Medical device SOPs

1.0 PURPOSE:

The purpose of this standard operating procedure is to establish a structured framework for the comprehensive data collection, analysis, reporting of information about the safety and efficacy of the product (Medical Devices) post-release into the market.

2.0 SCOPE

This procedure covers all products that have been transferred from product development to the post market surveillance. This procedure also addresses the requirement of Annexure-III in regulation EU 2017/745 and regulation EU 2017/746.

This is the primary document meeting the applicable regulatory requirement for post marketing surveillance and the supporting document for Risk Management and define the quality system manual of the company.

This procedure applied to the gathering the information for production and post production activities as required by ISO 149712:2019. Clause 10 (Risk Management). This procedure is a part of feedback process for evaluating the quality management system and whether or not the company is meeting customer needs the procedure service the potential input for receiving feedback and outline the method that this feedback may be received as required by ISO 13485:2016.

3.0 REFERENCE

• EU ISO 14971:2019-Medical Devices: - Application of Risk Management to the Medical Devices
• ISO /TIR 24971:2020-Medical Devices-Guidance on the Applications of ISO 14971
• MEDDEV 2.7/1 Revision 4: Guidance on Medical Devices Clinical Evaluation: - A guide for the Manufacturer and Notified Body
• MEDDEV 2.12/2 Revision 2, January 2012: - Guideline on the medical devices post market clinical follow up (PMCF) studies
• Regulation EU 2017/745 and regulation EU 2017/746
• ISO 13485: 2016

7.0 PROCEDURE:

7.1 Post Marketing Surveillance (PMS) Plan

7.1.1 The transfer of the clinical evaluation file and the risk file from a product development project to the PMS file is planned in the product development plan accordingly to the product development procedure. Typically, the PMS plan for each product is initiated after the approval of design output (i.e. design freeze) and the PMS plan is approved at the end of the design transferred process along with commercial release of the product. The risk management plan for the post commercial launch is also typical including the part of PMS plan.

7.1.2 Individual PMS documents are initially approved according to the design and development procedure and the chances or control according to the change control procedure. File are indexed from their key documents. A PMS file for the product or product family is indexed using the PMS plan and the PMS report

7.1.3 (Reference-8.2.1 Para.2): The following elements shall include the collection and utilisation the following inputs: -

• Information concerning serious incidents including information from PSURs and field safety corrective action.
• Record refereeing to non-serious incidents and data on any undesirable side effect
• Information from trend reporting
• Relevant specialist or technical literature database and or registers
• Information including feedbacks and complaints provided by user/distributor and importers and publicly available information about similar medical devices and in-vitro diagnostics
• Any other decided area where company could gain specific experience from post production activities, the review of this experience shell forms a part of feedback process

7.1.4 (Reference-8.2.1 Para 2): Additional source of PMS data that should be considered in the preparation of PMS plan for the product or product family

• Information from the research and development activities within company or at any contract designer
• Information from the services and customer training personnel within or contracted by the company
• Information from the user of the product by any means by which the feedback maybe sought (e.g. customer survey)
• Information relating to the market experience of the similar product or the product with similar intended use e.g. for regulatory registers or incident database
• Frequency and nature of the clinical evaluation e.g. post market clinical studies or published specification that may be applicable.

7.1.5 Suitable indicator and threshold value shall we use in the continuously Risk assessment of the benefit/analysis and risk management

7.1.6 Complaints and investigation shall be included in the collection of PMS data

7.1.7 (Reference-8.2.1 Para 3): The information gathered in in this feedback process shell serve as a potential input management for the monitoring and maintaining the product requirement as well as the product process

7.2 Post Market Clinical Follow Plan Or Protocol

7.2.1 The post market clinical follow-up (PMCF) plan should be documented for each product or product family. The PMCF plan summarizes method for the collection of clinical data after product approval this term may be synonyms with the PMCF protocol.

7.2.2 Post market clinical followed in the continuous process that provide both input into updating the clinical evaluation report and is a part of post marketing surveillance.

