Consultant, Harmony, Pennsylvania, U.S.A.
§211.80 GENERAL REQUIREMENTS
(a) There shall be written procedures describing in sufficient detail the receipt, identifi- cation, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed. (b) Components and drug product containers and closures shall at all times be handled
and stored in a manner to prevent contamination.
(c) Bagged or boxed components of drug product containers or closures shall be stored off the floor and suitably spaced to permit cleaning and inspection.
(d) Each container or grouping of containers for components or drug product containers or closures shall be identified with a distinctive code for each lot in each shipment received. This code shall be used in recording the disposition of each lot. Each lot shall be appropriately identified as to its status (i.e., quarantined, approved, or rejected).
The general requirements again emphasize the need for written procedures, which are to be followed. Details on typical procedures and compliance issues are presented later under Section 211.100.
During storage, handling, and sampling, materials are potentially vulnerable to con- tamination. Warehouses are designed to allow easy access for delivery vehicles; however, this also allows access to rodents, insects, birds, extraneous dust, and vehicle exhaust fumes. This unwanted access can be minimized by separating the actual delivery area from the main storage area by doors or air curtains. Certain raw materials, such as sugar and starch, can attract pests and it is therefore important that any spillages be quickly cleaned up.
Cartons, barrels, and rolls of packaging materials should be stored on pallets or racks to facilitate cleaning, inspections, and pest trap placement. Since these precautions are still unlikely to completely prevent access to insects and other sources of contamination, extermination, or elimination, programs are required to control insects and rodents.
Pest monitoring and maintenance programs typically involve a combination of both chemical and nonchemical prevention and control techniques. Integrated pest management is a more effective program than through the utilization of any one technique. Rodents can usually be controlled by the placement of baitless traps; the use of poison bait is not acceptable in a pharmaceutical establishment. Insects are frequently eliminated by the use of electric exter- minators, whereas birds may be trapped and then removed from the premises.
Many companies have implemented procedures that outsource the inspection, monitor- ing, managed product use, and record keeping requirements for management of insect and rodents. These procedures often require employees to make a notation in a Pest Sighting Log to keep a running record of pest sightings. These procedures compliment the program in order to monitor effectiveness of the program on a continuing basis. This monitoring component of the program ties into the recurring application of pesticides, trappings, or cleaning.
When containers of materials are opened for sampling, the contents have an increased vulnerability for contamination from other materials, microorganisms, or foreign particulate
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matter (dust). Warehouse conditions may not be suitable for sampling raw materials. Many companies have dedicated sampling areas (see §211.84). Therefore, the sampling techniques used and the sampling environment should be specified and controlled through written pro- cedures. The procedure(s) should specify whether a separate room provided with improved air handling systems, readily cleanable surfaces, and availability of dust extraction hoods (i.e., similar to a dispensing operation) must be utilized during sampling. Sampling techniques to prevent contamination, including acceptable containers and labeling requirements, should also be specified in the sampling procedures.
The requirement for a distinctive code for each lot of components received can be met by retaining the supplier coding where this is adequate. However, most companies establish a material coding system to uniquely identify each material. The coding system allows the manufacturer to trace the material through the receipt, quarantine, sampling, testing, and release/rejection process. This requires that the distinctive number be physically applied to all of the containers within each shipment.
The regulation also requires status identification. This has been interpreted as physical labeling of container during the receipt, quarantine, sampling, testing, and release process. A label with provisions for initialing and dating at each stage from receipt to release to manufac- turing can be used. It is now becoming common for manufacturers to apply bar codes to materials, which can be used to effectively monitor the use and movement of the material through its life cycle.
§211.82 RECEIPT AND STORAGE OF UNTESTED COMPONENTS, DRUG PRODUCT CONTAINERS, AND CLOSURES
(a) Upon receipt and before acceptance, each container or grouping of containers of com- ponents, drug product containers, and closures shall be examined visually for appro- priate labeling as to contents, container damage or broken seals, and contamination. (b) Components, drug product containers, and closures shall be stored under quarantine
until they have been tested or examined, as appropriate, and released. Storage within the area shall conform to the requirements of Section 211.80.
Visual examination of materials on receipt is an important quality step. This should confirm that the correct material has been delivered. The delivery information should be checked against the purchase order to ensure that the part number, product code, or descriptions are correct and that the expected quantity for each component or material has been received. The procedure for verifying the receipt of materials should be captured in a written procedure. The procedure should require some notation on the shipping documents to indicate that the inspection has been performed. In some cases, a checklist is used and included with the receiv- ing forms.
