A. Instructions for Filling, Labelling and Packaging Pharmaceutical Drug Products and API’s for Commercial Purposes

B. Creation, Revision, and Approval for Artwork Used on Packaging Components

C. Receipt, Approval, and Use of Labels and Labelling

D. Container Closure Integrity for Sterile Drug Products

E. Packaging System Integrity for Sterile Medical Devices

1. Instructions for Filling, Labelling and Packaging Pharmaceutical Drug Products and API’s for Commercial Purposes

This document describes the preparation, approval and maintenance of Master Packaging Order (MPO) and Lot Packaging Batch Order (PBO) for Active Pharmaceutical Ingredients (API) and Drug Products manufactured by a GMP Manufacturing site.

Instructions for the direct packaging of APIs from final processing and isolation, into bulk Containers for use or sale without further packaging, will be included with the API Manufacturing Instructions.

If an API is repackaged into other containers and/or relabeled, such as for commercial sale or other internal uses, those activities are subject to the requirements in this practice document.

–           MPOs for APIs shall comply with the Regulatory Process Description (RPD) that is filed with the Regulatory Authorities for the product market(s).

–           MPOs for Drug Products shall comply with the Composition and Manufacturing Description (CMD).

–           An MPO shall be prepared for each product, package size and type by Qualified personnel and approved by the Site Production Team and Site Quality Team.

–           Each MPO shall:

* Contain a unitized component list [e.g., Bill of Materials (BOM)];

* Specify package size and type; and

* Specify the acceptable ranges (expressed as percentages) of Actual Yields and Accountabilities.

–           Each MPO must be complete, accurate, and describe in a logical order the sequence of activities necessary to fill, Label,and package the product.

–           MPOs and PBOs shall be maintained under change control according to the Site Standard Operating Procedures (SOP).

–           MPOs shall be maintained under document management to ensure that only one approved master exists for each product, package size, and type for each standard lot size at a time.

–           A PBO shall be prepared for each packaging lot and shall specify the Batch or lot size. Each PBO shall be Verified by a qualified person to be an accurate reproduction of the MPO.

For validated systems that make reproductions of the MPO, this verification by a qualified person is not necessary, as it is covered by validation of the system. The verification can be replaced by a check on the legibility of the printout.

–           Deviations from MPOs or PBOs shall be Investigated and documented.

–           A System shall be established at each Site to retain MPOs and Batch Records (i.e., PBOs) according to site record retention requirements.

–           Computerized Systems Used to Prepare MPOs and/or PBOs using Electronic Records and Electronic Signatures must be Validated.

–           Each MPO must list or reference:

* Stepwise filling, labelling, and/or packaging operations, including Process Parameters and Normal Operating Ranges (NOR);

* Package size in terms of weight, number, or volume;

* Product name, strength, dosage form, and reference code;

* Definitions of all packaging/labelling materials needed, including quantities (unitized), sizes, types, and reference codes;

* Major Equipment and packaging lines to be used;

* SOPs or instructions for equipment or critical component preparation, cleaning, set-up, and operation, as required;

* Statement of Theoretical Yields or accountabilities at key stages for product and printed Packaging Materials;

Acceptable yield variation limits for product and printed packaging materials; outside of which a Quality Assurance (QA) Investigation is needed;

* In-Process Controls (IPC) and corresponding limits, and frequency;

* Work-In-Process (WIP) packaging (e.g., bulk that are package at other Sites) if required; (Each MPO must list or reference – continued from prior page):

* Sampling and testing procedures or references to same;

* Time limits and environmental condition limits where relevant to quality of Intermediate materials or product;

* Special precautions, if any;

* Line clearance instructions;

* Instruction for retention of applicable records and batch documentation; and

* Provision for the document to be signed and dated by persons responsible for the PBO operations.

–           Each MPO shall be approved by Production Team and by Quality Team using full, legible, handwritten signatures or equivalent electronic signatures.

–           MPOs shall include the date of each approval and effective date.

–           Each Lot PBO shall be prepared as follows:

 *          An accurate copy is made of the MPO;

*           The Lot Number and lot size is defined (e.g., quantity of API or number of final packages to be produced);

*           Quantity and lot number of each component is calculated and printed on the PBO, based on the defined lot size; and

*          The resulting PBO is verified, signed, and dated by a qualified person.

