A basic premise of cGMP compliance for finished pharmaceuticals is that the process used for manufacturing is under control and that it yields the expected product in conformance with its specifications. Whether the product is manufactured in-house or at a contract manufacturer, control of the quality of the raw materials and components used is essential. In my experience, the control of material and component suppliers varies. Sometimes suppliers are audited during a visit to the supplier’s facility. Other times, the audit is performed with a questionnaire, and many times, the supplier is not audited at all. My own approach is to audit every supplier and, if possible, to audit the sources of the critical materials supplied by distributors.

No matter what kind of supplier audit is performed, raw materials and components must be approved by the quality unit before use. Only approved materials may be used in production. What is not so clear, however, is what should be done with materials that are not approved or have been rejected.

Look to the Past

To get some background into the rationale for the GMPs as they are now documented and practiced, it is often useful to look to the past. A good source that discusses the reasons that the cGMPs were written as they are can be found in the 1978 Preamble to the GMPs. (Ref: Federal Register, Sept. 29, 1978). This long document provides insights into both the FDA’s thinking and into the concerns of the pharmaceutical industry during the writing and refining of GMPs.

Getting back to the issue of rejected materials, the preamble indicates that rejected materials do not necessarily have to be destroyed. “Reprocessing, reworking, refining, diversion to other acceptable uses, returning to the supplier or destruction are all actions that may occur after a decision to reject and are in no way precluded by the rejection decision unless specifically stated by the manufacturer,” the document says.

Considerable attention is paid to the proposal that materials be either approved or rejected after testing. Several comments deal with the possibility that materials could be reprocessed or used for other purposes for which they were suitable.

“The commissioner agrees that destruction may not be the only way of disposing of materials which do not meet acceptance criteria. If materials are being tested for their acceptability for manufacturing a particular drug product and they do not meet those criteria, however, they must be rejected for that use,” according to the preamble. “There is no prohibition against the use of such materials after appropriate reprocessing or for other uses for which the acceptance criteria can be met… The commissioner believes the major concerns of FDA are that rejected materials are not inadvertently used in a product for which they are not acceptable and that any such material that is reprocessed and found suitable for reuse meets specifications, standards and characteristics for the intended use.”

The Issue of Where and When

For many manufacturers, the issue of where and when the inspection of containers and closures should occur is critical, since space is often limited and large inventories of containers and closures are not maintained, or the facility is using “just-in-time” manufacturing practices.

Here too the preamble provides guidance: “If suitable specifications for containers and closures are simple enough to permit a quick visual examination to determine the product’s acceptability, such an examination could be performed at the time of receipt without being in conflict with the quarantine requirements of these regulations. A certificate of testing received from a supplier would not preclude the necessity for examining containers and closures to determine that they are the same articles as are represented by the certificate. Any manufacturer who does not have such evidence of an article’s acceptability or does not alternatively quarantine the article until such evidence is obtained, is assuming an unacceptable risk that the article will be used and subsequently be found unsuitable.”

Another aspect deals with the bulk storage of raw materials and how to deal with receiving one lot when the storage tank still contains part of another. The obvious solution to this is to have more than one storage tank so that the lots can be maintained separately. Most large companies have separate tanks, but in smaller facilities, it is not uncommon to find only one tank for each component that is stored in bulk. It sometimes comes down to the cost of additional tanks, a lack of space and lack of understanding of the importance of lot-to-lot traceability.

This issue was raised during the comment period that led to the preamble. One comment raised issues relative to the handling of bulk components being held in storage tanks or silos, including the commingling of a new shipment with the remainder from previous shipments and how such lots should be identified.

The preamble provides an answer that still applies today: “Combining a new bulk shipment of a component in a bulk storage tank with the remainder of a previously-received, tested and approved component lot causes the compositing of the material. The result is that the previously approved material becomes an integral part of an unapproved new lot and cannot be used until such lot is approved for use. However, a manufacturer may choose not to commingle approved lots with unapproved lots of components in bulk storage. In some instances, a manufacturer may be able to test components appropriately before introduction to bulk storage as, for example, when a shipment of components is received with a valid certificate of analysis and where identification testing may be sufficient.”

The traceability of packaging components and raw materials is basic to the manufacturer’s ability to recall or retrieve product once it has been shipped and/or distributed. The need to assign a unique lot number to each receipt of materials was considered in the preamble.

“One comment… suggested that when a shipment of components contains more than one manufacturer’s lot number, the recipient be allowed the option of assigning a single code number for this shipment. The commissioner rejected this suggestion inasmuch as it would either complicate or negate tracing a component back to a particular manufacturer’s lot or the subsequent tracing of a particular lot of component used to a lot of drug products… The requirement is that each lot of each shipment be identified with a distinctive code,” the preamble indicates. “If a lot number furnished by the supplier is distinctive for each lot in each shipment, then the recipient, i.e., the drug product manufacturer, can use the lot number as the distinctive code. If, however, there is no lot number or the lot number is not distinctive for each lot in each shipment, then the recipient is responsible for designating his own distinctive code.”

Use-at-Risk Situations

A common question is whether it is acceptable to use components during or before testing, and as long as the drug product is not released until components meet specifications. This is the so-called “use-at-risk situation.” The preamble is very clear that this practice is not acceptable.

“As a general principle, such procedures would violate the precepts of good quality control because untested and possibly non-complying materials would be used in drug product processing. Although initially it would appear that the manufacturer merely assumes the risk of having to recondition or destroy a processed lot that was found to contain unsatisfactory components, containers or closures, the commissioner is concerned that processing while testing substantially increases the risk to the consumer that an unsatisfactory lot might erroneously be released.”

I am often asked why it is necessary to test each shipment of a manufacturer’s lot of material if the first receipt of the lot was tested and found to meet its specifications. A similar question was raised in the comments received on the proposed GMPs.

The preamble provides the answer: “The commissioner feels that examination of each lot of each shipment received is necessary even though a portion of the same lot has previously been received, tested and approved. Subsequent shipments may have been subjected to different conditions, which may have caused changes in materials so that, although one shipment of a particular lot has met specifications, another may not.”

The GMPs have changed since they were promulgated in 1978, but the basic underlying principles of testing and control still apply. Although we live in the hectic present, it is often worthwhile to take a minute and look to the past to understand current practices and procedures.

Efrem H. Zaret, Ph.D., president of EZ Associates Inc, consults in GMP compliance training, quality assurance and control, clinical supplies, logistics, regulatory affairs and product and package development. Reach him at 908-753-8566 or ef@ezassociates.com.