GMP Packaging and Labeling Control

MATERIALS EXAMINATION AND USAGE CRITERIA

(a)    There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.

(b)    Any labeling packaging materials appropriate written specifications may be approved an release for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.

(c)    Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.

    The terms labeling and packaging in the context of this section specifically exclude containers and closures, which are covered in Subpart E; advertising and promotional material are not subject to GMP regulation. However, unlabeled packaging such a corrugated shippers and dividers are to be included, although the evaluation and control may not need to be so extensive.
   
Labels and labeling errors have been the most frequent reason for product recall in recent years. The effective control of printed labeling (labels, inserts, cartons, foil) commences well before materials are ordered; it starts at the design and approval stage. For new or changed labeling there must be in place a procedure that clearly defines:

1.    Who is to review and approve the copy. This will usually include marketing, medical, legal, regulatory affairs, production, materials management, quality assurance, and editorial.
2.    What each function is to check and approve. With so many people involved, individuals may be tempted to assume that someone else has checked the various points. A typical system might include the following detailed responsibilities:
a.    Materials management – evaluate inventory situation, identify an implementation date that will comply with regulatory or company requirements while minimizing stock write-offs or production interruptions. Identify which countries take this product so that Regulatory Affairs can evaluate any regulatory requirements and potential impacts, including potential delays in implementation.
b.    Production – confirmation that equipment is available, or will be to introduce the change; adequate space for batch coding and expiry dating.
c.    Marketing (or other function) – identify whether the specific change will require modification to other materials, e.g., changes to a label may require changes to inserts and cartons – identify whether other pack sizes may need to incorporate the same or equivalent change.
d.    Medical – confirmation that any medical claims, warnings, dosage are correct.
e.    Legal & Regulatory Affairs – confirmation that the changes meet all legal and regulatory requirements in all countries that sell the product.
f.    Technical Service & Quality Control – identify any stability issues (primary pack changes).
g.    Editorial – to confirm grammatical correctness and absence of typographic and print errors or omissions.
h.    System Manager – to confirm that all appropriate approvals have been given and in the event of queries to recirculate through the system if necessary.
3.    Whether the change is mandatory or voluntary and the date of introduction. For voluntary changes this is likely to relate to depletion of inventories of existing labeling.
4.    Whether the labeling in question is interrelated with any other labeling and to note any impact. For example, a change to the dosage requirements on a label will almost certainly require amendment to inserts and cartons.
5.    The reviewers and approvers (item 1) should preferably be defined by name. Since the approval process is so important, it is essential that approvers have undergone adequate training in the system. Additional individuals should not be allowed to authorize new labeling or changes without having undergone this training.
6.    The feedback loop that confirms that the change has actually been introduced.
7.    A unique numbering system that clearly distinguished between labeling for different products and strengths and also between different versions of the same labeling.
8.    Ownership of the procedure. As with any system or procedure but especially one that involves so many people, there should be designated responsibility for operation and monitoring of the system itself. This individual should routinely identify any potential weaknesses in the operation of the system and have them corrected.
    Gang printing consists of printing different labeling on the same sheet and then cutting and separating the different labeling. This technique has high potential for mix-up during the cutting and separating stages, and most pharmaceutical companies now avoid this approach.

LABELING ISSUANCE
(a)    Strict control shall be exercised over labeling issued for use in drug product labeling operations.
(b)    Labeling conformity to the labeling specified in the master or batch production records.
(c)    Procedures shall be written describing in sufficient detail the control procedures employed for the issuance of labeling; such written procedures shall be followed.
(d)    procedures shall be utilized to reconcile the quantities of labeling issued, used, and returned, and shall require evaluation of discrepancies found between the quantity of drug product finished and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data. such discrepancies shall be investigated. Labeling reconciliation is waived for cut or roll labeling if a 100% examination for correct labeling is performed
(e)    All excess labeling bearing lot or control numbers shall be destroyed.
(f)    Returned labeling shall be maintained and stored in a manner to prevent mix-ups and provide proper identification.

PACKAGING AND LABELING OPERATIONS
    There shall be written procedures designed to assure that correct labels, labeling and packaging materials are used for drug products; such written procedures shall be followed. These procedures shall incorporate the following features:
(a)    Prevention of mix-ups and cross-contamination by physical or spatial separation from operations on other drug products.
(b)    Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots. Identification need not be applied to each individual container but shall be sufficient to determine name, strength, quantity of contents, and lot or control number of each container.
(c)    Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch.
(d)    Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch production record.
(e)    Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations. Inspection shall also be made to assure that packaging and labeling materials not suitable for subsequent operations have been removed. Results of inspection shall be documented in the batch production records.