The United States FDA is responsible for enforcing regulatory regulations for the drugs marketed and sold in the United States. For this purpose, many types of enforcement actions enable the agency to successfully eliminate manufacturer complaints and comply with the compliance requirement, one of which is the warning letters.

A warning letter is a part of communication by the FDA with the manufacturer to share their finding to remove the discrepancy found during their inspection and inform the status of the manufacturer's measures. The warning letters are the initial set of communication the FDA performs and do not necessarily indicate any serious threat to the pharma manufacturer's accreditation status.

What are the warning letters?

The United States FDA issues warning letters to pharma manufacturers to remove noncompliance if found. The Regulatory Procedures Manual - RPM, chapter 4, "Advisory Action," states the following information about warning letters.

"When it is consistent with the public protection responsibilities, and depending upon the nature of the violation, it is the Food Drug and Administration's practice to allow individuals and firms to take voluntary and prompt corrective action before it initiates an enforcement action."

According to RPM, warning letters are issued only for a significant regulatory violation, which may lead to enforcement action if it is not adequately addressed. According to this act, warning letters are informed and do not oblige the FDA to carry out an enforcement action. It communicates the FDA's opinion and cannot be sued.

In some cases, if the violation is not serious, the FDA will issue another warning letter if the response to the first warning letter is unsatisfactory and needs further improvement or corrective action.

In some cases, the FDA does not think it necessary to issue warning letters and will take enforcement action directly. Some of which include the following.

• Repeated or History of continual conduct and the individual/firm has been notified of the violation - for example, if a pharma manufacturer is violating regulations, and the F.D.A. has previously issued a warning letter. However, the manufacturer has not notified or implemented corrective actions.

• intentional or flagrant violation

• Possibilities of injury or death - for example, if a pharma manufacturer has been found using any toxic agent to  manufacture its product, and this product has been classified as dangerous for human consumption

• Violations under the 18 U.S.C. 1001 that are intentional. It includes manufacturing any falsified, fictitious, or fraudulent product.

What happens when a company gets a warning letter?

When a pharma manufacturer receives a warning letter, it is a serious issue, and if not adequately addressed, it can result in a fine or shutting down of production operations. So, for this purpose, the pharmaceutical manufacturer should take it seriously and start devising a plan to remove the violation stated in it.

Different warning letter types have different procedures, resulting in other resource allocations and lines of action. However, a typical process consists of the following.

• Acknowledge the letter receipt through the proper channel.

• Outline the set of activities that you plan to carry out to mitigate and remove the violations.

• In some cases, a pharma manufacturer takes in-house resources and expertise. However, in some cases, the pharma manufacturer can hire an external consultant to resolve the issue. The consultant must be experienced in resolving these issues. Especially those consultant that have an understanding of FDA requirements and can deal with these inspections easily

• Formulate corrective and preventive actions. It must include input from all the relevant stakeholders, such as Quality, Production, and Engineering. Another department can also be included depending on the nature of corrective actions required, such as the supply chain and information technology department,

• After devising CAPA, communicate your plans to the FDA in the stipulated timeline. This will enable FDA to work closely with the pharma manufacturer and plan a follow-up visit

Some warning letters

Let's discuss some warning letters, and see what the reason behind warning letters were and what FDA proposed

Warning letter No. 1: national chemical laboratories

The United States FDA issued a warning letter to National Chemical Laboratories in Philadelphia regarding its drug manufacturing facility. Additionally, the FDA inspectors inspected the facility previously, to which NCL responded with form 483. The FDA also acknowledged this in this letter.

Violations

In this warning letter the FDA indicated following violation

• Failure to validate and establish the regulatory of your components supplier test: The Company failed to provide component testing of BZK and establish the reliability of the component's supplier test analysis.

• Quality control failed to ensure that drugs manufactured are in compliance with CGMP and fail to meet established specification for identity, strength, quality and purity

The quality failed to provide adequate arrangements for the manufacturing of drugs. For example, was unable to give and keep a check on the production process.