If any physical damage has occurred to the container, its potential impact on quality must be considered. Broken seals on containers may indicate that the container has been opened somewhere during transit. An opened container may indicate that the material may have been exposed to unacceptable environmental conditions and may give cause for alert for rejec- tion of the container.
Containers should also be examined for physical deformation and for visible signs of spillage from other materials, as well as for potential rodent attack. Since the possibility of deliberate sabotage exists, the suppliers should be encouraged to use seals with unique designs or logos to minimize the potential for deliberate tampering and to make it easier for the inspection process to document deliberate tampering. Since seals on outer containers are sometimes broken or lost inadvertently during transportation, examination of any inner seals may be required before a final decision can be made. All of these situations will require additional evaluation of the materials and could ultimately result in rejections. A final inspection of material and components should be required prior to use and the inspec- tion documented in the batch record. This additional check is particularly important if each container has not been individually inspected or opened earlier. In fact, low-frequency
defects in packaging components are more often detected during the filling/packaging process than by sampling on receipt.
It is also essential to confirm the name of the supplier; this is elaborated upon in §211.84. When materials are purchased through agents, these should be requested to identify the actual producer. The purchase of raw materials and packaging components is usually controlled under a supplier contract. This contract should specify the quality of the material, the manu- facturer, manufacturer’s part number/material code, and the supplier’s code if different. The contract should specify the information to be included in the certificate of analysis (CoA) when one is required to accompany the material shipment. Usually, specific test results with specifications are also specified in the contracts. A supplier contract must also specify prior notification if any material supplier or specification changes, since a change in supplier or specification may have an impact on product quality. A change in product supplier will require additional testing to qualify the supplier. This will eliminate any potential impact on the final product. Accelerated stability studies comparing the current and new materials are required and also, on occasion, accelerated comparative stability on the dosage form itself.
Section (b) refers to storage under quarantine until release. The acceptability of a system as an alternative to physical separation has been indicated previously in §211.42(c), which states that these operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups during the course of the all procedures from receipt of materials to disposition of the final product. The separation can be accomplished by using fenced areas with controlled access or separate rooms within a warehouse area. §211.84 TESTING AND APPROVAL OR REJECTION OF COMPONENTS,
DRUG PRODUCT CONTAINERS, AND CLOSURES
(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.
The need to withhold materials for use until released by quality control is laudable and equates to the normal situation. However, there are occasions when, for a variety of reasons, materials arrive at a plant site and are required for immediate use. These situations could be exacerbated by lengthy component testing such as microbial evaluation. If a situation such as this occurs, the drug product manufacturer must make the decision to “manufacture at risk” while a material is undergoing testing. The product must be placed in quarantine immediately upon completion of manufacturing until the final release of the material in question. Manufacturing at risk runs the possible risk of a product rejection. Obviously, the manufacturer would be cog- nizant of these potential financial risks and before initiating such an action would evaluate material and product history and the magnitude of the added value. However, the Food and Drug Administration (FDA) has specifically stated that such an approach is not acceptable since this “increases the risk to the consumer that an unsatisfactory lot might erroneously be released.” If a manufacturer were to choose this route, the procedures to ensure that the lot is not released until all testing is complete must be written and followed closely.
Deliveries of material to bulk storage require special mention. It is frequently impractical to hold a delivery vehicle until material can be fully evaluated. In such cases, it is usual to ensure that the CoA accompanies the delivery and that the more sensitive tests are performed before the material is discharged into the bulk storage system. In the event that the full analysis identifies a problem, it may be necessary to quarantine the contents of the storage tank until a comprehensive evaluation has been performed.
When a second delivery of a previously released material is received, it is still necessary to sample and evaluate. The conditions to which the later delivery may have been exposed could have differed from the original delivery. The same level of evaluation may not be necess- ary, but any parameter that might be affected by shipping and storage conditions should be examined.
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(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as stat- istical criteria for component variability, confidence levels and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by §211.70.
