Goals
When you have completed this unit, you should be able to:
a. Apply the regulatory requirements related to oral dosage forms.
b. Perform an audit of oral dosage forms.
c. Use a range of information tools, from the contents of this unit to the Intranet in support of an audit of oral dosage forms.
d. Recognize compliance or non-compliance of regulations pertaining to requirements for oral dosage forms.
Definitions
Binder: a chemical that acts to hold granules in a tablet together.
Blender discharge: the processed material that is removed from the blender after the processing operation has been completed.
Critical Process Parameter(s): (CCP) a process step, process condition, or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the product meets its specification. The requirements or specifications of a product that can be measured and controlled to produce the desired quality of the product.
Dry Granulation: modification of the powder morphology using dry compaction forces.
Granulation: the process of creating granules.
Granule: a particle that has been mixed or blended to achieve a certain size, shape and composition. The act or process of forming or crystallizing into grains; as, the granulation of powder and sugar.
Oral solid: a dosage form taken by mouth that may include tablets, gelatin capsules, chewable tablets, or a form of sustained release delivery.
Oral solutions: a liquid dosage form taken by mouth containing an active drug product that is given to a patient. It may be a solution, elixir, or a suspension.
Particle size profile: the percentages of different sized particles that make up a passing granulation process
Wet granulation: adding a liquid to a powder that causes particles to bind together through capillary forces.
Explanation of Topic
What is an oral dosage form?
An oral dosage form may be either a liquid or a solid. Each form uses different manufacturing processes and equipment. This is important to an auditor because some items that are critical in one operation may not be critical to another.
Solid dosage form
Solid dosage forms may be:
Ø tablets
Ø gelatin capsules also known as gel caps
Ø capsules
Ø granules
Most solid dose forms usually contain five different types of ingredients. The first, the active pharmaceutical ingredient (API), delivers the therapeutic effect. The second chemical, a binder, is added to the batch to hold the solid (tablet/capsule) together. A disintegrator is added to help the body break down the tablet after administration. A base, which is an inert substance, may be added to provide size and weight to the tablet.
It must be compatible with the active pharmaceutical ingredient and not interfere with the therapeutic action of the active pharmaceutical ingredient. One other ingredient that is normally added is a food grade lubricant that prevents the tablet from being caught or stuck in the tableting press. An optional chemical that may be added is either a dye to give color to the tablet and/or a flavoring.
Equipment and processes used for the various manufacturing tasks should be assessed for validation/qualification and calibration status. Dedicated equipment is preferred, however not required. Either way appropriate measures should be in place for labeling, cleaning and storage, as well as in-use practices to protect the equipment, and ultimately the finished drug product from contamination.
Solid dose manufacturing process
Steps in the manufacturing process for most solid dose products are dispensing (weighing) ingredients, blending/mixing ingredients, dry granulation or wet granulation and drying, compressing/tableting, and in some cases, film-coating and/or tablet printing.
Blending/mixing is a process that mixes dry chemicals together to achieve a uniform mix. To use an analogy, if you bake a cake, this is the same as mixing the dry ingredients together. Examples of some equipment used are ribbon blenders, planetary blenders, or diffusion mixers.
The next step is granulation. Granulation uses the dry mixture from the previous step and converts it into larger particles (granules). Granulation is the modification of the powder through the addition of either a liquid (wet granulation), which causes particles to bind through capillary forces, or dry compaction (dry granulation), which forces the powder into uniform size granules. By making uniform size granules, these will then flow more easily into tableting equipment. Equipment used may be a high shear mixer granulator.
Typically, the liquid used for wet granulation is a solvent or water. The material, be it solvent or water, should be of suitable quality.
When a wet granulation step is audited, you should check batch records carefully against critical process parameters, which include rate and amount of solvent used, and length of granulation time. Following wet granulation, the granulated product is dried in temperature- controlled dryers. There are two processes that are used. The first is to spread the wet granulation onto trays, known as tray drying, and dry it in a carefully controlled oven.
A concern with tray drying is that it does not always assure uniform drying throughout the batch.
The second is to “fluidize” or suspend the wet granulation in air. The fluid bed dryer system is usually more effective in generating a uniform granulate of spherical particles.
The quality of the air supply needs to be checked.
