Goals
When you have completed this unit, you should be able to:
Ø Perform a packaging component supplier audit.
Ø Understand which worldwide requirements apply to packaging component suppliers.
Ø Use a range of information tools, including the contents of this module, in support of a packaging component supplier audit.
Ø Recognize compliance or non-compliance with regulations pertaining to packaging component supplier’s requirements.
Definitions
Gang-printed labeling: Labeling derived from a sheet of material on which more than one item of labeling is printed. (see example below). Gang printing is considered to be an unacceptable practice for some industry since it increases the potential for label mix-up.
Figure: Gang – printed labeling
Packaging materials: Any material employed in the packaging of a medicinal product, excluding any other packaging used for transportation or shipment.
Packaging materials: Any material employed in the packaging of a medicinal product, excluding any other packaging used for transportation or shipment.
Packaging Component – Critical (PCC): Is any printed packaging component, primary (product contact) component or device. Furthermore any secondary packaging component critical to the microbiological integrity, stability and/or administration of the product (e.g. Aluminium pillow packs around semi permeables).
Packaging Component – Non-Critical (PCNC): Is any non-printed or secondary (non contact) packaging component or device that does not fall within the definition of a PCC.
Printed packaging components: Packaging materials that are printed and/or otherwise decorated. Examples would include cartons, labels, leaflets.
Reconciliation: A documented comparison between the amount of input materials and the output product, taking into account waste, samples and other losses inherent in the process.
Explanation of Topic
Packaging components
Package components are defined as Packing components critical (PCC) or Package component – Non–critical (PCNC). In principle, there are differences between the way ‘Non-Critical’ and ‘Critical’ package component suppliers are handled from an auditing view. The differences are that suppliers of critical package components must have an on site supplier audit, where non- critical package component suppliers may only require a Supplier Quality Review (postal review). This training module will explain some manufacturing methods for package components and key GMP principles that should be considered and reviewed during the audit.
Packaging component manufacturing
For suppliers of either printed package components or product contact components it is imperative that processes are in place to ensure the components are meeting a well defined acceptable standard. Product contact package components can be utilized to protect and keep the medicine from deterioration. Examples include blister strips for solid dosage forms or sealed glass vials for freeze dried powders. In addition, certain components control the delivery of the drug such as metered dose aerosols. Printed package components such as cartons, labels and leaflets, are designed to ensure the healthcare provider and patient are given the appropriate information for safe and correct use of the medicine. Component supplier operations must be performed in a manner to minimize the risk of cross-contamination and mix-ups. Approved written procedures must be detailed and in place. They should include information for receiving, identifying, storing, handling, sampling, examining, and/or testing of materials. These procedures must be followed.
Key GMP principles to consider during the audit are:-
* Specification
* Identification and traceability
* On-line and segregation controls
* Change control
* Line clearance
* Contamination control
* Validation, Qualification or capability documentation
* Sampling
* Documentation
* Print security
* Special considerations
Specification
There should be a documented, controlled and approved specification for the components being manufactured. The specification normally consists of:-
* Physical attributes with ranges and limits
* Quality attributes and defect classifications
* Technical drawings
* Storage conditions and precautions
* Approved material grades
* Performance characteristics
Identification and traceability
The supplier shall have documented systems for unique identification of raw materials used as well as components produced. Records showing batch history, in process and final QC test results, quantity made, production records, change control records and distribution records.
In the event of a quality incident (e.g. deviation, complaint), records should be retained to allow traceability and history of the manufacturing in order to support an investigation and release decisions made.
Segregation and On-line controls
Component attributes/characteristics that should be checked either before, during or after operations include the following:
* General appearance of finished component is satisfactory
* Components are complete.
* Correct materials are being used with secure production of all sub-components.
* Printed details are correct and clearly readable.
* Specification codes for verification devices e.g. pharma code readers are entered from an approved independent source.
* Ensure verification devices (electronic or otherwise) e.g. pharma code readers, camera systems or count indicators are working and are appropriately challenged.
* Unprinted materials are removed from the operation and are not to be returned to the line.
Efforts to avoid or eliminate the risk of cross-contamination should be in place, for example, activities to segregate working lines, areas and personnel should be apparent.
