science and process understanding, sources of harm (e.g., failure modes of a process, sources of variability), and probability of detection of problems.
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Risk Assessment The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risk. When risk is expressed quantitatively, a numerical probability is used. Alternatively, risk can be expressed using qualitative descriptors, such as high, medium, or low, which should be defined in as much detail as possible. Sometimes a "risk score" is used to further define descriptors in risk ranking.
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Risk Assessment In quantitative risk assessments, a risk estimate provides the likelihood of a specific consequence, given a set of risk-generating circumstances. Thus, quantitative risk estimation is useful for one particular consequence at a time. Alternatively, some risk management tools use a relative risk measure to combine multiple levels of severity and probability into an overall estimate of relative risk.

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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 be proportional to the significance of the risk. Decision makers might use different processes, including benefit-cost analysis, for understanding the optimal level of risk control.
Risk control might focus on the following questions: Is the risk above an acceptable level? What can be done to reduce or eliminate risks? What is the appropriate balance among benefits, risks and resources? Are new risks introduced as a result of the identified risks being controlled?
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Risk Control Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds a specified (acceptable) level. Risk reduction might include actions taken to mitigate the severity and probability 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 risk after implementing a risk reduction process.
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Risk Control Risk acceptance 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 QRM strategy has been applied and that quality risk is reduced to a specified (acceptable) level. This (specified) acceptable level will depend on many parameters and should be decided on a caseby-case basis.
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Risk Communication Risk communication is the sharing of information about risk and risk management between the decision makers and others. Parties can communicate at any stage of the risk management process (dashed arrows). The output/result of the quality risk management process should be appropriately communicated and documented (solid arrows). Communications might include those among interested parties; e.g., regulators and industry, industry and the patient, within a company, industry or regulatory authority, etc. guidances.
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Risk Communication The included information might relate to the existence, nature, form, probability, severity, acceptability, control, treatment, detectability or other aspects of risks to quality. Communication need not be carried out for each and every risk acceptance. Between the industry and regulatory authorities, communication concerning quality risk management decisions might be effected through existing channels as specified in regulations and guidances.
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Risk Review Risk management should be an ongoing part of the quality management process. A mechanism to review or monitor events should be implemented. The output/results of the risk management process should be reviewed to take into account new knowledge and experience.

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Risk Review Once a QRM process has been initiated, that process should continue to be utilized for events that might impact the original QRM decision, whether these events are planned (e.g., results of product review, inspections, audits, change control) or unplanned (e.g., root cause from failure investigations, recall). The frequency of any review should be based upon the level of risk. Risk review might include reconsideration of risk acceptance decisions.
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Risk Management Methodology The pharmaceutical industry and regulators can assess and manage risk using recognized risk management tools and/ or internal procedures (e.g., standard operating procedures). List of some of these tools: Basic risk management facilitation methods (flowcharts, check sheets etc.); Failure Mode Effects Analysis (FMEA); Failure Mode, Effects and Criticality Analysis (FMECA);.

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Risk Management Methodology List of some of these tools: Fault Tree Analysis (FTA); Hazard Analysis and Critical Control Points (HACCP); Hazard Operability Analysis (HAZOP); Preliminary Hazard Analysis (PHA); Risk ranking and filtering; Supporting statistical tools.

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Risk Management Methodology It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance and drug (medicinal) product quality. QRM methods and the supporting statistical tools can be used in combination (e.g., Probabilistic Risk Assessment). Combined use provides flexibility that can facilitate the application of quality risk management principles. The degree of rigor and formality of quality risk management should reflect available knowledge and be commensurate with the complexity and/ or criticality of the issue to be addressed.
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Risk Management Methodology Failure Mode And Effects Analysis (FMEA) Subsystem/Name: DC motor Final Design: FMEA Date (Org.): Model year/Vehicle(s): Prepared/ Reviewed by: P = Probabilities of Occurrences S = Seriousness of Failure D = Likelihood that the Defect will Reach the customer R = Risk Priority Measure (P x S x D) 1 = very low or none 2 = low or minor 3 = moderate or significant 4 = high 5 = very high or catastrophic

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Risk Management Methodology

Failure Mode And Effects Analysis (FMEA)
No. Part Functi Failure Mechani Effect(s) Curre Name on sm(s) & nt P Mode Of Causes Part Failure Contr No. ol (s) of Failure 1 Drive MeasuIncorrect Wear Extensive 4 res speed and tear damage actual reading speed P.R.A. Recomm Actio ended n(s) S D R Correctiv Take e n Action(s) 80 Voltmeter Improve check procedure s

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Quality Risk Management (QRM)

Process consisting of well-defined steps which, when taken in sequence, support better decision making by contributing to a greater insight into risks and their impacts. It includes elements such as risk identification, assessment, mitigation, elimination and communication.

