To ensure a common understanding of Quality Risk Management (QRM) by both industry and regulators To facilitate moving to the Desired State To

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2 To ensure a common understanding of Quality Risk Management (QRM) by both industry and regulators To facilitate moving to the Desired State To facilitate communication and transparency To move from fire fighting to management of risk Quality Risk management explains A common language and process Potential methodologies for QRM Where QRM can add value Does not discuss a single tool, but The Right Tool for the Job approach Risk Management Tools High-level (Ideas and Concepts) Mid-Level (Quantitative and Qualitative) Low-Level (Real numbers and real time)

3 Often rely mixed kinds of information: Quantitative Qualitative Expert judgment Focus on systematic thinking: Define the risk question Organize information under categories, attributes Build decision making paths

4 Review of Risk Assessment Concepts for FMEA and HACCP Initiating a QRM process RM activities should be performed using systematic processes designed to coordinate, facilitate and improve science-based decision-making with respect to risk. Possible steps used Risk assessment :to initiate and plan a QRM process might include the following. (Ref. ICH Q9): Risk identification( define the problem and/or risk question, including pertinent assumptions identifying the potential for risk) 1. Risk analysis( different technique FMEA,HACCP,..) 2. Risk evaluation assemble background information and/or data on the potential hazard, harm or human health impact relevant to the Risk control

5 Review of Risk Assessment Concepts for FMEA and HACCP Risk control: Identify a leader and necessary resources; and specify a timeline, deliverables and appropriate level of decision-making for the risk 1. Risk reduction 2. Risk acceptance; Risk control: The following questions need to be asked 1. What can be done to reduce or eliminate risks? 2. What is the appropriate balance among benefits, risks and resources? 3. Are new risks introduced as a result of the identified risks being controlled?

6 Review of Risk Assessment Concepts for FMEA and HACCP Risk control: The following questions need to be asked 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? Risk communication and review appropriate systems should be in place, Examples of such changes include changes to control systems, changes to equipment and processes, changes in suppliers or contractors and organizational restructuring.

7 Principles of quality risk management: The two primary principles of QRM are: a) evaluation of the risk to quality should be based on scientific knowledge and ultimately linked to the protection of the patient; and b) the level of effort, formality and documentation of the QRM process should be commensurate with the level of risk. Normally, potential risks in relation to the following should be considered: materials and ingredients; physical characteristics and composition of the product; processing procedures; microbial limits, where applicable; premises; equipment; packaging; sanitation and hygiene; personnel human error; utilities; supply chain.

8 FMEA: Failure mode and effect analysis a) Potential Application: Evaluate equipment and facilities analyze a manufacturing process to identify high risk steps and/or critical Parameters. b) Description/attributes Assumes comprehensive understanding of the process and that critical process parameters (CPPs) have been defined prior to initiating the assessment tool ensures that CPPs will be met. Assesses potential failure modes for processes, and the probable effect on Outcomes and/or product performance Once failure modes are known, risk reduction actions can be applied to eliminate, reduce or control potential failures Highly dependent upon strong understanding of product, process and/or facility under evaluation Output is a relative risk score for each failure mode Module 03 Attachment No. 2.doc, Module 03 Attachment No. 3.doc Risk_Analysis.pdf

9 Severity of Effect S Occurrence Probability O S x O Detection* Criticality S x O x D SOD or Risk Number *Higher detection ability lowers risk score. 9

10 HACCP: Hazards analysis and critical control points Potential applications Better for preventative applications rather than reactive Great precursor or complement to process validation Assessment of the efficacy of CPPs and the ability to consistently execute them for any process Description/attributes Identify and implement process controls that consistently and effectively prevent hazard conditions from occurring Bottom-up approach that considers how to prevent hazards from occurring and/or propagating Emphasizes strength of preventative controls rather than ability to detect

11 QRM application during validation and qualification QRM principles can be used to narrow the scope of IQ, OQ and PQ to cover only the essential elements that can affect product quality. It can also be used to determine the optimal schedule for maintenance, monitoring, calibration and requalification. QRM application during commercial manufacturing risk assessment and risk control of product quality risks; adverse impact to patient health based on product quality defects; product supply interruption to patients; GMP and regulatory compliance risks; multisite risks; multiproduct risks; new facility and changes to existing facility, e.g. start-ups, new commercial manufacturing processes, technology transfers and product discontinuation

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15 Design Opportunities to impact risk using quality risk management Process Materials Manufacturing Facilities Distribution Patient 15

