FAQ - Revised schedule M
- Ganadhish Kamat- What are the key changes in the revised Schedule M?
- Inclusion of new concepts such as
- Pharmaceutical Quality systems (PQS),
- Quality Risk Management,
- Product Quality review
- Product Life cycle approach (Development, transfer, validation, continuous verification and improvement & discontinuation)
- Inclusion new requirements such as -
- Specific requirements for manufacture of Hazardous substances such as Sex Hormones, Steroids or Cytotoxic substances
- Specific requirements for biologics, radiopharmaceuticals, phytopharmaceuticals and investigational Pharmaceutical Products for Clinical Trials in Human
- Pharmacovigilance
- Reporting serious defects and ADEs to Licensing authority
- Reporting of product/process changes to Licensing authority
- Contract manufacturing (Loan license) & testing, Quality agreements.
- Self-inspection, Quality audits & supplier audits & approval
- Elaboration of existing requirements
- Handling of Market complaints
- Qualification of equipment
- Utilities such as HVAC & Water systems
- Requirements of plant and equipment for manufacturing of 11 categories of pharma products
- Production controls (Control of various stages)
- Quality control (Elaborated about Control of starting materials and intermediate, bulk and finished products/ Test requirements/ Batch record review/ Stability studies)
- Requirements for Sterile products
- Computer system controls and validation (Access controls, audit trail, electronic data controls & back-up)
- Change management.
- Good documentation practices including data integrity and ALCOA principle.
- What is Pharmaceutical Quality System?
A Pharmaceutical Quality System (PQS) refers to a comprehensive framework established within a pharmaceutical company to ensure that products consistently meet the required quality standards for their intended use. It encompasses organizational structure, processes, procedures, and resources designed to implement and maintain quality management practices throughout all stages of the product lifecycle. It is the responsibility of senior management to ensure establishment of PQS, make adequate resources available and ensure compliance through regular management reviews.
The main objectives of a Pharmaceutical Quality System include:
- Quality Policy and Objectives: Establishing a clear quality policy and defining quality objectives aligned with the company's mission and regulatory requirements.
- Quality Planning: Developing strategies, processes, and resources necessary to achieve quality objectives, including risk management plans and quality plans for individual products.
- Quality Risk Management: Identifying, assessing, controlling, and communicating risks associated with product quality throughout the lifecycle, including risks related to manufacturing processes, raw materials, and product use.
- Quality Control and Assurance: Implementing measures to monitor and verify the quality of products at various stages of manufacturing and distribution, including testing, inspection, and validation activities.
- Document Management: Establishing procedures for the creation, review, approval, distribution, and maintenance of documents related to quality management, including standard operating procedures (SOPs), specifications, and batch records.
- Change Control: Implementing processes for evaluating and managing changes to facilities, equipment, processes, procedures, and other aspects that may impact product quality.
- Training and Personnel Qualification: Ensuring that personnel are adequately trained and qualified to perform their roles effectively and in compliance with applicable regulations and quality standards.
- Complaints and Product Recall Handling: Establishing procedures for investigating and addressing complaints related to product quality and for managing product recalls when necessary.
- Supplier and Contract Manufacturer Management: Implementing processes for selecting, qualifying, monitoring, and auditing suppliers and contract manufacturers to ensure they meet quality standards.
- Continuous Improvement: Implementing mechanisms for ongoing evaluation, monitoring, and improvement of the PQS through feedback, data analysis, and management review.
By implementing a robust Pharmaceutical Quality System, companies can enhance product quality, ensure compliance with regulatory requirements, mitigate risks, and ultimately, protect patient safety. It provides a structured approach to quality management that fosters a culture of continuous improvement and excellence within the organization.
- What is Quality Risk Management? How is it implemented?
Quality Risk Management (QRM) is a systematic process for assessing, controlling, communicating, and reviewing risks associated with product quality, safety, and efficacy throughout the lifecycle of pharmaceutical products. It is an integral part of the Pharmaceutical Quality System (PQS) and is guided by principles outlined in (ICH) Q9.
Here's how Quality Risk Management is typically done:
- Risk Identification: The first step involves identifying potential risks to product quality, safety, and efficacy. This includes considering various factors such as manufacturing processes, raw materials, equipment, personnel, environmental conditions, and external factors like regulatory requirements and market expectations.
Risk Assessment: Once risks are identified, they are evaluated based on their severity, likelihood of occurrence, and detectability. This assessment helps prioritize risks and determine which ones require further mitigation efforts.
