Goals
When you have completed this module, you should be able to:
Ø Perform an audit of a material handling system.
Ø Use a range of tools and information, including the contents of this unit to support the audit of a material handling system
Ø Understand and apply appropriate GMP standards/regulations to an audit of a material handling system
Ø Recognize compliance or non-compliance of material handling systems to applicable regulations
Definitions
Charge in of materials: A quantity of ingredient material to be used in production placed into an item of manufacturing equipment.
Components: FDA defines this as any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product. The equivalent word in EU would be starting material. In this module the word component is used. The words are used interchangeably, depending on the stage of production, with a number of different terms such as: material, intermediate bulk, active pharmaceutical ingredient, excipient, starting material, raw material, goods.
Dispense: To remove a specific quantity of material from the primary material and portion into the individual secondary container for charging to a batch or prescription.
FEFO: An inventory management system where the products expired first are the ones sold first. Known by the abbreviation “FEFO”, First Expire; First Out. First In;
First Out (FIFO): An inventory method that requires the oldest material to leave the warehouse before newer material.
Material: When the word material is used in this training module it means both components and packaging materials.
Quarantine: The status of starting or packaging materials, intermediate, bulk, or finished products isolated physically or by other effective means while waiting a decision on their release decision.
Packaging Material: Any material employed in the packaging of an API or a medicinal product, excluding any outer packaging 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.
Rejected material: Material not meeting acceptance criteria.
Subdivide: To remove a chemical or raw material from a large container and divide/weigh it into smaller, pre-determined amounts.
Explanation of Topic
Introduction
Material handling starts when components and packaging materials are received onto a pharmaceutical or Active Pharmaceutical Ingredient (API) plant site and ends when the product/material is distributed. Material includes components or starting materials, (e.g., raw materials), API intermediates and excipients and packaging materials used for APIs or finished products.
Some examples of materials are:
Ø Solvents in tank wagons
Ø Chemicals received by API manufacturers
Ø Active Pharmaceutical Ingredients for finished products
Ø Printed packaging materials or labels used in packaging
Ø Primary packaging materials such as glass vials, plastic bottles and aluminum foil
Ø In-process materials such as bulk tablets, granulations, etc.
Material handling refers to one of nine stages within the pharmaceutical process.
Material Handling Stages
* Receiving materials
* Storing materials
* Sampling/testing materials
* Release of materials
* Transferring materials
* Subdividing/dispensing materials
* Charging in of materials
* Distributing materials
* Rejected/Returned/Recalled materials
Each of these stages should have a written approved procedure or series of procedures describing activities to be taken during each step. The goal of this training module is to describe how to audit a material handling system using the appropriate GMP standards.
The GMP requirements detailed in this module are directly applicable to finished dosage and API manufacturing sites and should be applied to other suppliers on a sliding scale, the scale being dependent on the product or service being audited.
In addition, the auditor should consider the risks associated with the material handling system that would potentially result in product not meeting customer specifications or regulatory requirements.
Focus of Audit
As an auditor, not only should you focus on what the material handling activities are but also how they take place throughout the plant. A suggested way to audit is to take a finished product and trace it back to its components and packaging material to see if the paper trail is intact.
Observing product at its various in-process stages, (how it is labeled, transported, and managed) will also provide you with valuable information. Focus on steps taken to ensure that there are no mix-ups, or potentials for contamination and/or cross contamination.
Observe how the quality of materials is preserved throughout handling. Review documentation of accountability for materials at various stages and assure that materials are protected and controlled.
Receiving materials
Materials that may be received by the site or company include: active pharmaceutical ingredients (APIs), API raw materials, API intermediates, excipients, intermediate drug products, packaging material and components for finished dosage forms.
Each material should have an approved and up-to-date specification. Materials should be purchased from an approved and/or certified vendor.
The approval/certification process should be defined. Packaging material must not react with product, absorb product or add anything to the product. Upon receipt, the site should inspect materials for damage to external shipping containers.
Containers should be sealed, intact, and clearly labeled. Damaged materials which show evidence of tampering should be segregated for further evaluation by Quality and/or designated personnel.
The materials should meet the approved specifications as assessed either by review of a Certificate of Analysis provided by the vendor or by testing. When the site receives the container(s), each container should be identified with the product name/nomenclature, product item code, lot number and retest or expiration date (if applicable). Containers of materials should have a unique identification lot number or code affixed to them. This unique code provides traceability from the material manufacturer to its use in the finished product.
Materials having the same vendor lot number that are received on different days should be assigned by different internal lot numbers. At a minimum, the site should conduct an identification test on all received material.
