GMP Process, Cleaning and Method Validation Manuals

Sterilization Process Validation

Steam Sterilization is the most common type of sterilisation employed in the pharmaceutical manufacturing environment. The principles of steam sterilisation apply to processes conducted within autoclaves as well as sterilization-in-place (SIP) processes. Editing testing.

For the sterilisation of fluids, e.g., vials and ampoules, a fluid load autoclave cycle is used. The steam (or superheated water) is used as a heat transfer medium to heat the contents of the vials/ampoules.

The moisture required for sterilisation is derived from the contents in the vial/ampoule. For the sterilisation of processing equipment, tubing, garments, etc., a porous load (equipment or hard goods) autoclave cycle is used. Air must be removed from the chamber and loaded before the sterilisation phase of the cycle. The steam is used to heat the load and to provide the moisture needed for sterilisation.

SIP processes are unique because of the equipment configurations involved. The system must be correctly designed to ensure adequate air and condensate removal, sequencing of the process, and maintenance of sterility post-cycle. The steam is used to heat the equipment and to provide the moisture needed for sterilisation.

Steam must be of suitable quality. Some EU regulatory authorities emphasise the quality of steam used for sterilisation. For porous load cycles (product contact equipment and hard goods cycles) and SIP processes, the steam, when condensed, should be of WFI quality with low levels of non – condensable gases (typically <0.35%v/v), a dryness fraction of 0.95 and show less than 25°C superheat. Methods to determine these parameters are described in BS EN 285.

High levels of non-condensable gases may prevent the attainment of sterilising conditions. Dryness fractions of <0.95 may lead to slow heat-up times and wet loads.

Superheated steam is a dry gas and is unsuitable due to the lack of water needed for sterilisation.

Generally, the development and validation of steam sterilization cycles follows

How to Prepare Master Validation Plan for Pharmaceuticals Quality Systems

Each VMP shall describe the scope of the activities and address relevant key elements of validation affected by the change, indicating the actions and documents that will be needed. The key elements are those factors that can have an effect on product quality.

The VMP shall identify all the components to be included within a validation project. Flow diagrams or matrixes can be useful to provide an overview and monitoring tool. A high-level process map or flowchart of the manufacturing process should be included.

Following the issue of the VMP, detailed risk assessments (system and component impact assessments ) should be carried out to identify items requiring qualification.

The content of the VMP should reflect the complexity of the extent of the validation activities to be undertaken. At a minimum, the VMP should address the following:

– Title, statement of commitment, and approval page.

– Summary description of the project and its scope.

– A statement of validation policy and the objectives of the validation activity

– References to other existing validation documents.

– A description of the organisation and responsibilities for validation

– The validation strategy to be adopted is opposite Facilities and Systems (process equipment and services including automated systems), Materials, Quality Control, and Personnel, including training.

– The intent with respect to Process Validation and Cleaning Validation for each of the drug product ranges.

– The documentation management and control system to be used.

– A description of the validation change management process.

– An indicative relative timescale plan.

– Clear acceptance criteria against which the outcome of the validation exercise will be judged.

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Process Validation of Bulk Drugs, Active Pharmaceutical Ingredients, and Intermediates

Process Validation itself is only one of the many elements of validation required to provide an organised approach to satisfy GMP requirements. For more complex validation activities, a Validation Master Plan should be produced to describe the approach for each validation element.

At the time of commencing Process Validation, the other related elements of validation should be in place, e.g.:

– Qualified and calibrated equipment, services, and validated computer systems.

– Validated analytical methodology and established specifications, materials, and suppliers. Critical in-process tests should also be established/validated.

– Cleaning validation plan and related validated analytical methodology.

– Trained personnel.

– Current SOPs encompassing the activities.

These requirements should be confirmed in a ‘Statement of Readiness to Proceed to Validation’

In a multi-step synthesis, the intent is to Validate all steps identified as Critical steps from process development and/or historical data and Control (routinely test) other steps. Critical steps are those containing Critical Parameters and/or Critical Activities.

Process validation is therefore required from the first API intermediate stages containing critical steps to the final API stage. For consistency of operation, some sites choose to validate all registered stages.

For outsourced registered stages, it is recommended that at least the final outsourced stage be validated, even if it does not contain identified critical steps.

Process Validation Guidelines for Formulated Products

Process validation must be ensured by testing that a process can repeatedly and reliably produce a formulated product of the required quality.

Information from R&D must be used to identify the critical process parameters to be tested during Process Validation to ensure batch reproducibility.

A risk assessment approach should be used to determine the scope and extent of validation.

A predefined number of validation batches (also called conformance batches) should be manufactured to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make an acceptable product. It should normally cover the manufacture of at least three consecutive batches of material.

Validation should be performed under conditions to be used for routine manufacture. The batch size should be the same as or representative of the intended commercial scale batches.

Sampling and testing should be carried out to ensure compliance with the most stringent requirements.

Cleaning and Cleaning Validation Practices for API Plant and Equipment

Design for Cleaning and Product Accommodation: The first activity in ensuring API plants can be effectively cleaned is to ensure cleaning is actively planned for in the plant/equipment design. Good design for cleaning should be built into plant/equipment specifications. The handover documentation should include a list of potential hot spots for new plants.

Trial cleaning can be conducted before production cleaning to determine how easily the plant/equipment can be cleaned. Trial cleaning can be used to collect data for a specific cleaning procedure and to identify hot spots. The results of trial cleaning should be evaluated to help establish optimal cleaning procedures. The justification for any cleaning approach should be based on understanding the impact each identified hot spot will have.

A new accommodation of a product into an existing plant should take account of the product’s attributes and the plant’s capability and design with respect to cleaning.

