Release Assessment Of Sterile Pharmaceutical Manufacturing Processes

Release is the final step in the pharmaceutical manufacturing process. For the release process of sterile drugs, more attention should be paid to the level of microbial control in the production process. This article starts with the main contents of inspection during release assessment and the key points of sterile drug production such as raw materials and excipients, process product control, production environment monitoring, bioburden and endotoxin control of pharmaceutical water, etc., and details the key points that should be paid attention to in the release of sterile drugs. All aspects of the process, in order to effectively improve the sterility assurance level of the sterile drug production process.

Part 1 Introduction

Batch release is the process of reviewing and approving all pharmaceutical production and control records. It is the final link in the production process and the last step to prevent substandard products from entering the market. Batch release shall be the responsibility of the quality department to determine compliance with all established and approved written procedures. Along with assessing whether a product is effective, sterile product evaluation also poses additional issues. The presence of microorganisms in sterile pharmaceutical preparations may reduce their effectiveness or render them hazardous to consumers. The severity of the consequences of the presence of microorganisms in sterile pharmaceutical preparations varies depending on the purpose of the preparation and the route of administration. Microbial contamination of sterile products is related to the degree of control of contamination risks in the entire process of production and use. Therefore, it is important to evaluate the control factors that may affect sterility assurance in the batch release process.

According to my country’s GMP regulations, each batch of drugs should be signed by the quality authorized person for approval and release [1]. The quality authorized person shall bear the responsibility of the person responsible for release. The person responsible for release is a position with great responsibility, especially for sterile drugs. Depending on the type of product, it is necessary to have rich professional knowledge and experience in chemistry, biology, and understanding of the production and manufacturing process. Before release, the person responsible for release should fully evaluate the sterile drug production records, production process monitoring data and inspection results to ensure that the entire drug production process meets the requirements of GMP regulations and that product quality meets corporate or pharmacopoeia standards. This article details the matters that should be paid attention to in the release of sterile drugs from the main contents of inspection during release evaluation and key points in the production of sterile drugs.

Part 2 Main Contents That Should Be Confirmed When Evaluating Sterile Products For Release

As part of the release review, the person responsible for release should conduct the following inspections of each batch of records:

•Check that all records are complete, including attached documents, signatures and dates;

•Ensure production batches are within approved batch ranges;

•Check whether the calculation is carried out according to the determined formula. Check whether the calculation results are executed correctly;

•During the document review process, ensure that the approval boxes are completed and signed for confirmation;

• Confirmation that the operator has signed off confirming that a step has been completed, but is not an independent verification that a step has been completed;

•Ensure that all modifications and corrections comply with Good Manufacturing Practice requirements;

•Check whether the label sample prints clearly and whether the dosage shown is correct;

•Check the authenticity of intermediate records when they are filed elsewhere;

•Any controllable changes have been taken into account;

•Any additional sampling, testing, inspection or investigation has been conducted or initiated;

•Check whether the finished product test results meet the requirements;

•Reported deviations in records have been investigated and corrective and preventive actions taken;

•The batch number, quantity, production date and expiration date of this batch of products.

Part 3 Specific Points To Pay Attention To When Releasing Sterile Drugs

(1) Raw and auxiliary materials. The quality of raw materials and excipients must be evaluated to confirm that they come from approved suppliers (in compliance with pharmacopoeia standards), and that the raw materials have been correctly received, sampled and tested by the company, and meet the quality standards determined by the supplier and manufacturer. In terms of sterility assurance, microbial limit testing should be covered. Only raw and auxiliary materials that have passed the test can be used in product production.

Raw materials and excipients generally include receipt, storage, use and other links. The release process should pay attention to each link, focusing on: the name and quantity of each batch of raw materials, intermediates or packaging materials; the name of the supplier and relevant qualification documents; supplier control Number or other identification number; internal number of the material; date of receipt; records of material use; inspection of raw and auxiliary materials through QC; documents of inspection and review of materials meeting established specifications; handling of unqualified raw materials, intermediates or packaging materials wait.

(2) Process product control. An important feature of sterile pharmaceutical production is the microbiological monitoring of the product at different stages of the production process. While this monitoring may not be directly related to the probability of sterility or non-sterility, this monitoring is a good indicator of whether something is or may be going wrong. Here, time limits should be established and justified for each processing stage between the initial synthesis of raw materials and final sterilization.

Monitoring content should include: microbial limits and bacterial endotoxin monitoring of incoming pharmaceutical ingredients and packaging ingredients; in-process bioburden monitoring using total bacterial count (TVC) technology; pre-sterilization filtration bioburden monitoring; disinfectant effectiveness testing, Includes testing for drug-resistant strains.

In terms of batch release, it is necessary to confirm that sampling has been carried out according to the pre-approved sampling plan and that all test methods should be validated. Any out-of-limit or out-of-trend results are evaluated and the impact on the batch evaluated.

In addition, records should detail: materials were used in the correct order; the length of time required for materials to be mixed and agitated; and how long equipment or products were kept clean to ensure they were used within the effective time.

The following should also be evaluated as part of intermediate production: the name, batch number or code of the intermediate; a complete list of raw materials and intermediates; the exact quantity or proportion of each raw material or intermediate, including units of measurement.

