1. Purpose
The purpose of this Guideline is to provide guidance in the GMP requirements for the labeling and packaging of investigational materials at all stages of manufacturing and packaging.
2. Scope and Applicability
This guideline can be applicable to the labeling and packaging of Active Pharmaceutical Ingredients (API) and API intermediates; and intermediate, bulk, and packaged Investigational Medicinal Product (IMP) for clinical use. The Guideline applies to pre-printed materials used for packaging and labeling operations.
3. Definitions
3.1 Packaging Material
Any material employed in the packaging of an API, intermediate or formulated product, excluding any packaging material used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.
3.2 Active Pharmaceutical Ingredient (API)
Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product that when used in the production of a drug becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body.
3.3 Bulk IMP
Product that has completed all manufacturing stages up to, but not including, primary packaging. For example, tablets not yet packaged into bottles/blisters.
3.4 Bulk Packaged IMP
Any Investigational Medicinal Product that is within its primary container-closure but has not been labeled or assembled in accordance with the clinical study protocol, e.g., tablets in blisters, solutions in vials.
3.5 Intermediate API
A material produced during the steps of processing of an API that undergoes further molecular change or purification before it becomes an API.
3.6 Intermediate IMP
Partly processed materials that will undergo further manufacturing steps before it becomes a bulk product e.g., tablet blends.
3.7 Material status
“Released”, “Rejected” or “Quarantined” or other comparable inventory designation (e.g., “Restricted Use”) for material. Status labels should also include information such as product name, code, batch number and description. Material status can be written/printed on the label or, when a validated computerized inventory system is used, can be in encrypted form on the label. The description and batch number should always be present in human readable form.
3.8 Packaged IMP
Any product packaged and labeled in accordance with a clinical study protocol for clinical use.
4. Responsibilities
4.1 R&D Line Management are responsible for ensuring procedures are in place which meet this guideline.
4.2 Pharmaceutical and Process Quality Assurance is responsible for approving master labels and releasing labeled packaging materials, including label examples.
5. Guideline
5.1 Packaging and labeling of API and Intermediate API
5.1.1 There must be documented procedures to ensure that correct packaging materials and labels are used.
5.1.2 Label operations must be designed to prevent mix-ups. There must be physical or spatial separation from other unlabelled materials/batches.
5.1.3 Each container of isolated intermediate or API must be labeled as soon as possible during processing, with at least the following information:
– Batch number
– Product name/code
– Storage conditions, when such information is critical to ensure quality
– Material status (written or encrypted)
– Note: Purchased API intermediates should be labeled to include the same information.
5.1.4 If the material is intended to be transferred outside the control of the site’s material management system, the name and address of the manufacturing site, quantity of contents, special transportation requirements, if any, and any special legal requirements must be included on the label (in addition to the information listed in Section 5.1.3).
5.1.5 Intermediate or API containers that are transported outside of the site’s control must be sealed in a manner such that, if the seal is breached or missing, the recipient will be altered to the possibility that the contents may have been altered.
5.1.6 For material with expiration or retest dates, these must be included on the label and/or certificate of analysis.
5.1.7 Packaged or labeled materials must be examined to ensure that that they have the correct label. This examination must be part of the packaging operation and documented in the production records.
5.1.8 Labeling for APIs intended for use in clinical trials should identify the material as being for investigational use. The “investigational use” label is not required for commercial API being used for clinical trials, or for investigational API stored within the own site, which is controlled through an electronic inventory system.
5.1.9 The applicable guidance given for IMP below should be applied for any pre- printed labeling used for API.
5.2 Receipt of Pre-Printed Packaging and Labeling Materials for IMP
5.2.1 There must be written procedures for the receipt, identification, quarantine, sampling, examination and/or testing and release, and handling of pre- printed packaging and labeling material. Note: There should be written procedures for receipt of released material from another site (e.g., Operations) to ensure that the guidance in this section is covered. It is not necessary for R&D to repeat operations performed at another sister site.
5.2.2 Pre-printed packaging/labeling materials must be received with at least a material description and suppliers batch number.