For example, dedicated production areas should be considered when the material of high pharmacological activity or toxicity is involved (e.g., penicillin, certain steroids, or cytotoxicity-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

Cleaning Methods: Cleaning methods must reflect actual equipment usage, be documented, and be carried out to predetermined acceptance criteria. Typical cleaning methods include water rinses, acid/base rinses, refluxing solvent washes, high-pressure water jets, manual cleaning, rinsing via spray ball, solvent recirculation (via filtration), and detergent cleaning.

This list is not exhaustive, and where possible, individual processes should also be designed to maximise ‘in-process’ cleaning (e.g. solvent rinsing via spray ball following the process through the plant/equipment).

Cleaning should be carried out as soon as practicable after completion of processing. Cleaning agents (e.g. detergents) may be used provided sufficient information is known about their formulation and toxicity to allow Acceptable Carryover Quantity (ACQ ) calculation.

The carry-over limits should also reflect the fact that cleaning agents should not be part of the process or product formulation, and as such, the acceptable residue levels will be low. By their nature, detergents are highly soluble, and residual levels should be reduced and minimised, considering the analytical methods available for quantification.

Where the API or residue being cleaned from the equipment is more toxic and less soluble than the detergent, a bracketing approach may be justified, i.e., that analysis for guiding substance is undertaken only. The justification must be documented in the appropriate validation documentation.

Cleaning and Cleaning Validation for Formulated Products

In Operations records for each changeover, confirming compliance with the predetermined acceptance criteria shall be produced and retained.

In R&D, during early development phases, when a worst-case cleaning validation approach or cleaning verification is employed, records for each changeover should be documented in process equipment log books to confirm that the equipment has been cleaned using the validated procedure or that verification has been successful before it can be used for the next product.

During later development phases, when replicating clinical trial batches of the same product are being manufactured, and the formulation and process are fixed, validated cleaning procedures should be undertaken and recorded more formally.

The exact approach taken shall be described in R&D SOPs. When Operations facilities are used to manufacture products for clinical trials, the approach adopted shall be documented and include a supporting rationale.

Each site/plant shall consider all product/equipment combinations. Grouping into product families (e.g. utilising the highest active agent variant or other worst-case example) and identical equipment groups is acceptable.

For product-dedicated equipment, a rationale and supportive data shall be generated to justify time limits or maximum campaign lengths between cleaning. ‘Test until clean’ (i.e. cleaning until an Acceptable Carryover Quantity (ACQ) is achieved) procedures should not be used. The level of cleaning required/number of repeat washings should be established during the technology transfer phase of product development and cleaning validation work for the product and equipment in question. Cases requiring additional cleaning following the routine cleaning procedure should be reported via the site/plant deviation reporting system.

Cleaning procedures should be designed to provide the simplest, practical, and reproducible process that results in carryover remaining below a scientifically derived limit. Whilst attempts should be made to optimise the efficiency of all cleaning processes, it is not necessary to clean until the carryover is below the analytical limit of detection (i.e. none detected). The acceptance criteria for carryover must be related to the pharmacological effect of the carryover product or to a defined default limit if this pharmacological effect information is not available.

If the acceptance limit for a changeover is lower than the analytical limit of detection, the equipment must either be dedicated, or an alternative, more sensitive detection method is developed.

Cleaned equipment should be stored dry and protected against contamination. Cleaning validation for packaging operations shall be considered in the same manner as manufacturing or processing operations. Cases where cleaning validation is not undertaken shall be justified.

Cleaning from a microbiological viewpoint is not considered within this document. I think the need for microbiological evaluation should be considered within the cleaning protocol. When it isn’t done, justification should be supported by a documented justification.

For certain products (e.g. penicillin, cytotoxics) it may not be permissible or practical to perform cleaning to the required levels to prevent cross-contamination routinely.

For new products introduced to an Operations site/plant, cleaning information (e.g. validated analytical methodology for determination of product residues, outline cleaning methods, etc.) shall be part of the technology transferred from the development function to the site/plant and form the basis of the site validation.

For established product technology transfer, the transferring Operations site shall ensure data is available for inclusion in receiving Operations site cleaning validation protocols.

Analytical Procedure (Test Methodology) Validation

Analytical procedures should be available for all stages of development, and their content should be appropriate to the development phase.

All analytical procedures used to generate data that could be included in a regulatory submission must be validated to the degree appropriate for the phase of development before use.

Analytical procedures that are used to test a commercial finished product, raw material, or packaging component must be validated before use.

Analytical procedures supporting other activities, such as validation of cleaning processes, should be validated to the degree appropriate to their intended use.

It is essential to establish that analytical procedures produce data that are sufficiently accurate and precise for their intended purpose. Analytical procedures should be validated / re-validated when:

– They are initially developed for a specific material and purpose.

– They are used for materials or purposes outside the validation studies’ original scope.

– The materials or relevant manufacturing process has been modified.

All departments or sites performing analytical procedure validation or re-validation should have Standard Operating Procedures (SOPs ) describing the process, responsibilities, and documentation requirements. All laboratory work must be conducted to appropriate GMP standards.

The Validation of Facilities and Systems in GMP Site

Each Direct Impact System shall be detailed in a validation plan detailing the validation activities to be undertaken to assure product quality.

Consideration may be given to the logical grouping of systems within the VPs. For example, Process Equipment, Process Services, Building / Building Services, Process(es) / Products(s). Each VP should demonstrate that the validation activities have been considered and will be organised in a structured manner.

The VP may include acceptance criteria, which would be reported against when the corresponding report is written.

NOTE: For projects involving a small number of Systems, it may be desirable to incorporate the contents of the individual Validation Plans into the VMP or one single Validation Plan.

