VAL-115 Process Validation for Liquid and Solid Dosage Manufacturing

5.1 Process Validation Overview

5.1.1 General Sequence of Activities

a. Determine the need for a validation study

b. Review process diagrams, manufacturing instructions and historical data

c. Prepare detailed protocol with acceptance criteria

d. Issue protocol and obtain approval

e. Conduct pre-validation activities

f. Conduct validation sampling, monitoring, and testing

g. Review results for each batch in the study

h. Compile results in a Process Validation Report

i. Audit and verify data

j. Issue Validation Report and obtain approval

5.1.2 Prerequisites for Process Validation

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

a. Approved master formula, master manufacturing instructions, and applicable SOPs;

b. Identification of Critical Process Parameters;

c. Equipment Qualification (including laboratory equipment) – facilities, utilities, systems, (including Computerized Systems), and equipment (including filling equipment used in the packaging operation of liquid and semi-solid processes) to be used shall have been qualified prior to validation of the manufacturing process;

d. Supporting processes that may affect process validation (e.g., equipment cleaning), shall be qualified;

e. Calibration of critical instruments;

f. Approved specifications for finished product, in-process testing, raw materials, and components;

g. Validated test methods shall be used;

h. Personnel taking part in the validation work shall have been trained and qualified before carrying out such work, with training records documented.

5.2 Process Validation Protocol

The validation protocol is a written plan stating exactly how the validation study will be conducted.  In general, the protocol explains what will be done to validate the specific process, how it will be executed, who will execute it, and what the acceptance criteria are.

Any deficiencies in the prerequisites detailed above must be resolved prior to proceeding with protocol execution or a justification documented in the protocol which will be approved by at minimum the Validation Manager, Quality Assurance Manager and the Process Owner or their delegates, by approving the protocol for execution.

5.2.1 Basic Document Format

Each protocol and report should contain on its cover page:

a. Protocol title, number, and version number

b. Product name, strength and item number

c. Signature and date of the protocol author, reviewer(s) and approvers

5.2.2 Objective

The objective of the protocol should be concisely stated.  In general, the objective of any study should be to assure that the process/product consistently meets all pre-  determined acceptance criteria and specifications and will provide a high degree of assurance that the process will produce a product that consistently meets site quality control specifications for the product.  The objective should also include a reference to the change control.

5.2.3 Scope

The scope should clearly define the product to be validated and the equipment in which the process will be validated.  The scope should clearly define those areas of validation that are included in the scope of the protocol and if not detailed elsewhere those areas that are not in the scope.  The scope should include:

Product name, item number, strength, and dosage form

Reference to formula under validation (e.g., Unit Formula number, product specification, manufacturing instruction [MI], including version number)

5.2.4 Responsibilities

The responsibilities for completing the various components of the validation study and for review and approval of the protocol should be outlined in the protocol.

5.2.5 References

All protocols will be written, conducted and reported on, in accordance with this document, SOP VAL-085Process Validation Guideline, and the code of GMP.  As such each protocol will reference these documents as applicable.

Reference to specific documents should be made to support the validation study.  At minimum, references should be made to all manufacturing documents used to manufacture, and if necessary pack the product.  Where applicable, version numbers should be included.

NOTE: Where such documents are adequately referred to in the general body of the protocol, an additional reference section is not necessary.

5.2.6 Validation Strategy

This section is to describe the validation strategy that will be used to ensure that the process is validated as per process validation requirements.  This section will detail if a prospective, concurrent or retrospective approach is to be taken and will describe the release for sale mechanism for each validation type.

The strategy should detail the number of batches to be included in the validation study and if product bracketing is to be used.  If there is a planned deviation from this SOP or from SOP VAL-085 Process Validation Guideline, a justification should be included in this section.

This section will also detail any trials or development batches that have been manufactured and will briefly describe the outcome if they are used to support the validation study.

When planning the initial validation of a new product, obtain and review copies of report(s) that contain information on any scale-up or trial batches made to date. These reports must be referenced in the validation protocol.

Process validations must be conducted at the intended operating conditions with minimal modifications to process parameters from batch to batch.  Since the primary objective is to establish the reproducibility of the production process, allowable modifications must be pre-defined in the protocol.

5.3 Manufacturing Process

5.3.1 Process Description

This section should give an overview of the process that should contain enough detail to determine the critical steps of the process and parameters to be monitored.  A process flow chart should be included in an appendix and referenced.  The process flow chart should detail all critical manufacturing steps.

5.3.2 Raw Materials

This section should contain a table of raw materials, including specification references and material codes.  The percentage/quantity per batch and per unit formula should also be included.

Raw materials (APIs and excipients) used in validation batches must meet all raw material specifications and have QA release approval prior to use.  The different lot numbers must be documented in the validation report.  If possible, different raw material lots should be used for each validation batch.