Other tests may be waived if the there is a Certificate of Analysis sent by the vendor and a procedure is in place defining a reduced testing program.
The site should keep receiving records for each respective material that is received at the site.
The receiving records should contain:
Ø Name/nomenclature, product item code, vendor lot number, site lot number
Ø Statement of when and amount of material received
Ø Results of physical examination
Ø Number of samples taken once sampling is completed
Ø Certificate of Analysis from vendor
Ø Certificate of cleaning for tank wagons (if applicable)
Ø Transit data such as temperature, date/time sent/arrived and container security features
Shipping requirements for temperature must be maintained during transit. Although dependent on characteristics of the goods, monitoring may or may not be necessary.
Product specifications should be clearly defined and documented. If the site receives labels, each different drug product, strength, dosage form, or quantity of content should be separated from each other and be uniquely identified. Only authorized personnel should be allowed access to the labels.
The site should have a procedure in place that directs what happens to a material if it is not used by its expiration date. The site should also have a system that tracks and reconciles the amount of goods ordered, the amount received and the amount used. There should also be a detailed site procedure in place for destruction of material waste.
Incoming materials should be processed immediately upon receipt to ensure that the materials are secured and stored under appropriate environmental conditions. Materials requiring cold storage and/or low humidity should be stored accordingly upon receipt.
Any doubt about material identity, any damage likely to affect the integrity or quality of the material, and any suspected contamination must be reported to the Quality Unit/Quality Assurance.
Storing materials
Suitable conditions for storing and sampling of starting materials and packaging materials must be provided.
Any special storage conditions required by specifications should be met. Once materials have been received, they must be stored under quarantine until tested or examined and released.
Quarantine status may be controlled either through an electronic/automatic system, providing the system is validated or a manual system controlled by status labeling. When material is released for use by Quality, it may be held in a storage area or warehouse until disposition. Material should be held under the environmental conditions (specific temperature or humidity, in the dark, etc.) indicated by the vendor or as supported by stability. Conditions should be monitored and recorded, as applicable.
Temperature mapping studies should be performed to demonstrate the suitability of the storage facilities and support choice of points to monitor temperature and to determine any special material storage location. The storage areas should be well maintained and clean. Access should be controlled and limited to appropriate personnel.
Rules for Storage
* Same materials with different batch numbers should be adequately segregated to avoid potential mix-ups.
* Released material should not be stored in the same area as rejected, returned or recalled materials.
* Cleaning solutions should not be stored next to in-process or finished pharmaceuticals/products.
* Materials should be stored off the floor.
* Process solvents should be stored in dedicated and/or cleaned tanks (according to a validated cleaning procedure).
Storage areas should be in good order. Procedures should be in place to ensure that material is within retest/expiration dates. Procedures for reconciliation should be in place as needed. This is of particular importance for labels and material that may be returned from production for storage.
Materials being held locally should follow the first in, first out (FIFO) rule. The oldest material should be used first. An inventory management system where the products expired first are the ones sold first may also be used. It is known by the abbreviation “FEFO”, First Expire; First Out.
Retest and/or expiration dates should always be checked before use. Packaging material including containers, and closures should be inventoried. The inventory should be current and be updated when material is either added or removed from the warehouse/storage area.
Storage areas should be in good order. Procedures should be in place to ensure that material is within retest/expiration dates.
Procedures for reconcilliation should be in place as needed. This is of particular importance for labels and material that may be returned from production for storage.
Sites may handle materials for clinical trials separately. If that is the case the same GMP principles should be applied. However systems may be more manual. Sites may also handle material for non-GMP purposes such as material for technical use. Non-GMP material should be stored separately .
Sampling/testing of materials
Each lot of components should at least be tested for identification. The site should have an approved detailed SOP or sampling plan which covers the sampling of the various types of components and packaging materials.
The SOP or plan should specify the quantity to be sampled based on a valid statistical sampling plan that takes into account criticality of material, material variability, past quality history of the supplier and the quantity needed for analysis and include retention samples as needed. For materials intended for parenterals, each container must be sampled.
All sampling should be performed in a way minimising risks of contamination. Thus samples of material intended for sterile/aseptic production may be done at the supplier or performed in connection with charging in of the material.
The SOP or plan should also specify the sampling method to use, the container to use, special instructions and the testing procedure to use once the sample has been taken.
Containers from which samples have been taken should be clearly marked as such, by whom and when. Sample containers should be clearly marked with product name, lot number, date taken, and quantity.
Figure: Sampling / testing of materials
Sampling should be performed in approved areas designed to minimize contamination from the environment and also cross contamination from other products. Only one material should be sampled at a time. Care should be taken that only one product is exposed at any time. The area used for sampling need to be qualified to the standard required.
