Review of FDA Warning Letters to Pharmaceuticals : Cause and Effect Analysis

 

Sanjay Kumar Jain¹, Dr. Rajesh Kumar Jain²

¹Ph.D Scholar, Nirma University, Ahmedabad, Gujarat, India

 

ABSTRACT:

Purpose: The purpose of this paper is to identify the cause and effect of increased number of warning letters issued by the USFDA year after year in spite of clarity in the guidance issued by the agency. Increased number of warning letters is matter of concern for the manufacturer, drug authority and society. This review of the warning letters would help to identity the recurring observations and learning to other organizations to avoid similar non-compliances. Methods: 85 warning letters issued to the drug substance and drug product manufacturers for three years (2014 to 2016) were reviewed and causes were classified in categories based on nature of observations. Pareto analysis was performed to identify the 4 top categories. Further review and Pareto analysis identified the causes of the observations under these top 4 categories. Results: Total observations are 580 reported in 85 warning letters for last 3 years. Pareto analysis of the observations revealed that the top four issues among all categories of the plants are contributing 82% of the total observations. These are related to poor quality system (195, 34%), followed by breach of data integrity (142, 24%), poor laboratory controls (76, 13%) and poor production controls (65, 11%). For manufacturing with sterile operation where the risk is high w.r.t. product quality and patient safety, the highest issues were related to poor aseptic behaviour i.e. 31.5% of the total 130 observations cited in the warning letters. Conclusions: It is evident from the review of warning letters for last 3 years that pharmaceutical industry need to Improve quality systems specifically investigation system, CAPA system, adherence to SOP compliance and sound stability program. Authors suggest that other manufacturer involved in drug product and drug substance shall regularly review these warning letters to learn to be proactive and implement the preventive actions to avoid the occurrence in their organization. There is need for Paradigm shift in quality culture and transparency with regulators while interacting during the audits. Quality, compliance and integrity are the pillars for any pharmaceutical organization to be successful.

 

 

 

 

 

1.0 INTRODUCTION:

FDA is USA based health regulatory agency (here after referred to as FDA) and is responsible for healthcare of the US citizens. As a part of verification of cGMP compliance, investigators from the agency perform inspections of the drug substance and drug product manufacturing sites. FDA Inspections are conducted for three reasons (1) Pre-approval inspection (PAI) before approval of the drug product (2) Regular cGMP inspection and (3) for cause audit. During inspection, if any non-compliance is observed, the investigator issues the observation on form 483, that is why the observations are popularly known as 483 observations. The manufacturer shall submit the response within 15 calendar days explaining the reason for existence of non-compliance, impact of the product quality and appropriate corrective action taken to avoid the recurrence. If the response is not satisfactory; observations are critical in nature and has direct impact on product quality, patient safety and data integrity, the FDA agency issues warning letters to the manufacturers. Number of warning letters issued by the FDA is increasing year after year inspite of clarity in the guidance issued by the agency. Increased number of warning letters is matter of concern for the manufacturer, drug authority and society, hence authors reviewed warning letters issued to pharmaceutical drug product/drug substance manufacturers for three years (Jan 2014 to Dec 2016) for cause and effect analysis. The searches were limited to those referencing drug product and drug substances involving aseptic processing and non-sterile processing. This review would help to identify the recurring observations and learning for other organizations to avoid similar non-compliances.

 

2.0 FDA INSPECTION SYSTEM:

The FDA's Drug Manufacturing Inspection Compliance Program is a system-based approach to inspection, and is very consistent with the robust quality system. FDA investigators are instructed to perform the inspection based on six systems categorised as (1) Quality system, (2) Production System, (3) Facilities and Equipment system, (4) Laboratory control system, (5) Materials system and (6) Packaging and Labelling system. The Fig1 shows the relationship among the six systems: the quality system and the five manufacturing systems. The quality system provides the foundation for the manufacturing systems that are linked and function within it. One of the important themes of the systems based inspection compliance program is that investigator can assess whether each of the systems is in a state of control.

