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Consistency of manufacture and change control A thorough understanding of the manufacturing process and effective control of change can best assure consistency of excipient quality from batch to batch. Implementation of changes may also have consequences for registration filings with regulatory agencies.

Changes in excipient manufacturing processes may result in changed physical or chemical properties of the excipient that are only evident during subsequent processing or in the finished dosage form. This is particularly important in the context of the pharmaceutical product approval process where bioequivalence comparisons are made between pivotal, clinical trial batch ("bio batch") production and commercial scale-up batches. Changes made to the excipient supplied for the commercial product from the excipient supplied for the bio batch should be such that they do not impact the quality and performance of the commercial drug product. Scale-up of excipients to commercial production may involve several stages and data may be required to demonstrate consistency between batches through the scale-up process.


Traceability Traceability of batch-related records to facilitate investigations and retrieval of product is also a key requirement of GMP.

A3. Application of GMP Principles

It is the responsibility of the excipient manufacturer to designate and document the rationale for the point in the manufacturing process at which appropriate GMP is to be applied. From this point on appropriate GMP should be applied. The manufacturer should apply a level of GMP to each manufacturing stage commensurate with the importance of that step in assuring product integrity. This may be demonstrated by means of the use of a risk assessment procedure (for example HACCP, FMEA).

The stringency of GMP in excipient production should increase as the process proceeds from early manufacturing to final stages, purification and packaging. Physical processing (for example granulation, coating or physical manipulation of particle size such as milling, micronising) as well as chemical processing of excipients should be conducted at least to the standards suggested by this Guide.

It should be recognised that all intermediates might not require testing. An excipient manufacturer should, however, be able to identify critical or key points in the manufacturing process where selective intermediate sampling and testing is necessary in order to monitor process performance.

A4. General Auditing Considerations

Audits of an excipient operation will be influenced by the purpose of the audit and the intended use of the excipient. The key stages of a production process should be examined to determine whether the manufacturer adequately controls these steps so the process performs consistently. Overall, an audit should assess the excipient manufacturer's capability to deliver a product that consistently meets established specifications.

The audit team may consist of engineers, laboratory analysts, purchasing agents, computer experts, maintenance or other appropriate personnel as appropriate to the scope and purpose of the audit. External auditors must respect confidentiality of the manufacturer’s processes and other disclosures.

Copyright © 2006 The International Pharmaceutical Excipients Council and Copyright © 2006 Pharmaceutical Quality Group

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