If sampling booths are used they should be qualified to ensure the fulfill the clean room standard required. Sampling should be performed by personnel and by methods approved by the Quality Unit/Quality Assurance under conditions and with a technique that will give a representative sample and preserve the initial quality of sample and sampled material with regard to microbiological, physical and chemical aspects.
The sampling method should specify the number of containers to be sampled, which part of the container to sample and the sample size. If samples are pooled (composited), it should be clear who will pool (composite) and homogenize them. Sampling utensils and sampling containers should be clean.
If reusable utensils are used for sampling potent or toxic materials, cleaning validation should be conducted and completed before the sampling procedure is accepted. It is not recommended that reusable utensils be used to sample these materials.
All samples should be adequately documented and labeled according to site procedure. Once a material is accepted by the site its status should be changed in the material control system using accepted site practices as outlined in an approved SOP. Materials beyond their retest date may be sampled and re-evaluated according to site procedures and supplier recommendations.
The criteria should be clearly defined with regards to frequency, tests to be performed and by whom and the number of times an expiration time can be extended.
Evaluation and Release
Deliveries of materials should be tested, evaluated and released by the Quality Unit/QA as appropriate, according to site procedures.
Transferring materials
As materials are moved throughout the facility, they should be clearly labeled and identified as to what stage they are in. Containers should be closed and sealed to prevent contamination, both from the environment and other products, and to prevent tampering.
Appropriate paperwork should accompany the transfer and be completed concurrently with the transfer. Precautions should be taken to keep materials secure during transfer.
This may include special seals both on the interior (primary seals), and on containers (secondary). Finished product labels should be securely transferred to prevent unauthorized access. The secure transfer of labels may be accomplished in a number of ways, including transfer in tamper proof “cages”, locked with numbered and labeled unique seals.
When material is transferred between areas, precautions should be taken to prevent:
Ø Product mix-ups
Ø Contamination of product or components
Ø Use of wrong material in manufacturing
Ø Tampering of product
Subdividing/Dispensing materials
At times it is necessary to subdivide material for use in pharmaceutical operations. The area in which the subdivision takes place should be a controlled area with only the material to be subdivided present in the area.
Containers, those currently holding the material and those the material will be placed into, should be free from dust and dirt. If a container is recycled, i.e., used for a different lot, the sticker or identification from the previous lot should be removed or defaced, with the current identification label visible and legible.
If a container that has been opened and/or previously subdivided, it should indicate on the container itself “OPEN” or “PARTIAL” along with the date of opening. This will prevent the container from mistakenly being used as a full container.
The subdivision process as outlined in the approved local SOP should be verified and documented by a second person.
The second person should check that:
Ø Material was released by Quality Control
Ø The expiration and/or retest date is present
Ø The material name and/or chemical nomenclature is present
Ø The lot number is present
Ø The expiration and/or retest date is present
Ø Weights of subdivided containers are present
Ø The date the material was subdivided and the initials of the employee responsible for the subdivision are present
When a component is removed from the original container, the new container needs to have the following information:
Ø Component name or item code
Ø Receiving or control number
Ø Weight or measure in new container
Ø Batch number for which the component was dispensed
Ø Product name, strength, and lot number
If a material is removed from the original container, it needs to be demonstrated that content is not compromised with regard to container integrity, impact on content from container as well as the stability of content.
Charging of materials
Written production and control procedures should be present to ensure that the batch to be formulated should be at 100% of the labeled or active ingredient. When charging materials, the material identification and weight of the charge-in material should be compared to the specified material and amount indicated in the batch record. Material charges should be verified and documented in the batch record by a second person. This person may be a supervisor or second operator. During charge in the following information needs to be verified:
Ø The material was released by Quality (unless other systems and controls are in place to verify release)
Ø The material name and/or nomenclature is present
Ø The lot number is present
Ø The expiration and/or retest date is present
Ø The weights of the material containers are present
Ø The date and initials of the operator who charged the material is present
Distribution of materials
Once product is released by Quality, it may be distributed through the channels established by the site or company. Material should be properly marked with name of the product, and lot number. Finished product should be placed in appropriate shipping containers to prevent damage to the product and maintain the storage conditions indicated for the product.
Contracted storage facilities should comply with GMP for receiving, storage, handling and distribution of materials
Rejected, returned, and recalled materials
Rejected material should be clearly marked and quarantined from other material in a restricted area. If the material was rejected during receipt, it should either be returned to the supplier or destroyed. All actions should be approved and documented by authorized personnel. The process for receiving returned goods must be described in an approved procedure. Returned goods must be clearly identified and segregated.