 

 

Fig 1 :The Six-Sestem Inspection Model

Source: Reference 1 as listed in this article

There has been a significant increase in the number of foreign inspections of pharmaceutical manufacturing plants in the past few years mainly due to the increase in the number of pre-approval inspections, routine GMP inspections and compliance follow-up activities. It has become clear that effective and efficient inspectional coverage has been crucial to the successful management of the foreign inspection program of FDA being resource-intensive nature and that can be achieved only through maintenance of consistency and uniformity of inspection and enforcement activities. The agency tries to utilize highly qualified Investigators and Analysts for the foreign inspection program who have extensive experience in conducting drug inspections with demonstrated track records of working effectively in a tight time frame and under considerable pressure¹.

 

Quality system is always part of the inspection along with other system randomly selected by investigator (s) at their own discretion.

 

 

Above comprehensive quality systems model, if implemented, will allow manufacturers to support and sustain robust, modern quality systems that are consistent with CGMP regulations. The overarching philosophy articulated in both the CGMP regulations and in robust modern quality systems is: Quality should be built into the product, and testing alone cannot be relied on to ensure product quality. FDA believes that the inherent flexibility of the CGMP regulations enable manufacturers to implement a quality system in a form that is appropriate for their specific operations².

 

3.0   FDA WARNING LETTERS:

FDA ensures the quality of drug products, medical devices and dietary supplements by carefully monitoring compliance with Current Good Manufacturing Practice (CGMP) regulations. These regulations contain minimum requirements for the methods, facilities, and controls used in the manufacturing, processing and packing of a regulated product. In short, CGMP rules in essence ensure the safety of a product³.

 

When FDA finds that a manufacturer has significantly violated FDA regulations, FDA notifies the manufacturer in the form of a Warning Letter. The Warning Letter identifies the violation, such as poor manufacturing practices, poor laboratory practices, data integrity issues, problems with claims for what a product can do, or incorrect directions for use. The letter also makes clear that the company must correct the problem and provides directions and a timeframe for the company to inform FDA of its plans for correction. FDA then checks to ensure that the company’s corrections are adequate⁴. 

The FDA provides an electronic reading room on its website that provides access to a great deal of useful information, including copies of Warning Letters issued by the FDA. Reviewing these letters can be useful because they provide insight into the inspection techniques and concerns of FDA inspectors. Understanding common violations mentioned in such notifications can prove beneficial to those firms undergoing inspections. Additionally, they can be used to perform gap analysis of the processes used in other organization in preparation for an FDA inspection.

 

4.0 WARNING LETTER REVIEW – CAUSE AND EFFECT ANALYSIS:

For this study, the FDA's website was searched to review the Warning Letters issued between Jan 2014 and Dec 2016. The searches were limited to those referencing drug product and drug substances involving aseptic processing and non-sterile processing, and the data were summarised.

 

Warning letters were divided in three categories based on the nature of products being manufactured at the site-

·        Solid Oral Drug Products

·        Sterile Drug Products

·        Drug Substance / Active Pharmaceutical ingredient

 

A study of warning letters issued for last three years (2014, 2015 and 2016) was done reveals that 85 sites were issued the warning letters. 17 warning letters were issued in year 2014, 18 warning letters in year 2015 and 50 warning letters in year 2016. There is increase in number of warning letter year after year as focus of the FDA was more on data integrity issues and FDA found serious breaches in the integrity of the documents generated by the firms during manufacturing, testing of the batches. A few firms with facility of both drug substance and drug product manufacturing plants were issued one warning letter; however authors reviewed the warning letters dosage form wise for cause and effect analysis. The Fig 2 represents the year wise numbers of warning letter issued to pharmaceutical manufacturers.

 

 

Fig 2 : Year wise warning letters (2014-2016)

Source: Authors, based on FDAwebsite

 

There are 3652 FDA registered manufacturing sites in 30 countries⁴. The analysis of warning letters for last 3 year’s reveals that the 85 warning letters were issued to manufacturers located in all regions across the globe which indicates that non-compliances are not specific to particular country, region or continent but are wide spread. Highest numbers of the warning letters (68%) are issued to manufacturers located in Asia followed by 15% in Europe and 10% in North America. (Fig 4)

 

 

 

Fig 3 : Warning letter – country wise (2014-2016)

Source : Authors, based on FDA website

 

Fig 4 : Warning letter continent wise (2014-2016)