• Failure to create and implement  adequate stability program

Your company failed to implement an adequate stability program. Moreover, procedures for out of specifications, deviations in manufacturing, cleaning validation, and written procedures for cleaning & maintenance of non-dedicated manufacturing equipment were also not present / in-sufficient

• In the previous and response your company failed to provide

• How does your quality function improve the oversight of manufacturing quality

• Assessment of insufficient Quality Unit on product quality

• Cleaning validation does not include testing of product residuals and justification of swabbing location

• Repeated observation

In previous inspections, the FDA highlighted similar violations. In the response, you suggested remedial actions. However, our current examination reveals that those corrective actions have not effectively been implemented.

Actions required

The FDA in this letter ask to provide the following

For the observation No. 1

Please provide

• Description of how you intend to test each component

• SOP for certificate of analysis and validation

• A summary of how you qualify and oversee contract facilities involved in testing of equipment you use

For the observation No. 2

Please provide

• Surety that the Quality Unit is given the required authority and resources

• CAPA to ensure the viability of the stability program

• Timeline for process qualification for each of your drug product

• Improvements in cleaning validation program

For observation No. 3

Ensure that commitments are fulfilled and implemented

Final Words

Every pharma manufacturer is responsible for eliminating all violations issued by the FDA. If not attended with appropriate action, the FDA will take action notice. Moreover, for every such pharma manufacturer, the FDA will withhold the FD export certificate and approval of the new application

Warning letter No. 2 Belmont eye Care LLC

The United States FDA issued a warning letter to Belmont Eye Care LLC. The main reason for the warning letter is that the products displayed on its website and products for sale in the United States are unapproved under section 505 (a) of the Food Drug & Cosmetic Act.

Background

The information obtained from the website and label indicates that these products are classified as drugs because they are used in the diagnosis and care of disease

Violation

The drug products are not generally recognized as safe and effective. Moreover, they are classified as new drugs under the FD&C act, 21 USD 321( p), which states that no new product can be introduced without approval on an approved application form.

Actions required

Since this product is listed as a drug, it cannot be introduced without prior approval from the FDA, according to sections 505a and 30d. You must file a new drug application in an approved form for evaluation and approval from FDA.

Warning later No. 3 Elemental herbs Inc. d/b/a All good

The United States FDA issued a warning letter to elemental herbs and found them violating cGMP guidelines CFR part 210 and 211. These drugs are adulterated as per section 5001 (a)(2)(b) of the FDA &C Act.

The product is also unapproved for sale in the United States. Additionally, the response that elemental herbs submitted is adequate and lacks detailed connective action details.

Violations

The manufacturer failed to establish adequate quality unit responsibilities and procedures applicable. You are required to please respond in writing to the following

• Quality unit failed to provide proper oversight of drug manufacturing

• Out-of-specification results generated by contract Labs and were not investigated

• Did not identify and provide any action to prevent the quality unit violation, and also failed to deliver a timeline

• Quality systems are inadequate

Actions required

• Please provide a detailed assessment of the Quality Unit's shortcomings and your remedial plan.

• Please also provide the authority and responsibilities of your quality unit

• Explanation and proof of support for quality by top management.

• Review and plan for your out-of-specification result.

Violations

• Fail to provide a program to assess the stability of drug products

• In the previous response, your proposed initiation date was not provided.

• You also fail to provide adequate stability protocols.

• The timeline for the remedial actions is also not provided

Actions required

Please provide the following

• Assessment and CAPA are used to show the stability of the program.

• Ensure the quality of drugs produced by contractors is by section 501 (a)(2)(b) of the FD&C Act.

• Engaging the cGMP consultant for implementing cGMP by 21 CFR 211.34

• Application by 505 (a) should be filed for new drugs

• The labeling of some of your products failed to comply with the approved formatting

About the Author:

Muhammad Asim Niazi

Muhammad Asim Niazi has a vast experience of about 11 years in a Pharmaceutical company. During his tenure he worked in their different departments and had been part of many initiatives within the company. He now uses his experience and skill to write interested content for audiences at PharmaSources.com.