Before placing returned goods into good stock, there must be an investigation. The investigation should include details of the storage (e.g., environmental conditions) and handling of the material prior to returning to the site. Returned goods must undergo physical examination and may require analysis.
The criteria for returning material/products to usable stock must be well defined, approved by QA and the final decision made by appropriately trained and qualified persons. In the event of a recall, returned materials should be segregated from all other material and clearly labeled as recalled material. All recalled material should be documented.
There should be an approved SOP that describes in detail what actions take place during a recall. Excess of printed packaging materials bearing batch numbers or other batch specific printing must be destroyed in connection with the line clearance procedure.
Training of Personnel
All personnel who are involved in receiving, weighing, transporting, storing, sampling, and distributing either work-in-process materials or finished product must be trained in their job functions, including applicable GMPs.
Summary
At all times, materials used in manufacturing and packaging should be under strict control. Care should be taken in transporting materials to prevent contamination, product mix-ups, and problems in manufacturing with wrong materials.
Key Parameters in Auditing a Material Handling System
Prior to the audit
Ø Review the type of products made at the site.
Ø Determine what type of materials the site receives.
During the audit of the material handling system
Inspect the warehouse.
Ø Verify that components, drug product containers, and closures are received, identified, stored, handled, sampled, tested, and approved or rejected according to the site’s SOP.
Ø Verify that materials are stored off the floor.
Ø Verify that environmental conditions monitored and recorded, as appropriate.
Ø Verify that there is controlled access to receiving and storage areas.
Ø Verify that pest control procedures are in place.
Ø Verify that the sampling area is a controlled environment designed to prevent contamination
Ensure that there are written procedures which describe how each of the previous operations are performed.
Challenge the system to decide if it is functioning correctly. If the handling and storage of components and packaging material are computer controlled, the program must be validated.
Ensure that receiving records contain:
Ø Name of the component, product or chemical nomenclature
Ø Name of the manufacturer/supplier if different
Ø Carrier
Ø Receiving date
Ø Vendor’s lot number
Ø Quantity received
Ø Control number or control information assigned by the site or company
Ø Certificate of cleaning for tank wagons
Verify that the site has an approved vendor list and that materials come from approved vendors.
Ø Determine if vendors are included in an audit program. Verify that components are identified after receipt and quarantined until released. Ensure that components are identified so the status (quarantine, approved, or rejected) is known. Review the criteria for removing components from quarantine and challenge the system. Determine what records are maintained in the storage area to document the movement of components to other areas.
Ensure the site has a system and procedure to manage rejected and returned components and packaging materials.
Review the sampling and testing procedures for components, and the process by which approved materials are released for use.
Ø Decide if these practices are adequate and followed.
Ø Determine if sampling is based on a statistically valid sampling plan.
Ø Determine if pooling/compositing of samples is allowed and if so, that the pooled sample/composite is representative
Ensure that the firm’s inventory system is valid and accurate for drug components, and packaging material including labels.
Ø Challenge inventory records by comparing the number of containers physically available against the quantity remaining on the inventory record or computer system.
Ø Investigate if there are significant discrepancies in these records.
Ø Ensure that inventory system can provide an accurate and complete listing of nrejected materials on site and verify
Ensure that the site has shown that the containers and closures are compatible with the product, will provide adequate protection for the drug against deterioration or contamination, are not additive or absorptive, and are suitable for use
Ø Verify that specifications for containers, closures, cotton filler, and desiccant, etc. are appropriate.
Ø Verify that appropriate testing is performed for cracks, glass particles, durability of material, metal particles in ointment tubes, compliance with compendium specifications, etc.
Ø Verify that cleaning procedures are adequate and containers are stored properly.
Ø Determine if preprinted containers are controlled as labeling, or as containers.
Verify the site is reviewing the labeling for accuracy.
Ensure that training has taken place for all personnel who handle materials.
Ø Verify that personnel have been trained in their job functions.
Ø Verify that they have been trained in the documentation functions.
Ø Verify that they are receiving GMP training on an ongoing basis.
Ensure that any changes to the material handling system follow the site’s/company change control procedure.
Ensure that there is uninterrupted traceability from finished product to source of materials.
Ensure that at least one specific identity test is conducted on each lot of each component.
Ensure that each lot of components and packaging material is identified with a distinctive code.
Ensure that representative samples are collected, tested or examined using appropriate means.
Ensure that materials are re-evaluated at a pre-determined frequency.
Ensure that the site performs a documented investigation into any unexpected discrepancy.