• Reevaluation of Stored Materials

• Disposal of rejected and waste material

• Material Status Indication

• Material Supplier Approval

• Raw Materials and Packaging Materials – Receipt

• Sampling of Production Materials and Finished Good

• Storage and Distribution of Drug Products, Medical Devices, and Related Materials

• Subdividing Dispensing & Transferring Materials to Production Areas

• Quarantine Shipment

1. 1. Reevaluation of Stored Materials

This practice document addresses the Reevaluation of materials stored for defined periods of time including, and not limited to, the following materials:

* Raw Materials (RM),

* Active Pharmaceutical Ingredients (API),

* Starting Materials,

* In-Process Materials,

* Intermediates, and

* Packaging Materials.

This practice applies to GMP Production Sites and operations where the materials are stored for use in the production of Pharmaceutical or Animal Health products.

APIs or Intermediates with Assigned Expiration Dates and which are intended for sale to customers outside of Site do not require reevaluation when stored in finished sealed packages in API manufacturing facilities or Distribution or Logistics Centers.

Reevaluation Intervals for APIs shall be based on accelerated or real-time stability data.

Maximum Reevaluation Intervals for all Materials shall not exceed the following limits, unless supported by analytical data to demonstrate that the material meets established criteria at the time of use:

* One year for intermediates and in-process materials;

* Two (2) years for starting materials and RMs (except for APIs used in Drug Product manufacturing); and

* Five (5) years for packaging materials.

Reevaluation Intervals should relate to any storage conditions stated on the Label and shall be Approved by the Site Quality Team. The Site Quality Team shall consider shorter reevaluation intervals based on the nature of the material (e.g., wet cake intermediates, mother liquor or solvent-based intermediates, dry intermediates).

Reevaluation Dates shall not exceed established expiration dates for materials that have expiration dates.

Materials Without Expiration Dates shall not be reevaluated beyond ten (10) years unless the reevaluation is approved by the Quality Team.

Extension of Reevaluation Dating for APIs beyond five (5) years should be supported with stability data and should be approved by the Site Quality Team.

The Material Status Designation should be changed from approved to Quarantine if by the reevaluation date such reevaluation has not been completed and a new reevaluation date assigned.

Minimum Testing Requirements [e.g., stability indicating tests or Validated release Test Methods (TM)] shall be established by the Site Quality Team for each material to be reevaluated.

Reevaluation Dates shall be able to be readily determined (e.g., appear on material status labels or in a Validated Computerized System).

For Intermediates or APIs that are Intended for Sale and that do not Have an Expiration Date, the reevaluation date shall be indicated on the label and/or Certificate of Analysis (COA).

1. 1. 2. Disposal of rejected and waste material

Rejected and Waste Pharmaceutical, Medical Device and Animal Health Materials and Products shall be expeditiously destroyed on Site or removed from the Site in accordance with local regulations and Site Environmental Health and Safety policy.

This practice applies to GMP operations where rejected and waste pharmaceutical, medical device and animal health materials and products are handled.

Rejected and Waste Materials and Products that need to be stored while awaiting Disposal shall be physically isolated in Dedicated Material Status Areas with each Container or each shrink-wrapped pallet load identified as rejected.

Handling, Collecting, and Disposing of Materials shall be conducted by Qualified personnel and in suitable facilities.

A Site Waste Disposal Team from the Environmental Health and Safety (EHS) Group shall be designated for each Site location and shall be responsible for the following:

* Approve Standard Operating Procedures (SOP) for control and disposal of all rejected and waste materials and products generated at the Site; and

*Sign manifest forms.

Storage Areas for rejected and waste materials are to be visibly identified and separate from Production modules. Collection points, including those inside production modules, for such materials are to be visibly identified and secured.

Accountability of Rejected and Waste Materials Stored in Storage Areas shall be maintained through:

* Performance of periodic inventories [e.g., every thirty (30) calendar days]   during the storage period; and

* Performance of a final inventory upon removal of the waste materials from the storage area for disposal.

Inventory practices shall be followed to verify the quantity of these materials and to ensure that the packaging is not tampered with prior to shipping the materials for destruction.

Materials and Products that are Considered as High Risk, High Value or Controlled Substances (e.g., Viagra, genotropine, psychotropics) shall be stored according to local regulations and in an area with the following security measures:

* Double barrier protection;

* Access controlled by electronic entry control system (card reader); or

* Close Circuit TV (CCTV) surveillance.

If required, classify materials or products as high risk, high value, or controlled substance.

Microbiology Laboratory and Production Area Biohazard Wastes shall be deactivated by Sterilization or incineration prior to disposal using a method that assures the wastes have been deactivated. Disposal of all other biohazard wastes shall be conducted according to site waste management procedure and shall be handled by personnel qualified specifically to handle such materials.

