A. Biological Test Methods Validation

B. Analytical Methods Validation

C. Equipment Cleaning Validation for Active Pharmaceutical Ingredients (APIs)

D. Equipment Cleaning Validation for Drug Products

E. Laboratory Equipment Qualification

F. Microbiological Methods Validation

G. Packaging Validation

H. Process Validation for Active Pharmaceutical Ingredients (API)

I. Process Validation for Drug Products and Medical Devices

J. System Validation

K. Validating Aseptic Processing – Active Pharmaceutical Ingredients (API)

L. Validation of Analytical Methods for Equipment Cleaning

M. Validation Requirements and Documentation

A. Biological Test Methods Validation

The following guidance will address the Validation practices of non-compendial or alternate Biological Test methods and the Verification of Compendial biological Test Methods to demonstrate that a test method is suitable for its intended purpose.

Biological test methods must be developed, documented and have sufficient detail so that a Qualified Laboratory Analyst can accurately perform the test in an environment suitable for the Test Methods and using the required Test Methods materials. All Test Methods shall be maintained under change control.

The scope of this article applies to all GMP operation responsible for the validation of biological test methods associated with products in or intended for the marketplace including testing performed for release or stability evaluation of:

* Regulatory Starting Materials,

* Active Pharmaceutical Ingredients (API),

* Intermediates,

* In-Process Materials,

* Drug Products,

* Biologics,

* Medical Devices, and

* Raw Materials (RM).

Biological Test Methods shall be validated unless the method employed is included in the current edition of an official pharmacopoeia (e.g., EP, JP, or USP) or other recognized standard references. Verification of a compendial biological test method must demonstrate that the test method is suitable for its intended purpose.

This guidance applies to biological test methods. The following are examples of biological test methods:

* Microbiological assay of antibiotics;

* Potency Bioassays (e.g., vitamins);

* Immunochemical assays [e.g. Enzyme Linked Immunosorbent Assay (ELISA)];

* Virus titration; and

* In vivo and in vitro (cell-based) biological assays.

Validation of a Bacterial Endotoxin test (BET) is not addressed in this article.

Specificity must be demonstrated for verification of all compendial (e.g., EP, JP, USP) biological test methods under actual use conditions in the laboratory, including any minor variations in the Test Methods.

Non-Compendial or Alternate Biological Test Methods shall be validated and must be shown to be equivalent to the compendial or regulatory filing method. Validation shall include consideration of the following validation characteristics applicable to the method:

* Accuracy,

* Precision,

–     Repeatability,

–     Intermediate Precision (intra-laboratory), and

–     Reproducibility (inter-laboratory),

* Specificity, and

* Quantitation Limit (QL).

Robustness of the biological test method shall be considered during method validation if not addressed during method development.

Validated alternate biological test methods shall be submitted to the Regulatory Authority, when required, prior to implementation.

Biological Test Method Validation or Verification Studies shall be performed and documented according to an Approved Protocol that defines the parameters being evaluated, the acceptance criteria for each parameter and the Test Methods. The protocol must be approved by the Laboratory Manager prior to execution of the validation studies.

A Method Validation or Verification Report shall be prepared that documents the results of the validation or verification study, including the evaluation of each parameter and comparison against acceptance criteria. Any Deviations from the protocol must be documented and the impact of the deviations discussed in the report.

Qualified Personnel shall be identified with the following roles and responsibilities in regards to biological test method validation or verification:

* The Laboratory Manager at the Site conducting the validation or verification is responsible for assuring that the biological methods are validated or verified and for reviewing and approving the Final Report; and

* The Quality Authority, independent of the Laboratory Manager, at the Site conducting the validation or verification study is responsible for reviewing and approving the final report for compliance with applicable Site policies and procedures.

Automated Systems used as a part of a biological test method and Computerized Laboratory Systems shall include Validation of the computerized system. Qualified Personnel shall perform:

* Validation studies, and

* Verification of compendial methods.

Written and Approved Procedures shall describe the preparation, Laboratory labelling, storage, and use of laboratory Reagents, solutions, buffers and Reference Standards.

Test Equipment used in the execution of the biological test method protocol must be qualified and have a current Calibration status.

Biological Test Method Validation and Verification Studies shall be documented and retained in accordance with site record retention requirements.

The Need for and Degree of Revalidation shall be determined by the Laboratory Manager. Changes to be considered in determining the need for and extent of revalidation include, and are not limited to:

* Changes to the biological test method (e.g., new or modified sample preparation procedure, change to detection conditions, change to instrument settings and/or operating conditions);

* Changes to the sample being tested (e.g., process change for API or change in composition of the product); or

* Changes in compendial or regulatory requirements (e.g., ICH, EMEA).

Legacy Methods – the need to validate a legacy biological method that has not been previously validated or is not a compendial method shall be based on an impact assessment by the responsible Site Quality Team. Legacy methods shall be assessed against this guidance to ensure available method documentation is current and reflects the method. A Retrospective Validation approach may be used to support the biological method validation.

B. Analytical Methods Validation

The Purpose of this document is to define the requirements for Validation of Analytical Methods. The objective of validation of an analytical method is to demonstrate that it is suitable for its intended purpose.

Scope – this document applies to analytical methods associated with products in intended for the marketplace. This includes testing performed for release or stability evaluation of Active Pharmaceutical Ingredient (API) Starting Materials, Intermediates from the point at which the API starting material is introduced into the process, APIs, Drug Product In-Process Materials, finished drug products, drug product Raw Materials (RM) and Medical Devices.

Analytical methods shall be validated unless the method employed is included in the current edition of an official pharmacopoeia (e.g., EP, JP, or USP) or other recognized standard references.

This guidance applies to, and is not limited to, the following types of chemical analytical methods:

* Identification tests;

* Quantitative tests for impurities;

* Limit tests for the control of impurities;

* Quantitative tests of the active moiety in samples of API, drug product, medical devices, or dissolution samples; and

* Quantitative tests on drug product for other selected component(s) in the drug product.

This guidance also applies to methods used to evaluate physical properties (e.g., particle size). This guidance does not apply to the validation of microbiological or bioanalytical methods or Test Methods (TM) associated with Equipment Cleaning Validation.

Analytical Method Validation shall include consideration of the following validation characteristics:

* Accuracy,

* Precision,

–      Repeatability,

–      Intermediate Precision (intra-laboratory), and

–      Reproducibility (inter-laboratory),

* Specificity,

* Detection Limit (DL),

* Quantitation Limit (QL),

* Linearity,

* Range, and

* Robustness.

Notes:

Data for one characterization may be used to meet the requirements of another characterization. Robustness of the method shall be considered during method validation if not addressed during method development.

Reproducibility is not required for method validation. However, reproducibility may be used in place of intermediate precision.

Typical validation characteristics applicable to different types of methods (e.g., limits, identification, quantification) are presented in Tables 1 and 2. For test methods used to evaluate physical properties, intermediate precision shall be considered, at a minimum.

System Suitability -depending on the nature of the analytical method, a set of criteria shall be established during development or validation to verify performance of the analytical method or system.

Validation Documentation and Records for Method Validation shall meet requirements set out in respective guidance for validation documentation.

The Method Validation Protocol must document the validation parameters being evaluated, the acceptance criteria for each parameter, and the test method(s). The protocol must be Approved by the Lab Manager prior to execution of the validation studies.

The Method Validation Report documents the results of the validation study, including the evaluation of each parameter and comparison against acceptance criteria. Any Deviations from the protocol must be documented and the impact of the deviations discussed in the report. The report shall also include or reference relevant results (e.g., robustness) collected during development.

Both the Site Quality Team, independent of the Lab Manager and Lab Manager are responsible for reviewing and approving the validation report for compliance with applicable Site policies and procedures.

The Need for and Degree of Revalidation shall be determined by the Lab Manager. Changes which may require revalidation of analytical method include, but are not limited to:

* Changes to the analytical method (e.g., new or modified sample preparation procedure, change to separation or detection conditions, change to instrument settings and/or operating conditions);

* Changes to the sample being tested (e.g., process change for API or change in composition of the product);

* Changes in compendial or regulatory requirements (e.g., ICH, EMEA); or

* New data become available (e.g., discovery of new impurity).

Legacy Methods – the need to validate a legacy analytical method that has not been previously validated or is not a compendial method shall be based on an impact assessment by the responsible Site Quality Team. A Retrospective Validation approach may be used to support the analytical method validation.

Specificity shall be determined for the validation of:

* Identification tests,

* Determination of impurities (quantitative and limits tests), and

* Assays (including potency and dissolution).

If an individual analytical method lacks the required specificity, other supporting analytical method(s) must compensate for lack of the specificity.

Identification Tests with Suitable Specificity shall be able to discriminate between the compounds of interest and other substances that are likely to be present in the sample, such as excipients, impurities, and degradation products.

Assay  and Impurity Test(s) for chromatographic procedures shall use representative chromatograms to demonstrate specificity and each chromatographic component shall be labelled. Similar considerations shall be given to other separation techniques.

Critical separations in chromatography shall be evaluated for the active ingredient at the concentration specified in the analytical method and for impurity(s) at Specification level(s), when possible.

Specificity can be demonstrated by the resolution of the two components that elute closest to each other.

If Impurities or Degradation Products Are Available, the API, drug product or medical device shall be spiked with impurities to demonstrate the specificity of the analytical method.

For assays, specificity is established by demonstrating that the analytical response of the analyte of interest is unaffected by the presence of other components in the sample. For an impurity test, specificity is established by demonstrating that the impurities are separated from each other and/or from other components in the sample matrix.

If Impurities or Degradation Products Are Not Available for use in demonstrating specificity then samples that are known to contain the impurities and/or degradation products will be used to demonstrate specificity, when available.

For stability indicating methods, such demonstration shall include drug product, API, or medical device samples stored under relevant stress conditions (e.g., light, heat, humidity, acid/base hydrolysis, and oxidation). In cases where degradation pathways have been established, degradation products have been identified, and authentic substances are available there is no need to perform forced degradation.

Alternatively, specificity is demonstrated by comparing the test results of samples containing impurities or degradation products to a second well-characterized method [e.g., compendial method or other validated analytical method (independent procedure)].

For the assay, the two results shall be compared; and for the impurity tests, the impurity profiles shall be compared.

If samples containing the impurities and/or degradation products are not available, chromatographic peak purity assessment (e.g., diode array or mass spectrometry detection) may be useful to show that the analyte chromatographic peak is not attributable to more than one component.

Analytical method for quantitative impurity and assay methods (including methods for dissolution and Content Uniformity). It shall be demonstrated directly on the analyte and/or with mixtures of the analyte and sample matrix using the proposed analytical method.

Linearity shall be evaluated by visual inspection of a plot of signals as a function of analyte concentration or content. If there is a linear relationship, test results shall be evaluated by statistical methods (e.g., by calculation of a regression line using the method of least squares).

In some cases, to obtain linearity between assays and sample concentrations, the test data may need to be subjected to a mathematical transformation prior to the regression analysis.

Data from the regression line itself may be useful to provide mathematical estimates of the degree of linearity.

The correlation coefficient (r), y-intercept, slope of the regression line and residual sum of squares must be reported. A plot of the data shall be included in the analytical method validation report.

For the establishment of linearity, a minimum of five (5) concentrations or levels is typical. Use of other approaches must be justified.

The Specified Range of an Analytical Method is derived from linearity studies and depends on the intended application of the method. The specified range is established by confirming that the analytical method provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical method.

The following minimum specified ranges shall be considered for APIs:

* Assay: from 80 -120 percent of the test concentration; and

* Determination of an impurity:from the Reporting Level (e.g., QL) of an impurity to 120 percent of the specification.

The following minimum specified ranges shall be considered for finished drug product:

Assay: from 80 -120 percent of the test concentration;

* Content Uniformity: a minimum of 70 -130 percent of the test concentration, unless a wider more relevant range, based on the nature of the dosage form (e.g., metered dose inhalers), is justified;

* Dissolution testing: ±20 percent over the specified range (e.g., if the specifications for a controlled released product cover a region from 20 percent after one hour, up to 90 percent after twenty-four (24) hours, the validated range would be 0 -110 percent of the label claim); and

* Determination of an impurity: from the reporting level of an impurity to 120 percent of the specification. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the detection or quantitation limit shall be commensurate with the level at which the impurities must be controlled.

For validation of impurity test methods where specifications have not yet been set, the range around a suggested (probable) limit shall be used. If assay and purity are performed together as one test and only a single standard is used, linearity, accuracy and precision must be demonstrated from the reporting level of the impurities to 120 percent of the assay specification.

Accuracy shall be established across the specified range of the analytical method. This applies to assay methods, including methods for dissolution and content uniformity, and to quantitative impurity methods for API, drug product and medical device.

The Accuracy of API Assays shall be demonstrated by one of the following methods:

a) Application of the analytical method to an analyte of known purity (e.g., reference material);

b) Comparison of the results of the proposed analytical method with those of a second well-characterized method, the accuracy of which is stated and/or defined; or

c) Accuracy may be inferred once precision, linearity, and specificity have been established.

The Accuracy of Drug Product Assays shall be demonstrated by one of the following:

a) Application of the analytical procedure to placebo mixtures of the drug product components to which known quantities of the API to be analyzed have been added; or

b) In cases where it is impossible to obtain samples of all drug product components, it is acceptable either to add known quantities of the analyte to the drug product or to compare the results obtained from a second, well characterized method, the accuracy of which is stated and/or defined.

Impurities (Quantitation) – accuracy shall be assessed on samples (API or drug product) spiked with known amounts of impurities. In cases where it is impossible to obtain samples of certain impurities and/or degradation products, it is considered acceptable to compare results obtained by an independent procedure.