7.2.3 The PMCF plan shell specify the method and procedure for proactively collecting and evaluating the clinical data with the aim of:-

1. Confirming the safety and performance of the device throughout its expected lifetime.
2. Identifying the previously unknown side effect and monitoring the identified side effect and contraindications.
3. Identifying and analysing the emergent risk on the basis of factual evidence
4. Ensuring the continued acceptability of the benefit risk ratio.
5. Identify the possible systematic misuse or off label used of the device be the view to verifying that the intended purpose is correct

7.2.4 The PMCF plan shall include at least: -

1. The general method and procedure of the PMCF to be applied such as gathering the clinical experience gained, feedback from user screening of scientific literature and other sources of clinical data.
2. The specific method and procedure of the PMCF to be applied such as evaluation of the suitable register or PMCF studies
3. A rational for the appropriateness of the method and procedure referred to the point A and B.
4. A reference to the relevant part of clinical evaluation report.
5. The specific objective to be addressed by the PMCF
6. An evaluation of the clinical data relating to the equivalent or similar devices
7. Reference to any relevant clinical studies, harmonized standards used by the manufacture or relevant guidance on the PMCF and a detailed and adequately justify time schedule for PMCF activities (e.g. Analysis of PMCF data and reporting) to be undertaken by the manufacture.

7.2.5 The PMCF finding shall be analysed to produce a PMCF report and use this information as an input into the risk management system and if necessary to initiate corrective and preventive action

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1.0 PURPOSE:

This procedure defines (Company name) requirement for submitting and maintaining the Canadian medical devices licence in accordance with the Canadian medical devices regulations.

2.0 SCOPE

This procedure is the primary document meeting the applicable regulatory requirement for Canadian licence as defined in company name quality system manual.

3.0 REFERENCE

• SOR/ 98 - 282 health Canada medical devices regulation
• Medical devices application form website

4.0 DEFINITIONS

• CMDR- Canadian Medical Devices Regulation
• MDSAP- Medical Devices Single Audit Program
• TPD- Therapeutic Products Directorate

8.0 PROCEDURE:

8.1 Overview

8.1.1 New or modified product may not be released for the sale or distribution in the Canada until the required regulatory submission documentation is completed.

8.1.2 Canadian licence required annual renewal. All Paper box with instruction is provided annually by the Canadian governments and sent to the official company correspondent this paper is to be completed by quality management.

8.1.3 A device licence will be filled with the health Canada as applicable in accordance with the CMDR for the class of devices. The classification requirement and applicable licence requirement identified in the current CMDR will be followed

8.1.4 Amended licence will be applied for when product changes required and amendment licence to be submitted new or amendment certificate will be forward to the Minister within 30 days.

8.1.5 If there is a change to the quality system certificate the company is required to notify health Canada and submit a copy of the updated certified in 30 days. Discontinuation of the certified required notification of health Canada within 30 days. The recognised registrar is required to notify health Canada within 15 days of these changes.

8.1.6 Therapeutic product directorate (TPD) applies Canada's medical devices regulations

8.1.7 For class I devices, medical devices establishment licence is not necessary if important through a distributor that has a valid establishment licence.

8.1.8 Class I medical devices do not required application for Canadian medical devices licence

8.1.9 Class II, III and IV medical devices do required application for Canadian medical devices licence

8.2 Development For Canadian licensing

8.2.1 For any medical devices that the company internet to distribute in Canada the classification of the devices must be determine first classification in accordance with the classification rule found in schedule 1 (Section 6) Part 1 of CMDR

8.2.2 Verification of devices classification can be achieved by contacting health Canada directly

Device licensing division health Canada

e-mail: - device_listing@hc-sc.gc.ca

Tel: +1- (613) 957-7285

8.2.3 Product Shell be Developed in accordance with the regulatory requirement.

Class II, Class III and Class IV devices require that the company has a certified ISO 13485 quality management system. A MDSAP certification audit will be necessary pair to sale in Canada evidencing compliance to the Canadian medical devices’ regulations. Health Canada Has a list of approved Registrar on their website: (website direct link mentioned in the SOP)