Drug Products, Active Pharmaceutical Ingredients (API), Medical Devices, and Drinkable Alcohol that become rejected or other classes of waste material subject to potential misuse shall be rendered unusable and destroyed in a manner that prevents off-Site use or consumption.

Outdated and Obsolete Packaging Materials and Excess Coded Labeling Materials shall be destroyed as soon as practical. Complete records shall be kept of the identification of the material by name and Packaging Material Lot Number, quantity destroyed, person(s) involved, and date.

Materials and Product Destruction Plan(s) shall be developed by the Site Waste Disposal Team for rejected and waste materials and products. The plan shall be approved by the Site Waste Disposal Team and a copy of the approved plan provided to the Site Quality Team.

The Quantities of Rejected and Waste Materials and Products Disposed shall be reconciled. If the quantity cannot be reconciled, site security team should be contacted.

Empty Containers shall be disposed of and SOPs, if the containers were formerly used for any of the following items:

* Raw Materials (RM),

* In-Process Materials,

* Intermediates,

* APIs,

* Drug products,

* Components,

* Biohazard materials, or

* Laboratory waste.

1. 1. 3. Material Status Indication

Material Status Indication is to be provided either by a Validated Computerized System, use of status labels, or clearly designated locations, unless otherwise specified in this

Current status of all the following materials should be readily identifiable:

* Raw Materials (RM);

* Starting Materials;

* Packaging Materials including Labeling;

* In-Process Materials;

* Drug Products;

* Intermediates;

* Medical Devices;

* Components;

* Active Pharmaceutical Ingredients (API);

* Returned Goods, including Recalled product;

* Materials determined to be Acceptable for Rework/Reclaim;

* Rejected Materials; and

* Materials with Direct or Potential Indirect Product Contact, including cleaning materials and other items.

This practice document applies to GMP operation sites, manufacturing functions and Logistics Centers responsible for the Production, control, and distribution of Pharmaceutical and Animal Health, drug products, APIs, and medical devices.

Raw Material Lots, Component Lots and Packaging Material Lots, upon receipt, shall undergo the following steps:

* Assigned a Raw Material Lot Number, Component Lot Number,or Packaging   Material Lot Numbers;

* Provided status indication or protection; and

* Immediate inspection for, and removal or defacing of any status indicators on the received materials.

Each Container that has been Sampled is to be identified by a readily visible label as having been sampled.

Standard Material Status Categories to be used:

* Approved -materials tested or examined by the Quality Team and declared acceptable by written notice;

* Quarantine -materials expected to be approved, but not yet fully tested or approved;

* Quarantine-HOLD -material, regarding which some evidence exists to suggest might not be approvable for its originally intended purpose, and disposition of which is yet to be determined (Note: Quarantine-HOLD status cannot be assigned to a portion of a Lot unless a new Batch Number or Lot Number is assigned to the questionable portion.);

* Recalled -finished product recalled from the market, final disposition of which has not been determined [may involve other Market Action materials];

* Acceptable for Rework/Reclaim -material that has been declared in writing by the Site Quality Team to be reworkable or reclaimable by following a specific,     approved, written procedure;

* Sampled -containers of material that have been sampled and/or evaluated in place (e.g., Near IR); and

* Rejected -material found unsuitable for approval, reclaim, or rework that should therefore be destroyed or returned to a non-Site Supplier.

Approved, Quarantine, and Quarantine-HOLD status labels should identify;

*       Date applied, Batch or lot number, and Name of the person who applied the status label

*       When Status of a Material is Downgraded, immediate action should be taken to alter all of its status indications.

*       Rejected Material should be physically isolated in Dedicated Materials Status Areas or controlled using a validated computerized system. Status labels signifying rejected status should be applied to each container of the lot or to at least two sides of the unitized pallet containing the drums/containers unless the materials are stored in a automated warehouse controlled by a validated computerized system.

Visible status indication shall be applied as soon as rejected materials leave the automated warehouse for on-site disposal or waiting to be shipped for off-site destruction During transport of rejected material, measures should be taken to ensure that it is attended when unsecured.

Quarantine-HOLD Material is to be physically isolated in dedicated material status areas or controlled using a validated computerized system.

Recalled Material is to be physically isolated from all non-recalled materials, clearly identified as recalled material with status labels or area signs, and stored in secure, dedicated material status areas or controlled using a validated computerized system until disposition is determined. (Recalled material may have to be retained for possible regulatory inspection.)

Returned Goods that have been outside Site custody shall be assigned Quarantine-HOLD status and moved into Quarantine-HOLD dedicated areas immediately after the initial receipt and inspection process has been completed or controlled using a validated computerized system. The Quarantine-HOLD status shall continue until sufficient information is available for the Quality Team to reclassify the status.

Returned Materials Other than Drug Products, APIs or Medical Devices (e.g., in-process materials, RMs, packaging materials, or components), that have been outside Site custody, are to be held in Quarantine status until sufficient information is available for the Quality Team to assign a new status.