Change control
A good pharmaceutical manufacturing site requires consistent packaging quality. It is the responsibility of the packaging component manufacturer to control manufacturing processes to ensure consistent conformance to the packaging component specifications.
Changes in component manufacturing processes may result in changes of physical properties of component or final pharmaceutical product that may not be evident on visible inspection of the component. It is important to a manufacturing site that any changes made to the component should not impact the quality and performance of the package component. Also any regulatory implications are assessed as part of the change process.
Line clearance
Line clearance is an essential element in product mix up prevention and needs 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
* Verification that any electronic data is wiped from consoles etc.
* Clearance after maintenance activity or major interruptions as appropriate.
* Line clearance 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.
The line clearance should be documented, signed and an independent check completed and signed before the area is released for use.
Contamination control
The facilities should be designed and laid out to appropriately reduce the risk of contamination from the environment and permit effective cleaning. Personnel gowning and hygiene practices are part of contamination control efforts that may be applicable.
The supplier should define the appropriate environmental conditions for handling and storage of the component(s) being manufactured. Guidance for minimum conditions can be found in PS 9000 Pharmaceutical Packaging Materials, as well as programs such as ISO 9001:2000 and ISO 9004:2000 for pharmaceutical packaging materials.
Validation and Qualification
Ensure the processes are adequately validated, qualified and/or demonstrated according to the quality critical parameters of the component being manufactured. This may be demonstrated in the form of capability studies.
Sampling
There should be an SOP that defines package component sampling. The components sampled should be representative of the batch and sampling should be conducted to prevent contamination from the sampling method. Any packaging materials that meet appropriate written specifications should be formally approved and released for use. Any components that fail to meet such specifications must be rejected to prevent distribution. Samples taken away from the line should not be returned to the line. They should be reconciled and placed in dedicated containers for destruction.
Documentation
The appropriate SOPs and batch records must be followed when documenting any information or data associated with a component manufacture. Other pertinent types of documentation include:
* Records of how and who set up a particular machine
* Records of what standards were used to set-up and run the line/machine
* Records of adjustments or repairs
* Records of 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
There should be formal review and issuance of Certificates of Conformance under the authority of the QA/QC organization. The review should include a formal batch record review to confirm and provide assurance that the final release conditions have been satisfied. Issuance of Certificates should meet company format requirements as defined in the vendor quality agreement.
Approved batch templates must be generated and maintained. The templates should have specific instructions pertaining to the packaging component and controls. The documentation should contain references to materials/components to be used, the storage conditions and special requirements for the finished packaging component.
The documentation normally contains the following:
* Code number/specification number for each batch quantity
* Unique batch number according to a predefined numbering system
* A list of all raw materials used in the processing of the lot, including:
– The raw material’s supplier’s name and lot number.
– The quantity required
– Special handling, usage or storage notes, if applicable
* Detailed packaging component instructions
– Line clearance checks
– Material verification
– Instructions for packaging component operations
– Instructions for labeling
– Process control instructions and acceptance limits
– Sampling
– Special handling requirements
– Any customer specific requirements
Print security
Special attention should be given to how assurances are made for print security and media management. The processes should be assessed during the audit to ensure no corruption of print media occurs during transfer or storage of electronic artwork files.
There are agreed processes of artwork approval and good practices for changing artwork including customer approval, version history, change history and archiving of old versions of artwork. There should be set-up and maintenance procedures to include initial printed material verification against an approved source such as artwork, confirmation of press set up and documented procedure and schedule for cleaning.
Printing plates should be uniquely identified and access controlled. Verification of the print impression should be completed against a controlled master version as part of the make-ready and approval to run the job. If reference standards, such as color matching books are used, they should be appropriately controlled. Gang printing is not a preferred practice due to the potential risk of mix-up.
However, if performed stringent controls should be in place. To reduce the risk of unprinted material in the finished component, processes should be employed in the printing process. The processes include double sheet detectors for sheet fed printing machines and sensors that alarm or highlight depression of printing plates form the print medium. In addition, systems should be evident to ensure material that is out side of print registration or images with ink starvation are securely flagged for segregation and removed.
For manufacturer/suppliers who supply labels on reels, in the case of missing labels these should not be replaced and the number of splices allowed per a reel should be defined. Where digital printing is utilized, processes should be controlled to ensure the correct electronic artwork files for the job are in the digital printing press and there are security measures for printed products.