8.2.4 Class 1 medical devices do not require a certified ISO 13485 quality management system, but it require the following procedure to be implement:

• Corrective and preventive action
• complaint handling
• Product recall
• mandatory problem reporting

8.2.5 The company shall have the procedure that outline the following activities:

• Design control
• Technical file management
• Risk analysis
• Complaint management

8.2.6 The company shell has established the following element for product intended for sale in Canada

8.2.6.1 Production controls

• Product specification
• Production work instruction
• Quality inspection and test method for product
• Packaging and storage requirement

8.2.6.2 Device Master record

8.2.6.3 Technical file

8.2.6.4 Es sential requirement checklist

8.2.6.5 Risk management file

8.2.7 For devices containing a measurement function:

Documentation needs to be produced to show that the measurement can perform within stated tolerance. Reference of procedure, test reports etc. need to be included and record maintained.

8.2.8 For devices containing software

Software development required additional documentation for the verification validation testing that was completed as well as reference to procedure, test report and Standards, etc.

8.2.9 Labelling Requirement of Medical Devices  

Product labelling shall be evaluated as a part of design control procedure labelling shell comply with health Canada requirement.

The labelling shell include the following information:

• The name of device the name and address of manufacturer
• The identifier of the devices including the identifier of any medical devices that is a part of system test kit, medical devices group, medical devices family or medical devices group family
• In case of class III and class IV the control number;
• If the contents are not rapidly apparent and indication of what the package contain expressed in terms appropriate to the device such as the size network length volume or number of units
• The word sterile if the manufacturer intended device to be sold in a sterile condition
• The expiry date on the devices if the devices have one to be determined by the manufacturer on the basis of components that has the sorter projected useful life
• Unless self-evidence to be intended user the medical condition’s purpose and uses for which the devices is manufacture sold or represented including the performance specification of devices if those specification are necessary for proper use
• The direction for use, unless directions or not required for the devices to be used safely and effectively and
• Any special storage condition applicable to the device

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1.0 PURPOSE:

The purpose of this document is to ensure that records and data within (Company Name) quality management system are controlled in such a way that they remain legible readily identifiable and retrievable for at least as long as is required by the regulatory requirement and (company name) business needs.

2.0 SCOPE

This procedure covers all records generated within the (company name) quality management system.

This is the primary document meeting the applicable regulatory requirement for the record control as define in (company name) quality system manual.​

7.0 PROCEDURE:

Records are maintained so that they remain legible, readily identifiable and retrievable.  

7.1 Record Completion

7.1.1 Enter event such as action taken, data, observation etc. as they occur

7.1.2 Do not pre-date or post-date the record.

7.1.3 Complete record for your own actions; never you Signatures initial or equivalent for another person

7.1.4 Complete all field on a form, if not applicable to put a line in the field, initial and date

7.1.5 Use Black or blue indelible ink to complete the forms

7.1.6 Correct error by putting one line through such that the original data is still legible, write a correction above or to the side of the original entry, initial and date.

7.1.7 When the data is transferred from raw data to the another document, “Verified transferred to xxx, initial, date”

7.1.8 Sign or initial in the same format as is recorded in the signature register

7.1.9 Date format is as mention in the Good Documentation Practices SOP. e.g. dd-mm-yy or mm-dd-yy or dd-mm-yyyy.

7.2 Record management in destruction

7.2.1 Paper record may be scan to the appropriate file name and forwarded to the document controller electronically or physically sent to them to perform the task. The person scanning the record is also responsible for the destruction of the paper record, once it has been securely filed.

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1.0 PURPOSE

To provide procedure for Qualified Person responsible for Pharmacovigilance role and responsibilities.

2.0 SCOPE: 

This procedure is applicable for qualified person for responsible for pharmacovigilance (QPPV) role and responsibilities.

3.0 RESPONSIBILITY:

4.0 DEFINITIONS:

Pharmacovigilance: Pharmacovigilance is the science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.

