Guidance for Industry
(Continued)

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

Draft - Not for Implementation

XI. VALIDATION

A. Process Validation Strategy

A written program should be established and followed for validating the manufacturing processes for all APIs. Validation studies should ensure that a specific manufacturing process is capable of performing in a reliable and consistent manner and results in a homogeneous API that consistently meets predetermined specifications.

Validation should embrace steps in the processing of APIs that are critical to the quality and purity of the final API, and should include:

1. Definition of the API in terms of its critical quality attributes. Among the attributes that should be considered are chemical purity; qualitative and quantitative impurity profiles; physical characteristics such as particle size, bulk and tap density; polymorphic forms; moisture and solvent content; homogeneity; and microbial quality (if the product is susceptible to microbial contamination).

2. Identification of process parameters that could affect the critical quality attributes of the API. Critical parameters should be determined by scientific judgement and typically should be based on knowledge derived from research, scale-up batches, or manufacturing experiences.

3. Determination of the range for each critical process parameter expected to be used during routine manufacturing and process control. Data to substantiate the ranges for critical process parameters generally should be obtained from laboratory- or pilot-scale batches, unless a specific parameter can only be determined from a production-scale batch.

Examples of processing steps that could be defined by the API manufacturer as critical include:

1. Phase changes, such as dissolution or crystallization;

2. Phase separation, such as filtration or centrifugation;

3. Steps that cause chemical changes;

4. Steps that alter temperature or pH;

5. Mixing of multiple raw materials; and

6. Steps that cause changes in surface area, particle size, bulk and tap density or homogeneity. Critical process parameters (e.g., reaction times, reaction temperatures, reactant ratios, concentrations, pressures, pH, and impurity levels) should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

Process validation should confirm that the impurity profile for each API is within the limits specified and is comparable to the profile determined during process development or for batches used for pivotal/toxicological studies.

B. The Validation Protocol

A written validation protocol should be established that specifies how process validation will be conducted. The protocol should be reviewed and approved by the quality control unit and other designated organizational units.

The validation protocol should include the following:

1. Purpose and scope of the validation;

2. Functions and responsibilities of all organizational units involved in the validation;

3. Type of validation to be conducted with appropriate justification for type chosen;

4. Number of process validation runs;

5. Quality of materials used in the process (e.g., recovered vs. fresh solvents);

6. Description of the process (e.g., discussion of the chemistry, unit operations, process flow diagram);

7. All major process equipment used, its type/design, and its installation and operational qualification (IQ/OQ);

8. The critical quality attributes of the API;

9. The critical process parameters and operating ranges;

10. Sampling plans (i.e., sampling points, frequency, quantities, and procedures for collecting samples);

11. Specifications and test data to be collected;

12. Acceptance criteria needed to conclude that the validation has been successful; and

13. Steps to follow in the event of a process validation failure.

The above information need not be incorporated in the validation protocol if the protocol makes specific reference to other documents that contain the information (e.g., COA’s, development reports, and IQ/OQ reports). Any changes to the validation plan should be documented with appropriate justification.

C. Prospective Validation

Prospective validation should be conducted prior to the commercial distribution of an API produced by a new or substantially modified process. This validation approach should involve obtaining and evaluating documented processing and analytical control information for multiple batches manufactured, sampled, and tested according to a preestablished validation plan.

When prospectively validating a process, data from laboratory- and/or pilot-scale batches should identify critical quality attributes and specifications, critical steps, control ranges, and in-process tests. Scale-up batches could be used to generate data to confirm or refine earlier work, and production-scale batches should provide data showing consistency of the process.

The number of process runs should depend on the complexity of the process or the magnitude of the process change being considered. Although three consecutive, successful production lots should be used as a guide, there could be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). If a validation lot fails for reasons unrelated to process performance (e.g., power failure or equipment breakdown), that lot should be removed from the validation study and an additional validation run conducted.

Validated analytical methods capable of quantifying API quality attributes should be used during process validation. Resulting data should be evaluated and included in a validation report approved by the same organizational units that approved the protocol.

D. Concurrent Validation

FDA considers concurrent validation to be a subset of prospective validation. The Agency recognizes that in a limited number of cases it may be impossible to complete validation of an API process in a timely manner when data from replicate production runs are unavailable because:

1. Only a limited number of API batches intended for clinical or orphan drug products have been produced;

2. API batches are produced infrequently (e.g., limited market demand, complex multi-step API processes with long completion times); or

3. APIs batches are produced by a modified process (e.g., a validated process goes outside the proven acceptable range of a critical operating parameter and the batch is subjected to intensive analytical tests).

