Goals
When you have completed this module, you should be able to:
* Perform a packaging and labeling audit.
* Know and understand which of the worldwide requirements apply to packaging and labeling operations.
* Use a range of information tools, including the contents of this module to the Intranet,
in support of a packaging and labeling audit.
* Recognize compliance or non-compliance of regulations pertaining to packaging and labeling requirements.
Definitions
Blinding: A procedure in which one or more parties to the Clinical Study are kept unaware of the treatment assignment(s) until code break after clean file.
Cleaning: Operation which terminates a production process, incl. dismantling and wet cleaning of the equipment as well as removal of all materials, products and documentation from the equipment and room/surrounding area. The cleaning must be finished by a documented check by a second person.
Cut labeling: labels that have been cut from a sheet and are individual labels. Gang-printed labeling: labeling derived from a sheet of material on which more than one item of labeling is printed. (see example below)
Line-clearance: Operation which must be made immediately before a production process is started. Line-clearance includes:
* Verifying that the Cleaning has been performed at termination of the previous batch
* A documented check that the equipment/area is still in a clean status The operation above must be performed by a person not involved in the Cleaning of the line/area.
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. Over-printing: where text and objects in the foreground print directly on top of any background objects. An example of label overprinting would be printing the expiration date on the label.
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. Packaging records: the complete collection of documentation associated with the packaging of a lot of drug product.
Primary packaging material: The packaging, which is in direct contact with the Formulated Product, Intermediates, Excipients and APIs (including devices for delivering dosages).
Printed packaging materials: packaging materials that are printed and/or otherwise decorated.
Reconciliation: the act of ensuring that the quantity of issued labels equal the quantity used plus the returned labels and scrapped labels, within narrow preset limits.
Secondary packaging material: The packaging, which is not in direct contact with the Formulated Product, Intermediates, Excipients & APIs – usually contains the Primary Pack.
Explanation of Topic
What are packaging and labeling operations?
Packaging and labeling operations are designed to ensure that the finished drug product is free from damage, accurately labeled, and contains what is indicated on the package. The main purpose of labeling is to communicate essential information about medical products to health care providers and patients. Packaging and labeling operations must be performed in a manner to minimize the risk of cross-contamination and mix-ups. It is a fact that a large percentage of all product recalls are caused by errors of packaging or labeling.
Labeling and packaging materials should be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product. Any labeling or packaging materials that meet appropriate written procedures may be approved and released for use. Any labeling or packaging materials that fail to meet such specifications must be rejected to prevent their use in operations.
Approved written procedures must be detailed and followed. They should include information for receiving, identifying, storing, handling, sampling, examining, and/or testing of labeling and packaging materials. Appropriate procedures and systems must exist which guarantee that all labeling conforms with marketing, regulatory, legal, research, technical and quality requirements.
The patient is depending on the product that they receive to be the correct strength, the correct product, and free from contamination. If the package has been misbranded, or mislabeled, it may cause the patient harm. That is why it is important that drug products have been strictly controlled during packaging and labeling operations. When performing a Quality Assurance audit, the GMP Systems approach should be used.
The following systems, at a minimum, should be reviewed:
Ø Packaging and Labeling
Ø Quality System
Ø Material System
The following parts of a packaging and labeling operation will be further explained in this section.
Ø Essential packaging and labeling information
Ø Mix up risks and prevention
Ø Cross contamination
Ø Packaging Order
Ø On-line controls
Ø Sampling
Ø Labeling
Ø Documentation
Ø Reconciliation
Ø Rework
Ø Line Clearance
Ø Clinical Trial Material
Essential packaging and labeling information
The packaging and labeling must include:
* Identification of the product
* Final finished dose form (tablets, capsules, injection)
* Strength of each individual unit
* The manufacturer, packager, or distributor
* The manufacturing batch number
* The expiration date
* Standard dosage requirements
* Frequency of dose
* National Drug Code (product distributed in the US market)
* Additional national requirements, if any
* Storage statement
* Declaration of net quantity of contents (count, weight, measure,etc)
* Precautions to observe if there are incompatibilities with other medical conditions or products, as well as awareness of possible side effects
* Package inserts, patient information leaflets
For Medicinal Products Intended for Clinical Trials the detailed requirements for information to be included in the label can be found in the regulations. It is crucial that total and absolute control be exercised when using printed packaging components. All products and components at every stage must be clearly identified.