5.0 PROCEDURE:

5.1 Role and Responsibilities

5.1.1 The QPPV should be qualified, with documented experiences and training in all aspects of phai'inacovigi1ance.

5.1.2 Establishing and maintenance of pharmacovigilance system.

5.1.3 Influence the quality system and PV activities.

5.1.4 Access to PSMF and verify it is accurate and up to date.

5.1.5 Having awareness of any conditions or obligations adopted as part of the marketing authorizations and other commitments relating to safety.

5.1.6 Having awareness of risk minimization measures.

5.1.7 Being aware of and having sufficient authority over the content of risk management plans,

5.1.8 Being involved in the review and sign-off of protocols of Post Authorization ion Safety Study (PASS).

5.1.9 Having awareness of PASS requested by a competent authority including results of such studies.

5.1.10 Ensuring conduct of pharmacovigilance and submission o1 all pharmacovigilance - related documents in accordance with the legal requirements and GVP.

5.1.11 Ensuring the necessary quality, including the correctness and completeness, of pharmacovigilance data submitted to the competent authority.

5.1.12 Ensuring a full and prompt respou.se to any request from the competent authorities for the provision of additional information necessary for the benefit risk evaluation of a medicinal product.

5.1.13 Providing any other information relevant to the benefit-risk evaluation to the competent authorities.

5.1.14 Providing input into the preparation of regulatory action in response to emerging safety concerns (e.g. variations, urgent safety restrictions, and communication to patients and healthcare professionals).

5.1.15 Acting as a single pharmacovigilance contact point for the competent authorities on a 24-hour basis and also as a contact point for pharmacovigilance inspections.

5.1.16 QPPV: oversight the functioning of the system in all relevant aspects, including its quality system e.g. Standard operating procedures. contractual arrangements, database operations, compliance data regarding quality, completeness and timeliness of expedited reposing and submission or' periodic update reports, audit reports and training of perso.me! in relation to pharmacovigilance.

5.1.17 QPPV should be aware of the validation status of the adverse reaction database. The QPPV should also be informed of significant changes that are made to the database (e.g. changes that could have an impact on pharmacovigilance activities).

5.1.18 The name and 42-hour contact details of the QPPV and back-up procedures.

5.1.19 Individual, usually an employee of a pharmaceutical company, who is personally responsible for the safety of the human pharmaceutical products marketed by that company in Country

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1.0 PURPOSE

To provide procedure for the process for determining the seriousness criteria of adverse events (AE). Prioritization of the reports as per the required timeline serious versos non serious.

2.0 SCOPE: 

This SOP document applicable to all pharmacovigilance safety staff in PVG departments and Case/Report collection, triage (The term comes from the French verb trier, meaning to separate, sift or select. It is the process of determining the priority of patients' treatments based on the severity of their condition. This rations patient treatment efficiently when resources arc insufficient for all to be treated immediately), prioritization of expedited and non-expedited reports and processing personnel.

4.0 DEFINITIONS:

Pharmacovigilance: Pharmacovigilance is the science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.

5.0 PROCEDURE:

5.1 Reporting timeline us per the seriousness.

5.1.1 Time frames for other types of serious reporting vary among countries, depending on source, expectedness, and outcome.

5.1.2  Day 0- The regulatory reporting time clock is considered to start on the date when any personal of the Marketing Authorization Holder first receive a case report that trill Tills minimum criteria as well as the criteria for expedited reporting. In general, this date shouts be considered day 0.

5.2 Serious Criteria. Ari adverse event is considered serious if it meets one or more of the following criteria:

5.2.1 Death

5.2.2 Life-Threating

5.2.3 inpatient hospitalization. or prolongation of existing hospitalization

5.2.4 Persistent or significant disability or incapacity

5.2.5 Congenital anomaly (birth defect)

5.2.6 Medically significant (i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.

5.2.7 If an event has been determined to be serious, it is important to choose all appropriate criteria5.; therefore, it is possible for an event to have more than one serious criterion. e.g. A heart attack might result in both hospitalization and death.

5.2.8 The event serious criteria provided by a reporter cannot be downgraded to non- serious by the company.

5.2.9 In adverse event report forms, the serious criteria are reported at a report level and not an event level. So medical concept and scientific judgment should be exercised in conjunction with a review of the event description when determining serious criteria for each event.