Risk= Probability, Severity & Detectability

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Quality Risk Management (QRM): Case study

[1] Using a raw material for processing, which is not released by Quality Control Department. (PIC/S 5.31): Only starting materials which have been released by the Quality Control Department and which are within their shelf life should be used. (WHO TRS 961 14.15): Only starting materials released by the QC department and within their shelf-life should be used. [2] Release of intermediate product for packing before the complete analysis by Quality Control Department.
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Quality Risk Management (QRM): Case study

A Company defends this practice with justification of applying a Risk Management Approach. Assigning a Risk Priority Number (RPN), in terms of:  Severity (1-5)  Probability (1-5)  Detectability (1-5)

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Quality Risk Management (QRM): Case study

[1] Using a raw material for processing, which is not released by Quality Control Department. Severity = 5 (Severity is assigned 5 number because we
believe such practice is not the best practice and this bears a risk which can even result in discarding the product if it fails to comply the Quality Control Test.)

Note: Manufacturer purchase the materials from an approved vendor and they do the regular audit of the supplier.

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Quality Risk Management (QRM): Case study

Probability = 3 (Probability is assigned only 3 number
because such issue will not occur frequently. Such issue will be occurring only once in a few months).

Detectability = 1 (Detectability is assigned only 1 number

because the test is being carried out simultaneously and the batch will be released only after assuring the release from the Quality Control Department).

So when calculating the RPN (5 ' 3 ' 1) = 15. In the context of Risk Factor, this seems to be a very safe risk, which can be taken without any hesitation.
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Quality Risk Management (QRM): Case study

[2] Release of intermediate product for packing before the complete analysis by Quality Control Department. Severity = 5 (Severity is assigned 5 number because we
believe such practice is not the best practice and this bears a risk which can even result in discarding the product if it fails to comply the Quality Control Test.)

Note: The manufacturing process is a validated process and In-Process Control test is done as per the routine schedule.).
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Quality Risk Management (QRM): Case study

Probability = 2 (Probability is assigned only 2 number
because such issue will not occur frequently. Such issue will be occurring only once in a year, during marketing emergency situations).

Detectability = 1 (Detectability is assigned only 1 number

because the test is being carried out simultaneously and the batch will be released only after assuring the release from the Quality Control Department).

So when calculating the RPN (5 ' 2' 1) = 10. In the context of Risk Factor, this seems to be a very safe risk, which can be taken without any hesitation.
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Product Quality Review

 Regular, periodic or rolling quality reviews of all medicinal products, including export-only products, should be conducted with the objective of verifying  the consistency of the existing process  the appropriateness of current specications for both starting materials and nished product to highlight any trends and to identify product and process improvements.

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Product Quality Review

 Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least: (i) a review of starting materials and packaging materials used for the product, especially those from new sources; (ii) a review of critical in-process controls and nished product results; (iii) a review of all batches that failed to meet established specication(s) and their investigation;

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Product Quality Review

(iv) a review of all signicant deviations or nonconformances, the related investigations and the effectiveness of resultant corrective and preventive actions taken; (v) a review of all changes made to the processes or analytical methods; (vi) a review of dossier variations submitted, granted or refused; (vii) a review of the results of the stability monitoring programme and any adverse trends;

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Product Quality Review

(viii) a review of all quality-related returns, complaints and recalls and the investigations performed at the time; (ix) a review of adequacy of any other previous corrective actions on product process or equipment; (x) for new dossiers and variations to the dossiers, a review of post-marketing commitments; (xi) the qualication status of relevant equipment and utilities, e.g. heating, ventilation and airconditioning (HVAC), water, or compressed gases; (xii) a review of technical agreements to ensure that they are up to date.
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Product Quality Review

 The manufacturer and marketing authorization holder, where different, should evaluate the results of this review and an assessment should be made whether corrective and preventive action or any revalidation should be undertaken. Reasons for such corrective actions should be documented. Agreed corrective and preventive actions should be completed in a timely and effective manner. There should be management procedures for the ongoing management and review of these actions and its effectiveness should be veried during selfinspection. 19.11.2011 1101 PHAM 500 JBK1101CC 44

Product Quality Review

Quality reviews may be grouped by product type, e.g. solid dosage forms or liquid dosage forms or sterile products, where scientically justied. Where the marketing authorization holder is not the manufacturer, there should be a technical agreement in place between the various parties that denes their respective responsibilities in producing the quality review. The authorized person responsible for nal batch certication, together with the marketing authorization holder, should ensure that the quality review is performed in a timely manner and is accurate.
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-Jaya Bir Karmacharya E-mail: jayabir61@yahoo.com Tel: 9843069869/5522023

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