Special considerations
Braille
Where Braille has been incorporated into a printed package component there shall be a system for ensuring symbols meet appropriate regulatory and market requirements and comply to specifications for size and embossed height.
Counterfeit
It is important that basic security at the suppliers is followed to ensure that all print media including waste is stored securely and render unusable prior to secure disposal. The preferred mode for controlled destruction of materials with proprietary information is supervised incineration. This control helps in the fight against counterfeit material. In some markets a variety of anti- counterfeiting measures have been put into place e.g. the use of holograms.
Intellectual Property
Intellectual property is the intangible property that is the result of creativity (such as patents or trademarks or copyrights). It is important that components are reviewed in relation to the registration of trademarks, copyrights or patents as this could have impact on potential future changes to specification and registration details. In the case of rubber stoppers the exact details of formulation may not be disclosed by the supplier (if intellectual property) and minor changes in formulation may have a direct impact on final pharmaceutical product stability. Expectations for notification/approval authority of changes by the site should be spelled out in Business and/or Quality Agreements, respectively.
Examples of common manufacturing and printing methods for package components Molding
Figure: Diagram of Blow molding machine
Broken down to its fundamental components, an injection machine is comprised of 3 functional units:
1. Injection – which melts and transmits the plastic granules.
2. Mold – the design portion which produces a specialized product
3. Clamping – which provides the controlled pressure to open and close the mold.
Injection blow molding is normally used for high quality bottles. Compared to extrusion blow molding, injection molding gives better definition of details and better control of thickness of the material. Important quality considerations are:
* Traceability of the polymer is maintained, that only virgin polymer is used (not regrind polymer).
* Key manufacturing parameters such as Temperature and Pressure
* Testing of polymer, for example, Melt Flow Index
* Maintenance and cleaning of the molds, cavities and barrel.
* Controls and confirmation of the critical specifications during manufacturing. For example, thickness of walls confirmed through QC inspection as a part of in-process testing.
Glass manufacturing
The glass production process can be said to consist of four steps:
1. The glass melt in the furnace,
2. The formation of the bottle
3. Annealing process
4. Inspection
There are in general four types of glass:
Type i. Neutral glass Borosilcates glass – The borosilicate glass is any silicate glass having at least 5% of boric acid in its composition. Due to its properties, this is the glass commonly used for ampoules and vials in the pharmaceutical industry.
Type ii. Soda lime Silica glass Aqueous parental use where pH is lower than 7. Surface treated (e.g. sulphated)
Type iii. Soda Lime Silica – only moderate hydrolytic resistance. Non-aqueous parental use. Aqueous oral products.
Type iv. Soda Lime Silica – Low hydrolytic resistance. Non-aqueous solids for oral use. Applications such as for oral liquids.
Some quality aspects to consider during the audit are:
* Glass formation and ratio of raw materials in the furnace. For example, the level and quality of cullet.
* Assurance that lubricants, particulates and sulfate coatings from the process are burned off in the Annealing oven (also known as the Lehr oven).
* Quality of tools
* Control of Lehr – temperature, speed, cooling by fans, filter of fans.
* Inspection process – electronic verification of size and dimensions, ‘go’/’no go’ gauges and in process challenges.
Tubular Glass Containers
Tubular glass is utilized to manufacture and form Ampoules, Vials and cartridge tubes by a process of cutting or breaking and hot shaping. Dust is generally extracted during the process. The critical controls are blowing /air extraction and temperature and speed of Lehrs.
Printing
The processes for production of printing plates should be controlled. Master specifications should be internally maintained and available for inspection. The buyer site should retain the right to inspect as necessary to confirm current status, make modifications as necessary and to be notified, and possibly approve, any changes. The expectations should be defined in the Quality Agreement.
Gravure printing foil
Gravure printing process is where the image is etched below the surface of the plate (gravure cylinder). Gravure is most often used for either very high quality printing or long run printing such as the printing of foil and laminates.