Mix-up risks and prevention
Defects related to packaging, labels and leaflets are the most common reasons for recalls. Thus it is important to identify risks for mix-up during packaging and label operations and to ensure there are appropriate procedures in place for mix-up prevention. Mix-ups may occur if personnel are not aware of the risk, if layout of premises or procedures are not adequate.
The following should be reviewed/considered:
Personnel should be trained in mix-up prevention
Packaging lines should be physically separated and clearly marked with ongoing activities
Material for packaging and labeling should be stored in a secure way preventing mix-up. Particular attention should be paid to printed primary packaging material and labels.
Review how printed packaging material is controlled, received, approved, stored, dispatched, transported, used and returned. They should preferably be coded and code read in-line to check the identity.
Material with additional printing – batch number and expiry date -should never be returned to the storage area.
Bulk tablets should be clearly labeled and transported and stored with tamper evident seals and identity ensured before packaging
Line clearance procedures should be thorough and performed according to a detailed checklist with two persons involved
Packaging lines should be equipped with code readers. Codes should be entered via a master. Doing it from a label, carton or leaflet could result in a 100% of the printed component being wrong. During packaging code readers should be checked regularly.
During packaging, checks should also be made to ensure criteria for rejection are met. Samples and rejects should never be returned to the packaging line.
Limits for yield should be in place and justified.
Cross contamination
The risk with regards to containment and prevention of cross contamination during packing operations should be assessed.
Special considerations and any regulatory requirements need to be followed when packing products such as Beta-Lactams, hormones and cytotoxics.
The risk approach normally includes:
* Consideration of other products being packed in the facility or at the site.
* Dedicated facility/packing line where appropriate.
* Design decision of packing line to prevent cross contamination.
* Design of utilities including HVAC.
* Movement and flow of people and products.
* Equipment selection and use.
* Cleaning validation and methods employed.
Packaging Order
Before packaging can take place, an approved Packaging Order must be generated. The Packaging Order consists of specific instructions pertaining to the packaging and control of a finished drug product. The Packaging Order is the equivalent of a batch sheet that details the activities that must be performed both in packaging and labeling, the materials/components that must be used, and the storage conditions and special requirements for the product.
The Packaging Order must contain the following:
* Product name, product-size-finish number, product strength, product form (i.e. tablets, suspension, etc), Code Number, Package Size (Quantity, weight, or volume of product in final container), Expiration Date.
* Finished lot bulk number
* Theoretical Yield
* A list of all packaging supplies and labeling used in the processing of the lot, including:
Ø The name and component number and lot number (if applicable) of each packaging and labeling component
Ø The quantity required
Ø Special handling and usage notes
* Detailed packaging instructions
Ø Line clearance checks
Ø Directions for receipt and identity check of materials
Ø Directions for filling and packaging operations
Ø Directions for labeling
Ø Process control instructions and acceptance limits
Ø Directions for sampling
Ø Handling and storage requirements
Ø Special handling requirements
Ø Where appropriate, an example of the relevant packaging supplies and
labeling with the lot number and expiration date affixed
* An example of the relevant packaging supplies and labeling with the lot number and expiration date affixed
On-line Controls
On-line controls for the packaging line must be in place. Items that should be checked before, during, or after operations are that:
* lines and equipment have been cleared of bulk material, labeling and packaging materials, and documentation from previous operations, including any computer screens or systems holding information pertinent to the batch.
* the general appearance of finished packages is satisfactory
* the packages are complete
* the correct product and packaging materials are being used
* over-printed details are correct and clearly readable
* all line monitors, indicators, and readers are working or have worked correctly Special attention should be paid to checking the accuracy of variable information, such as batch numbers and expiration dates to packaging components on line.
Printed and embossed information on packaging materials must be clear, easy to read, and resistant to fading or erasing. In process test equipment e.g. Leak test equipment to realize integrity of blister sealing should be on the equipment and maintenance schedule.
The in process testing should be completed as appropriate to demonstrate the integrity on the blister is maintained throughout the packing order. Any failures should be documented, investigated and appropriate actions taken.
Special controls should be applied to the management of trial and experimental packing work to ensure the same level of compliance and assurance is applied for this type of work around packing, documentation and labeling compared to routine work.
Sampling
Samples taken away from the line should never be returned to the line. They should be placed in dedicated containers, clearly marked.