The response factor of the API can be used to quantitate the impurities and/or degradation products. Alternatively a surrogate (e.g., compound whose structure and properties are closely related to the impurity of interest) may be used to demonstrate accuracy.

For API and drug product quantitative impurity methods, accuracy may be inferred when the acceptance criteria for specificity, linearity and precision are met.

Accuracy: If determination of accuracy is required (i.e., not inferred), the following accuracy requirements shall apply. For assay methods (including methods for dissolution and content uniformity), and quantitative impurity methods for APIs and drug products, accuracy shall be assessed using a minimum of nine (9) determinations over a minimum of three (3) concentration levels covering the specified range of the analytical method [e.g., three (3) concentrations with three (3) replicate sample preparations each].

Results from each of the nine (9) determinations must be reported. Accuracy shall be reported for each concentration level by one of the following methods:

a) As percent recovery by the assay of a known added amount of analyte in the sample; or

b) As the difference between the mean and the accepted true value together with the confidence intervals.

Precision shall be considered at three (3) levels:

* Repeatability,

* Intermediate precision, and

* Reproducibility.

Validation of tests for assay (including dissolution and content uniformity), quantitative determination of impurities, and physical properties shall include precision. Precision is expressed as the variance, standard deviation, or relative standard deviation (RSD). Either intermediate precision or reproducibility is evaluated. It is not necessary to evaluate both.

Repeatability shall be assessed using a minimum of nine (9) determinations covering the specified range for the procedure [e.g., three (3) concentrations with three (3) replicate sample preparations each]. This applies to assay methods (including methods for dissolution and content uniformity) and quantitative impurity methods.

Intermediate Precision is established depending on the circumstances under which the method is intended to be used.

The effects of operational and environmental variables on the precision of the analytical method shall be established. Typical variations to be studied include days, analysts, and equipment. It is not considered necessary to study these effects individually.

Reproducibility is assessed by means of an inter-laboratory study. Reproducibility shall be considered in case of the standardization of an analytical procedure across multiple Sites.

Detection Limit (DL) shall be at or below the reporting limit for the compound under test. DL shall be required for limit tests except where the Quantitation Limit (QL) is established. DL is determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected. The DL and the method used for determining the DL shall be presented in the validation report.

If DL is based on visual evaluation or based on signal-to-noise ratio, the presentation of the relevant instrument response is considered acceptable for justification. In cases where an estimated value for the DL is obtained by calculation or extrapolation, this estimate shall subsequently be validated by the independent analysis of a suitable number of samples known to be near or prepared at the DL.

Quantitation Limit (QL) is established for quantitative tests for impurities. The QL and the method used for determining the QL shall be presented in the validation report. The QL shall be validated by the analysis of a minimum of three (3) samples known to be near or prepared at the QL and demonstrating accuracy and precision. At a minimum, the QL shall be at or below the reporting limit for the compound under test.

Robustness shall be considered during either the method development phase or validation and depends on the type of procedure under study. Robustness shall demonstrate the reliability of an analysis with respect to deliberate variations in method parameters. If measurements are susceptible to variations in analytical conditions, the analytical conditions must be controlled or a precautionary statement included in the procedure.

Data collected during robustness studies shall be used to set or verify system suitability requirements.

System Suitability Test Parameters to be established for a particular method depend on the type of method being validated.

Typical system suitability parameters for chromatographic systems to consider during validation are:

* Peak resolution (R) of the peaks of interest and/or other components;

* The RSD of replicate injections for precision (repeatability);

* The tailing factor (T) for peak asymmetry; and

* The Sensitivity check

–           A Sensitivity Test Solution is used, or alternatively,

–           Column efficiency.

C. Equipment Cleaning Validation for Active Pharmaceutical Ingredients (APIs)

This good practice applies to all GMP sites where Active Pharmaceutical Ingredients (API) are manufactured.

Product Changeover Cleaning Procedures must be Validated for all Product Contact Equipment (both Major and Minor Equipment) used for multi-product Production, Subdivision and sampling of APIs and those Intermediate steps that are subsequent to the introduction of the API Starting Materials.

Cleaning measures used to perform Interval Cleaning and Dedicated Equipment Campaign Cleaning shall follow Approved procedures, but are not required to be validated. Dedicated equipment Campaign cleaning shall include visual inspections for cleaning Verification.

Where equipment is used only for process steps before the addition of API starting materials, equipment cleaning shall follow approved procedures and shall require cleaning verification.

Equipment Cleaning Validation shall be defined in Validation Master Plans (VMP) and/or Validation Project Plans (VPP). The VMP or cleaning validation project plan shall include a list of systems requiring cleaning validation and the validation approach to be used.

Equipment Cleaning Validation shall either be based upon the most difficult to clean product in a group of products that uses the same cleaning procedure, or cleaning validation shall be performed individually on each product.

Fully Automated Cleaning Procedures, such as automated Clean-In-Place (CIP), shall include validation of both the Computerized System employed and the cleaning cycle.

An Equipment Cleaning Validation Protocol shall be established that specifies how validation will be conducted and shall include or reference, at least the following:

* Approval page with approval signatures and date of final approval;

* Cleaning procedure or Instruction-Records to be validated;

* Products addressed by the Protocol;

* Description of equipment;

* Residue materials to be removed (e.g., prior product or cleaning agents);

* Cleaning and sanitizing materials to be used;

* Analytical Methods;

* Sampling Plans, including rationale for sampling sites;

* Sampling Methods; and

* Acceptance criteria.

If Equipment Cannot be 100 Percent Visually Inspected, validated sampling methods (e.g., swabbing or Rinsate) must be used to routinely determine residues after cleaning. Swabbing shall be used only for routine verification where rinsate is not feasible and 100 percent visual inspection is not possible, unless a rationale is provided. When safe and practical, sampling shall be performed. When it is not possible or feasible to sample, documented rationale must be available. Swabbing and rinsate sampling methods must be validated by the use of recovery studies. The sampling method used during routine verification must also be used during validation.

Analytical Methods Used for Cleaning Validation must be validated and have sufficient sensitivity to detect the established acceptable level of residues.

Rinsate or Swabbing Method Recovery Studies with recoveries of 50 percent or greater are considered acceptable. When recovery values are less than 70 percent, the recovery value must be used as a correction factor in the calculation of results or limits. For recoveries of greater than 100 percent, no recovery values are to be used as a correction factor, but they shall have a practical upper limit.

Training and Qualification in the use of validation sampling (swabbing and rinsate techniques), visual inspections, and analytical methods shall be part of the training Records for personnel performing these functions.

If equipment (e.g., boroscope) is used to aid in visual inspections, the user must be trained and qualified in use of the equipment.

Validation shall consist of at least three consecutive, successful executions (i.e., no failures related to the cleaning procedure between the successful executions) of the cleaning procedure. When the Worst Case approach is used, validation trials shall be performed on the most difficult to clean compound. Also when the worst case approach is used, additional cleaning validation trials, using the next most difficult to clean product, may be conducted prior to completion of the three validation trials of the most difficult to clean product. Failure of a validation trial for the next most difficult to clean product is equivalent to a failure of the validation trial for the most difficult to clean product. Validation trials shall be executed using one or more of the following options:

* Cleaning validation executions performed at the end of a regularly scheduled campaign; and/or

* Changeover cleaning conducted within a campaign.

Criteria for Equipment Cleaning Validation for major equipment shall be as follows:

* Visibly Clean; and

* Removal of residue (i.e., therapeutic and/or Non-Therapeutic Material) to predetermined acceptance criteria, where required. Criteria for equipment cleaning validation for minor equipment shall include the requirement to be visibly clean.

A Validation Report referencing the relevant protocol(s) shall discuss the results from the execution of the protocol and shall be approved. A Final Report shall be issued following completion of the validation study. Interim Reports are required when the time between the start of the validation study and completion of the entire study is greater than a specified period of time.

Any Deviation from the approved protocol shall be documented with justification. All process deviations shall also be documented and reviewed as to their impact on validation. Reports shall contain results, deviations (if any), references to cleaning procedures and protocols used, recommendations and conclusions.

The conclusion of the report shall confirm whether the cleaning process met all of the acceptance criteria. The conclusion shall state whether the process is validated.

A New Therapeutic Material must be evaluated by Site Quality Team and Production Team and an assessment report(s) issued that addresses the probable impact of the new material on the current cleaning validation plan.

If the worst-case approach is used, the new material shall be evaluated to determine if it is the most difficult to clean compound for the cleaning procedures selected. If it is not determined to be most difficult to clean, the new product may be incorporated into the existing Matrix with no impact on the validation of the procedures. Test data for at least one cleaning cycle of the new product must be obtained. The sampling and testing methods to be used during the one cleaning cycle of the new product must be consistent with those that would be used during validation.

A report must be prepared and approved that summarizes the cleaning test data from the first time the procedure(s) is used to clean the new product, to verify that the matrixing (i.e., worst case approach) was appropriate. The report must be approved by Site Quality Team and Production Team. If the new material is determined to be the most difficult to clean compound, then the existing procedure(s) or new procedure(s) shall be validated with at least three consecutive, successful executions of the cleaning procedure on the new material.

A New Non-Therapeutic Material (includes cleaning material) must be evaluated by the Site Quality Team and Production Team and an assessment report(s) issued that addresses the probable impact of the new material on the current cleaning validation plan.

Failures During Validation (i.e., visual and/or analytical result failures) must be documented and Investigated according to established Site Standard Operating Procedures (SOP).

All Planned and Unplanned Changes with potential direct or indirect effect on validated cleaning practices shall be addressed by established change control and/or investigation procedures. The Site Production Team and the Site Quality Team must approve the impact analysis of the change(s) and the determination if Revalidation or further actions are required. Such changes include, and are not limited to, those potentially affecting any of the following:

* Production process;

* Cleaning methods;

* Cleaning materials;

* Sampling methods;

* Analytical methods;

* Configuration of equipment or equipment assembly;

* Change in Batch/Lot size (especially smaller);

* Change in product mix produced in the equipment;

* Change in equipment surface area (including piping, minor equipment, or columns); or

* Change in Residue Acceptability Limit (RAL) or Maximum Allowable Residue (MAR).

Periodic Review of Validated Changeover Cleaning Procedures relative to all Equipment Units is required. The periodic review shall include the review of change control documents, cleaning procedure deviations, and cleaning result investigations. An assessment of the validated state of the cleaning procedure for the equipment shall be written into the conclusion of the Cleaning Periodic Review Report. This report must be approved by Site Quality Team and Production Team.

D. Equipment Cleaning Validation for Drug Products

This good practice document defines the cleaning Validation requirements for GMP facilities and equipment involving the manufacturing of Drug Products.

This procedure applies to all Pharmaceutical Production Sites where drug products are manufactured and/or packaged for Pharmaceutical or Animal Health.

Equipment Changeover Cleaning Procedures must be validated for all Product Contact Equipment (both Major and Minor Equipment) used for multi-product production, Subdivision, and sampling of drug products and In-Process Materials.

Cleaning Measures Used to Perform Interval Cleaning and Dedicated Equipment Campaign Cleaning shall follow Approved procedures. Interval cleaning does not require validation. Cleaning shall include visual inspections for cleaning Verification.

Dedicated equipment cleaning validation is required for any of the following conditions:

* When a cleaning agent is used;

* The product is sensitive to microbiological growth; or

To establish the product Campaign length with respect to potential microbiological contamination, using one cleaning exercise only.

An Equipment Cleaning Validation Program shall be defined in [e.g., Validation Master Plan (VMP) or Validation Project Plan (VPP)].

Equipment Cleaning Validation for Changeover Cleaning shall be performed by applying one of the following approaches:

* Product Matrix (Grouping) Approach – perform validation using the most difficult to clean product(s) produced in an Equipment Train in which all the products use the same cleaning procedure (i.e., Worst Case product); or

* Individual Product Approach – perform validation of the cleaning procedure for each product produced in an equipment train.

Residue Acceptability Limit (RAL) for Therapeutic Dose (RALT) must be calculated based on each product that is to be processed in a specific equipment train. The limit for each compound or product, “A” may be calculated and used for a specific subsequent product, “B” or a worst case limit for all A/B Combinations may be used. If a worst case limit is used for equipment producing multiple compound types, the most conservative limit for all compound types produced in the equipment must be selected.

Microbial Acceptability Limits, if Applicable and Cleaning Agent Acceptability Limits for Equipment Cleaning shall be established, justified and validated. A Risk Assessment shall be performed to determine the need to establish microbial limits. Automated Cleaning Systems, such as automated Clean-In-Place (CIP) and cleaning cycles shall be validated.

An Equipment Cleaning Validation Protocol must be prepared and approved. The protocol shall include or reference, at least, the following:

* Cleaning Procedure/Instruction-Records to be validated;

* Products addressed by the protocol;

* Description of equipment including equipment surface area;

* Residue materials to be removed;

* Cleaning and sanitizing materials to be used;

* Campaign lengths, if applicable;

* Cleaning parameters to be evaluated;

* Analytical Methods;

* Microbiological Test Methods (TM), if applicable;

* Sampling plans, including rationale for the selection of specific sites identified for sampling;

* Sampling methods;

* Acceptance criteria;

* Validation strategy (e.g., number of validation runs); and

* Maximum time interval between use and cleaning or between cleaning and use, if applicable.

Analytical Methods, Microbiological methods and Sampling Methods (Rinsate or Swabbing) used to determine residue levels after cleaning must be validated.

Swabbing shall be used as the primary sampling method for validation unless it is not possible to swab because of safety concerns or accessibility. Exceptions to this requirement must be justified and approved by the Validation Committee (VC).