Risk Analysis: In this step, the identified risks are analyzed to understand their root causes, mechanisms, and potential consequences on product quality and patient safety. Various tools and techniques such as Failure Mode and Effects Analysis (FMEA), Hazard Analysis and Critical Control Points (HACCP), and Fault Tree Analysis (FTA) may be used for this purpose.
Risk Evaluation: After analysis, risks are evaluated to determine if they are acceptable or if further action is needed to reduce their impact. Factors such as the level of risk tolerance, regulatory requirements, and potential benefits versus risks are considered during this evaluation.
Risk Control: Once risks are evaluated, appropriate control measures are implemented to mitigate or eliminate them. This may involve modifying processes, improving equipment design, enhancing training programs, implementing additional testing or monitoring procedures, or making other changes to reduce risk levels.
Risk Communication: Throughout the QRM process, effective communication is essential to ensure that stakeholders are informed about identified risks, mitigation strategies, and their roles and responsibilities in managing risks. Clear and transparent communication helps facilitate decision-making and ensures alignment across the organization.
Risk Review: QRM is an iterative process, and risks should be regularly reviewed and reassessed to account for changes in processes, products, regulations, or other factors that may impact risk levels. This ongoing review helps ensure that risk management strategies remain effective and relevant over time.
By systematically applying Quality Risk Management principles, pharmaceutical companies can proactively identify and address potential risks to product quality and patient safety, thereby enhancing the reliability and consistency of their products while meeting regulatory requirements. QRM is used during product development, system or process development, validations, for assessment of impact of any quality or system failure, assessment of changes etc.
Use of QRM during Product development - During development QRM is used to identify Critical Material Attributes, Critical Process Parameters and establish Control Strategies based on the risk priority. Each of the material attributes for every material to be used and each processing stage is evaluated by team of experts with good product and process understanding to identify all possible failure modes (what can go wrong). For each of the failure mode, its severity (of effect on the CQA), likelihood of occurrence (chance of that failure occurring) and detectability (existing controls in the system/process which can detect if such failure occurs) are assessed based on past knowledge or knowledge gained from various experiments conducted during development process. This assessment could be qualitative by assigning risk as High, Medium or Low or Quantitatively by rating severity, likelihood and detectability on the scale of 1 to 5 or 1 to 10 (higher being more risky). The product of the three numbers thus assigned is called Risk Priority Number (RPN). Depending upon the RPN, risk is categorized as High, Medium and Low and appropriate mitigation plan is established either to reduce the likelihood (for example by establishing safe limits for material attributes or process parameters) or improve the detectability (for example by introducing online monitoring of parameters, in-process checks etc)
Use of QRM for assessment of impact of Quality failure - QRM is also useful for assessing the impact of quality failure events such as market complaints, stability failures, product failures etc on the product already in the market. Based on the available data, nature of the defect, Severity, likelihood and detectability is determined and based on the risk to patients, actions are decided such as Type of the recall, extent of the recall, public notification etc. For example, the failure indicates risk to sterility of injectable product, the Severity is high, and Detectability is low so in such case even if the likelihood is low, recall will be required till retailer. On the contrary if there is a market complaint about defect in product with low severity which can be easily detected by the pharmacist during dispensing or by the patient during use, the recall may be avoided if likelihood is low or may be restricted to wholesaler if the likelihood is medium.
- What is Product Quality review? How frequently it is done?
Product Quality Review (PQR) is a systematic assessment conducted by pharmaceutical manufacturers to evaluate the consistency of product quality over time. Typically, the Product Quality review is done annually. The purpose of the Periodic Product Quality Review is to ensure ongoing compliance with established quality standards and to identify any trends, deviations, or potential issues that may affect product quality, safety, or efficacy. While the guideline mentions review of certain aspects, there is no clarity about what is to be reviewed and how the review is to be documented. I have given my suggestions in the parenthesis for each of the aspect.
The PQR shall include:
- Review of starting materials and packaging materials used for the product, (I suggest capturing information about vendor changes, vendor approval status, last audit done and next due, summary of lots received, approved and rejected for each material from different vendors, trend analysis of CMAs using statistical tools such as run chart)
- A review of critical in-process controls, and finished product results (Trend analysis of test results using statistical tools such suitable control charts should be done. The trend analysis should be done throughout the year before the batch release. Any out of trend result should be investigated to identify the cause and appropriate corrective action should be implemented if the assignable cause is identified. Impact assessment should be done on the product quality. Some out of trend results may require rejection of the batch even if the batch meets the specification if there is chance of batch failing during the shelf life. For example, a batch showing degradation impurity higher than normal trend, which may go out of limit on storage. Summary of the trend analysis along with investigations conducted and actions taken should be included in PQR. Process capability should also be determined for all CQAs. If CPk is below 1.33, causes for the same should be identified and addressed so that product remains robust and chances of failure due to random variability are minimized);
- Although not specified in the Schedule M, I suggest performing trend analysis of Critical Process Parameters to evaluate whether the process continues to remain in validated state. Any process drifts should be investigated to understand the reason.
- A review of all batches that failed to meet established specifications and their investigation; (I suggest providing tabular summary of the batches manufactured, batches approved and rejected. Additionally summary table of all the rejected batches, with reason for rejection, root cause of failure and actions taken should be included)
- A review of all significant deviations or non-conformity, the related investigations and the effectiveness of resultant corrective and preventive actions taken; (I suggest providing tabular summary of the deviations, root causes of deviation or non-conformity, actions taken and if any repeat deviation of similar nature observed after CAPA. Absence of repeat incidence indicates effectiveness of CAPA)
- A review of all changes made to the processes or analytical methods; (Provide tabular summary of the changes done, reason/justification for changes and supporting qualification activities or stability studies)
- A review of dossier variations submitted, granted or refused (It may be noted that currently dossier variations are required only for Biologics for which MA is granted by CDSCO. I am not aware of any such system existing in India for the small molecules and subsequently approved products which are manufactured against license granted by Licensing Authority (LA) of state FDA. During recent seminar organized by Pharmexcil in Goa, Joint DCGI clarified that in absence of specific guideline from CDSCO, relevant WHO guideline should be followed. Based on this clarification, WHO TRS 981 Annex 3 may be followed for submission of changes to LA)
- A review of the results of the stability monitoring program and any adverse trends; (Provide tabular summary of stability batches charged during the review period, reasons for charging on stability, summary of results of stability samples analyzed during the review period along with comments about whether the results were within normal trends, summary of investigations in case of stability failures observed, root causes identified and CAPA implemented, actions taken on the batches in the market)
- A review of all quality related returns, complaints and recalls and the investigations performed at the time; (Provide separate summaries for complaints, returns and recalls. Although rule requires only quality related returns to be included, I suggest including all returns. In case of complaints provide summary table for all the market complaints received for the product during review period, summary of investigations, root causes and CAPA. In case of returns provide summary of Product returns, reason for returns, summary of testing done on returned goods if any and the actions taken. In case of Recalls, provide summary of batches recalled, reason for recall, quantity distributed, quantity received back, summary of any testing done and action taken on the recalled product such as destruction)
- A review of adequacy of any other previous corrective actions on product processes or
equipment; (Provide summary of CAPAs identified for the product in previous review period, their completion status and CAPA effectiveness (occurrence of similar defect failure observed post implementation of CAPA)
- Post marketing commitments for new dossiers and variations to the dossiers; (I am not aware about any post marketing commitments given to regulatory agency in India. If any commitment is given, review should provide evidence of complying to such commitment)
- The qualification status of relevant equipment and utilities, e.g., heating, ventilation and air conditioning, water or compressed gases and a review of the results of monitoring the output of such equipment and utilities; (Include summary of all critical utilities, their periodic qualification dates, next due dates, summary of trend analysis of utilities such as water, failures observed if any and impact assessment done on the product, reference of the qualification protocols and reports, reference to annual review reports)
- A review of technical agreements to ensure that they are up to date. (Provide summary of all technical agreements related to products including agreements with contract manufacturing / testing partners, agreements with suppliers of raw and packaging materials, date of agreement and validity date)
- Although not required by the rule, I suggest inclusion of summary of retention sample inspection which should be done once in a year on batches selected based on the sampling plan
- Although not required by the law, I suggest including summary of any process validations conducted during the review period along with the reasons for validating and the outcome of validations.
Each section should include conclusions drawn based on the data reviewed and actions identified if any. Continuous Improvement: PQRs provide an opportunity for manufacturers to identify areas for improvement in manufacturing processes, quality systems, and product performance. Lessons learned from PQRs are used to implement corrective actions, optimize processes, and enhance product quality and consistency over time. Product Quality Reviews, thus help ensuring product quality, safety, and efficacy throughout the product lifecycle.
Product Quality Review (PQR) is a systematic assessment conducted by pharmaceutical manufacturers to evaluate the consistency of product quality over time. Typically, the Product Quality review is done annually. The purpose of the Periodic Product Quality Review is to ensure ongoing compliance with established quality standards and to identify any trends, deviations, or potential issues that may affect product quality, safety, or efficacy. While the guideline mentions review of certain aspects, there is no clarity about what is to be reviewed and how the review is to be documented. I have given my suggestions in the parenthesis for each of the aspect.
The PQR shall include:
- Review of starting materials and packaging materials used for the product, (I suggest capturing information about vendor changes, vendor approval status, last audit done and next due, summary of lots received, approved and rejected for each material from different vendors, trend analysis of CMAs using statistical tools such as run chart)
- A review of critical in-process controls, and finished product results (Trend analysis of test results using statistical tools such suitable control charts should be done. The trend analysis should be done throughout the year before the batch release. Any out of trend result should be investigated to identify the cause and appropriate corrective action should be implemented if the assignable cause is identified. Impact assessment should be done on the product quality. Some out of trend results may require rejection of the batch even if the batch meets the specification if there is chance of batch failing during the shelf life. For example, a batch showing degradation impurity higher than normal trend, which may go out of limit on storage. Summary of the trend analysis along with investigations conducted and actions taken should be included in PQR. Process capability should also be determined for all CQAs. If CPk is below 1.33, causes for the same should be identified and addressed so that product remains robust and chances of failure due to random variability are minimized);
- Although not specified in the Schedule M, I suggest performing trend analysis of Critical Process Parameters to evaluate whether the process continues to remain in validated state. Any process drifts should be investigated to understand the reason.
- A review of all batches that failed to meet established specifications and their investigation; (I suggest providing tabular summary of the batches manufactured, batches approved and rejected. Additionally summary table of all the rejected batches, with reason for rejection, root cause of failure and actions taken should be included)
- A review of all significant deviations or non-conformity, the related investigations and the effectiveness of resultant corrective and preventive actions taken; (I suggest providing tabular summary of the deviations, root causes of deviation or non-conformity, actions taken and if any repeat deviation of similar nature observed after CAPA. Absence of repeat incidence indicates effectiveness of CAPA)
- A review of all changes made to the processes or analytical methods; (Provide tabular summary of the changes done, reason/justification for changes and supporting qualification activities or stability studies)
- A review of dossier variations submitted, granted or refused (It may be noted that currently dossier variations are required only for Biologics for which MA is granted by CDSCO. I am not aware of any such system existing in India for the small molecules and subsequently approved products which are manufactured against license granted by Licensing Authority (LA) of state FDA. During recent seminar organized by Pharmexcil in Goa, Joint DCGI clarified that in absence of specific guideline from CDSCO, relevant WHO guideline should be followed. Based on this clarification, WHO TRS 981 Annex 3 may be followed for submission of changes to LA)
- A review of the results of the stability monitoring program and any adverse trends; (Provide tabular summary of stability batches charged during the review period, reasons for charging on stability, summary of results of stability samples analyzed during the review period along with comments about whether the results were within normal trends, summary of investigations in case of stability failures observed, root causes identified and CAPA implemented, actions taken on the batches in the market)
- A review of all quality related returns, complaints and recalls and the investigations performed at the time; (Provide separate summaries for complaints, returns and recalls. Although rule requires only quality related returns to be included, I suggest including all returns. In case of complaints provide summary table for all the market complaints received for the product during review period, summary of investigations, root causes and CAPA. In case of returns provide summary of Product returns, reason for returns, summary of testing done on returned goods if any and the actions taken. In case of Recalls, provide summary of batches recalled, reason for recall, quantity distributed, quantity received back, summary of any testing done and action taken on the recalled product such as destruction)
- A review of adequacy of any other previous corrective actions on product processes or equipment; (Provide summary of CAPAs identified for the product in previous review period, their completion status and CAPA effectiveness (occurrence of similar defect failure observed post implementation of CAPA)
- Post marketing commitments for new dossiers and variations to the dossiers; (I am not aware about any post marketing commitments given to regulatory agency in India. If any commitment is given, review should provide evidence of complying to such commitment)
- The qualification status of relevant equipment and utilities, e.g., heating, ventilation and air conditioning, water or compressed gases and a review of the results of monitoring the output of such equipment and utilities; (Include summary of all critical utilities, their periodic qualification dates, next due dates, summary of trend analysis of utilities such as water, failures observed if any and impact assessment done on the product, reference of the qualification protocols and reports, reference to annual review reports)
- A review of technical agreements to ensure that they are up to date. (Provide summary of all technical agreements related to products including agreements with contract manufacturing / testing partners, agreements with suppliers of raw and packaging materials, date of agreement and validity date)
- Although not required by the rule, I suggest inclusion of summary of retention sample inspection which should be done once in a year on batches selected based on the sampling plan
- Although not required by the law, I suggest including summary of any process validations conducted during the review period along with the reasons for validating and the outcome of validations.
- Are there any new requirements for equipment qualification and validation?
As per the new rules, the manufacturers need to demonstrate through documentary evidence that the premises, supporting utilities, equipment and processes have been designed in accordance with
the User requirement specifications (URS) and requirements for good manufacturing practices [design qualification (DQ)]; have been built and installed in compliance with
their design specifications [installation qualification (IQ)]; operate in accordance with their functional specifications [operational qualification (OQ)]; and consistently produce a product / output meeting its predetermined specifications and
quality attributes [performance qualification (PQ)]. Any changes to the premises, facilities, utilities, equipment or processes,
which may affect the quality of the product, directly or indirectly, need to be qualified and validated before implementation. Qualification and validation is not to be considered as one-off exercise but an on-going program based on a periodic review and change management. The commitment for initial qualification and validation and maintaining continued validation status is to be documented in validation master plan.
- How life cycle approach of Process validation different from current approach?
The life cycle approach of process validation includes three stages.
Stage 1 - Process design: In this stage the final process is fully established based on the development data, data from tech transfer and scale up trials. All critical material attributes and critical process parameters are identified and adequately controlled. All set points for machine parameters, process parameter limits, speed ranges etc are fully established during this stage.
Stage 2 - Process Performance Qualification - Multiple consecutive batches are executed following the process established during Process design stage. Exhaustive sampling is done based on the approved sampling plan designed to evaluate performance of each manufacturing step. The sampling plan is also designed to evaluate consistency within the batch and in between the batches. The data of process parameters and test results of various samples collected as per the sampling plan are compiled in the PPQ report and statistical tools are used to evaluate consistency within and in between batches. For PPQ to be considered to be successful, apart from the batches meeting release specification, they should also meet the pre-defined acceptance criteria for consistency.
Stage 3 - Continued verification stage - Trend analysis of Critical process parameters and Critical Quality Attributes is performed prior to release of each post PPQ batch to verify that the parameters are within normal trends. Any out of trend values are investigated to understand the reason and also to evaluate its impact on the quality and stability of the batch before release. Such evaluation helps in ensuring that the process continues to remain in validated state. Summary of such trend analysis and the investigations carried out are provided in Periodic Product Quality Review report.
Any changes to the process are evaluated for need for revalidation.
- What controls are required on the computerized systems and electronic records?
All GMP-related computerized systems need to be validated. The depth and scope of validation depends on the
diversity, complexity and criticality of the application. Appropriate installation qualification and operational qualification shall demonstrate the suitability of
computer hardware and software to perform intended tasks. Commercially available software (such as chromatography software) that has been qualified does not require the same level of testing. Validation of such software should include testing of configurations / customization done to meet company requirements (for eg. configuration of privileges and access controls). Computerized systems are required to have sufficient controls to prevent unauthorized access or changes to data. Systems should not allow omissions in data (e.g., the system being turned off or disconnected to prevent data captured). Any changes to data, should be allowed only to authorized people and system should retain all changes including the original values, new values, date and time stamp, identify pf person and reason for changes. Where critical data are being entered manually, there should be an additional check on the accuracy of the
data entered (for eg. microbial counts for environment monitoring). Incidents related to computerized systems that could affect the quality of products or the reliability of
records or test results should be recorded and investigated. Changes to the computerized system shall be made through a change control procedure and appropriate validations should be done to ensure that system works as designed after the implementing the changes. Records should be kept of all changes, including
modifications and enhancements made to the hardware, software and any other critical component of the
system including bug fixes and patches. A validated back-up system shall be provided so that there is no permanent loss of records due to system
breakdown or failure. Any backup media should be stored in secured location with appropriate protection such as fireproof rooms, cabinets etc. Means of ensuring data protection shall be established for all computerized
systems.
- What controls are specified for outsourcing of manufacturing & testing activities?
Following controls are specified to control outsourced activities such as manufacturing and testing -- Establishing Quality agreement / contract to clearly define responsibilities of contract giver and contract acceptor with respect to all the activities such as but not limited to technology transfer, incoming material controls, inventory controls, manufacturing controls, change notification, deviation controls, investigations, complaint handling, testing and product release.
- Periodic audits of contract acceptor by the contract giver to ensure compliance to GMPs and adherence to established procedures.
- Ultimate responsibility for quality including providing all technical information, monitoring of activities and final release of lies with the contract giver.
- Contract acceptor is responsible for carrying out all the activities in adherence to GMPs, approved procedures and terms defined in the contract.
- Establishing Quality agreement / contract to clearly define responsibilities of contract giver and contract acceptor with respect to all the activities such as but not limited to technology transfer, incoming material controls, inventory controls, manufacturing controls, change notification, deviation controls, investigations, complaint handling, testing and product release.
- Periodic audits of contract acceptor by the contract giver to ensure compliance to GMPs and adherence to established procedures.
- Ultimate responsibility for quality including providing all technical information, monitoring of activities and final release of lies with the contract giver.
- Contract acceptor is responsible for carrying out all the activities in adherence to GMPs, approved procedures and terms defined in the contract.
- What new controls are specified for ensuring quality of incoming materials?
Some of the significant changes related to controls on incoming materials are given below -- Starting materials are required to be purchased only from the approved suppliers and, where possible, directly
from the manufacturer.
- Quality agreement need to be established with the vendor to define the specifications, critical aspects of the production
and controls. including handling, labelling and packaging
requirements as well as complaints and rejection procedures.
- The containers from each shipment need to be checked at least for integrity of package
and seal, the delivery note, and the supplier’s labels. Damage to containers, or seal and any other problem that might adversely affect the quality of a material need to be recorded and reported to quality department and investigated.
- All incoming materials to be checked to ensure that the consignment corresponds to the order and the containers need to be cleaned externally to make them from any dust gathered during transit.
- If one delivery of material is made up of different batches, each batch must be considered as separate for
sampling, testing and release.
- The materials need to be appropriately labelled with details such as (a) the name of the material and the internal code reference where applicable;
(b) the batch number given by the supplier and, on receipt, the control or batch number given by the
manufacturer, if any;
(c) the status of the contents (e.g., in quarantine, on test, released, rejected); and
(d) where appropriate, an expiry date or a date beyond which retesting is necessary. When fully
validated computerized storage systems are used, not all of the above information need be in a
legible form on the label.
- Only raw materials which have been tested as per the specification and released by the QC and which are within their shelf life or retest date should be allowed to be used.
- The raw materials other than APIs, may be released for use without specific batch testing, based on vendor's Certificate of analysis, provided that vendor has performed all the tests included in the specification, at least identity test has been performed and provided that the material is received from approved vendor who's test results are demonstrated to be reliable based on-site audit and statistical data analysis of earlier test results.
- An identity test needs to be conducted on a sample from each container of starting material except where the starting materials are received from a single product manufacturer or plant, received directly from the manufacturer, in the
manufacturer’s sealed container and reliability of manufacturer’s QA system is verified through regular on-site audits conducted by the
purchaser or by an officially
accredited body.
Specific Questions -
- Starting materials are required to be purchased only from the approved suppliers and, where possible, directly from the manufacturer.
- Quality agreement need to be established with the vendor to define the specifications, critical aspects of the production and controls. including handling, labelling and packaging requirements as well as complaints and rejection procedures.
- The containers from each shipment need to be checked at least for integrity of package and seal, the delivery note, and the supplier’s labels. Damage to containers, or seal and any other problem that might adversely affect the quality of a material need to be recorded and reported to quality department and investigated.
- All incoming materials to be checked to ensure that the consignment corresponds to the order and the containers need to be cleaned externally to make them from any dust gathered during transit.
- If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing and release.
- The materials need to be appropriately labelled with details such as (a) the name of the material and the internal code reference where applicable; (b) the batch number given by the supplier and, on receipt, the control or batch number given by the manufacturer, if any; (c) the status of the contents (e.g., in quarantine, on test, released, rejected); and (d) where appropriate, an expiry date or a date beyond which retesting is necessary. When fully validated computerized storage systems are used, not all of the above information need be in a legible form on the label.
- Only raw materials which have been tested as per the specification and released by the QC and which are within their shelf life or retest date should be allowed to be used.
- The raw materials other than APIs, may be released for use without specific batch testing, based on vendor's Certificate of analysis, provided that vendor has performed all the tests included in the specification, at least identity test has been performed and provided that the material is received from approved vendor who's test results are demonstrated to be reliable based on-site audit and statistical data analysis of earlier test results.
- An identity test needs to be conducted on a sample from each container of starting material except where the starting materials are received from a single product manufacturer or plant, received directly from the manufacturer, in the manufacturer’s sealed container and reliability of manufacturer’s QA system is verified through regular on-site audits conducted by the purchaser or by an officially accredited body.
- Part I - 2.3.2
(F) requires a review of dossier variations submitted, granted,
or refused as part of PQR. However, since currently there is no system / guideline available for submitting changes to dossier in India, how to handle such changes?
During recent seminar organized by Pharmexcil in Goa, Joint DCGI clarified that in absence of specific guideline from CDSCO, relevant WHO guideline should be followed. Based on this clarification, WHO TRS 981 Annex 3 may be followed for submission of changes to LA.
- Part I - 6.10: (Complaints & adverse reaction) requires the licensing authorities to be informed if a
manufacturer is considering action following the faulty manufacture, product
deterioration, a suspect product or any other serious quality problems with a product. Please clarify what procedure to be followed for such communication and is there any timeline for the same.
- Part I - 6.11 (Complaints & adverse reaction) requires the licensee to have a pharmacovigilance system in place for collecting, processing and forwarding the
reports to the licensing authorities for information on the adverse drug reactions emerging from the use of
drugs manufactured or marketed by the licensee. What exactly needs to be done to comply with requirement?
CDSCO has a guidance on Pharmacovigilance of Biologics (issued in 2017). I have not come across any approved guidance document for small molecules although there is on draft guidance available from CDSCO. The draft guidance however is not in line with global guidance documents and has few additional requirements such as reporting all serious ADEs to regulatory agency within 15 days even if they are known. Guidance also requires causality assessment which is typically not required for approved products. The pharmacovigilance function within a pharmaceutical company is responsible for various activities aimed at monitoring and ensuring the safety of its products throughout their lifecycle. Some of the key activities performed by the pharmacovigilance function include:Adverse Event Reporting: Receiving, documenting, and processing (assessing expectedness and seriousness) reports of adverse events (AEs) and other safety-related information associated with the company's products from healthcare professionals, consumers, clinical trials, literature, and regulatory authorities.
Safety Database Management: Maintaining and managing a comprehensive safety database to collect, store, and analyze adverse event reports and other safety-related data.
Signal Detection: Analyzing safety data to identify potential safety signals, patterns, trends, or emerging risks associated with the use of the company's products.
Risk Assessment and Benefit-Risk Evaluation: Conducting thorough evaluations to assess the risks and benefits of the company's products, including analyzing individual case safety reports (ICSRs), aggregate data, and conducting benefit-risk assessments.
Regulatory Reporting: Ensuring timely and accurate reporting of adverse events and other safety-related information to regulatory authorities in compliance with regulatory requirements and guidelines.
Risk Management Planning: Developing and implementing risk management plans (RMPs) to mitigate identified risks and optimize the safe use of the company's products.
Safety Surveillance Activities: Conducting ongoing monitoring and surveillance of the safety profile of the company's products through various channels, including literature review, signal detection, and periodic safety updates.
Safety Communication: Collaborating with regulatory authorities, healthcare professionals, consumers, and other stakeholders to communicate safety-related information, including issuing safety advisories, updating product labels, and providing risk minimization materials.
Quality Assurance and Compliance: Ensuring compliance with pharmacovigilance regulations, guidelines, and internal quality standards through ongoing monitoring, audits, and quality assurance activities.
Training and Education: Providing training and education to internal staff, healthcare professionals, and other stakeholders on pharmacovigilance principles, reporting requirements, and safety-related topics.
Setting up own PV function is quite expensive. The major expenses include, hiring medical professionals, PV software & database licenses, Subscription for ADE databases for literature searches, call center setup etc. For medium and small size companies, it will be more economical to outsource this activity to contract service providers. The guideline does not mention about outsourcing this activity, so it will be better to take concurrence from state FDA. - Part I - 14.16
- (Materials) requires verification of the identity of the contents of each container of starting
material, whereas section 19.7.2 allows sampling from proportion of the containers where a validated procedure
has been established to prevent labeling errors. How to deal with this contradiction?
An identity test needs to be conducted on a sample from each container of starting material except where the starting materials are received from a single product manufacturer or plant, received directly from the manufacturer, in the manufacturer’s sealed container and reliability of manufacturer’s QA system is verified through regular on-site audits conducted by the purchaser or by an officially accredited body. These controls provide adequate assurance about error free labeling and the identity of individual containers is verified from the label. This should be described in sampling SOP. Rapid non-destructive test methods such as NIR, Raman spectroscopy may be used for such checks in place of classical ID test mentioned in the monograph.
Adverse Event Reporting: Receiving, documenting, and processing (assessing expectedness and seriousness) reports of adverse events (AEs) and other safety-related information associated with the company's products from healthcare professionals, consumers, clinical trials, literature, and regulatory authorities.
Safety Database Management: Maintaining and managing a comprehensive safety database to collect, store, and analyze adverse event reports and other safety-related data.
Signal Detection: Analyzing safety data to identify potential safety signals, patterns, trends, or emerging risks associated with the use of the company's products.