*            The approved PBO is used to collect original PBO data and, when completed, becomes an integral part of the Lot Record.

–           All Products and Packaging Components are to be inspected upon receipt into the filling, labelling, or packaging area and verified against the PBO.

–           Reference Codes on labels and labelling must match the reference codes listed on the MPO and PBO.

2. Creation, Revision, and Approval for Artwork Used on Packaging Components

–           This practice document defines the process for the preparation and approval of artwork used in the packaging of Drug Products and Medical Devices, from creation of the artwork through receipt at the plant of Master Labelling and printing.

–          This practice document applies to any GMP site with responsibilities for the preparation and approval of artwork for preprinted packaging components used in the packaging of marketed drug products and medical devices or Professional Samples.

–           This document does not address promotional materials that may contain legal Labelling.

–     An Editor’s Copy (EC) must be prepared by a Qualified market representative and provided to Artwork Center colleagues for new or revised artwork. The EC must be complete and correct in content and format.

–           Artwork staffs are Responsibilities include, and are not limited to:

* Review of the EC for clarity and addressing any open issues;

* Preparation of labelling, graphical elements, layout (e.g., dimensions), and color of printed packaging components;

* Forwarding the locked electronic file or hardcopy output of the artwork (i.e., draft master labelling) to the Market colleagues (e.g., medical, legal, regulatory, marketing) for approval;

* Preparation of final master labelling and forwarding master labelling to the Printer;

* Review and approval of Printer Proofs, if required; and

* Assignment of identification number to the artwork for version control.

     –      Market Colleagues are responsible for proofreading the new or revised artwork against the EC and approving the artwork. Proofreading shall include, but is not limited to, Verification of the following:

*           Character to character;

*           Graphic elements (e.g., graphs, charts, colors, logos, barcodes, placement); and

*           No unexpected changes occurred.

A procedure shall be available in each market that defines the roles and responsibilities of the market colleagues and the purpose of their approval related to proofreading artwork.

Market colleagues shall not approve artwork if further changes are expected, except for minor Production related changes generated at the Site.

     –      A Multidisciplinary (e.g., Medical, Legal, Regulatory, Marketing, Quality) Review of the Artwork Content shall be performed and the artwork content verified for correctness based on available product information and governing regulations. Grammar, syntax, and if required, Braille text, shall be reviewed for correctness.

     –      Labelling and Packaging Component Printers must be approved and a Quality Agreement must be in place.

     –      Artwork Center Colleagues must receive a clear, legible and correct Editor’s Copy from the market colleagues before they can proceed with the artwork changes.

For EC changes generated at a Site, the EC may be developed by the Site colleagues.

Minor production related changes to the artwork can be made without market colleagues’ approval provided there is a written agreement from the market colleagues. Examples of minor production related changes may include the addition of relevant barcodes, color bars, or minor repositioning of copy for improved printability.

Changes to the EC generated at a Site must be clearly marked on the EC, initialed by the person making the change, and dated. Artwork Center colleagues must proofread such changes as part of the Artwork Center’s responsibility.

–           Artwork shall be created or revised electronically by Artwork colleagues based on the EC. Upon finalization, the electronic artwork shall be locked such that the artwork cannot be manipulated while it is in the review process. The output of the electronic artwork is generated from the locked file and compared to the EC.

A procedure shall be available at each Artwork Center for assigning version numbers to the master labelling.

     –      Artwork Center Colleagues shall review the new or revised artwork against the EC to ensure:

*           There are no omissions or changes from the EC. This review may be

*           performed either manually or using electronic systems; and

*           Artwork is graphically and technically correct.

     –      Artwork Center Colleagues must receive the signed copies of the final artwork from the responsible market colleagues indicating approval by a multi-disciplinary (e.g., Medical, Legal, Regulatory, Marketing, Quality) review of the artwork content.

Electronic Signatures are allowed if the system is Validated and compliant with electronic signature and Electronic Record requirements.

–           Master Labelling(s) shall be generated and maintained by the Artwork Center colleagues, after receipt of the artwork approval. The master labelling must match the artwork that was approved by the market colleagues as well as the result of any minor production related changes executed after market colleague approval.