Following drying, the product is blended with lubricating materials and ground into a powder. It is important to note that the lubricant processing step may affect drug availability in the final tablet form, as the release of the active pharmaceutical ingredient in some products is “timed” by varying lubricant blending time and concentration.
The powder blend is then divided into uniform single portions for delivery to patients.
This is known as unit dosing and may be accomplished by compression. The final powder is poured into high-speed compression machine that uses pressure and a punch-and-die system to form and emboss the tablets. The tablet press speed must be controlled, along with the flow of materials into the compression machine. In-process tests, such as thickness, hardness, disintegration and weight, should be performed.
During compression, tablets may be embossed with unique identification symbols/numbers.
Punches should be kept in a locked area and be carefully maintained.
Some tablets may then be coated with a film. This film process uniformly coats or covers the solid dosage form with either a thin transparent layer of a wet chemical (coating) or a capsule. Once the coat is applied, it is then dried. Film coating protects the drug from its surrounding environment (e.g. air, moisture, and light) by improving stability and retaining the potency of the active ingredient.
The length of time the film coating solution can be held and the environmental conditions should be specified in an approved SOP and followed carefully. The coating solution needs to be monitored and tested for microbiological content.
After compression and film coating, if the tablet requires it, unique symbols and numbers may be printed on the tablet.
Encapsulation
Granules or powders may also be filled into hard gelatin capsules. These capsules are usually purchased from an outside vendor. The capsules may be filled using various technologies, which include dosing discs, pelleting equipment or others.
Soft gel capsules require specific equipment and technical development and are performed by specialized contractors.
Completion of manufacturing process
When auditing, ask to see tablets and capsules. The individual dose should be either carved into a tablet or printed on a capsule in addition to an identifying code or name.
The dry bulk tablets/capsules are packed into labeled totes or plastic-lined drums ready for final packaging. Ensure the container is securely closed. If transported from one location to another for further processing, there needs to be tamper evident closure applied to the container.
Solution/Suspension oral dosage form
Oral solutions/suspensions are liquid formulations where the active pharmaceutical ingredient is dissolved in a solvent, along with flavors and preservatives if required. The bulk solution/suspension is filled into finished dose containers, capped and labeled.
For oral solutions/suspensions the order of addition of solid ingredients to the solvent, the temperature at which the solvent should be maintained, the mixing speed and time, the holding time and in process assurance of dissolution, are among the critical process parameters.
For oral solutions, the temperature of both the solution and environment should be controlled to prevent microbial growth and loss of potency. The air should also be controlled and monitored. Liquids may be particularly susceptible to microbial and other contamination. Therefore special measures must be taken to prevent any contamination.
For oral suspensions it is of utmost importance to ensure that the liquid doesn’t segregate.
Appropriate controls should be put in place to ensure homogeneity of batches filled.
Review data that support storage times and transfer operations. There should be established procedures and time limits for such operations to address the potential for segregation or setting as well as other unexpected effects that may be caused by extended holding or stirring.
Oral solutions/suspensions are common for clinical trial material.
Oral solution/suspension dose manufacturing process
Equipment used for batching and mixing of oral solutions and suspensions is relatively basic. Generally, these products are formulated on a weight basis with the batching tank on load cells. The design of the batching tank with regard to the location of the bottom discharge valve may present problems. Ideally, the bottom discharge valve is on level with the bottom of the tank.
Transfer lines are generally hard piped and easily cleaned and sanitized. In some cases manufacturers use flexible hoses to transfer products. Such hoses should be labeled, cleaned and stored in a manner that protects from contamination.
A key aspect in process validation for solutions/suspensions should be to assure that the drug substance and preservatives (if used) are dissolved. Parameters such as heat and time should be measured. Assessment of in-process assay results of the bulk solution during and/or after compounding according to predetermined limits, are also important aspects of process validation. Review the firm’s development data/documentation for their justification of the process.
What should be audited?
An oral solid or oral solution/suspension audit should include an examination of the all of the six GMP Systems:
Ø Quality Ø Facility and Equipment
Ø QA Laboratory Ø Material Handling
Ø Production Ø Packaging and Labeling
This training module will not include detailed information about the Packaging and Labeling system and the Laboratory system for oral dose products. In-process control laboratories are often different from other laboratories and part of the production area and in-process controls may be performed by operators. As an auditor you need to cover these laboratories as including training of the staff.