Sampling Method (Rinsate or Swabbing) Recovery Studies shall be conducted as defined. When recovery values are less than seventy (70) percent, the recovery value must be used as a correction factor in the calculation of results or limits. For recoveries of greater than one hundred (100) percent, no recovery values are to be used as a correction factor, but the recovery values must have a practical upper limit.

Personnel Responsible for Equipment Cleaning Validation and Sampling must be trained to perform a specific task. Training shall be documented.

Validation consists of three consecutive, successful executions (i.e., no failures related to the cleaning procedure between the successful executions) of the cleaning procedure. When the product matrix (grouping) approach is used, a validation exercise shall be performed on the most difficult to clean product(s) (Marker). When the product matrix approach is used, additional cleaning validation exercises using the next most difficult to clean product may be conducted prior to completion of the three validation exercises of the most difficult to clean product (e.g., when the worst case material is made infrequently).

Failure of a validation exercise for the next most difficult to clean product is equivalent to a failure of the validation exercise for the most difficult to clean product. Validation exercises shall be executed using one or more of the following options:

* Cleaning validation exercises performed at the end of a regularly scheduled campaign; and/or

* Cleaning validation exercises conducted at campaign lengths less than the maximum campaign length, as long as at least one exercise is at full campaign length.

Criteria for Equipment Cleaning Validation for both major and minor equipment shall be as follows:

* Visibly Clean; and

* Analytical verification of residue removal (i.e., therapeutic and/or Non-Therapeutic Material) to predetermined acceptance criteria.

For minor equipment, visual inspection alone is acceptable when the visual detectable quantity is at or below RAL, and there is approved documentation with justification. Safety Factor (SF) for Calculating Each Maximum Allowable Residue (MAR) for Therapeutics (MART) and Non-Therapeutics (MARN) shall be as follows:

Safety Factor (SF) for calculating each Maximum Allowable Residue (MAR) for therapeutics (MARt) and Non – therapeutics (MARn) shall be as follows:

Footnote (a) – A safety factor of 1 / 100 shall be used for calculation of MARt for oral products unless the product toxicity, potency, or safety (e.e. cytotoxic or hormones) is a concern in which case, as SF of 1 / 1000 shall be used.

Maximum Allowable Time Intervals Between Use and Cleaning must be demonstrated in at least one cycle of equipment use and cleaning by the execution of the cleaning procedure, and shall be documented during the validation exercise.

Maximum Allowable Time Intervals for the Periods between the Completion of Cleaning and Next Use shall be evaluated. If this time period potentially impacts the cleaning status of the equipment then the time interval must be specified and validated.

A Validation Report shall be prepared and shall include, at least:

* A list of products and equipment included in the cleaning validation study;

* The validated parameters and ranges; and

* References to the cleaning procedures used.

Cleaning Procedures for Products New to the Site must be evaluated by the Quality Team and Production Team and an assessment report(s) issued that addresses the probable impact of the new material on the current cleaning validation plan.

If the worst case approach is used, the new product shall be evaluated to determine if it is the most difficult to clean compound for the cleaning procedures selected. If it is not the most difficult to clean, the new product may be incorporated into the existing matrix with no impact on the validation of the procedures. At least one cleaning validation exercise must be performed for each cleaning procedure on the new product in the equipment train. A report must be written and approved to summarize the cleaning data for the new product.

If the new product is determined to be the most difficult to clean compound, then the existing procedure(s) or new procedure(s) shall be validated with at least three (3) consecutive, successful executions of the cleaning procedure on the new product

If the worst case approach is not used, the cleaning procedures for the new product shall be validated.

If the new product is the one with the lowest RAL, then an evaluation must be performed to determine if validation of the most difficult to clean product with the new RAL is required, or whether the A to B individual product approach is to be used.

A New Non-Therapeutic Material (e.g., cleaning agent) used in product contact equipment must be evaluated by the Site Production Team and Site Quality Team and an assessment report(s) issued that addresses the probable impact of the new material on the current equipment cleaning validation plan.

Failures During Validation (i.e., visual and/or analytical result failures) must be documented and Investigated according to established Site procedures.

All Planned and Unplanned Changes with potential impact on validated cleaning procedures shall be addressed by established change control and/or investigation procedures. The VC must approve the impact analysis of the change(s) and the determination if Revalidation or further actions are required. Such changes include, and are not limited to, those potentially affecting any of the following:

* Production process;

* Cleaning methods;

* Cleaning materials;

* Sampling methods;

* Analytical methods;

* Microbiological methods, if applicable;

* Equipment configuration or equipment assembly;

* Number of Lots/Batches in a campaign;

* Maximum time interval between use and cleaning, or between cleaning and use, if applicable;

* Change in lot size (especially smaller);

* Change in group of products produced in the equipment;

* Change in equipment surface area (including piping, minor equipment, columns); and

* Change in RAL and/or MAR.

Periodic Review of Validated Changeover Cleaning Procedures relative to all Equipment Units is required.

E. Laboratory Equipment Qualification

This good practice procedure defines the minimum requirements for Qualification of Simple, Moderate and Complex laboratory equipment that is used in an analytical laboratory in a Good Manufacturing Practices (GMP) environment associated with products in or intended for the marketplace.

The extent of the qualification activities shall be defined in the Site Validation Master Plan (VMP). Laboratory equipment qualification program(s) shall be established and maintained at each GMP site (e.g., Pharmaceutical and Animal Health) defining the responsibilities, criteria and documentation requirements for the qualification of laboratory Equipment used at that Site.

Client/server applications and Custom Software controlling laboratory equipment shall follow this procedure. The addition of new non-software laboratory equipment to existing Validated client/server or Custom Systems will follow this procedure.

Equipment that is exempt from qualification must be defined in the Site’s local Standard Operating Procedures (SOP) or VMP.

This procedure applies to Laboratory Equipment that is used for GMP testing performed for Active Pharmaceutical Ingredients (API), API Starting Materials and Intermediates from the point at which the API starting material is introduced into the process, Drug Products, In-Process Materials, Raw Materials (RM), Medical Devices, and Biologicals. This procedure also applies to the analysis of samples supporting validation activities (e.g., process, method, cleaning).

The System Owner is responsible for ensuring that the laboratory equipment requiring qualification is:

* Qualified prior to GMP use

* Qualified to an extent that is consistent with its intended use and suitable for its intended use; and

* Maintained in a qualified state [e.g., Preventive Maintenance (PM), Calibration, Periodic Review, and change control] until the equipment is removed from service.

Equipment Classification for Qualification Purposes – laboratory equipment shall be categorized into one of the following classifications:

* Simple,

* Moderate, or

* Complex.

All New Laboratory Equipment shall be assessed to determine the need for and extent of qualification. Legacy equipment shall be assessed to evaluate the need for qualification based on current use, performance, and extent of procedures. Equipment in place at the time of the approval of this procedure is considered to be legacy equipment.

The Need to Qualify Laboratory Equipment shall be based on the intended use of the instrument. The evaluation to determine the need to qualify the equipment shall be performed, prior to use following an Approved assessment process that is defined and documented at each Site (e.g., SOP, VMP, checklist, forms).

The Need to Requalify Equipment shall be assessed through documented periodic review. Requalification may also be initiated after repair, upgrade, modification, or change of use through the change control process.

Laboratory Equipment That Requires Qualification shall be uniquely identified and referenced in Site documents (e.g., Site VMP, equipment log, SOPs, calibration list).

Qualification Requirements and Requirements for Vendor Quality System Evaluation shall be based on the classification of the equipment and its intended use

Laboratory Equipment Qualification Documentation (e.g., Plans and/or Protocols) shall be based on the equipment classification. Qualification documentation shall identify or reference responsibilities, required activities, and acceptance criteria.

Site Colleagues Conducting Qualification Activities described in this procedure shall be trained to perform their specific tasks. Training shall be documented. The use of vendors and/or Consultants in performing qualification tasks shall be documented. Documentation of training credentials shall cover tasks performed during qualification training (e.g., certificates of qualification training) and must be obtained for vendors and contractors. If training credentials are not available, the training shall be documented.

Documentation [e.g., User Requirement Specifications (URS), Technical Manuals, Owners Manual] must be available for equipment, within the scope of this procedure, that describes what the equipment must be capable of doing in order to fulfil the needs of the laboratory.

Qualification Testing shall verify that all components of the system meet approved pre-determined acceptance criteria. Qualification testing shall be documented.

Installation Qualification (IQ) shall verify that all components have been properly installed and meet the manufacturer’s recommendations. IQ shall be performed for simple, moderate and complex equipment. Legacy Systems do not require IQ. IQ for legacy systems shall be considered in cases of relocation or requalification.

Operational Qualification (OQ) shall be designed to verify the equipment’s operation according to pre-determined Specifications. Legacy systems OQ may be supported by an established calibration program. OQ for legacy systems shall be considered in cases of relocation or requalification.

Performance Qualification (PQ) shall provide documented evidence that the equipment produces the intended results under normal operating conditions. Simple equipment does not require PQ. Legacy systems PQ may be supported by an established calibration program. PQ for legacy systems shall be considered in cases of relocation or requalification.

The Completion of the Qualification Activities (i.e., IQ/OQ/PQ) shall be documented and approved by the system owner and the Quality Team signifying that the equipment is acceptable for use. Deviations resulting from execution of the qualification shall be addressed as defined in Site procedures.

Site Defined Procedures shall be followed for any changes to the equipment after completion of qualification testing.

Documentation for Qualified Equipment Maintenance and Operation shall be available prior to use of the equipment.

Laboratory Equipment Requiring Ongoing Calibration shall be entered into the Site calibration program following the completion and approval of qualification activities.

A Plan or Documented Procedure (e.g., SOP) shall be available to define the process for retiring a piece of equipment. This process shall describe all activities needed to decommission the qualified equipment including records retention.

F. Microbiological Methods Validation

This good practice document addresses the Validation of non-compendial or alternate microbiological Test Methods (TM) or the Verification of Compendial microbiological test methods to demonstrate that a test method is suitable for its intended purpose. Microbiological methods may be placed into two (2) general categories:

* Qualitative (presence/absence tests), and

* Quantitative (enumeration tests).

The microbiological test method must be developed, documented and have sufficient detail so that a Qualified Lab Analyst can accurately perform the test in an environment suitable for the test method and using the required test method materials. All test methods shall be maintained under change control.

This procedure applies to all GMP sites and operations responsible for the validation or verification of microbiological methods used to test the following:

* Drug Products,

* Raw Materials (RM) and Active Pharmaceutical Ingredients (API),

* In-Process Materials and Intermediates and

* Stability samples

Microbiological methods include, the following tests:

* Microbial Limits and

* Test for Specified Organisms.

This procedure does not apply to the validation of test methods used to determine and monitor pre-filtration Bioburden.

All Compendial (e.g., EP, JP, USP) Microbiological Methods are considered to be validated but the suitability of the test method must be verified under actual use conditions in the laboratory, including any minor variations (e.g., change in buffer) in the test method.

All Non-Compendial Microbiological Methods shall be validated and the suitability of the test method must be verified under actual use conditions in the laboratory. Validation of non-compendial microbiological methods shall address the following parameters:

* Accuracy;

* Precision, including Repeatability and Reproducibility;

* Specificity;

* Detection Limit (DL);

* Quantitation Limit (QL);

* Linearity, and

* Range.

Not all validation parameters apply to the validation of every non-compendial microbiological method (see Table 1).

Microbiological Methods Validation or Verification shall be performed and documented according to an Approved Protocol that defines the parameters being evaluated, the acceptance criteria for each parameter, and the TMs. The protocol must be approved by the Lab Manager prior to execution of the validation studies.

A Method Validation or Verification Report shall be prepared that documents the results of the validation or verification study, including the evaluation of each parameter and comparison against acceptance criteria. Any Deviations from the protocol must be documented and the impact of the deviations discussed in the report.

Qualified Personnel shall be identified with the following roles and responsibilities in regards to microbiological test method validation or verification:

* The Lab Manager at the Site conducting the validation or verification is responsible for assuring that the microbiological methods are validated or verified according to this procedure and for reviewing and approving the Final Report; and

* The Quality Team, independent of the Lab Manager, at the Site conducting the validation or verification study is responsible for reviewing and approving the final report for compliance with applicable Site policies and procedures.

Automated Systems used as a part of a microbiological test method and computer-related laboratory systems shall include Validation of the Computerized System.

Microbiological Methods for Production Materials or Products that have Anti-microbial Activity or Inhibitory Effects on the Recovery of Microorganisms shall include a validated neutralization step, if required by the test method (e.g., Test for Specified Organisms, Microbial Limits Test).

Qualified Personnel shall perform:

* Validation studies, and

* Verification of compendial methods.

Written and Approved Procedures shall describe the preparation, labeling, storage, and use of laboratory Reagents, solutions, buffers, Reference Standards, Microbiological Culture Media, Microbial Cultures, and Biological Indicators (BI).

Test Equipment used in the execution of the microbiological test method protocol must be Qualified and have a current Calibration status.

Microbiological Methods Validation or Verification Studies shall be documented and retained in accordance with site record retention requirements.

Alternative Microbiological Methods must be validated and must be shown to be equivalent to the compendial or regulatory filing method. Validated alternative microbiological methods shall be submitted to the Regulatory Team, when required, prior to implementation.

Legacy Methods – the need to validate a legacy microbiological method that has not been previously validated or is not a compendial method shall be based on an Impact Assessment by the responsible Site Quality Team. Legacy methods shall be assessed against this procedure to ensure available method documentation is current and reflects the method. A Retrospective Validation approach may be used to support the microbiological method validation.

Verification of Compendial Microbiological Methods or Validation of Alternate Microbiological Methods (e.g. automated or rapid methods) shall be based on the method and shall include, and not be limited to:

a. Quantitative Methods (e.g., Microbial Limits Test):

* Membrane Filtration and plating; and

* Direct inoculation (e.g., pour plate, spread plate, or multiple tube method).

b. Qualitative Methods (e.g., Tests for Specified Organisms).