Labeling
The use of cut labels should be discouraged or minimized. If cut labeling (and other loose packaging components with a pre-printed Lot Number and Expiration Date) is used, packaging and labeling operations must following special control procedures. All cut labels must be stored and transported in a secured container. Controls used for routine labeling activities include
* Use of appropriate electronic or electromechanical equipment to conduct a 100% examination for correct labeling during or after completion of finishing operations.
* Use of a visual inspection to conduct a 100% examination for correct labeling during or after completion of finishing operations or hand-applied labeling. Such examination must be performed by one person and independently verified by a second person.
* Monitoring of printing devices on, or associated with, manufacturing lines used to imprint labeling upon the drug product unit label or case to assure that all imprinting conforms to the print specified in the batch production record.
Documentation
The appropriate SOPs and packaging batch records must be followed when documenting any other information associated with packaging or labeling. Other pertinent types of documentation include records of:
* who has set up a particular machine
* how they have done it
* adjustments or repairs
* second checks
Batch and/or packaging documentation must include:
* Exactly what has been done?
* What has been used?
* When the operation was performed?
* Who performed the operation?
Reconciliation
Reconciliation limits must be established based on process history and supplier capability. When reconciliation limits are exceeded, a formal investigation must be initiated. The reconciliation must consist of a comparison between the theoretical usage (based upon output) and actual usage (based upon actual counts, where possible). Validated electronic counting equipment data may be used to determine usage.
Any discrepancies that are outside the acceptable limits must be investigated and satisfactorily accounted for prior to Quality Assurance release. Once the production order has been finished, it should be held in a hold status/unreleased status until approved by the QA/QC department and final release conditions have been satisfied.
Rework
Appropriate SOP’s should be in place describing how the supplier handles rework activities. Product for rework should be clearly marked and stored in a safe and secure manner until used. The rework activity should be clearly defined in an approved protocol or batch sheets. The rework documentation could include but not is not exclusive to:- Packing order details, details of rework activity, details of any inspections, acceptance criteria, line clearance, reconciliation.
Cleaning and Line Clearance
Cleaning and Line clearance are essential element in product mix up prevention. A packaging and labeling process will start with line clearance and terminate with cleaning.
Cleaning and line clearance need to focus on:
* Input materials on the line from the previous batch
* Samples and waste from the previous batch
* Documents on the line from the previous batch
* Clearance after maintenance activity or major interruptions as appropriate.
Both activities need to be documented and cover all areas, not just the machine or line:
* The whole machine, including hoppers, conveyers, reject stations, etc
* The floor around the line
* Benches, cupboards, shelves around the line
* Pallets.
* Potential product traps on machines
The activities should be documented, signed and an independent check completed and signed before the area is released for use.
Clinical Trial Material
Packaging and labeling of investigational medicinal products involves added complexity in comparison to marketed products due to the lack of fixed routines, variety of clinical trial designs, consequent packaging designs, the need, often, for randomizations and blinding and increased risk of product cross-contamination and mix up.
Furthermore, there may be incomplete knowledge of the potency and toxicity of the product and a lack of full process validation, or, marketed products may be used which have been repackaged or modified in some way. During packaging of investigational medicinal products, it may be necessary to handle different products on the same packaging line at the same time.
The risk of product mix up must be minimized by using appropriate procedures and/or, specialized equipment as appropriate and relevant staff training. Packaging and labeling of investigational medicinal products are more liable to errors, which are also harder to detect, than marketed products, particularly when “blinded” products are used. Mislabeling precautions such as label reconciliation, line clearance, and in-process control checks by appropriately trained staff should be intensified.
Key Parameters of a Packaging and Labeling Audit
Prior to the audit
* Obtain a list of products that are packaged and labeled at the site.
* Review compliance status of the site by checking for recalls associated with site, results of last inspections.
* Determine if the site functions as the label manufacturer, if so, then an audit of the
* printing area should be included.
During the audit
* Perform a walk through of the packaging and labeling area.
Ø Verify if other products are packed in the same facility and if controls for prevention of cross contamination are in place.
Ø Verify that each packaging line is physically separated or segregated from each other.
Ø Verify that name and batch number are displayed at each station or line during operation.
Ø Verify that cut labels, if used, are stored and transported in separate closed containers.
Ø Verify that containers used for filling are clean before use.
Ø Verify that if different strengths of the same product are packaged on the same lines, all line clearance procedures have been thoroughly followed before a different strength is introduced.