16 Risk analysts estimate probabilities of being outside (or inside!) of design limits, given various scenarios. v 2 v 1 design space Design parameters and their intersection in a design space concept v 3 What is the chance (probability) of falling outside of the design space per unit time? 16

17 Vendor Management Across the Life Cycle Attach_1_Vendor Management Life Cycle.pdf Pre-requisite Specifications : The specification of raw materials need to be in compliance with pharmacopeial specification(current) ( verified) in addition to additional physical test that have direct impact on the quality of the products; Bulk and Tap density. Particle size distribution. Manufacturing/packaging/labelling details. Materials Safety Data Sheets. Logistic information (lead time to produce, delivery time, etc). Certificates regarding Quality system, residual solvents, etc... BSE/TSE evaluation. Analytical test method &validation.

18 A full technical package (or the open part of the Drug Master File)). A letter of authorization to access the drug master file. Stability data (accelerated and long term) to support the assigned shelf life. Impurity profile: if any of the material s related substances / impurities is not compendial, the known impurities must be ordered from the supplier. A GMP certification, Certificate of suitability (COS)

19 Quality and Regulatory compliance Change control/deviation management Recall and complaints Quality Management system Product Quality review Process validation approach Cleaning validation A representative sample and its certificate of analysis. Material should comply to USP, and whenever applicable, to EP and BP 2.2 Optional supporting documents List of customers to whom the material had been supplied List of inspection notes conducted on the supplier Copies of last FDA inspection list of observations (FDA 483) or equivalent, if applicable. List of approvals ISO certification Quality agreement with manufacturer ; Benefits??. Quality Agreement Template.docx

20 Quality and Regulatory compliance In certain circumstances where it is necessary to purchase material from a manufacturer other than the approved one, the secondary manufacturer must satisfy all the above conditions and the material must be chemically and physically equivalent to the approved one. A supplemental application shall be prepared according to FDA guidelines, which contains 3 months of accelerated stability data and full comparative dissolution profile. This supplement has to be approved by the FDA before the new supplier material can be used in manufacturing of batches

21 Quality and Regulatory compliance A scale-up batch using the new raw material is made & placed on accelerated conditions (40 0 C & 75%RH) for 3 months. If stability data supports the product quality, then routine production may begin. An extra process validation batch must be prepared for new raw material vendor Qualifying / Certifying a material is based on the following: Consistent Conformance to specifications. Proper implementation of quality agreements. Audit results.

22 Quality and Regulatory compliance Total supplier evaluation Consistent conformance to specifications: Achieved by trending all test data Fulfillment of Quality agreements. These should include: Traceability Modification on process or specifications. Packaging / Labeling / Size of packaging & quantity must be defined. Delivery conditions. Confidentiality. Audit (see point No. 4.4). Audits: Measure the gap between a reference and the reality. Have confidence in the supplier.

23 Supplier Audits Supplier Questionnaire Supplier Vendor Qualification Questionnaire.doc Supplier audit template Aide Mémoire Inspection template.pdf

24 Table 1: Summary of Quality Assessment Procedure Requirement Non Critical Raw material Critical Raw material Registered Intermediate/ API TSE/BSE Assessment Tanker Cleaning Assessment Supplier/Manufactures Questionnaire Manufacturer Audit ** Historical Performance* ** cgmp Compliance History ** 3rd party certification* ** ** Contract Agreement Quality Agreement ** *(if available), - Required, ** - Dependant on risk assessment performed on material being purchased.

25 Change Control process Definition of Change: A change is defined as an action which leads to a situation which is different than what was observed before the change took place. Change control system is not applied to like to like changes i.e. replacement of worn components/ parts with a new item of identical specification. Adjustments within validated limits are not regarded as changes provided they do not change the validation status. Any significant changes in SOP(s), Specifications, test methods, batch documents Product, Material, utilities, equipment and systems impacting the drug product quality will be handled through the change control. All changes that have the potential to impact product quality (identity, strength, purity, bioavailability, regulatory filings) must be evaluated. The types of changes requiring notification should be defined and agreed to by both the firm and the supplier. The system for Change Control is overseen by the Quality organization, but may be managed by another function All changes are assessed from a Technical, Quality, Regulatory, Stability, Safety, Environmental and business standpoint with the appropriate personnel involved in the review. The impact of the change to the affected areas, processes and systems is evaluated and communicated All changes requiring a change to the filed process will be communicated to the appropriate agencies