5.2.10 Death- For the adverse event results in death, because of any reason, the serious criterion of death is selected. If the only available information is that the patient died, then serious criterion of death should be selected for the death event. Follow-up should be attempted to obtain the actual cause of death and other event details.

5.2.11 Life-Threatening- The term life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe (e.g., pancreatic failure or breathing difficulty). As reporters may have different interpretations of life-threatening situation possible, an appropriate follow-up must be pursued to validate that the event posed the patient at an immediate risk of death.

5.2.12 Please refer the below table to assess the actual life threating scenarios-

5.3 Hospitalization. - Hospitalization is considered when an event causes Hospitalization or prolongation of existing a Hospitalization. Hospitalization should be selected even if a patient is admitted to a hospital but released on the same day.

5.3.1 Hospitalization is considered if following situations exists:

5.3.1.1 In-patient hospitalization as a direct result of the event

5.3.1.2 Event resulted in the duration of the existing hospitalization get prolonged

5.3.1.3 Hospice care provided in a hospital facility.

5.3.2 Hospitalization is not considered if following situations exists:

5.3.2.1 Patient visits to the emergency room or outpatient clinic but was not admitted for inpatient hospitalization.

5.3.2.2 Hospitalization was not caused by the event, rather than by other factors like social (non-medical) reasons, treatment reasons, elective hospitalizations, or protocol requirements in study case.

5.3.2.3 Patient had admission for observation (e.g. following an overdose).

5.3.2.4 Patient had hospice care anywhere outside of a hospital facility (e.g. patient home or nursing home).

5.3.3 If a hospitalization is due to a surgical procedure and qualifies as on AE (e.g., the event is a pre-existing condition that worsened or a nor-elective procedure) consider the event being treated as arthritis) and consider Hospitalization as seriousness criteria for this event, and describe the surgical procedure (e.g., knee replacement) in the narrative.

5.3.4 If the only information provided in the report is that the patient was hospitalized, the case should be considered as non-valid, the term " hospitalization”’ should be considered as serious AE.

5.3.5 If other adverse event or events are reported and it is noted that the patient hospitalization reason was not provided, in the report an appropriates attempt should be taken to know the reason of hospitalization if follow up attempt is possible.

5.3.6 Hospitalization scenarios-

5.3.6.1 Please refer the below table to consider hospitalization.

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1.0 OBJECTIVE:           

To lay down the procedure for preparation and approval for the process of PSUR and PBRER reports. The SOP intended to provide the benefit and benefit risk evaluation profile of the pharmaceutical product by Ministry of Health for the submission to the health authority at defined time frame. The main objective of a PBRER is to present a comprehensive, concise, and critical analysis of new or emerging information on the risks of the medicinal product, and on its benefit in approved indications, to enable an appraisal of the product's overall benefit-risk profile in the context of cumulative information. The PSUR is therefore a tool for post authorization evaluation at defined time points in the lifecycle of a product.

2.0 SCOPE:

The main focus of each PBRER and. PSUR is the evaluation of relevant new safety information from the available data sources, placed within the context of any pertinent efficacy/effectiveness information that may have become available since the international birth date (IBD), or (DIBD).

The PBRER and PSUR should include cumulative knowledge of the 'product while retaining focus on new information, i.e., the overall safety evaluation and integrated benefit-risk evaluation will take into account cumulative information. Similarly, as knowledge of the safety of a medicinal product may be derived from evaluation of data associated with uses other than the approved indication.

4.0 DEFINITIONS

Data Lock Point (DLP): The date designated as the cut-off date for data to be included in aggregate report. It is based on the International Birth Date (IBD) for PSUR.

European Union Reference Date (EURD) List

The EURD list is a comprehensive list of active substances and combinations of active substances contained in medicinal products subject to different marketing authorizations, together with the corresponding Union reference dates, frequencies for submission of PSURs and related DLP and is maintained by the EMA. The Union reference date corresponds to the date of the first marketing authorization in the Union of a medicine containing that active substance or that combination of active substances, or alternatively the earliest of the known dates of the marketing authorizations for a medicine containing that active substance or that combination of active substances.

