Study on the Changes of FDA Finished Pharmaceuticals Warning Letters between 2011 and 2021

Jiang Yang,Yang Yue,

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China;2.School of Pharmaceutical Science,Tsinghua University,Beijing 100084,China)

Abstract Objective To explore the trends in the distribution of countries to which FDA warning letters for Finished Pharmaceuticals have been issued over the past 10 years,and whether there are changes in the number of GMP violations,and to study their possible causes.Methods Public data on FDA warning letters and inspections were retrieved and analyzed using statistical methods for different classifications.Results and Conclusion Asia was the continent that received the most GMP warning letters in the last 10 years.More inspections were conducted in developed countries than that in developing countries,but they received a small number of warning letters.Quality control unit responsibilities were the most variable within all violation codes.The number of warning letters issued by Center for Drug Evaluation and Research (CDER) for Finished Pharmaceuticals increases with the number of inspections,and the enforcement of GMP by domestic drug manufacturers is better than that of overseas drug manufacturers.In addition,drug manufacturers in developed countries are better at GMP implementation than developing countries.GMP compliance in China has become better in recent years,but it still receives more inspections and warning letters.FDA inspections of Finished Pharmaceuticals become more stringent in the last 10 years,and many quality unit issues are affected by both personnel qualifications and personnel numbers.

Keywords: inspection;FDA;warning letter

1 Introduction

FDA inspections are conducted primarily to determine whether the company/process being inspected complies with FDA guidelines and with the provisions of the Federal Food,Drug,and Cosmetic Act (FD&CA).After each inspection,the FDA issues a written list of non-compliances found during the inspection,also known as a “Form 483”.Typically,“Form 483” contains comments directly related to the violations described above.Meanwhile,the Form 483 does not contain references to clauses,but each observation made by the inspector should be directly traceable.“Form 483” is submitted to the management of the company at the end of the inspection to inform the inspection of the poor conditions found.The comments in “Form 483” are one of the criteria that define the compliance status of the site.Companies should ensure that corrective and preventive actions are taken to adequately address these issues and improve any ancillary systems that are also deficient but not listed on the “Form 483”[1].Upon receipt of the “Form 483”,the company should respond to FDA and provide a timeline for corrections based on the company’s response and the establishment inspection report (EIR),FDA will classify the inspection results into three categories.

(1) No action indicated (NAI): No noncompliances conditions or operations are found during the inspection process (or the non-compliances conditions found do not require further regulatory action).FDA inspectors will not issue any written non-compliance,which can also be referred to as “zero 483”.

(2) Voluntary action indicated (VAI): The FDA recommends that companies take corrective measures,which will not lead to further consequences as long as they actively correct the situation and provide sufficient evidence in accordance with the FDA’s requirements.

(3) Official action indicated (OAI): The company has one or more major deficiencies in the quality system (major deficiencies),a serious violation of the FDA GMP.The FDA will take regulatory action,including the issuance of warning letters.

When FDA finds that a manufacturer has committed a serious violation of FDA regulations,FDA usually notifies the firm in the form of a warning letter.The warning letter identifies the violation and makes clear that the company must resolve the problem,provides direction and a timeline for the company to inform FDA of its correction plan.The FDA then conducts a follow-up inspection to ensure that the company’s corrections are adequate[2].

This study attempts to explore the distribution trends of Finished Pharmaceuticals warning letters issued by FDA to countries over the past 10 years,as well as any changes in the number of GMP violations and their possible causes.

2 Methods

2.1 Data source

For the purpose of the current study,we selected the available data from the FDA,including warning letters involving GMP-related Finished Pharmaceuticals sent by Center for Drug Evaluation and Research (CDER) to manufacturing companies and summary inspection data issued by the FDA from July 1st,2011 to June 30th,2021.

2.2 Inclusion/exclusion criteria

The FDA ensures drug quality by carefully monitoring drug manufacturers’ compliance with GMP.Drug GMP regulations contain minimum requirements for the methods,facilities,and controls used in the manufacture,processing,and packaging of drug products.The regulations ensure that products are safe for use and have the ingredients and strengths they claim to have.One of the regulations,21 CFR part 211,is primarily for finished pharmaceuticals.

By reading each warning letter issued by CDER from July 1st,2011 to June 30th,2021,we selected those related to Finished Pharmaceuticals GMPs and recorded the violations of 21CFR Part 211.Warning letters that are not part of the Finished Pharmaceuticals and that do not contain 21CFR Part 211 are excluded.