5.2.3 Pre-printed packaging/labeling material must conform to established specifications.
5.2.4 Records must be maintained for the receipt, examination or testing, and disposition of the material. 5.2.5 Pre-printed packaging/labeling materials must be physically or administratively quarantined. Status-labeling of pre-printed packaging/labeling material should be clear and unambiguous and include the following:
– Batch number
– Material name and/or code
– Material status (written or encrypted)
5.3 Label Issuance and Control for IMP
5.3.1 Access to pre-printed label storage areas must be limited to authorized personnel.
5.3.2 Labels indicating a “released” status, where used, must be stored securely and access restricted.
5.3.3 Where applicable, the number of units to be packaged or labeled should be specified prior to starting the operation. Reconciliation must be made at the end of the process, and any discrepancies investigated.
5.3.4 Obsolete labels and packaging material must be destroyed.
5.3.5 The use of printing devices used to print labels must be controlled through standard operating procedures to ensure that imprinting conforms to the print specified in the production record.
5.3.6 Printed labels must be carefully examined for proper identity and conformance to the specifications in the master label record. Results of the examination must be documented.
5.3.7 A copy of each type of pre-printed label used must be kept in the production record.
5.4 Packaging and labeling Operations for IMP – General
5.4.1 Material status must be clear. It can be written/printed on the label or, when a validated computerized inventory system is used, can be in encrypted form on the label. The description and batch number should always be present in human readable form, except in the case of blinded materials where different controls apply (see Section 5.4.8).
5.4.2 There must be documented procedures to ensure that correct packaging materials and labels are used, including specific procedures for the generation, handling and approval of master labels.
5.4.3 Label operations must be designed to prevent mix-ups. There must be physical or spatial separation from other unlabelled materials/batches.
5.4.4 Within the EU, or where required elsewhere by local regulations, material with an expiration or retest date should include this information on the label. In the US, the expiry date is not required to be on the label, and can be supplied on the certificate of analysis.
5.4.5 Packaging and labeling facilities must be inspected immediately before use to ensure that materials not needed for the next operation have been cleared from the area. This examination must be documented in a logbook and/or the production record.
5.4.6 Packaged or labeled materials must be examined to ensure that they have the correct label. This examination must be part of the packaging operation and must be documented in the production records.
5.4.7 Procedures must be in place to describe the generation, distribution, handling and retention of any randomization code used for labeling investigational product, where these activities are controlled by R&D.
5.4.8 A system must be in place to allow for identification of any blinded investigational medicinal product. The system must allow for the identification of the product, any necessary traceability codes, and the batch number of the blinded product to be readily ascertained.
5.5 Packaging and labeling Operations – Intermediate IMP, Bulk IMP and Bulk Packaged IMP
5.5.1 The following sections apply to Bulk Packaged IMP if the labeling operation is not continuous with packaging.
5.5.2 Intermediate, Bulk and Bulk Packaged IMP must be labeled as soon as possible during processing, with at least the following information:
– Batch number
– Product name/code
– Storage conditions, when such information is critical to ensure quality
– Material status (written or encrypted)
5.5.3 If Intermediate, Bulk or Bulk Packaged IMP is to be transferred outside the control of the site’s material management system, the name and address of the manufacturing site, quantity of contents, special transportation requirements, if any, and any special legal requirements must be included on the label in addition to the information listed in Section 5.5.2. This information must be included with the shipment if individual units are not labeled (see Section 5.5.4).
5.5.4 It is not required that individual units of Bulk Packaged IMP be labeled prior to transportation to another site for further processing. The storage and transportation of individual, unlabelled Bulk Packaged IMP should have specific controls written into Standard Operating Procedures to prevent mix-ups.
5.6 Packaging and labeling Operations – Packaged Investigational Medicinal Product
5.6.1 Labels must be designed so that the information and language on the labels satisfies local regulatory requirements.
5.6.2 Labels used in a blinded study must be checked to ensure that they look identical throughout the labeling run, e.g. positioning of label text.
5.7 Retest/Expiry Date Extension of Packed Investigational Medicinal Product
5.7.1 In the case of retest/expiry date extension, an additional label must be affixed to the packed Investigational Medicinal Product (note that retest/expiration dates are not required to be included on the label for US clinical supplies, and can be supplied with a certificate of analysis).
5.7.2 This additional label must include the new retest/expiry date and the batch number.
5.7.3 The new label may be superimposed on the old retest/expiry date, but not on the original batch number.
5.7.4 This labeling operation may be performed on the study site by the clinical trial monitor or the clinical trial site pharmacist, in accordance with specific procedures and under contract, if applicable. The operation should be checked by a second person.
5.7.5 Documented evidence of this additional labeling must be available in the trial documentation and in the local study master file.