Guidance 017 – Process Validation for Drug Products and Medical Devices Pharmaceuticals quality assurance & validation procedures GMPSOP

Process Validation for Drug Products and Medical Devices

Introduction

This GMP guideline provides guidance in the validation of manufacturing process for drug products and medical devices.

1. Critical Process Parameters -rationale for defining the critical parameters of a process should be documented, including Probable Adverse Consequences to be expected when critical process parameter ranges are not met.

Critical process parameters should be determined by a review of available historical data generated during development and/or manufacturing, or by experimentation. Each critical step is evaluated by observing the effect that potential critical process parameters have on quality attributes. This approach is used to establish the Proven Acceptable Range (PAR) that process parameters can vary without an unacceptable impact on the acceptance criteria established for the critical quality attributes.

The Normal Operating Range (NOR) should be within or equal to the PAR.

A documented Risk Assessment such as comparison of the margin between the NOR and the PAR, Process Capability analysis, or statistical evaluation may be used to determine the critical parameters.

A process step that includes one or more critical parameters should be considered as a critical step.

2. Validation Protocol Contents should include or reference, at least, the following:

Validation approach to be used (e.g., prospective, concurrent, matrixing, bracketing, retrospective) with justification for approach chosen;

Brief description of product, including product name, dosage form, and strength where applicable;

Master manufacturing instructions or Device Master Record (DMR) to be validated;

Brief description of process with a summary and/or process flow diagram of critical processing steps to be evaluated and critical parameters to be monitored;

Acceptance criteria for the following:

– Acceptability (meeting established critical quality attributes and specifications);

– The number of consecutive successful validation batches/lots needed to show consistent control of the process.

– Equivalency to existing drug products (where applicable) by comparison to previously produced batches/lots (commercial, development, or biobatches).

– Requirements to conduct homogeneity and hold time studies, if applicable;

Sampling plan, including type, amount, and number of samples, together with any special sampling or handling requirements.

Critical process parameters and operating ranges, including justification for these Ranges.

Calibration of any critical equipment used specifically for the validation studies (e.g., one-time studies on validation batches/lots using portable equipment, measuring equipment);

Plan for the number of batches/lots to be put on stability, if any; and

Methods for recording and evaluating results (e.g., statistical analysis).

3. On-Line or In-Line Monitoring may be used, in lieu of discrete sampling (e.g., to demonstrate homogeneity or acceptance criteria).

4. Homogeneity should be demonstrated throughout the batch, when required by the validation protocol.

A sampling plan for the homogeneity study should be provided that justifies the number of individual locations and the number of samples to be taken from the product batch [e.g., for blend uniformity]. The bulk should be representatively sampled based on product type (e.g., aqueous solution or solid dosage), mixing container geometry and process (e.g., mixing mechanism) on completion of process step. Additional sampling on completion of discrete critical steps may also be performed. Sampling should not impact on the quality of the final bulk mixture. If possible, sampling should target areas of product in the equipment that have the greatest potential to be non-uniform. Representative samples should be drawn after critical process steps (e.g., freeze drying, filtering, blending). Sampling plans should take into account start-up requirements (e.g., line flushing or discard procedures), process control frequency (fill weight, hardness), line stops or interventions, and the final units. Specific tests selected should demonstrate physical, and/or chemical homogeneity.

The individual samples should meet the acceptance criteria defined for the homogeneity test(s).

5. Powder Blend Uniformity of dry powder mixes (e.g., oral solids, suspensions, or inhalation) should be conducted to demonstrate homogeneity of active ingredients.

– Samples should be taken from the specific areas of the blender that have the greatest potential to be non-uniform; or

– Samples may be taken from discharge streams or drums if it is not practical to take from the blender.

6. Bracketing and Matrixing elements to consider when defining the worst case(s) include:

– Number of specific drug product strengths;

– Slight variations in formulations within a drug product family (e.g., flavors or dyes);

– Number of drug product batch/lot sizes involved;

– Critical quality attributes;

– Critical process parameters; and

– Batch/lot size effects on equipment or processing capability.

– Consistency should be demonstrated among the results of validation batches/lots. Where bracketing or matrixing is used, the study should be included in a plan or protocol, and discussed in a final report.

7. Holding Time (Including Bulk Storage Time) Studies may be conducted during development or carried out in conjunction with process validation batches/lots and should be representative of full-scale holding conditions at or greater than normal operating conditions.

