5/23/2014

FDA Guidedance for Industry v.s. Tomco coding solution and quality control

http://tomcocm.blogspot.com/2014/05/fda-guidedance-for-industry-vs-tomco.html

วันพฤหัสบดีที่ 22 พฤษภาคม พ.ศ. 2557

FDA Guidedance for Industry v.s. Tomco coding solution and quality control

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parts of FDA Guidedance for Industry

X. Subpart F – Production and Process Control: Requirements For Quality Control

  1. What does the DS CGMP rule require quality control personnel to do?
    The DS CGMP rule requires quality control personnel to ensure that your manufacturing, packaging, labeling, and holding operations ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record.
    (21 CFR 111.105)
  2. What operations does the DS CGMP rule require quality control personnel to perform?
    The DS CGMP rule requires quality control personnel to perform operations that include:
    • Approving or rejecting all processes, specifications, written procedures, controls, tests, and examinations, and deviations from or modifications to them, that may affect the identity, purity, strength, or composition of a dietary supplement (21 CFR 111.105(a));
    • Reviewing and approving the documentation setting forth the basis for qualification of any supplier (21 CFR 111.105(b));
    • Reviewing and approving the documentation setting forth the basis for why meeting in-process specifications, in combination with meeting component specifications, will help ensure that the identity, purity, strength, and composition of the dietary supplement are met (21 CFR 111.105(c));
    • Reviewing and approving the documentation setting forth the basis for why the results of appropriate tests or examinations for each product specification selected under 21 CFR 111.75(c)(1) will ensure that the finished batch of the dietary supplement meets product specifications (21 CFR 111.105(d));
    • Reviewing and approving the basis and the documentation for why any product specification is exempted from the verification requirements in 21 CFR 111.75(c)(1), and for why any component and in-process testing, examination, or monitoring, or other methods will ensure that such exempted product specification is met without verification through periodic testing of the finished batch (21 CFR 111.105(e));
    • Ensuring that all representative samples are collected (21 CFR 111.105(f));
    • Ensuring that all reserve samples are collected and held (21 CFR 111.105(g));
    • Determining whether all specifications established under 21 CFR 111.70(a) are met (21 CFR 111.105(h));
    • Laboratory operations (21 CFR 111.110);
    • Operations regarding material review and disposition decisions (21 CFR 111.113);
    • Operations regarding equipment, instruments, and controls (21 CFR 111.117);
    • Operations regarding components, packaging, and labels before use in the manufacture of a dietary supplement (21 CFR 111.120);
    • Operations regarding the master manufacturing record, the batch production record, and manufacturing operations (21 CFR 111.123);
    • Packaging and labeling operations (21 CFR 111.127);
    • Operations regarding returned dietary supplements (21 CFR 111.130); and
    • Operations regarding product complaints (21 CFR 111.135).
  3. Who conducts a material review and disposition decision?
    Quality control personnel conduct all required material reviews and make all required disposition decisions (21 CFR 111.87). However, qualified individuals who are not assigned as quality control personnel may participate in the material review, e.g., by providing relevant information or analysis (72 FR 34752 at 34865).
  4. When does the DS CGMP rule require quality control personnel to do to conduct a material review and disposition decision?
    The DS CGMP rule identifies five circumstances when quality control personnel must conduct a material review and make a disposition decision (21 CFR 111.113(a)):
    • A specification established in accordance with 21 CFR 111.70 is not met (21 CFR 111.113(a)(1));
    • A batch deviates from the master manufacturing record, including when any step established in the master manufacturing record is not completed and including any deviation from specifications (21 CFR 111.113(a)(2));
    • There is any unanticipated occurrence during the manufacturing operations that adulterates or may lead to adulteration of the component, dietary supplement, or packaging, or could lead to the use of a label not specified in the master manufacturing record (21 CFR 111.113(a)(3));
    • Calibration of an instrument or control suggests a problem that may have resulted in a failure to ensure the quality of a batch or batches of a dietary supplement (21 CFR 111.113(a)(4)); or
    • A dietary supplement is returned (21 CFR 111.113(a)(5)).
  5. When does the DS CGMP rule require quality control personnel to reject a component, dietary supplement, packaging or label?
    The DS CGMP rule requires quality control personnel to reject a component, dietary supplement, packaging, or label when:
    • There is a deviation or unanticipated occurrence during the production and in-process control system that results in or could lead to adulteration of a component, dietary supplement, or packaging, or could lead to the use of a label not specified in the master manufacturing record (unless quality control personnel approve a treatment, an in-process adjustment, or reprocessing to correct the applicable deviation or occurrence) (21 CFR 111.113(b)(1)).
    • When a specification that you are required to establish is not met (unless quality control personnel approve a treatment, an in-process adjustment, or reprocessing, as permitted in 21 CFR 111.77) (21 CFR 111.113(b)(2)).
  6. When does the DS CGMP rule require documentation of a material review and disposition decision?
    The DS CGMP rule requires the person who conducts a material review and makes the disposition decision to document the material review and disposition decision at the time of performance.
    (21 CFR 111.113(c))

