Excipient manufacturability

Information on existing or new excipients can be described and provided to the FDA in an NDA directly. Alternatively, the manufacturers of excipients may prepare and submit type IV Drug Master Files (DMF) to support the use of an excipient in one or more NDAs. The DMFs are discussed in FDA s regulations under 21 CFR Section 314.420 and the FDA-issued Guidance for Drug Master Files (8). When authorized by the DMF submitter (i.e., the excipient manufacturer) and cross-referenced by an NDA submitter, the FDA reviews the DMF to make determinations on the safety, manufacture, and quality of the excipient use in the new drug that is the subject of the then pending NDA. The DMF becomes active when reviewed in conjunction with the review and approval of an NDA. 

Presented together by the British, European, Japanese, and U S. Pharmacopeias, the first Interpharmacopeial Open Conference on Standards for Excipients was convened in Orlando, FL, from January 30-February 1, 1991 (Table 1). Attended by 165 participants, representation included 11 countries, 59 pharmaceutical or excipient manufacturers or suppliers, three regulatory agencies (FDA, EEC, and HPB), and seven pharmacopeias (the presenters and the French, Italian, and Spanish Pharmacopeias) [17]. In preparation for this conference, USP convened open meetings on Magnesium Stearate and Lactose attended by almost every major manufacturer from Europe and the United States. 

Excipients manufacture The manufacture of novel excipients may be provided in an application or supporting DMF. Typically these excipients are noncompendial and are used in specialized dosage forms and drug delivery systems. CDER chemists are responsible for the scientific reviews and evaluation of the records and data associated with the manufacture of these novel excipients. The review will include starting materials, key intermediates, reagents, and solvents. cGMP inspections by the Field usually will be performed on request from CDER. 

In an attempt to increase the likelihood of regulatory and pharmaceutical industry acceptance of new excipients, excipient manufacturers have made several attempts to foster a regulatory environment that provides mechanisms for acceptance of new and novel excipients. Attempts to create a preapproval review or formal status for excipients have not been successful, and are likely not to be in the interests of the industry nor economically feasible for regulatory agencies. 

Efforts to create mechanisms for obtaining some indicia of regulatory acceptance of excipients have been more successful. One notable effort by industry along these lines was the creation of the International Pharmaceutical Excipients Council (IPEC) in 1991. IPEC was formed to represent the interests of both excipient manufacturers and users (pharmaceutical companies), and is notable for a number of initiatives on behalf of the industry these include the following ... 

All of these efforts were directed at standardizing excipient manufacture and use, and have been important in creating a regularized regulatory environment for excipients. Nevertheless, these steps are primarily directed toward the safety and use evaluation of existing excipients, and do little to provide any indicia of acceptability for novel ingredients. 

As a consequence of the uniqueness of excipient manufacture as discussed above, the starting point for applying GMP principles, the manufacturing environment, manufacturing equipment, manufacturing processes, and other applications for nonpharmaceutical grades of the material all impact the application of GMP requirements. 

Raw materials must always be approved by the Quality Unit before use by production. Each lot of raw material should be sampled and the laboratory should perform at least an identity test in addition to verifying from the supplier Certificate of Analysis (COA) that the lot test results conform to the excipient manufacturer s specification. Upon approval, the status of the lot is changed from unapproved or quarantine to approved or available. The raw material lot status can be identified by use of approval labels on the container or pallet, movement of the raw material lot to the approved section of the warehouse, or by changing the lot status in a computerized inventory system. 

Installation qualification is an exercise that shows the equipment has been installed properly, as specified either by the equipment manufacturer or by the purchaser. Operation qualification demonstrates that the equipment operates as intended. The operation of the equipment is compared to the equipment manufacturer s specification or the excipient manufacturer s design specification. Finally, the performance qualification shows that the equipment performs as intended. Where production equipment is involved, performance qualification usually involves running a trial substance such as water or a production batch. 

As noted, excipient manufacture should take place using qualified equipment and a validated process. Generally excipient equipment has been in place for many years so that classical methods of qualification, which is done as new equipment is commissioned, are inapplicable. To retrospectively qualify the installation, operation, and performance of equipment, it is suggested to rely on historical records. For installation and operation qualification, a protocol is prepared that illustrates how maintenance and production records will be used to support the hypothesis that the equipment was installed properly and is operating as intended. Then the protocol is executed by reviewing the maintenance and production records for the supporting data. Finally a report is prepared that includes the data from the records, which support the conclusion that the installation and operation of the equipment conforms to protocol requirements. It is suggested that maintenance and production records for a minimum of one year but preferably five years be reviewed. 

The most accepted validation method is prospective. This validation approach relies on completion of the validation before commercial production begins and requires the manufacture of at least three consecutive batches during protocol execution. The batches are evaluated for conformance to the protocol requirements a report is prepared and approved. Then the lots are released for sale and production commences using the validated process. For excipient manufacture, where the material has been produced for quite some time, this approach is usually inappropriate. 

The validation approach excipient manufacturers prefer is retrospective because of the preponderance of production data they have available to support the hypothesis that the process operates reliably. In order for a process or process step to be considered for retrospective validation, it should have operated for at least one year with... 

When the specification for a compendial excipient differs from the compendial monograph (e.g., additional tests, different analytical methods, or different acceptance criteria) the test results will be accepted from the excipient manufacturer s COA. However, the excipient should still conform to the monograph in an official compendium if there is such a monograph otherwise, justifications must be provided, and labeling needs to be changed to state plainly that the article does not meet the compendial requirement. 

USP < 1078 > provides the following guidelines for the excipient manufacturer and the purchaser to use in establishing standards for excipient materials provided. 

While the COA is the excipient manufacturer s responsibility, once the material is received, it is the drug product manufacturers responsibility to verify the product and ensure that it is properly tested, handled, and stored. Upon receipt of a shipment, each lot of excipient will be withheld from use until the lot is sampled, tested, or examined according to the written procedures. The quality control (QC) personnel will examine each container for (i) manufacturer s name, (ii) manufacturer s lot number, (iii) leaks or spills, (iv) contamination, (v) breached containers, (vi) proper labeling, and (vii) material safety data sheet and determined material hazards. 

This book is intended for formulation scientists, analytical scientists and engineers, regulatory and compendia personnel, procurement personnel, preclinical scientists, excipient manufacturers, quality control and assurance personnel, and distributors. 

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