8. Validation Reports should include or reference, at least, the following:

– Reference to validation protocol number and version, and any supplementary documentation describing changes to the protocol;

– Test results;

– Discussion of the data compared to their respective acceptance criteria;

– Review of critical process parameters from batch/lot production records;

– Comparison with previously produced batches/lots (e.g., commercial, development, or biobatches), where applicable;

– Description of any deviations or failures, and their impact on the validation; and

– Conclusions including any recommendations to correct deficiencies.

9. Retrospective Validation Data Sources include, but are not limited to, the following:

– Batch/lot processing and packaging records;

– Process control charts;

– Maintenance log books;

– Change control records (e.g., process equipment, facilities, and utilities);

– Process performance (e.g., capability studies); and

– Finished product data, including trend(s), verification data (medical devices), and storage and stability results.

– Batches/lots included in the review should be consecutive and should include those most recently manufactured. Batches/lots are to be representative of routine production where possible, including any batches/lots that failed to meet specifications.

– Generally, data from ten to thirty (10 -30) consecutive batches/lots should be examined to assess process consistency, but fewer batches/lots may be examined if justified (for example where annual production levels are low).

10. Major Changes -examples of major changes to an established process that require consideration of revalidation include, and are not limited to, the following:

Process changes that can affect the release, metering, or other characteristics of the dose delivered to the patient, for example:

– Changes to Active Pharmaceutical Ingredients (API) and critical excipients (change in API Site or manufacturer, route of synthesis for APIs, impurity profile, chemical or physical characteristics); and

– Major facility changes (e.g., Site, new aseptic area);

– Changes to major equipment such as size, design, or principle of operation;

– Changes in the acceptable range of a critical process parameter or a planned shift of the NOR that increases the risk of deviation and has the potential to adversely impact product quality;

– New reworking and/or reprocessing procedure;

Fundamental change to manufacturing process or technology, for example:

– Batch/lot size;

– Dry to wet granulation or vice versa;

– Change from one type of drying process to another (e.g., oven tray, fluid bed, microwave);

Changes that could affect acceptable microbiological quality of the drug product;

For medical devices, any change that affects form, fit, or function of the device (e.g., material, components, manufacturing or assembly processes, and replacement of equipment); and

Biopharmaceutical -example(s) such as filtration, concentration or mixing parameters, lengthening maximum hold time, and shipping conditions.

Changes in the process that result in a change in the Regulatory Process Description (RPD) should be addressed through the change management system.

11. Minor Changes may require consideration of revalidation or completion of supplemental studies to support the change. Examples of minor changes include, and are not limited to, the following:

Changes to equipment with the same design and operating principle;

Changes, which are unlikely to have measurable impact on product quality or performance, as determined by risk assessment;

Change within a single Site using the same equipment as previously validated;

Change in existing code imprint (e.g., changing from numeric to alphanumeric, addition of an ink code imprint, or change to ink used for a solid dosage form where the ink is already used on approved products); and

Change of imprint by embossing, debossing, or engraving on a solid dosage drug product, with the exception of modified release dosage forms.

12. APIs and Excipients used in a validation study should meet all chemical, physical, and microbiological specifications. Any changes to an API, excipient, carrier vehicle, or to the manufacturing process should be assessed for their potential to affect characteristics of the drug product or medical device. Changes determined to affect product quality should be validated, including a comparison to the previously produced batches/lots (e.g., commercial, development, or biobatches).

For changes to the API in drug products with multiple strengths, with similar formulations and processes, a worst case matrix approach qualification can be conducted considering a bracket design that covers multiple product strengths.

13. Sterile and Aseptically Filled Drug Products and Aseptically Processed Medical Devices include large and small volume parenterals, ophthalmics, and dry powder products. Process validation of such products should include evaluation of the critical steps (e.g., formulation, mixing, filtration, lyophilization, and filling processes).

The process validation protocol for sterile and aseptically filled drug products and aseptically processed medical devices should include assessment of, at least, the following:

In-process assay of bulk tank and bioburden testing, where applicable;

Environmental conditions (e.g., temperature and humidity control, air classification, pressure differentials), where applicable;

Removal of oxygen, where applicable;

Dose and/or content uniformity;

Fill weights or volume controls;

Moisture content, where applicable; and

Foreign matter including particulates.

