Production and Process Controls_2021.pdf

PRODUCTION AND PROCESS CONTROLS [email protected] PRODUCTION SYSTEM The Production System Includes: ❖ measures and activities that control the manufacture of in-process materials and the final drug products ❖ establishing, following, and documenting the performance of approved manufacturing pro...

PRODUCTION AND PROCESS CONTROLS [email protected] PRODUCTION SYSTEM The Production System Includes: ❖ measures and activities that control the manufacture of in-process materials and the final drug products ❖ establishing, following, and documenting the performance of approved manufacturing procedures Typical Pharmaceutical Manufacturing Operations 1. Written procedures and deviations 2. Charge-in of components Production and Process Controls 3. Calculation of yield 4. Equipment identification 5. Sampling and testing of in-process materials and drug products 6. Time limitations on production 7. Control of microbiological contamination 8. Reprocessing Written procedures and deviations  Written procedures for production and process control are designed to assure that the dosage forms have the identity, strength, quality, and purity they are represented to possess.  These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality assurance (QA) unit-QA is not expert in each area of the operation.  QA would be to confirm this review by a responsible person and to further review the document for possible adverse impacts on quality and safety Written procedures and deviations  Written production and process control procedures are followed in the execution of the various production and process control functions-Bath manufacturing Records (BMRs)  Documentation at the time of performance. Any deviation from the written procedures shall be recorded and justified  Written standard operating procedures (SOPs) define how things are to be done and provide a basis for the training of new or relocated personnel. Having provided written and approved procedures, the next (and more difficult) stage is to ensure that they are followed. Written procedures and deviations This involves training and verification steps. Employees must be given training in all relevant procedures. This should include an understanding and awareness of the purpose of the procedures and why they need to be followed. As with all training, it should be confirmed that the employee has actually learned the relevant information and there should be a record of the successful completion of the training Written procedures and deviations  A combination of some, or preferably all, of the following approaches provides data on compliance: ✓ Regular monitoring of compliance by supervisors and managers as they do their daily work-informal but it allows immediate identification and correction of potential compliance problems- further demonstrates to employees that management does consider compliance to be important. ✓ A more systematic review of compliance can also be performed by supervisors and managers on a less frequent basis—perhaps monthly. This again would be done by comparing actual activities with written procedures. This more systematic approach ensures that no department, process, or shift is ignored. Written procedures and deviations ✓ QA, along with departmental management, performs an audit of each function. A written report should be issued and if possible any deficiencies should be quantified thereby allowing trends to be monitored. Management would be expected to evaluate the audit report, identify the root causes of any noted deficiencies, and to specify appropriate corrective action. Written procedures and deviations ✓ Independent audit from outside of the plant adds another level of review. This is similar to three above but may involve personnel from another facility or corporate staff. Also included in this category are regulatory audits such as those by SAHPRA and FDA. ✓ The routine quality assurance check of batch records also provides basic information on compliance. This should also be used to review deviation frequency, evaluation, and corrective action and to confirm compliance with registration data. Written procedures and deviations The persistent finding of noncompliance issues by QA should signal that management is not giving enough attention to the subject, that training is not adequate, or that procedures are too complex. QA should then work with the appropriate managers to identify the causes and to initiate corrective action. Written procedures and deviations THE COMPUTERIZATION OF PROCESS DOCUMENTATION CAN IMPROVE THE EFFECTIVENESS OF COMPLIANCE. THE PRODUCTION SYSTEM CAN BE DESIGNED SO THAT ONE STAGE HAS TO BE COMPLETED AND ANY RELEVANT DATA ENTERED INTO THE COMPUTER BEFORE THE NEXT STAGE CAN BE INITIATED. PROCESS CONTROL LIMITS CAN ALSO BE INCLUDED AND ANY ATYPICAL RESULTS CAN BE MADE TO AUTOMATICALLY INITIATE MANAGERIAL REVIEW. It would be difficult, if not impossible, to draft an operating procedure that will meet all circumstances.  On occasion, deviations from the defined procedure will occur or will be necessary (for example, to evaluate a change). There are usually two types of deviations: planned or unplanned. ❖ Planned deviations may be permitted provided there is a planned deviation system that allows for the appropriate documentation and approvals (including QA) prior to execution. ❖ Unplanned deviations can be accidental or deliberate.  Written procedures and deviations Written procedures and deviations    In either case, an investigation is typically performed, potential impact on involved batches is determined, and corrective and preventative action (CAPA) generated. CAPA could include procedural modification or personnel discipline. Obviously, in an effective compliant operation, deviations should not be a common occurrence. However, a review and appraisal of changes to production and process control procedures should be considered in the broader concept of a change control. The Change Control Process A consistent achievement of product quality is dependent on the availability of defined/ approved/validated procedures and the application and adherence to these procedures by trained personnel-important to evaluate change potential impact and where necessary provide appropriate evaluation and/or actions. Change control process is a proactive management system that facilitates a review of any proposed change and monitors the impact of the change. The system should prevent changes that could adversely affect product quality or conflict with regulatory requirements. The Change Control Process Charge-in of components-key points (a) The batch shall be formulated with the intent to provide not less than 100% of the labelled or established amount of active ingredient. (b) Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:  (1) component name or item code,  (2) receiving or control number,  (3) weight or measure in new container,  (4) batch for which component was dispensed, including its product name, strength, and lot number. Charge-in of componentskey points (c) Weighing, measuring, or subdividing & dispensing of components  Manual operation: ✓ Each container of component dispensed to manufacturing shall be examined by a second person to assure that: (1) The component was released by the quality control unit. (2) The weight or measure is correct as stated in the batch production records. (3) The containers are properly identified.  