The VP should identify the validation life cycle activities to be undertaken. For each validation life cycle activity, the procedures to be followed and associated responsibilities, by role or function, for generation, review, and approval should be recorded in accordance with the requirements for Validation Documentation.

The VP should identify and document the ruling SOPs and their relationship.

The VP should record each system’s approach to the Component Impact Assessment and where the assessment results will be recorded.

The VP should identify the documentation system to be used to manage change control and the extent to which formal change control applies to the documents at each stage.

A new VP should be prepared for projects involving significant changes to existing Systems. The existing VP may be used as a reference document. The VP shall be prepared and approved early in the project. After that, it will be subject to formal change control.

Information Technology Infrastructure Qualification for a GMP Facility

In both new and existing cases, a risk assessment must be performed to establish the qualification (and any specific documentation) requirements. If, in the case of existing components, the risk assessment confirms that they are reliable then they do not need to be tested.

Simply ensure that information about the components is recorded ‘as is’. The information must be sufficient to allow the components to be replaced and reconfigured to resume operation as soon as possible if necessary.

As a minimum a qualification plan that describes the retrospective qualification exercise for the existing infrastructure, plus technical and configuration specifications for each component or system needs to be in place and the items must be recorded in the asset register.

New infrastructure components must follow an established procurement and qualification process and similarly, sufficient information must be available to allow the component to be specified, maintained, repaired, or replaced.

Development Environments: In the special case of ‘thrash and crash’ environments, e.g. ‘sandboxes’ and other development regions of the infrastructure, the interactions, if any, between the development region and the wider infrastructure (if a connection exists between the two regions) must be formally assessed for any security and compliance risks and qualification process must be followed.

Qualification Documentation: Adequate documentation is an essential part of the qualification and infrastructure management processes and all deliverables must be documented. Lack of adequate records will cause costly delays, errors, and in some cases possible unwanted actions from regulators. The documented evidence is necessary to demonstrate the qualification of infrastructure components.

Each deliverable may be a separate document or combined for routine and simple changes and may cover one component which itself may be representative of a class of components.

Qualification of common and routine changes may be covered by a predetermined change procedure and the qualification deliverables documented on the change request documentation.

General Guidance on Analytical Test Method Validation

Pharmacopoeia methods included in a specific official monograph are mostly considered validated. However, the suitability of compendia analytical procedures must be verified under actual conditions of use. It is recommended to demonstrate the absence of interference with the compendia method, thus specificity (if applicable) should be assessed. Intermediate precision and stability of the sample solution should also be investigated using the compendial method for the particular API. Demonstration of the applicability of the method for use in the analysis of the specific product/material should be accomplished by the analysis of the material using the pharmacopeia method. System suitability requirements of the method should be met, and for raw materials, the results should conform to the expected result for that grade of material.

Risk Assessment and Prioritization in Analytical Test Method Validation

The need to validate an analytical test method should be based on an impact assessment. Per ICH Q7A, the degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

Those analytical test methods that should be validated, and are included in the scope of this document, include:

– Registered analytical test methods.

– Methods used to test a critical attribute.

– Methods used to monitor a critical process parameter.

– Other methods that may be used to decide what affects final API product quality.

System Suitability in Analytical Test Method Validation

System Suitability is a predetermined set of tests and applied method requirements that are used to determine if an analytical method is performing within its validated parameters and is acceptable for its intended use. The method validation exercise may include statistical interpretation of data to provide adequate justification for reduced System Suitability Testing (SST) and numbers of standard and sample injections.

Analytical Test Method Validation – Precision and Accuracy

Reproducibility: Reproducibility is not normally performed during method validation. Reproducibility expresses the precision between laboratories and is assessed by means of an inter-laboratory trial.

Reproducibility should be considered when an analytical procedure is to be used in multiple laboratories or sites.

Reproducibility can be assessed in a formal collaborative validation study using multiple laboratories or by comparison of results reported for the same sample by multiple laboratories (e.g. in registration documentation). Execution of Analytical Technology Transfers provides a means of assessing inter-laboratory equivalence using an analytical transfer study.

Repeatability: Repeatability expresses the precision under the same operating conditions over a short interval of time.

Repeatability is also termed intra-assay or within-run precision.

Analytical Test Method Validation – Quantitation and Detection Limit

The quantitation limit is an important parameter when dealing with quantitative assays for low levels of compounds in sample matrices. The quantitation limit is normally established and confirmed for methods used to determine impurities or degradation products.

In many cases, it may be appropriate to prescribe a quantitation limit, which is at an analytically significant level, rather than necessarily attempting to establish the absolute level, at which quantitation becomes unacceptable. Impurities methods normally fall into this category. The ICH standards Q3A and Q3B define thresholds for reporting impurities and degradation products below which impurities need not be quantitated or reported. For these cases, it should be determined that the quantitation limit is at or below the reporting level.

Linearity, Range, and Specificity in Analytical Test Method Validation

Recommended Linearity Acceptance Criteria: The assay need not give results that are directly proportional to the concentration (amount) of analyte in the sample for the test method to be valid. However, the desire to have a linear relationship reflects a practical consideration, since a linear relationship should be accurately described with fewer standards.

A validated method may be sufficiently linear to meet accuracy requirements in the concentration range in which it is intended to be used. When inferring accuracy from a linearity study, linearity could be considered acceptable if results, as compared to a standard, meet the accuracy criteria. A plot of the data should visually appear to be linear. Suggested acceptance criteria (for API Raw Material, In-process Control, and early intermediate material tests) for an acceptable linear relationship may be a test method having a minimum correlation coefficient (r) of > 0.95.

