Warning Letters 2016 – Data Governance & Data Integrity

by Barbara Unger, GMP Quality Expert and GMP Regulatory Intelligence Editor-in-Chief

In 2015 we published a collection of FDA GMP warning letters that included deficiencies in data governance and data integrity.  Here we provide the same information for 2016 drug GMP warning letters. These should serve as a resource for GMP audit staff and QA staff as they evaluate their own firms and contract sites for gaps in these areas.  In this introduction, we provide tables and graphs identifying the dates of the warning letters, firms to which they were issued, and the country where the facility is located.  We also provide a table that shows the trends over time for location of countries where facilities receiving these warning letters were located, beginning in 2008.  And, finally, we provide a tabulation of the regulations most frequently cited for these deficiencies in 2015 and 2016.

Table 1 lists the warning letters that include data integrity deficiencies, the date of issuance, and the country where the facility is located.  Note that the first two warning letters were from inspections in 2015 but published in 2016 and were not counted in last years’ tally, so I included them here.  I’ve color coded the country column and have included all European countries in a single group.

TABLE 1:  Warning Letters with Data Integrity Deficiencies

12/15/2015 Chan Yat Hing Medicine Factory China
12/30/2015 Irvine Stem Cell Treatment Center US
1/29/2016 Ipca Laboratories Limited India
3/3/2016 Emcure Pharmaceuticals India
4/1/2016 Sri Krishna Pharmaceuticals Ltd. Unit II India
4/7/2016 Apotheca Supply Inc US
4/12/2016 Florida Institute of Reproductive Sciences USA
4/14/2016 Polydrug Laboatoreis Pvt Ltd India
5/12/2016 Tai Heng Industry Co Ltd. China
5/16/2016 BBT Biotech GMBH Germany
5/19/2016 Megafine Phrma LImited India
6/16/2016 Shanghai Desno Chemical Pharmaceutical Co. China
6/21/2016 Chongquing Lummy Pharmacuetical Co China
6/22/2016 Guuangzhou Haishi Biological Technology Co China
7/12/2016 GenPak Solutions LLC USA
7/19/2016 Ziamen Origin Biotech Co Ltd China
8/2/2016 Adamson Analytical Laboratories Inc. USA
8/4/2016 Zhejiang Medicine  Co Ltd Xinchang Pharmaceutical Factory China
8/5/2016 Noven Pharmaceuticals USA
8/10/2016 Hushou Aupower Sanitary Commodity Co Ltd. China
8/11/2016 Zhejiang Hisoar Pharmaceutical Co China
8/12/2016 Unimark Remedies Ltd India
8/15/2016 Frontida USA
8/25/2016 Pan Drugs Limited India
8/25/2016 Lima & Pergher Industria e Comercio S.A. Brazil
9/6/2016 Hebei Yuxing Bio-Engineering Co. Ltd. China
9/12/2016 Mappel Industria de Embalagens, SA Brazil
9/15/2016 Nippon Fine Chemical Co. Japan
9/26/2016 Delarange Cosmetics and Healthcare BV Netherlands
9/29/2016 Laboratoire Sintyl S.A. Switzerland
9/29/2016 Yangzhou Hengyuan Daily Chemical Plastic Co Ltd China
10/13/2016 Teva Pharmacuetial Works Private Limited Company Hungary
10/18/2016 Interpharm Praha A.S. Czech Republic
10/19/2016 Beijing Taiyang Pharmaceutical Industry Co Ltd China
11/8/2016 Sekisui Medical Co Ltd Japan
11/8/2016 Srikem Laboratories India
11/10/2016 Dongying Taindong Pharmacutical Co Ltd China
12/8/2016 Baoying Couonty Fukang Medical Applicance Co. Ltd China
12/8/2016 Antibioticos Do Brasil Ltda Brazil
12/15/2016 Natura Bisse International S.A. Spain
12/23/2016 Wockhardt Limited India

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Table 2 identifies the countries where the facilities are located for both this year’s tally and for last year.  China received the most warning letters of this type in CY2016, with India close behind.  Considering both years together, India received 19 warning letters and China received 16 warning letters with data integrity deficiencies.  India received essentially the same number of warning letters in the two years, but China saw a dramatic increase from 2 to 10 in the two years.  Note that in CY2016, seven (7) firms in the US received warning letters with data integrity deficiencies.  Brazil and Japan are new to the list this year with 3 and 2 warning letters respectively.  Figure 1 shows the same information as a graphic.