If validation is being carried out as a result of a change to an existing process, documented justification should be provided in the validation protocol if any of the above applicable parameters are not to be assessed. Media fill, environmental monitoring, and moist heat terminal sterilization process studies that support the process being validated should be referenced in the validation protocol.

14. Dry Powder Inhalers -validation should include evaluation of the mixing process (where applicable) and filling process.

In addition to the general protocol requirements, the process validation protocol for dry powder inhalers should include assessment of, at least, the following:

– Emitted dose uniformity; this should assess both inter and intra inhaler dose uniformity;

Fill weight or volume and number of deliveries from the container;

Airflow resistance;

Aerodynamic assessment of fine particles using a multi-stage impactor;

Compliance with finished product specification, including any microbiological requirements; and

Comparison with the previously produced lots (e.g., commercial, clinical, development, or biobatches).

Device Parameters:

Robustness of Process Capability of component manufacturing and finished device assembly processes demonstrated; and

Compliance of component(s) to specification including extractables data for components in the drug/airway path and in intimate mucosal contact. Validation should be initiated as the result of a component change. Drug/Device Combination Parameters:

Respirable Fraction of delivered dose.

15. Metered Dose Inhalers

The validation protocol should include, at a minimum, assessment of the following parameters:

Moisture content;

Delivered dose uniformity; this should assess both inter and intra inhaler dose uniformity. The dose uniformity should be assessed from the last nominal shot to exhaustion using three (3) canisters from, at least, two (2) different batches/lots;

Fine particle dose using a multi-stage impactor or impinger;

Fill weight or volume and number of dose deliveries from the container;

Foreign matter including particulates;

Compliance with finished product specification; and

Comparison to the previously produced lots (e.g., commercial, clinical, development or biobatches).

Device Parameters:

Robustness of Process Capability of component manufacturing and finished device assembly processes demonstrated; and

Compliance of component(s) to specification; including extractables data for components in the drug/airway path and in intimate mucosal contact. Validation would be initiated as the result of a component change. Drug/Device Combination Parameters:

Respirable Fraction of delivered dose.

16. Oral Solutions and Suspensions include drug products such as elixirs, emulsions, solutions, gels, syrups, tinctures, and suspensions.

The process validation protocol for oral solutions and suspensions should include assessment of, at least, the following:

In-process assay of bulk before filling (where applicable);

Homogeneity sampling plans should include representative samples from:

– Throughout the bulk suspension;

– Top and bottom of solutions, and

– During the filling operation;

Rheological properties such as viscosity, thixotropy (where applicable);

Potency;

Fill volume, including assessment of consistency and reproducibility of filling process; and

Other tests such as pH, specific gravity, and refractive index, as applicable. If validation is being carried out as a result of a change to an existing process, documented justification should be provided in the validation protocol if any of the above applicable parameters are not to be assessed.

17. Semi-Solid Drug Products include suppositories and topical drug products such as emulsions, gels, lotions, creams, ointments, and transdermal patches. The process validation protocol for semi-solids should include assessment of, at least, the following:

Solubility of API in carrier vehicle, where applicable;

Microbiological purity, including an assessment of consistency between batches/lots of microbial levels and isolated organisms;

Fill volume, generally an in-process measurement based on bulk density;

Rheological properties such as viscosity, thixotropy, (where applicable);

Appearance (for example, absence of grittiness, smooth, phase separation);

Potency; and

For transdermal products (patches) adhesion, package integrity, and dose uniformity should also be considered.

18. Oral Solid Dosage Forms – validation should include an evaluation of any critical mixing, granulation, milling, drying, blending, compression or encapsulation, coating, and printing processes. The process validation protocol for oral solid dosage forms should include assessment of, at least, the following:

In-process controls, including individual weights and weight uniformity, moisture, hardness, thickness, friability, and disintegration, as applicable;

Five (5) point dissolution profile including points close to one hundred (100) percent dissolution. Use of an alternative number of points should be documented and justified;

Inspection attributes such as evaluation of defects throughout the process, (e.g., capping, splitting, and twining);

Potency and dose uniformity;

Samples should be taken throughout each validation batch/lot and tested for content uniformity to demonstrate there has been no segregation of the blend during the compression or encapsulation process; and

Sample sizes for blend uniformity should be the approximate weight (e.g., 1-3x) of the dosage unit If validation is being carried out as a result of a change to an existing process, documented justification should be provided in the validation protocol if any of the above applicable parameters are not to be assessed.