1. Purpose
The purpose of this guideline is to describe the way that packaging operations should be conducted.
2. Scope and Applicability
This guideline is applicable to any manufacturing sites, its joint ventures, licensees and contract manufacturers performing packaging and re-packaging, including re- labeling and changing of leaflets.
3. Definitions
3.1 Finished Product
A product which is packaged and labeled for supply to a wholesaler, hospital, pharmacy, doctor or patient.
3.2 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.
3.3 Primary Packaging Material
The packaging which is in direct contact with the Formulated Product, Intermediates, Excipients & APIs (includes Devices for delivering dosages).
3.4 Secondary Packaging Material
The packaging which is not in direct contact with the Formulated Product, Intermediates, Excipients & APIs – usually contains the Primary Pack.
3.5 Bulk Formulated Product
A pharmaceutical product (Formulated Drug/Formulated Product) held in large intermediate or shipping containers and ready to be filled into primary containers.
3.6 Repackaging Operations
The activities required to replace, or add to, the primary and secondary packaging included in a finished product to meet a specific market need, or to replace faulty/obsolete primary or secondary packaging, e.g. tablet blisters, patient leaflets and cartons.
3.7 Over-labeling
The addition of a label, usually to a primary pack or carton, to obscure the original labeling and supersede it with the text on the added label.
3.8 Component
Secondary packaging components essential to the function or stability of the product, although not in direct contact with the product, should be regarded as primary materials or components. Examples include blister packaging of single dose pipettes (needed for stability), ampoules stated to be sterile on the outside, needle covers of syringes, inks for print on primary plastic containers, capping for stoppers etc.
3.9 Primary Packaging Operation
The activities required to fill the bulk formulated product into primary containers and seal or fit closure. This includes addition of desiccants, wadding, etc., if contained within the sealed/closed primary pack. In the case of sterile products, the primary packaging operation is carried out as an integral part of the manufacturing operation. In the case of non-sterile products, the primary packing operation may be discontinuous with the manufacture of the bulk formulated product, and may be done in a different facility/site. The primary packaging operation may include the addition/attachment of the legal labeling to the primary container.
3.10 Secondary Packaging Operation
The activities required to convert a primary packaged formulated product to a finished product. It embraces the addition/attachment of the legal labeling to the primary container (if not done at the end of the primary packaging stage) and inclusion of the patient leaflet. It may include applying/inserting additional patient information materials, inserting the primary container/patient leaflet into a tray/carton and over wrapping the tray/carton.
4. Responsibilities
Each site carrying out primary, secondary packaging and/or repackaging operations on commercial products should have a written procedure, consistent with this guideline, to describe the way packaging operations will be conducted and documented at the site.
5. Guideline
5.1 General Aspects
5.1.1 The packaging operations should comply with official GMP requirements and any other additional company requirement covered in this Guideline or in other documents authorized by the company.
5.1.2 Packaging operations should be conducted in suitable buildings, facilities and conditions. The facilities should provide appropriate environmental protection, segregation and containment for the products being packaged, so as to eliminate the risk of cross contamination, mix ups and/or substitutions.
5.1.3 There should be a Master Batch Packaging Record for each product to be packaged, and packaging batch specific copies made from these.
5.1.4 All commercial finished products should bear a batch number and an expiry date on both primary container labels and cartons.
5.2 Handling of Printed Packaging Materials
5.2.1 Printed packaging materials should be stored and transported in closed containers identified by name, code number and control number.
5.2.2 Printed packaging materials should be stored in secure areas. Additional security measures may be necessary when storing or transporting packaging components used for high value products, particularly components containing anti- counterfeiting devices e.g. holograms.
5.2.3 To minimize the risk of mix-ups, bar-coded roll labels should be used whenever possible, and the bar codes should be read on line just prior to adherence to the primary container.
5.2.4 Over printing of labels and cartons with batch number and expiry date should preferably be performed on line.
5.2.5 If not overprinted on line, packaging materials should be overprinted in a partitioned area. The operation should be documented. Line clearance procedures should be applied also to the overprinting operation.
5.2.6 Specimens of all printed components used should be added to the Batch Packaging Record. Note: When overprinting is made on line, this includes a specimen of the overprinted labels.
5.2.7 Excess overprinted packaging materials should be destroyed as soon as possible. Excess packaging materials not overprinted may be returned to store, only if identified by code number and control number and if the integrity of the material during handling is ensured. The return should be recorded.