In such cases, firms should do all of the following:

1. Document the reasons for not completing process validation before shipment of the API;

2. Perform all of the elements of prospective validation, as discussed in Section XIII.C., exclusive of replicate production run testing, before releasing any batch for distribution;

3. Conduct intensive in-process monitoring and testing, along with intensive testing of each API batch, to show that each production run resulted in an API meeting its predetermined quality characteristics and specifications (such data should also be assessed under the validation protocol to determine consistency of the process);.

4. Provide for the Quality Control unit to evaluate batch production records, in-process controls, and analytical data from each process run to determine whether each batch should be released.

The level of intensive in-process and final API testing should be greater than levels for validated routine production runs, and should only be reduced to routine levels after the process has been determined to be validated. In addition, data from production runs that are evaluated as part of the validation studies should encompass the operating ranges that are approved for use during routine process control.

The Agency cautions that this validation approach should be applied with discretion so as not to:

1. Unduly delay completion of, or avoid performing, meaningful validation; or

2. Distribute API batches manufactured before completion of validation for a prolonged period of time.

This approach should not be viewed as a viable alternative where the number and frequency of API production runs permit timely completion of validation prior to API distribution. If analysis of data shows that the process used to manufacture the distributed batches was not, in fact, validated, no additional batches should be distributed until corrections have been implemented and the process has been determined to be validated.

E. Retrospective Validation

Retrospective validation could be conducted for a well-established process that has been used without significant changes (e.g., changes in raw materials, equipment, systems, facilities, or in the production process) that affect the critical quality attributes of the API. This validation approach should be used only when there is sufficient history on past API batches to demonstrate the process consistently produces acceptable products, and where:

1. Critical quality attributes and critical process parameters have been identified and documented;

2. Appropriate in-process specifications and controls have been established and documented;

3. There have not been excessive process/product failures attributable to causes other than operator error or equipment failure unrelated to equipment suitability; and

4. Impurity profiles have been established for the existing API.

In addition to the information described in Section XIII.B., the validation protocol should include the batch selection criteria and analytical data that will be evaluated to determine consistency of the process.

The number of batches to review will depend on the process, but, in general, data from 10 to 30 consecutive batches should be examined to assess process consistency. The review should include any batches that failed to meet specifications. All batches within the selected review period should have been manufactured by the same process and have the same documented history of controls and tests as current APIs. Additional testing of retained samples may be warranted to obtain the necessary data to retrospectively validate the process.

Data obtained should be evaluated by appropriate personnel, and a final validation report summarizing the results and appropriate conclusion should be prepared. This report should be reviewed and approved by the organizational units that approved the original protocol.

Retrospective validation could also be employed to provide additional data to supplement prospective validation and either build confidence in a particular manufacturing process or impugn it as test results are received.

XII. CHANGE CONTROL/REVALIDATION

A. Change-Control System

To provide mechanisms for ongoing process optimization and ensure a continuing state of process control, a formal change control system should be established to evaluate and approve proposed changes to specifications, test procedures, raw materials, facilities, support systems, equipment (including computer hardware), processing steps, packaging materials, and computer software.

The change-control program should include procedures to:

1. Prevent unauthorized modifications to a validated system;

2. Evaluate proposed changes against development and technology transfer documents;

3. Identify and evaluate all proposed changes to assess their potential affects on the API process and determine if, and to what extent, revalidation is needed;

4. Ensure that all documents affected by changes are promptly revised; and

5. Determine the impact of changes on the critical chemical and physical attributes of the API (e.g., impurity profiles, stability, and particle size).

Any proposals for changes should be drafted, reviewed, and approved by the appropriate organizational units, and reviewed and approved by the quality control unit.

Changes implemented to improve process yields should be evaluated carefully to determine if these result in new or higher levels of impurities. The impurity profile of the resulting batches should be comparable to the impurity profile of the API batches used in drug safety and clinical  testing. Process changes should also be evaluated to ensure that these do not have an adverse effect on analytical methods due to increased interference caused by new or higher levels of impurities and by-products. Analytical methods should be modified as necessary to ensure they are capable of detecting and quantifying impurities.

Dosage form manufacturers should be notified of changes in the API production process that could affect the critical attributes of the API (e.g., impurity profile, crystal form, particle size, residual solvent content, or stability) and thus have a significant impact upon the dosage forms produced from that API.

B. Change-Control Classification

The change-control program should provide for a classification scheme to evaluate changes in raw materials, manufacturing sites, scale of manufacturing, manufacturing equipment, and production processes. This classification procedure should be used in determining what level of testing, validation, and documentation is needed to justify changes to a validated process.

