The ultimate intent of manufacturing in the pharmaceutical industry is to produce safe and effective medicines that are appropriate for patients, as well as having met all regulatory and legal requirements. While pharmaceutical products are known to fail at times, even though they may have been manufactured according to GMP quality systems, there continues to be an ongoing problem within the industry concerning failure of pharmaceutical products.
A pharmaceutical product is considered to be a failure when it does not comply with the pre-established requirements for identity, strength, purity, safety or effectiveness. The consequences of a pharmaceutical product failing can include product recall, regulatory warning, risk of harm to patient and financial loss to the manufacturer.
Understanding the causes of failure of pharmaceutical products and developing and implementing effective remedial actions for the prevention of additional failures is critical for compliance with regulatory requirements and for patient safety.
Some common types of product failures are as follows:
Batch Failures – a batch of product does not meet in-process or final release specifications.
Stability Failures – a product deteriorates before its shelf life ends.
Bioavailability Failures – a drug that is not released or absorbed as expected.
Microbiological Failures – contamination from microorganisms in sterile or non-sterile products.
Packaging or Labelling Failures- an incorrect or defective labelling, sealing or tampering issue with a product.
The presence of these types of failures indicate that there are gaps in Quality Systems, Manufacturing Processes or Raw Material Control; therefore, there must be a Root Cause Analysis (RCA) performed to identify the cause of the failure.
Using lactose or starch that has a microbial contamination as a raw material can lead to an overall microbiological failure in the manufacture of solid dosage forms.
Remedies:
Examples:
Examples of equipment malfunction or calibration errors could include some of the following:
Examples:
Examples:
Failures in the pharmaceutical industry can happen at any time yet how they are managed indicates a company’s focus on quality. The approach taken to handle these issues should be based on sound science, formal processes and preventive activities; specifically, identifying root causes, establishing effective corrective action/preventive action (CAPA) systems and developing a strong quality culture within the organization.
When organizations view their failures as an opportunity for improvement instead of a setback, they have the ability to enhance their systems therefore advancing towards zero-defects – defined as true pharmaceutical quality and ensuring the safety of patients.
Understanding the causes of failure of pharmaceutical products and developing and implementing effective remedial actions for the prevention of additional failures is critical for compliance with regulatory requirements and for patient safety.
What Is Pharmaceutical Product Failure?
Pharmaceutical product failure refers to when a medicine doesn't meet one (or more) of its quality requirements (Quality Attributes) during the time it is being manufactured, the time it is tested or even when it is sold on the shelf to patients.Some common types of product failures are as follows:
Batch Failures – a batch of product does not meet in-process or final release specifications.
Stability Failures – a product deteriorates before its shelf life ends.
Bioavailability Failures – a drug that is not released or absorbed as expected.
Microbiological Failures – contamination from microorganisms in sterile or non-sterile products.
Packaging or Labelling Failures- an incorrect or defective labelling, sealing or tampering issue with a product.
The presence of these types of failures indicate that there are gaps in Quality Systems, Manufacturing Processes or Raw Material Control; therefore, there must be a Root Cause Analysis (RCA) performed to identify the cause of the failure.
Sources of Most Common Manufacturer Product Failures
Most failed products are caused by different types of sources that lead to product failure; thus being able to identify the underlying cause is the first step in implementing the proper corrective and preventive actions.A. Issues with Raw Materials
The quality of the raw materials used in the production process impact the quality of the finished product. Possible reasons due to which quality of raw materials can affect the finished product include:- Products that do not meet the official pharmacopeial specifications.
- Raw materials that are contaminated, improperly stored or had the potential to degrade.
- Manufacturers that have quality consistency issues.
Using lactose or starch that has a microbial contamination as a raw material can lead to an overall microbiological failure in the manufacture of solid dosage forms.
Remedies:
- Have a robust vendor qualification and auditing program in place.
- Perform incoming product tests for identity, purity and microbial contamination.
- Place raw materials in controlled storage environments.
B. Manufacturing Process Issues
Manufacturing errors are one of the most common reasons of pharmaceutical product failure.Examples:
- Mishandled mixing or granulation has resulted in products that do not meet content uniformity specifications.
- Improperly dried products result in products being damaged by moisture during storage.
- The wrong compression forces have produced tablets that had hardness failure.
- Poor cleaning of manufacturing equipment has created cross-contamination between different brands of products being produced at the same time.
- Validate, test and optimize your manufacturing process (Process Validation).
- Train manufacturing operators to follow the manufacturer's standard operating procedures.
- Utilize automated systems to utilize in-process controls (IPC).
- Implement line clearance checks and verification of equipment cleaning before production runs begin.
C. Equipment Malfunction or Calibration Errors
Equipment malfunction or calibration error can also lead to invalid processing/testing results.Examples of equipment malfunction or calibration errors could include some of the following:
- Non-uniform/poorly coated products due to clogged spray nozzles
- Improper dryer/sterilizer temperatures
- Malfunctioning scales/HPLC systems
- Establish preventive maintenance and calibration schedules to be performed periodically.
- Qualify equipment and processes before using equipment.
- Monitor trends for equipment performance to detect any significant error.
D. Packaging and Labeling Defects
Defective packaging or labeling impacts the quality of a product because packaging is used for protecting/maintaining product stability and for identifying the product. For example, defective packaging could include the following:- Leaking seals in blister packs
- Incorrect batch number and/or expiration date printed on product
- Broken/torn tamper proof seals
- Validation of the packaging process through the inspection of the integrity of the seals.
