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Prevention of Contamination— In evaluating the adequacy of measures taken to prevent contamination of materials in the process, it is appropriate to consider the following factors:
  • Type of system (e.g., open or closed. Closed systems in chemical plants are often not closed when they are being charged or when the final product is being emptied. Also, the same reaction vessels are sometimes used for different reactions)
  • Form of the material (e.g., wet or dry)
  • Stage of processing and use of the equipment and/or area (e.g., multi-purpose or dedicated)
  • Continuous versus (discrete) batch production.
Other factors that should be considered in evaluating an excipient plant are the degree of exposure of the material to adverse environmental conditions, the potential for cross-contamination from any source, the relative ease and thoroughness of clean-up, and sterile versus nonsterile operations.
Documentation— An excipient manufacturer should recognize the need for appropriate evaluation and utilization of proper standards and test procedures for raw materials before they are introduced into the process. In addition, as chemical processing proceeds, a chain of documentation should be established that includes the following:
  • A written process
  • Identification of critical processing steps
  • Appropriate production records
  • Records of initial and subsequent lot or batch numbers
  • Records of raw materials used
  • Intermediate test results with meaningful standards.
The production of some excipients involves processes in which chemical and biochemical mechanisms have not been fully characterized; therefore, the methods and procedures used in their production will often differ from those applicable to the manufacture of finished dosage forms.
It should be recognized that all intermediates need not require testing. An excipient manufacturer should, however, be able to identify critical or key points in the process where selective intermediate sampling and testing is necessary in order to monitor process performance. The records should become more complete as the end of the process approaches. The finishing steps and packaging steps should be conducted under appropriate conditions to avoid contamination and mix-ups and be appropriately documented.
Inspection of an excipient operation may depend on the purpose of the audit and intended use of the excipient. Operational limitations and validation of the significant processing steps of a production process should be examined to determine that the manufacturer adequately controls steps to ensure that the process performs consistently. Overall, an inspection should determine the excipient manufacturer's capability to deliver a product that consistently meets the specifications listed in the marketed application or the product specifications needed for research purposes. A team consisting of auditors, engineers, laboratory analysts, purchasing agents, computer experts, or other appropriate personnel should participate in the inspection when resources permit. Confidentiality of the manufacturers' processes must be respected by external auditors.
A good starting point for an excipient plant inspection is a review of the following areas.
  • Nonconformance—This could be because of the rejection of a lot or batch that did not meet specifications, customer complaints, return of a product by a customer, or recall of a product. The cause of the nonconformance should have been determined by the manufacturer, a report of the investigation prepared, and subsequent corrective action initiated and documented. Records and documents should be reviewed to ensure that nonconformances are not the result of a poorly developed or inconsistent process.
  • Complaint files—Customers may report some aspects of product attributes that are not entirely suitable for their use. These may be caused by impurities or inconsistencies in the excipient manufacturing process.
  • Change control logs
  • Material Review Board documents or equivalent team reports
  • Master formula and lot or batch production records—Frequent revisions may reveal problems in the excipient production process.
  • Specifications for the presence of unreacted intermediates and solvent residues in the finished excipient
  • Storage areas for rejected products.
Significant Processing Steps
Significant processing steps are those steps that are required to produce an excipient that meets the established physical and chemical criteria. These steps should be identified by the excipient manufacturer. Significant processing steps can involve a number of unit operations or unit processes. Unit operations include physical processing steps involving energy transfer where there is no chemical change of the molecule. Unit processes include those processing steps wherein the molecule undergoes a chemical change.
Significant processing steps can include, but are not limited to, the following:
  • Phase changes involving either the desired molecule, solvent, inert carrier or vehicle (e.g., dissolution, crystallization, evaporation, drying, sublimation, distillation, or absorption)
  • Phase separation (e.g., filtration or centrifugation)
  • Chemical changes involving the desired molecule (e.g., removal or addition of water of hydration, acetylization, formation of a salt)
  • Adjustments of the solution containing the molecule (e.g., adjustment of pH)
  • Precision measurement of added excipient components, in-process solutions, recycled materials (e.g., weighing, volumetric measuring)
  • Mixing of multiple components
  • Changes that occur in surface area, particle size, or lot or batch uniformity (e.g., milling, agglomeration, blending).
Documentation and Record Keeping
Documentation required for the early steps in the process should provide a chain of documentation, but need not be as comprehensive as in latter parts of the process. The minimum documentation that should be applied in order to promote uniformity in excipient GMP inspections is:
  • the assignment of a unique lot or batch number to the released or certified excipient
  • the preparation of a lot or batch record
  • demonstration that the lot or batch has been prepared using GMP guidelines from the processing point at which excipient manufacturing practices have been determined to apply
  • demonstration that the lot or batch is homogeneous within the manufacturer's specifications (This does not necessitate final blending of continuous process material if process controls can demonstrate compliance to specifications throughout the lot or batch.)
  • demonstration that the lot or batch is not commingled with material from other lots or batches for the purpose of either hiding or diluting an adulterated batch
  • demonstration that the lot or batch has been sampled in accordance with a sampling plan that ensures a representative sample of the lot or batch
  • demonstration that the lot or batch has been analyzed using scientifically established tests and methods designed to ensure that the product meets standards, specifications, and characteristics
  • demonstration that an excipient has stability data to support the intended period of use. (These data can be obtained from actual studies on the specific excipient or from applicable model product studies that can reasonably be expected to simulate the performance of the specific excipient.)
Complete documentation should exist when:
  • the excipient can be identified and quantified for those processes where the molecule is produced during the course of the process (In this regard, a theoretical yield should be established with appropriate limits, and there should be an investigation if the actual yield falls outside the limits.)
  • a contaminant, impurity, or other substance likely to adversely affect the purity or form of the molecule is identified and subsequent attempts are made to remove it
  • any significant aberration occurs outside of the normal manufacturing process.
Complete documentation should be continued throughout the remainder of the process for all significant processing steps until the excipient is packaged and transported to the end user.
Product Lot or Batch Consistency and Audit
Excipient manufacturing plants often produce laboratory or pilot lots or batches. Scale-up to commercial production may involve several stages, and data should be reviewed to demonstrate the adequacy of the scale-up process. Scale-up may introduce significant problems in consistency among lots or batches. Pilot lots or batches should serve as the basis for establishing in-process and finished product purity specifications.
Typically, manufacturers will generate reports that discuss the development and limitation of the manufacturing process. Summaries of such reports should be reviewed to determine if the plant is capable of adequately producing the excipient. The reports, where appropriate, serve as the basis for the validation of the manufacturing and control process, as well as the basic documentation to demonstrate that the process performs consistently.
A review of a process flow chart is helpful in understanding the various processing stages. As part of the review of the processing records, the critical stages and sampling points should be identified. The normal limits from in-process testing should be determined, along with the action to be taken by the manufacturer should these specifications not be met. For example, an in-process test result may show the presence of some unreacted material which may indicate that the process time should be extended.