XI. Subpart G – Production and Process Control System; Requirements For Components, Packaging, And Labels And For Product That Is Received For Packaging Or Labeling As A Dietary Supplement

  1. Requirements for Components
    1. What visual examinations does the DS CGMP rule require me to conduct for components of dietary supplements?
      The DS CGMP rule requires you to visually examine the supplier's invoice, guarantee, or certification, and each immediate container or grouping of immediate containers, in a shipment of components.
      (21 CFR 111.155(a) and (b))
    2. How long does the DS CGMP rule require me to quarantine components?
      The DS CGMP rule requires you to quarantine components until:
      • You collect representative samples (21 CFR 111.155(c)(1));
      • Quality control personnel review and approve the results of any tests or examinations conducted on the representative samples (21 CFR 111.155(c)(2));
      • Quality control personnel approve the components for use in the manufacture of a dietary supplement (21 CFR 111.155(c)(3)); and
      • Quality control personnel release the components from quarantine (21 CFR 111.155(c)(3)).
    3. Does the DS CGMP rule require me to assign a unique identifier to components?
      Yes. The DS CGMP rule requires you to identify each unique lot within each unique shipment of components you receive (and any lot of components you produce) in a manner that allows you to trace the lot to the supplier, the date received, the name of the component, the status of the component (e.g., quarantined, approved, or rejected), and to the dietary supplement that you manufactured and distributed.
      (21 CFR 111.155(d)(1))
    4. When does the DS CGMP rule require me to use the unique identifier that I assign to components?
      The DS CGMP rule requires you to use this unique identifier whenever you record the disposition of each unique lot within each unique shipment of components you receive and any lot of components you produce.
      (21 CFR 111.155(d)(2))
    5. How does the DS CGMP rule require me to hold components?
      The DS CGMP rule requires you to hold components under conditions that will protect against contamination and deterioration, and avoid mix-ups.
      (21 CFR 111.155(e))
    6. What does the DS CGMP rule require to be included in a Certificate of Analysis that accompanies a component?
      The DS CGMP rule requires a certificate of analysis to include:
      • A description of the test or examination method(s) used;
      • Limits of the test or examinations; and
      • Actual results of the tests or examinations.
      (21 CFR 111.75(a)(2)(ii)(B))
    7. Does the DS CGMP rule establish any requirements specific to animal-derived ingredients?
      No. However, you are responsible to comply with any other regulations applying to foods containing animal-derived ingredients. For example, if you manufacture a dietary supplement containing cattle-derived material, you would be responsible to comply with the requirements for cattle-derived material established in 21 CFR 189.5. As another example, if you manufacture a dietary supplement containing ingredients derived from fish, you would be responsible to comply with applicable requirements for fish and fishery products in 21 CFR part 123.
      (72 FR 34752 at 34838)
  2. Requirements for Packaging and Labels
    1. What visual examinations does the DS CGMP rule require me to conduct for packaging and labels?
      The DS CGMP rule requires you to visually examine the supplier's invoice, guarantee, or certification, and each immediate container or grouping of immediate containers, in a shipment.
      (21 CFR 111.160(a) and (b))
    2. How long does the DS CGMP rule require me to quarantine packaging and labels?
      The DS CGMP rule requires you to quarantine packaging and labels until:
      • You collect representative samples and, at a minimum, conduct a visual identification of the immediate containers and closures (21 CFR 111.160(c)(1));
      • Quality control personnel review and approve the results of any tests or examinations conducted on the packaging and labels (21 CFR 111.160(c)(2));
      • Quality control personnel approve the packaging and labels for use in the manufacture of a dietary supplement (21 CFR 111.160(c)(3)); and
      • Quality control personnel release the packaging and labels from quarantine (21 CFR 111.160(c)(3)).
    3. Does the DS CGMP rule require me to assign a unique identifier to packaging and labels?
      Yes. The DS CGMP rule requires you to identify each unique lot within each unique shipment of packaging and labels in a manner that allows you to trace the lot to the supplier, the date received, the name of the packaging and label, the status of the packaging and label (e.g., quarantined, approved, or rejected), and to the dietary supplement that you distributed.
      (21 CFR 111.160(d)(1))
    4. When does the DS CGMP rule require me to use the unique identifier that I assign to packaging and labels?
      The DS CGMP rule requires you to use this unique identifier whenever you record the disposition of each unique lot within each unique shipment of packaging and labels.
      (21 CFR 111.160(d)(2))
    5. How does the DS CGMP rule require me to hold packaging and labels?
      The DS CGMP rule requires you to hold packaging and labels under conditions that will protect against contamination and deterioration, and avoid mix-ups.
      (21 CFR 111.160(e))
  3. Requirements for Received Product
    1. What visual examinations does the DS CGMP rule require me to conduct for received product (i.e., product that I receive for packaging and labeling as a dietary supplement (and for distribution rather than for return to the supplier))?
      The DS CGMP rule requires you to visually examine the supplier's invoice, guarantee, or certification, and each immediate container or grouping of immediate containers, in a shipment.
      (21 CFR 111.165(a) and (b))
    2. How long does the DS CGMP rule require me to quarantine received product?
      The DS CGMP rule requires you to quarantine received product until:
      • You collect representative samples (21 CFR 111.165 (c)(1));
      • Quality control personnel review and approve the documentation to determine whether the received product meets specifications (21 CFR 111.165(c)(2));
      • Quality control personnel approve the received product for packaging or labeling as a dietary supplement (21 CFR 111.165(c)(3)); and
      • Quality control personnel release the received product from quarantine (21 CFR 111.165(c)(3)).
    3. Does the DS CGMP rule require me to assign a unique identifier to received product?
      Yes. The DS CGMP rule requires you to identify each unique lot within each unique shipment of received product in a manner that allows you to trace the lot to the supplier, the date received, the name of the received product, the status of the received product (e.g., quarantined, approved, or rejected), and to the product you packaged or labeled and distributed as a dietary supplement.
      (21 CFR 111.165(d)(1))
    4. When does the DS CGMP rule require me to use the unique identifier that I assign to received product?
      The DS CGMP rule requires you to use this unique identifier whenever you record the disposition of each unique lot within each unique shipment of the received product.
      (21 CFR 111.165(d)(2))
    5. How does the DS CGMP rule require me to hold received product?
      The DS CGMP rule requires you to hold received product under conditions that will protect against contamination and deterioration, and avoid mix-ups.
      (21 CFR 111.165(e))
  4. Requirements for Rejected Components, Packaging, Labels and Received Product
    1. What does the DS CGMP rule require me to do with rejected components, packaging, and labels, and with rejected products received for packaging or labeling as a dietary supplement?
      The DS CGMP rule requires you to clearly identify, hold, and control under a quarantine system for appropriate disposition any component, packaging, and label, and any product you receive for packaging or labeling as a dietary supplement, that is rejected and unsuitable for use in manufacturing, packaging, or labeling operations.
      (21 CFR 111.170)

