Does the prospect of getting an FDA 483 letter keep you up at night?
You're certainly not alone. Compliance pressures in pharma have never been higher. The FDA issued 3,344 observations to pharma companies in 2018. However, the best time to comply with cGMP for quality isn't after you've failed an inspection, it's before you receive a warning.
One way to ensure that a 483 doesn't show up in your mailbox is by understanding what the most common compliance issues in the pharmaceutical industry are so that you can focus on those areas.
Let's look at the five prevalent compliance issues and how you can put safeguards in place to avoid them.
5 Widespread Compliance Issues in the Pharmaceutical Industry (and How to Avoid Them)
The US FDA releases an annual data summary of inspection observations by industry. In 2018, pharma companies received 3,344 observations for 390 different categories of noncompliance. Nearly one-third (29%) of these observations fit into just ten categories, which tells a clear story about common compliance challenges at pharmaceutical companies.
When you focus on these top ten reasons for a 483 observation and combine the data into categories, even clearer patterns emerge from the data.
429 organizations received a 483 letter related to noncompliance for creating or following SOPs or issues with records-keeping. 322 struggled to design and implement effective controls, while maintenance and testing were an issue for 137 pharma companies.
It's common for pharmaceutical startups and scale-ups to experience growing pains as you approach market approval. Your ways of doing things may seem to work until an FDA inspector uncovers issues which have been overlooked, such as a batch of maintenance records which weren't reviewed the week your lab manager went on vacation. Fortunately, there's an easier path than just hoping for the best when an FDA inspector arrives on site.
1. Lack of Written Procedures or Failure to Follow Written Procedures
21 CFR 211.22(d)
"The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed."
The FDA issued 208 citations for noncompliance with 21 CFR 211.22(d). 483 observations in this category comprised nearly 7% of all warnings to pharmaceutical companies last year.
According to veteran FDA investigator Kristen Evans, the spike in 483 observations for written procedures could be a result of increased focus by regulators. “It might be because we're putting more emphasis on this regulation and the need for firms to adopt modern quality system concepts.”
Probably the most significant concern for anyone responsible for implementing, deploying, and maintaining a QMS is effectively documenting procedures and work instructions that are easy to understand and execute.
Clear SOPs aren't just a regulatory requirement, however. Strong procedures are a roadmap for quality. Consistent procedures lower noncompliance, deviations, and ineffective data. Common SOP pitfalls can include not collaborating, unclear responsibilities, or a lack of process.
SOPs should be living documents. Creating and maintaining these documents should be a collaborative effort between the QC unit, leadership, and employees. It’s not enough to pull together a document at the QC unit level and route it for necessary signatures. Employees should feel empowered to provide feedback and communicate.
Unclear roles and responsibilities
SOPs can be deliberately vague without mentioning specific roles. A document may say “the laboratory is responsible for,” instead of “the laboratory manager.” Clearly defined roles and responsibilities make it easier for employees to comply with quality processes, and it helps the QC unit link training activities to procedures.
Difficult format or language
2. Failures in Laboratory Controls
21 CFR 211.160(b)
"Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans or test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling or drug products conform to appropriate standards of identity, strength, quality, and purity."
Pharmaceutical companies received 127 citations for failed laboratory controls in 2018 or nearly 4% of total pharma 483 observations. Scientifically sound laboratory controls provide accurate, trustworthy lab data. cGMP for sound lab controls include:
- Scientifically sound and appropriate specifications, standards, and test procedures
- Monitoring the reliability, accuracy, precision, and performance of test procedures and instruments
- Identification and handling of test samples
An FDA laboratory inspection focuses on both lab operations and raw data to determine whether a pharma organization is compliant with cGMP. You can expect an inspector to look at:
- Lab records and logs
- Analytical procedures
- Raw lab data
- Lab equipment
Scientifically sound lab procedures is an enormous responsibility. Procedures, raw data, and management records are all necessary evidence of quality-driven operations. Raw data can tell a story about compliance and management, including instrument calibration, employee adherence to SOPs, and management investigations to find the root cause of operations.
3. Faulty Production Record Reviews
21 CFR 211.192
"There is a failure to thoroughly review any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has been already distributed.”
There were 107 observations issued in 2018 to pharma companies who didn't meet standards for the investigation of discrepancies or failures. CFR dictates that the pharma QC unit must review and approve all drug production and control records, including packaging and labeling records to determine compliance with SOPs. If there is a discrepancy or failure, the QC is responsible for performing a thorough investigation and creating a report which includes conclusions and follow-up actions.
