The Government of India amended Drugs and Cosmetics Rules 1945 to revise the Schedule M. Since there are significant changes with respect to existing rules, some manufacturers especially the small and medium manufacturers may find it difficult to understand the requirements specified in the revised document and may face difficulty in complying with the same.
What are the key changes in the revised Schedule M?
Revised schedule M has following key changes –
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.
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.
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.
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 –
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.
This section should be disconnected and cleaned during product changeover. This will prevent any residual material from the vertical pipe accidentally falling in the product. Removing of the horizontal section for cleaning during product changeover, will ensure effective cleaning and will also facilitate verification by visual observation as well as swab sampling.
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?
Typically, all such areas handling such materials should have 100% fresh air supply unless the processing is done in closed system. I suggest doing thorough risk assessment while designing the HVAC system to ensure that adequate safety controls are built in.
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?
Retrospective validation approach is outdated. It involves assessment of test results of past batches to arrive at conclusion about capability of process to meet desired quality This approach is not scientific as it does not involve identifying all critical process parameters and material attributes, evaluation of each processing stage for verifying its ability to meet desired outcome, assessment of consistency within the batch and across the batches for various quality attributes. Due these lacunae, I suggest not using this approach even though it is allowed in the rules.
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?
Any water purification technique can be used for generating purified water and WFI provided that it is validated to produce water of desired quality. Reverse osmosis is used where the TDS of input is high. Ion-exchange resin-based plants can perform the same function when TDS levels are relatively lower. EDI is used as final polishing unit in conjunction with RO or Ion exchange resins.
WFI can be produced using either single column or multi-column distillation units or using vapor compression technology. Only advantage of multi-column over single column is energy efficiency.
So, if a manufacturer has Ion exchange resin-based plant or single column distillation plant, there is no need to replace them as long as they produce water consistently meeting desired quality.