XII. Subpart H – Production and Process Control System: Requirements for a Master Manufacturing Record

  1. Does the DS CGMP rule require me to establish a master manufacturing record?
    Yes. The DS CGMP rule requires you to prepare and follow a written master manufacturing record for each unique formulation of dietary supplement that you manufacture, and for each batch size, to ensure uniformity in the finished batch from batch to batch (21 CFR 111.205(a)). The master manufacturing record must establish controls and procedures to ensure that each batch of dietary supplement you manufacture meets those specifications (21 CFR 111.205(b)(2)).
  2. What specifications does the DS CGMP rule require the master manufacturing record to identify?
    The DS CGMP rule requires the master manufacturing record to identify specifications for the points, steps, or stages in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record.
    (21 CFR 111.205(b))
  3. What does the DS CGMP rule require the master manufacturing record to include?
    The DS CGMP rule requires the master manufacturing record to include:
    • The name of the dietary supplement to be manufactured and the strength, concentration, weight, or measure of each dietary ingredient for each batch size (21 CFR 111.210(a));
    • A complete list of components to be used (21 CFR 111.210(b));
    • An accurate statement of the weight or measure of each component to be used (21 CFR 111.210(c));
    • The identity and weight or measure of each dietary ingredient that will be declared on the Supplement Facts label and the identity of each ingredient that will be declared on the ingredients list of the dietary supplement (21 CFR 111.210(d));
    • A statement of any intentional overage amount of a dietary ingredient (21 CFR 111.210(e)) (the amount of overage should be limited to the amount needed to meet the weight or measure of each dietary ingredient that will be declared on the Supplement Facts label of the dietary supplement) (72 FR 34752 at 34884);
    • A statement of theoretical yield of a manufactured dietary supplement expected at each point, step, or stage of the manufacturing process where control is needed to ensure the quality of the dietary supplement, and the expected yield when you finish manufacturing the dietary supplement, including the maximum and minimum percentages of theoretical yield beyond which a deviation investigation of a batch is necessary and material review is conducted and disposition decision is made (21 CFR 111.210(f));
    • A description of packaging and a representative label, or a cross-reference to the physical location of the actual or representative label (21 CFR 111.210(g)); and
    • Written instructions, including the following:
      • Specifications for each point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record (21 CFR 111.210(h)(1));
      • Procedures for sampling and a cross-reference to procedures for tests or examinations (21 CFR 111.210(h)(2));
      • Specific actions necessary to perform and verify points, steps, or stages in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record (21 CFR 111.210(h)(3));
        • Such specific actions must include verifying the weight or measure of any component and verifying the addition of any component (21 CFR 111.210(h)(3)(i)); and
        • For manual operations, such specific actions must include one person weighing or measuring a component and another person verifying the weight or measure, and one person adding the component and another person verifying the addition (21 CFR 111.210(h)(3)(ii));
      • Special notations and precautions to be followed (21 CFR 111.210(h)(4)); and
      • Corrective action plans for use when a specification is not met (21 CFR 111.210(h)(5)).