26 Classification of change: Changes will be divided in to two main groups depending upon the impact they have on product quality. 1. Major: All changes that may have a direct impact upon final product quality. This includes changes to: 1. Registration material 2. Manufacturing process 3. Methods and limits used as basis for release 4. Product specifications 5. Shelf life 6. Batch documents 7. Manufacturing and test equipment 8. Facilities, Systems, Equipment's, Manufacturing environment and utilities. Minor: All changes which are not major and may have indirect impact upon product quality

27 Mechanism of review change Change Control Template.doc

28 Execution and Evaluation of Change Following approval of the temporary change request by the appropriate functions and the completion of all actions required for the change the process is executed using the new material. Depending on the regulatory impact assessment the resulting material may need to be segregated and controlled to ensure compliance The evaluation of the change is performed at a number of levels as follows The resulting material produced as part of the temporary change is then evaluated by Routine testing of the material for all materials Use tests to produce the final product for critical materials and API Intermediates Extra testing to evaluate the material produced and ensure that it is within expectations for critical materials and API Intermediates The validation completion report is drafted and approved as per the normal site procedure. All prior to release and prior to implementation requirements are assessed and tracked to closure as per the site systems.

29 Closure of the Change Control Package A closure summery report is prepared verified and provide evidence that all requirements of the temporary change request have been met. This may include that all the assess the likely implications of the change on the existing process/activity/condition/ product/parameter changes are studied completely with all the necessary actions were completely executed Confirmation that all prior to release and prior to implementation requirements are fulfilled. If there are some requirements that will remain pending after closure then this will be highlighted and are managed by other site systems. The final document is approved by the original approvers of the change Technical, Quality unit and Business areas. Material may be released following approval of the change. For any regulatory requirement that remain pending, the appropriate control of the material and documentation should be maintained. If the change does not perform as expected then the temporary change request will be discontinued and cancelled and the resulting material destroyed. The change request remains temporary until all the appropriate regulatory agencies approval is received. The change then progresses through the site system and the change can be made permanent.

30 Monitoring performance Regular, typically on an annual basis, the supplier s performance should be assessed. Periodic full testing of material Quality for example number of not right first-time deliveries Complaint situation Product Quality Review (registered intermediates and APIs) Assessment of changes Reaction on audit and remediation plan ( Response times for complaints and questions Regulatory or cgmp/compliance issues (critical materials, registered intermediates and APIs) Specification (results on certificate of analysis and own results) Statistical Evaluation of Quality Control data for critical parameters to identify any adverse trends Packaging, sealing Labeling Delivery dates and quantities

31 In the light of an increasing presence of counterfeit and sub-standard products this aspect gains even more importance This development is also reflected by the fact that various initiatives have been taken such as the founding of the FDA Counterfeit Drug Task Force, the European Commission s Public consultation in preparation of a legal proposal to combat counterfeit medicines for human use (adaptation of directive 2001/83 EC) and the WHO Program IMPACT (International Medical Products Anti-Counterfeiting Taskforce). The entire supply chain from the manufacturer to the customer should be assessed and qualified from a quality perspective; For temperature/ humidity sensitive materials, the use of data loggers should be considered in order to have documented evidence that the product was stored at the required conditions during transportation. As any changes on the original container e.g. by repackaging, relabeling are considered as an additional risk for alteration or contamination, these should, whenever possible, be avoided. Additional measures need to be followed after supplier qualification and management activities related to packaging can be considered and may increase the supply chain security for APIs; A) Use of tamper-resistant packaging closure by the manufacturer, a manufacturer-specific design of the seal is recommended to be used B) Evaluation of the label by the customer: the label on the material matches the reference label provided by the manufacturer C)Assessment of the CoA against an authentic manufacturers CoA

32 Periodic Requalification and re-verification The decision for auditing/re-auditing suppliers of critical raw materials should be risk based. In this regular risk assessment the performance of the supplier, regulatory requirements and criticality of the material should be considered. The result of the assessment should be documented. The supplier of registered intermediates and APIs should be audited on a regular basis Requalification is necessary for the manufacturer if; a) Any significant changes observed/reported without prior notifications from the manufacturer, a complete requalification need to be done to identify and assess the root cause of this change b) Frequent failure of the materials supplied. C) Subcontracting of manufacturing without approval from the agent/authorities. Any other reasons?? Implementation of Quality risk Management in the pharmaceutical field from PICSImplementation of ICH Q9 in the pharmaceutical field from PICS.pdf Any questions?

33 The End Amjad Ganma, M.Sc (London) Quality Unit Manager Tabuk Pharmaceutical Manufacturing Co., Tabuk, Saudi Arabia Per. Off. amjad@tpmc.com.sa Mobile num: