It appears to be a common misconception amongst importers that simply because they are importing from an outsourced manufacturing base, they will be exempted from FDA regulations. They might think to themselves, what are the chances of my shipment being inspected by the FDA? That’s only for the locally produced brands.
However, as it just so happens, this thinking might get you into a lot of trouble. Over the years, the instances of the FDA thoroughly inspecting companies that have their manufacturing units based in China has increased manifold.
Reports show that in just five years, from 2011 to 2016, the number of inspections for the drug manufacturing units based in China grew an astounding 66 percent. To top that off, it is expected that this number will continue to grow over the coming years, as stipulated by the Food Safety Modernization Act of 2011.
Given the recent pandemic that had its origin in China, it is quite inevitable that strict measures will be adopted by the FDA to ensure that any food and drugs imported into the country are compliant with previously set quality standards.
Many countries in the world base their framework of consumer protection on good manufacturing practice (GMP). In addition to that, several large regulatory bodies such as the U.S. Food and Drug Administration (FDA) based their inspections on domestic GMP compliance and enforcement.
However, as the number of companies that outsource their production to China and other countries grew, the FDA had to step up their vigilance as well. Now, the FDA is increasingly involved in inspecting goods that have their manufacturing bases abroad as well.
It is important to note that even though the products are being produced in a foreign country, in case the FDA comes across any instances of noncompliance, it is the importer who has to face the consequences of the supplier’s lack of compliance.
Therefore, it is highly recommended that you do not take your GMP compliance for granted- in fact, think of it as an opportunity to not only avoid negative repercussions at the hands of the FDA but also to boost your product quality and therefore prevent any unsafe products from reaching the consumers through your brand.
4 TYPES OF FDA INSPECTIONS THAT YOU SHOULD BE PREPARED FOR:
To ensure compliance with GMP standards, it is important to first acquaint yourself with the different types of inspections that the FDA carries out. There exist different criteria based on which the FDA will initiate different inspections- but it’s important to be familiar with all of them.
The Pre-Approval Inspections for First-Time Product Applications:
The pre-approval inspection (PAI) is in place to assess the capabilities of a manufacturing plant. It is in place to determine whether the plant is capable of manufacturing the products that it is applying for. Therefore, any manufacturing plant that applies for the first time is subjected to the following pre-approval inspections:
- New drug application (NDA) and abbreviated new drug application (ANDA)
- Biologic license application (BLA)
- Premarket approval application for medical devices (PMA)
- New animal drug applications (NADA) and abbreviated new animal drug applications (ANADA)
Once the manufacturing firm has applied with the FDA, the authority will review the application remotely and then ensure that the facilities and conditions present at the manufacturing site comply with the minimum requirements of the GMP regulation.
Once the precursory review is carried out, the inspector would then make a recommendation either in favor of or against an FDA approval for the applicant, based on the results of the pre-approval inspection. You must get permission from the FDA before you can legally sell products in the U.S.
What are the Main Objectives of the Pre-Approval Inspection?
1. To carry out a thorough assessment of the readiness of the manufacturer in producing commercial products. This helps to decide whether or not the quality system in place in the factory can sufficiently oversee production and ensure that quality concerns are catered to at all points. The quality assurance system needs to be capable of overseeing the entire manufacturing process efficiently.
2. To ensure that there is complete conformance to the application. This is vital because the FDA has to ensure that all points stated in the application, such as processing methods or analytical methods, are the same on-site. Any discrepancy may lead to a cancellation of approval by the FDA.
3. To authenticate and verify the data provided to the FDA, whether electronically or manually.
Similar to other routine inspections, in case the inspection results are not satisfactory, the manufacturers will receive a notice during the pre-approval inspection on form 483; form 483 is the primary way through which the FDA prompts manufacturers of any noted violations.
In case the supplier is unable to meet the criteria of the pre-approval inspection and therefore fails the inspection, the FDA would then issue an “Official Action Indicated” result.
This bars the supplier from legally selling or distributing the products in the U.S unless a subsequent inspection is carried out and passed by the supplier, which verifies that any violations noted in the initial inspection have been promptly corrected by the manufacturer.
A product-Specific, Post-Approval Inspection:
In certain cases, a post-approval inspection may be carried out by the authorities, even after successfully passing the pre-approval inspection. These inspections are generally related to a specific product and are carried out to access certain factors that are essential to ensuring the quality of the products and may have been skipped during the pre-approval inspection.
Such an inspection will often take place eight to twelve months after the approval of the pre-market application by the FDA.
In the case of medical devices, the FDA keeps verifying the Medical Device Reporting (MDR) requirements while carrying out the post-approval inspection.
It is important to note that while the post-approval inspection is being carried out, the inspection team will focus on process validations and change controls; this means that inadequately-controlled mechanisms will lead to problems such as performance issues, complaints, and the need to repair products frequently.
System-Based, Routine Inspections:
It is essential to keep in mind that regardless of the product being manufactured or the location of the factory, suppliers must always remain prepared for routine inspections.
It is common for routine inspections (also known as surveillance inspections) to occur at least every two years or so- this is because the FDA is bound by law to inspect Class I and Class II medical devices at least every two years. So whether you’ve committed any violation of existing laws or are working perfectly in line with all compliances, you should expect an inspection every two years.
However, the GMP regulations are often adapted to the ongoing environmental and therefore can take place more frequently as well, to take account of how well suppliers are abiding by the law.
Such routine inspections can be broadly divided into two categories:
- Full/Comprehensive inspection: these are the inspection of four subsystems. It is helpful for you to be fully prepared for this in case you have never undergone a full inspection before.
Abbreviated Inspection:
- This is the inspection of two subsystems. This is likely to occur if you’ve already gone through a full/comprehensive inspection before.
When talking about a full or abbreviated inspection of a pharmaceutical facility, it is likely to always include inspection of the quality system. In the case of medical devices, the inspection is likely to include corrective and preventive action (CAPA) system and the Quality System Inspection Technique (QSIT).
However, it is impractical for the FDA to conduct a thorough inspection of every area of a supplier’s facility at each inspection. Therefore, the FDA is likely to conduct an abbreviated inspection in case the supplier being inspected has a satisfactory record with the CGMP.
But, if you have a history of being non-compliant in certain areas, you are much more likely to face a comprehensive inspection- this is possible even if you have passed the last inspection.
It is likely for the inspector to alternate between different subsystems for abbreviated inspections.
For-Cause Inspections Following Up on Pastor Suspected Violations:
In case your manufacturer has committed some violations or has allegations of noncompliance, the FDA will conduct for-cause inspections.
The for-Cause Inspections Can Be of Two Types:
- Follow-up compliance inspections performed to verify corrective actions after the FDA has taken regulatory action
- Inspections performed in response to specific events, reports, or information
The FDA has Several Ways Through which it Can Find Out About GMP Compliance:
- Results of a sample analysis
- Observations made during prior inspections
- Product recalls or market withdrawal
- Consumer or employee complaints
- Adverse reaction reports
- Suspicion of fraud
Keep in mind that inspections related to issues that have been previously reported are unannounced and do not follow any script. Therefore, there’s little that you can do to specifically prepare for such an inspection, except for making sure that you are fully compliant with all relevant and up to date regulations.
For-cause inspections are meant to verify directed or suspected quality issues. Therefore, the inspection team will attempt to find the core causes of the problem, so that they can provide appropriate corrective actions for factory management.
ARE YOU AT HIGH RISK WHEN IT COMES TO FDA INSPECTION?
A decade ago, a large number of foreign facilities were lined up with the FDA for approval to distribute in the U.S because there was no requirement for the FDA to inspect foreign facilities. However, the situation has changed drastically ever since.
With the passing of the Food and Drug Administration Safety and Innovation Act, authorities successfully removed any distinction between foreign and domestic facilities, and therefore the FDA adopts a risk-based approach for determining inspection frequency.
Depending on the risk associated with each case, the FDA decides which manufacturers to inspect and how often. They base their inspections in terms of priority, starting with those that may offer the highest public risk first.
The Following are Some of the Risk Factors that the FDA Assesses:
- The inherent risk of product – Some products may have intrinsic properties where deficiencies in quality would have a more adverse public health impact than others.
- Market novelty – A product that’s recently been introduced to the market often presents a greater risk.
- Complexity – More complexity in a product or its associated manufacturing processes may require greater oversight.
- Facility inspection record – Any prior inspection results, GMP compliance history, and previous inspection frequency can indicate risk.
Therefore, the frequency of FDA inspections will depend upon the type of facility that you’re operating. Some facilities will inherently require more inspections than others.
The next question comes to, which products does the FDA consider high-risk?
When it comes to understanding how the FDA prioritizes its inspections, it’s helpful to understand different classifications. A Class I to Class III classification exists, with the highest priority given to Class III and lowest to Class I.
But, when it comes to “for-cause” inspection, the FDA may still prioritize Class I if such a facility is a viable health hazard.
The following are some of the high-risk food products:
- Atmosphere-packaged products
- Acidified and low-acid canned foods
- Seafood
- Custard-filled bakery products
- Dairy products
- Fruits and vegetables
- Spices
- Shell eggs
- Infant formula
- Medical foods
In addition to that, the FDA makes it a priority to inspect life-saving drugs and devices, and those that are in critically low supply.
WHAT TO EXPECT BEFORE AN FDA INSPECTION?
When you’re acquainted with the different sorts of FDA examinations. It assists with understanding the cycle paving the way to, during, and after an assessment. A significant contrast between foreign and domestic inspections is the obligation to provide an earlier notification given to the foreign facilities. Which is not provided to domestic suppliers or producers.