Calculations of Residue Limits for Medicinal Products for Equipment Cleaning During Cleaning Validation

The Maximum Allowable Residue for Therapeutics and Residue Acceptability Limit for Therapeutic Dose should be calculated based on each product that is to be processed in a specific equipment train and determined by the formulas and equations. A common default Maximum Allowable Residue for Therapeutics is not more than ten (10) ppm.

The calculated and default Maximum Allowable Residue f or Therapeutics should be compared and the lower of the two (2) used. A Toxicity limit may also be calculated and compared to the default Maximum Allowable Residue and the NMT 10 ppm, and the lower of the three limits chosen.

How to Group Product and Equipment and Select the Worst Case Product in Cleaning Validation

Any plan to group products or equipment for the purpose of cleaning validation should be based on the premise that the items grouped share the same cleaning procedure. Use of the term ‘same’ in this context means equivalent and applies to the cleaning methodology and parameters. If two or more procedures or automated programs share the same methodology and parameters but have different titles, document numbers, or program identifiers then it should be possible to apply the results of the cleaning validation across all those procedures. When determining if two procedures are equivalent, the following points should be considered as to their criticality in achieving the final result:

– Cleaning agent and cleaning agent concentration

– Liquid used for rinsing

– Temperature

– Scrubbing, rinsing and drying times

– Flow rate

– Agitation

– The extent of manual intervention required to produce expected results

Rinsate and Swab Sampling Procedure in Test Method Development and Validation

The cleaning evaluation for a given product, intermediate, or drug product excipient provides the basis for the rationale of which material(s) should be tested for during the analysis. The analytical method selected shall be able to detect residual products at the acceptance level specified. Specific test methods are not required. Specificity experiments should be based on the type and purpose of the method being considered.

Method of Visual Inspection and Quantitation in Cleaning Validation

Visual inspection is the minimum requirement for all cleaning and test regimes required for Cleaning and Cleaning Validation. There are five aspects of visual inspection discussed in this procedure:

– Visual inspection following or during manual cleaning.

– Visual inspection of dedicated equipment

> Interval cleaning

> Campaign cleaning

– Routine Visual inspection of multi-purpose equipment

– Visual inspection during validation (e.g. most difficult to clean product approach)

– Visual Quantitation

> Laboratory Studies

> Difficult-to-clean inactive raw materials

Investigating Unknown Chromatographic Peaks During Cleaning Verification

Because unknown peaks observed in chromatograms for cleaning verification samples cannot be assumed to provide an equivalent response to a known standard, specific compound, Relative Response Factors are typically not assigned to unknown peaks. Based on the approach used at a number of GMP sites, the following considerations should be made to ensure investigations take place for potential contaminants that may negatively impact the next product manufactured in that equipment:

Documentation and Records for Cleaning Activities and Evaluation

In order to appropriately document the development of the cleaning requirements for a material and/or equipment train, it is recommended that a cleaning evaluation report be prepared. This may be a single report or several reports; there is no requirement for a document to be titled, “Cleaning Evaluation Report’. This may be fulfilled by documenting the evaluation within a separate report, the site cleaning validation master plan, validation project plan, or validation protocol as appropriate for the site.

The evaluation may be equipment – centric or process – centric and may include or reference relevant information.

Identifying Critical Process Parameters for Manufacturing of Medicinal Products

Any step or unit operation determined to be critical should be evaluated to determine if it contains one or more critical process parameters. The parameters must have some influence on critical quality attributes to be considered for evaluation as critical. The degree of control over the parameter will determine if it is critical. It is possible to have a critical step that does not contain any critical parameters if control of process parameters is tight.

This portion of the analysis requires both knowledge of the process and manufacturing equipment. An example might be a fully automated compression step. The step is critical but complete control over the parameters leads to defined noncritical process parameters. Critical parameters identified during the research and development phase are not necessarily reflective of production-scale equipment. The analysis of the process at this level is analogous to a failure modes and effect analysis without estimating the frequency of failure or severity of the effect.

Process Validation Approaches for Medicinal Products and Medical Devices

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 the process step. Additional sampling on the completion of discrete critical steps may also be performed. Sampling should not impact 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).

Equipment Cleaning Validation for Active Pharmaceutical Ingredients (API)

A Cleaning Evaluation should be conducted, documented, and approved by the Site Quality and Production Teams. This evaluation may be a single report or several reports and may be equipment-centric or process-centric and document or reference the required information. The purpose of this documentation is to justify the decisions made in developing the cleaning validation protocols. This evaluation should determine or consider for each equipment unit:

What material(s) are being cleaned – include consideration of at least the following items:

– Process Intermediates;

– APIs;

– Raw Materials;

– Cleaning and sanitation agents;

– Solvents;

– Bacterial Endotoxins, when applicable; and

– Microorganisms, when applicable.

What residues will be tested for ;

– Solubility of residues in cleaning agents (including cleaning and rinse solvents);

– Cleaning parameters and applicable ranges (e.g., concentrations, temperatures, times);

– Cleaning method (e.g., spray ball, flooding, power hosing);

– Extent of equipment disassembly;

– Residual acceptance criteria;

– Sampling method(s) to be used;

– Potential for degradation by-products or conversion products;

– Stability of material(s) being cleaned under the proposed cleaning conditions;

– Suitability of the cleaning agent(s) for the materials of construction of the equipment;

– Equipment surface finish (e.g., stainless steel, glass, polypropylene);

– Rationales for decisions on which materials to test, the limits for testing, and the method of verification; and

– Evaluation of campaign length.

Demonstration and Calculation of Equivalence Criteria of Impurities for API Process Validation

Demonstrating equivalence is needed in all API validations, but this guidance is applicable to APIs prepared by chemical synthesis. Additional analysis (not described here) may be needed to evaluate the physical attributes of the API, where requirements are defined for the corresponding Drug Product. A change in an API process should be evaluated to determine if revalidation of the drug product process may be necessary.