International Birth Date (IBD)

The date of the first marketing authorization for any product containing the active substance granted to any company globally.

Periodic Benefit Risk Evaluation Report (PBRER)

Periodic Benefit Risk Evaluation Report (PBRER) PBRER is a common standard for periodic benefit-risk evaluation reporting on marketed products (including approved drugs that are under further study) among the ICH regions.

Development International Birth Date (DIBD)

The date of the sponsor's first authorization to conduct a clinical trial in any country worldwide. This is considered being the Health Authority approval date in the country where the first study for a specific compound is being conducted.

Reference Safety Information (RSI)

In principle, the safety information contained within the Company Core Data Sheet (CCDS), which is referred to as Company Core Safety information (CCSI), is used as RSI for PSUR. The CCSI includes information such as contraindications, special warnings and special precautions for use, interaction with other medicinal products and other forms of interaction, pregnancy and lactation, effects on ability to drive and use machines, undesirable effects, and overdose.

5.0 PROCEDURE:

5.1 Procedures of Aggregate Reports (PSUR/PBRER) production.

5.1.1 A calendar will be maintained by the pharmacovigilance Department of the company. The PSURs and other aggregate reports are sent to the appropriate Competent authorities (CAs) by the QPPV.

5.1.2 The reports shall be authored using the standard template for our Regulatory Authorities or as per the recommended template by our competent authority. PVG department will prepare the report within 30 days of the required submission date, and will forward the final PSUR to HOD and QPPV within 10 days of the required submission date to review the report and provide comments and request for change, if any, and will ensure that the report arrives at the relevant regulatory authorities, as appropriate.

5.1.3 The preparation and submission timelines can be changed with respect to the regulatory requirement with prior discussion with the QPPV.

5.2 Process timeline-

5.2.1 The pharmacovigilance process for safety reporting is continuous throughout the reporting interval. Safety information is gathered, reviewed, and appropriately documented by the safety teams. The resulting information is collected for reporting through the PSUR/PBRER process

5.2.2 The formal PSUR/PBRERs process may begin approximately 75 to 90 days before the DLP to allow the team adequate time for information gathering and review. However, at any time during the reporting interval, the team may gather information and supporting documentation that will be used to populate the upcoming PSUR/PBRER production.

5.2.3 This information may come from meetings with teams such as the Safety Team and
Marketing Team, and the other team involve in pharmacovigilance activity. The PSUR/PBRERs are completed and ready for submission by day 60 after the DLP to meet requirements globally.

5.2.4 PSURs are written to provide an evaluation of the benefit-risk balance of a medicinal product for submission by Marketing Authorization Holders (MAH) at defined time points during the post-authorization phase to review the safety profile of their products and ensure that the SmPC and Package Leaflet are up to date.

5.2.5 Each PSUR is created and submitted according to the DLP, reporting period, and submission deadline requirement from each regulatory authority. PSURs will be prepared from IBD for 6 monthly for first 2 years of authorization, annually for subsequent years and thereafter 3 yearly at renewal. However, the competent authority may still request the submission of a PSUR at any given time.

5.2.5 PSUR  should  be submitted as follows as per GVP module

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1.0 OBJECTIVE:

This Standard Operating Procedure (SOP) has been written to describe the procedure of searching, screening and review of medical and scientific literature, abstract, medical journal and published medical articles to identify the ICSR and a signal in literature fir the assessment of patient safety and efficacy and effectiveness information.

2.0 SCOPE:

This (SOP) Standard Operating Procedure explain the process of screening and review of medical and scientific literature, abstract, medical journal and published medical articles. The process explained in this SOP will be applicable on pharmacovigilance activity after the SOP effective date. It applies to all safety and pharmacovigilance working members of company who delegate these responsibilities to perform systematic literature review for the below objectives:

Screening and review of global literature sources search with respect to the relevant regulatory requirements and guidance for submission and reporting.

