In the pharmaceutical industry, having the integrity of your product as a major objective is a mandatory requirement. All items produced should be manufactured to a level of safety, efficacy and purity that has been established prior to entering into commerce. A non-conformance is the term used for any manufacturing, product or system process that is unable to meet these criteria.
Failure to manage non-conformance can lead to; recalls from the market, citations from regulatory agencies and a loss of confidence in your business. By understanding what non-conformance is and what its causes are; as well as developing strategies to keep your products in compliance with the standards and requirements of maintaining quality, you will be able to improve your company continuously.
This article explains the definition of non-conformance and discusses some of the most frequent causes and ways to develop processes to avoid them.
Non-Conformance (NC) represent any instance of deviation from specified standards, norms or requirements, whether they occur at receipt of raw materials or any point through to distribution. Compliance with Current Good Manufacturing Practices (cGMP) requires a manufacturer to ascertain that it meets the standards set forth in the established standard operating procedures (SOP); there can be no deviation from these SOPs without documentation, investigation and resolution.
Types of actions that fall under NC are numerous. The following are a few examples:
- Out-of-Specification (OOS) results on test samples.
- Labels or packaging that are incorrect.
- A malfunction of the manufacturing equipment that occurred during the manufacturing process.
- Incomplete record of the batch manufacturing process.
- Unapproved raw materials or processes being used.
- In the context of non-conformance, any instance of non-compliance with the specified quality requirements should be considered as a signal that the company's quality system is inadequate or requires improvement.
Examples of critical nonconformance include:
- Contaminated batches of product
- Use of expired raw materials
- Missing critical processing steps
All of the above types of critical nonconformance result in rejected batch product, product recall or regulatory escalation of compliance issues related to patient safety.
Examples of major nonconformances include:
- Inadequate qualification of equipment
- Inadequate adherence to approved procedures
- Improper change control or deviations from approved procedures
Examples of minor nonconformance include:
- Missing signature(s) in logbooks
- Document formatting errors
- Minor delays in equipment calibration
All minor nonconformance, even if they are minor issues, can escalate into major compliance risks if they are ignored or repeated.
Common reasons for non-conformance found during inspections and audits include:
1. Regulatory Implications: Non-conformances often result in the issuance of an FDA Form 483 or Warning Letter. Ongoing issues may ultimately lead to import alerts, license suspensions or product bans.
2. Operational Implications: Re-work, batch rejections and downtime in production are all result of higher manufacturing costs and the wasted use of resources.
3. Reputational Implications: Product recalls and regulatory compliance failures directly impact the company's reputation, credibility and Trust of Patients.
4. Patient Safety Implications: Non-conformance issues impacting the strength, purity or sterility of the product constitute a serious health risk.
As such, the prevention and proactive management of non-conformance are an essential part of the pharmaceutical quality system.
The establishment of a robust system for the tracking of communications between manufacturing, purchasing and delivery provides the foundation for a strong and effective system for the management of non-conformance.
To effectively promote continual improvement the following Strategies have been developed and implemented throughout the Organization:
Track metrics regarding your company's necessary operations by tracking the following KPIs:
Non-compliance in the pharmaceutical industry is an unfortunate reality; however, the number of times this occurs and its impact on the company can be reduced through the establishment of a proactive approach to prevention. A proactive preventive strategy includes having a process for improving systems and training and providing training programs that reinforce Good Manufacturing Practices (GMPs). The goal of an effective CAPA system is to help the manufacturer maintain as high a degree of quality as possible by preventing future non-compliance through identification of both the cause and corrective actions.
In addition to protecting the patient from potentially harmful product, preventing non-compliance allows for the preservation of trust with clients and the general public and also preserves the credibility of the pharmaceutical industry as a whole.
Failure to manage non-conformance can lead to; recalls from the market, citations from regulatory agencies and a loss of confidence in your business. By understanding what non-conformance is and what its causes are; as well as developing strategies to keep your products in compliance with the standards and requirements of maintaining quality, you will be able to improve your company continuously.
What is Non-Conformance in Pharmaceuticals?