In this study,the criteria of United Nations Conference on Trade and Development (UNCTAD)were cited to classify developed and developing countries[3,4].The developed countries included the United States,Canada,Japan,Denmark,South Korea,Germany,Australia,France,Spain Israel,Italy,Switzerland,the United Kingdom,the Czech Republic,Ireland,and the Netherlands.

In the following statistical analyses (regression analysis,one-sample t-test,and Mann-Whitney test),North Korea was excluded because it had the number of warning letters but not the number of inspections.

2.3 Data extraction

We divided the time into two periods: July 1st,2011-June 30th,2016 and July 1st,2016-June 30th,2021.Warning letters that met the criteria were categorized and coded according to 21CFR part 211 in the following nine areas:

A=Organization and Personnel;

B=Buildings and Facilities;

C=Equipment;

D=Control of Components and Drug Product Containers and Closures;

E=Production and Process Controls;

F=Packaging and Labeling Control;

G=Holding and Distribution;

H=Laboratory Controls;

I=Records and Reports.

2.4 Statistical analysis

By data extraction,the number of violations was categorized by type codes and years,and the categories with values of 0 in both time periods were removed.The number of violations in the two time periods was analyzed by chi-square test using SPSS software.P-value less than 0.05 was taken as the criterion for significant differences,and the data with significant differences were bolded.

In this study,we defined the warning letter incidence as the ratio of the number of warning letters to the number of inspections.

Regression analyses,single-samplet-test,and Mann-Whitney test were conducted by usingRfor the relationship between the number of overseas warning letters and the number of inspections,the difference between the incidence of domestic warning letters and the incidence of overseas warning letters,and the difference between the incidence of overseas warning letters in developing and developed countries,respectively.

3 Results

From July 1st,2011 to June 30th,2021,the FDA CDER issued a total of 920 warning letters,of which 260 were GMP-related Finished Pharmaceuticals warning letters,accounting for 28.3% of the total number of CDER warning letters.Among them,243 Finished Pharmaceuticals GMP warning letters were related to this study.These Finished Pharmaceuticals warning letters contained a total of 839 violations,with an average of 3.45 violations per warning letter(Fig.1).

Fig.1 Screening process of FDA’s Finished Pharmaceuticals warning letter

Asia is the continent that received the largest number of GMP warning letters in the last 10 years.China and India are the two countries that received the largest number of warning letters,61 and 52 respectively.More inspections were conducted in developed countries than that in developing countries,but they received a small number of warning letters (Table 1).Of the 233 companies that received warning letters,11 received two warning letters.

Table 1 Number of warning letters,inspections and OAIs in the countries of producers from July 1st,2011 to June 30th,2021

Analysis of the number of violations of the Finished Pharmaceuticals GMP reveals that between July 2011 and June 2016,there were 65 warning letters and 250 violation items.Meanwhile,between July 2016 and June 2021,there were 178 warning letters and 589 violation items.Eight of the 37 violation codes were significantly different (P＜ 0.05)between the two time periods,and the responsibilities of quality control unit were the most variables within all violation codes (4%-12.1%,P=0.000 3,Table 2).

4 Discussion

4.1 Relationship between warning letters and the countries/regions

FDA usually notifies manufacturers of serious violations of GMP regulations in the form of warning letters.Because of geographic conditions,there is a significant difference in the number of inspections inside and outside the United States[5].In order to verify whether there is a correlation between the number of warning letters for Finished Pharmaceuticals outside the United States and the total number of inspections for drug quality assurance(hereinafter referred to as the number of inspections),we conducted a regression analysis using the natural logarithm of the number of warning letters for countries outside the United States (y) and the square root of the number of inspections for countries outside the United States (x) as the dependent and independent variables,respectively.Then,the following linear regression equation was obtained (Fig.2).

Fig.2 Relationship between the number of warning letters and the number of inspections outside the United States

ThePvalue of linear regression equationF-test is 4.248 × 10-10＜ 0.01,therefore,we believe that there is a strong correlation between the number of warning letters and inspections outside the United States.Since the slope 0.110 78 ＞ 0,combined with the functional properties ofyandy=ln(x),it can be concluded that there is a positive correlation between the number of warning letters for overseas preparations and the number of inspections.It means that the number of warning letters for overseas preparations increases with the number of inspections.