Process validation should confirm that the impurity profile (e.g. for process-related impurities and volatile impurities, i.e. residual solvents) for each API is within the limits specified. Therefore, for all equivalency studies, it is expected that the results of the validation batch testing be within registered specifications. It is also expected by ICH Q7a that the impurity profile for validation batches be comparable to or better than historical data. This is consistent with expectations for post-approval changes to API processes.

For older processes, the registered specifications may or may not accurately reflect the most recent historical data. In cases where the specifications may not be reflective of more recent historical data, it is recommended that additional criteria, such as meeting the upper statistical limit of historical data, be considered for validation equivalence criteria.

Equivalency Comparison of Medicinal Product Validation Batch Data to Reference Batches

A new or modified medicinal product should be demonstrated to be equivalent to the previously produced product. Comparisons must be done as part of process validation studies for new products and significantly modified processes that require validation.

For new products, the equivalency of validation data (e.g. finished product, critical in-process tests, or critical parameters) to biobatch(es) or pivotal clinical batches is shown. For all equivalency studies, it is expected that the results of the validation batch testing be within registered specifications.

In cases where the specifications may not be reflective of recent process capability, it is recommended that additional criteria such as meeting the upper statistical limit of historical data, be considered for validation equivalency criteria.

Establishing and Extending Clean Equipment Hold Times

The clean equipment hold time is defined as the time between the last step of the cleaning procedure (e.g. drying or sanitization) to the start of the next equipment use for manufacturing. This includes a pre-rinsing step, if used.

A recent international guide has stated that risk approaches are acceptable in differentiating efforts and decisions for cleaning equipment.

There are two main risks associated with clean equipment hold time:

– The risk of contamination of clean equipment with dust, etc. due to exposure to the environment. For this risk, it is required that equipment either be held clean in a controlled clean environment or protected from the environment. This type of potential contamination may or may not be visible during visual inspection;

– The potential for microbiological proliferation. This is only a risk with equipment stored under conditions favorable to microbial growth (e.g. water wet or non-protected under non – controlled storage conditions such as high humidity). Therefore “environmental exposure” may not always result in microbiological risk (e.g. if equipment is not water wet and if the clean equipment is held in a controlled clean environment).

Because of the above two risks, It requires that equipment be protected from the environment and not stored water wet for the API and Drug Products.

Evaluating Non-Cleaned Equipment Hold Times for Cleaning Validation Medicinal Products

The non-cleaned equipment hold time period is defined from the “end of manufacturing” to the start of cleaning. The end of manufacturing is when the individual equipment piece is emptied of the material contained within (e.g. when no additional product is removed for further processing).

The beginning of cleaning is defined as when a cleaning activity is initiated on the equipment. Examples include pre-rinsing initiation or post-campaign flush, placing an item into a solution for soaking, or a CIP cycle being started.

Maximum allowable time intervals for periods between API equipment use and cleaning (non-cleaned or “dirty” hold time) are required to be specified unless there is an approved documented rationale or data demonstrating the time interval is non-critical. For drug products, the intervals must be demonstrated in at least one cycle of use and cleaning, and it must be documented in the validation.

Non-cleaned equipment hold times for APIs are not required to be validated. A recent international guide has stated that risk approaches are acceptable in differentiating efforts in cleaning equipment based on intended use.

Evaluation of Changes for Potential Impact on Process Validation

Evaluation of the validation impact of the proposed change(s) should include assessment against pre-established acceptance criteria, including (where applicable):

– Impact on product acceptability: Documentation of the nature of the change and its expected impact(s) on Critical Quality Attributes of the final API or drug product;

– Impact on product equivalence: Does the quality of material produced by the changed process compare favorably to acceptable material prepared previously? Consider all attributes that may be affected by the change.

– Impact on control of critical process parameters: It is recommended that the critical process parameters risk assessment be re-evaluated to determine if the proposed change alters the risk associated with control of process parameters that impact product quality.

– Impact on product uniformity (e.g. homogeneity of API or blend uniformity of DP); and

– Impact on the ability of the process to consistently provide a product that meets all quality expectations.

Swab and Visual Inspection Sampling Locations Guidance for Process Equipment

If swabbing is used as the sampling method, product-contact surfaces should be swabbed in locations from which there is a likelihood of contamination or carryover to a subsequent product and from the most difficult-to-clean areas. If a rinsate method is used, a measured volume of solvent used for the final rinse should thoroughly wet all product contact surfaces and should be circulated, where applicable, through all product contact lines before it is visually inspected or tested in the laboratory for residues. Rinsate recovery studies can be based on worst-case product groupings, and/or by a grouping of worst-case materials of construction.

In – Process and Bulk Drug Product Holding Times

Although there are no specific regulations or guidance documents on bulk product holding times, good manufacturing practice dictates that holding times should be validated to ensure that in-process and bulk products can be held, pending the next processing step, without any adverse effect on the quality of the material. This practice is supported by indirect references made to determining holding times in various FDA guidance documents, and FDA regulations as follows:

– “If a firm plans to hold bulk drug products in storage…..stability data should be provided to demonstrate that extended storage in the described containers does not adversely affect the dosage form”

– “Stability data also may be necessary when the finished dosage form is stored in interim containers prior to filling into the marketed package. If the dosage form is stored in bulk containers for over 30 days, real-time stability data under specified conditions should be generated to demonstrate comparable stability to the dosage form in the marketed package. Interim storage of the dosage form in bulk containers should generally not exceed six months”.