Master labelling may be hard copy output or electronic, if generated and housed within a validated system, which is compliant with electronic signature and electronic record requirements. The master labelling shall be sent to the

Printer. A copy of the master labelling shall also be sent to the responsible Site Quality Team to be used for inspecting and releasing materials.

When an electronic version of the artwork is sent to the Printer for plate preparation, the responsible site colleagues shall make it explicitly clear that if Printer’s proofs are not requested by the Artwork Center colleagues, it is the Printer’s responsibility to ensure the print plates and resulting printed components accurately reflect the content of the master labelling.

–           If a Printer’s Proof is Required by Market or Artwork Center colleagues prior to printing, the Artwork Center colleagues must define the allowable types of proofs in advance:

* The Printer is not permitted to start printing prior to receiving approval that the Printer’s proofs are acceptable; and

* The Artwork Center colleagues must review and approve the Printer’s proofs to ensure they accurately reflect the electronic artwork and market colleagues’ expectations;

–           No unapproved differences or changes;

–           Subjective aesthetics are acceptable (e.g., print readability, color preparation, gradations); and

–           Print quality.

Market colleagues may also be asked by Artwork Center colleagues to review the Printer’s proofs.

3. Receipt, Approval, and Use of Labels and Labelling

–           Labels (Product) and Labelling shall be printed, received, stored, used, and reconciled according to procedures Approved by the Site Quality Team and the Site Production Team designed to prevent label mix-up or mislabelling.

     Note-Blank Label Stock, whether or not preprinted, that has no product specific information is not defined as labels or labelling. Blank stock items are Packaging Materials subject to all approved controls for packaging materials but not to the additional controls required for labels and labelling.

Master Labelling Copies and Master Labelling shall be created and approved according to site procedure. Packaging validation needs to be performed.

–           This practice applies GMP Production Sites and operations responsible for the receipt, approval, and use of labels and labelling for Active Pharmaceutical Ingredients (API), Medical Devices,and Drug Products.

–           Production Use of Unapproved Labels or Labelling is prohibited.

–           Use of Gang-Printed Labelling should be permitted for individual folding cartons (IFC) provided that there is a 100% inspection by a bar code reader at the label manufacturer and the packaging site. The use of gang printed labelling is prohibited for:

* Cartons with Braille,

* Primary labels, and

* Any IFC’s used to package products shipped to the United States unless the IFCs from gang-printed sheets are adequately differentiated by size, shape, or color.

–           On-Line Labelling Operations for Pharmaceutical Products must use product Container roll labels except for low volume products where Cut Labels can be used with Quality approval.

–           Computerized Systems used for printing and reconciliation (i.e., Accountability) of labelling shall be Validated.

–           Labelling Control Practices at Contract Vendors shall be addressed in the Quality Agreement.

–           Printing or Embossing on labels and labelling, including on-line Coding, shall be distinct, fade resistant, and resistant to erasure.

–           Label Shipments shall be inspected and the amount received determined by

Materials Management personnel or the Site Quality Team, upon delivery.

Inspection shall determine that packaging of the shipment meets site requirements and that packaging integrity of the labelling has not been compromised. The amount received shall be determined according to an approved Standard Operating Procedure (SOP).

–           All Labels and Labelling Materials Received shall be examined and tested by the Site Quality Team to determine conformance to Specifications. Examination shall include detailed comparison with an approved copy of the master for the labelling. Samples shall not be returned to stock.

–           Complete Records of Receipt and Disposition shall be kept for each shipment of each Lot of labels and labelling and shall include:

* Documentation of visual inspection of each shipment for packaging integrity;

* Dates of receipt and approval and names of the Qualified personnel performing the receipt and inspection activities;

* Supplier name and Lot Number;

* Identity of the material, including site Label Revision Number;

* Individual quantity and number of containers received;

* Specimen of the inspected label or labelling;

* Packaging Material Lot Number and any site terminology, if different from suppliers;

* Name of manufacturer, if different from supplier, and manufacturer lot number; and

* Results of examination and any testing required to ensure conformance to specification.