XIII. Subpart I – Production and Process Control System: Requirements for a Batch Production Record

  1. Does the DS CGMP rule require me to establish a batch production record?
    Yes. The DS CGMP rule requires you to prepare a batch production record every time you manufacture a batch of a dietary supplement.
    (21 CFR 111.255(a))
  2. What does the DS CGMP rule require regarding the batch production record?
    The DS CGMP rule requires that:
    • Your batch production record accurately follow the appropriate master manufacturing record; and
    • You perform each step in the production of the batch.
    (21 CFR 111.255(c))
  3. What does the DS CGMP rule require the batch production record to include?
    The DS CGMP rule requires the batch production record to include complete information relating to the production and control of each batch (21 CFR 111.255(b)). Specifically, the DS CGMP rule requires the batch production record to include:
    • The batch, lot, or control number of the finished batch of dietary supplement, each lot of packaged and labeled dietary supplement from the finished batch of dietary supplement, and each lot of dietary supplement, from the finished batch of dietary supplement, that you distribute to another person for packaging or labeling (21 CFR 111.260(a));
    • The identity of equipment and processing lines used in producing the batch (21 CFR 111.260(b));
    • The date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross-reference to records, such as individual equipment logs, where this information is retained (21 CFR 111.260(c));
    • The unique identifier you assigned to each component (or, when applicable, to a product that you receive from a supplier for packaging or labeling as a dietary supplement), packaging, and label used (21 CFR 111.260(d));
    • The identity and weight or measure of each component used (21 CFR 111.260(e));
    • A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing (21 CFR 111.260(f));
    • The actual results obtained during any monitoring operation (21 CFR 111.260(g));
    • The results of any testing or examination performed during the batch production, or a cross-reference to such results (21 CFR 111.260(h));
    • Documentation that the finished dietary supplement meets specifications established in accordance with 21 CFR 111.70(e) and (g) (21 CFR 111.260(i));
    • Documentation, at the time of performance, of the manufacture of the batch, including the date on which each step of the master manufacturing record was performed and the initials of the persons performing each step (21 CFR 111.260(j));
    • Documentation, at the time of performance, of packaging and labeling operations, including:
      • The unique identifier you assigned to packaging and labels used, the quantity of the packaging and labels used, and, when label reconciliation is required, reconciliation of any discrepancies between issuance and use of labels (21 CFR 111.260(k)(1));
      • An actual or representative label, or a cross-reference to the physical location of the actual or representative label specified in the master manufacturing record (21 CFR 111.260(k)(2)); and
      • The results of any tests or examinations conducted on packaged and labeled dietary supplements (including repackaged or relabeled dietary supplements), or a cross-reference to the physical location of such results (21 CFR 111.260(k)(1));
    • Documentation at the time of performance that quality control personnel reviewed the batch production record, approved or rejected any reprocessing or repackaging, approved and released (or rejected) the batch for distribution, and approved and released (or rejected) the packaged and labeled dietary supplement, including any repackaged or relabeled dietary supplement (21 CFR 111.260(l));
    • Documentation at the time of performance of any required material review and disposition decision (21 CFR 111.260(m)); and
    • Documentation at the time of performance of any reprocessing (21 CFR 111.260(n)).

XIV. Subpart J – Production and Process Control System: Requirements for Laboratory Operations

  1. What does the DS CGMP rule require regarding facilities to perform testing and examinations?
    The DS CGMP rule requires you to use adequate laboratory facilities to perform testing and examinations.
    (21 CFR 111.310)
  2. What laboratory control processes does the DS CGMP rule require me to establish and follow?
    The DS CGMP rule requires you to establish and follow laboratory control processes that include:
    • Use of criteria for establishing appropriate specifications (21 CFR 111.315(a));
    • Use of sampling plans for obtaining representative samples (21 CFR 111.315(b));
    • Use of criteria for selecting appropriate examination and testing methods (21 CFR 111.315(c));
    • Use of criteria for selecting standard reference materials used in performing tests and examinations (21 CFR 111.315(d)); and
    • Use of test methods and examinations in accordance with established criteria (21 CFR 111.315(e)).
  3. Does the DS CGMP rule require quality control personnel to review and approve the laboratory control processes I establish and follow?
    Yes.
    (21 CFR 111.315)
  4. How should I determine which reference materials to use in performing tests and examinations?
    Reference materials should be appropriate to the assay procedure for which they are used. We recommend that you use compendia reference standards whenever possible. If no compendia reference standard exists, we recommend that you establish appropriately characterized in-house materials prepared from representative lots. Such in-house materials should be of the highest purity that can be obtained by reasonable effort and should be thoroughly characterized to ensure their identity, purity, quality, and strength.
    (72 FR 34752 at 34892)
  5. What does the DS CGMP rule require me to do regarding laboratory methods I use for testing and examination?
    The DS CGMP rule requires you to:
    • Verify that the laboratory examination and testing methodologies are appropriate for their intended use (21 CFR 111.320(a)); and
    • Identify and use an appropriate scientifically valid method for each established specification for which testing or examination is required to determine whether the specification is met (21 CFR 111.320(b)).
  6. What is an example of a scientifically valid method?
    An example of a scientifically valid method can be one that is based on scientific data or results published in, for example, scientific journals, references, text books, or proprietary research.
    (72 FR 34752 at 34893)
  7. Does the DS CGMP rule require me to use a "validated" scientific method to perform tests or examinations?
    No, it requires you to use a scientifically "valid" method. However, we recommend that you use a "validated" scientific method whenever one is available.
    (72 FR 34752 at 34893)
  8. What does “validating” a scientific method involve?
    In general, “validating” a scientific method involves evaluating the method on multiple occasions or in multiple test facilities. Official methods are validated in collaborative studies using several laboratories under identical conditions. Other method validations are conducted in a single laboratory by repeating the same test multiple times. Typical validation characteristics include accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness.
    (72 FR 34752 at 34893)
  9. Where can I find validated methods?
    Validated methods can be found in official references, such as AOAC International, United States Pharmacopoeia (USP), and others
    (72 FR 34752 at 34893)
  10. What should I do if I modify a validated method?
    If you modify an officially validated method, you should:
    • Document the reason for the modification;
    • Have data to show that the modified method produces results that are at least as accurate and reliable as the established method for the material being tested; and
    • Have complete records of any testing and standardization of laboratory reference standards, reagents, and standard solutions you use in your laboratory operations.
    (72 FR 34752 at 34894)