Receiving Docks and Loading Docks are to be organized in such a way that incoming materials and outgoing materials of different status designations are adequately separated from each other to prevent mix-ups, and/or provided with visible status indication controls.

Locations for Quarantined or Approved Drug Products, Medical Devices or APIs may be used without requiring status labels on each container, provided that:

* Prominent signs are displayed in Quarantine Areas that read “All Material in this Area is Quarantined Unless Otherwise Labeled”;

* Prominent signs are displayed in Approved Areas reading “All Materials in this Area are Approved”;

*The areas are bounded by walls, colored lines, or chains (e.g., supported by wall hooks or portable stanchions), or by colored netting or tarpaulins that cover the material; and

* No material of any status other than that designated is to be stored in the location.

Upgrading of Any Status Designation should be approved by the Site Quality Team. Stock Rotation Practices shall be on a First-In-First-Out (FIFO) and/or First-Expire-First-Out (FEFO) basis for use of all Approved materials unless there is written supervisory approval to allow temporary deviations from this process. Used Containers that bear status labels or status indicators should have such status indicators physically removed or clearly defaced (e.g., crossed out) as soon as the container is emptied and before it is moved from the area.

1. 1. 4. Material Supplier Approval

This practice document defines the process for identifying Suppliers to be audited and the process for conducting and documenting such audits and approving suppliers.

Disposable items, such as filters, filter cloths, and drums used for storage of materials (non-product contact), sanitizing agents, regeneration materials and certain quality control lab Reagents are not included in the scope of this practice document.

This practice applies to GMP production sites and operations responsible for purchasing production materials for use in Active Pharmaceutical Ingredients (API), Drug Products and Medical Devices.

Production Materials shall be purchased only from Approved or Conditionally Approved Suppliers.

Each Supplier will be assigned two classifications:

* Supplier Audit Rating, and

* Supplier Status.

Both classifications are specific with regard to manufacturing location(s) and production material concerned.

A Supplier Audit Rating shall be assigned as one of the three following categories and represents one of the measures used to determine whether a specific production material manufactured at specified location(s) may be purchased from the supplier:

* Acceptable Supplier -audit rating of a supplier which recommends that  may continue current business, initiate new business, and may purchase additional similar product types (e.g., Magnesium Stearate vs. Sodium Stearate) without conducting additional audits;

* Conditionally Acceptable Supplier -audit rating of a supplier which recommends that  may conduct business with the supplier, but with additional testing requirements or other conditions, as specified by the Site Quality Team; or

* Unacceptable Supplier -audit rating of a supplier which recommends that  should suspend current business and shall not initiate new business with the supplier.

A Supplier Status is a status assigned to a supplier to indicate whether a specific production material manufactured at a specific location may or may not be ordered from the supplier. There are three types of Supplier Status:

* Approved Supplier -supplier status that indicates production materials specified may be ordered from the supplier when manufactured at a specific location;

* Conditionally Approved Supplier -supplier status that indicates production materials specified may be ordered from the supplier when manufactured at a specific location only when certain conditions have been satisfied, as defined in the Supplier Audit Report, or as otherwise defined by Site Quality Team; and

* Unapproved Supplier -supplier status that indicates production materials specified may not be ordered from the supplier when manufactured at a specific location.

Two Types of Production Material Supplier Lists shall be maintained:

* Supplier Audit Master List, and

* Site Approved Supplier List.

The Site Quality Team shall be responsible for the following audit related activities:

* Review and issue Supplier Audit prioritization and schedules;

* Conduct Supplier Audit;

* Issue Supplier Audit Report;

* Assign Supplier Audit Rating;

* Send copy of the Supplier Audit Report which includes the Supplier Audit Rating to:

            –           Quality Audits Team,

            –           Representative of the supplier audited,

            –           Site Quality Team;

            –           Site Leadership Team; and

            –           Site Procurement team at all  Sites involved with the Supplier;

* Follow up on any Supplier Audit action items or findings;

* Update in the Supplier Audit Master List (Supplier Audit Database) the manufacturer and location of materials procured and the user Sites that procure them; and

* Determine if an approved supplier of a specific production material requires another audit before supplying a similar and/or different product type to .

1. 1. 5. Raw Materials and Packaging Materials – Receipt

This practice document defines the receipt and storage of Raw Materials (RM), Components and Packaging Materials used in the manufacture and packaging of Active Pharmaceutical Ingredients (API), Drug Products and Medical Devices.

Receiving and storage procedures for raw materials, components, and packaging materials shall be designed to ensure the identity, quantity, and conformance to Specification of each shipment of each Supplier Lot of material.

This practice applies to GMP production sites and operations responsible for the receipt of raw materials, components, and packaging materials for use in the production of Pharmaceutical or Animal Health products.

Raw Materials, Components, and Packaging Materials shall, upon receipt, be Verified by examination of receipt records and inspection of Labeling and materials to be:

* Free from apparent physical damage and contamination;

* The proper material correctly identified; and

* The correct quantity, according to the matching Site purchase order.