The Suitability of Compendial Microbiological Test Methods shall be verified under actual use conditions according to the compendia applicable to the product’s market(s) and include, and not be limited to, the following:

* Recovery of the challenge microorganisms; and

* Demonstration of neutralization efficacy and absence of neutralization toxicity, when Neutralizing Agents are used.

The Microbiological Method Validation or Verification Protocol shall include, and not be limited to, the following:

* A clear definition of the method and its purpose;

* Identification of specific test conditions (e.g., pH, water, incubation temperature range, equipment, positive and negative controls);

* Neutralization procedures, if required;

* List of the microorganisms that will be used during the test method validation or verification;

* Description of the validation or verification methodology (e.g., number of sample sets and replicates, data evaluation procedures);

* Establishment of acceptance criteria;

* Documentation requirements; and

* Validation parameters to be evaluated (e.g., parameters listed in Table 1).

The Microbiological Test Methods Validation or Verification Report shall include, and not be limited to, the following:

* An overall summary of the results;

* Inclusion or reference to the supporting raw data;

* Discussion of all deviations, corrective actions, and resulting changes;

* Conclusion; and

* Approval signatures and dates.

Microorganisms used in microbiological methods validation or verification shall be specified and based on the requirements stated in the applicable compendial test chapters.

If required by the Method, Aseptic Technique and Sterile equipment, materials and reagents shall be used during microbiological methods validation or verification.

Due to the Inherent Variability of Some Microbiological Test Methods, the validation or verification of a microbiological method must include consideration of the following:

* Inherent antimicrobial and/or inhibitory properties, and

* Recovery of microorganisms from the sample.

Pure Microbial Cultures used during microbiological methods validation or verification shall be prepared from microbiological control cultures developed by Site or purchased from a recognized culture Supplier such as American Type Culture Collection (ATCC) or National Collection Type Culture (NCTC).

The Preparation, Growth, and Storage of Microbial Cultures shall be standardized and include, at least, the following:

* Use of liquid cultures or confluent growths on solid media;

* Incubation of the microbial cultures within the recommended temperature range and time; and

* Storage of the purchased working and stock microbial cultures according to the manufacturer’s recommendation.

If Growth is Inhibited during the Test Method Verification, the method shall be modified to ensure the validity of the test results by neutralizing or removing the antimicrobial activity of the test product or material. Antibiotics may not be susceptible to neutralization by chemical means, but rather by enzymatic treatment (e.g., penicillinase). Such enzymes may be used where required.

When Verifying a Quantitative Microbial Limits Test, the inoculation of the microbial suspension shall be added directly to the test sample preparation (product or material). When verifying a qualitative microbial limits test, the inoculation of the microbial suspension shall be added to the prescribed growth medium at the time if mixing with the test sample preparation. The inoculum size of the microbial suspension must be not more than one hundred (100) cfu and the volume of the suspension shall not exceed one percent of the volume of diluted product.

A minimum of three (3) experiments using different product Lots, if possible, shall be conducted. The most concentrated formulation of a product shall be used for the method verification studies, as long as all other excipients are equivalent in concentration or make-up. If excipients are not equivalent in concentration or make-up, method verification studies shall be performed for all product strengths. Exceptions are permitted if the excipients in question are considered microbially inert and would have no effect upon microbial recovery.

Verification of the Microbial Limits Test must demonstrate recovery of the viable microorganisms by comparing recovery results from the following three (3) treatment groups:

* Test Group -the test sample preparation (quantitative) or the prescribed growth medium with test sample preparation (qualitative) is inoculated with challenge microorganisms and the test method is performed;

* Viability Group -the level of inoculum is measured in the absence of both the test sample and the test method; and

* Control Group – a diluent solution, without test sample (quantitative) or a diluent solution in prescribed growth medium without test sample (qualitative) is inoculated with challenge microorganisms and the test method is performed.

(Note: this group is used only when neutralization agents are employed.)

For the verification of a test method, the test method must demonstrate that recovery of a low level of inoculum [not more than one hundred (100) cfu] is not inhibited by the test sample or the test method. This shall be demonstrated when the recovery of microorganisms is similar between the test group and the viability group.

If neutralizing agents (e.g., chemical inhibitors, surface active agents, or enzymes) are employed in the test method, the neutralization efficacy and the absence of neutralization toxicity studies must be demonstrated. Neutralization efficacy shall be demonstrated when the recovery of microorganisms is similar between the test group and the control group. The absence of neutralization toxicity shall be demonstrated when the recovery of microorganisms is similar between the control group and the viability group.

From the comparisons of the three (3) treatment groups, each verification study that employs neutralizing agents shall demonstrate that the neutralization method employed is effective in inhibiting the antimicrobial properties of the product (neutralizing agent efficacy) without impairing the recovery of the viable microorganisms (neutralizing agent toxicity).

For quantitative test methods, microbial growth comparisons between each of these treatment groups must not differ by a factor greater than two (2) [i.e., fifty (50) percent to two hundred (200) percent]. For qualitative methods, the specified microorganisms must be detected.

To demonstrate acceptable recovery from the product or material for a quantitative test, the lowest possible dilution factor of the prepared sample must be used for the test method. To demonstrate acceptable recovery from the product or material for a qualitative test, the shortest incubation period prescribed by the required compendia must be utilized.

When Acceptable Microbial Recovery is not Possible due to antimicrobial activity or poor solubility of the test sample, the following process shall be followed in order:

* Further protocols with modifications to the method shall be developed.

* If inhibition of growth by the test sample cannot otherwise be avoided, the inoculation of the microbial suspension may be added after the neutralization, dilution, or filtration step. (Note: This step is applicable only to quantitative tests).

* If acceptable microbial recovery still cannot be met for one or more of the challenge microorganisms, the test method with the best microbial recovery is used to test the product or material.

Accuracy of a non-compendial test method shall be established across a specified range of the test method:

* Use pure microbial cultures for each microorganism that must be identified;

* Prepare a suspension of microorganisms at the upper test range and serially dilute to the lower test range;

* Calculate the expected cell count of the microbial culture at a minimum of five (5) serial dilutions;

* Analyze a minimum of two (2) replicates at each of five (5) concentrations across the range of the test method; and

* Obtain an acceptance criteria in the range of seventy (70) percent to one hundred thirty (130) percent recovery of each microorganism based on a comparison of the actual test results with the results expected from the dilutions using the upper test range used as a reference of one hundred (100) percent.

Precision of a non-compendial test method shall be determined as a measure of a test method’s repeatability and/or reproducibility under normal operating conditions:

* Use pure microbial cultures for each microorganism that must be identified;

* Prepare a suspension of microorganisms at the upper test range and serially dilute to the lower test range;

* Analyze a minimum of two (2) replicates at each of five (5) concentrations across the range of the test method;

* Repeat the analysis on a 2nd suspension; and

* Perform a statistical evaluation of the data [e.g. coefficient of variation (i.e., relative standard deviation) in the range of fifteen (15) percent to thirty (30) percent for an acceptable microbial count].

Specificity of a non-compendial test method shall be determined during validation by screening the test method against a range of representative microorganisms and sample types to demonstrate that the test method is fit for its purpose. All representative microorganisms must be successfully isolated and counted from the specified sample types.

Detection Limit (DL) of a non-compendial test method shall be determined by an analysis of samples with known concentrations of microorganisms:

* Use an original sample prior to any incubation step;

* A minimum of five (5) spiked replicates shall be evaluated for each microorganism to be detected; and

* Establish the minimum level at which a microorganism, when present in the sample, can be detected during the time frame of the assay.

Quantitation Limit (QL) of a non-compendial test method shall be determined by an analysis of a minimum of five (5) replicates at each of five (5) concentrations across the range of the test method. The QL shall establish the minimum level at which a microorganism when present in the sample can be quantified during the time frame of the assay.

Linearity of a non-compendial test method shall be evaluated across the range of the test method during validation:

* Prepare a suspension of microorganisms at the upper test range and serially dilute to the lower test range;

* Analyze a minimum two (2) replicates at each of five (5) concentrations across the range of the test method; and

* Plot the data points and perform a statistical evaluation of the data (e.g., correlation coefficient where r2 =0.9 or better).

Range of a non-compendial test method shall be demonstrated by verifying that the test method provides acceptable precision, accuracy, and linearity, within or at the extremes of a specified interval.

Reproducibility of a non-compendial test method shall demonstrate that different operational and environmental variables (e.g., different analysts, different equipment, different reagents, different laboratories) do not impact the reliability of the test method under normal laboratory operating conditions. Non-compendial quantitative test methods must be tested for reproducibility and shown to be precise and accurate when used in two (2) or more laboratories, performed with different equipment, and performed by two (2) or more analysts. A reproducibility experiment must include test samples prepared from a homogeneous or composite sample by at least two (2) different analysts on more than one day, and methods executed in two (2) or more laboratories.

Robustness of a non-compendial test method shall demonstrate that small, deliberate changes to test method parameters do not affect the reliability of the test method. Changes of up to twenty (20) percent on such items as critical reagent concentrations, instrument operation parameters, and incubation temperatures shall be evaluated.

For each test method, the Site Quality Team must decide whether robustness is required and document the decision and rationale.

Proposed Changes to Validated Test Methods shall be evaluated according to Site change control procedures by the Lab Manager prior to implementation and the test method shall be Revalidated as necessary. The revised method must be shown to be, at least, equivalent to or better than the validated method. Results of the revalidation shall be documented, approved and retained according to Site record retention requirements.

Changes in the Manufacturing Process and/or Formulation for APIs and drug products shall be evaluated according to Site change control procedures by the Lab Manager for the need to revalidate or verify applicable test methods.

G. Packaging Validation

Packaging Processes for Pharmaceutical and Animal Health products shall be Validated.

This good practice guidance document addresses the validation of the primary packaging of oral solid tablets and capsules and the secondary packaging and Labeling for all Drug Products and Medical Devices.

Primary packaging of all other drug products (e.g., Sterile drug products, inhalers, solutions and suspensions and semi-solid drug products) is not addressed in this document.

The validation approach for all commerical products and processes including packaging shall be defined in Validation Master Plans (VMP) and/or Validation Project Plans (VPP).

This procedure applies to all pharmaceuticals Production Sites and operations responsible for packaging of commercial drug products and medical devices for Pharmaceutical and Animal Health.

Packaging Process Validation is required in the following cases, unless there is documented justification for not performing validation:

Introduction of a New Product;

* Start-up of a new facility, transfer of a packaging process from one facility to another, or transfer of a non-portable line to a new location within the same facility;

* When new or modified equipment impacts a Critical Quality Attribute or a Critical Process Parameter of the packaging process;

* When there is a new or changed package [as determined by the Validation Committee (VC)] that has an impact on the packaging process; and

For Legacy Systems and Processes covered under this procedure that have not been previously validated.

A Validation Protocol shall be established that specifies how validation will be conducted. The protocol shall specify critical steps, critical process parameters, sampling requirements and  acceptance criteria and shall be Approved before validation activities begin.

Prospective Validation shall be used in validating a substantially modified or new packaging process. The rationale for the decision shall be documented and justified.

Concurrent Validation may be used for well-understood and documented processes. The decision to carry out concurrent validation shall be justified, documented and approved by the VC.

Retrospective Validation maybe used in a few specific circumstances. The decision to carry out retrospective validation shall be justified, documented and approved by the VC.

Matrixing and Bracketing -solid oral products using a previously validated packaging process for the similar packaging (e.g., same Container, Closure or Label) only require that the filling process be validated. -Prerequisites for Packaging Process Validation Studies include and are not limited to, the following:

* Bulk Hold Time studies, if applicable.

* Approved Bill of Materials, Master Packaging Instructions and applicable Standard Operating Procedures (SOP);

* Critical Quality Attributes and Critical Process Parameters shall have been identified. The rationales for the Critical Process Parameters and the Probable Adverse Consequences to be expected when their ranges are not met shall be documented. Settings for Critical Process Parameter Ranges, such as line speeds and temperature ranges shall have been qualified;

* System Qualification (e.g., equipment, facilities, utilities and Computerized Systems)-Direct Impact Systems, associated critical Change Parts and Critical Components used in the packaging process must have been qualified prior to validation of the packaging process;

* Equipment Cleaning Validation shall be performed concurrently or completed with packaging validation. Cleaning and line/visual inspection instructions must be approved;

* Calibration of critical instruments shall be completed.

* Qualified personnel to prepare the validation runs and perform other work associated with the validation study; and

* Approved Specifications for finished packaged product.

Any exception to these requirements must have a documented assessment describing the impact on the validation study and the exception must be approved by the VC.

Packaging Validation Studies must be executed using Packaging Materials with the same specifications as those intended for routine production in accordance with the following guidelines:

Packaging materials are purchased from an Approved Supplier;

* A documented evaluation must be completed with regard to the impact of tablet or capsule thickness, weight, friability and breakage on the validation of the packaging process. For secondary packaging of tubes, bottles, or other containers of semisolids or liquids, an evaluation of potential leakage, breakage, and damage to the filled units must be considered;

* A documented evaluation must be completed with regard to the impact of color on any visual sensors or staining of the equipment, where applicable;

* The use of placebo requires precautions to be taken at the Site to assure segregation and control relative to both the placebo and use of defaced or test labeling; and

* If final label copy is not yet approved, equivalent-labeling materials may be used with VC approval.

Where a Change, Outside the Normal Operating Range (NOR), is Required to a Critical Process Parameter During a Validation Study the effect of the change shall be assessed for its impact on the validation study; this may include a requirement to restart the study using the new value of the parameter. The previous validation runs shall be evaluated and their Disposition documented in the report. The impact of the change on the validation shall be documented in the validation report.