Table 2:  Number of Data Integrity Associated Warning Letters by Country

Country Number of Warning Letters with Data Integrity
CY2015 CY2016
China 2 14
India 10 9
US 0 7
Europe 2 6
Brazil 0 3
Japan 0 2
Thailand 1 0
TOTAL 15 41

Figure 1:  Data Integrity Warning Letters by Country

 Figure 2 captures data from 2008 through 2016 on a country by country basis.  Some countries are consistently present in multiple years including the US, China and India and the ‘Europe’ category.  A few countries are present only in one or two years.  Note that the US has warning letters with data integrity deficiencies in all years except 2013,2014 and 2015 and is in fact the third most frequent country for 2016 warning letters of this type.

Figure 2

 Table 3 shows the regulations cited in the warning letter deficiencies.  Many of the deficiencies identified in the collection for CY2016 do not cite a governing regulation.  Many are ‘conclusions’ or ‘Data Integrity Remediation’ instructions from the FDA to which the firm must respond.  Many of the letters are issued to API manufacturers and do not cite 21 CFR 211 which applies to finished product. In addition to the regulations cited below, the following regulations were each cited once:  211.100(b), 1271.50(a), 211.165(e), 211.180(e), 211.137(a), 211.180(a), 211.101, 211.186(a) and 211.42(c).

Table 3:  Most Frequent Regulation Citations in CY2016

CFR Reference Number of Times Cited Title of CFR Section
211.68 7 Automatic, Mechanical, and Electronic Equipment
211.22 5 Responsibilities of the Quality Control Unit
211. 194 3 Laboratory Records
211.160 3 General Requirements, Laboratory Controls
211.165 2 Laboratory Controls
211.188 2 Batch Production and Control Records

Table 4 shows the same data for the years 2008-2014.  In addition to the regulations cited in the table are 211.25, 211.166, 211.182, and 211.192.  As in the past fifteen-plus years, FDA has focused on enforcement of the predicate rules.  The notable difference between 2016 and 2008 – 2014 is the appearance of 211.22 and 211.165.  For both groups, the categories of “Laboratory”, whether controls, records or general requirements is predominant.

 Table 4:  Most Frequent Regulation Citations 2008-2014

CFR Reference Number of Times Cited Title of CFR Section
211.68 13 Automatic, Mechanical, and Electronic Equipment
211.194 6 Laboratory Records
211.160 2 General Requirements, Laboratory Controls
211.180 2 General Requirements for Records and Reports
211.186 2 Master Production and Control Records
211.188 2 Batch Production and Control Records


In 2017 I look for much of the same in terms of warning letter deficiencies in the area of data integrity. I would expect the number of warning letters issued to China to continue to increase assuming foreign inspections are not curtailed as part of potential cost cutting under the new administration.  I would also expect to see more focus on electronic records issues in batch records and in the manufacturing area as FDA expands their focus out from the laboratory.  Compliance in this area continues to bedevil the industry, both domestic and foreign manufacturing sites.  Perhaps one potential remedy is to have firms’ internal GMP audits and assessments focus in depth on this area.  Remediation here often takes time and can be expensive if new instrumentation or software is required.  But, better to identify problems if they exist than wait to have FDA point them out.  It’s important to remember that FDA and other health authorities are sharing their findings, so companies with these problems generally need to deal with multiple regulatory authorities.  And those who are contract manufacturers must also address potentially unhappy clients.  Remediation of official health authority actions are necessarily more expensive than finding and correcting issues internally.

Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483sInspector ProfilesEnforcement Analytics, and GMP Regulatory Intelligence. Contact me if you ever have questions at tony@fdazilla.com.

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