In addition for bulk raw materials received in bulk carriers (e.g., tank trucks or railroad tank cars) that are not pressurized, tamper-evident seals shall be verified as being in place and intact on openings and on capped discharge lines. Where the bulk carrier may also be used for transport of other bulk materials (i.e., non-dedicated tankers), evidence of cleaning (e.g., cleaning certificate) from the prior load shall be examined.

Materials not meeting the above requirements shall not be accepted and the Site Quality Team immediately notified about the unacceptable material.

Following a Successful Inspection or Examination, the received materials shall be promptly stored under Quarantine status, and subsequently sampled by Qualified personnel.

Materials with Direct or Potential Product Contact, such as process or product filters, filter aids, cleaning agents, and lubricants, shall be received in the same manner as raw materials, components, and packaging materials. Sampling and testing requirements for these materials shall be defined by the purchasing specification.

Each Supplier Lot of Either Raw Materials, Components, or Packaging Materials shall be assigned a Raw Material Lot Number, Component Lot Number,ora Packaging Material Lot Number, respectively, for each shipment of each supplier lot received.

Raw Materials, Components, and Packaging Materials shall be received for use in site products only if they are purchased from Approved Suppliers.

Intact Container Seals and the Absence of Container, Damage or Evidence of Contamination shall be verified for materials received in bags, drums, or any other container except bulk carriers (e.g., tank truck or railroad tank car) during or immediately after unloading of each container or group of containers.

Containers or lids shall be cleaned prior to opening or use (e.g., for sampling). Unprotected areas of product contact surfaces of discharge chutes, line, or hoses used for unloading bulk carriers shall be cleaned prior to unloading.

Labeling for Internal Production Control shall be completed after receipt and before sampling, and should display the following information:

* Name of the material per specification;

*The Site material code; and

* The Site Lot Number.

Complete Records for the receipt of materials shall be kept for each shipment of each lot and shall include the following:

* Purchase order copy;

* Packing slip or delivery note;

* Identity of the material by its name in the specifications;

* Total quantity and number of containers received;

* Supplier name and supplier lot number, if available;

* Name and location of manufacturer, if known;

* A Site lot number assigned to each shipment of each lot (to be used for recording Disposition, use, and reconciliation of the shipment);

* Date of receipt and the name or names of qualified personnel who received the material; and

* Relevant comments made by personnel during receipt.

1. 1. 6. Sampling of Production Materials and Finished Goods

This practice document defines the requirements for a sampling program for:

* Raw Materials (RM),

* Starting Materials,

* Packaging Materials,

* Labeling,

* In-Process Materials,

* Intermediates,

* Active Pharmaceutical Ingredients (API),

* Drug Products,

* Biologics,

* Medical Devices,

* Medical Device Components, and

* Materials with Direct or Potential Product Contact.

A Sampling Program, Which Includes Written Sampling Plans and Methods Approved by the Site Quality Team shall be available at each Site to achieve and not be limited to, the following:

* Obtain representative samples;

* Label sample Containers;

Identify containers sampled;

Maintain sample records; and

* Provide instructions for sample storage.

All Sampling shall be conducted following a written and approved sampling plan. Sampling Plans and Methods shall be included or referenced in Standard Operating Procedures (SOP), Manufacturing and Packaging Instructions, Device Master Record (DMR)or Specifications, as applicable.

For Commodity Materials, the Site Quality Team shall perform an assessment to determine the need for sampling. If sampling is required, a sampling plan and a sampling method shall be established.

Reserve Samples representative of each Batch or Lot of APIs and raw materials (RM) (other than Solvents, gases, hazardous or toxic materials, and water), used in the Production of drug products, and medical devices with Expiration Dates shall be taken in twice quantities needed to perform all required tests except sterility and pyrogen testing.

Sampling shall be performed by Qualified personnel.

Sampling Areas shall be designed to:

* Prevent contamination of open containers, materials, and the sampler;

* Prevent Cross Contamination by Other Materials, products, and the environment; and

* Protect the sampler during the sampling operation.

Sampling Plans shall be based on, and not limited to, the following:

* Regulatory commitments;

* Statistical (e.g., ANSI) rationale;

* Quality history of the Supplier and

* Quantity needed for analysis and reserve samples.

Sampling Methods shall include details and any special controls, or precautions to ensure that the integrity of material being sampled is maintained, and to protect the safety of the sampler.

Sample Containers shall protect the physical, chemical, and biological properties of the sample. Samples for sterility testing shall be taken in Sterile containers, and samples for Bacterial Endotoxin tests shall be taken in containers essentially free of endotoxin. Aseptic Technique shall be used when required.

Raw Material (RM) or Packaging Material Containers That Have Been Sampled shall be marked or labeled to show that samples have been removed. Permanently installed vessels (e.g., tanks, blenders, manifolds) and tanker trucks are exempt from such labeling.