Changes in non-critical process parameters may prove necessary during packaging validation to improve the performance of the packaging process while ensuring that the process produces product that meets acceptance criteria. Such changes shall be documented and justified in the validation report and evaluated for their impact on the validation exercise. Documentation and approval of such changes shall be carried out according to the relevant Site SOPs.

Validation Test Conditions -packaging validation shall be conducted at or within the NOR defined in the packaging instructions.

Packaging Validation Acceptance Criteria shall be established with consideration for the special needs of each product and/or process being validated. Each run shall meet acceptance criteria identified in the validation protocol. Exceptions to this must be  evaluated, reviewed, and approved (if acceptable) in the validation report.

Successful Packaging Validation Runs shall be conducted according to the packaging instructions referenced in the validation protocol.

The Number of Packaging Validation Runs carried out and data collected shall be sufficient to provide enough data for the evaluation of packaging process reproducibility.

For new processes or validation of major process changes, a minimum of three (3) consecutive runs is typical for packaging process validation. Use of a different number of validation runs [i.e., other than three (3)] must be documented and justified based on process knowledge.

The duration and size of a packaging validation run (e.g., entire Lot or defined portion of a lot) shall be determined by the VC based on a technical evaluation, Risk Assessment and experience with the packaging process.

A validation run may be excluded from the validation sequence of consecutive runs if failure to meet acceptance criteria has been Investigated and documented to be the result of non-process related cause such as equipment failure or operator error. Replacing a run excluded for a non-process-related cause does not require that the validation sequence be restarted. The decision to exclude a run or runs must be documented and justified in the validation report.

Packaging Environment Conditions (e.g., temperature, humidity, special lighting, Air Classification, vibration) that represent critical process parameters shall be defined in the protocol. In these cases, confirmation that the environmental conditions were maintained during the validation exercise shall be included in or referenced by, the validation report

Process Monitoring must be conducted during validation by qualified personnel to Verify, at least, the following:

* Equipment cleanliness;

* Proper line clearance between lots;

* Correct, approved packaging materials;

* Adherence to packaging instructions and applicable SOPs;

* Operation of the packaging process within approved ranges (e.g., speeds and temperatures); and

* Start-up and shut down procedures.

Changes to Approved Protocols –where a change to an approved protocol is required prior to the start of execution, the protocol shall be reissued as the next version and shall be approved by all the same approval authorities as the original protocol before starting the validation exercise.

When a change that impacts an acceptance criterion is needed after protocol execution has already begun, options that must be considered are:

* The work shall be discontinued and restarted following approval of a new, revised protocol, that includes the reason for the change; or

* Supplemental documentation shall be prepared, approved and issued via the same approval process as followed for the original protocol. The supplement shall specify the reason for the change and the point in the protocol at which it becomes effective. Approval of the supplemental documentation must precede execution of the change. Documentation of changes made during the validation exercise must be included or referenced in the validation report and shall include the reason for the change.

Validation Failures – failure of any validation run to meet the requirements of the protocol shall be investigated according to site SOPs. Conclusions of the investigation shall include a determination of the effect of the run failure on the packaging validation and further actions to be taken, if any, including possible replacement of the failed validation run. Reference to the failed run and investigation shall be made in the validation report.

A Validation Report referencing the relevant protocol(s) shall discuss the results from the execution of the protocol and shall be approved. A Final Validation Report shall be issued following completion of the validation study. Interim Validation Reports are required when the time between the start of the validation study and completion of the entire study is greater than a period of time specified in the documented Site policy.

Any Deviation from the approved protocol shall be documented with justification. All packaging process deviations shall also be documented and reviewed as to their impact on validation.

The conclusion of the report shall confirm whether the validation runs have met all of the acceptance criteria. The conclusion shall state whether the packaging process is validated and is approved for use in routine packaging.

Release of Validation Lots – the conditions under which commercial lots are packaged shall comply with all regulatory registrations and other regulatory requirements. Status of validation material shall be controlled. Before a packaging validation lot can be released for commercial use or distribution, the VC shall ensure that:

* For prospective validation, the final report is approved; and

* For concurrent validation, at least an interim report is approved.

Pending approval of the validation report, validation lots may be shipped to another site or Contract Vendor under Quarantine provided systems are in place to prevent commercialization of the products using this packaging process.

Reprocessing shall be documented and evaluated as a planned deviation. The investigation shall determine the impact on the process and product. The need for and extent of requalification, Revalidation, and stability testing shall be determined by the VC and approved by the Site Quality Team and  the Site Validation Team.

Change Control – all changes that may affect product quality or reproducibility of the packaging process shall be evaluated for likely impact on the process or product. The determination of major or minor change, need for, and extent of requalification, revalidation and stability testing shall be determined by the VC.

If validation of a process involves a regulatory change, a Product Change Proposal (PCP) and a Product Change Request (PCR) are required.

Major changes to Primary Packaging Materials, equipment, utilities, facility, procedures, or the packaging process require validation.

Minor changes may require a documented, expanded test program or other evaluation using the Site change management system.

A Periodic Review is required as described in the site procedure. Such periodic reviews consist of a documentation review of packaging records, including deviations, investigations and Trends as well as change control documents. It shall verify that:

* The systems and processes are still operating in a validated state of control; and

* There have not been major changes to the process either as single changes or as cumulative changes.

If the review findings indicate the packaging process is not under control an investigation shall be conducted to determine impact on the packaging process and product, and to determine potential need for revalidation and/or any other corrective actions.

H. Process Validation for Active Pharmaceutical Ingredients (API)

This guidance document applies to all API production sites and operations responsible for manufacturing APIs for the use in Pharmaceutical or Animal Health products.

Production Processes used for producing an Active Pharmaceutical Ingredient (API) and/or a critical Intermediate shall be Validated. All commercial products and processes at the GMP site and the validation approach for each process shall be defined in Validation Master Plans (VMP) and/or Validation Project Plans (VPP).

Validation of packaging for non-sterile APIs is not in the scope of this procedure.

This procedure addresses Process Validation and Revalidation for existing, new and modified API processes used for the manufacture of commercial materials including:

* Processes using chemical synthesis;

* Classical Fermentation processes (for production of small molecules); and

* Biopharmaceutical Processes [for production of macromolecular Drug Substances (DS) such as proteins].

The Site’s Validation Committee (VC) shall be accountable for ensuring that process validation is executed as per established procedure.

Process Validation shall include, at a minimum, all critical steps of the API process from the step at which the API Starting Material is introduced through all subsequent steps to the finished API. The evaluation of critical steps shall be documented and Approved by the VC.

A step containing a parameter critical to the quality of the final API is deemed a critical process step and shall be included in the validation.

A Validation Protocol shall be established that specifies how validation will be conducted. The protocol shall specify critical steps, Critical Process Parameters, sampling requirements and acceptance criteria, and shall be approved before validation activities begin.

The extent of the validation effort shall be based on a Risk Assessment.

Prospective Validation shall be used in validating a substantially modified or new process.

Retrospective Validation of legacy processes may be used in a few specific circumstances. The decision to carry out retrospective validation shall be documented and justified. The decision to use retrospective validation shall be approved by the VC.

Concurrent Validation may be used for well-understood and documented processes. The decision to carry out concurrent validation shall be documented and justified. The decision to use concurrent validation shall be approved by the VC.

Prerequisites for Process Validation include, and are not limited to, the following:

Approved Master Manufacturing Process Instructions, Manufacturing Process Instructions, Records and applicable Standard Operating Procedures (SOP);

* Identified critical process parameters and Critical Quality Attributes;

* Qualified equipment, facilities, utilities and Computerized Systems. Exceptions to this requirement must be approved by the VC;

* Qualified or validated supporting processes that may affect process validation (e.g., Filtrationor Sterilization);

* Compatibility with product-contact equipment for leachables and extractables;

* Calibration of critical instruments;

* Approved Specifications for finished product and Raw Materials (RM) and established In-Process Controls (IPC) and decision criteria for them;

* Validated Test Methods required for release of products . Suitably qualified or validated test methods shall be used to support non-routine data generated during validation studies; and

* Qualified personnel to prepare the validation Batches and perform other work associated with the validation study.

Any exception to these requirements must have a documented assessment describing the impact on the validation study and the exception must be approved by the VC.

For validation of biopharmaceutical and classical fermentation processes, prerequisites also include:

* Documentation of the origin, source, and history of cell line materials;

* Fully characterized Master and Working cell banks; and

* Suitable environmental controls and cleaning programs for control of foreign growth.

Additional prerequisites for validation that are applicable only to biopharmaceutical processes include:

* Documented evidence of the viral safety of the cell banks (pertains to mammalian cells only); and

* Documented demonstration of process viral clearance using qualified scaled-down models (for mammalian processes only).

Raw Materials (RM) used in the manufacture of validation batches shall be purchased, stored and approved according to established procedure.

Critical Process Parameters, Critical Process Parameter Ranges and Critical Quality Attributes of the process being validated must be identified and justified.

The VC is responsible for ensuring that the ranges proposed in the validation protocol for critical process parameters are correct and have supporting documentation. Such information shall be obtained from, for example, the technical transfer information or historical Site documentation, and shall be included or referenced in the validation protocol.

Where a Change is Required to a Critical Process Parameter During a Validation Study the effect of the change shall be assessed for its impact on the validation study; this may include a requirement to restart the study using the new value of the parameter. The previous validation batches shall be evaluated and their Disposition documented in the report. The impact of the change on the validation study shall be documented in the validation report.

Changes in non-critical process parameters may prove necessary during process validation to improve the performance of the process while ensuring that the process produces product that meets acceptance criteria. Such changes shall be documented and justified in the validation report and evaluated for their impact (individual and cumulative) on the validation exercise. Documentation and approval of such changes shall be carried out according to the relevant Site SOPs.

Equivalence for a Finished API Produced by Chemical Synthesis and/or a Classical Fermentation Process must include evaluation of the impurity profiles, including residual Solvents. No new unqualified impurities exceeding 0.1 percent are to be present when compared to the previously produced material. Existing impurities must be within established limits or be within justified statistical limits (e.g., +/-3 sigma around the mean) of historical data. Alternative equivalence criteria must be justified and approved.

Equivalence of other critical chemical and physical attributes shall also be demonstrated.

Validation Test Conditions -process validation shall be conducted using standard production conditions. Evaluation of challenge conditions that pose the greatest chance of process or product failure compared to ideal operating conditions shall be documented during process development and/or process robustness studies.

Processing Time Limits -if a specific processing time (e.g., normal or extended processing time of an in-process solution or suspension) is critical to product quality, evaluation of the limits for the processing time shall be conducted in a manner such as that used for critical process parameters.

For biopharmaceutical processes:

* The biochemical stability of process intermediates under processing conditions (e.g., due to pauses in processing) shall be demonstrated either at manufacturing scale or lab scale. This can be accomplished at manufacturing scale by conducting studies using samples of process intermediates taken from the full scale DS manufacturing process (e.g., by holding of samples rather than holding the full-scale batch);

* Processing time limits shall be designed to account only for the stability of individual pools. Cumulative processing time studies representing the summation of maximum unit operation processing times are not required. Hold time for materials used in the process (such as for buffers or growth media) shall be established when there is potential impact on product quality.

Bracketing or Matrixing may be used where multiple Process Parameters or equivalent Equipment Items are involved. The purpose and rationale for the bracketing or matrixing approach used must be documented and justified in the validation protocol.

Validation Batch Size shall be the same size as the intended standard commercial scale batches. Normal allowed variations in linear scale changes shall be specified in Site SOPs with justification. Where ranges in batch size outside of the normal allowed variation are proposed for the commercial process, it must be demonstrated or justified that variations in batch size do not adversely alter the characteristics of the finished product.

For synthetic processes, small-scale commercial batches may be validated where the manufacture of full-scale intended commercial size batches is not practical.

A concurrent validation approach may be used for linear scale changes from the validated batch size. The Number of Process Validation Batches prepared and data collected shall be sufficient to provide enough data for the evaluation of process reproducibility.

For new processes or validation of major process changes, a minimum of three consecutive batches is typical for process validation. Use of a different number of validation batches (i.e. other than 3) must be documented and justified, based on process knowledge.

Each batch shall meet all acceptance criteria identified in the validation protocol. Exceptions to this must be evaluated, reviewed, and approved (if acceptable) in the validation report.

A validation batch may be excluded from the validation sequence of consecutive batches if failure to meet acceptance criteria has been Investigated and documented to be the result of a non-process-related cause, such as equipment failure or operator error.

Replacing a batch excluded for a non-process-related cause does not require that the validation sequence be restarted. The decision to exclude a batch or batches must be documented and justified in the validation report.

A Successful Validation Batch shall be manufactured as per the Manufacturing Process Instructions referenced in the validation protocol. Each validation batch shall:

* Meet the product specifications relevant to the process validation, and

* Satisfy the acceptance criteria established in the validation protocol.

Homogeneity of the API Batch shall be demonstrated during process validation, unless it has been previously demonstrated for the validated batch size.

When assessment of a planned change indicates a potential impact on batch homogeneity, homogeneity shall be demonstrated for the modified process.

For synthetic processes, the need to demonstrate homogeneity of isolated critical intermediates (e.g., intermediates for commercial sale, or isolated intermediates for which a critical quality attribute has been defined) shall be evaluated according to established Site procedure, or evaluated on a case-by-case basis. For biopharmaceutical processes evidence of adequate mixing must be demonstrated during full-scale validation (such as viral inactivation or pooling).

If homogeneity or Mixing Studies are not performed as part of process validation, a documented justification explaining why this study was unnecessary shall be provided or referenced in the validation documentation.