5.2.8 All printed packaging materials must be accounted for at receipt and during usage.
5.3 Handling of Bulk Formulated Product
5.3.1 The packaging operation may be started before the bulk formulated product has been released by Quality Assurance/Quality Control. See Section 5.9.
5.3.2 Packaging of products of similar appearance in close proximity to one another should be avoided unless there is adequate physical segregation of the packaging operations.
5.3.3 Special attention should be paid to the risks involved in handling and storing of filled but not yet labeled products. During intermediate storage such products should be stored in closed (preferably sealed) and labeled containers.
5.4 Start-up Inspection (including Line-Clearance)
5.4.1 Before starting a packaging operation an inspection should be made and documented in the Batch Packaging Record comprising: Line clearance of the packaging and labeling facilities to check that drug products, packaging materials and documents from previous operations are removed. The line clearance procedure should be double-checked. Concerning check-lists for line clearance. A check of the identity of bulk formulated products and packaging materials against the material list in the Batch Packaging Record. (If a manual identity control is performed it should be double-checked.) A check of the quantity of bulk formulated products and printed packaging materials against the Batch Packaging Record. The quantities should be double-checked. A check of the first packaged item to verify e.g. overprinting, content, appearance, closure.
5.4.2 The name and batch number of the product being handled should be displayed at each packaging station or line.
5.4.3 Containers for filling should be clean before filling. All contaminants, e.g. glass fragments and metal particles, should be avoided.
5.4.4 If a packaging operation is not completed within a working day, appropriate steps should be taken to protect the integrity of the product and packaging materials, and prevent product, materials and documents from being removed from the line.
5.5 In-Process Controls
5.5.1 Checks should be made to ensure that any electronic code readers, label counters or similar devices are operating correctly.
5.5.2 During the packaging operation in-process controls should ensure that the packaged product is in accordance with set standards and specifications. These should include: General appearance and completeness of the packages Integrity of seals and closures Fill quantity Correctness and clarity of overprinting and embossing Correct functioning of line monitors Continuity of bulk formulated product and packaging material identity and quality General checks on tidiness/cleanliness of the packaging line and surrounding area
5.5.3 Packed or partially packed product that has been removed for examination, or involved in a deviation, should be reintroduced to the packing operation only after special inspection, investigation and approval by authorized personnel. Note: this should be allowed only if the product has not been removed from the immediate vicinity of the packaging operation.
5.6 Labeling of Primary Packed Product
Filling and sealing should be followed as quickly as possible by labeling of the primary container, including a batch number and expiry date. If the fill/seal and primary labeling operations are discontinuous, the primary containers should be marked with a unique identification code (whenever possible), and secured in containers which are each marked with the name, dose/strength, quantity of primary containers and batch (lot) number.
5.7 Reference Sample
Reference samples of finished products should be drawn according to an established sampling plan.
5.8 Yield Calculation and Reconciliation of Materials
5.8.1 After completion of the filling, packaging and labeling operations a comparison should be made between the quantity of printed packaging material items issued and the quantity of such items used as: Accepted, labeled and packaged units Samples Rejected labeled units and the number of items not otherwise used.
5.8.2 There should be procedures for yield calculation for each packaging operation, based on the quantity of bulk formulated product and number of primary containers filled (primary packaging operations), the quantity of packaging components used and secondary packed units produced (secondary packaging operations).
5.8.3 The results should be entered in the Batch Packaging Record. Discrepancies from pre-set deviation limits should be carefully investigated and recorded. The material should not be released until an acceptable explanation of the discrepancy has been reached.
5.8.4 Excess overprinted packaging materials should be handled as described in Section 5.2.7.
5.9 Handling of Finished Product
5.9.1 Packaged finished product should be quarantined until released by Quality Assurance/Quality Control. This does not preclude shipment between quarantined sections of non-contiguous warehouses, providing that the product stays within the control of the company.
5.9.2 The release procedure should be formalized and include: A check on the status of the bulk formulated product if packaging was initiated ahead of release. An evaluation of the Batch Packaging Record. A check that all printed components are the approved versions for distribution in the markets concerned A check that finished product has not been released from the site to the markets concerned with later approved versions of printed components. If this is the case finished product with superseded printed components must be repackaged (see Section 5.10).
5.10 Repackaging
5.10.1 The number of repackaging operations should be kept to a minimum.
5.10.2 Repackaging should be carried out in accordance with the requirements for normal packaging operations and repackaged product should pass through a formal release procedure.
5.10.3 Over-labeling of finished products should not be performed. Addition of e.g. price information or similar is allowed. Original labels should not be removed.