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  • the type of system (for example open or closed). Enclosed systems in chemical plants often are not closed when they are being charged and/or when the final product is being emptied. In addition, the same reaction vessels are sometimes used for different reactions,

  • the form of the material (for example wet or dry),

  • the stage of processing and use of the equipment and/or area (for example multi-purpose or dedicated),

  • continuous versus batch production.

A6. Documentation and Record Review

Documentation required for the early steps in the process need not be as comprehensive as in the latter stages of the process. It is important that a chain of documentation exists and that this is complete when:

  • the excipient can be identified and quantified for those processes where the molecule is produced during the course of the process. For batch production a theoretical mass balance may also be established with appropriate limits, as deviations from tolerance are a good indicator of a loss of control,

  • an impurity or other substance likely to adversely affect the impurity profile or form of the molecule is identified and subsequent attempts are made to remove it.

As chemical-processing proceeds, a chain of documentation should be established which includes:

  • a documented process,

  • the identification of critical processing steps,

  • appropriate production records,

  • records of initial and subsequent batch numbers,

  • records of raw materials used,

  • comparison of test results against meaningful standards.

If significant deviations from the normal manufacturing process are recorded there should be evidence of suitable investigations and a review of the quality of the excipient.

Complete documentation should be continued throughout the remainder of the process for quality-critical processing steps until the excipient is packaged and delivered to the end user. The batch should be homogenous within the manufacturer’s specifications. This does not necessitate the final blending of continuous process material if process controls can demonstrate compliance to specifications throughout the batch.

In order to promote uniformity in excipient GMP inspections the following basic requirements should be established:

  • that a unique batch number is assigned to the excipient which enables it to be traced through manufacture to release and certification,

  • that suitable controls are in place for the preparation of a batch record for batch processing and/or a production record, log sheet or other appropriate documentation for continuous processing,

  • demonstration that the batch has been prepared using GMP guidelines from the processing point at which excipient GMP has been determined to apply,

  • confirmation that the batch is not combined with material from other batches for the purpose of either hiding or diluting an adulterated batch,

  • records showing that the batch has been sampled in accordance with a sampling plan that ensures a representative sample of the batch, Copyright © 2006 The International Pharmaceutical Excipients Council and Copyright © 2006 Pharmaceutical Quality Group Page 28

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