–           Storage of Labels and Labelling (including laser masks, rubber mats, and items related to labels and labelling that contain product information) shall include:

* Storage in a continuously secure manner in a Limited Access Area or Restricted Access Area qualified personnel;

* Restricted access areas shall be used to store individual container labels and API shipping container labels. Other labelling shall be stored in limited areas; and

*  Segregated storage by labelling lot number with proper identification provided for labels and labelling for each different product, strength, dosage form, quantity of contents, or other differentiating factors.

–           Transport and Handling of Labels and Labelling, including laser masks, rubber mats, and related items with product information shall be performed in a manner designed to maintain the security and limited access to the labels and labelling, and shall include, and not be limited to:

* Transport of printed labelling (e.g., roll labels, cut labels, preprinted glass cartridges) in properly identified, separate, and sealed containers;

* Handling practices that maintain the unitized packaging of labelling (e.g., only a single preprinted lot number shrink-wrapped on a single pallet);

* Prohibiting return of labels or labelling with lot codes or other batch-specific information to stock after completion of the Batch. Such items shall always be destroyed;

* Segregation of labels and labelling that are assigned Reject or Quarantine-Hold status until disposed and Segregation of outdated or obsolete labels until disposed.

Label and Labelling Issuance for Use in Production shall be strictly controlled and performed only by qualified personnel to other qualified personnel. The issuance and receipt of labels and labelling are recorded in the Packaging Batch Records.

–           Each Laser Mask, Rubber Mat, and/or Related Items with Product, Lot/Batch, Manufacturing Date or Expiration Date Information must be verified against the Packaging Batch Order (PBO).

–           Verification of Labels and Labelling Identification and Quantity shall be performed upon delivery to the packaging area and shall be recorded in the Packaging Batch Record. Verification shall include identity, quantity, and conformance to batch record requirements. Verification of quantities shall be performed by comparing the quantities received on the packaging line against the quantities listed in the Packaging Batch Order.

–           If Labels or Labelling are Not Immediately Transported to the Packaging Line After Issuance, (e.g., secured within a common staging area servicing several packaging lines) systems and/or controls must be employed to ensure the labels are securely stored and there is adequate spatial or physical separation to prevent mixing of labels and labelling items staged for different lots or batches.

–           Reconciliation of Labels and Labelling Used for a Lot/Batch shall be performed by one person from Site Production Team and verified by second person. Reconciliation calculations shall be verified by Site Quality Team as part of Batch Record review. Reconciliation shall compare the actual quantity used, (including samples), actual quantity returned to stock (where permitted), and quantity destroyed, against the quantity issued. Reconciliation results shall be kept with the Packaging Batch Records.

–           Reconciliation may be waived for cut or roll labels or labelling when on-line one hundred (100) percent electronic label or labelling verification is performed. When such verification is not done for any portion of a lot, reconciliation shall be performed.

–           Discrepancies in Reconciliation or Yield Tolerances, which exceed acceptable limits, shall be investigated, any impact on product quality determined, and corrective actions taken, when necessary.

–           Physical Barrier or Spatial Segregation shall be maintained between different packaging and labelling operations.

–           Packages Removed From the Module or Defined Packaging Area as Samples or for any other reason shall not be returned to the lot or batch.

–           Units Completing the Packaging/Labelling Operation shall be inspected:

* At the beginning of the batch or lot;

* At the completion of the batch or lot;

* At the beginning of a shift;

* At the end of a shift;

* Periodically [maximum of four (4) hours between inspection]; and

* After maintenance or changes that might impact labelling quality. Inspection attributes include, at least, the following:

* Correct label and labelling and revision as specified on the Packaging Batch Order;

* Label adhesion;

* Correct coding;

* Correct appearance; and

* Proper packaging and labelling, as defined in the labelling instructions in the Packaging Batch Order.

The Site Quality Team shall approve the entire inspection procedure prior to use.

–           Proper Functioning of Equipment such as label verifiers, code readers, label counters, printing equipment, and coding equipment shall be checked and recorded at startup and at the end of labelling operations, and after any change or maintenance activity during the run on that piece of equipment. All packaging and labelling equipment shall be qualified, and all control systems and packaging operations shall be validated prior to use.

–           Off-Line Packaging, Hand Printing, or Coding Operations shall employ the same types of controls as on-line operations including cleaning, inspection, staging, checks before and during operations, return to storage, accountability, and material removal at completion.