Automated equipment Operation: ✓ Requires only one person to verify these operations and assure (c)(1)(3) (d) Component addition: (e.g., order of addition) Charge-in of componentskey points  Manual Operation: Require one person to add and a second to verify  Automated equipment Addition: Require one person to verify  The requirement to “formulate with the intent to provide not less than 100% . . . of the active ingredient” requires some explanation.  Most active ingredients show assay results that are not exactly 100%.  With inherent errors in analytical methodology in the order of 1% to 2%, it is not possible to precisely determine the “true” assay value. Consequently, it is acceptable to use material that is within the acceptable specification without specific adjustment to accommodate batch analytical variations.  Requires determination of actual yields and %theoretical yield ✓ at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product.  Yield calculations ✓ performed by one person ✓ independently verified by a second person  Yield calculations by automated equipment ✓ independently verified by one person Calculation of Yield-key points Calculation of Yield-key points On the basis of historical data, an acceptable range for actual yield at each appropriate stage can be calculated. This range is sometimes set so that 95% of batches produced will fall within the range when the process is operating correctly. The purpose of this is to alert management to atypical situations that may require investigation. Low yields may not only signal potential problems, but also indicate opportunities for process improvement with subsequent cost benefits. (a) Requires proper identification (ID) of all equipment at all times during production Equipment identificationkey points ✓ compounding and storage containers ✓ processing lines ✓ major equipment to indicate their contents and the phase of processing of the batch when necessary  This regulation requires that all equipment and lines always bear a label showing their status: ✓ clean, to be cleaned, or with the product name and lot number and, if necessary, the phase of processing.  The labelling of containers of material in process should clearly define the product, batch number, and state of processing (e.g., granule, bulk tablet, etc.). Where several containers are involved, they should be numbered sequentially. This is of particular value in the event that a problem is later identified and needs to be investigated. Equipment identification-key points (b) Requires identification and recording of a major equipment by a distinctive ID number or code in the batch production record ✓ to show the use of a specific equipment for manufacture of each drug product batch ✓ ID by equipment name allowed in lieu of a distinctive ID number or code if only one of a particular type of equipment exists in a facility  The intent of this subsection is to allow identification, at some future date, of the specific piece of equipment involved. This is particularly appropriate where a manufacturer may have several different pieces of the same equipment, which may not behave identically. If the manufacturer has only one piece, then reference by name alone will suffice. Sampling and testing of in-process materials and drug products-key points (a) Requires establishing and following written procedures  To assure batch uniformity and integrity of drug products  That describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of inprocess materials of each batch  To monitor the output and validate the performance of those manufacturing processes responsible for causing variability in the characteristics of in-process material and the drug product Sampling and testing of in-process materials and drug products-key points (a) Requires establishing and following written procedures  Such control procedures shall include, but are not limited to, the following (characteristics), where appropriate: (1) Tablet or capsule weight variation (2) Disintegration time (3) Adequacy of mixing to assure uniformity and homogeneity (4) Dissolution time and rate (5) Clarity, completeness, or pH of solutions (6) Bioburden/microbial testing Sampling and testing of in-process materials and drug products-key points (b) Requires establishing valid in-process specifications for such characteristics that ✓ are consistent with drug product final specifications ✓ are derived from previous acceptable process averages and process variability estimates where possible ✓ are determined by the application of suitable statistical procedures where appropriate. ➢ Examination and testing of samples shall assure that the drug product and in-process material conform to specifications. Sampling and testing of in-process materials and drug products-key points (c) Requires testing of in-process materials for identity, strength, quality, and purity as appropriate Requires QA to approve or reject the in-process materials during the production process, e.g. ✓ at commencement or completion of significant phases ✓ or after storage for long periods (d) Requires identification and control of the rejected in process materials under a quarantine system ✓ designed to prevent their use in manufacturing or processing operations for which they are unsuitable  ✓  ✓   Requires to establish time limits for the completion of each phase of production when appropriate to assure the quality of the drug product. Any deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. The main purpose of this regulation is to indicate that certain processes are sufficiently sensitive that time limits need to be established for their completion. This could be especially important for: Time limitations on production-key points  a. Material vulnerable to microbial attack-bulk injections are usually required to be filled into the final container within 48 hours-microbial contamination could result in high levels of pyrogens.  b. Materials subject to oxidation may be protected with nitrogen. Effective nitrogen protection may be difficult at the bulk stage; also, failure of the nitrogen system could result in batch rejection.  c. Tablet granulations or other bulk solids may absorb or release moisture on storage, making them more difficult to process or even accelerating decomposition. Time limitations on production-key points Control of microbial contamination-key points (a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.  The USP 29 General Information chapter <1111> Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use addresses total plate count criteria for bacteria and yeasts/moulds. (b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.  VALIDATION OF ASEPTIC PROCESSING ✓ Treatments of product components and processing equipment to remove particulate matter, sterilize, and depyrogenate are critical for effective aseptic processing ✓ Environmental qualifications (Air quality, people, time limitations, product filtration)media fills  VALIDATION OF ETHYLENE OXIDE STERILIZATION-clean room garments  VALIDATION OF RADIATION STERILIZATION Control of microbial contaminationkey points Reprocessing-key points (a) Requires establishing and following procedures Prescribing a system for reprocessing batches that do not conform to standards or specifications Steps to ensure that the reprocessed batches will conform with all established standards, specifications, and characteristics (b) Reprocessing shall not be performed without the review and approval of the QA department. Process Validation-Will be covered later  The FDA in “Guidelines on General Principles of Process Validation” defines process validation as “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.”