Batch Homogeneity Demonstration of Active Pharmaceutical Ingredient Preparation

Homogeneity is the acceptable distribution of chemical and physical properties within a batch, based on predefined criteria. The intent of examining homogeneity during the validation is to demonstrate

that the quality of a sample collected from any location within a batch is representative of the quality of the entire batch.

For large molecules, the evaluation of homogeneity must consider the consistency of the profile of heterogeneity of product-related molecular variants. This profile should be consistent throughout a batch and similar between batches.

Unless previously performed in another study, an examination of API homogeneity must be performed during process validation. If homogeneity was shown in a previous study, the following should be considered to determine if this study is still applicable:

– Was the API prepared by the same process?

– What processing changes have been made, and what potential impact (if any) do these changes have on API homogeneity?

– Was the API prepared in the same (or equivalent) equipment?

Documentation model for Continuous Quality Verification

The rate of moisture removal is rapid during the first phase of drying, with mostly unbound, free water being removed. The product temperature changes very little during this phase because of evaporative cooling. The second phase removes free moisture from the surfaces of particles, and the rate of evaporation during this phase is relatively constant.

This phase exhibits a gradual, relatively small increase in product temperature. In the third and final drying phase, moisture migrates from the inner interstices of particles to the outer surface, and this becomes the limiting factor that reduces the drying rate during this period. The drying rate declines during this phase, and product temperature increases as evaporative cooling has little effect on the particles.

Excessive moisture remaining in the product mix results in an inconsistent tablet dissolution profile, so the moisture of the dried granulated mixture has been identified as a critical quality attribute. Over-drying the product results in some erosion of particle size and adversely affects the compression of the product mix into tablets, so too low a moisture level is also detrimental.

Documentation to Foster Continuous Quality Verification

Process validation is used to provide assurance that the processes used to manufacture pharmaceutical products result in products that possess the required critical quality attributes (e.g. strength, identity, purity, safety, and efficacy).

Continuous Quality Verification is an alternative approach to process validation. One of the primary differences for verification compared to a conventional discrete, 3 – batch process validation approach is that the process is continually monitored, evaluated, and adjusted (when necessary) to achieve defined Critical Quality Attributes using validated in-process measurements, tests, controls, and process end points.

Continuous Quality Verification is applicable to all types of products and processes (e.g. Biopharmaceuticals, API, and drug products) and may be used with new, legacy, batch, and continuous processes. The principles may be applied during the development of a new process or product, or for the improvement and/or redesign of an existing process. Continuous Quality Verification may be applied to an entire process, or to defined critical manufacturing steps/unit operations.

The principles may be applied during the development of a new process or product, or for the improvement and/or redesign of an existing process. Continuous Quality Verification may be applied to an entire process, or to defined critical manufacturing steps/unit operations.

Guidance on Selection Criteria of Dose and Toxicity Data

For consistency, the use of Acute Oral LD₅₀ values obtained using rats as the study population is recommended to be used. The justification for utilizing rat acute oral LD₅₀ values is based on a commonly referenced article on this subject. Layton et al suggest that a safety factor to be used in calculating the Acceptable Daily Intake (ADI) be in the range of 1×10^-3 to 5 x 10^-6. This factor is based on small mammal and oral rat data. The MAR formula, therefore, requires the overall safety factor of 5x 10^-6{5 x 10^-4 in the No Observable Effect Level (NOEL) calculation and another 1 x10^-4 in the ADI calculation, which incorporates the NOEL}.

The ADI is used in the Toxicity Maximum Allowable Residue (MAR) calculation. The safety factor of 5×10^-4 has been reported in other literature articles for NOEL and appears to generally be accepted in the industry. In cases where rat acute oral LD₅₀ values are not available, but other species’ toxicity data are available, the acute oral LD₅₀ value of the next largest mammal can be used. Likewise, if oral LD₅₀ LD₅₀ data are not available, LD₅₀ data from other administration routes may be used.

Inspection Attributes in Packaging Validation of Non-Sterile Drug Products

Applicability of Harmonizing Acceptable Quality Levels (AQLs): Each application is suggested to be evaluated on a case-by-case basis to determine which defects are critical, major, and minor, for that specific package or product line. Depending on the specific package and dosage form, some of the attributes or defects listed below may not be applicable, additional defects may be warranted, or the description of the defect further specified. Definitions of defects may vary from site to site, so the classification is highly dependent on the interpretation and specific definition of the defect. The concepts of AQL (Acceptable Quality Limit) and UQL (Unacceptable Quality Level) may be non-uniformly applied in setting acceptance or statistical quality control criteria.

The “95 percent” level of high probability of acceptance may not be accepted at all GMP sites or for some dosage forms; It could be too low or high (4). Thus, it may be impractical to establish a uniform system of AQLs and/or UQLs for package defects. The uses of AQL and/or UQLs and their ranges are examples of statistically derived levels for acceptance or rejection. The basic requirements are that the acceptance criteria for sampling, testing, and for acceptance levels be based on appropriate statistical quality control criteria. Sound statistical methodology should be applied to the procedures for testing attributes that impact the quality of drug products and the evaluation of the results to determine acceptance or rejection of the drug product lot.

Laboratory Equipment Qualification

Performance Qualification (PQ) should ensure that the instrument is performing as specified and configured in accordance with the intended use in the laboratory.

The PQ instructions or protocol for an off-the-shelf piece of equipment, including vendor-provided documentation, should be approved by the Quality Authority prior to execution.

For moderate equipment, the PQ requirements may be met through the initial calibration provided that the calibration includes the range of intended use at the Site, which is conducted as part of the qualification exercise.

For complex equipment, PQ should include testing using all modules of the equipment and should be reflective of the intended end-use.

PQ may be achieved through method transfer or method validation if the intended end use of the equipment is addressed.

Moderate equipment routine use of system suitability and/or control samples may satisfy PQ requirements.