Ø Verify that packaging and labeling materials not suitable for use have been removed from the area.
Ø Verify that samples are not returned to the line.
Ø Verify that the correct Packaging Order is on the line, and if approved changes have been made, they are clearly indicated.
Ø Verify that all finished labeled product is inspected.
Ø Verify that all in-line controls are being conducted.
Ø Verify that product waiting to be packed is clearly marked and segregated from the product that is being packaged.
Ø Verify that labels are transported in a container that segregates different types of labels.
Ø Verify that the material and personnel flow is adequate to prevent a mix-up.
Ø Inspect cleared packaging and labeling areas and verify that all product, labels, and packaging materials have been removed from the area, equipment and trash.
* Perform a walk through of the area where labels are issued and stored.
Ø Ensure that the labeling area is appropriately secure and the labels stored in segregated containers or locations.
Ø Ensure that there is adequate storage for labels and labeling, both approved and returned labels after issuing.
Ø Verify that labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents are stored separately with suitable identification.
Ø Verify that access to the storage area is limited to authorized personnel.
Ø Ensure that there is sufficient control of labels which are similar in shape, size, and color for different products.
* Ensure that there is a system in place to control the issuing of printed components, including the examination of issued labels and that a reconciliation process for used labels is in place.
Ø Verify that there is a written and approved procedure.
Ø Verify that only authorized personnel issue labels.
Ø Verify that all printed materials have been examined for identity and conformity to the labeling and packaging requirements as specified in the master or product records.
Ø Verify that there is a record of this examination.
Ø Ensure that there is a written and approved procedure for reconciliation. This procedure should include:
o a method for reconciling the quantity of issued, used and returned.
o a pre-set limit for discrepancies or means to determine the limit.
Ø Verify that a documented procedure is in place that allows uncoded materials to be returned to stock.
Ø Review label/labeling procedures and records.
* Ensure that all personnel are trained and qualified to perform their function.
Ø Review training records for selected individuals to ensure that they have received adequate GMP training and job skills training.
Ø Ensure that there is a written procedure describing the training program and the steps needed to qualify an operator.
* Ensure that there is an approved acceptance procedure for all packaging and labeling materials.
Ø Verify that written approved procedures exist and are current.
Ø Verify that incoming packaging components have a unique reference number for identification.
Ø Verify that samples of incoming packaging and labeling components are tested/inspected and undergo an approval process.
Ø Verify that materials that fail to meet acceptance specifications are rejected and quarantined.
Ø Ensure that documentation exists for the receipt of each shipment of different labeling and packaging material which includes:
o receipt
o examination or testing
o status (either accepted or rejected).
* Ensure that a control system is in place for implementing changes in packaging and labeling operations.
Ø Verify that there is an approved, written change control procedure in place.
Ø Verify that changes are consistent with the Authorization to Market and are monitored within a change control system.
Ø Verify that there is a system for the control of all master documents
Ø For master documents,
o ensure that the Packaging Order is an accurate version of the master packaging instructions that were approved in the authorization to market document for the drug product.
o verify that working copies of a master document are only released after a signature had been obtained.
o ensure that changes to the master packaging order are reviewed, authorized, and issued by the appropriate department following the approved change control procedure..
o verify that only qualified individuals may make changes to a document.
o verify that these individuals have signed the document verifying its accuracy.
Ø For in-process individual Packaging Orders (working copy):
o ensure only authorized personnel make changes to the document.
o ensure that only authorized personnel document and approve the changes.
o ensure that the changed Packaging Order has been signed by qualified individuals who verify its accuracy.
o when changes have been made to an individual Packaging Order, ensure that employees using this order have been notified or the document marked to indicate the changes.
* Ensure that that there is some type of 100 percent electronic or visual verification or dedicated lines for finished product cut labels, similar in appearance, which are used for immediate labeling on the lines.
Ø Verify that any electronic code readers, label counters and similar devices are checked for proper operation.
Ø Verify that computer systems used to control inspection equipment are secure, and designed to prevent unauthorized changes by mechanics and operators.
Ø Verify that procedures exist emphasizing the strict control of on-line printing and the use of cut labels.
Ø Verify that product and packaging components are checked for:
o sufficient quantity.
o identification.
o conformance to packaging specifications.
* Ensure that filled, unlabelled containers are controlled.