–           Filling and Sealing shall be followed by labelling. If labelling cannot be performed immediately, filled and sealed containers shall be segregated for labelling at later time.

–           Unlabeled Filled Drug Products must be properly identified and stored in a limited access area. Identification does not have to be on each drug product container but must be sufficient to determine name, strength, quantity, and lot or control number of all containers involved.

–           After the Completion of the Packaging of a Lot/Batch, Excess Labels, and Labelling Materials shall either be returned to the storage area or destroyed. Cut labels or labelling shall only be returned to the storage area in unopened, unitized containers as received from the labelling supplier. Excess labels or labelling materials coded with lot number or other identification specific to a lot/batch shall be accounted for and destroyed.

–           Copies of all Labels and Labelling Materials used to package a lot shall be retained in the Batch Records for that lot. At a minimum, copies of all labelling shall be collected from the beginning of the packaging operation and consideration shall be given to collecting additional samples when the following events occur:

*           Roll splices,

*           Roll changes,

*           Shift changes, and

*           Maintenance or work interruption.

–           Obsolete and Out-of-Date Labels and Labelling Materials shall be expeditiously destroyed. Complete records shall be kept of the types and quantities destroyed.

–           Off-Line Hand Labelling, Label Removal, and Similar Non-Automated Operations must be given special attention and specifically approved by the Site Quality Team and Site Production Team.

–           Cut Labels shall be verified by, at least, one of the following methods:

* One hundred (100) percent electronic/electromechanical verification system; or

* One hundred (100) percent visual inspection with the examination performed by one person and independently verified by a second person. Electronic/electromechanical verification systems must be

designed to reject the container or stop the labelling operation if a label cannot be positively verified (i.e. failsafe).

4. Container Closure Integrity for Sterile Drug Products

–           The Suitability of All Container Closure Systems for Sterile Drug Products manufactured and/or packaged by the site shall be determined.

–           The Effects of Environmental Stresses, Handling, and Simulated Use on Container Closure suitability shall be determined for new or changed container closure systems.

–           The Container Closure Sealing Process for sterile drug products shall be Validated to ensure that the integrity of the container closure system will protect the product over its shelf life.

–           Written and Approved Standard Operating Procedures (SOP) shall describe packaging/sealing equipment set-up, operation, and maintenance. Equipment and systems used in the sealing processes for packaging sterile drug products shall be qualified or validated.

–           Validation Studies shall be conducted by Qualified personnel and shall be documented.

–           Critical Process Parameters and Critical Process Parameter Ranges that affect container closure integrity shall be identified during the validation process for each container closure configuration.

–           The Microbial Ingress Test shall be used to validate the integrity of the container closure system. The immersion method shall be used unless another method is justified (e.g., aerosol method).

–           Non-Microbial Methods for Container Closure Integrity Testing [e.g., Residual Seal Force (RSF)] shall be used during routine production and shall be correlated to the microbial ingress test. In-Process Control (IPC) sampling for container closure integrity testing shall be representative of the packaged lot. Sampling and test procedures shall be written and approved.

–           Action Levels and Specifications for Non-Microbial Methods for Container Closure Integrity Testing shall be established and validated for drug products sealed in glass vials having elastomeric closures.

–           Product Containers Sealed by Fusion (e.g., Glass and Plastic Ampoules) and Form-Fill-Seal (FFS) shall be one hundred (100) percent integrity tested.

–           Product Packaged to Maintain Vacuum or Gas Headspace shall be tested for maintenance of the vacuum or gas headspace at specified intervals over the product shelf life.

–           Stability Samples shall be tested for container closure integrity over the shelf life of the product and at Batch/Lot Expiration Date.

–           Instruments and Elements (I/E) used to monitor, control, or test container closure integrity shall be Calibrated according to an approved schedule.

–           Packaging Materials shall be purchased from Approved Suppliers and received in the same manner as Raw Materials (RM). Testing and release requirements for these materials shall be defined by specifications and include, and not be limited to, dimensional tests.

–           Changes to the Process for Packaging Components by the Component Manufacturer shall be evaluated by the Site Quality Team to determine the potential impact on container closure integrity. The Site Quality Team shall consult, as necessary, with principals from, and not limited to, the following:

*           Regulatory Affairs (RA),

*           Site Production, and

*          Site Packaging Design and Development.