The audit of the quality system should include a documentation review of deviations, annual product reviews/product quality reviews, change control, product release, documentation management, training/personnel, and consumer complaints in conjunction with the execution of the audit as outlined for oral solids and solutions. The relevant auditor training units should be followed.
Critical manufacturing steps include the selection, weighing, measuring and identifying of components, and addition of components during processing. The manufacturing process should define the parameters for the performance of critical steps (in accordance with the validated manufacturing process). For oral solids, these steps may include amount and order of addition of ingredients to the blender; mixing/blending times; critical process parameters for granulation and drying; tablet press settings and speed; coating solution manufacturing steps and application of coating solution parameters.
For capsules the specific dose template and speed of encapsulation are additional critical process parameters. Each critical step in the manufacturing process should be performed and documented by a responsible individual and checked by a second responsible individual.
Critical Process Parameters for Oral Solutions/Suspensions
a. Order of addition of solid ingredients
b. Maintenance temperature
c. Mixing speed and time
d. Holding time
e. In-process assurance of dissolution
f. Uniformity (potential segregation of suspensions)
Critical Process Parameters for Oral Solids
a. Amount and order of addition of solid ingredients
b. Mixing/blending time
c. Process parameters for granulation and drying
d. Tablet press/compression settings and speed
f. Coating solution steps and process parameters
Critical Process Parameters for Capsules
a. Speed of encapsulation
b. Size of template for doses
Note: The Critical Process Parameters mentioned are generally applicable however, it needs to be considered that development work may have highlighted additional Critical
Process Parameters which have an impact on final quality. The auditor(s) should consider this while assessing the process.
Batch documentation must include the recording of deviations from the approved process (for example: mixing and /or holding times); testing of in-process material; and the determination of actual yield and its percent of theoretical yield.
Sampling
A written sampling plan or protocol derived from validation exercises should be in place to assure batch uniformity and integrity of the drug product. The plan should state how sampling and testing will be conducted, define roles and responsibilities and acceptance criteria. Sampling plans are expected to state how, when, from where, as well as delivery and handling of sampled materials. Precautions to protect sample integrity must be incorporated in the procedures, especially for microbiological test samples.
Sample sizes of the approximate equivalent weight of the dosage unit should be sampled to test for uniformity. Compendial specifications, those specifications found either in
Pharmacopeia/National Formulary and /or the Official Methods of Analysis of the Association of official Analytical Chemists, should be used; however specifications should be tighter where supported by historical data.
Solid Dosage forms
Sampling should be performed at the blending of the granulation stage. The granulation should be sampled and tested for uniformity, potency, and physical characteristics.
Samples should be taken from specific areas of the blender, which have the greatest potential to be non-uniform. If the process calls for large or tumbler type blenders, granulations or blends can be sampled at the time of transferring product or directly from drums the product is transferred into. When sampling from drums, samples from the top, middle and bottom of each drum should be collected.
The physical characteristics that blends should be tested for are particle size and loss-on- drying if the wet granulation process is used. Particle size profiles are used to demonstrate equivalence between batches (comparability). A major physical parameter used to demonstrate equivalence between batches (comparability) is the particle size profile. Particle size profiles are particularly important for tablets made by wet granulation. The size and even the type of granule can affect the pore size in a tablet and have an effect on dissolution. Another test, typically performed on the granulation (particularly when the wet granulation process is used), is loss-on-drying (LOD) and/or moisture content.
Oral solution/suspension dosage form
Liquid products in which the product is suspended present manufacturing and control challenges. Sampling plans should include considerations to assure that separation has not occurred and sample integrity is maintained. Samples should be taken from the beginning, middle and end and should not be composited.
Facilities and equipment
Facilities and equipment should be arranged to provide protection from external influences. This includes the segregation from general traffic patterns for security and product integrity reasons (personnel, material and process flow patterns within the facility).
In-line equipment should be qualified before use according to the firm’s policies and procedures. This includes permanent and/or moveable types of equipment such as air fed suites, metal detectors, monitoring devices. Actions should be defined such as precautionary measures when moving equipment from one location to another, as well as the specifications for cleaning, set-up and use.