Sample Storage Conditions shall be designed to protect sample integrity. Such conditions shall be consistent with the normal or approved label storage conditions with respect to temperature, humidity, light, and other applicable environmental factors.

A Description of the Sample Received for Testing should be retained as part of the Laboratory Records.

Preparation of Composite Samples or Subdivision of a Sample shall be described in SOPs.

Samples Removed from a Container shall not be returned to the material from which they have been taken, to preserve the integrity of the material that was sampled.

Resampling should be done according to a sampling plan approved by the Site Quality Team.

Use of Samples taken by the supplier prior to shipment (“preshipment” samples or “tailgate” samples) should be approved by the Site Quality Team.

Shipping of Samples to an Off-Site Facility for Testing (i.e., to another Site or an external laboratory) should be performed in a manner that will maintain the integrity of the sample during shipping, including protection from the normal shipping conditions (e.g., moisture, temperature, breakage).

Sample Destruction -after testing is complete, samples shall be destroyed following a written and approved SOP. Samples should be disposed of in a manner that precludes further use as per Environmental Health and Safety (EHS) requirements.

Sampling of Hazardous or Toxic Materials shall be evaluated by Environmental Health and Safety principals, the Site Production Team, and Quality Team for the potential impact on personnel safety and health, and the environment. If a determination is made to not sample such materials, a Certificate of Analysis (COA) should be obtained and reviewed by the Site Quality Team, showing that these raw materials (RM) conform to established specifications.

Containers of Materials to be Sampled shall be cleaned before opening; then opened, sampled, and resealed in a manner that protects the integrity of both the sample and the material being sampled (i.e., prevents mix-ups and contamination from environmental conditions).

Samples for Sterility Testing shall be representative of the entire batch, and include samples from parts of the batch most at risk of contamination. For aseptically filled products, samples shall include containers from the beginning, middle, and end of the batch and after any significant work interruption.

Sample Labels shall contain or reference (e.g., barcode), and are not limited to, the following information:

* Material name and code;

* Batch or Lot Number;

* Date of sampling;

* Sample source (e.g., drum number); and

* Identification of person taking the sample.

If a bar coded label is used on the sample container, the label should include a unique identification code that is traceable to the sampling record.

Training and Qualification of Samplers shall include, and are not limited to:

* All applicable sampling plans and sampling methods;

* Precautions necessary to protect the sample being taken from becoming contaminated or mixed up with other samples;

* Precautions necessary to protect the container being sampled from contamination or being mixed up with other materials; and

* Handling precautions and protective gear necessary for the safety of the samplers and others.

Sample Records [e.g., Laboratory Records, Batch Records] shall enable tracing the sample test results to the actual sample and shall include, and are not limited to, the following:

* Material name and code,

* Sample source,

* Quantity of sample,

* Batch or lot number,

* Identification of sampler,

* Date sample taken, and

* Date sample received in lab.

Reserve Samples of each API Batch or Lot used to manufacture a drug product or finished medical device bearing an expiration date shall be retained at the drug product or medical device manufacturing Site using the API, unless otherwise stated in the Quality Agreement.

The reserve samples shall be retained for, whichever of the following is longest:

* At least one year after the expiration date of the last lot of the drug product or medical device containing the API; or

* At least one year after the expiration date of the API batch, or

* At least three (3) years after distribution of the batch.

For APIs with Reevaluation dates, reserve samples shall be retained for at least three (3) years after the batch is completely distributed by the API manufacturer.

Reserve Samples of each Raw Material Lot (other than solvents, gases, hazardous or toxic materials, or water) shall be retained for at least two (2) years after approval of the drug product in which the raw material (RM) was last used. Retention of reserve samples of raw material lots used in medical devices shall be defined in a Site SOP.

Quantity of Reserve Samples of each API batch, raw material lot, each drug product lot, and each medical device lot shall consist of at least twice the quantity necessary to perform all tests, except for sterility and pyrogen testing, required for approval of the product.

The Packaging Configuration for API Reserve Samples shall be the same as or equivalent to the packaging configuration of the marketed product. If equivalent packaging configurations are used, documented evidence should be maintained to demonstrate that the packaging configurations are equivalent to or more protective than the packaging configurations used for marketed product.

Storage Conditions for All Reserve Samples shall be consistent with material’s labeling.

Reserve Samples of Each Lot of Drug Product shall be retained for at least one year after the expiration date, or three (3) years after distribution if the product does not contain an expiration date.

Reserve Samples of Each Lot of Finished Medical Devices with an Expiration Date shall be retained for at least one year after the expiration date. Retention of reserve samples of each lot of finished medical devices without an expiration date shall be defined in a Site SOP (e.g., medical device included in a stability program, Risk Analysis).

Storage of Reserve Samples of Drug Product shall occur in the same immediate Container Closure System and packaging configuration as the marketed drug product.