Matrices and Bracketing of Medicinal Products in Process Validation

Matrixing across different products may be applied to the packaging validation of the final dosage form, for example, to evaluate the packaging of different products in a common packaging presentation. As with other uses of bracketing and matrixing, the risk of using this strategy for the potential products encompassed by the matrixing plan should be considered, documented, and approved.

The use of bracketing/matrixing for the validation of a manufacturing process across different products should be approached with caution because of the risk of overlooking other possible effects of the change. The use of this type of bracketing/matrixing requires a good understanding of the processes involved and the risks being assumed. For example, in the evaluation of a change of a critical material for different products, the excipient interactions, critical process parameters, and critical quality attributes (CQAs) are not necessarily the same for each product. The effect of the change in the CQAs may be different for each product. A product sensitive to the change may experience a failure in a CQA (e.g. dissolution) while in the case of a product not sensitive to the change, it may experience no effect at all in its CQAs.

Considerations for Selecting Packaging Lot Sizes During Packaging

Example:

Manual packaging process

Batch Size:

2000 units

Process:

Sterile units in their sealed primary package are hand-labeled (pre-printed with lot number and expiration date) by 4 operators and then placed on a conveyor which takes the labeled units to a packaging station where 4 units are manually placed into a manually assembled, pre – labeled carton by 2 operators. The cartons are conveyed to a second packaging station where they are manually transferred into a shipping container.

Evaluation:

All packaging operations are manual, each step of the process can be 100% verified by the operator conducting the process step. The physical handling of the sealed sterile unit is assessed to determine if the operator can inadvertently induce a sterility breach under routine packaging conditions, no such risk is found. Container closure integrity is assured via separate studies. Placement of the labeled unit into a carton does not impact the quality of the product or affect any batch record specific to the labeling of the product. The software and system used to generate the labels have been qualified. The pre-labeled cartons meet specifications and are approved for use by incoming inspection. Transfer of the cartons into the shipping container does not impact the quality of the product or affect any batch record specific to the labeling of the product.

Potential Critical Packaging Process Parameters and Validation Practices

Quality risk assessments are suggested to be used for determining the level of criticality of equipment and parameters. See guidance on Risk Assessment in Validation. Each packaging application should be evaluated on a case-by-case basis to determine impact assessments and which parameters are critical. Critical packaging process parameters and normal operating ranges, including justification or reference for these ranges, are to be determined before validation and included in the packaging validation protocol. Some examples of critical process parameters ranges to be determined in pre-studies, line trials, or qualifications may include:

– Time

– Temperature

– Pressure

– Torque

– Speed

– Count quantity

– Fill Weight and Variation

– Inert atmosphere (liquid)

– Environmental Humidity

Process Validation Sampling Practices for Non-Sterile Liquid and Semi-Solid Drug Products

Suspensions on the other hand, by the nature of their formulation, are prone to separation or settling and pose special concerns for sampling and testing. For oral suspensions, there is an additional concern with uniformity, particularly because of the potential for segregation during manufacture and storage of the bulk suspension, during transfer to the filling line, and during filling. Depending upon the viscosity, many suspensions require continuous or periodic agitation during the filling process. If delivery lines are used between the bulk storage tank and the filling equipment, some segregation may occur, particularly if the product is not viscous. During each process step in which separation or settling could occur, comprehensive sampling and testing should be performed to ensure that the process is performing as designed.

Process Validation Sampling Practices for Non – Sterile Solid Dose Drug Products

There are many concerns regarding blend uniformity sampling, for example:

– Inappropriate sample thief technology;

– Powder segregation of samples may occur after sampling.

– Difficulty in proving that the blender sample plan will be representative of worst case locations;

– Segregation of blend that can occur during discharge, storage, and transport prior to
final processing.

Sampling concerns can be overcome if the sampling method is known and demonstrated to be capable. Refer to Appendix A for validation sampling guidelines for this category of product.

Periodic Review (revalidation) of Validated Processes and Systems

Routine revalidation is only required for high-risk processes (e.g. sterile/aseptic). The types of processes that are typically involved in routine revalidation include sterilization and aseptic processing (e.g. autoclaves, de-pyrogenation tunnels, steam-in-place systems, and aseptic filling lines).

If Routine revalidation is required, it is typically conducted using a concurrent validation approach. The testing is executed on a preset frequency against a standardized pre-approved protocol or SOP.

If the time for routine revalidation is utilized to make changes to a process or the validated system supporting a process (e.g. change a loading pattern in an autoclave), then the revalidation should proceed in two steps. In this case, the previously validated parameters should be requalified to demonstrate the process has remained in a state of control since the previous re-qualification. Then the changes are made and the process is validated prospectively. The routine revalidation process should be based on conducting at least one validation run. The details of the tests required (for example: load configuration, and container size) should be defined in the routine revalidation procedure.

Release of pre-validation and Validation Batches of Medicinal Products for Commercial Use

Product batches manufactured prior to completion of PV activities may include Demonstration (demo) batches, sometimes called ‘proof of concept’ batches, pre-validation batches, or engineering batches. These are typically manufactured for the purpose of examining a new process or a process with a significant planned change that requires revalidation, to ensure that the process operations are understood and work as planned before beginning production of validation batches.

Demo/engineering batches may also include material produced for clinical/formulation studies, or API batches prepared to enable validation of the Drug Product manufacturing process (prior to preparation of the API validation batches).

Each manufactured batch or campaign of batches must be reviewed individually when determining the suitability of the product for commercial use. It is preferable to pre-plan manufacturing of these batches using normal site change control procedures.