By defining the incidence of warning letters,we can assess the implementation effect of GMP in pharmaceutical manufacturers.Taking the foreign countries as the sample and the incidence of warning letters in the USA as the reference,we can perform a single-samplet-test to assess whether there is a significant difference in the implementation effect of the of GMP between the domestic and foreign drug manufacturers.Since theP=0.000 813 5 ＜ 0.01,it can be concluded that there is a significant difference between the incidence rate of warning letters for Finished Pharmaceuticals in foreign countries (3.505 4%,216/ 6 162) and the incidence rate in the USA(0.305 5%,27/ 8 839).This may be partly due to the FDA’s continuous efforts to improve the quality,safety,and efficacy of drugs to protect public health.On the other hand,it may be related to the difficulty of the FDA’s inspections abroad.

In addition,we also studied the difference in the incidence of warning letters between developing countries and developed countries using the Mann-Whitney test.Since the test resultP=2.522 × 10-5＜ 0.01,it can be concluded that there is a difference in the implementation effect of GMP between drug manufacturers in developing countries and developed countries.

FDA measures the extent to which sites comply with GMP regulations through site inspection scores(SIS)[6].SIS is a new metric introduced by FDA in fiscal year (FY) 2017[7],which models and predicts SIS by using artificial intelligence to learn from inspection data over a ten-year period[8].When sites are inspected and receive classification results (NAI,VAI,or OAI),these results are translated into SIS.In the years since its introduction,the US,EU,and Canada scored well ahead of the global average.Meanwhile,China,India,and Latin America scored below average.But China’s overall SIS has shown an increasing trend over the past few years and has gradually approached the average[9].Between July 2011 and June 2021,the FDA issued two warning letters to 11 companies,nine of which were from India,implying its poorer GMP compliance and coinciding with its lower SIS.FDA also cited India as one of the key factors influencing the low SIS scores.

4.2 The changes of warning letter violation content

Our analysis of the trend of FDA warning letters for Finished Pharmaceuticals over the years reveals that there is a significant change in their numbers around July 2017 and a stabilization in the following years (Fig.3).Meanwhile,the analysis of the number of inspections shows that the quantity of inspections per year is stable and even tends to decrease in recent years.A survey of relevant FDA guidance revealed that the FDA released “Integration of FDA Facility Evaluation and Inspection Programs for Human Drugs: A Concept of Operations” on July 6,2017.It is an unprecedented concept of operations agreement reached by CDER and the Office of Regulatory Affairs(ORA),which can integrate facility evaluation and inspection of human drug products to improve the quality of facility and regulatory decision information of FDA[10].Therefore,we speculate that the increase in warning letters may be related to the enhanced inspection practices and increased inspection transparency of the guidance.

Fig.3 Changes in the number of warning letters and inspections of Finished Pharmaceuticals between July 2011 and June 2021

A chi-square test of the violation item in the warning letters for the last 10 years of responsibilities of quality control unit shows that theP=0.000 3 ＜ 0.05,it means between the time period of July 2016-June 2021 and July 2011-June 2016,there is a significant difference in the occurrence of the violation term.There is a huge increase in the number of the former time period compared to the latter time period,and the percentage change is also the largest.In 2006,the FDA issued guidance defining the concept of a quality unit (QU),and the cGMP clearly gave the QU the authority to create,monitor,and implement quality systems.The QU does not assume the responsibilities of other units of the manufacturing organization,such as production personnel,engineers,and developers.21CFR 211.22 also provides further clarification of the responsibilities of the QU[11].

In late 2016,the FDA issued quality protocol guidance,emphasizing the responsibilities of the quality control unit,following which the number of related warning letters increased[12].Under a quality system,the product and process development unit,the production unit and QU will remain independent.In few cases,one person can perform both production and quality inspection.This person would still be responsible for implementing all controls and reviewing production results to ensure that product quality standards are met.In this case,the FDA recommends that additional periodic review of QU activities be performed by another compliance officer who is not involved in the manufacturing operation.It is evident that problems in the quality control unit may not only stem from under-qualified personnel but also equally be affected by inadequate staff deployment.

5 Conclusion

The number of Finished Pharmaceuticals warning letters issued by CDER increases with the number of inspections,and the enforcement of GMP by domestic drug manufacturers is better than that of overseas drug manufacturers.In addition,drug manufacturers in developed countries are better at GMP enforcement than that of developing countries.China has become more compliant with GMP in recent years,but it still receives more inspections and warning letters.

Furthermore,FDA inspections of Finished Pharmaceuticals have become more stringent over the past 10 years,and many prominent quality unit issues are influenced by both personnel qualifications and the number of personnel.