Screening and review of local medical literature and unpublished manuscripts as per the company's global and local literature strategy by monitoring relevant local journals and/or local databases, unpublished manuscripts, with respect to the countries where the Company's medicinal product have a Marketing Authorization (MA).

Identifying safety information including Individual Case Safety Reports (ICSRs) or Other Safety Information (OSI) related to the marketed company products. The review and analysis of literatures to support the preparation of aggregate reports like (PSUR) Periodic Safety Update Reports and (PBRERs) Periodic Benefit Risk Evaluation Reports.

To support signal detection and identification and signal management.

For the preparation of safety-related documents in response to the requests from Competent authority

4.0 DEFINITIONS

4.1 Day zero:

The regulatory clock start date, is when a valid ICSR irrespective of language, containing the minimum criteria has been received by Company or any personnel acting on behalf of NPT like, business partner, company safety staff, including medical representatives.

4.2 Responsible Person:

The QPPV will be performing both literature screening and literature review. The QPPV will be requesting full text articles if partially published, the QPPV will requests an additional information from an author is required.

4.3 Literature Screening & Review tool:

A tool will be developed to add the results of both the literature screening and the review of the results; includes the actions taken with specific results (taken into consideration that the article includes relevant safety information for aggregate reporting assessment. A template of the project-specific literature screening & review log will be created.

4.4 Strategy of literature search form:

A form approved by the pharmacovigilance department of Company outlining the literature search strategy like frequency, date of first search to be performed, concerned product, spelling and alternative name for each active constituent and excipient/adjuvant, search parameters and any additional specific search terms will be created for targeted and better results.

4.5 SME for literature search:

A person who has extensive knowledge in literature search and screening will be developed who will be called, as (SME) Subject Matter Expert to develops the literature search strategy and prepare the initial search string per product with the help of a particular template required to be designed.

5.0 PROCEDURE:

5.1 The search coverage:

In addition to the general adverse drug reaction and events the searched will also include the other safety information like, Prospective and retrospective reports of product exposure during pregnancy (maternal and paternal) for product not indicated in pregnancy, irrespective of pregnancy outcome; this includes exposure during conception, pregnancy, childbirth, abnormal, normal and unknown pregnancy outcome, Neonatal exposure via breast milk, Lack of effect, Overdose (accidental or intentional), Medication error/Maladministration (including wrong route or unknown route of administration), Product misuse, Product abuse, Off-label use, Product dependency, Occupational exposure, Use of a Product in a paediatric or elderly population (if not part of the approved. indications), Suspected. adverse reactions to quality defect or falsified Product (counterfeit), and Suspected transmission of an infectious agent via a Product.

5.2 Valid case:

A valid case must have at least the four elements while report receiving to become a case valid that is;

• Identifiable patient,
• Identifiable reporter
• Suspect drug
• Valid adverse reaction or fatal outcome.
• If the case reported has any of the missing information, then a follow is attempted to ensure the case becomes valid for reporting and analysis.

5.3 Potential Safety Signal:

5.3.1 Information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.

5.3.2 New aspects of a known association may include changes in the frequency, distribution (e.g., gender, age, and country), duration, severity, or outcome of the adverse reaction.

5.4 Safety signal management:

5.4.1 A set of activities performed to determine whether known risks related to the product have changed, based on information received from ICSR assessment, aggregate data from active surveillance system or studies, scientific literature information of the medicinal product or any other relevant source.

5.4.2 It also includes any related recommendations, decisions, communication and tracking in response to the assessments. The activities might include signal detection, validation, prioritization, assessment, action and recommendation.

5.5 Search data repository:

5.5.1 A literature search document repository should be created to maintained and archive the already search literature for future reference and referral purpose.

5.6 Procedure Preparing the Literature Search Strategy for ICSRs or Signals:

5.6.1 The SME and the SME assistant will prepare a literature search string plan as per the requirement of the regulatory design by utilizing a template and the product specific search string will be reviewed and updated on annual basis.