Selection of Critical Process Parameters for Process Validation

A Critical Process Parameter is “a process parameter whose variability has an impact on a Critical Quality Attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.” Identifying the CPPs for a new process is the essential component of defining the process control strategy. Identifying the CPPs is a means of documenting our process understanding. Process validation then confirms that the process control strategy is effective in assuring product quality. Documentation of process knowledge must include justification for the selection of the CPPs and substantiation of the operating ranges for these parameters. This documentation also provides the basis for justifying the critical process steps that must be validated to show consistent control of the manufacturing process.

Two objective criteria must be met for a process parameter to be considered a potential CPP:

– Running the process outside the proven acceptable range for the parameter results in a significant risk of producing material of unacceptable quality;

– The difference in quality is carried through the process to the finished product (intermediate for sale, API, or DP) where it results in the product not meeting one or more p re – determined Critical Quality Attributes.

Semi – Solid Dosage Forms – Critical Process Parameters

Creams/ointments typically contain one or more drug substances dissolved or dispersed in an aqueous, oil, or a suitable base. Creams possess a fluid consistency and have traditionally been called oil-in-water or water-in-oil emulsions. They also could be dispersions of long-chain fatty acids or alcohols that are water-washable or miscible.

Some common manufacturing processes are mixing, heating/cooling, dispersion /homogenization, deaeration, transfer, and other techniques for these viscous substances.

Solid Oral Dosage Forms – Potential Critical Process Parameters

Critical process parameters and critical quality attributes that need to be monitored during process validation for a bulk solid oral dosage formulation depend on its presentation (e.g. compressed tablet, coated tablet, capsule) and its drug release characteristics (immediate release – IR or modified release – MR). The following table of process parameters and attributes can be used as a guide for use in process validation. Each application should be evaluated on a case-by-case basis to determine which parameters and attributes are critical.

Solvent Recovery Validation Example

If the potential for significant variability in the feedstock of the used solvent exists, it is recommended that validation batches be prepared over a significant period of time to encompass the likeliness for variability in the used solvent feedstock. A good practice that has been used is to include validation batches made with an intervening time interval between each, as shown in the example provided later in this guidance (see acceptance criteria section). The increased risk introduced by potential variability in the feedstock is therefore addressed by evaluating more validation batches over a longer time period.

Concurrent validation: Concurrent validation is typically appropriate for solvent recovery validation. Validation may typically be done over an extended period of time rather than necessarily including consecutive batches, and releasing individual solvent batches that meet validation acceptance criteria poses no appreciable risk to customers of our API and drug products (i.e. solvent is a raw material rather than a final product).

Process controls: A computer simulation is sometimes used to predict volumes where fractional cuts in the distillate should be made. The simulation typically uses analytical data from analysis of the used solvent feed batch and known analytical requirements established for the start of each cut. When a simulation is used, it is recommended that the effectiveness of the computer simulation to predict process control points be shown.

Test Deviations during Validation

Deviations may be identified by the tester during the execution of the protocol or by a reviewer. Where a protocol error is identified, it is recommended that the deviation procedure makes a clear distinction between typographical and other minor errors where the intent of the protocol is still clear, and errors that require correction to allow the test to be executed. It is considered acceptable to hand-amend (per applicable site documentation practices) typographical and other minor errors that have no impact on the test method or acceptance criteria. Where correction is required to allow the test to be executed, including determining whether the test passes or fails, then a deviation should be raised.

Document the deviation: The deviation should be documented according to the applicable procedure or protocol. This should include the assignment of a reference number to the deviation, the test section (and run number, where applicable), the test step (where applicable), a description of the deviation, and the signature and date of the person recording the deviation.

Validation Activities during Technology Transfers

Technology transfers of existing APIs or DP processes to a different site often involve a change in registration documentation for the product, to include the new location. This will likely prompt a regulatory inspection at the receiving site and/or regulatory scrutiny (e.g. of analytical methods, critical process parameters, etc.) of the registration documents. Therefore, validation requirements for production and support systems at the receiving site should be considered at an early stage of the technology transfer process. The Site Validation Master Plan should also be updated accordingly.

Validation Considerations for Rework and Re-process of API

To clarify validation considerations for reprocessing and re-work steps, definitions of these terms are listed below:

Re-process introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process.

Continuation of a process step after an in-process control test has shown that the step is incomplete and is considered to be part of the normal process, and not re-processing.

Re-work – Subjecting an Intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain an acceptable quality intermediate or API (e.g., re-crystallizing with a different solvent).

Validation Documentation

A validation planning document should be considered for use for larger-scale projects that encompass multiple systems and processes. A planning document may be a separate document or combined with other documents such as testing or change control documents.

The planning document should contain, or at least reference, the following information, as applicable:

– A description of systems (e.g., system boundaries, system level impact assessments) and/or processes included in the project;

– The validation approach that will be followed;

– Key roles and responsibilities;

– Testing strategy;

– Project documentation requirements; and

– Sequence of activities and execution.

Shipping Validation for Biopharmaceutical Materials

Temperature excursions can occasionally occur as a result of inadequate thermal protection under unexpected or unusual circumstances in routine shipments. Temperatures outside of the allowable shipping range can often be attributed to shipment delays, unanticipated temperature extremes during shipment, or incorrect shipping methods. In addition, the position of primary containers within the shipping container should be carefully considered to prevent unintended warming or freezing as a result of proximity to external conditions or cooling sources.

These factors are typically considered in shipping container selection and designing the qualification study.

Even with careful planning and rigorous qualification testing, excursions may occur from time to time under extreme and unanticipated conditions. Properly placed temperature monitoring devices included in shipments record the severity and the duration of excursions and set the foundation for investigating the root cause and product impact evaluation. The severity and duration of the excursion and the amount of stability data available may dictate the final disposition of the batch.