Retention Time for Reserve Samples of an API in an Over-The-Counter (OTC) Drug Product or Medical Device that is exempt from bearing an expiration date is three (3) years after distribution of the last lot made with that batch of API.

Regulatory Exceptions: Reserve Samples of Drug Products shall be visually examined at least once per year for evidence of deterioration unless such examination would affect the integrity of the sample. Any evidence of reserve sample deterioration shall be investigated. The results of the examination shall be recorded and maintained with other stability data on the drug product.

The identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample. It is permissible to sample only a portion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labeled.

Procedures are in place to ensure the identity of contents of each container. Containers from which samples have been drawn are identified.

For Products Heat Sterilized in the Final Container, sterility testing shall include samples from the coolest part of the batch.

A retention sample should represent a batch of finished products as distributed in the European Economic Area (EEA) and may need to be examined in order to confirm non-technical attributes for compliance with the marketing authorisation or EU legislation. Therefore retention samples should in all cases be located within the EEA.

Where an operational Mutual Recognition Agreement (MRA) is in place and reference sample are retained at a manufacturer located in a country outside the EEA, separate retention samples should be kept within the EEA.

1. 1. 7. Storage and Distribution of Drug Products, Medical Devices, and Related Materials

This practice document defines the storage and distribution requirements for Drug Products, Medical Devices and related Production Materials stored at GMP sites or Logistics Centers, and/or transported between sites or from sites to Logistics Centers.

This practice applies to Production Sites and Logistic Centers where Pharmaceutical and Animal Health drug products, medical devices, and related production materials are stored, and/or from which such items are distributed.

Storage Areas with clean, dry, and orderly conditions chosen to ensure quality and security shall be provided for all production materials, drug products, and medical devices. Production materials, drug products, and medical devices shall not be stored unprotected outside buildings.

Environmental Storage Conditions shall be Approved by the Quality Team and shall be based on temperature, humidity, exposure to light, and any other environmental factors known to affect the stored material.

Storage Conditions that Match Temperature and Humidity Requirements (i.e., labeled storage conditions) shall be provided for all production materials, drug products, and medical devices.

Temperature shall be monitored against defined limits and when humidity control is required (e.g., as stated on a Label or Specification), humidity shall also be monitored against defined limits.

Security of Stored Items shall be ensured by establishing and maintaining a system of access control and authorization for entry for each storage area.

Drug Product Lots, Medical Device Lots, and/or Production Materials Lots shall be stored in Dedicated Material Status Areas according to the current status assigned to the material or product.

Storage Off the Floor with Sufficient Cleaning/Inspection Space, or alternative measures for cleaning, shall be provided for all production materials, drug products, and medical devices.

Transport of Production Materials or Products from areas that make penicillins, cephalosporins, other β-lactam antibiotics, or cytotoxic and other highly sensitizing materials to areas that process any other product is prohibited.

Approved Products shall be used or shipped based on a First-In-First-Out (FIFO) and/or First-Expire-First-Out (FEFO) basis. Temporary Deviation is permitted when approved by the Quality Team.

Different Lots or Batches, including Raw Material Lots, Packaging Material Lots, other production materials, and products, shall be kept physically separate in storage.

Drug Product Lots, Medical Devices Lots, or Production Materials Lots with a Status Other than Approved shall be transported or shipped:

* From one Site to another Site only with written approval by the Quality Team of the sending Site and establishment of the same material status upon receipt at the receiving Site; or

* From a Contract Vendor to any Site only with prior written approval by the Site Quality Team of the receiving Site and establishment of the same material status upon receipt at the receiving Site.

Transportation Conditions shall prevent alterations to the potency, purity, or physical properties of any product. Transportation procedures for products requiring special conditions (e.g., temperature controls) shall be based on stability data.

Security Measures for vehicles carrying inbound packaged drug product and/or medical devices, or intended for outbound packaged drug product and medical devices, shall be established to ensure that the identification of the driver and carrier are properly verified.

Preshipment Vehicle Inspections for Cleanliness and Integrity shall be performed prior to loading.

Before Unloading, Vehicle Inspections shall be conducted to identify any unusual damage from load shifts during transit or problems involving structural integrity or cleanliness of the carrier vehicle.

During and Immediately after Unloading Site products from a carrier, all containers shall be inspected to verify that:

* Observable onboard merchandise appears properly labeled and free from apparent damage or contamination;

* Shipment quantities match quantities and merchandise expected (e.g., verify against the manifest or packing list); and

* Security seals applied to the carrier are in place.

Receipt of Drug Products and Medical Devices Shipped Under Quarantine Status shall be performed according to specific procedures that include removal from Quarantine only after receipt of written authorization from the shipping Site Quality Team and Verification that the status is being changed on the correct lot.

Drug Products and Medical Devices Received shall be protected from potential mix-up with other incoming and outgoing drug products and medical devices by spatial separation and by promptly moving the received materials to the correct storage locations.