Stability Requirements -for processes that are new to a Site, a new chemical entity, or where it is believed that the change may affect stability, such as a Rework process, at least one API batch manufactured according to the validated process and meeting the stability testing requirements defined in the site procedure shall be placed on stability.

Changes to Approved Protocols –where a change to an approved protocol is required prior to the start of execution, the protocol shall be reissued as the next version and shall be approved by all of the same approval authorities as the original protocol before starting the validation exercise. When a change that impacts an acceptance criterion is needed after protocol execution has already begun, options that must be considered are:

* The work shall be discontinued and restarted following approval of a new, revised protocol that includes the reason for the change; or

* Supplemental documentation shall be prepared, approved, and issued via the same approval process as followed for the original protocol. The supplement shall specify the reason for the change and the point in the protocol at which it becomes effective. Approval of the supplemental documentation must precede execution of the change. Documentation of changes made during the validation exercise must be included or referenced in the validation report and shall include the reason for the change.

Data Verification -relevant batch documentation shall be reviewed according to Site SOPs prior to inclusion in the validation protocol or report. The data in a validation protocol or report shall also be independently verified, as indicated by signature and date of the verifier, to confirm that information such as test results have been accurately transferred from the original documents or recorded data.

Validation Failures -failure of any validation batch to meet the requirements of the protocol shall be investigated according to Site SOPs. Conclusions of the investigation shall include a determination of the effect of the batch failure on the process validation and further actions to be taken, if any, including possible replacement of the failed validation batch. Reference to the failing batch and investigation shall be made in the validation report.

A Validation Report referencing the relevant protocol(s) shall discuss the results from the execution of the protocol and shall be approved. A Final Report shall be issued following completion of the validation study. Interim Reports are required when the time between the start of the validation study and completion of the entire study is greater than a specified period of time, per documented Site policy.

Any Deviation from the approved protocol shall be documented with justification. All process deviations shall also be documented and reviewed as to their impact on validation.

The conclusion of the report shall confirm whether the validation batches have met all of the acceptance criteria. The conclusion shall state whether the process is validated and is approved for use in routine manufacturing.

Release of Validation Batches -the conditions under which commercial batches are produced shall comply with all regulatory registrations and other regulatory requirements. Status of validation material shall be controlled.

Before a validation batch can be released for commercial use or distribution, the VC shall ensure that:

* For prospective validation, the final report is approved; and

* For concurrent validation, at least an interim report is approved.

Pending approval of the validation report, validation batches may be shipped under Quarantine to another affiliate site or Contract Vendor, provided systems are in place to prevent commercialization of Drug Product using this material.

Rework Processes, when used, shall be validated.

An approved protocol is required to define the validation of the rework procedure, how validation will be executed, the expected results, the acceptance criteria and the requirement for stability testing, if warranted. A concurrent validation approach may be used.

Relevant approvals shall be obtained for rework processes outside the current regulatory filing

Non-routine Reprocessing shall be documented and evaluated as a planned deviation. The investigation shall determine the impact on the process and product. The need for and extent of, requalification, revalidation, and stability testing shall be determined by the VC and approved by the Site Quality Team and the Site Validation Team.

Reprocessing that is applied to the majority of batches shall be included as part of the standard manufacturing process and included in the validation of that process.

Recovery of Materials -the following processing measures used in the production of APIs must be validated:

* Recovery of APIs from recycle streams; and

* Second recovery from mother liquors prepared by critical steps. Equipment Heels may be processed using any of a variety of strategies. Regardless of how it is done, heels used for final API must be produced by a validated process. Validation of processing that produces heel material may be included with validation documentation prepared for the process, or documented as a separate study.

This procedure does not apply to biopharmaceutical processes, where recovery of product from secondary streams or equipment heels is not practiced.

Change Control -all changes that may affect product quality or reproducibility of the process shall be evaluated for likely impact on the process or product. The determination of major or minor change, need for and extent of, requalification, revalidation and stability testing shall be determined by the VC.

If validation of a process involves a regulatory change, a Product Change Proposal (PCP) and a Product Change Request (PCR) are required.

Major changes to materials, equipment, facility, procedures or process require validation.

Minor changes may require a documented, expanded test program or other evaluation using the Site change management system.

Periodic Review is required as described in site policy. Such periodic reviews shall consist of a documentation review of manufacturing and analytical Records, including deviations, investigations, process Trends and change control documents and shall verify that:

* The systems and processes are still operating in a validated state of control; and

* There have not been major changes to the process either as single changes or as cumulative changes.

If the review findings indicate the process is not under control, an investigation shall be conducted to determine impact on the process and product, and to determine potential need for revalidation, and/or any other corrective actions.

Record Retention -process validation records shall be held at the manufacturing location according to the site requirements.

I. Process Validation for Drug Products and Medical Devices

This guidance document applies to all GMP production site sand operations responsible for manufacturing commercial drug products, biopharmaceuticals, medical devices and in-process materials used in the production of commercial drug products.

Production Processes used for producing a Drug Product, Medical Devices, biopharmaceuticals or In-Process Material for a drug product shall be Validated.

All commercial products and processes at the GMP site and the validation approach for each process shall be defined in Validation Master Plans (VMP) and/or Validation Project Plans (VPP).

Process validation shall include critical steps in the manufacturing and filling of the product into the primary package for those dosage forms where the filling process may potentially affect a Critical Quality Attribute. Filling of tablets and capsules and Labeling and secondary packaging of all drug products and medical devices are defined in point 7 of this document.

Process validation for medical devices shall include the processes to manufacture Component(s) of the device and the assembly processes employed to build a finished medical device.

This procedure addresses process validation and Revalidation of existing, new and modified processes used for production of commercial drug products and medical devices (including drug/device combination products). Drug products and medical devices that require process validation include, and are not limited to, the following:

Sterile drug products and medical devices including injection devices (i.e., syringes, pen injectors);

* Dry powder inhalers;

* Metered dose inhalers;

* Solutions and suspensions;

* Semi-solid drug products; and

* Oral solid dosage forms.

The Validation Committee (VC) shall be accountable for ensuring that process validation is executed as defined in this procedrue.

A Validation Protocol shall be established that specifies how validation will be conducted. The protocol shall specify critical steps, Critical Process Parameters, sampling requirements, and acceptance criteria and shall be Approved before validation activities begin.

Prospective Validation shall be used in validating a substantially modified or new process.

A Concurrent Validation Approach may be used for a well-understood process. The decision to carry out concurrent validation shall be justified and documented. The decision to use concurrent validation shall be approved by the VC.

A Retrospective Validation of legacy processes may be used in a few specific circumstances.

The decision to carry out retrospective validation shall be justified and documented. The decision to use retrospective validation shall be approved by the VC.

Prerequisites for Process Validation include and are not limited to, the following:

* Approved master formulation, Master Manufacturing Process Instructions and applicable Standard Operating Procedures (SOP) or approved Device Master Record (DMR) for medical devices;

* Identified critical process parameters and critical quality attributes;

* Qualified equipment – facilities, utilities and Computerized Systems. Exceptions to this requirement must be approved by the VC;

* Qualified or validated supporting processes that may affect process validation (e.g., Filtration, inspection, Sterilization, Media Fills, leachables and extractables for product contact components) shall be qualified and/or validated;

* Calibration of critical instruments;

* Approved Specifications for finished product, Raw Materials (RM), components, and established In-Process Controls (IPC) and the decision criteria for them;

* Validated Test Methods (TM) shall be required for release of products. Suitably qualified or Validated Test Methods shall be used to support non-routine data generated during validation studies;

* Qualified personnel to manufacture the validation Batches or Lots and perform other work associated with the validation study.

Any exception to these requirements must have a documented assessment describing the impact on the validation study and such exceptions must be approved by the VC.

Raw Materials (RM) and Components used in the manufacture of validation batches/lots shall be purchased, stored and approved according to site procedure.

Critical Process Parameters, Critical Process Parameter Ranges, and Critical Quality Attributes of the process being validated must be identified and justified.

The VC is responsible for ensuring that the ranges proposed in the validation protocol for critical process parameters are correct and have supporting documentation. Such information shall be obtained from, for example, the technical transfer information, design of experiments (DOE), or historical Site documentation, and shall be included or referenced in the validation protocol.

Where a Change is Required to a Critical Process Parameter During the Validation Study, the effect of the change shall be assessed for its impact on the validation study. For medical devices, this assessment shall include evaluation of the impact of the change on device functionality (safety and efficacy), and the capability of assembly process.

The change may require restarting the validation study using the new critical process parameter value(s). The previous validation batches/lots shall be evaluated and their Disposition documented in the report. The assessment of the impact of the change on the validation study shall be documented in the validation report.

Changes in non-critical process parameters may prove necessary during process validation to improve the performance of the process while ensuring that the process produces product that meets acceptance criteria. Such changes shall be documented and justified in the validation report and evaluated for their impact (individual and cumulative) on the validation exercise.

Documentation and approval of such changes shall be carried out according to the relevant Site SOP.

Validation Test Conditions -process validation shall be conducted using standard production conditions as defined in the approved Master Manufacturing Process Instructions or approved DMR for medical devices, and the applicable SOPs referenced in the validation protocol.

Evaluation of challenge conditions that pose the greatest chance of process or product failure compared to ideal operating conditions shall be documented during process development and/or process robustness studies.

Hold Time Study -if a specific in-process Bulk Hold Time is critical to product quality, evaluation of the limit for the in-process hold time shall be conducted in a manner such as that used for critical process parameters.

Bracketing or Matrixing of a validation exercise may be used where variants such as multiple strengths, batch/lot sizes, Process Parameters, equivalent formulations (e.g., within a product family such as change in flavors or dyes) or equivalent Equipment Items are involved. Typically a Worst Case approach is used when bracketing or matrixing.

The purpose and rationale for the bracketing or matrixing approach used must be documented and justified in the validation protocol.

Validation Batch/Lot Size shall be the same size as the intended standard commercial size batches/lots. Normal allowed variations in batch/lot size changes shall be specified in Site SOPs with justification.

When batch/lot size ranges are proposed for the commercial process that are outside the normal allowed variation, there must be documentation justifying or demonstrating that the planned variation in batch/lot size will not adversely alter the characteristics of the finished product. Bracketing may be used for validation of different batch/lot sizes.

A concurrent validation approach may be used for batch/lot size changes from the validated batch/lot size.

The Number of Process Validation Batches/Lots shall be sufficient to provide enough data for the evaluation of process reproducibility.

For new processes or validation of major process changes, a minimum of three (3) consecutive batches/lots is typical for process validation. Use of a different number of validation batches/lots [i.e., other than three (3)] must be documented and justified.

Each batch/lot shall meet all acceptance criteria identified in the validation protocol. Exceptions to this must be evaluated, and reviewed and approved (if acceptable) in the validation report.

A validation batch/lot may be excluded from the validation sequence of consecutive batches/lots if failure to meet acceptance criteria has been Investigated and documented to be the result of a non-process related cause, such as equipment failure or operator error. Replacing a batch/lot excluded for a non-process-related cause does not require that the validation sequence be restarted. The decision to exclude a batch/lot or batches/lots must be documented and justified in the validation report.

A Successful Validation Batch/Lot shall:

* Meet the product specifications relevant to the process validation, and

* Satisfy the acceptance criteria established in the validation protocol.

Homogeneity (Including Blend Uniformity) shall be included or referenced in the validation protocol for drug product and medical device process steps where homogeneity is defined as a critical attribute.

Homogeneity shall be demonstrated for a modified process, when assessment of a planned change indicates a potential impact on batch homogeneity.

Biopharmaceutical Processes typically involve steps where evidence of adequate mixing must be demonstrated during full-scale validation. If homogeneity or Mixing Studies are not performed as part of process validation, a documented rationale explaining why this study was not necessary shall be provided or referenced in validation documentation.

Stability Requirements -samples from at least one batch/lot manufactured according to the validated process and meeting the stability testing requirements defined in site policy shall be placed on stability if one of following situations occurs:

* For processes that are new to a site,

* For a reformulated product, or

* Where it is believed that the change may affect stability (e.g., a Rework process, lengthening of the bulk hold time, new medical device component).

Changes to Approved Protocols -where a change to an approved protocol is required prior to the start of execution, the protocol shall be reissued as the next version and shall be approved by the same approval authorities as the original protocol before starting the validation exercise.

When a change that impacts an acceptance criterion is needed after protocol execution has already begun, options that must be considered are:

* The work shall be discontinued and restarted following approval of a new, revised protocol that includes the rationale for the change; or

* Supplemental documentation shall be prepared, approved, and issued via the same approval process as followed for the original protocol. The supplement shall specify the rationale for the change and the point in the protocol at which it becomes Effective. Approval of the supplemental documentation must precede execution of the change.

Documentation of changes made during the validation exercise must be included or referenced in the validation report and shall include the rationale for the change.

Data Verification -relevant batch/lot documentation shall be reviewed according to Site SOPs prior to inclusion in the validation protocol or report. The data in a validation protocol or report shall also be independently verified, as indicated by signature and date of the verifier, to confirm that information such as test results, data summaries and graphs have been accurately transferred from the original documents or recorded data.

Validation Failures -failure of any validation batch/lot to meet the requirements of the protocol shall be investigated according to Site SOPs. Conclusions of the investigation shall include a determination of the effect of the batch/lot failure on the process validation and further actions to be taken, if any, including possible replacement of the failed validation batch/lot.

Reference to the failing batch/lot and investigation shall be made in the validation report.

A Validation Report referencing the relevant protocol(s) shall discuss the results from the execution of the protocol and shall be approved.

Any Deviation from the approved protocol shall be documented with justification. All process deviations shall also be documented and reviewed as to their impact on validation.