Precautions must be taken during manufacturing to control the environment surrounding the manufacturing process in order to protect both the product and personnel. Tablets and capsules are susceptible to airborne contamination because of the manipulation of large quantities of dry ingredients. To prevent cross-contamination, the weighing, mixing, granulation, drying and/or tableting (compression) operations should be segregated and conducted in a closed environment. Air pressure differentials between processing areas should be established to assure containment of materials and to eliminate cross-contamination issues. Temperature, humidity, and dust collection control must be in place and monitored frequently to prevent cross-contamination and possible product quality impact (degradation).
Parts of the production equipment, which contact the product, should not react with, add to, or absorb the drug product. Production equipment should be checked and calibrated at scheduled intervals. All out-of-tolerance results discovered during calibration of critical instruments should result in an investigation. Measuring, weighing, recording and control equipment should be of the appropriate range and precision for the intended operation. Controls should be established to assure the integrity of the punches and dies used in compressing tablets.
All equipment and containers used to manufacture a drug should be labeled at all times.
The label should identify the contents of the container or equipment including the batch number and the stage of processing. If the equipment is “in use” the tags and charts associated with the equipment should indicate the product number, product name and strength and batch number. For reusable equipment/containers, previous labels must be removed or defaced. If reusable filters are part of the equipment ensure they are product specific if needed. Equipment used during the manufacture of a batch should be identified in the batch record.
Equipment and utensils must be cleaned at appropriate intervals to prevent contamination and malfunction. Time limits for cleaning of production equipment after use must be established and followed. There should also be requirements established for re-cleaning of processing equipment after a specific period of disuse.
In different parts of the world certain products, e.g. hormones, may need to be considered differently from a cross-contamination risk. As an auditor you need to review the policy of the company to ensure that handling of potent products has been considered and is handled appropriately to site requirements.
Equipment and containers not in use should be tagged (“clean”, “to be cleaned/dirty” or equivalent wording). Clean tote bins, drums, Glen bowls, fluid beds and other clean equipment should be covered at all times when not in use to minimize potential contamination.
Additionally, requirements should be in place for proper equipment use and maintenance, as well as the performance of failure investigation(s), implementation of corrective and preventative plans, and measures to be taken to recover in the event of a system failure.
For example, the option for manual re-inspection processes should a mechanical system fail.
Material handling
Raw materials should be weighed in a separate area to prevent cross contamination. To prevent cross contamination, air pressure differentials should assure that materials do not migrate outside of weighing area. The air pressure differentials should be documented.
Daily balance checks should be performed on balances used to weigh raw and in-process materials. Pay attention to cleaning procedures between products.
Components and product containers
Written procedures describing how components, drug product containers, and closures are received, identified, stored, handled, sampled, tested, and approved or rejected must be adhered to and available for review. If the handling and storage of components is computer controlled, the program must be validated. Receiving records must provide traceability to the component manufacturer and supplier. In addition, these records should also include the receiving date, manufacturer’s lot number, quantity received, and control number (unique number assigned by the receiving area). The component container should also be identified by this unique identification code (component container units used in the packaging of the batch and documented within the batch record). This unique code provides traceability from the component manufacturer to its use in the finished product .
Line Clearance
Line clearance procedures to avoid product, component, labeling materials, and equipment mix-up are expected to be in place. The intended purpose being to confirm the previous batch materials have been removed, appropriate cleaning has been performed and, with the onset of the next operation, the respective processing area(s) is/are devoid of extraneous materials. It is suggested, that a checklist approach be utilized to document and verify that all mechanical and printing equipment has been broken-down, cleaned, inspected and all previous materials removed. Execution of the checklist should be by an independent person not involved with the cleaning activities.
The checklist must be reviewed and inspected by another individual and final approval granted by Quality Assurance/Control prior to set-up. Quality Assurance/Control is responsible for oversight of line clearance activities.
Process Inspection Controls
Appropriate procedures are to be in place to identify and evaluate in-process materials for defects. Defects should be defined and categorized. Defects and specific acceptance criteria should be defined and utilized based on process validation data. Information obtained from data collection should be tracked and trended.
It is common industry practice to utilize in-line metal detectors to inspect tablets following compression. As part of the initial machine qualification and the resulting specifications that are defined for sensitivity settings, processing settings should be established and challenged during routine production.
Only under controlled conditions should rework/reworking be permissible. The circumstances must be defined, monitored and may require approval for each event.
Each event should be clearly documented and undergo the same review processes as a routine batch. Such events should be as a result of a clearly defined and justified root cause that has had an extensive product impact assessment. It is expected that these types of events are not frequent, are trended and have corrective and preventative actions implemented.