Returned Goods are to be promptly relocated from the unloading dock to an area dedicated to Returned Goods. Expiry Dates of Drug Products and Medical Devices shall be monitored and products approaching their Expiration Date shall be removed from inventory according to  policies and procedures. Drug Product and Medical

Device Distribution Records shall be maintained at the responsible Site and/or Logistic Center that indicate where such products were shipped to and where the products were received from, to enable traceability of the drug products and/or medical devices during a Market Action (e.g., Recall).

Distribution Quality Representative shall be designated for distribution operations. Drug Products and Medical Devices That are Picked and Packed for Shipment shall be verified to ensure accuracy of the shipment. Verification may include a weight check or barcode reader.

Damaged Cases shall be examined to ensure that the product inside is not damaged. It may be necessary to open a damaged case to inspect the product inside. Damaged Product shall be destroyed. Any questions regarding the determination of damaged product shall be directed to the Distribution Quality Representative.

Wooden Pallets are prohibited in areas where product is exposed. A risk assessment is required to justify use of wood pallets in other Production Areas.

Wood Packaging Material (including pallets, crating, packing blocks, drums, cases, load boards, pallet collars, skids) made of coniferous and non-coniferous raw wood, used in international trade shall be treated [e.g., heat (HT) or methyl bromide (MB) fumigation] to eliminate potential Pests in the wood. Such treated wood materials shall be marked to indicate the treatment method used (e.g., HT or MB).

Markings shall be legible, permanent and not transferable, and placed in a visible location on at least two (2) opposite sides of the article being certified. Recycled, remanufactured, or repaired wood packaging material shall be recertified and re-marked.

1. 1. 8. Subdividing Dispensing & Transferring Materials to Production Areas

When Materials are Subdivided into another Container or containers, or when materials are dispensed, the new container(s) shall be fully identified with at least the following:

*      Material name and item code;

*      Site Batch Number or Lot Number;

*      Weight or measure and unit of measure in new container;

*      Container number, if applicable;

*      Lot or batch for which material is intended to be used (including product name, lot or batch number, and strength if applicable); and

*     Indication of Approval by the Quality Team.

This practice document applies to GMP sites and operations where materials are subdivided and transferred to Production areas for use in the manufacturing of a Medical Device, Drug Product, or Active Pharmaceutical Ingredient (API) for Pharmaceutical or Animal Health.

When Materials are Dispensed, every container of a material intended for manufacture shall be identified, and both the identity and quantity of the dispensed material Verified prior to delivery to the processing area.

Dispensing Records for Each Component Lot, Raw Material Lot, Packaging Material Lot and Lot (or Batch)of Intermediate or In-Process Material should be maintained to allow reconciliation of use in subsequent production of a medical device, drug product or API, or other dispensing of the material, compared to the original lot (or batch) quantity.

Components, Raw Materials (RM), and Packaging Materials are to be examined upon receipt into processing areas for proper identification, status indication, and appearance; also, quantity received is to be verified against quantity expected.

Physically Separated, Dedicated Area(s) shall be used for subdividing and dispensing materials.

Areas Used for Subdividing and Dispensing (including dust collectors in the area, manifolds, and/or hoses in the area for remote dust collectors, and other equipment used) shall be cleaned between materials and a log kept of both the area usage and cleaning.

1. 1. 9. Quarantine Shipment

This document describes the practices and communication necessary to ensure that, under the conditions of Quarantine shipment, there is no risk of unreleased (or unapproved in the case of staging for launches) product being delivered to the next recipient in the supply chain (next manufacturing step or customer) without proper notification.

This document describes practices for shipping the following types of materials under Quarantine between Sites and 3rd parties (and vice versa):

* Excipients,

* Intermediates

* Printed materials,

* Active Pharmaceutical Ingredients (APIs) and Starting Materials,

* Bulk material (Drug Product),

* Semi-finished goods (drug product),

* Clinical finished goods destined for clinical testing sites,

* Finished goods (drug product), and

* Medical Devices.

Quarantine Shipments Types include:

* Exceptional Quarantine Shipments, and

* Routine Quarantine Shipments.

GMP sites and Approved 3rd Parties that send and receive the materials under quarantine shall have quality systems in place to ensure that all such materials:

* Are received under Quarantine,

* Are controlled, and

* The release of the associated finished product will not occur until these materials are properly and completely evaluated and released.

GMP sites and Approved 3rd Parties that send the materials under quarantine shall inform the receiving site and other recipients of the quarantine shipment details immediately and agree on the necessary steps to be taken, when the sending site identifies an issue after the material has left the sending site.