Ø Verify that approved procedures and controls are in place to identify unlabeled filled containers or packages.
Ø Verify that unlabeled filled and sealed packs are labeled as soon as possible after filling.
Ø Verify that approved procedures are in place to prevent any mix-ups or mislabeling from occurring.
* Ensure that there are adequate packaging records including specimens of all labels used.
Ø Verify that packaging records contain the following:
o Listing of equipment used in packaging operations.
o Evidence of line clearance.
o The dates and times of packaging operations.
o The signature of persons responsible for the packaging operations,
o Inspection of the packaging areas and equipment for suitability and cleanliness.
o The initials of operators involved in packaging operations.
o The name, item code, quantity required, and samples of packaging supplies and labeling with lot number and expiration date affixed.
o Records of checks for identity of bulk drug products, packaging supplies, and labeling.
o Signature of qualified and trained staff members performing inspection of packaging lines.
o A record of market package samples taken.
o Accountabilities for bulk drug product, packaging supplies, and labeling, including amounts used, destroyed, or returned to stock.
o Detailed information about deviations from normal packaging steps, unusual situations, and problems. These situations may require a complete
investigation, and where possible, assignment of cause, and corrective actions.
Ø Ensure that there are established accountability limits.
o If accountability limits are exceeded, ensure that an investigation is initiated.
* Ensure that there is a system for destruction of labels and packaging materials.
Ø Verify that the firm has an approved procedure for destruction of labels which includes:
o Method of destruction
o Documentation for the destruction
Ø Verify that obsolete and outdated label, labeling, and other packaging materials are destroyed with accompanying proper documentation.
Ø Verify any unused batch-coded packaging materials are accounted for, destroyed, and quantity and destruction documented.
* Ensure that complete investigations are performed and documented for any unexpected discrepancy.
Ø Verify that there is an approved, written procedure for reconciliation and accountability discrepancies that occur that are larger than the preset limit.
This procedure should include:
o How to conduct the investigation
o What information should be included in the investigation
o How the investigation should be documented.
Ø Verify that deviations from normal packaging steps, unusual situations, and problems are analyzed. If they need a complete investigation that, where
possible, assignment of cause, and corrective actions are included.
* If the firm uses cut labeling:
Ø Verify that there is an approved, written procedure for 100% inspection of cut labeling or roll labeling Ensure that there is an approved process and documentation for receiving returned labels and storing returned labels.
Ø Verify that labels and printed materials are identified with proper identification, maintained and stored to prevent mix-ups.
* Ensure that all incoming labels are adequately inspected for accuracy.
* Ensure that printing devices used on line are monitored.
Ø Verify that in-process printing is checked frequently for accuracy and legibility and recorded.
Ø Verify that electronic code readers, vision inspection systems, label counters or other similar devices are calibrated and part of a preventive maintenance program.
Ø Verify that electronic code readers, vision inspection systems, label counters or other similar devices are challenged prior to start-up and periodically during packaging, to assure proper operation.
Ø Verify that the results of these challenges are documented.
* Ensure that the following in-process checks are established and challenged on a regular basis.
Ø Product number, lot number, expiration date verified 100% or statistically verified
Ø Weight checker
Ø Metal detector
Ø Bar code readers
* Ensure that procedures are in place to control and evaluate rejected material from automated operations.
* Ensure that if the firm is producing tamper-resistant packaging it is conforming to all specific regulations.
* Ensure that all packaging and labeling operations have been validated including computerized processes.
* Ensure that there is an approved check-in procedure for starting operations of a packaging line.
Ø Verify that there is documentation or a check list used each time before a line is to run to ensure that:
o All materials and components from the previous job have been removed
o All line and area cleaning has been completed and checked
o All clearances have been approved and authorized
o All necessary paperwork has been issued for the next job
o The details of the new job are correct
o The line has been set up correctly
o All machine settings and counts are as specified on the packing record
o All containers are intact, undamaged, clean and free from any extraneous contamination, kept covered until such time as they need to be loaded onto the machine
* Ensure that product sampling frequency is established, justified, and includes documented checks of:
Ø Torque
Ø Induction or heat seal
Ø Weight
Ø Packaging
Ø Printing
* Ensure that there are systems in place to control areas with product exposure to the
environment and prevent cross contamination such as:
Ø Appropriate HVAC system
Ø Independent air handling units
Ø Appropriate personnel controls
Ø Cleaning regime