Risk Assessment and Benefit-Risk Evaluation: Conducting thorough evaluations to assess the risks and benefits of the company's products, including analyzing individual case safety reports (ICSRs), aggregate data, and conducting benefit-risk assessments.
Regulatory Reporting: Ensuring timely and accurate reporting of adverse events and other safety-related information to regulatory authorities in compliance with regulatory requirements and guidelines.
Risk Management Planning: Developing and implementing risk management plans (RMPs) to mitigate identified risks and optimize the safe use of the company's products.
Safety Surveillance Activities: Conducting ongoing monitoring and surveillance of the safety profile of the company's products through various channels, including literature review, signal detection, and periodic safety updates.
Safety Communication: Collaborating with regulatory authorities, healthcare professionals, consumers, and other stakeholders to communicate safety-related information, including issuing safety advisories, updating product labels, and providing risk minimization materials.
Quality Assurance and Compliance: Ensuring compliance with pharmacovigilance regulations, guidelines, and internal quality standards through ongoing monitoring, audits, and quality assurance activities.
Training and Education: Providing training and education to internal staff, healthcare professionals, and other stakeholders on pharmacovigilance principles, reporting requirements, and safety-related topics.
- As per Part I -14.26.3 packaging material to be used for pharmaceutical
products shall be in accordance with the requirements prescribed in Indian
Pharmacopoeia (IP). Does this mean that each lot of packaging materials need to be tested for all the parameters specified in IP?
Many of the checks prescribed in IP like MVTR etc are characteristic of the resin / material used and the mould used for the container. As long as these remain unchanged, these parameters do not change. Hence, there is no need to perform these checks on each consignment to demonstrate compliance to IP. ID check using technique like FTIE may be done to ensure that there is no change in material along with some important check such as weight of the container. - Part I - 17.3.1.2(g) states that "the name and the address of the manufacturer or the company and the person responsible for placing the product on the market" should be printed on the product label. Who's name needs to be printed?
According to such requirement should not be part of the Schedule M, because labeling requirements are described in Rule 96 of the Drug rules. Since Schedule M has been copied from WHO guideline, this sentence must have been erroneously retained and "or" in the WHO guideline must have been replaced by "and" making it mandatory. According to me there is no need to comply with this, however, I suggest seeking clarification from respective licensing authority so that drug inspectors don't site this as an non-compliance. - Part VIII (Oral solids) 1.9 requires the corridor shall be maintained at a higher
pressure than the cubicles, and the cubicles at a higher pressure than
atmospheric pressure. While pressure differential measurement between the corridor and the cubicles can demonstrate that the corridor is maintained at higher pressure, how can we demonstrate that the cubicles are maintained at higher pressure that the atmosphere?
- Part VIII (Oral solids) 1.41 requires dust extraction ducting shall be designed with
sufficient transfer velocity to ensure that dust is carried away and does not
settle in the ducting. Periodic checks shall be performed to ensure that there
is no build-up of the dust in the ducting. How to perform such check?
- Part VIII (Oral solids)1.64 requires air containing dust from highly toxic processes
or solvents or flammable vapors to be not recirculated to the HVAC
system. Is this required for all the areas such as granulation, coating etc?
- Part XII (APIs) 4.3.2 - WHO drinking water is specified as minimum quality for water to be used in processing. Can this be used in final stages of API processing?
WHO drinking water specification does not include specific limits for parameters such as Total dissolved solids (TDS) and Hardness. Using such water in large quantity in final stages can result in high salt content in the API and it may fail in tests such as sulphated ash. Although allowed in the rules, I recommend using Purified water to be used in the final stage of processing.
- Part XII (APIs) 12.4.5 allows use of retrospective validation approach in exceptional cases where certain conditions are met. Can this approach be used for old products?
- Part XIII (Requirement of plant and equipment) 11.1 - Recommends use of Reverse Osmosis (RO) or Electro-deionization water treatment unit and multi-column distillation unit for water treatment for use in parenteral preparations, why can't we use other water purification techniques such as Ion-exchange units for generating Purified water and single column distillation unit or vapor compression unit for generating WFI?
- Part XIII (Requirement of plant and equipment) 11.1 subsection 7(1) - Recommends use of visual inspection units (preferably conveyor belt type and composite white and black assembly supported with illumination). Can automated inspection machine be used instead?
Well done. Shall revert.
ReplyDelete"It shall be ensured that
ReplyDeleteshelf life of formulation product shall not exceed with that of active raw materials used" this statement is removed in revised schedule M.
That is right thing to do.
Delete