FDA authorities are not obliged to inform domestic firms preceding assessment or inspection. While they’ll generally give notice to foreign providers before review.
The FDA contacts offices picked for foreign reviews utilizing email, fax, or postal mail, and works with office agents to plan a suitable time for the investigation.
Notwithstanding certain exemptions, the FDA won’t give an assessment agenda to the arranged investigation way for neither domestic nor foreign reviews.
WHAT CAN YOU EXPECT WHILE THE INSPECTION IS UNDERWAY AT THE FACILITY?
Most of the FDA investigations will normally take one to three days, contingent upon the extent of the examination and on-location discoveries. A group of at least two investigators may therefore be required for longer examinations if required.
The FDA assessment group will hold an “opening meeting” with the industrial facility on board and any other relevant staff before the review starts. This gathering is pointed towards educating the producer regarding the reason and extent of the examination.
The inspection team discusses the discoveries with all the representatives as they evaluate the workplace and the facility. Proficient staff ought to be accessible to address inquiries all through the whole examination measure.
The factory should have all relevant documentation ready for inspectors. Some important documents to have available include:
- Equipment calibration and maintenance reports
- Internal investigations into root causes of production failures
- Process validation reports
- Production and process control reports
- Deviation reports
- Internal audit reports
- Statistical evaluation of product data
- Shipping records
- CAPA procedures
- Product recall and rejection reports
- Customer complaint files
- Personnel qualifications
- Training procedures
Samples of goods, raw materials, work in progress, and labels can be obtained by inspectors during inspection for testing and review. To record violations, they may also take pictures of the facility, objects, or records as desired.
USE THE CLOSING CONFERENCE TO YOUR ADVANTAGE:
At the completion of the inspection, you also should expect a “closing conference” to discuss findings or deficiencies found on site. During the closing meeting, inspectors will review two forms of conditions and practices: FDA will review features:
- Those that could be upgraded
- Those that inspectors deem to be reviewable violations
This post-inspection meeting creates an opportunity for factory representatives to ask any questions that they might have.
It’s also a chance to talk about the findings openly and detect any inaccuracies before submitting the final results.
The closing conference is the last forum for the supplier to refute or make corrections to the report before their inspection report is published by FDA officials.
WHAT CAN YOU INSPECT ONCE THE INSPECTION HAS ENDED:
FDA inspection team will give a form 483 to the industrial facility at the end of the meeting if the infringement is found during the investigation.
Form 483 contains a rundown of observations made during the investigation. The inspection team will convey and disclose these records to the supplier during the end conference. In any case, a form 483 doesn’t represent the last FDA report concerning the facility’s GMP compliance.
The FDA will deliver an Establishment Inspection Report (EIR) within 30 days of the investigation. The EIR mirrors the FDA’s true assurance of a manufacturing plant’s GMP compliance.
- Results may require the manufacturing plant to make extra efforts, contingent upon the issues discovered during the investigation:
- No Action Indicated: Given if no infringement was noticed.
- Deliberate Action Indicated: Given when infringement is found, however, the issues don’t legitimize further administrative activity. Improving GMP compliance is voluntary for this situation.
- Official Action Indicated: Given if infringement found requires further administrative actions and obligatory restorative activities.
HOW TO RESPOND TO FORM 483S AND WARNING LETTERS:
While not legally necessary, within 15 business days, the recipient of a 483 should respond in writing to the FDA to prevent further regulatory action.
The FDA almost always reacts by releasing a warning letter if the firm fails to respond to the 483. Where significant breaches have been found and/or if the company’s reaction to the 483 was insufficient. The FDA delivers a warning letter. Within 15 days, the firm is expected to respond to the warning letter.
A warning letter, including import notices, product seizures, and injunctions, serves as a basis for further regulatory compliance.
Important Steps in Response to a 483 or a Letter of Warning Include:
- Answer each object, regardless of the number of observations listed. To ensure consistency, restate questions verbatim.
- Clearly show compliance with the results of the FDA and the action sought. At the closing meeting of the inspection, verify the validity of FDA findings, not after.
- Establish a CAPA plan and include a corrective schedule.
- Seek any required clarification of what the FDA needs to fully comply with GMP.
- To verify the compliance of your CAPA strategy, expect a reinspection at your supplier’s factory.
CONCLUSION:
To recognize and fix GMP enforcement issues at your manufacturing plants promptly, do not wait for an FDA inspection.
Because an increasing number of international factories are applying for the production of products overseas which is covered by FDA regulations. It is better to plan your supply chain for an inspection. It also consumes a lot of effort and time to guarantee FDA inspection compliance and proper conformity to U.S. laws.
One way to detect GMP enforcement deficiencies at the facility of your supplier is a third-party GMP pre-audit. You should coordinate with your supplier to create and execute a CAPA plan with these findings to guarantee GMP compliance before the official FDA inspection.
Although inspections of foreign facilities are pre-announced, delaying enforcement until the very last moment can escalate to inspection failures.