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

DATECOMPANYCountry
12/15/2015Chan Yat Hing Medicine FactoryChina
12/30/2015Irvine Stem Cell Treatment CenterUS
1/29/2016Ipca Laboratories LimitedIndia
3/3/2016Emcure PharmaceuticalsIndia
4/1/2016Sri Krishna Pharmaceuticals Ltd. Unit IIIndia
4/7/2016Apotheca Supply IncUS
4/12/2016Florida Institute of Reproductive SciencesUSA
4/14/2016Polydrug Laboatoreis Pvt LtdIndia
5/12/2016Tai Heng Industry Co Ltd.China
5/16/2016BBT Biotech GMBHGermany
5/19/2016Megafine Phrma LImitedIndia
6/16/2016Shanghai Desno Chemical Pharmaceutical Co.China
6/21/2016Chongquing Lummy Pharmacuetical CoChina
6/22/2016Guuangzhou Haishi Biological Technology CoChina
7/12/2016GenPak Solutions LLCUSA
7/19/2016Ziamen Origin Biotech Co LtdChina
8/2/2016Adamson Analytical Laboratories Inc.USA
8/4/2016Zhejiang Medicine  Co Ltd Xinchang Pharmaceutical FactoryChina
8/5/2016Noven PharmaceuticalsUSA
8/10/2016Hushou Aupower Sanitary Commodity Co Ltd.China
8/11/2016Zhejiang Hisoar Pharmaceutical CoChina
8/12/2016Unimark Remedies LtdIndia
8/15/2016FrontidaUSA
8/25/2016Pan Drugs LimitedIndia
8/25/2016Lima & Pergher Industria e Comercio S.A.Brazil
9/6/2016Hebei Yuxing Bio-Engineering Co. Ltd.China
9/12/2016Mappel Industria de Embalagens, SABrazil
9/15/2016Nippon Fine Chemical Co.Japan
9/26/2016Delarange Cosmetics and Healthcare BVNetherlands
9/29/2016Laboratoire Sintyl S.A.Switzerland
9/29/2016Yangzhou Hengyuan Daily Chemical Plastic Co LtdChina
10/13/2016Teva Pharmacuetial Works Private Limited CompanyHungary
10/18/2016Interpharm Praha A.S.Czech Republic
10/19/2016Beijing Taiyang Pharmaceutical Industry Co LtdChina
11/8/2016Sekisui Medical Co LtdJapan
11/8/2016Srikem LaboratoriesIndia
11/10/2016Dongying Taindong Pharmacutical Co LtdChina
12/8/2016Baoying Couonty Fukang Medical Applicance Co. LtdChina
12/8/2016Antibioticos Do Brasil LtdaBrazil
12/15/2016Natura Bisse International S.A.Spain
12/23/2016Wockhardt LimitedIndia

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

CountryNumber of Warning Letters with Data Integrity
CY2015CY2016
China214
India109
US07
Europe26
Brazil03
Japan02
Thailand10
TOTAL1541

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 ReferenceNumber of Times CitedTitle of CFR Section
211.687Automatic, Mechanical, and Electronic Equipment
211.225Responsibilities of the Quality Control Unit
211. 1943Laboratory Records
211.1603General Requirements, Laboratory Controls
211.1652Laboratory Controls
211.1882Batch 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 ReferenceNumber of Times CitedTitle of CFR Section
211.6813Automatic, Mechanical, and Electronic Equipment
211.1946Laboratory Records
211.1602General Requirements, Laboratory Controls
211.1802General Requirements for Records and Reports
211.1862Master Production and Control Records
211.1882Batch Production and Control Records

Conclusion:

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.

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