If any additional tests, beyond those established in the material specifications, are necessary for product / process specific evaluation, the tests, methods, and acceptance criteria must be documented in the validation protocol.

5.3.3 Identification of Process Steps and Critical Process Parameters

A Critical Process Parameter is an operating variable that may be a set point or is assigned a range (Critical Process Parameter Range) with acceptability limits, outside of which exists potential for unacceptable variation in a Critical Quality Attribute.  Critical Process Parameters and operating ranges must be identified in the validation protocol.

5.3.4 Equipment Qualification

List the process step and the equipment used and document the qualification status of the equipment used to manufacture, pack and test the product.  Reference the qualification documentation.  The equipment should be the same for each validation run.  Different equipment may only be used if considered equivalent (Design and Function).

5.3.5 Utility and Critical Systems Qualification

List the utilities and critical systems used to support the manufacturing process and document the qualification status.  Reference the validation documentation.

5.3.6 Analytical Method Qualification

Verify that the analytical methods are current and that the method validation, fit for use qualification and / or transfer is complete.  Verify that the product specifications are current.

Analytical methods that follow a specific monograph of the British Pharmacopoeia, European Pharmacopoeia or United States Pharmacopoeia are considered validated test methods, therefore their validation status is not required to be documented.

Validation tests that require development and product specifications that require establishment must be discussed with Quality Assurance and Regulatory Affairs, where applicable.

If there is insufficient data to set a specification, then a statement must be included in the report that identifies a target value or range, what further data collection is necessary, and how the additional information will be reported, once collected.

5.3.7 Calibration

All critical instruments that are used to control, measure or monitor direct or indirect process parameters should be within calibration throughout the validation study.  List all critical instruments and calibration status.  Attach or reference the calibration details and verify calibration status during the validation study.

5.3.8 Standard Operating Procedures and Training

Verify that the required Standard Operating Procedures are current, approved and that the appropriate persons have been trained in those procedures.

5.3.9 Environmental Monitoring

Environmental monitoring must be included during validation for those processes that require manufacturing to be conducted in a controlled environment.  Monitoring may include temperature, relative humidity, and microbiological environmental sampling.  Monitoring may be performed by exception.

5.4 General Sampling, Monitoring and Assessment Procedure

Verify each unit operation by monitoring operating conditions, sampling and testing, or both.  If the initiation of validation is for a modification, then those stages not affected by the processing step to be modified may be eliminated from the sampling and monitoring plan, assuming no benefit is anticipated from collecting this information.  The rationale behind not including this testing must be stated in the protocol.  Evaluation of processing stages that follow the modified step must be considered individually for impact and included in the study accordingly.

Critical Processing Parameters should be identified, and where possible, monitored, sampled or tested.  These points may include intermediates and finished products.  The protocol must include the type, amount and number of samples to be collected, where samples are to be taken, and any special sampling or handling requirements.

If necessary, a detailed description of the sampling procedure must be included.  Sample amounts must be based on the amount required by the test method, sampling device, and dosage size as per Site sampling procedure.  The protocol should allow for recording of sample number, sample time and date and sampled by information.

This section should also define the critical areas to be monitored based on the critical process steps.  Critical processing points will be identified on a case-by-case basis and included in the validation protocol.

General sampling techniques for different product types are detailed below.

5.4.1 Homogeneity

Sampling plans must be developed to demonstrate homogeneity throughout the batch. The bulk/blend must be representatively sampled based on product type, mixing container geometry and process (e.g., mixing mechanism) on completion of the processing step.  Additional sampling on completion of discrete critical steps may also be performed.  Sampling must not impact on the quality of the final bulk mixture.

Representative samples must be drawn after critical process steps.  Sampling plans must take into account start up requirements, process control frequency, line stops or interventions, and the final units.  Specific tests selected shall demonstrate physical and/or chemical homogeneity.

Sample sizes for homogeneity are product specific and shall be based on the requirements as per SOPVAL-100 Process Validation Sampling.

5.4.2 Oral Solid Dosage Forms

Static bulk powders and granulations should be sampled from a minimum of 10 points throughout the blender or vessel in which it is contained, using a clean, dry sample thief.  The location of the points to be sampled will depend on the critical point analysis, and the objective of the test (eg blend uniformity, dead spot characterisation etc) and should be detailed in a plan/diagram.

A minimum of 10 points should be sampled over the duration of the tabletting / encapsulation process for a batch under evaluation, including samples from the start, middle and end of the batch.  Tablets / capsules should be collected at the final point in this step of the process (that is, post metal detector).  Each time point sampled should be collected in a separate container.

