11/4/2016

LessonsLearnedfromFDAInspectionsofForeignAPIFacilities|PharmaceuticalTechnology

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Lessons Learned from FDA

Inspections of Foreign API Facilities

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A study of recent inspection observations allows for baseline

trending and continuous improvement.
Sep 08, 2015 By Lisa Tung, Maria Eng
Pharmaceutical Technology
Volume 39, Issue 18, pg s8s13

Disclaimer: The opinions expressed in this article do not necessarily reflect

FDAs position on the matter being discussed.

Monty Rakusen/Getty Images

Since 2007, foreign drug inspections

have increased three-fold, from 200 to
600 in 2013 (1, 2). As more drugs are
produced overseas, particularly in areas
where regulatory oversight may differ
compared to that in the United States or
Europe, it is crucial to ensure that
products entering the supply chain are
safe, effective, and of high quality.

FDA has been ramping up inspections of international drug manufacturers

during the past decade to improve drug safety. The heparin recall of 2007
2008, which resulted when oversulfated chrondroitin sulfate was used to
substitute for the active ingredient in heparin, illustrates the serious harm that
substandard pharmaceutical drug products can cause to consumers. The
contamination originated from pig slaughterhouses in China, affecting mostly
the US market, but also citizens from 10 other countries worldwide (3).
To prevent situations like this, FDA regulates manufacturers of API and
finished dosage form (FDF) drug products through standards, regulations,
and guidelines promulgated from the Federal, Food, Drug, and Cosmetic Act.
Through statutory law, authorities given to FDA allow for regulations known as
current good manufacturing practices (cGMPs) to assure control of
manufacturing processes. Throughout the drug process, manufacturers must
meet minimum requirements for identity, strength, quality, and purity of drug
products by monitoring system practices and operations (4). By ensuring
quality control at each stage of the drug production, contamination,
deviations, and failures are more likely to be prevented. Areas such as
buildings and facilities, equipment, personnel qualification and training,
starting materials, laboratory, packaging and labeling, and production units
are all evaluated during a drug inspection (4). If manufacturers are not
compliant with cGMPs, they can be issued a FDA Form 483 listing areas of
noncompliance, in order of significance.
This project analyzed all FDA inspections performed outside of the US from
January through December 2013, to pinpoint problem areas for compliance.
The majority of inspections were conducted in Europe, at 33.76% and Asia, at
63.39%. The International Conference on Harmonizations (ICHs) Q7, Good
Manufacturing Practice Guide For Active Pharmaceutical Ingredients (5, 6)
was utilized to categorize results.

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11/4/2016

LessonsLearnedfromFDAInspectionsofForeignAPIFacilities|PharmaceuticalTechnology
Between January 1 through December 31, 157 API plant inspections found
839 observations of noncompliance within ICH Q7. The five most problematic
areas, in order of descending frequency, were found to be in ICH Q7 sections
11, Laboratory Controls; 12, Validation; 6, Documentation and Records; 5,
Process Equipment; and 8, Production and In-Process Controls. Based on a
Pharmaceutical Inspection Co-operation Scheme (PIC/S) questionnaire, these
data were analyzed to determine which operations were most prone to
noncompliance in API facilities outside the US. The projects overall goal was
to determine which types of deficiencies API manufacturers were most
commonly cited for during inspections. By understanding the types and
trends of violations found from inspectional outcomes, future resources and
knowledge could be directed in specific areas, to help manufacturers
improve quality control and assurance (QC and QA).
Materials and methods
Data for the project were compiled from an internal database known as the
mission accomplishment and regulatory compliance services (MARCS)
compliance management system (CMS). It is an internal, web-based
enterprise architecture application that links to other FDA resources and is
used to manage compliance-related work activities (7). Records and
documents associated with inspections that were conducted by FDA are
placed under work activities and case numbers in the MARCS-CMS. By
utilizing the advanced work search function and the advanced output options,
work ID, work type (CDER-Evaluate Foreign GMP Inspection), firms,
inspection profiles, work country, inspection start date, inspection end date,
and inspection initial classification were fields used to generate the data. The
calendar year of January 1 to December 31, 2013 was used to assemble
relevant data into an Excel spreadsheet. Formatting and sorting of cells was
then completed to distinguish between API and FDF sites.
Through the class code filter, the following codes were defined as APIs: CBI
(recombinant/non-recombinant protein drug substance of biologic origin),
CEX (starting/intermediate derived from plant/animal extraction), CFN (nonsterile API by fermentation), CFS (sterile API by fermentation), CRU (nonsterile starting/intermediate [not plant/animal]), CSN (non-sterile API by
chemical synthesis), CSS (sterile API by chemical synthesis), and CXA
(purified API derived from plant/animal extraction). Once API manufacturing
sites were separated from FDF manufacturers, further grouping was used to
distinguish between sites that received a FDA Form 483 of objectionable
conditions: voluntary action indicated (VAI) or official action indicated (OAI)
from those not receiving one; no action indicated (NAI). The spreadsheet was
further filtered to include VAI and OAI under the inspection initial classification
column, and then each FDA Form 483 was pulled from the MARCS-CMS
database.
Observations listed in the FDA Form 483 were categorized against the ICH
Q7 guideline (6). In addition to the introduction (Section 1), ICH Q7 features
the following sections:
2. Quality Management
3. Personnel
4. Buildings and Facilities
5. Process Equipment
6. Documentation and Records
7. Materials Management
8. Production and In-process Controls
9. Packaging and Identification Labeling of APIs and Intermediates
10. Storage and Distribution
11. Laboratory Controls
12. Validation
13. Change Control
14. Rejection and Re-use of Materials
15. Complaints and Recalls
16. Contract Manufacturers (including laboratories)
17. Agents, Brokers, Traders, Distributors, Repackers, and Relabellers
18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation
19. APIs for Use in Clinical Trials.
Each section is further broken down into multiple subsections that highlight
more specific details. For example, under Section 6, Documentation and
Records, further subsections include:
6.1 Documentation System and Specifications

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LessonsLearnedfromFDAInspectionsofForeignAPIFacilities|PharmaceuticalTechnology
6.2 Equipment Cleaning and Use Record
6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging
Materials
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6.5 Batch Production Records
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Documentation of each citation was recorded under each corresponding

subsection of ICH Q7. Breakdown of data was evaluated in each section,
subsection, geographic region, and country. Foreign API drug manufacturers
included countries outside the US, in Asia, Australasia, Europe, North
America, and South America.

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