Source : Authors, based on FDA website

 

If the 483 observations* cited by the investigator are critical in nature i.e. having direct impact on product quality, patient safety and breach of data integrity, the agency issues the import alert to the manufacturer. The manufacturer under import alert cannot export the product to the USA until the import alert is lifted by the agency. Total 26 manufacturers were placed under import alert which is 30.6% of the warning letter issued by the agency. Out of 26, 46% manufacturers placed under import alert were from China and 34% from India (Fig 5). Before revoking the import alert, the agency verifies cGMP compliance and ensures that there are no more product quality, patient safety and data integrity issues at the manufacturing site.

 

 

Fig 5: Warning Letter turned into Import Alert (2014-2016)

Source : Authors, based on FDA website

 

*483 Observation is objectionable conditions cited by FDA investigator on the Form 483.

 

The authors reviewed all the cited observations in the warning letters and categorised them as listed below in Table 1. For the reporting period, a total of 580 observations were reported in 85 warning letters for last 3 years. Pareto analysis (see the Fig 6) of the observations revealed that the top four issues among all categories of the plants are contributing 82% of the total observations. These are related to poor quality system (195, 34%), followed by breach of data integrity (142, 24%), poor laboratory controls (76, 13%) and poor production controls (65, 11%). For manufacturing with sterile operation where the risk is high w.r.t. product quality and patient safety, the highest issues were related to poor aseptic behaviour i.e. 31.5% of the total 130 observations cited in the warning letters. This analysis clearly gives a pattern of the observation and author felt to further perform the pareto analysis of top 4 issues (observations).

 

Table 1 : Observations cited in warning letters (2014 to 2016)

Nature of Observation	API	Non - Sterile	Sterile	Total
Poor quality system	90	78	27	195
Breach of Data Integrity	86	45	11	142
Poor Laboratory control	33	34	9	76
Poor Production control	25	30	10	65
Poor validation system	2	11	7	20
Delaying, Denying, Limiting, or Refusing a Drug Inspection	8	2	1	11
Cross contamination	2	2	0	4
Poor Micro Practices	NA	2	23	25
Poor Aseptic Behaviour	NA	0	41	41
Inadequate Visual Inspection Program	NA	0	1	1
Total	246	204	130	580

Source : Authors, compiled from information available on FDA website

 

Author further performed the pareto analysis of following top 4 issues (observations) to drill down the root cause.

I.       Poor quality system (195) – (Point 4.1)

II.      Breach of data integrity (142) – (Point 4.2)

III.    Poor laboratory controls (76) – (Point 4.3)

IV.   Poor production controls (65) – (Point 4.4)

 

 

4.1 POOR QUALITY SYSTEM:

An effective pharmaceutical quality system is vital to enhance the quality and availability of medicines around the world in the interest of public health. It shall be implemented throughout the product lifecycle and should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained. An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement⁵.

 

 

Fig 6 : Pareto Analysis - WL observations (2014 to 2016)

Source : Authors, compiled from information available on FDA website

 

 

Adequate investigation for quality issues like complaint, deviation, OOS, product recall etc. is vital so as to identify the root cause and determine CAPA to avoid the recurrence. Pareto analysis of poor quality system (Fig 7) revealed that cause of 80% of this category of the observation is due to Inadequate investigation, Role of Quality unit is not defined as required by CFR part 210, SOP not available / Inadequate SOP, Inadequate stability program testing of finished product not performed and Poor documentation practice.

 

 

Table 2 – Major cause of Poor Quality system (2014-2016)

Category of causes in warning letter	Frequency	Category of causes in warning letter	Frequency
Inadequate investigation	46	Inadequate CAPA system	6
Role of Quality unit	22	Poor vendor management	6
SOP not available / Inadequate SOP	18	SOP  not followed	4
Inadequate stability program	17	Inadequate Analytical Method validation	3
Testing of DP not performed	15	Inadequate change management system	3
Poor documentation practice	12	Inadequate complaint handling system	3
Poor Training Management	11	Poor Deviation management system	1
Testing of incoming material not performed	9	Failed to initiate FAR	1
Poor validation control	8	Poor labelling practice	1
Inadequate OOS handling management	7	Inadequate record keeping	1

Source : Authors, compiled from information available on FDA website

 

 

Fig 7 : Pareto Analysis - Poor Quality System  (2014 to 2016)

Source : Authors, compiled from information available on FDA website

4.2 DATA INTEGRITY BREACH:

FDA has increasingly observed CGMP violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s ability to protect the public health. These data integrity-related CGMP violations have led to numerous regulatory actions, including warning letters, import alerts, and consent decrees⁶.