XV. Subpart K – Production and Process Control System: Requirements for Manufacturing Operations

  1. How does the DS CGMP rule require me to design or select manufacturing processes?
    The DS CGMP rule requires you to design or select manufacturing processes to ensure that product specifications are consistently met.
    (21 CFR 111.355)
  2. How does the DS CGMP rule require me to conduct manufacturing operations?
    The DS CGMP rule requires you to conduct all manufacturing operations in accordance with adequate sanitation principles.
    (21 CFR 111.360)
  3. What precautions does the DS CGMP rule require me to take to prevent contamination during manufacturing operations?
    The DS CGMP rule requires you to take all necessary precautions during the manufacture of a dietary supplement to prevent contamination of components or dietary supplements, including the following specific precautions:
    • Performing manufacturing operations under conditions and controls that protect against the potential for growth of microorganisms and the potential for contamination (21 CFR 111.365(a));
    • Washing or cleaning components that contain soil or other contaminants (21 CFR 111.365(b));
    • Using water that, at a minimum, complies with the applicable Federal, State, and local requirements and does not contaminate the dietary supplement when the water may become a component of the finished batch of dietary supplement (21 CFR 111.365(c));
    • Performing chemical, microbiological, or other testing, as necessary to prevent the use of contaminated components (21 CFR 111.365(d));
    • Sterilizing, pasteurizing, freezing, refrigerating, controlling hydrogen-ion concentration (pH), controlling humidity, controlling water activity (aw), or using any other effective means to remove, destroy, or prevent the growth of microorganisms and prevent decomposition (21 CFR 111.365(e));
    • Holding components and dietary supplements that can support the rapid growth of microorganisms of public health significance in a manner that prevents the components and dietary supplements from becoming adulterated (21 CFR 111.365(f));
    • Identifying and holding any components or dietary supplements, for which a material review and disposition decision is required, in a manner that protects components or dietary supplements that are not under a material review against contamination and mix-ups with those that are under a material review (21 CFR 111.365(g));
    • Performing mechanical manufacturing steps (such as cutting, sorting, inspecting, shredding, drying, grinding, blending, and sifting) by any effective means to protect the dietary supplements against contamination (21 CFR 111.365(h));
    • Using effective measures to protect against the inclusion of metal or other foreign material in components or dietary supplements (21 CFR 111.365(i));
    • Segregating and identifying all containers for a specific batch of dietary supplements to identify their contents and, when necessary, the phase of manufacturing (21 CFR 111.365(j)); and
    • Identifying all processing lines and major equipment used during manufacturing to indicate their contents, including the name of the dietary supplement and the specific batch or lot number and, when necessary, the phase of manufacturing (21 CFR 111.365(k)).
  4. What does the DS CGMP rule require me to do with a rejected dietary supplement?
    The DS CGMP rule requires you to clearly identify, hold, and control under a quarantine system for appropriate disposition any dietary supplement that is rejected and unsuitable for use in manufacturing, packaging, or labeling operations.
    (21 CFR 111.370)

