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Sep 08, 2015

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Lessons Learned from FDA

Inspections of Foreign API FacilitiesA study of recent inspection observations allows for baseline

trending and continuous improvement.

By Lisa Tung, Maria Eng

Pharmaceutical Technology

Volume 39, Issue 18, pg s8–s13

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

FDA’s position on the matter being discussed.

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 Harmonization’s (ICH’s) Q7, Good 

Manufacturing Practice Guide For Active Pharmaceutical Ingredients  (5, 6)

was utilized to categorize results.Top News

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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 project’s 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 manufacturersimprove 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 assemblerelevant 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 (non-

sterile API by fermentation), CFS (sterile API by fermentation), CRU (non-

sterile 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 classificationcolumn, 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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Demand is driving expansion and consolidation

of formulation and clinical trial materials services.

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Continues to Grow

Contract biopharmaceutical manufacturing has

been growing steadily and is expected to reach

$4.1 billion by 2019.

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6.2 Equipment Cleaning and Use Record

6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging

Materials

6.4 Master Production Instructions

6.5 Batch Production Records

6.6 Laboratory Control Records

6.7 Batch Production Record Review.

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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