For All Quarantine-Shipments, the following requirements should be in place:

* Manufacturing Deviations are closed and manufacturing documents have been reviewed;

* Manufacturing process is robust (i.e., risk of need for re-sampling is low);

* The sending site has systems in place to keep track of materials shipped under quarantine;

* The sending site maintains all documents required for Quarantine shipment (e.g. Risk Assessments, assessment of 3rd party’s ability to receive Quarantine shipments). If the sending site is a 3rd party, the receiving PGM Site also should keep a full set of the documents;

* The receiving site should have procedures in place to receive goods under Quarantine;

* The receiving site has capacity and systems in place to store Quarantine material; and

* The receiving site has systems in place that assure Quarantine materials remain in Quarantine status pending notification by the Sending Site of status change, and to track Lot status and history.

Exceptional Quarantine Shipments of Intermediates:

The basic requirement for exceptional Quarantine shipments of Intermediates is a pre-shipment document exchange between the sending and the receiving sites for each lot or group of lots) shipped using a Quarantine Shipment Form (QSF).

Any transitional shipping site (if any) shall be informed by sending them a copy of the QSF but it is not necessary that they approve the shipment.

Routine or Standard Quarantine Shipments of Intermediates:

In addition to the requirements listed in this practice document, the following requirements should also be in place at the receiving site for routine or standard Quarantine shipments of Intermediates:

* Evaluation of added value of Quarantine shipment should be documented. The added value should justify the risk;

* Formal agreement between sending and receiving sites including a description of responsibilities;

* Procedures that describe receipt of goods under Quarantine, as a minimum;

* Deviation system and procedures that accommodate use of the material before it is released by the sending site (for example, packaging at risk); and

* Procedures and systems to check that all components are released before next or final stage release is given.

Any transitional shipping site (if any) should be informed of this standard shipment procedure, but need not approve the process.

Exceptional Quarantine Shipments of Finished Products:

The basic requirement for this is a pre-shipment document exchange between the sending and the receiving sites for each lot shipped, using a Quarantine Shipment Form (QSF).

In addition to the requirements listed in this practice document the following controls should be in place:

For all exceptional shipments to a site, before a QSF can be issued:

The receiving site should have procedures and systems in place to ensure that goods are released by the sending site before final release to the market is given by the receiving site.

In addition, if the receiving site is a 3rd party [e.g., Logistics Service Providers (LSPs) or a local distributor]the following controls should also be in place:

The 3rd party receiving site is approved, based on:

            –           Robust quality systems especially in the areas of training, product segregation, deviation handling, SOPs, and complaint handling;

            –           Computerized systems controlling goods;

            –           Quality record (audits, incident level);

            –           Coverage of Quarantine-shipment in Quality Agreement; (Exceptional Quarantine Shipments of Finished Products.

There is close Site Quality Assurance (QA) oversight (a person within Site having that responsibility as part of his/her job function) of the 3rd party; and

The Site QA oversight should approve and takes responsibility for securing each individual Quarantine shipment (part of QSF to be signed by Quality Assurance oversight).

The Quality Manager for the sending site shall be informed about the shipment(s) by issuing a copy of the QSF. For shipments to 3rd parties the responsible Logistics QO

Regional Managers should approve the shipment(s) by signature on the QSF. In addition, any transitional shipping site (if any) shall be informed by receiving a copy of the QSF, but they do not need to approve the shipment.

Routine or Standard Quarantine Shipments of Finished Products:

Only products demonstrating a robust manufacturing and testing performance shall be shipped using this process. In addition to the requirements from this Practice, the following controls should be in place:

* Risk Assessment for the shipping route, which takes into consideration the control and communication of the release status, the level of control provided by the receiving site’s systems, the sophistication of sending and receiving site systems to control and manage inventory; and

* Assessment of added value.

If the receiving site is a 3rd party the following additional requirements should be in place:

The 3rd party receiving site is approved based on:

            –           Robust quality systems; especially in the areas of training, product segregation, deviation handling, SOPs, and complaint handling;

            –           IT systems controlling material status;

            –           Restricted number of people having the right to change status (site needs to have a QO group);

            –           Good quality record (audits, low incident level); (Routine or Standard Quarantine Shipments of Finished Products

Coverage in Quality Agreement (QA) signature needed on the Quality Agreement in addition to local signatures);

Close Site QA oversight; and

Systems to release goods such as:

            –           Site having access to 3rd Party Systems;

            –           Site and 3rd Party Systems linked; or

            –           Site system is at 3rd Party.

Any transitional shipping site should be informed of this standard shipment procedure, but does not need to approve the process.

Labels to Identify Quarantine Shipments shall be used if deemed necessary and designed and agreed to by the sending and receiving sites, and described in their SOPs. The Quarantine Shipment Authorization (QSF) shall contain at a minimum:

* Product Name,

* Item Number of Sending Site,

* Batch/Lot number(s),

* Quantities,

* Expiry date,

* Name and Address of Receiving Site,

* Justification for sending,

* Shipping Order,

* Date of Shipping,

* Planned release date,

* Name, Function/Title, Signature and Date of Approver at Sending Site, and

* Name, Function/Title, Signature and Date of Approver at Receiving Site stating clear acknowledgment of Acceptance of Request.