Changes should be categorized as minor or major depending on the nature and extent of the changes, and the effects these changes could impart on the process. In all cases, scientific judgement should determine what additional testing and validation studies are needed to justify a change in a validated process.

A minor change should be defined as one that is unlikely to have a detectable impact on the critical attributes of the API. Such changes would not shift the process in any discernible manner, and might be implemented with minimal testing and revalidation. For example, "like-for-like" equipment replacements where equipment is repaired to its initial validated state or in which identical or similar equipment is introduced into the process, would unlikely affect the process if adequately installed and qualified.

A major change should be defined as one that would likely significantly affect the critical quality attributes of the API. For example, a change in solvent used for the final crystallization could significantly affect the impurity profile, physical attributes, and other critical quality attributes of the API. Such changes should be justified by additional testing, and if appropriate, revalidation.

XIII. REPROCESSING/REWORKING OF APIs AND INTERMEDIATES

A. Reprocessing by Repeating a Chemical Reaction

Due to the potential for formation of by-products, reprocessing an API or intermediate by repeating a chemical reaction (adding fresh reagents or solvents to unreacted or base material and starting over) should be preceded by a careful evaluation to ensure that the quality of the final API is not adversely impacted.

Where such reprocessing occurs, written process change procedures should be approved by the quality control unit that clearly specify the conditions and limitations of repeating chemical reactions. In addition, the procedures should establish how this type of reprocessing will be evaluated, and what additional tests will be conducted on the reprocessed material to show that the resulting material is of a purity and quality comparable to that normally produced by the process. These tests should include, as appropriate, purity, impurity profiles, stability testing on initial reprocessed lots, and testing for physical attributes.

B. Reprocessing by Physical Manipulations

Intermediates and API batches that occasionally do not conform to specifications for percent transmittance/color, or critical attributes (e.g., purity, impurities, particle size) can be reprocessed by repeating a crystallization step or other physical manipulation steps (e.g., dissolution, filtration, milling, blending) that are part of an established process.

If it becomes necessary to more than occasionally reprocess batches by physical manipulation, a thorough investigation should be conducted and documented to determine the adequacy of the original process. Appropriate actions should be taken to minimize the risk of recurrence. For example, if investigation of the nonconformance and/or review of the process reveals an abnormally high rate of batches that need to be recrystallized, it would be reasonable to incorporate the recrystallization as part of the normal process.

All reprocessing procedures should be reviewed and approved by the quality control unit. These procedures should specify the conditions and limitations for reprocessing by physical manipulations and require an evaluation of each nonconforming batch to determine its suitability for reprocessing. For example, one or more recrystallizations from the final solvent might be justified, but continuous reprocessing of batches until they meet a given quality specification would indicate a problem with the original process. A specific record should be generated to document reprocessing steps and subsequent handling and incorporated into the original batch record.

Appropriate tests should be conducted on reprocessed batches to ensure that reprocessing does not adversely affect the quality or purity of the API or intermediate. These tests should include, as appropriate, purity, physical attributes, and impurity profiles. In all cases, the significance of the nonconformance and its impact on the critical quality attributes of the API or intermediate should determine how much analytical data is sufficient to justify the reprocessing.

Reprocessing operations should be subjected to appropriate evaluation to show that these steps consistently perform the expected functions and result in batches that comply with all established standards, specifications, and characteristics.

C. Reworking of APIs and Intermediates

Reworking batches that do not conform to established standards or specifications by using processing steps that are different from the validated process should involve extensive evaluation and documentation to show that the reworked product is of equivalent quality to that produced by the original process.

Reworking operations should be subjected to appropriate evaluation to show that such reworking does not adversely affect the quality or purity of the API or intermediate. Where routine analytical methods are inadequate to characterize the reworked batch, alternative methods should be used.

XIV. CONTROL OF CHEMICAL, BIOLOGICAL, AND PHYSICAL CONTAMINANTS

Written procedures should be implemented to prevent objectionable chemical, biological, and physical contamination, including cross-contamination in APIs and intermediates.

Dedicated production, which may include facilities, air handling equipment and/or process equipment, should be employed where both of the following conditions exist:

1. Contaminants pose a special danger to human or animal health. In the case of human health, these include, but are not limited to, penicillin, cephalosporins, cytotoxics, toxins, and infectious agents; and

2. There are no effective methods for cleaning and removing contaminant residues from buildings, facilities, and equipment to levels below those determined by suitable medical and toxicological assessment to pose no serious health risk to the consumer.

If a reasonable possibility exists that an API or intermediate has been exposed to cross-contamination, the substance should be tested for the presence of the potential contaminant. APIs and intermediates that exceed established limits for such contaminants should not be used in further manufacturing.

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