 

Pareto analysis of data integrity breach (Fig 8) category revealed that cause of 80% of this category of the observation is due to Noncompliance to CFR Part 11, Falsification of data, Retesting without justification or till passing results are obtained, not recording the entry at the time of activity in GMP document, Missing raw data. These observations are made in all functions like quality control lab, production floor etc. Breach of data integrity is one of the biggest reason that agency has put the manufacturing sites under import alert as the documents generated by the firms are not reliable and few examples observed by the investigator during the inspection raises the question on all the documents generated by the firm. As per FDA guidance Data integrity refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA)⁶.

 

Table 3 –Major Causes of Data Integrity Breach (2014-2016)

Category of causes in warning letter	Frequency
Noncompliance to CFR Part 11	35
Falsification of data	23
Retesting without justification	15
Recording after the fact (not contemporaneous)	14
Missing raw data	12
Data deletion	11
Back dating / Predating	10
Destruction of GMP document	7
Trial testing	6
Poor documentation practice	2
Failing records found in scrap	1
Incomplete raw data	1

Source : Authors, compiled from information available on FDA website

 

 

 

 

Fig 8 : Pareto Analysis – Data Integrity Breach  (2014 to 2016)

Source : Authors, compiled from information available on FDA website

 

4.3 POOR LABORATORY CONTROL:

Adequate laboratory control is important to demonstrate that results generated by the laboratory are accurate, reliable and true as one of the checkpoint in the  decision to release the batch in the market is made based on the review of certificate of analysis. Pareto analysis of poor laboratory control (Fig 9) category revealed that cause of 80% of this category of the observation is due to Inadequate controls for computerized system, instruments not complying to CFR part 11 requirement, Inadequate laboratory control and inadequate procedures, analytical methods.

 

 

 

Table 4 –Major causes of Poor Laboratory control

Category of causes in warning letter	Frequency
Inadequate controls for computerized system	22
Non-Compliance to CFR part 11	15
Inadequate laboratory control	10
Inadequate SOP	7
Inadequate analytical methods / Specification	4
Poor Microbiological control	4
Poor documentation practice	4
Poor validation control	3
Incomplete raw data	2
Sample tested before it is received in Lab	1
Stand-alone chromatographic systems	1
Test not performed	1
Sample tested before it is received in lab	1

Source: Authors, compiled from information available on FDA website

 

 

Fig 9 : Pareto Analysis - Poor Laboratory control (2014 to 2016)

Source : Authors, compiled from information available on FDA website

 

4.4 POOR PRODUCTION CONTROL:

Production control is needed to ensure consistent and robust product quality of the products manufactured by the firm. Improper GMP practices, poor design of the facility may result into mix-up, cross contaminations. Inadequate facility, equipment maintenance may also result into product contamination specifically when the product is coming directly in contact with machine part. Pareto analysis of poor production control (Fig 10) category revealed that cause of 80% of this category of the observation is due to Poor Equipment maintenance, inadequate document management, inadequate facility design / management, inadequate cleaning procedure and Poor Engineering system.  

 

Table 5- Major causes of Poor Production Control

Category of causes in warning letter	Frequency
Poor Equipment maintenance	16
Inadequate document management	8
Inadequate facility design / management	6
Inadequate cleaning procedure	4
Poor Engineering system	4
No procedure for preparation of master production and control records	3
Poor facility maintenance	3
Inadequate pest and rodent control	2
Inadequate batch record	2
Inadequate SOP	2
Poor validation control	2
No determination of actual yields at mfg stage	1
Inadequate washing facility	1

Source : Authors, compiled from information available on FDA website

 

 

 

Fig 10 - Pareto Analysis : Poor Production control

Source : Authors, compiled from information available on FDA website

 

5.0   DISCUSSION AND CONCLUSION:

In connection with the warning letter issued to one of the organization, an interview with owner (familiar to the authors) of the pharma company was arranged to know the cause and effect of warning letter / Import alert. Interaction revealed that as a result of the FDA Import Alert/Warning letter US business had stopped, and overall business has gone down by 15-20 % in the last 2 years and consequently market value of the company has gone down and so has shareholder wealth.  