Label, carton, leaflet printing
Flexography is the major process used to print packaging materials such as cartons, corrugated containers, labels, foils etc. In the typical flexo printing sequence the substrate is pulled through a series of stations, or print units, each with a single color. The various colors normally Cyan, Yellow, Magenta and Black build up the various tones by overlaying of these basic colors. The plates are flexible and are positioned around a plate cylinder.
If a step and repeat process is employed to replicate images of artwork across a plate to cover the web of print media, there should be appropriate steps in place to ensure that all such images are an exact copy of the approved artwork and no adulteration of the artwork happens during the step and repeat process.
Figure: Label, carton and leaflet printing
After printing the printed sheets or reels are normally guillotined or die cut to provide the product of the appropriate size. See print security section above for quality aspects to consider during the audit.
Syringe Manufacture
Diagram of a hypothermic syringe, retraction of the plunger creates the vacuum to draw up materials, which can then be discharged by pushing on the plunger. Its rubber head makes an airtight seal against the walls of the barrel.
There are many manufacturers of syringes, and while each one uses a slightly different process, the basic steps remain the same:
1. Needle formation
2. Plastic component molding
3. Piece assembly,
4. Packaging,
5. Labeling and
6. Shipment.
The needle is normally produced from steel, which is heated and drawn through a die design to meet the size requirements. Most needles are purchased from specialist manufacturers.
The syringe tube can be manufactured by injection molding or glass manufacture as required. When all of the component pieces are available, final assembly can occur. As the tubes travel down the conveyer, the ends that cap the tube are affixed. Graduation marks are applied as appropriate, and the needle and safety cap can be attached at this time.
Manufacture should be in a clean environment and final component free from contamination.
The quality components used to manufacture syringes should be checked during each phase of the manufacture. Components should be checked to ensure size; shape and consistency are within specifications. Measuring equipment with the defined accuracy and precision should be used for measurement of the components.
Forces to activate the plunger, dismantle the syringe, removal of cap and removal of needle should be tested, reported and controlled. The reporting of quality attributes during manufacture is often completed on Statistical Control Charts where the manufacturing process can easily be monitored.
Key Parameters of a Packaging Component Audit
Prior to the audit
Ø Develop an understanding of the vendor manufacturing process specific to company requirements
Ø Obtain a list of company components that are manufactured at the site.
Ø Review recent rejections, complaints and issues, of the receiving site(s) and the respective statuses.
Ø Review any Quality Agreements and relevant registration requirements.
Ø Review compliance status of the site by checking for service history, recalls associated with the site, recent regulatory inspections (if applicable) and outcomes.
Ø Review previous audit reports and actions
During the audit
Perform a walk through of the manufacturing area.
Ø Ensure the production areas are clean and tidy.
Ø Ensure the fabric is in good condition and appropriate design for control of the process.
Ø Verify each line is physically separated or segregated from each other.
Ø Verify the manufacturing process and dress discipline is suitable for prevention of contamination.
Ø Verify containers used for filling are clean before use.
Ø Verify line clearance procedures have been thoroughly followed before a new order/batch is introduced.
Ø Verify non-conforming raw materials, not suitable for use, have been identified and removed from the area and is secure.
Ø Verify samples are not returned to the line.
Ø Verify the correct order is on the line, and if approved changes have been made, they are clearly indicated.
Ø Verify all in-line controls are being conducted.
Ø Verify unprinted material, defect material and material not meeting the specification is securely segregated throughout the process to avoid mix-ups.
Ø Verify product, waiting to be packed, is clearly marked and segregated from the product that is being packaged. For example, printed and non-printed material labels.
Ø Verify that before raw materials are delivered to the line, they have been identified and released to the approved specification.
Ø Verify the materials and personnel flow is adequate to prevent a mix-up.
Ø Inspect cleared packaging component areas and verify that all materials have been removed from the area, including refuse.
Perform a walk through of the area where raw materials are received, issued and stored.
Ø Ensure current specifications are accessible, agreed, approved and utilized.
Ø Ensure environmental controls are in place to maintain temperature and relative humidity at acceptable levels where temp/RH sensitive materials are stored.
Ø Ensure the area is appropriately secure and materials are stored in segregated containers or locations.
Ø Verify that access to the storage area is limited to authorized personnel.
Ø Ensure sufficient secure control of material of non-conforming product.
Ø Ensure all raw material is adequately labeled as to their identity and there is an unambiguous system for material status.