The conclusion of the report shall confirm whether the validation batches/lots have met all of the acceptance criteria. The conclusion shall state whether the process is validated and is approved for use in routine manufacturing.

Release of Validation Batches/Lots -the conditions under which commercial batches/lots are produced shall comply with all regulatory registrations and other regulatory requirements. Status of validation material shall be controlled in accordance with site procedure.

Before a validation batch/lot can be released for commercial use or distribution, the VC shall ensure that:

* For prospective validation, the Final Validation Report is approved; or

* For concurrent validation, at least, an Interim Validation Report is approved.

Pending approval of the validation report, validation batches/lots may be shipped to another affiliate site or Contract Vendor under Quarantine, provided systems are in place to prevent commercialization of drug product or medical device using this material.

Rework Processes, when used, shall be validated.

An approved protocol is required to define the validation of the rework procedure, how validation will be executed, the expected results, the acceptance criteria and the requirement for stability testing, if warranted. A concurrent validation approach may be used.

Relevant approvals shall be obtained for rework processes outside the current regulatory filing.

Reprocessing that is not part of the standard manufacturing process shall be documented and evaluated as a planned deviation. The investigation shall determine the impact on the process, product, validation status, and stability testing. The need for and extent of any validation activities resulting from the investigation shall be determined by the VC and approved by the Site Quality Team and the Site Validation Team.

Reprocessing that is applied to the majority of batches shall be included as part of the standard manufacturing process and shall be included in the validation of that process.”

Change Control -all changes that may affect product quality or reproducibility of the process shall be evaluated for likely impact on the process or product. The VC shall determine whether the change is a major or minor change, and the impact on the validation status and/or stability testing.

If validation of a process involves a regulatory change, a Product Change Proposal (PCP) and a Product Change Request (PCR) are required.

Major changes to raw materials, components, equipment, utilities, facility, procedures, or process require validation.

Minor changes may require a documented, expanded test program or other evaluation using the Site change management system.

To Change an Active Pharmaceutical Ingredients (API) Supplier, validation work must be conducted following an approved protocol that demonstrates the change will have no adverse impact on finished drug products, medical devices or processes.

Periodic Review is required as described in site procedure. A documentation review of manufacturing and analytical records, including deviations, investigations, process Trends (if there are sufficient data) and change control documents shall verify that:

* The processes are operating in a validated state of control; and

* There have not been major changes to the process either as single changes or as cumulative changes.

If the review findings indicate the process is not in a state of control, an investigation shall be conducted to determine the impact on the process and product, and to determine the potential need for revalidation and/or any corrective actions.

Record Retention -all process validation records shall be held at the manufacturing location according to the requirements stated in site policy.

J. System Validation

This practice defines the validation requirements for Systems (facilities, utilities and equipment, including process control systems, process analytical technology systems and information systems) that support Regulatory Compliance and used in the production or storage and distribution of Active Pharmaceutical Ingredients (API), Intermediates, Drug Products, Medical Devices or Biologics.

Any of the above systems for which proper operation can be fully assured through routine Calibration and/or Preventive Maintenance programs may not require validation.

This procedure applies to new systems used in the production or storage and distribution of APIs, intermediates (subsequent to the introduction of the API starting materials), drug products, medical devices or biologics.

Documentation should be available that describes the system, what the system does and how the system performs its functions (e.g., Purchase Order, vendor technical manuals, requirements, Specifications, process knowledge report etc).

The Extent of the Validation of a System shall be based on Risk Assessment, such that critical aspects (e.g. critical functions, controls, and attributes) and other system components or functions are verified to be fit for intended use.

A Risk Assessment shall be performed for the system. The risk assessment shall be based on the impact to product quality and patient safety. Additional items for consideration include the level of standardization, level of complexity, configuration, customization, intended use and vendor quality system assessment where applicable.

Validation Activities, Deliverables and Responsibilities of Subject Matter Experts shall be defined and documented (e.g., validation plan, verification plan, Approved procedure, or Protocol).

Assessment of Vendor Quality Systems, as a component of the risk assessment, shall be considered to determine the extent of validation and potential leveraging of vendor documentation to support the validation effort. The assessment method chosen shall be based on the criticality of the system, the complexity of the system, and previous experience with the vendor.

The Design of a System with critical aspects shall be reviewed to ensure the system meets applicable regulatory requirements and is suitable for its intended use. This review shall be documented [e.g., Design Qualification (DQ), validation report, or design review].

Testing [(e.g., verification, qualification, validation, commissioning, Factory Acceptance Test (FAT), Site Acceptance Test (SAT)] shall be conducted and documented (e.g., protocols, test scripts, use cases, commissioning checklists). Such testing shall provide evidence to adequately assess that a system is fit for intended use and that all critical aspects of the system meet Quality Authority approved pre-determined acceptance criteria.

A Report shall be prepared summarizing the results of the validation effort [e.g., Installation Qualification (IQ), Operational Qualification (OQ), Performance Qualification (PQ) report, Validation Report & Verification Report].

Change Management Procedure(s) shall be established and internal and External Consultants conducting validation activities shall be trained to perform their specific tasks. Training shall be documented in the form of work instruction or manual.

Standard Operating Procedures (SOP) shall be prepared, approved and implemented.

The Quality Authority at each GMP site shall approve the validation documents and shall be responsible for ensuring the implementation of established validation Systems.

Information Technology (IT) subject matter experts such as site IT shall serve as the Quality Authority and approve all validation and related documentation for IT infrastructure for which they are responsible to manage.

K. Validating Aseptic Processing – Active Pharmaceutical Ingredients (API)

This guidance document defines the Validation requirements for aseptic processing of an Active Pharmaceutical Ingredient (API) in a defined manufacturing system configuration using aseptic processing simulation tests.

This procedure applies to all GMP sites where APIs are aseptically processed.

Aseptic Processing Simulation Tests shall be performed according to an Approved Protocol and shall simulate the process from the point of Sterilization through to the completion of the manufacturing and packaging operations, including any aseptic operation(s) performed during API compounding. The aseptic processing simulation test shall include any material holding times in the processing equipment after the material is considered Sterile.

Aseptic Processing Simulation Tests shall not increase the potential for microbial, particulate, or other contamination of the manufacturing system or the API.

Aseptic Processing Simulation Test Materials shall be received and processed in the same manner as Raw Materials. Testing and release requirements shall be defined by Specifications.

Processes and Support Systems Directly Affecting Production of Sterile APIs shall be qualified and/or validated prior to conducting aseptic processing simulation tests and shall include, and not be limited to, the following:

* Water treatment and distribution systems;

* Compressed gas and process gas systems;

* Filtration Systems (i.e., liquid, gas, and vent);

* Clean Steam generation and distribution systems;

* Heat exchange systems;

* Vacuum systems;

* Equipment, including Vacuum Leak Testing, when applicable (e.g. Pneumatic Transfer equipment);

* Sterilization and Depyrogenation processes;

* Equipment cleaning procedures;

* Solvent handling, storage and distribution systems; and

* Air handling systems, including local HEPA Unidirectional Airflow stations.

Aseptic API Processing shall be requalified at least every two years, if the API has been manufactured during the two-year interval.

The Validation Committee (VC) shall determine the need to requalify aseptic API processing, as well as the number of aseptic processing simulation tests that shall be required to requalify the process when there have been:

* Changes to the manufacturing system, manufacturing process, or HVAC system; or

* Where an Investigation conclusion indicates the need for requalification after a confirmed sterility test failure.

Approved, Validated Microbiological Methods shall be used to analyze the aseptic processing simulation test material.

APA Personnel and APA Support Personnel shall be Qualified prior to participating in aseptic processing simulation operations.

All APA Personnel and APA Support Personnel shall participate  in a minimum of one aseptic processing simulation test at least every two years. New APA personnel and APA support personnel shall be included in the next scheduled aseptic processing simulation test and shall not perform unsupervised critical operations in the Air Classification Grade – A area until they have participated in a successful aseptic processing simulation test. Observing is not considered participation.

Environmental and Personnel Monitoring shall be performed during aseptic processing simulation.

Following an Aseptic Processing Simulation Test, the room and equipment shall be cleaned immediately (i.e., start within 4 hours) to prevent contamination of subsequent manufacturing operations.

Aseptic Processing Simulation Test Results shall be based on a Qualitative criterion (i.e., growth or no growth).

An Aseptic Processing Simulation Failure shall be declared when there is any positive result (i.e., growth) with no Assignable Cause. All aseptic processing simulation test failures shall be investigated, documented and a cause for the failure assigned, if possible. The manufacturing system shall not be used for production until remedial action has been taken and the required new aseptic processing simulation tests are successfully completed.

An Aseptic Processing Simulation Test shall be invalidated when events unrelated to aseptic processing occur that impact the validity of the simulation. An aseptic processing simulation test shall be declared invalid when any of the following conditions occur:

* Failure of the Growth Promotion Test; or

* Incorrect incubation conditions (e.g., exceeding the maximum incubation temperature limit).

In the case of a Microbiological Culture Medium growth promotion test failure, an aseptic processing simulation test shall be declared invalid. The manufacturing system can be used for production on a temporary basis, if the cause for the microbiological culture medium growth promotion test failure involves: laboratory testing error; media infertility caused by faulty preparation; or media infertility due to an incorrect ratio of sterile placebo material to liquid medium.

When there is no assignable cause for the microbiological culture medium growth promotion failure, the manufacturing system shall not be used for production until remedial action has been taken and a new aseptic processing simulation test is successfully completed.

Aseptic Processing Simulation Tests applicable to the process include, and are not limited to:

* Equipment sterilization,

* Aseptic addition of materials to previously sterilized vessels,

* Transitions between vessels,

* Milling,

* Vessels under vacuum (pneumatic transfer equipment),

* Aseptic manipulations,

* Sampling, and

* Final primary packaging of the API.

Aseptic Processing Simulation Tests shall include, and not be limited to, the following:

* For initial validation of aseptic processing, a minimum of 3 consecutive, successful simulations (i.e., no failures with no process related assignable cause between the successful executions) performed on separate days and/or shifts;

* For routine Revalidation of aseptic processing, one successful process simulation test performed at least every two years;

* All personnel who perform aseptic processing or aseptic processing support activities to be included in at least one aseptic processing simulation test every two years;

* Be of sufficient duration to simulate all typical activities and interventions; and Simulate aseptic processing from the point of sterilization to the final API packaging step.

Aseptic Processing Simulation Test Batch/Lot Sizes shall be established based upon the following considerations:

* Enough material to simulate all activities and interventions; and

* Maximum amount of material that can be tested in the laboratory (e.g., Membrane Filtered or direct incubation).

The Aseptic Processing Simulation Test Protocol shall address the following:

* Production instructions and Standard Operating Procedures (SOP) intended to be simulated;

* Number of personnel, activity level, changes, and breaks;

* Complexity and aseptic manipulations;

* Duration of simulation test;

* Amount of material to be processed and tested;

* Planned interruptions and interventions; and

* Maintenance and environmental monitoring, including personnel monitoring.

Aseptic Processing Challenges shall be incorporated in the simulations. Examples include, and are not limited to, such conditions as:

* Simulation of processing immediately following the end of a manufacturing Campaign and prior to cleanup, if residual product does not inhibit microbial growth;

* Processing hold times;

* Maximum number of persons in the processing area; and

* Equipment breakdowns.

Test Material Used in Aseptic Processing Simulation Tests shall be evaluated and selected based on factors that include and are not limited to, the following:

* The nature of the process to be simulated (i.e., liquid vs. powder operation);

* Ease of removal/cleaning of the test material from the processing equipment;

* Quantity of test material required; and • Ability of test material to support microbial recovery. In certain situations more than one test material may be used for different parts of the simulation process (e.g., liquid phase and dry phase).

Aseptic Processing Simulation Test Material shall be sterilized by a validated method. Test material shall not inhibit microbial growth when dissolved in or mixed with culture media and incubated or membrane filtered and incubated. Examples of test material include:

* Polyethylene glycol 8000,

* Lactose,

* Mannitol,

* Water for Injection (WFI); and

* Physiological (0.9 percent) saline solution.

The Entire Quantity of the Aseptic Processing Simulation Test Material used in the qualification study shall be tested.

Aseptic Processing Simulation Testing shall be performed as either:

* A single continuous test that simulates the entire aseptic processing configuration; or

* A series of individual unit operations, including transitions between discrete unit operations and holding times that are part of the operation, which when combined simulate the entire aseptic processing configuration (e.g., liquid phase and dry phase).

Test Results From Each Unit Operation in an Aseptic Processing Simulation shall be cumulative when calculating the microbial contamination of the entire process. If any unit operation fails, the entire aseptic processing simulation fails. Aseptic processing simulation need only be repeated for the failing unit operation.

Aseptic Processing Simulations requiring blanketing with sterile, inert gas shall use sterile air in order not to inhibit growth when aerobic incubation conditions are employed.

Aseptic Processing Simulation Tests shall be performed prior to the next scheduled requalification in the case of the following events:

* Confirmed sterility test failure where an investigation concludes the need for requalification; and/or

* When there has been a significant change. Examples of such changes include, but are not limited to:

(a)     Changes to the manufacturing process and/or associated systems;

(b)     Modifications to equipment directly contacting the API or API-contact surfaces of Containers;

(c)     Changes to the quality of airflow that directly contacts API contact surfaces; (d) Major changes of production personnel (e.g., addition of one or more new shift, new group of operating personnel); and

(e)     Procedural changes potentially affecting aseptic processing.

Powdered Simulation Test Material shall be reconstituted with either:

* A sterile diluent, such as WFI, when it is subsequently membrane filtered prior to testing for microbial contamination; or

* Sterile liquid microbiological culture medium, when the simulation test material is incubated directly.