XVI. Subpart L – Production and Process Control System: Requirements for Packaging and Labeling Operations

  1. What does the DS CGMP rule require me to do regarding packaging and labels?
    The DS CGMP rule requires you to:
    • Take necessary actions to determine whether the packaging for a given dietary supplement meets specifications so that the condition of the packaging will ensure the quality of your product (21 CFR 111.410(a));
    • Control the issuance and use of packaging and labels and reconciliation of any issuance and use discrepancies; however, label reconciliation is not required for cut or rolled labels if a 100 percent examination for correct labels is performed by appropriate electronic or electromechanical equipment during or after completion of finishing operations (21 CFR 111.410(b));
    • Examine packaging and labels for each batch of dietary supplement, before conducting packaging and labeling operations, to determine whether the packaging and labels conform to the master manufacturing record (21 CFR 111.410(c)); and
    • Be able to determine the complete manufacturing history and control of the packaged and labeled dietary supplement through distribution (21 CFR 111.410(d)).
  2. Does the DS CGMP rule require me to place a batch, lot, or control number on the packaged and labeled dietary supplement?
    No. Putting a batch, lot, or control number on the packaged and labeled dietary supplement is one way to satisfy the requirement in 21 CFR 111.410(d) that you be able to determine the complete manufacturing history and control of the packaged and labeled dietary supplement through distribution. However, you have flexibility to develop and use other mechanisms to satisfy this requirement. For example, if you make one type of product that you distribute to a select few customers, you may be able to trace the dietary supplement using dates on distribution records to such customers, by using different containers, or by labeling other than a batch, lot, or control number affixed to the label.
    (72 FR 34752 at 34900)
  3. What does the DS CGMP rule require me to do regarding filling, assembling, packaging, labeling, and related operations?
    The DS CGMP rule requires you to fill, assemble, package, label, and perform other related operations in a way that ensures the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record, using any effective means, including:
    • Cleaning and sanitizing all filling and packaging equipment, utensils, and dietary supplement packaging, as appropriate (21 CFR 111.415(a));
    • Protecting manufactured dietary supplements from contamination, particularly airborne contamination (21 CFR 111.415(b));
    • Using sanitary handling procedures (21 CFR 111.415(c));
    • Establishing physical or spatial separation of packaging and label operations from operations on other components and dietary supplements to prevent mix-ups (21 CFR 111.415(d));
    • Identifying, by any effective means, filled dietary supplement containers that are set aside and held in unlabeled condition for future label operations, to prevent mix-ups (21 CFR 111.415(e));
    • Assigning a batch, lot, or control number to each lot of packaged and labeled dietary supplement from a finished batch of dietary supplement and each lot of dietary supplement, from a finished batch of dietary supplement, that you distribute to another person for packaging or labeling (21 CFR 111.415(f));
    • Examining a representative sample of each batch of the packaged and labeled dietary supplement to determine whether the dietary supplement meets specifications established in accordance with 21 CFR 111.70(g) (21 CFR 111.415(g)); and
    • Suitably disposing of labels and packaging for dietary supplements that are obsolete or incorrect to ensure that they are not used in any future packaging and label operations (21 CFR 111.415(h)).
  4. When may I repackage or relabel a dietary supplement?
    You may repackage or relabel a dietary supplement only after quality control personnel have approved such repackaging or relabeling.
    (21 CFR 111.420(a))
  5. What does the DS CGMP rule require me to do regarding repackaging and relabeling?
    The DS CGMP rule requires that:
    • You examine a representative sample of each batch of repackaged or relabeled dietary supplements to determine whether the repackaged or relabeled dietary supplements meet all required specifications (21 CFR 111.420(b)); and
    • Quality control personnel approve or reject each batch of repackaged or relabeled dietary supplement prior to its release for distribution (21 CFR 111.420(c)).
  6. What does the DS CGMP rule require me to do with a packaged and labeled dietary supplement that is rejected for distribution?
    The DS CGMP rule requires you to clearly identify, hold, and control under a quarantine system for appropriate disposition any packaged and labeled dietary supplement that is rejected for distribution.
    (21 CFR 111.425)

