Subpart E: Control of components and drug product containers and closures

• General requirement:• There shall be written procedures describing

in sufficient detail the receipt, identification, storage, handling, sampling, testing and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.

• Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.

• Bagged or boxed components of drug product containers , or closures shall be stored off the floor and suitably spaced to permit cleaning and inspection.

• 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).

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• Receipt and Storage of Untested components, Drug Product Containers, and Closures:

• Upon receipt and before acceptance, each container or grouping of containers of components, drug product containers, and closures shall be examined visually for appropriate labeling as to contents, container damage or broken seals and contamination.

• Components, drug product containers and closures shall be stored under quarantine until they have been tested or examined, as appropriate, and released.

• Visual examination of materials on receipt is an important quality step. This should confirm that the correct material has been delivered, and if any physical damage has occurred.

• • Broken seals on containers may indicate that the

container has been opened somewhere during transit. And the material may have been exposed to unacceptable environmental conditions.

• The possibility of deliberate sabotage is very real as well, and suppliers should encouraged to use seals with unique designs or logos to minimize this potential foe 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.

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• Containers should also be examined for physical deformation and for visible signs of spillage from other materials as well as for potential rodent attack. These situation will require additional evaluation and could result in rejections.

• • Users of components during the production process

should also be required to conduct visual inspection prior to use.

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• In fact, low frequency defects in packaging components are more often detected during the filling/packaging process than by sampling on receipt.

• • It is essential to confirm the name of suppliers, when

materials are purchased through agents, these should be requested to identify the actual producer, otherwise the agent may interchange producers according to availability and price and without notification.

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• Any change in supplier may have an impact on product quality. To eliminate any potential impact it may be necessary to perform additional testing other than that included in the specification.

• • Section b refers to storage under quarantine till

release.•

• Testing , and Approval or Rejection of Components, Drug Product Containers and Closures:

• 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.

• There are occasions when a variety of reasons materials arrive at a plant site and are required for immediate use. The reason for this could include that delivery, rejection of the scheduled delivery, unexpected increase in sales, or rejection of the scheduled batch of drug product.

• Deliveries of material to bulk storage requires special mention. It is usually impractical to hold a delivery vehicle until material can be fully evaluated. In such cases it is usual to ensure that the certificate of analysis 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.

• • Any parameter that might be affected by shipping and storage conditions

should be examined.•

• 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 a statistical criteria for component variability, confidence levels and degree of precision desired, the past quality history of the suppliers and the quantity needed for analysis.

• Quality variability would rarely be a reason for increasing sample size.• • For new suppliers, it may be necessary to apply more extensive

sampling and evaluation until consistency is demonstrated.• • This could be the case of 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 optimization studies.•

• C- Sampling should be collected in accordance to the following procedures:

• • 1-The containers of components selected shall be

cleaned where necessary, by appropriate means.• 2-The containers should be opened, sampled, and

released in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers and 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 subdivision shall not be composited 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.

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• The process of sampling can itself pose risks of contamination. For this reason containers may need to be cleaned, a vacuum system is effective.

• • Containers should be opened for sampling in an acceptable

environment that will not expose the material for further risks.• • For drug substances and excipients it is preferable to provide a

sampling area with environmental conditions similar to that the manufacturing area.

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• An alternative is useful a portable laminar flow hood with dust extraction capability that can be placed over the materials to be sampled. This negates the need to move materials from quarantine to another area for sampling and then returning to quarantine afterword.

• • Materials requiring microbiological evaluation need to be sampled

under more rigorous conditions involving the use of sterile equipment. Employees must be properly trained in such sampling techniques.

• • 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 compositing of these samples would be scientifically invalid.

• D- Samples shall be examined and tested as follows:

• 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.

• Each component shall be tested for conformity with all appropriate written specifications for purity, strength and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier.

• 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 analysis through appropriate validation of the supplier’s test results at appropriate intervals.

• 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 identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier’s test results through appropriate validation of the supplier’s test results at appropriate intervals.

• When appropriate, components shall be microscopically examined.

• Each lot of a component, drug product container, or closure that is liable to contamination with filth insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.

• Each lot of a component, drug product container or closure that is liable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.

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• Components, containers and closures used for production of pharmaceuticals must obviously comply with their quality specifications.

• • As suppliers introduce effective procedures and embrace

the principles of vendor certification, the need for customer testing is reduced.

• • For new supplier it will usually be necessary for the

customer to perform full testing.•

VENDOR CERTIFICATION

• Vendor certification is a system that assure that a supplier’s product is produced under controlled conditions, resulting in consistent quality conformance. Being based on the principle of defect, prevention, rather than defect detection and inspection, it significantly reduces the need for customer inspection. Vendor certificate is a supplier-customer partnership and can only be successful with the full involvement and agreement of both partners.

CUSTOMER TEAMS

• The team will include representatives from manufacturing, packaging engineering, purchasing and quality assurance with support, as appropriate, from other disciplines such as finance and research and development. The initial task of the team will be to define the objectives and potential benefits and to write a process that can be used as a basis for discussion with suppliers.

CUSTOMER INSPECTION

• After it has been confirmed that a supplier has a controlled process, there usually will be a period when both parties evaluate material quality and compare data. This provides the needed assurance that supplier and customer have of comparable evaluation ability and minimize future potential for disagreements that are due to tests results rather than atypical product. The customer may also wish to revert to comprehensive evaluation at intervals as an additional assurance.

DECERTIFICATION

• Certification results in a high level of reliance on the supplier: reduced incoming inspection, reduced inventories, higher output. Any failure by the supplier can therefore have serious consequences and may require decertification of that supplier for that material.