In pharmaceutical industry, the term non-conformance is an indicator of a deviation from standard practices, that is done either during manufacturing or delivery of goods, which can negatively impact quality, process control and regulatory compliance.Non-Conformance (NC) represent any instance of deviation from specified standards, norms or requirements, whether they occur at receipt of raw materials or any point through to distribution. Compliance with Current Good Manufacturing Practices (cGMP) requires a manufacturer to ascertain that it meets the standards set forth in the established standard operating procedures (SOP); there can be no deviation from these SOPs without documentation, investigation and resolution.
Types of actions that fall under NC are numerous. The following are a few examples:
- Out-of-Specification (OOS) results on test samples.
- Labels or packaging that are incorrect.
- A malfunction of the manufacturing equipment that occurred during the manufacturing process.
- Incomplete record of the batch manufacturing process.
- Unapproved raw materials or processes being used.
- In the context of non-conformance, any instance of non-compliance with the specified quality requirements should be considered as a signal that the company's quality system is inadequate or requires improvement.
Types of Non-Conformance
The classification of nonconformance within the pharmaceutical industry is primarily based upon the extent to which a particular issue has the potential to impact product safety, product efficacy or regulatory compliance. Classifying these types of nonconformance allows pharmaceutical manufacturers to put appropriate corrective action plans in place to minimize any adverse consequences of the nonconformance.1. Critical Nonconformance
Critical Nonconformance involves direct implications on patient safety, product effectiveness and/or regulatory compliance.Examples of critical nonconformance include:
- Contaminated batches of product
- Use of expired raw materials
- Missing critical processing steps
All of the above types of critical nonconformance result in rejected batch product, product recall or regulatory escalation of compliance issues related to patient safety.
2. Major Nonconformance
Major non-conformance does not directly impact product safety but has a significant effect on process control and data integrity of products.Examples of major nonconformances include:
- Inadequate qualification of equipment
- Inadequate adherence to approved procedures
- Improper change control or deviations from approved procedures
3. Minor Nonconformance
Minor nonconformance has limited or indirect effect on both product quality and GMP compliance.Examples of minor nonconformance include:
- Missing signature(s) in logbooks
- Document formatting errors
- Minor delays in equipment calibration
All minor nonconformance, even if they are minor issues, can escalate into major compliance risks if they are ignored or repeated.
Common Causes of Non-Conformance
Non-conformance is seldom an accident. The most common reasons for non-conformance are weak processes, human error and inadequate system design.Common reasons for non-conformance found during inspections and audits include:
1. Human Error
Operators might not follow procedure, misinterpret document instructions and fail to include all activities as required. There are several reasons why operators make mistakes, including a lack of proper training or education, fatigue and/or the lack of clear procedures.2. Improperly Documented Procedures
Inadequately documented, outdated Standard Operating Procedures (SOPs) often result in inconsistent application of procedures by the operator. When procedures are either vague or missing instructions, deviations from procedure will occur.3. Unmaintained Equipment
Malfunctioning or poorly calibrated equipment can impact variability of the process and negatively affect the accuracy of test results.4. Raw Material Quality Problems
Raw materials that are insufficiently manufactured or contaminated will deviate from the manufacturer’s stated product specifications. Poorly developed supplier qualification programs add to this problem.5. Variations in the Process
Elements of the process, including but not limited to, temperature, pressure, mixing time and others that are not controlled result in the characteristics of the product being different from what they should be.6. Errors in Documentation
Errors in the batch record, missing information, backdated entries and incomplete records are frequently noted in FDA warning letters.7. Changes without Documented Change Control
Modifying the process or equipment without evaluating the risk of such modifications can introduce new and/or unexpected risks into the process.The Effect of Non-Conformance
Failing to address or manage issues of non-conformance can represent serious risks both to companies and patients.1. Regulatory Implications: Non-conformances often result in the issuance of an FDA Form 483 or Warning Letter. Ongoing issues may ultimately lead to import alerts, license suspensions or product bans.
2. Operational Implications: Re-work, batch rejections and downtime in production are all result of higher manufacturing costs and the wasted use of resources.
3. Reputational Implications: Product recalls and regulatory compliance failures directly impact the company's reputation, credibility and Trust of Patients.
4. Patient Safety Implications: Non-conformance issues impacting the strength, purity or sterility of the product constitute a serious health risk.
As such, the prevention and proactive management of non-conformance are an essential part of the pharmaceutical quality system.