- Implement barcode-scanning verification system for labels.
- Perform 100% visual checks of critical packaging parameters.
E. Stability and Degradation Issues
Research has demonstrated that drugs can degrade over time due to changes in environmental conditions such as heat, light, moisture or interaction with packaging materials. Some common visible signs of degradation are:- Color or odor change
- Potency loss or the formation of degradation products
- Failure to meet disintegration or dissolution criteria
- Conduct real-time and accelerated stability studies according to ICH Q1A (R2).
- Choose appropriate packaging such as blister foil, amber bottles or desiccants.
- Label products with appropriate storage conditions like “Store below 25°C”.
F. Microbiological Contamination
Contamination is critical with sterile products including injectable, ophthalmic and ointment formulations. Some of the sources of microbial contamination come from:- Poor aseptic practices
- Contaminated water systems
- Inadequate environmental monitoring
- Unvalidated sterilisation or filtration processes
- Implement a comprehensive contamination control strategy
- Validate sterilisation and filtration processes
- Routinely monitor cleanrooms for viable and non-viable particulate matter
- Provide thorough training of personnel in aseptic technique
G. Human Error
Human error is a significant contributor to deviations and failures of pharmaceutical products even with automation.Examples:
- Incorrect weighing or adding ingredients.
- Not following SOPs.
- Incomplete documentation for a batch.
- SOPs should be simplified and more user-friendly.
- Training should be more intensive and competency evaluations should be strengthened.
- Create a double-check system for critical operations.
- Create a "Just Culture" in which employees can report mistakes without fear.
H. Errors in Analytical Testing
Errors in laboratories can lead to misleading determinations about the quality of the product.Examples:
- Improperly taking samples or handling samples.
- Inaccurate or ill-calibrated instruments.
- Errors in applying methods or maintaining data integrity.
- Analytical methods should be validated for specificity, accuracy and precision.
- Maintain data integrity according to the principles of ALCOA +.
- A second person should independently review all data.
Remedies and Corrective Actions
When a failure is identified, a proper immediate containment and long term corrective actions must be followed.A. Root Cause Analysis (RCA)
- Use root cause analysis (RCA) tools like 5 Whys, Fishbone Diagram or FMEA for determining true root causes.
- Human error is considered as a cause of the failure if there is proven evidence to support it.
B. Corrective and Preventive Action (CAPA)
- Implement shorter term corrective actions to contain the issue.
- Establish long term preventive actions to prevent re-occurrence of the failure.
- Follow up audits or trending must be completed to verify the effectiveness of the CAPA.
C. Reprocessing or Reworking
- Asses the ability to reprocess the affected batch using validated conditions and not affecting the quality of the product.
- Get approval from QA and regulatory before reprocessing the affected batch.
D. Enhance Quality Oversight
- Strengthen your company’s deviation and change control systems.
- Conduct more extensive in-process monitoring during the manufacturing process.
- Conduct risk based audits of Critical Suppliers and Processes.
E. Continuous Process Verification (CPV)
- Use real time monitoring of critical process parameters and product characteristics.
- Utilize predictive data analytics to provide early warning of the ability to drift from the process.
F. Personnel Training & Culture
- Conduct refresher training of employees that should focus on GMP compliance and quality awareness.
- Promote a culture of accountability and ownership for the quality of the product.
G. Quality Risk Management (QRM)
- Conduct ICH Q9-based risk assessment for processes, materials and equipment.
- Focus on preventive strategies for quality rather than reactive corrections.
Preventive Actions Against Product Failure
1. QbD and Design Quality into the Product
Using the QbD principles during the product development phase will get a better understanding of which products have critical quality attributes (CQAs) and process parameters (CPPs).2. Process Validation
Establish the consistency of the process throughout manufacturing, as well as through multiple batch processes, utilizing the worst-case method of operation.3. Supplier Qualification
Regularly evaluate and audit raw material suppliers to ensure consistency in providing superior quality items to the customer.4. Environmental Control
Controls are in place to control temperature, humidity, cleanliness of the manufacturing area.5. Electronic Record & Automation
Utilizing either EBR & Automated Monitoring Systems minimizes human error.6. Change Control
A formal risk assessment must be performed on all proposed changes (equipment, process, material) prior to implementation to allow for evaluation.7. Product Quality Review (PQR)
Every year a report will be written to summarize the results of a review of product trends; deviations; product complaints; and stability with the intent of developing new opportunities for improvement.Consequences of Repeated Product Failure
Multiple product failures result in a series of negative consequences.- FDA Warning Letters or Import Alerts.
- Product recalls or withdrawals.
- Loss of client trust and brand equity.
- Financial loss associated with re-making and destroying batches of non-conforming product.
Failures in the pharmaceutical industry can happen at any time yet how they are managed indicates a company’s focus on quality. The approach taken to handle these issues should be based on sound science, formal processes and preventive activities; specifically, identifying root causes, establishing effective corrective action/preventive action (CAPA) systems and developing a strong quality culture within the organization.
When organizations view their failures as an opportunity for improvement instead of a setback, they have the ability to enhance their systems therefore advancing towards zero-defects – defined as true pharmaceutical quality and ensuring the safety of patients.
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.