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APPENDIX A AUDITING CONSIDERATIONS
A1. Introduction
Many excipients are used in food, cosmetic or industrial products as well as in pharmaceuticals. Thus environmental conditions, equipment and operational techniques employed in excipient manufacture are often those of the chemical industry as opposed to the pharmaceutical industry. Chemical processes can produce impurities from side reactions. Careful process control is therefore essential to minimise levels of impurities and contamination.
Excipients are often manufactured on a large scale utilising continuous processing and automated process controls. Production equipment and processes vary depending on the type of excipient being produced, the scale of production and the type of operation (for example batch versus continuous process).
This appendix is intended to aid in the preparation by an excipient manufacturer for an audit. Both external and internal auditors (see also 8.2.2) will find this appendix useful in identifying the significant issues with respect to GMP and quality that require examination. This section will assist excipient manufacturers in identifying the key deliverables when adopting the GMP standards listed in the other sections of this Guide and help in planning an audit to verify the quality of the excipient manufacturing process and the manufacturer’s quality management system.
For additional information on auditing refer to the IPEC-Americas Good Manufacturing Practices Audit Guideline for Bulk Pharmaceutical Excipients. Also for guidance on the auditing process refer to the IQA PQG Monograph No 5 Pharmaceutical Auditing.
A2. GMP Principles
A2.1 Control of impurities and contamination
In general, the pharmaceutical customer does not perform further chemistry or purification steps on the excipient and it is used as purchased. Consequently, impurities present in the excipient are likely to be present in the drug product. Although dosage form manufacturers have some control over excipient quality through specifications, the excipient manufacturer has greater control over the physical characteristics, quality and the presence of impurities in the excipient they produce.
External contamination of the excipient can arise from the manufacturing environment. However, chemical processes used to manufacture excipients are often performed in closed systems that afford protection against such contamination, even when the reaction vessels are not located in buildings. The external environment may require suitable controls to avoid potential contamination wherever the excipient or in-process material is exposed.
A2.2 Excipient properties and functionality
Excipients are frequently used in different types of drug products where physical characteristics, such as particle size, may be important. While the finished dosage form manufacturer is primarily responsible for identifying the particular physical characteristics needed, it is also the responsibility of the excipient manufacturer to control excipient manufacturing processes adequately to ensure consistent conformance to excipient specifications. Wherever possible, consideration should be given to the end use of the excipient. This is particularly important if the excipient is a direct component of a sterile drug product or one that is claimed to be pyrogen-free.
A2.3 Consistency of manufacture and change control
A thorough understanding of the manufacturing process and effective control of change can best assure consistency of excipient quality from batch to batch. Implementation of changes may also have consequences for registration filings with regulatory agencies.
Changes in excipient manufacturing processes may result in changed physical or chemical properties of the excipient that are only evident during subsequent processing or in the finished dosage form. This is particularly important in the context of the pharmaceutical product approval process where bioequivalence comparisons are made between pivotal, clinical trial batch ("bio batch") production and commercial scale-up batches. Changes made to the excipient supplied for the commercial product from the excipient supplied for the bio batch should be such that they do not impact the quality and performance of the commercial drug product. Scale-up of excipients to commercial production may involve several stages and data may be required to demonstrate consistency between batches through the scale-up process.
A2.4 Traceability
Traceability of batch-related records to facilitate investigations and retrieval of product is also a key requirement of GMP.
A3. Application of GMP Principles
It is the responsibility of the excipient manufacturer to designate and document the rationale for the point in the manufacturing process at which appropriate GMP is to be applied. From this point on appropriate GMP should be applied. The manufacturer should apply a level of GMP to each manufacturing stage commensurate with the importance of that step in assuring product integrity. This may be demonstrated by means of the use of a risk assessment procedure (for example HACCP, FMEA).
The stringency of GMP in excipient production should increase as the process proceeds from early manufacturing to final stages, purification and packaging. Physical processing (for example granulation, coating or physical manipulation of particle size such as milling, micronising) as well as chemical processing of excipients should be conducted at least to the standards suggested by this Guide.
It should be recognised that all intermediates might not require testing. An excipient manufacturer should, however, be able to identify critical or key points in the manufacturing process where selective intermediate sampling and testing is necessary in order to monitor process performance.
A4. General Auditing Considerations
Audits of an excipient operation will be influenced by the purpose of the audit and the intended use of the excipient. The key stages of a production process should be examined to determine whether the manufacturer adequately controls these steps so the process performs consistently. Overall, an audit should assess the excipient manufacturer's capability to deliver a product that consistently meets established specifications.
