FDA finds most basic GMP quality control and quality assurance violations


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Facts and trends from recent Warning Letters

Poor testing of starting materials, packaging materials, finished products as well as inadequate control and management of GMP-required processes in quality control areas are regulatory violations that FDA inspectors mention in nearly one out of every two warning letters sent out in fiscal year 2020 (FY 2020). Thus, the "hit list" of the 10 most common GMP deficiencies is similar to that of the previous year (FY 2019) (see Figure 1).

In total, 84 Warning Letters were issued for GMP violations in FY 2019; in FY 2020, there were 70.

It is notable that in FY 2020, violations of section 211.84 were cited in 28 or 40% of all Warning Letters. Compared to 26% in FY 2019 (22 of 84 Warning Letters), this is a significant increase.

The following sections will take a closer look at examples of deviations from the quality testing requirements for finished drug product components and container closure systems described in 211.84.

Following are first two key statements from the requirements of this paragraph in the original wording:

Testing and approval or rejection of components, drug product containers, and closures.
(Subpart D-Equipment)

Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/ closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier's test results through appropriate validation of the supplier's test results at appropriate intervals.

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These two paragraphs already hint at the problem that caused a warning letter for many of the inspected companies: the acceptance and further processing of raw materials, starting materials, auxiliary materials as well as primary packaging materials and container closure systems without incoming inspection and only on the basis of the supplier's certificates.


Fig. 1: Comparison of the frequency of cited paragraphs of 21 CRF 211 in the warning letters of fiscal years 2019 and 2020.

In the Warning Letters, this GMP violation is then formulated as follows:

"Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality."

"Your firm failed to conduct at least one test to verify the identity of each component of a drug product."

"Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals."

In the case of starting materials, the FDA thus requires at least one identity test for each batch, provided that all other information on the supplier's certificate has been compared (validated) with the company's own analyses at appropriate (risk assessment!) intervals, thus confirming the reliability of the certificate. The same applies to the incoming inspection of containers/closures; here the FDA expexts a visual inspection at least. A closer look at the warning letters for this paragraph reveals that only manufacturers of oral and topical dosage forms are affected. Manufacturers of sterile products are not among the addressees. A look at the localization of the sites shows that this is not only a problem for manufacturers from the Far East (Table).

A detailed examination of the findings, some of which are described in detail in most of the warning letters, is also revealing.

Manufacturers of topical medicines (USA)

Starting materials (including dimethyl sulfone) are used directly in the manufacturing process without further testing for identity, purity, content, etc. This also applies to the excipient glycerol. This also applies to the excipient glycerol, which has not been tested for the highly toxic impurities ethylene glycol and diethylene glycol before use in production. There is FDA guidance on this very subject entitled "Testing of Glycerin for Diethylene Glycol" with precise details on how glycerin is to be tested.

Location of
production site

Number of
Warning Letters

USA 10
China 5
India 4
Europe 4
Kanada, Australia, Indonesia,
Bahamas, Trinidad & Tobago
1 each

Manufacturer of oral dosage forms (India)

No incoming inspection of the active pharmaceutical ingredients used in the manufacturing process is performed; only the unverified data from the supplier's certificate of analysis is used as the quality basis. A Standard Operating Procedure (SOP) for supplier qualification has been established; however, the FDA's criticism of this SOP is that this document does not include a validation program to confirm the reliability of the supplier's certificate.

In each Warning Letter, FDA requests documents that directly relate to the GMP violation and must demonstrate that a GMP-compliant corrective action has been taken as defined in the appropriate section of 21 CFR 211 ("In response to this letter, provide ...").

For 211.84, this is essentially the following documentation:

  • A compilation of the chemical and microbiological specifications for receiving inspection and release by quality control of all components required for the manufacture of the drug product (active pharmaceutical ingredients).
  • A description of how the components are tested for compliance to the specifications.
  • Information on establishing robust reliability testing of the information on the supplier certificates of analysis. FDA also requires information on the initial validation and periodic revalidation of these claims for this purpose.
  • A commitment to perform at least one identity test as an incoming check for each batch of components.
  • A summary of the results of incoming testing of all components performed as part of the reliability testing of supplier certificates.
  • An SOP on the supplier certificate validation program.
  • A summary of the procedures for qualification and monitoring of external laboratories performing testing on finished drug products.
  • A report on the comprehensive review of the entire material system. This report should include information on the qualification of all suppliers of components, packaging materials, and closure systems and on expiration dates or re-test periods. FDA would also like to see credible justification that quality control is capable of preventing the use of inappropriate materials.
Validation in Pharmaceutical Analysis - Live Online Training


13/14 March 2024

Validation in Pharmaceutical Analysis - Live Online Training

Analyses of warning letters usually provide very useful insights that can be used to review GMP-relevant operations in all areas, from quality assurance, quality control, production, and equipment to supplier qualification, etc. This can make a valuable contribution, especially in the context of preparing for an upcoming FDA inspection.

Note: You will find more information about a broader analysis of the "Top Ten Failures" of recent Warning Letters on the ECA members' area soon.


Dr. Gerhard Becker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and
compliance topics.


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