Packaging and Identification Labelling of APIs and Intermediates

General

The focus of this chapter is mainly on packaging and labelling operations of APIs and intermediates intended for shipment to third parties and it is not the intention that all requirements have to be met for internal transport at one site under the manufacturers control.

Also a lot of requirements are established for pre-printed labels or labels that are printed by on site computer and stored. In the API industry most labels are printed on demand, and therefore these requirements are not applicable.

The written procedure describing the receipt, identification, quarantine, sampling, examination and/or testing is only applicable for pre-printed labels or labels that are printed by on site computer and stored. For labels which are printed on demand, written procedures describing the receipt, identification, quarantine, sampling, examination, and/or testing and release, and handling of blank labels - bearing no information at all - are not applicable. (A label is only considered as a label if product or batch related information is imprinted).

2 Packaging Materials

Appropriate packaging materials to be used should be defined in the master production instruction. For APIs and, when appropriate, for commercially available intermediates the suitability of packaging materials should be supported by product stability testing.

Typically most APIs are stored and shipped in fibre drums with polyethylene liners or polyethylene bags. The inner lining or bag in direct contact with the API should be of food grade plastic (if intended for shipment to the U.S.) or comply with local regulations. The inner packaging should be controlled by the company with respect to identity and traceability.

It is industry practice to inspect cleaned containers for defects and cleanliness. Sanitising containers does not imply sterilisation. In most instances, sterilisation is not applicable for API packaging materials.

Rules regarding cleaning for re-used containers are:

• For the same product
  Visual inspection should be enough, effectiveness of cleaning should have been demonstrated (e.g. by cleaning validation).
• For multi-use
  Cleaning procedure has to be validated, or at a minimum, depending on the stage of manufacture, analytical verification has to be performed.

Remarks: Only applicable if product is in direct contact with the surface of the container, and not if in-liners are used (PE bags etc.)

3 Label Issuance and Control

For the API industry, computer printed labels are a norm and pre-printed labels are exceptions. Most of the ICH statements addressed pre-printed labels. Computer printed labels are typically printed "on demand" basis and little or no storage is needed.

An access to the label storage area is only applicable for pre-printed labels or labels that are printed by on site computer and stored. For labels printed "on demand" blank roles of label are not applicable.

The requirement to reconcile the quantities of labels remains on pre-printed labels or labels that are printed by on site computer and stored.

For labels printed on demand also procedures should be in place to check "number of labels demanded", "number of labels printed", number of labels put on the drums", "number of labels attached to the batch record or other traceable documents, e.g. shipping / dispensing documents" , "number of labels destroyed".

Additionally a check that the label(s) conform to the master should be documented in the batch record or other dispensing records.

Discrepancies referred to should be treated as critical deviations and thus the results of the investigation should be approved by the Quality Unit and include measures to be taken to prevent reoccurrence.

Returned labels are not likely to occur if "on demand" printed labels are used. If too much labels have been demanded, they should be destroyed and this activity should be documented in the batch record.

Programmable printing devices used to print labels on demand should not be subject to validation.

Printing devices may be controlled by a template, which may be changed by designated personnel according to an established procedure(s).

The examination of printed labels regarding proper identity and conformity with a master should be documented in the batch record or other documentation systems in place, e.g. dispensing records.

4 Packaging and Labelling Operations

Additionally to primary packaging and labelling after completion of production re-labelling with customer specific information as part of manufacture/dispensing/shipment is common practice. These activities have to be documented in the batch record or other systems in place, e.g. dispensing records.

Mix-ups during labelling operations are avoided by one labelling operation at the same time, only one batch to be labelled (not to be interpretated as stored) on one pallet or in a defined area (spacially separated). Also barcode systems correlating batches to labels could be used to prevent mix-ups.

For those APIs that have a retest date which is extended and mentioned on the label, the label must be replaced to reflect the extended retest date.

Examination results for correct labelled APIs and intermediates should be documented but not necessarily in the batch record, however the documentation could be attached to the batch record. Also other systems which are retrievable could be used.

Containers that are transported outside the control of the manufacturer should be sealed. It is recommended that company specific seals should be used particularly as imported material are often opened by customs and it should be apparent that such opening and re-sealing has taken place.