Campaign manufacturing is a common practice. If this practice is considered acceptable controls must be apparent to ensure that if a failure does occur, all batches within the campaign are included in the investigation(s) and product assessment.
Summary
The overview of the auditor’s job during an oral Solid/Solutions Area for each step of the manufacturing process is to verify that:
Ø the appropriate approved SOPs are being followed
Ø the facility is able to prevent cross contamination through personnel controls, design of the facility and equipment including the air handling system.
Ø the process is validated and meets acceptance criteria for critical process parameters.
Ø the data trail is intact with no gaps. This allows authorized individuals to make responsible decisions for release of the product.
Ø appropriate sampling is conducted at the correct stages of production.
Ø all GMP controls are in place and functioning.
Ø all operating personnel understand and are trained in the GMP requirements that pertain to them and perform their job functions accordingly.
Key Parameters in Auditing an Oral Solid/Solution Facility
Prior to the audit
Ø Review product complaints and determine if they are process related. If they are process related, follow up on them during the audit.
Ø Review appropriate Inspection Guidance documents, including the FDA Compliance Program, and other applicable regulatory agency requirements.
Ø Review previous audit reports and actions taken following observations.
Ø Obtain a list of products manufactured at the site. Determine if any of the products are potent and thus a greater risk from cross contamination
Ø Obtain a flow chart for the manufacturing process and identify critical processing steps/areas to focus on during audit.
Ø Obtain a flow chart for the manufacturing facility indicating personnel and material flow.
Ø Select a representative product to be audited, identifying potency and containment requirements.
During the audit
Perform a walk through of the manufacturing area and observe the general appearance (i.e. housekeeping, personnel appearance, personnel flow) of the facility.
Ø Obtain a blank batch record or use the manufacturing process flow chart to follow the process during the walk through.
Ø Observe the manufacturing areas to see if there is any accumulation of product dust in the corridors, on equipment, on window ledges.
Ø Verify that materials are not being stored in corridors outside weighing areas, compression or granulation areas.
Ø Review the construction, size and location of the facilities in relation to the surroundings.
Ø Review the products manufactured and the procedures used for the isolation of processes to prevent contamination.
Ø Verify that cross-contamination measures, e.g. segregated enclosed areas with controlled air handling systems, are in place.
Ø Ensure that dress codes are followed by employees when moving from one processing area to another. These should prevent cross contamination of in- process material and finished product.
Ø Verify that employees move from one process to another without causing cross contamination of product and process materials.
Ø Determine if the manufacturing area is designed to protect in-process materials from cross contamination from other in-process products.
Ø Determine if the manufacturing area is designed to protect in-process materials from contamination from the surrounding environment.
Ø Verify that computer systems used in manufacturing/packaging operations are validated,
When walking through of the manufacturing process, observe and gather specific information about the following:
Ø Equipment
° Verify that it is uniquely identified.
° Verify that cleaning status is identified.
° Verify that clean equipment is stored separately from dirty equipment.
° Verify equipment has been qualified and is in good condition.
° Verify equipment identified in the batch record against field equipment is the same, noting calibration and maintenance status.
° Determine if equipment is used for manufacturing more than one product.
° Determine that equipment is cleaned thoroughly by reviewing the equipment use, maintenance and cleaning log.
° Determine how cleaning is documented.
° Ensure that critical equipment is qualified according to the facility’s established IQ/OQ procedure.
° Ensure that sterilization and cleaning has been validated.
° Review calibration status of balances.
Ø Materials Receiving Area
° Ensure that approved procedures are in place for inspection, sampling, testing and release of incoming materials (raw materials, packaging components, excipients, etc.).
° Confirm, through observation, that procedures are being followed.
° Determine if raw materials, intermediate products, or final products require special storage conditions or handling procedures.
° If special storage is needed, confirm that controls are in place to ensure these conditions are met throughout the holding, manufacturing, packaging, and distribution process.
° Review calibration status of balances in the weighing area.
Ø Utility systems
° Determine what type of water is used in the process and in equipment cleaning.
° Determine if any compressed gases or other utilities are used in the manufacturing process.
° Ensure that if any utilities contact the product they have been qualified.
° Ensure that if filters are used in the process they have been qualified or validated according to the established approved facility procedures.