The audit team may consist of engineers, laboratory analysts, purchasing agents, computer experts, maintenance or other appropriate personnel as appropriate to the scope and purpose of the audit. External auditors must respect confidentiality of the manufacturer’s processes and other disclosures.
An audit should focus on the quality-critical processing steps that are necessary to produce an excipient that meets the established physical and chemical criteria. These steps should be identified and controlled by the excipient manufacturer. Quality-critical processing steps can involve a number of unit operations or unit processes.
Quality-critical steps can include, but are not limited to, the following:
• phase changes involving the desired molecule, solvent, inert carrier or vehicle (for example dissolution, crystallisation, evaporation, drying, sublimation, distillation or absorption),
• phase separation (for example filtration or centrifugation),
• chemical changes involving the desired molecule (for example removal or addition of water of hydration, acetylation or formation of a salt),
• adjustments of the solution containing the molecule (for example pH adjustment),
• precise measurement of added excipient components, in-process solutions, recycled materials (for example weighing or volumetric measurements),
• mixing of multiple components,
• changes that occur in surface area, particle size or batch uniformity (for example milling, agglomeration or blending).
A5. Audit Check Points
A good approach for an excipient plant audit is a review of the following areas:
• nonconformances, such as the rejection of a batch that did not meet specifications, customer complaints, return of a product by a customer or retrieval of a product. The manufacturer should have determined the cause of the non-conformance, 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,
• customer complaint files, such as reports that some aspect of the product is not entirely suitable for use, since these may be caused by impurities or inconsistencies in the excipient manufacturing process,
• change control logs to ascertain whether the company evaluates their significant changes to decide if the customer and/or regulatory authority should be notified,
• nonconforming products meeting or Material Review Board documents and/or equivalent records that demonstrate that the disposition of nonconforming product is handled in an appropriate manner by responsible individuals,
• master formula and production records for frequent revisions that may reveal problems in the excipient production process,
• evidence for the presence of unreacted intermediates and solvent residues in the finished excipient,
• materials management systems to ensure adequate control over nonconforming materials so they cannot be sold to customers or used in manufacturing without authorisation,
• review of a process flow diagram to aid understanding of the various processing stages. The critical stages and sampling points should be identified as part of the review of the processing records,
• review of contamination control measures.
In evaluating the adequacy of measures taken to prevent contamination and cross-contamination of materials in the process, it is appropriate to consider the following risk factors:
• the type of system (for example open or closed). Enclosed systems in chemical plants often are not closed when they are being charged and/or when the final product is being emptied. In addition, the same reaction vessels are sometimes used for different reactions,
• the form of the material (for example wet or dry),
• the stage of processing and use of the equipment and/or area (for example multi-purpose or dedicated),
• continuous versus batch production.
A6. Documentation and Record Review
Documentation required for the early steps in the process need not be as comprehensive as in the latter stages of the process. It is important that a chain of documentation exists and that this is complete when:
• the excipient can be identified and quantified for those processes where the molecule is produced during the course of the process. For batch production a theoretical mass balance may also be established with appropriate limits, as deviations from tolerance are a good indicator of a loss of control,
• an impurity or other substance likely to adversely affect the impurity profile or form of the molecule is identified and subsequent attempts are made to remove it.
As chemical-processing proceeds, a chain of documentation should be established which includes:
• a documented process,
• the identification of critical processing steps,
• appropriate production records,
• records of initial and subsequent batch numbers,
• records of raw materials used,
• comparison of test results against meaningful standards.
If significant deviations from the normal manufacturing process are recorded there should be evidence of suitable investigations and a review of the quality of the excipient.
Complete documentation should be continued throughout the remainder of the process for quality-critical processing steps until the excipient is packaged and delivered to the end user. The batch should be homogenous within the manufacturer’s specifications. This does not necessitate the final blending of continuous process material if process controls can demonstrate compliance to specifications throughout the batch.
In order to promote uniformity in excipient GMP inspections the following basic requirements should be established:
• that a unique batch number is assigned to the excipient which enables it to be traced through manufacture to release and certification,
• that suitable controls are in place for the preparation of a batch record for batch processing and/or a production record, log sheet or other appropriate documentation for continuous processing,
• demonstration that the batch has been prepared using GMP guidelines from the processing point at which excipient GMP has been determined to apply,
• confirmation that the batch is not combined with material from other batches for the purpose of either hiding or diluting an adulterated batch,
• records showing that the batch has been sampled in accordance with a sampling plan that ensures a representative sample of the batch,
• records that the batch has been analysed using scientifically established test methods designed to assure that the product meets the established standards, specifications and characteristics,
• adequate stability data to support the intended period of use of the excipient. These data can be obtained from historical data, 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.
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