Changes to the container closure system, which require regulatory approval or notification shall be managed through the Product Change Proposal (PCP)/Product Change Request (PCR) system.

–           Failure to Meet the Established Container Closure Integrity Specifications shall result in a Quality Assurance (QA)Investigation.

5. Packaging System Integrity for Sterile Medical Devices

–           This practice document defines the requirements for determining the suitability of Packaging Materials and the evaluation and testing of the integrity of Packaging Systems for Sterile Medical Devices manufactured and/or packaged by GMP sites.

–           This practice applies to GMP Production Sites and operations responsible for producing sterile medical devices for Pharmaceutical or Animal Health.

–           The Effects of Environmental Stresses, Handling, and Simulated Use on packaging system suitability shall be determined for new or changed packaging systems.

–           The Packaging System Sealing Process for sterile medical devices shall be Validated to ensure that the integrity of the package will protect the product over its shelf life.

–           Written and Approved Standard Operating Procedures (SOP) shall describe packaging/sealing equipment set-up, operation, and maintenance. Equipment and systems used in the sealing processes for packaging sterile medical devices shall be Qualified or validated.

–           Validation Studies shall be conducted by Qualified personnel and shall be documented.

–           Critical Process Parameters and Critical Process Parameter Ranges that affect the packaging system integrity shall be identified during the validation process for each package configuration. These critical parameters and ranges shall be defined and provided in an SOP, and shall be controlled and monitored.

–           In-Process Controls (IPC) sampling and testing procedures for verifying packaging system integrity shall be written and approved. IPC sampling for packaging system integrity testing shall be representative of the packaged lot.

–           The Final Sterile Medical Devices Packaging System shall be evaluated or tested to validate the integrity of the packaging system, using one of the following methods:

*           Visual inspection;

*           Microbial barrier properties testing;

*           Seal/closure evaluation; or

*           Physical testing.

–           Seal Integrity shall be sufficient to demonstrate that the seal is impermeable and continuous by using physical tests. Physical or non-microbial methods for packaging system integrity testing shall be used during routine production. Such physical testing together with microbial barrier property testing of materials establish the sterile packaging system integrity.

–           The Microbial Barrier Properties of Packaging Materials shall be evaluated using one of the following two methods:

*           Methods for impermeable materials; or

*         Methods for porous materials.

–           The Microbial Challenge Method used to determine the microbial barrier properties of the packaging material must be validated, according to an established Protocol, to demonstrate:

*           Acceptable Repeatability of the method; and

*           The ability to differentiate among packaging materials, examples of which are described in pharmacopoeias.

–           If the Final Medical Device Package is not Closed by Sealing (e.g., Sterilization wraps, packaging for sterile fluid path products, reusable Containers), the closure system shall be demonstrated to provide acceptable microbial barrier properties.

–           The Use of Peelable Seals shall demonstrate the following:

*           The seal is uniform; and

*           Upon peeling, the fiber shedding and splitting or tearing of the packaging material are within established limits to ensure that the utility of the medical device is not impaired.

–           Stability Samples shall be tested for packaging system integrity over the shelf life of the medical device and at Batch/Lot Expiration Date.

–           Instruments and Elements (I/E) used to monitor, control, or test packaging system integrity shall be Calibrated according to an approved schedule.

–           Packaging Materials shall be purchased from Approved Suppliers and received in the same manner as Raw Materials (RM). Testing and release requirements for these materials shall be defined by Specifications and include, and not be limited to, dimensional tests.

–           Changes to the Process for Packaging Components by the Component Manufacturer shall be evaluated by the Site Quality Team to determine the potential impact on packaging system integrity. The Site Quality Team shall consult, as necessary, with principals from, and not limited to, the following:

 *           Regulatory Affairs (RA),

*         Site Production, and

*         Site Packaging Design and Development.

Changes to the packaging system, which require regulatory approval or notification shall be managed through the Product Change Proposal (PCP)/Product Change Request (PCR) system.

–          Packaging System Integrity Specifications for Sterile Medical Devices shall be established and failure to meet such specifications shall result in an Investigation.