It was admitted that Culture of quality is vital to sustain the compliance in the organization. Management has the realisation that quality culture is mandatory if the firm want to be in this business.  Following reasons were cited for issuance of Warning letter and Import alert.

·        Limited Management oversight

·        Lack of complete understanding of US FDA expectations

·        Business taking priority over Compliance.   

 

Following actions are undertaken to improve the culture of quality. (1) Periodic Quality review meeting (2) Appointment of Subject Matter Expert (SMEs) (3) Automation.

 

Following steps shall be taken to build quality culture in the organization, suggested by senior industry person during the interview -

·        Emphasis on quality by senior leaders

·        Increasing employee oversight and empowerment

·        Reward and recognise quality excellence

·        Establish environment of Trust and collaboration

·        Science based decision making

 

His message to other industry friends to ensure compliance and avoid such notices (Warning letter and import alert) were as below -

·        Do automations to the extent positive to avoid human errors and ensure reproducibility (less variation) of the process

·        Recruitment of right people, their training and engagement to retain.

·        Focus about data integrity issues in all the functions like laboratory, production, engineering, warehouse etc.

·        Facilitate continual improvement

·        Science based decisions

 

FDA warning letters are available on FDA website as electronic data and can be accessed by anyone. The investigators are very knowledgeable on US regulatory expectations for API, non-sterile drug product, and aseptic processing operations for sterile products. In Warning Letters for both aseptic processes and non-sterile manufacturing, expectations seem to be the same regardless of the size of the manufacturing operation, location of site. They are also consistent whether the manufacturing site is within or outside of the US.

 

Total 85 FDA warning letters were reviewed issued from Jan 2014 to Dec 2016 and 26 out of 85 manufacturing sites were placed on Import alert and these manufacturers further cannot sale the products in USA market from affected sites. Top 4 reasons for warning letters are Poor Quality system, Breach of Data Integrity, Poor Laboratory control and Poor production control.

 

Authors suggest that other manufacturer involved in manufacturing of pharmaceutical product drug product and drug substance shall regularly review these warning letters to learn to be proactive and implement the preventive actions to avoid the occurrence of the quality issues in their organization. It is evident from the review of warning letters for last 3 years that pharmaceutical industry need to improve quality systems specifically investigation system, CAPA system, adherence to SOP compliance and sound stability program. There is need for Paradigm shift in quality culture and transparency with regulators while interacting during the inspections. Firms need to exercise more control on laboratory control system specifically for computerised system to avoid any manipulation and breach of data integrity. Any observation about breach of data integrity will shake the confidence and trust of regulator. Any findings about data integrity breach would result into stoppage of the business for USA market. Quality, compliance and integrity are the pillars for any pharmaceutical organization to be successful.

 

6.0 REFERENCES:

1.       https://www.fda.gov/iceci/inspections/inspectionguides/ucm075021.htm (Accessed on 16 Sept 2017)

2.       Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations, U.S. Department of Health and Human Services Food and Drug Administration, September 2006, Pharmaceutical CGMP Regulations

3.       Rozembajgier Mike (2012),“FDA Warning Letters What Can Be Learned?”,Pharmaceutical Processing, NOV/DEC 2012, pp 42 – 43

4.       https://www.fda.gov (Accessed on 25 Sept 2017)

5.       Guidance for Industry, “Q10 Pharmaceutical Quality System”, U.S. Department of Health and Human Services Food and Drug Administration, April 2009

6.       Guidance for Industry, Data Integrity and Compliance With CGM, Draft Guidance,  U.S. Department of Health and Human Services Food and Drug Administration, April 2016, Pharmaceutical Quality/Manufacturing Standards (CGMP)

 

 

 

 

 

 

Accepted on 26.04.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(7): 3219-3226.