° Verify that there are air pressure differentials between corridors to process rooms as described in an approved facility SOP and that they are documented.
° Ensure that there are dust filters in place within the air system and that they are regularly maintained and recorded on a preventative maintenance schedule.
° Vacuum system
In the oral solid manufacturing area, observe various process steps and confirm that critical operating parameters are in place, monitored and documented.
Ø Verify that weighing, blending/mixing, granulation, tableting/encapsulation, and coating operations are in compliance.
Ø Determine documentation items to be reviewed based on observations.
Ø Request SOPs and documentation from Facility escort as observations warrant during the walk through.
Ø Review manufacturing procedures, such as blending parameters and tableting rates or speed, granulating parameters, holding times (granulation storage, tablet storage, film coating solution storage), and development data to support a manufacturing process change.
Ø Observe the addition of drug substance and powder components to manufacturing vessels to determine if operations generate dust.
Ø Observe sampling of in-process material. Confirm samples are disposed of and not returned to batch.
Ø Ensure that the batch record being used for the process 1) is concurrent with the process in terms of entries, 2) is the current and approved batch record for the process being performed, and 3) follows good GMP documentation practices.
Ø Determine that the appropriate in-process controls are in place and documented.
Ø Determine if there are any solvents used in the manufacturing and/or cleaning processes and if so, are they recovered for re-use.
Ø Determine if these solvents are reused in the process and if they are checked for quality.
Ø Ensure that the environment surrounding the manufacturing process is monitored.
Ø Rationale for any PAT technologies in use.
In the oral liquid/solution manufacturing area, observe various process steps and confirm that critical operating parameters are in place, monitored and documented and that the process is in control.
Ø Determine if the holding time is realistic from a microbial perspective.
Ø Determine if the solution is bactericidal/bacteriostatic.
Ø Determine if it will support microbial growth.
Ø Determine if a preservative is added.
Ø Assess the filling operation.
Review bulk storage of product.
Ø Determine that storage conditions are within specifications.
Ø Determine what bulk storage holding times are and that data exists to support this holding time.
Ø Identify deviations from any of these specifications.
Review how product is packaged for shipping and storage.
Ø Determine how the product is packed and what materials are used.
Ø Determine if there is container closure data to support each of the packaging configurations.
Ø Refer to Packaging and Labeling auditor training unit for performance of this system’s audit.
Ensure that the quality system is in place.
Ø Verify that the quality unit is consulted for the appropriate approvals concerning SOPs, manufacturing process changes, equipment qualification, and scientific decisions.
Ø Verify that all production personnel have undergone scheduled GMP training and job skills training as established in the facility training SOPS.
Perform a walk through of the in-process quality laboratory.
Ø Identify appropriate Quality Standards, and test specifications for the product being followed.
Ø Ensure that appropriate/ required tests are performed
Ø Ensure that all test results meet the established acceptance criteria.
Ø Ensure that all equipment is within calibration and that methods are validated.
Ø Handling and disposition of samples
Review validation documentation, process documentation, and SOPs.
Ø Determine if the following topics are included in approved SOPs:
° receipt, testing and storage of raw materials
° detailed methods for manufacturing including equipment to be used, identified critical process parameters, acceptance criteria and specifications.
° maintenance schedule and cleaning of both electronic (computer) and process equipment, including detailed methods of cleaning and testing, cleaning schedule for non-dedicated equipment, cleaning schedule for equipment used in campaigns, post cleaning testing for equipment release.
° a detailed method for performing and documenting investigations of manufacturing excursions
° a documented method for making changes in either manufacturing equipment or manufacturing processes (i.e. an approved change control procedure).
° sampling of in-process material including the method, frequency and quantity of samples.
° record retention policy for manufacturing and testing records.
Ø Compare the approved, validated process record to the Master Formula
Record and to the current Batch Record to identify any discrepancies
Ø Determine if the facility is following their SOPs.
Ø Using the development report for the specific product you are following, review the key decisions and rationale behind the determination of physical/chemical specifications for raw materials, selection of manufacturing equipment, choice of manufacturing process, in-process controls, and finished product specifications.
Ø Review equipment cleaning validation and cleaning methods performance documentation.
Ø Review personnel training records for GMP training and job skills training.
Ø Use of IPC charts and personnel’s authority levels to change settings on equipment if needed to bring the process back in line.
Ø Mix-up prevention SOPs