Effective Management of Non-Conformances
Non-Normalities are to be addressed systematically from their initial identification all the way through to corrective action for this issue. A number of actions must happen at each step, as follows:1. Identification and Reporting
Non-conformances can be identified during an in-process inspection, through testing or through an audit. As soon as non-conformance has been detected, it needs to be documented with all relevant details.2. Categorization
Non-conformances must either be categorized as critical, major or minor in terms of severity and potential to impact the quality of the product or the safety of patients.3. Investigation
Using root cause analysis techniques, a root cause analysis should be conducted on the non-conformance. Examples of these tools include the 5 Why’s, Fishbone (Ishikawa) diagrams and FMEA (Failure Mode and Effect Analysis).4. Corrective and Preventive Actions (CAPA)
CAPA will define corrective actions to be taken to resolve the current event of non-conformance and will outline the actions that must occur to prevent recurrence. As part of this process, a practical time frame should be established and defined corrective actions will be confirmed as effective.5. Records Retention
All records will be retained in compliance with 21 CFR Part 211.192 under all circumstances. Non-conformance will not be closed until it has been confirmed that the actions taken to correct the issue were effective.The establishment of a robust system for the tracking of communications between manufacturing, purchasing and delivery provides the foundation for a strong and effective system for the management of non-conformance.
Ways to Prevent Non-Conformance
Preventing non-conformances is generally much more cost effective than trying to do so through corrections. In addition, there are various proactive strategies which can reduce the occurrence of non-conformances while promoting a culture of continual improvement within your organization.To effectively promote continual improvement the following Strategies have been developed and implemented throughout the Organization:
1. Acquire an enhanced training program
The requirement for all employees to participate in a regular, competent-based training program reinforces the requirement for compliance (to be in accordance with). The need for refresher training combined with on-the-job training further reinforces what the employees should know and how to do this.2. Update standard operating procedures (SOPs) periodically
Standard Operating Procedures (SOPs) must be updated at least once every year based on any regulatory changes or after a process change occurs. SOPs must be clear and easy to follow and all operators must be able to access them.3. Implement Robust Equipment Qualification and Maintenance
Preventive Maintenance (PM) and calibration programs must be developed for all equipment. Use of automated processes and alarms should assist operators with minimizing the opportunity for errors.4. Strengthen the Supplier Qualification Process
Regularly audit and monitor suppliers to ensure they are supplying quality raw materials and packaging components. Poor quality inputs to any process are generally one of the main causes of non-conformance.5. Use Real-Time Process Monitoring
Utilize process analytical technology (PAT) and statistical process control (SPC) to detect process deviations early and correct before process stability is disrupted.6. Conduct Regular Internal Audits
Internal Audits are internal evaluations that help identify any areas of compliance that may have or can be missed during the regulatory process and allow for corrective action plan (CAPA) development from these findings.7. Data Integrity Training
All relevant employees within the organization must be trained on ALCOA+ (Attributable, Legible, Contemporaneous, Original, Accurate) principles. Breaches of data integrity are commonly noted on inspection reports.8. Quality-Culture Development
Creating a quality-culture environment will encourage employees to report deviations. If an organization has a strong quality focus over our production environment, there are less hidden problems.9. Enhanced Inter-Department Communication
Establishing a cross-departmental communication process will allow potential issues to be identified at an early stage. Quality Assurance, Production, Maintenance and Research & Development need to work collaboratively.Continuous Improvement and Trend Analysis
Avoiding failure to meet requirements should never be just a single-time solution. Continual evaluations over time will reveal trends or metrics that display a common occurrence, requirement for improvement or both.Track metrics regarding your company's necessary operations by tracking the following KPIs:
- Number of deviations per batch.
- CAPA closure timelines.
- Audit finding recurrence rate.
- Batch rejection percentage.
Non-compliance in the pharmaceutical industry is an unfortunate reality; however, the number of times this occurs and its impact on the company can be reduced through the establishment of a proactive approach to prevention. A proactive preventive strategy includes having a process for improving systems and training and providing training programs that reinforce Good Manufacturing Practices (GMPs). The goal of an effective CAPA system is to help the manufacturer maintain as high a degree of quality as possible by preventing future non-compliance through identification of both the cause and corrective actions.
In addition to protecting the patient from potentially harmful product, preventing non-compliance allows for the preservation of trust with clients and the general public and also preserves the credibility of the pharmaceutical industry as a whole.
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.