The validation protocol should include as a minimum, the following:

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

b. Homogeneity sampling plans for powder blends shall include a minimum of 10 individual locations from across the lot;

c. Dissolution profile (where applicable) including points close to 100 percent dissolution (the number of samples is to be assessed based on the product, up to five points should be considered);

d. Freedom from defects throughout the process, such as capping, splitting, and twining;

e. Potency and dose uniformity; and

f. Compliance with finished product specification.

Samples shall be taken throughout each validation lot and tested for content uniformity to demonstrate there has been no segregation of the blend during the compression or encapsulation process.  Blend uniformity samples may be sampled directly from the blender immediately prior to discharge. Samples shall be taken from the specific areas of the blender that have the greatest potential to be non-uniform. If it is not practical to take samples from the blender, samples may be taken from the discharge stream or drums.

Sample sizes for blend uniformity shall be the approximate equivalent weight of the dosage unit.

5.4.3 Bulk Liquids (Solutions and Suspensions)

Bulk liquids include drug products such as elixirs, emulsions, solutions, gels, syrups and suspensions.

Following the completion of a given processing step bulk liquids may be sampled from the manufacturing vessel, during transfer from the manufacturing vessel to the holding vessel or from the holding vessel, using a suitable sampling device.  Care must be taken to ensure that no further processing of the bulk takes place following sampling (eg due to further stirring).  Homogeneity samples for suspensions should be taken from the top, middle and bottom and at least two other points through the bulk.  A minimum of top, middle and bottom samples should be taken for solutions.

Packed liquids samples should be taken from a minimum of 7 points over the duration of the packaging process, including start, middle and end samples. If there are any critical occurrences during the packaging run which may affect the product, then samples should also be collected at start-up immediately following such an event.   The rationale behind collection and/or testing of these samples should be outlined in the protocol.

The validation protocol should include as a minimum, the following:

a. Compliance to specifications (physical and chemical) of any API or excipient that is suspended in the dosage form;

b. Compliance to specifications (physical and chemical) of any API or excipient;

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

d. Rheological properties

e. Potency;

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

g. Microbiological purity; and

h. Comparison to the previously produced lots (commercial or development).

Where validation is being carried out as a result of a change to an existing process, documented justification shall be provided in the validation protocol if any of the above applicable parameters are not to be assessed.

5.4.4 Semi Solid

Semi-Solid Drug products include suppositories and topical drug products, such as emulsions, gels, lotions, creams and ointments.

Following the completion of a given processing step semi solid products may be sampled from the manufacturing vessel, during transfer or from the holding vessel, using a suitable sampling device.  Care must be taken to ensure that no further processing of the bulk takes place following sampling (eg due to further stirring).  Homogeneity samples for semi solid products should be taken from the top, middle and bottom and at least two other points through the bulk.

Packed liquids samples should be taken from a minimum of 7 points over the duration of the packaging process, including start, middle and end samples. If there are any critical occurrences during the packaging run which may affect the product, then samples should also be collected at start-up immediately following such an event.   The rationale behind collection and/or testing of these samples should be outlined in the protocol.

The validation protocol should include as a minimum, an assessment of the following:

a. Solubility of API in carrier vehicle, where applicable;

b. Homogeneity sampling plans shall include representative samples from throughout the lot;

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

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

e. Rheological properties (e.g. viscosity);

h. Appearance (for example, absence of grittiness, smooth); and

g. Potency.

5.4.5 Stability Samples

Each validation study should be assessed for the need for stability studies, and the decision justified in the validation protocol.  Document if stability is required prior to approval of batch release.

At least one validation lot shall be placed on stability for processes that are new to a site, reformulated products, or where it is believed that the change may affect stability, such as a rework process.

Where stability studies are required, a separate stability protocol is prepared by Quality Assurance and referenced in the validation protocol.  Stability requirements may need to be confirmed with Regulatory compliance

5.4.6 Microbiological Samples

The number of samples and the sample locations required for microbiological analysis should be documented.  If microbiological sampling is required, at minimum samples from the start, middle and end of the process should be sampled and tested.

5.4.7 Retention Samples

If samples are required for retention, the number of samples and sampling locations should be documented.

5.5 Testing Requirements and Acceptance Criteria

The criteria that will be used to record and evaluate each batch should be clearly stated in the protocol.  The following should be considered when setting validation acceptance criteria.

Acceptance criteria (including in-process and finished product specifications) must be listed for all testing and monitoring requirements specified in the protocol.

For tests without established specifications used to characterise the process (such as bulk density), a “for information only” criteria may be used.  Rationale and justification for application of “for information only” criteria to test criteria must be included in the protocol.

Each batch must meet all release for sale acceptance criteria specified in the relevant product specification.

Results of in-process testing must be used to demonstrate reproducibility at significant points of the process for potential correlation of in-process parameters with final product test results, and to indicate uniformity throughout the batch.