XVII. Subpart M - Holding and Distributing

  1. What does the DS CGMP rule require me to do when holding components, dietary supplements, packaging, and labels?
    The DS CGMP rule requires you to:
    • Hold components and dietary supplements under appropriate conditions of temperature, humidity, and light so that the identity, purity, strength, and composition of the components and dietary supplements are not affected (21 CFR 111.455(a));
    • Hold packaging and labels under appropriate conditions so that the packaging and labels are not adversely affected (21 CFR 111.455(b));
    • Hold components, dietary supplements, packaging, and labels under conditions that do not lead to the mix-up, contamination, or deterioration of components, in-process materials, dietary supplements, packaging, and labels (21 CFR 111.455(c));
  2. What does the DS CGMP rule require me to do when holding in-process materials?
    The DS CGMP rule requires you to:
    • Identify and hold in-process material under conditions that protect against mix-up, contamination, and deterioration (21 CFR 111.460(a)); and
    • Hold in-process material under appropriate conditions of temperature, humidity, and light (21 CFR 111.460(b)).
  3. What container-closure system does the DS CGMP rule require me to use to hold reserve samples of packaged and labeled dietary supplements?
    The DS CGMP rule requires you to use the following container-closure systems to hold reserve samples of dietary supplements:
    • If you are distributing a packaged and labeled dietary supplement, the DS CGMP rule requires you to keep the reserve samples in a container-closure system that is the same as the container-closure system in which the dietary supplement is distributed.
    • If you are distributing a dietary supplement for packaging and labeling, the DS CGMP rule requires you to keep the reserve samples in a container-closure system that provides essentially the same characteristics to protect against contamination or deterioration as the one in which you distributed the dietary supplement for packaging and labeling elsewhere. For example, if you distribute product in bulk using a polyethylene bottle that can hold 50 kilograms of the product, and there is an air space above the product, you would hold the reserve samples in a polyethylene bottle with an air space. However, you would use a bottle sized to fit the smaller amount you are holding in reserve.
    (21 CFR 111.83(b)(1); 21 CFR 111.465(a)(2); 72 FR 34752 at 34904)
  4. How does the DS CGMP rule require me to hold reserve samples of packaged and labeled dietary supplements?
    The DS CGMP rule requires you to hold reserve samples under conditions consistent with product labels or, if no storage conditions are recommended on the label, under ordinary storage conditions. For example, if the product label states “Keep this product refrigerated,” you would store the reserve sample in a refrigerator.
    (21 CFR 111.465(a)(1))
  5. How long does the DS CGMP rule require me to hold reserve samples of packaged and labeled dietary supplements?
    The DS CGMP rule requires you to hold reserve samples of packaged and labeled dietary supplements for:
    • One year past the shelf life date (if shelf life dating is used); or
    • Two years from the date of distribution of the last batch of dietary supplements associated with the reserve sample.
    (21 CFR 111.83(b)(3) and 111.465(b))
  6. What does the DS CGMP rule require me to do when distributing dietary supplements?
    The DS CGMP rule requires you to distribute dietary supplements under conditions that will protect the dietary supplements against contamination and deterioration.
    (21 CFR 111.470)

XVIII. Subpart N - Returned Dietary Supplements

  1. What does the DS CGMP rule require me to do with a returned dietary supplement?
    The DS CGMP rule requires you to identify and quarantine a returned dietary supplement until quality control personnel conduct a material review and make a disposition decision.
    (21 CFR 111.510)
  2. When does the DS CGMP rule require me to destroy, or otherwise suitably dispose of, a returned dietary supplement?
    The DS CGMP rule requires you to destroy, or otherwise suitably dispose of, any returned dietary supplement unless the outcome of a material review and disposition decision is that quality control personnel approve the salvage of the returned dietary supplement for redistribution, or approve the returned dietary supplement for reprocessing.
    (21 CFR 111.515)
  3. When may I salvage a returned dietary supplement?
    You may salvage a returned dietary supplement only if quality control personnel conduct a material review and make a disposition decision to allow the salvage.
    (21 CFR 111.520)
  4. What does the DS CGMP rule require me to do with a returned dietary supplement that quality control personnel approve for reprocessing?
    The DS CGMP rule requires that:
    • You ensure that any returned dietary supplements that are reprocessed meet all product specifications established for the finished batch to ensure the quality of the dietary supplement(21 CFR 111.525(a)); and
    • Quality control personnel approve or reject the release for distribution of any returned dietary supplement that is reprocessed (21 CFR 111.525(b)).
  5. When does the DS CGMP rule require me to conduct an investigation of my manufacturing processes and other batches following the return of a product?
    The DS CGMP rule requires you to conduct an investigation of your manufacturing processes and each of those other batches to determine compliance with specifications if the reason for a dietary supplement being returned implicates other batches.
    (21 CFR 111.530)