Ø Ensure that there is a system so materials are not used outside the recommended shelf life.
Ensure that there is an approved acceptance procedure for all raw materials.
Ø Verify written approved procedures exist and are current.
Ø Verify incoming materials have a unique reference number for identification.
Ø Verify incoming materials are tested/inspected and undergo an approval process.
Ø Verify materials that fail to meet acceptance specifications are rejected and quarantined.
Ø Ensure documentation exists for the receipt of each shipment of materials which includes:
– Receipt
– Examination or testing status (either acceptable or rejected).
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 for the job.
Ensure a control system is in place for implementing changes in manufacturing.
Ø Verify that there is an approved, written change control procedure in place.
Ø For master documents,
– Ensure that the Order is an accurate version of the master packaging component instructions that were previously company approved.
– Verify working copies of a master document are only released after a signature had been obtained.
– Ensure that changes to the master component order are reviewed, authorized, and issued by the appropriate department following the approved change control procedure.
– Verify only qualified individuals may make changes to a document.
– Verify that these individuals have signed the document verifying its accuracy.
Confirmation of control systems for in-process visual or electronic verification devices.
Ø Verify electronic code readers, vision inspection systems, label counters or other similar devices are calibrated and part of a preventive maintenance program.
Ø Verify 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 results of these challenges are documented.
Ø Verify computer systems used to control inspection equipment are secure, and designed to prevent unauthorized changes by mechanics and operators.
Ø Verify that electronic verification devices, such as pharma code readers, are set up utilizing a controlled approved specification.
Ø Verify that components are checked for:
– Sufficient quantity
– Identification
– Conformance to packaging specifications
Ø Verify in-process printing is checked frequently for accuracy and legibility and the periodic check is recorded.
Ensure adequate manufacturing records exist.
Ø Verify batch records contain the following:
– Listing of equipment used in operation
– Evidence of line cleaning and inspection of the component equipment
– The dates and times of operation
– The signature of persons responsible for the operation
– The initials of operators involved in operation
– The name, item code, quantity required.
– Records of checks for identity of raw materials and respective labeling.
– Signature of qualified and trained staff members performing inspection lines.
– A record of samples taken.
– Traceability of raw materials.
– Detailed information about deviations from normal operational steps, unusual situations, and issues
Ø Ensure that there are established reconciliation limits where applicable.
– If reconciliation limits are exceeded, ensure that an investigation is initiated.
Ensure that there is a system for destruction of waste printed packaging component material.
Ø Verify that the firm has an approved procedure for destruction of printed components which includes:
– Method of destruction
– Documentation for the destruction
– Verify if these responsibilities are outsourced they are controlled and maintained by the firm.
Ensure complete investigations are performed and documented for any unexpected discrepancy.
Ø Verify an approved, written procedure for reconciliation and accountability discrepancies, that occur, are larger than the preset limit. This procedure should include:
– How to conduct the investigation
– What information should be included in the investigation
– How the investigation should be documented.
Ø Verify that deviations from normal processing steps, unusual situations, and problems are analyzed. If they need a complete investigation that, where possible, assignment of cause, and corrective actions are included.
Ensure procedures are in place to control and evaluate rejected material from automated operations.
Ensure manufacturing of tamper-resistant packaging conforms to specific regulations and company policies.
Ensure operations have been validated including computerized processes.
Ensure there is an approved set up procedure for starting manufacture.
Ø Verify that there is documentation or a check list used each time before a line is to run to ensure that:
– All materials and components from the previous job have been removed
– All line and area cleaning has been completed and checked
– All clearances have been approved and authorized
– All necessary paperwork has been issued for the next job
– The details of the new job are correct
– The line has been set up correctly
– All machine settings and counts are as specified on the packing record
– All raw materials are intact, undamaged, clean and free from any extraneous contamination, kept covered until such time as they need to be loaded onto the machine
Ø Ensure that product sampling frequency is established, justified.
Ø Print security
– Ensure the system for artwork/proof approval is considered secure
– Ensure the system to control plates and origination material is considered secure.
– Ensure procedures cover: Plate generation and control (security), plate unique numbering, plate and artwork secure disposal, plate issue and return.
– Ensure reference standards are current and controlled.