The quantity of material that should be sampled will depend upon the testing required. Manufacturers usually sample a quantity of material at least twice the size needed for testing when the cost of the material is not prohibitive. This allows for retesting if out of spe- cification results are obtained or material is spilled or contaminated during testing. During the qualification process for new suppliers, the qualification procedure may require more exten- sive sampling and evaluation until consistency in the product is demonstrated. This could also be the case for a new dosage form, which, although validated using a minimum of three batches, could still undergo process improvement/optimization. Additional amounts of sample could allow more extensive evaluation of the material in relation to these optimiz- ation studies.
(c) Samples shall be collected in accordance with the following procedures:
(1) The containers of components selected shall be cleaned, where necessary, by appropriate means.
(2) The containers shall be opened, sampled, and resealed in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used when necessary. (4) If it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions shall not be made into composites for testing. (5) Sample containers shall be identified so that the following information can be determined: name of the material sampled, the lot number, the container from which the sample was taken, the date on which the sample was taken, and the name of the person who collected the sample.
(6) Containers from which samples have been taken shall be marked to show that samples have been removed from them.
The process of sampling can itself pose risks of contamination. For this reason, containers may need to be cleaned prior to sampling—a vacuum system is very effective for a large container. Generally, an air-blowing system should be avoided because this is more likely to spread a potential problem. Small containers may be wiped down with an appropriate solvent or dis- tilled water. Containers should be opened for sampling in an acceptable environment that will not expose the material to further risk of contamination. For drug substances and excipi- ents, it is preferable to provide a sampling area with environmental conditions similar to those in manufacturing. This sampling area may be a designated room near or adjacent to the ware- house. Containers and closures can usually be sampled in the warehouse, but any outer pro- tective coverings should be securely replaced.
Materials requiring microbiological evaluation need to be sampled under more rigorous conditions involving the use of sterile equipment and a sterile environment for such sampling. The procedures used for sampling should be specified in written procedures. Employees must be properly trained in such sampling techniques and the training must be documented prior to sampling.
The regulations do not preclude the composing of samples for testing, except as indicated in (c)(4). If there is some doubt about the homogeneity of a component, it may be advisable to evaluate this by taking samples from various positions in the container. Obviously, the compo- siting of these samples would be scientifically invalid.
Upon completion of sampling of a container, the container must be labeled to indicate that material was removed from the container. The quantity of material removed should be included on the label as well as the date and the person sampling the material. It is very import- ant to ensure that the container from which the material is removed is resealed in a manner to prevent contamination when returned to the quarantine area. Barrels may be taped, bottles may have a stretch plastic film placed securely around the top, boxes should be taped, or other appropriate measures should be undertaken to ensure that the container is resealed. Some containers may include closures that prevent contamination and therefore no further sealing is required.
(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.
(2) Each component shall be tested for conformity with all appropriate written speci- fications for purity, strength, and quality. In lieu of such testing by the manufac- turer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.
(3) Containers and closures shall be tested for conformance with all appropriate written procedures. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that, at least, a visual identi- fication is conducted on such containers/closures by the manufacturer and pro- vided that the manufacturer establishes the reliability of the supplier’s test results through appropriate validation of the supplier’s test results at appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that is liable to con- tamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.
(6) Each lot of a component, drug product container, or closure that is liable to micro- biological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.
Components, containers, and closures used for production of pharmaceuticals must obviously comply with their quality specifications. As suppliers introduce effective pro- cedures and embrace the principles of vendor certification, the need for customer testing is reduced. However, basic caution and the Current Good Manufacturing Practice (CGMP) regulations do require that some testing be performed. For a new supplier, it will be necessary for the customer to perform full testing for a minimum of the first three lots of materials received from the supplier or the number of lots designated in the manufacturer’s sup- plier/vendor qualification procedure. Manufacturers should require that suppliers provide certificates of analysis, which can be used to compare supplier and customer results as a requirement of the ongoing maintenance of a qualification of a supplier process. The vendor approval status indicates that the supplier has submitted a predetermined number of lots of materials, which has been tested by the manufacturer with all tests meeting predetermined specifications.
After a supplier has been qualified, the certificates of analysis provided with each lot should refer to all of the agreed tests in the specification. Actual numerical values should be given for quantitative tests and limit tests should include the specification limit. Upon receipt of the material CoA, the manufacturer must compare customer and supplier results and ensure that all of the specifications are within the contracted limits. The CoA must be signed and dated by a competent person from the supplier. Any significant differences in
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results between supplier and customer must be investigated and the cause identified and