XIX. Subpart O - Product Complaints

  1. What are some examples of product complaints?
    Examples of product complaints are: foul odor, off taste, illness or injury, disintegration time, color variation, tablet size or size variation, under-filled container, foreign material in a dietary supplement container, improper packaging, mislabeling, or dietary supplements that are superpotent, subpotent, or contain the wrong ingredient, or contain a drug or other contaminant (e.g., bacteria, pesticide, mycotoxin, glass, lead).
    (21 CFR 111.3)
  2. Does the DS CGMP rule establish requirements for handling complaints about the inherent safety of a dietary supplement?
    No (72 FR 34752 at 34763 and 34765). However, we encourage firms to investigate all complaints in a consistent way, regardless of whether the complaints relate to the quality of the dietary supplement or to the inherent safety of a dietary ingredient (72 FR 34752 at 34910). We also note that manufacturers, packers, and distributors whose names appear on the label of dietary supplements marketed in the United States are required to submit to FDA any report received of a serious adverse event associated with such dietary supplement when used in the United States (section 761 of the Federal Food, Drug and Cosmetic Act (the Act) (21 U.S.C. 379aa-1)) (see also question 8 below).
  3. What does the DS CGMP rule require me to do during the review and investigation of a product complaint?
    The DS CGMP rule requires that:
    • A qualified person review all product complaints to determine whether the product complaint involves a possible failure of a dietary supplement to meet any of its specifications, or any other requirements of part 111, including those specifications and other requirements that, if not met, may result in a risk of illness or injury (21 CFR 111.560(a)(1));
    • A qualified person investigate the product complaint if it is determined that the product complaint does involve such a failure (21 CFR 111.560(a)(2));
    • Quality control personnel review and approve decisions about whether to investigate a product complaint and review and approve the findings and follow-up action of any investigation performed (21 CFR 111.560(b)); and
    • The review and investigation of the product complaint extend to all relevant batches and records (21 CFR 111.560(c)).
  4. Am I subject to the requirements for product complaints if I am a packager, labeler, or distributor rather than a manufacturer?
    Yes. The DS CGMP rule requires any person in the manufacturing chain who receives a product complaint to comply with the requirements for product complaints (21 CFR 111.1; 72 FR 34752 at 34909). This is true regardless of the source of the product complaint – i.e., regardless of whether you receive the complaint from a consumer or from another firm in the manufacturing chain (72 FR 34752 at 34909).
  5. What should I do if I am a packager, labeler, or distributor and I conclude that the problem in a product complaint is unrelated to any process under my control?
    We recommend that you contact the manufacturer so that the manufacturer can determine whether the product complaint involves a possible failure of a dietary supplement to meet any of its specifications, or any other requirements of part 111, including those specifications and other requirements that, if not met, may result in a risk of illness or injury.
    (72 FR 34752 at 34909)
  6. Am I subject to the requirements for product complaints if I manufacture dietary ingredients rather than dietary supplements?
    You are not subject to the requirements for product complaints if you manufacture dietary ingredients and do not sell the dietary ingredients directly to consumers (72 FR 34752 at 34791). However, if you are a manufacturer of dietary ingredients, and you receive complaints about a dietary supplement, we recommend that you share those complaints with those in the manufacturing chain associated with that dietary supplement's manufacture so others may take corrective action as needed (72 FR 34752 at 34798). In addition, we encourage you to evaluate the complaint to determine if it may involve a problem with the manufacture of the dietary ingredient (72 FR 34752 at 34792).
  7. Does the DS CGMP rule require me to report any product complaints to FDA?
    No. The DS CGMP rule addresses the internal processes and controls that persons who manufacture, package, label, or hold dietary supplements must follow rather than any procedures for reporting any product complaints to us (72 FR 34752 at 34909). However, we recommend that firms who receive product complaints notify us about any illness or injury, because, for example, we may have additional expertise or data that may be helpful in investigating the complaint or determining whether the problem applies to more than one product. We encourage you to include this recommendation in the written procedures you develop for handling product complaints (72 FR 34752 at 34909). Information about how to notify us about a product complaint is available on our Internet site (Ref. 2).
  8. What should I do if I receive a product complaint involving serious illness or injury?
    We encourage firms who receive a product complaint involving serious illness or injury to consult with a health care provider and to include such a consultation in its written procedures for handling product complaints (72 FR 34752 at 34909). In addition, be advised that in 2006 Congress enacted the “Dietary Supplement and Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462), which established a new statutory requirement for mandatory reporting to FDA of serious adverse events (section 761 of the Act (21 U.S.C. 379aa-1)). This law defines “serious adverse events” as those adverse events that result in death, a life-threatening experience, an inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect, or that require medical or surgical intervention to prevent such serious outcomes (based on reasonable medical judgment). Among other things, this law also has specific provisions for how serious adverse event reports are to be submitted to FDA and recordkeeping requirements relating to adverse event reports. We encourage firms who are unsure as to whether an adverse event should be reported to FDA to contact us for assistance (72 FR 34752 at 34909). FDA has also published guidance for industry about mandatory dietary supplement adverse event reporting and recordkeeping requirements, entitled "Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act," (Ref. 3).

XX. Subpart P – Records and Recordkeeping

  1. What does the DS CGMP rule require regarding the records that I make and keep?
    The DS CGMP rule requires that:
    • You keep written records for one year past the shelf life date (if shelf life dating is used), or for 2 years beyond the date of distribution of the last batch of dietary supplements associated with those records (21 CFR 111.605(a));
    • Records be kept as original records, as true copies (such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records), or as electronic records (21 CFR 111.605(b)); and
    • All electronic records comply with 21 CFR part 11 (21 CFR 111.605(c)).
  2. What does the DS CGMP rule require me to do to make records available to FDA?
    The DS CGMP rule requires you to:
    • Have all required records, or copies of such records, readily available during the retention period for inspection and copying by FDA when requested (21 CFR 111.610(a)); and
    • Make suitable reader and photocopying equipment readily available to FDA if you use reduction techniques, such as microfilming (21 CFR 111.610(b)).

XXI. References

We have placed the following references on display in the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. You may see them at that location between 9 a.m. and 4 p.m., Monday through Friday. As of November 9, 2010, FDA had verified the Web site address for the references it makes available as hyperlinks from the Internet copy of this guidance.
  1. FDA. Guidance for Industry: Product Recalls, Including Removals and Corrections.
  2. FDA. Report a Problem. How to Report Problems With Products Regulated by FDA.
  3. FDA. Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act.
1.This guidance has been prepared by the Division of Dietary Supplement Programs in the Center for Food Safety and Applied Nutrition at the U.S. Food and Drug Administration.
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