• E- Any lot of components, drug product containers and closures that meets the appropriate written specifications of identity, strength, quality and purity and related tests under paragraph d) may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.

• Any lot of components, drug product containers and closures that not meeting the specification is to be rejected.

• • This does not preclude recovery by an appropriate rework

or inspection procedure provided the material after this rework meets the specification.

• • However, this could become a problem if specifications

are set without full regard to their impact on product quality.

• For example, if color standards for cartons are set as specifications, this could prevent the use of slightly atypical material in an urgent situation- even though the quality impact may be negligible. In such instances it may be advisable to include certain noncritical parameters as action levels, provided the procedures clearly define who makes the decision.

• • There is an obvious need for supplier and customer to agree on

specifications; without such an agreement, there could be some pressure to use atypical components simply to avoid financial loss.

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Use of Approved Components, Drug Product Containers and Closures

• Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.

• - Using oldest stock first helps to reduce the possibility of contamination and to assure that material conforms to appropriate requirements.

• Since it may be desirable to package using a single lot of components, containers or closures, an exemption from strict use of oldest stock first is provided.

• Other legitimate uses of the exemption are for evaluation of a new supplier, or new equipment or processes with respect to preferred lot of materials, or the temporary physical inaccessibility of the oldest stock.

• • Materials management systems now include a need to reevaluate material

after a predetermined time and prior to use. This will further minimize the chance that materials in an unsuitable condition will be used.

Retesting of Approved components, Drug Product Containers and closures.

• Components, drug product containers, and closures shall be retested or re-examined, as appropriate, for identity, strength, quality and purity and approved or rejected by the quality control unit as necessary, e.g., after storage for long periods or after exposure to air, heat or other conditions that might adversely affect the component, drug product container and closure.

• During storage, degradation may occur, moisture may be absorbed or materials may simply become covered in dust.

• Re-evaluation time-scales are usually developed from historical data. Except for particularly sensitive materials, it is usual to settle or one time period often one year.

• The product release label or the system should clearly indicate when materials are to be re-evaluated.

• This reevaluation will not usually require full testing but only examination of those parameters known to be subject to change.

• For infrequently used materials, reevaluation may be delayed until the material is required.

• Under normal circumstances materials well be used before they become eligible for reevaluation. Consequently, when reevaluation is necessary the material should be investigated.

• Degradation is not always linear, and in some instances a limited accelerated stability study may prove advisable.

• For sensitive materials must be stored under the appropriate conditions where these are specified. Where not specified it may still be advisable to identify and use positions in the warehouse that are least susceptible to the adverse climate changes.

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Rejected components, Drug Product Containers and closures

• Rejected components, drug product containers and closures shall be indentified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

• Although a segregated reject area is not required if an adequate control system exists, many companies do segregate reject materials. This is an added precaution against inadvertent use.

• FDA investigators frequently use a visit to the reject area as a potential source of deficiencies. If rejections occur it is possible to assume that the vendor process is not adequately under control, and an evaluation of the cause should have been performed and documented

Drug Product Containers and Closures

• A- Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.

• B- Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.

• Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.

• Standards or specifications, methods of testing, and where indicated, methods of cleaning, sterilizing and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.

• USP provides information on specifications and test methodology for a range of container materials. These include:

• Light transmission for glass and plastics

• Chemical resistance for glass

• Arsenic extraction from Type 1 glass.

• Biological tests on plastics used for parenterals.

• Physicochemical tests on plastics used for parenterals.

• Biological tests on plastics used for ophthalmic products.

• Chemical tests on polyethylene containers for dry oral dosage forms.• •

Subpart F: Production and Process Controls

• Written procedures; deviations• • (a) There shall be written procedures for production and process control

designed to assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

• (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified

Charge-in of components

• Written production and control procedures shall include

the following, which are designed to assure that the drug products produced have the identity, strength, quality, and purity they purport or are represented to possess:

• • a) The batch shall be formulated with the intent to provide

not less than 100 percent of the labeled or established amount of active ingredient.

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• (b) Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:

• • (1) Component name or item code;• (2) Receiving or control number;• (3) Weight or measure in new container;• (4) Batch for which component was dispensed, including its

product name, strength, and lot number

• (c) Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that:

• • (1) The component was released by the quality control unit;• (2) The weight or measure is correct as stated in the batch

production records;• (3) The containers are properly identified.• (the batch by one person and verified by a second person).•

• Calculation of yield.• • Actual yields and percentages of theoretical

yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall be performed by one person and independently verified by a second person.

Equipment identification.

• • (a) All compounding and storage containers, processing lines, and

major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.

• • (b) Major equipment shall be identified by a distinctive identification

number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product. In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive identification number or code.

Sampling and testing of in-process materials and drug products.

• (a) To assure batch uniformity and integrity of drug

products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

• Such control procedures shall include, but are not limited to, the following, where appropriate:

• (1) Tablet or capsule weight variation;• (2) Disintegration time;• (3) Adequacy of mixing to assure uniformity and

homogeneity;• (4) Dissolution time and rate;• (5) Clarity, completeness, or pH of solutions•

• (b) Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing of samples shall assure that the drug product and in-process material conform to specifications.

• (c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.

• • (d) Rejected in-process materials shall be identified and

controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

Time limitations on production

• When appropriate, time limits for the completion

of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented.

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Control of microbiological contamination.

• (a) Appropriate written procedures, designed to prevent

objectionable microorganisms in drug products not required to be sterile, shall be established and followed.

• (b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.

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Reprocessing.

(a) Written procedures shall be established and followed prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics.

• (b) Reprocessing shall not be performed without the review and approval of the quality control unit.