A clearly defined workflow for review and investigations is crucial to ensure nothing is omitted. There are numerous ways organizations can become non-compliant with CFR 211.192, which include:
- Failure to review all logs
- Downtime logs, cleaning logs, and clearance logs should all be subject to review
- Procedural failures
- Laboratory workers cannot review their own work or batch records
- Lack of shared procedures
The QC unit and operations team should have a unified set of standards and SOP for batch record review to ensure there isn’t any confusion around parameters.
4. Absence of Written Procedures
21 CFR 211.100(a)
"There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess."
86 citations were issued for a lack of written procedure for production and process controls. While 211.100 observations for an absence of written procedures came in fourth in 2018, there’s a clear pattern of pharma organizations struggling to create SOPs for quality, production, and process. If you combine 211.100 and 211.22(d) observations into a supercategory for improper SOPs, it comprises a staggering 294 total observations. That’s nearly 9% of all 483 pharma observations last year!
FDA CFR directs that pharma organizations must create written procedures for production and process control. These SOPs must include all requirements for drug identity, strength, quality, and purity. SOPs should be reviewed and approved by the operational and QC units. Organizations must document compliance with these SOPs, and create a record with clear justification any time operations deviates from the SOPs.
In addition to noncompliance or issues of inadequate SOPs, analysis of 483 observations issued for CFR 211.100 in a recent year are often related to management and training. Excerpts from 483 letters have included the following language:
- Your firm has not established appropriate written procedures.
- There are documented instances of failure to follow SOP.
- Your firm's QC unit failed to approve procedures.
- SOP revisions are not documented appropriately.
- No records of CGMP training specific to SOPs.
- Both the GM and the Production Supervisor stated that they were unaware of [the SOP].
- Your SOP [is] in English. However, one operator...cannot read English.
Many of these issues can be corrected with better transparency and workflows. eQMS can enable the QC unit and production leads to collaborate more effectively throughout the approval and revision process, and ensure all necessary records are updated.
5. Improper Cleaning/Sanitizing/Maintenance
21 CFR 211.67(a)
"Equipment and utensils are not cleaned, maintained or sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product."
81 483 observations were issued in pharma for noncompliance with 21 CFR 211.67(a). Improper cleaning, sanitizing and maintenance observations comprised over 2% of total observations in 2018.
FDA CFR dictates that "equipment and utensils are sanitized, maintained, and cleaned appropriately to prevent malfunctions or contamination."
SOPs should be followed for cleaning and maintenance, including:
- Responsibility for cleaning
- Maintenance and cleaning schedules
- Detailed work instructions of methods
- Protecting clean equipment from contamination
- Inspecting equipment for cleaning before use
- Maintaining records of maintenance, cleaning, sanitizing, and inspection
Analysis of 483 observations for 21 CFR 211.67(a) in one recent year revealed the following reasons for noncompliance at pharmaceutical organizations:
- Maintenance activities have been performed "as needed" and logged on loose paper.
- 43 of approximately 55 maintenance records weren’t signed by the responsible employee.
- Cleaning records were not reviewed and approved after tasks were performed.
- SOPs failed to instruct technicians to record data for each maintenance activity.
Many 483 observations within this category result from visible maintenance or cleaning issues. Observations have cited equipment which is out-of-order or issues such as holes in a laboratory ceiling or rust which could compromise a clean environment. However, many result from improper procedures and aren't necessarily the result of a dirty lab.
Frequent review of SOPS is necessary to ensure there are written procedures to protect drug quality and avoid contamination. Clear workflows in an eQMS can prevent the risk of activities which aren't reviewed or appropriately approved in compliance with cGMP.
Steering Clear of Pharmaceutical Compliance Issues
No pharmaceutical company wants its first interaction with an FDA inspector to result in a 483 letter. While organizations who receive a 483 can correct non-compliance issues, receiving an FDA letter is a sign that your organization has overlooked important quality processes. The costs of quality and operational issues which go uncorrected are much higher long-term than the costs of continually complying with FDA best practices.
Compliance issues rarely result from willful rebellion against cGMP. Most commonly, organizations receive a 483 observation because something was overlooked. Perhaps the lab manager forgot to review maintenance records after a week on vacation. Maybe lab employees lost the updated SOP and have been using an older copy at the point-of-work. Noncompliance issues are the result of broken workflows, collaboration, and simple human error. Fortunately, you can avoid many of these common issues with better visibility and a QMS that supports quality-driven operations.
Qualio is the first cloud-based electronic quality management system (eQMS) built specifically for fast-growing startups and scale-up organizations in the life sciences industry
Our lightweight eQMS is designed based on the the latest FDA guidance, including FDA 21 CFR Part 820 and 21 CFR Part 11. Qualio offers easier compliance off-the-shelf, with simple features for end-to-end traceability, automated quality processes, and streamlined communications. Click here to schedule a demo and learn how Qualio can help you avoid an FDA 483 observation.