5.7 ICSR search string:

1. The product trade name
2. Active ingredient name
3. Synonyms if any
4. Adverse drug event/Reaction

5.8 Search string for identification of signals.

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1.0 OBJECTIVE:

This Standard Operating Procedure (SOP) has been written to explain the process for determining the seriousness criteria of adverse events (AE), Prioritization of the reports as per the required timeline serious versus non-serious.

2.0 SCOPE

This SOP applicable to all pharmacovigilance safety staff in PVG departments and Case/Report collection, triage. It is the process of determining the priority of patient’s treatments based on the severity of their condition. This rations patient treatment efficiently when resources are insufficient for all to be treated immediately), prioritization of expedited and non-expedited reports and processing personnel.

5.0 PROCEDURE:

5.1 Reporting time line as per the seriousness

5.1.1Time frames for other types of serious reporting vary among countries, depending on source, expectedness, and outcome.

5.1.2 Day 0- The regulatory reporting time clock is considered to start on the date when any personnel of the MAH first receive a case report that full fills minimum criteria as well as the criteria, for expedited reporting. In general, this date should be considered day 0.

5.2 Serious Criteria. An adverse event is considered serious if it meets one or more of the following criteria:

5.2.1 Death

5.2.2 Life-threatening

5.2.3 Initial inpatient hospitalization or prolongation of existing hospitalization Persistent or significant disability or incapacity

5.2.4 Congenital anomaly (birth defect)

5.2.5 Medically significant (i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.

5.2.6 If an event has been determined to be serious, it is important to choose all appropriate criteria; therefore, it is possible for an event to have more than one serious criterion. Eg: A heart attack might result in both hospitalization and death.

5.2.7 The event serious criteria provided by a reporter cannot be downgraded to non-serious by the company.

5.2.8 In adverse event report forms, the serious criteria are reported at a report level and not an event level. So medical concept and scientific judgment should be exercised in conjunction with a review of the event description when determining serious criteria for each event.

5.3 Death- For the adverse event results in death, because of any reason, the serious criterion of death is selected. If the only available information is that the patient died, then serious criterion of death should be selected for the death event. Follow-up should be attempted to obtain the actual cause of death and other event details.

5.4 Life-Threatening- The term life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe (e.g., pancreatic failure or breathing difficulty). As reporters may have different interpretations of life-threatening situation, if possible, an appropriate follow-up must be pursued to validate that the event posed the patient at an immediate risk of death.

4.4.1 Please refer the below table to assess the actual life-Threatening scenarios-

5.5 Hospitalization- Hospitalization is considered when an event causes Hospitalization or prolongation of existing a hospitalization. Hospitalization should be selected even if a patient is admitted to a hospital but released on the same day.

5.5.1 Hospitalization is considered if following situations exists:

• In-patient hospitalization as a direct result of the event
• Event resulted in the duration of the existing hospitalization get prolonged
• Hospice care provided in a hospital facility.

5.5.2 Hospitalization is not considered if following situations exists:

5.5.2.1 Patient visits to the emergency room or outpatient clinic but was not admitted for inpatient hospitalization.

5.5.2.2 Hospitalization was not caused by the event, rather than by other factors like social (non-medical) reasons, treatment reasons, elective hospitalizations, or protocol requirements in study case.

5.5.2.3 Patient had admission for observation (e.g. following an overdose).

5.5.2.4 Patient had hospice care anywhere outside of a hospital facility (e.g. patient home or nursing home).

5.5.3 If a hospitalization is due to a surgical procedure and qualifies as an AE (e.g., the event is a pre-existing condition that worsened or a non-elective procedure) consider the event being treated as arthritis) and consider Hospitalization as seriousness criteria for this event, and describe the surgical procedure (e.g., knee replacement) in the narrative.

5.5.4 If the only information provided in the report is that the patient was hospitalized, the case should be considered as non-valid, the term "hospitalization" should be considered as serious AE.

5.5.5 If other adverse event or events are reported and it is noted that the patient hospitalization reason was not provided, in the report an appropriate attempt should be taken to know the reason of hospitalization if follow up attempt is possible.

5.5.6 Hospitalization scenarios-

Please refer the below table to consider hospitalization.

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