5.1 Material/Component Specification and Purchasing Control

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

Do the CGMP regulations require a contract laboratory to have a quality control unit for the operations it performs?

Is a dosage form manufacturer required to conduct full monograph testing on a USP ingredient used in a drug product?

What information should be contained in a component supplier's certificate of analysis?

Is pressure sensitive labeling on a roll considered to be cut labeling? 

Do the CGMP regulations require a contract laboratory to have a quality control unit for the operations it performs?

Reference: 
21 CFR 210.2(b), Application of current good manufacturing practice regulations; 
210.3, Definitions; 
211.22, Responsibilities of quality control unit

Yes. By definition, testing and quality control of drug products are part of manufacturing. At section 210.2, the regulations explain that where persons engage in only some operations subject to provisions of parts 210 and 211 (of Title 21), persons need only comply with those regulations applicable to the operations they perform. Therefore, a contract laboratory is subject to those portions of the CGMP regulations that cover activities it performs.

We would expect that many of the laboratory's activities would fall under Subpart I, Laboratory Controls, of the CGMP regulations. (Other provisions, such as those pertaining to personnel qualification, recordkeeping, facilities, and laboratory animals would also apply.) 

The responsibilities of a quality control unit are pervasive in the CGMP regulations, and many lab functions require review and approval of a quality control unit. For example, per section 211.160, the quality control unit must review and approve test procedures and laboratory control mechanisms.

It should be clear, therefore, that section 211.22 applies to a contract laboratory and that the lab would have to have a quality control unit. However, that unit's responsibilities would only extend to the CGMP operations that the lab performs.

What's more, be aware that in smaller establishments, as might be the case in a contract laboratory, the responsibilities of a quality control unit may be assigned to as few as one or two individuals. In a larger organization, of course, an effective quality control unit may warrant a larger staff. This is consistent with the definition of quality control unit, at section 210.3(b).

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework sections 1.1, 5.5, 6.4.

Is a dosage form manufacturer required to conduct full monograph testing on a USP ingredient used in a drug product?

Reference: 
21 CFR 211.84, Testing and approval or rejection of components, drug product containers, and closures;
211.160(b), General Requirements [Subpart I - Laboratory Controls]

This question has several facets, namely, what tests need be done and who performs them.

The tests that need to be performed are those to ensure that established specifications for the component have been met. The CGMP regulations, at section 211.160(b) require the dosage form manufacturer to establish appropriate component specifications. If the manufacturer adopts all of the component monograph specifications then all of those specifications would have to be met as demonstrated by laboratory testing. A firm may commit itself to those specifications, for example, in an approved new drug application.

A firm would also adopt full monograph specifications for a USP component if the material is an active ingredient in a USP drug product where the dosage form monograph requires use of an active ingredient that meets the active ingredient monograph. The firm could exempt itself from this USP requirement if it labels the USP end product with a specific disclaimer as to how the dosage form does not meet USP specifications.

The next facet relates to who performs the component tests. Before the dosage form manufacturer incorporates the ingredients, the testing must have been completed. Section 211.84(a) specifies that each lot of components, drug product containers, and closures shall be withheld from use until sampled, tested, or examined, as appropriate, and released for use by the quality control unit. Component means ingredient and therefore both actives and excipients require testing. The CGMPs give firms considerable latitude when it comes to who does the testing. The dosage form manufacturer may elect to: (1) Perform the tests itself; (2) have the tests done by a contract laboratory; (3) have tests done by the component supplier; or, (4) perform a combination of these options.

Where a firm elects to have the component supplier perform testing, section 211.84(d)(2) states that "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 analysis through appropriate validation of the supplier's test results at appropriate intervals."

We have found that establishing reliability of the supplier's analysis generally involves comparing results of independent tests against the supplier's corresponding certificates of analysis (COAs), usually accomplished by initially conducting full testing on a number of lots. In addition, audits of the supplier's laboratory operations, while not explicitly required by CGMPs, can be enlightening. That's because some chemical suppliers are merely distributors or brokers who might be photocopying the makers' results on their own letterhead, thereby representing that they conducted the analysis themselves. This might only be revealed through a supplier audit. Moreover, this audit may be the only way to establish that the laboratory controls, specifications, standards, sampling plans, and test procedures are scientifically sound.

The CGMPs require that the reliability of the supplier's results be conducted at appropriate intervals. Some FDA investigators have included on an FDA-483 that the manufacturer has not conducted this "Vendor Validation" at least once per year. This is an inappropriate citation because the regulations don't specify the frequency, as per 211.84. There is no requirement to conduct this validation annually. Manufacturers have the discretion to determine the interval, and, on a case by case basis, we assess whether or not that interval is appropriate. For instance, if a firm discovers problems with ingredients that contradict COAs, then that may indicate that the frequency of the test comparisons is insufficient.

Contact for further info: Brian G. Nadel, HFD-325 (301) 594-0098, e-mail nadelb@cder.fda.gov 

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 4) December, 1998.
This same text is also reprinted in Framework sections 5.2 and 5.5.

What information should be contained in a component supplier's certificate of analysis?

Reference: 
21 CFR 211.84(d), Testing and approval or rejection of components, drug product containers, and closures.

Except for at least one specific identity test which the drug product manufacturer must perform (in addition to periodic validation of the supplier's test results), the report of analysis (commonly called a certificate of analysis) would cover the remaining required component tests to ensure conformity with specifications for purity, strength, and quality.

Much of the information in the reports of analysis would parallel the same information that the drug product manufacturer's own laboratory (or contract laboratory) would determine and document. This information would include, at a minimum, the name and lot number of the component, the date of testing, the methods used, results of the tests expressed in quantitative terms whenever the test itself is quantitative (rather than pass/fail), the range of acceptable test results, the report date, and the signature of the responsible party that issues the report. If the component has an expiration date, that information should also be in the report.

Contact for further info: Michael J. Verdi, HFD-322, 301594-0095, e-mail: verdim@cder.fda.gov 

Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 2), June, 1996.
This text is also reprinted in Framework section 5.5 .

Is pressure sensitive labeling on a roll considered to be cut labeling? 

References: 
See 21 CFR 211.122(g), Materials examination and usage criteria.

No, not unless peeled off the roll prior to being brought to the labeling line. Some misinformation appears to have been circulated in the pharmaceutical industry that FDA considers pressure sensitive labeling to be cut labeling -- this is not correct. Pressure sensitive labeling on a roll is roll labeling which does not require 100% verification, unless a firm wants to eliminate reconciliation, in which case 100% verification must be performed. However, if any type of labeling is received on rolls but is removed from the rolls by peeling them off or cutting off individual pieces prior to being brought to the labeling line, then we consider the pieces to be cut labeling.