Incubation Chambers shall be qualified, Calibrated, alarmed and continuously monitored throughout the incubation period.

Test Samples shall be incubated for a minimum of 7 calendar days at 20 -25o C followed by a minimum of 7 calendar days at 30 -35o C.

Growth Promotion Testing, in which the simulation test material is tested for potential inhibition, shall be performed using microorganisms selected according to the applicable Compendia and at least one isolate taken from the environment for which optimum growth conditions (e.g., incubation temperature) have been determined. The simulation test material shall undergo growth promotion testing as follows:

* Initially to qualify the simulation test material; and

* Routinely on the test material used in each aseptic processing simulation test. Growth promotion testing shall be performed following completion of the incubation period.

Growth Promotion Testing shall be performed as follows:

* Replicate samples of sterile microbiological culture medium containing the dissolved simulation test material, shall be inoculated with less than 100 cfu of each challenge organism;

* Replicate samples of the sterile microbiological culture medium, which do not contain the simulation test material, shall also be inoculated with challenge organisms; and

* Growth must be evident within 5 days in all inoculated containers after incubation at the temperature range specified for the challenge organism(s).

When a Growth Promotion Test Fails, an investigation shall be conducted. The investigation shall result in one of the following conclusions:

* Assignable Cause -Laboratory Related:

If the assignable cause is related to laboratory testing (e.g., faulty test technique, incorrect incubation temperature for the samples, non-viable challenge cultures, incorrect culture) then the growth promotion test may be repeated once on the aseptic processing simulation test lots/batches. If the repeat test results are normal and confirm the presumed assignable cause, then the aseptic processing simulation test shall be declared acceptable. If the repeat test fails, the aseptic processing simulation test shall be declared invalid;

* Assignable Cause -Related to Medium Infertility:

If the assignable cause is related to an error in microbiological culture medium preparation (e.g. overheating, incorrect composition, incorrect gas headspace) or growth inhibition due to an incorrect amount of placebo material in the case of dry powder, the aseptic processing simulation test shall be declared invalid. Corrective measures shall be identified, implemented, and one successful aseptic processing simulation test completed to confirm the presumed massignable cause; or

* No Assignable Cause:

If an assignable cause cannot be identified, then one successful aseptic processing simulation test shall be completed before the manufacturing system may be used.

Acceptance Criteria for Microbial Contamination Using a Qualitative Test shall be no growth.

An Event Log shall be maintained by a qualified person in the Aseptic Processing Area (APA) during each aseptic processing simulation test to record events (e.g., unplanned interventions) and observations that are not addressed in the aseptic processing simulation test protocol. The event logs shall be reviewed by the validation committee and the review documented. The event logs shall be retained according to site validation documentation retention policies.

Aseptic processing simulation tests may also be videotaped. If the Aseptic processing simulation is videotaped, the videotape must be reviewed by a qualified person and the results summarized and included in the final report. Videotapes shall be retained according to site validation documentation retention policies

Microorganisms found in contaminated units shall be subjected to genus and species identification methodology.

An Investigation shall be conducted for an aseptic processing simulation test failure and shall include, and is not limited to, consideration of the following:

* Environmental and personnel monitoring data;

* All sterilization process data including calibration data;

* APA cleaning and sanitization;

* APA and APA Support Personnel training;

* HEPA Filter Integrity;

* Sterilizing Filter Integrity;

* Equipment cleaning, sterilization and operation;

* Manufacturing process; and

* Identification of the microbial contaminant(s).

When an Aseptic Processing Simulation Test Fails Due to an Assignable Cause, corrective action must be taken and documented. The root cause and the corrective action shall dictate the number of aseptic processing simulation tests required to demonstrate that the process is operating within the expected parameters. When an assignable cause is identified for a failing test, the rationale for product disposition shall be documented.

When an Aseptic Processing Simulation Test Fails and There is No Assignable Cause, the aseptic processing must be revalidated with a minimum of three consecutive, successful aseptic processing simulation tests completed prior to using the aseptic process for sterile API manufacturing.

In Case of a Failure Where There is No Assignable Cause, the investigation shall include a review of all batches/lots produced since the last successful aseptic processing simulation test.

Change Control and Revalidation Measures shall be implemented for all aseptic processing operations to identify, document, and review changes (e.g., to equipment, procedures, cleaning, and sterilization) that impact the validated state of the aseptic processing operation. The Validation Committee (VC) shall:

* Perform an annual review of approved and implemented changes, including equipment maintenance, calibration, and environmental data, to determine the cumulative impact on validated aseptic processing operations;

* Recommend revalidation and/or requalification requirements; and

* Document annual review results.

Requalification Measures shall be determined by the VC and shall include at least one successful aseptic processing simulation test. At a minimum, aseptic processing simulation tests shall be performed every two years.

Equipment Cleaning Procedures shall be developed and validated for removing simulation test material.

Aseptic Processing Simulation Test Documentation shall include, and not be limited to, the following:

* Identification of the aseptic processing simulated;

* Identification of the aseptic processing train and equipment used;

* Type of container / Closure used;

* Number and identification of personnel participating;

* List of manual interventions;

* Simulation test material used;

* Environmental monitoring performed;

* A copy of the batch record used;

* Acceptance criteria; and

* Rationale for the process challenges chosen.

A Final Report on Each Aseptic Processing Simulation Test shall be generated and shall include summary data from the batch record and environmental/personnel monitoring. The report shall document a conclusion regarding the acceptability of the aseptic processing simulation test and shall be approved by the VC.

When Incubating Test Samples for 14 days at one temperature range (e.g., 28-33 C), the selected incubation conditions must be shown (e.g., validated and documented) to give results equivalent to incubation at two different temperature ranges.

L. Validation of Analytical Methods for Equipment Cleaning

The purpose of this guidance document is to define the requirements for the development and validation of sampling methods and Analytical Methods used to detect residue on equipment as part of equipment cleaning.

This procedure applies to GLP laboratories performing analytical methods to detect residue on equipment after cleaning of equipment used in the Production of products in or intended for the marketplace.

Selection of Analytical Methods for use in Equipment Cleaning shall include consideration of the following factors:

* Type of residue being measured (e.g., organic, inorganic);

* Sampling method (e.g., swab or Rinsate); and

* Residue Acceptability Limits (RAL) in the analytical sample.

Use of a Specific or a Non-Specific Method is acceptable for determining residues after cleaning. If a specific method is used, it must be capable of detecting and quantifying the analyte of interest in the presence of other materials that may also be present in the sample. If a non-specific method [e.g., Total Organic Carbon (TOC)] is used the response must be considered to be from the analyte of interest.

Analytical Methods, Including the Sampling Methods used to determine residues after cleaning must be validated.

Validation of Analytical Methods Used to Detect Residue in Equipment shall include consideration of the following characteristics:

* Specificity,

* Linearity,

* Sensitivity,

* Repeatability and Recovery,

* Stability of the standard and sample (swab and rinse solutions); and

* Intermediate Precision.

Sensitivity of Analytical Methods must be sufficient to detect [Detection Limit (DL)] and quantify [Quantitation Limit (QL)] the target analyte at or below its established RAL.

The Swab Sampling Technique must address the following factors:

* Swab type (including wipes) and size;

* Composition of the swabbing solvent (i.e., solution that is used to wet the swab prior to sampling of the equipment surface); and

* Composition of the swab recovery solution (i.e., solution used for extraction). Swabbing Techniques must be described or referenced in a Standard Operating Procedure (SOP).

The Stability of Residue on Swabs (i.e., stability performed on stored swabs) shall be determined.

Analyte Residue Recovery, which includes recovery of the analyte from both a representative equipment surface and the sampling technique (e.g., swab), shall be challenged as part of the analytical method validation. These challenges must demonstrate that analyte residues are recoverable from expected product contact surface material and the sampling material per the requirements of this procedure.

A Method Validation Protocol must be prepared to document the validation parameters being evaluated, the acceptance criteria for each parameter and the Test Methods (TM). The protocol must be Approved by the Lab Manager prior to execution of the validation studies.

Colleagues that Perform Activities (e.g., Sampling and Testing) in Support of the Validation must be Qualified.

A Method Validation Report shall be prepared that references the protocol and documents the results of the validation study, including evaluation of each parameter, comparison against the acceptance criteria, and conclusions. Any Deviations from the protocol must be documented and the impact of the deviations discussed in the report.

The validation report must be approved by the Lab Manager and a representative of the Site Quality Team, independent of the Lab Manager at the Site where the validation work is conducted.

Legacy Methods – if a legacy method has not been previously validated, and is required to be validated according to local regulatory requirements, the method must be assessed by the responsible Site Quality Team to determine the need to validate according to the requirements in this procedure. A Concurrent Validation approach may be used to support the analytical method validation.

M. Validation Requirements and Documentation

* This guidance document defines the general Validation requirements and documentation for Systems [facilities, utilities, and equipment, including process control systems, Process Analytical Technology (PAT) Systems and computer/automation systems] and processes that support the Production (e.g. product, cleaning, and Sterilization), storage, and distribution of Active Pharmaceutical Ingredients (API), Drug Product, Medical Devices or Biologics of a GMP site.

* This procedure describes the quality system for validation documentation and Approval requirements for subordinate validation procedures covering systems validation Equipment Cleaning, Process Validation and packaging validation.

Scope: This procedure applies to New Systems and processes at all GMP sites where APIs, drug products, medical devices or biologics are produced, stored and distributed. This procedure also applies to Centre Functions where validation takes place [e.g., for IT (Information Systems)].

Validation Documentation shall be reviewed and approved by Subject Matter Experts (SME). Validation-related documentation shall be planned, reviewed and approved to ensure the following:

* Technical correctness and completeness;

* Regulatory Compliance – Practices;

* Regulatory Compliance – Registration;

* Compliance with written Site requirements and quality standards; and

* Authorization to implement.

Site Quality Team SMEs must review and approve the following validation documentation types, where applicable:

* Plans,

* Science and risk based assessments,

* Tests and/or acceptance criteria for critical aspects,

* Final Design Review, and

Other principals [e.g., System Owner, Production, Technical Services, Engineering, Information Technology (IT), other SMEs] may review and approve validation documents, as needed and may be part of a committee [e.g., Validation Committee (VC)].

Current Elements of the Validation Program shall be defined and documented [e.g., in a Validation Master Plan (VMP), Site Standard Operating Procedures (SOPs)]. Such documentation shall contain information on at least the following:

* Validation approach or policy;

* Summary of facilities, equipment, systems and processes to be validated;

* Organizational structure of validation activities;

* Planning and scheduling (e.g., what needs to be done when);

* Change management;

* Reference to existing documentation (e.g., individual discipline validation plans for cleaning and production processes, project verification plans, SOPs).

A Validation Plan [e.g., Validation Project Plan (VPP), Project Commissioning and Qualification Plan (PCQP), Verification Plan (VP), change control document, testing document, Protocol, SOP] shall be used to document validation activities.

The Scope of Validation, at a minimum, shall include those areas of potential risk to product quality, patient safet and/ or regulatory compliance. If a risked based approach is used to narrow the scope of validation, the approach shall be documented [e.g., Impact Assessment, quality Risk Assessment, functional assessment, Failure Mode & Effects Analysis (FMEA)].

Prospective Validation is the preferred validation approach. The use of Concurrent Validation, or Retrospective Validation approaches and associated rationale for using the approach of choice shall be documented (e.g. in a VMP, VP, PCQP, or protocol) and approved.

System Documentation [e.g., User Requirement Specifications (URS), Requirements Document, Specifications, Vendor Operation and Maintenance Manuals, Purchase Order, Product and Process Development Reports, Formulation Development Summary] must be available that describes the system including what the system does, and how the system performs its functions. The documentation will be used to confirm that aspects of the system or process critical to product quality are included in the scope of the validation activities.

Test Documentation (e.g., protocols, test scripts, checklists, use cases) shall be available that define the details of specific validation testing required and predetermined acceptance criteria.

Deviations that occur during validation shall be documented and Investigated in accordance with Site procedures or as defined in validation documentation (e.g., plans, test documents, protocols). Corrective actions taken or corrective action plans shall be reviewed and approved prior to, or concurrent with, approval of the final report.

Prior to Moving from One Validation Phase to the Next any deviation(s), including incomplete items from a prior phase, shall be assessed to determine the impact on the next phase. The assessment shall be documented and approved by responsible person(s) in accordance with Site procedures or validation document requirements.

A Design Review shall be conducted and documented to ensure the system meets procedure, product and process quality, and regulatory requirements and is considered fit for its intended use.

Before Approving Validated Systems or Processes for Routine Production Use, approved SOPs shall be available for the use, control, and maintenance of systems and processes.

A Final Report (e.g., Final Qualification Summary Report, Final Validation Report, Verification Report) is used to summarize and document completed validation activities. An Interim Report shall be used when additional studies are to be executed but a review of the current results and validation status is required (e.g., for Batch or Lot release during a concurrent validation study).

A Change Management Procedure (e.g. project change management, quality change management) shall be established and followed, during validation activities and upon completion of validation activities. The extent of change management and rationale(s) for the approach shall be based on impact of the change on product quality, patient safety and regulatory compliance, where applicable.

For product and process changes this is to ensure that validated systems and processes are maintained in a validated state.

Documentation system to be validated for control, implementation, maintenance and archival of GMP documents.

Validation Documentation shall be retained in accordance with site document retention policies and procedures.

Facilities, Systems, Equipment and Processes, Including Cleaning, shall be periodically evaluated (e.g., Periodic Review) to confirm that they remain validated. The frequency of periodic evaluation shall be based on risk.

This evaluation shall be documented and approved. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for Revalidation.