A successful validation lot shall be manufactured as per the manufacturing instructions referenced in the validation protocol and shall meet the product specifications relevant to the process validation, together with satisfying any additional acceptance criteria described in the validation protocol.

A validation batch may be dropped from sequence if failure to meet acceptance criteria is due to a non-process related cause, and has been fully investigated and proven to be such. Documentation of the reason for batch elimination, replacement intentions, and a reference to the formal investigation report must be generated.

If a validation batch fails to meet the acceptance criteria, and results in a change to the process steps and/or acceptance criteria, the original validation protocol may be amended and re-approved as the next version.

Three consecutive, successful batches must then be manufactured to demonstrate that the modified process is under control, and reproducible.  All failed batches must be referenced in the validation report.

5.6 Process Validation Report

The final Validation report references the relevant protocol(s) and summarises the results of the validation study.  Using the protocol as a guide, this document includes a review of the results of each phase of the study, and provides summaries and illustrations of the data.  The report should provide sufficient information to detail the validation study without requirement to review the validation protocol.  The report is reviewed and approved by the same persons or designees that reviewed and approved the protocol.

A final report should be issued following completion of the validation study.  Interim reports are required for concurrent validation batches. Interim reports should contain where relevant the same details as a final report.

5.6.1 Document Format

Each report should contain on its cover page:

– Report title, number, and revision number

– Product name and strength

– Signature and date of the protocol/report author, reviewer and approvers.

5.6.2 Objective

The objective of the report should be concisely stated.  In general, the objective of the report should be to assure that the process/product consistently meets all pre-  determined acceptance criteria and specifications and will provide a high degree of assurance that the process will produce a product that consistently meets site quality control specifications for the product.

5.6.3 Scope

As in the protocol, the report should clearly define the product to be validated.  The protocol number and version and the change control number should be referenced. If the protocol version is not version 1, rationale for the protocol version must be provided.  Any supplemental documentation should also be referenced.  An explanation for supplemental documentation should be provided.

5.6.4 Responsibilities

The responsibilities for review and approval of the report should be detailed.

5.6.5 Validation Strategy

An overview of the validation strategy as detailed in the validation protocol should be detailed in the report. Any departures from the planned strategy should be detailed in this section.

5.6.6 Manufacturing Process

An overview of the manufacturing process should be detailed in the report.  A process flow chart should be included in an appendix and referenced.

5.6.7 Results

5.6.7.1 Qualification and Calibration Status

An overview of the equipment, utilities, and analytical method qualification status should be documented.  An overview of the calibration status at the time of execution should be documented.

5.6.7.2 Standard Operating Procedures and Training

An overview of training in the relevant SOPs as detailed in the protocol should be documented.

5.6.7.3 Sampling, Testing and Results

Document the sampling performed during the validation study.  Comment on the data collected during the study and summarise using tables and graphical illustrations where applicable.

Provide a summary of in-process data and dosage form testing, and include control charts for each batch where appropriate.

Discuss critical process parameters and operating ranges recorded during manufacture of validation batches.

Include a process analysis of critical steps, observations, and ranges.

Ensure that all data has been transcribed accurately into the report and is reported to the same number of significant figures as the specification or acceptance criteria.

Document and justify any changes to non-critical process parameters whose change may have proved necessary during validation to improve the performance of the process while ensuring that the process produces product that meets acceptance criteria.

5.6.7.4 Stability

Comment on the status of batch stability and reference the stability protocol.

5.6.8 Data Verification

Relevant lot documentation shall be reviewed prior to inclusion in the validation report.  The data in a validation report shall also be independently verified, as indicated by signature and date of the reviewer to confirm that information such as test results have been accurately transcribed from the original documents.

5.6.9 Deviations

Deviation from the protocol, process instructions, or batch(es) must be described as detailed in SOP VAL-075Validation Deviation Management.

5.6.10 Conclusions

This section must summarise the results obtained, and state if the acceptance criteria outlined in the validation protocol have been met.  The status of deviations documented during the validation study must be briefly mentioned in the conclusion.  The conclusion should give a clear and unambiguous statement of the validation status and whether the process is approved for use in routine manufacture.

5.7 Additional Requirements

5.7.1 Change of Vendor of Raw Material

Any changes to an API, excipient, carrier vehicle, or to the manufacturing process that have the potential to affect characteristics of the drug product shall be validated, including a comparison to the previously produced lots (e.g., commercial or development).  The revalidation will be performed under the appropriate Change Control and should follow the requirements of this SOP for protocol and report generation and execution.  Refer to SOP VAL-105Raw Material Evaluation.

5.7.2 Document Retention

All completed protocols supplements and reports shall be maintained as per site procedure for controlled documents.