In addition, the following should be detailed in the batch records: the procedures to be followed; the range of process parameters used; methods or reference methods used for critical equipment preparation (such as cleaning, assembly, etc.); sampling instructions and process controls, if necessary List acceptance criteria; time limits for completing individual processing steps and/or the entire process; expected yield ranges, etc.

(3) Environmental monitoring and assessment. Environmental monitoring is an important means of assessing whether environmental quality within pharmaceutical facilities can be effectively controlled. A plan should be developed and approved for environmental monitoring of the sterile production process. The formal plan should include monitoring of planktonic bacteria, settled bacteria, suspended particles, and the hygiene conditions of staff and surface microorganisms in facilities and equipment. The location of sampling (monitoring points) should be evaluated and generally selected as a location that may be detrimental to product production. For abnormalities in environmental monitoring data, deviation investigations must be conducted to determine the root cause and take corresponding corrective and preventive measures. Especially when the A-level area exceeds the standard, detailed evaluation is required to determine whether the batch is suitable for release. Before release review, it should be confirmed that environmental monitoring has been carried out according to the plan.

Environmental monitoring generally uses the following methods to take samples:

① Passive air sampling: settling dish;

②Active air sampling: volumetric air sampler;

③Surface sample: contact (RODAC) dish;

④ Surface sample: swab;

⑥Finger plate (required by personnel engaged in filling work);

⑦Sleeves/blouse panels (required for staff participating in filling activities);

⑧Particle counting.

Environmental monitoring should be carried out throughout the entire aseptic filling process. Batch-related monitoring not only includes the filling period, but also includes the following stages: preparation stage; filling stage, and post-filling monitoring of key surfaces of the filling machine (including filling pumps, filling needles, etc. that are in contact with the liquid) ).

(4) Bioburden and endotoxin control of pharmaceutical water. As pharmaceutical water is the most widely used substance in general sterile drugs, especially injections, appropriate preparation, storage and distribution methods should be adopted to ensure that endotoxins are always at the specified level during use. Circulatory systems and user points of use require regular monitoring of endotoxin and microbial loads. For example, the FDA stipulates that the endotoxin concentration is <0.25EU/mL, the microbial load concentration is no more than 10CFU/100mL (using R2A agar as the culture medium, using membrane filtration method), and heat-resistant bacteria are not allowed to be detected.

Various controls should be in place around the water system. If any control failure occurs, the risk should be assessed as soon as possible. Usually water system records are not included in batch production records, but the batch record review process should fully understand any deviations in the water system during the production process, and evaluate the impact of deviations on the production process and product quality, especially related to the risk of endotoxin contamination. Influence.

(5) Quality control (QC) inspection. The specific items and methods of QC inspection should be determined according to the type and nature of the product and relevant regulations, and inspection records for this variety of products should be established. Inspection records should include the following:

① Complete data of all tests conducted to ensure compliance with established specifications and standards;

② The samples received for testing should be described, including the name or source of the material, batch number, and manufacturer and/or supplier;

③ Reference basis for test methods;

④ A description of the sample weight or dimensions used in each test, as described in the method;

⑤ The preparation and test data of all reference standards, reagents and standard solutions must be provided;

⑥All complete original records generated during the inspection process should be fully archived;

⑦Records of all calculations related to the test, such as measurement units, conversion factors and equivalent factors;

⑧ Statement of test results and how they compare to established acceptance criteria;

⑨ Reasons for any modifications to established analytical methods need to be provided;

⑩OOS investigation.

(6) Sterilization and depyrogen control. Sterilization or depyrogenation needs to be considered at different stages of the aseptic production process. Some operations are performed during the production process, and some are directly purchased sterile raw and auxiliary packaging materials. For sterile primary and secondary packaging materials, the inspection certificate provided by the supplier must be evaluated to determine the effectiveness of sterilization. In addition, pharmaceutical manufacturers should supervise and evaluate the manufacturing and sterilization effects of sterile products undertaken by suppliers through supplier audits.

For sterilization and depyrogenation processes performed during production, the batch release process must include the evaluation of all control parameters. These processes involve containers, vials, stoppers, etc. For terminally sterilized products, sterilization is performed on the finished product. Importantly, sterilization records should be used for each sterilization run and should be approved as part of the batch release process.

This process is necessary to inactivate endotoxins under depyrogenation. For products that are aseptically filled using glassware, depyrogenation using a dry heat tunnel oven is a critical part of the process. The regulatory standard for FDA endotoxin deactivation (depyrogenation) process verification is to pass the endotoxin challenge test, that is, the temperature of the depyrogenation oven and the residence time of the equipment in the oven must be within the control parameters (generally should be greater than 250°C, 30min), can reduce high-dose endotoxin (>10,000EU/device) containers by 3 log10. USP’s newly released “DRY HEAT DEPYROGENATION” has revised the standard for depyrogenation, that is, endotoxins in processed samples should not exceed 0.1EU.

With moist heat sterilization, the most basic requirement associated with autoclave operation is to ensure that air is removed from the sterilizer prior to sterilization, as hot air is a very poor medium for achieving sterility. Therefore, sterilization failures in autoclaves with porous loads are almost always due to air being trapped in the load. Another area to evaluate is ensuring the load is dry; a wet load due to steam quality issues is a sign of non-sterility.

In addition, many companies have used a large number of sterile disposable plastic equipment to reduce various risks caused by the sterilization process on the premise of meeting compatibility.

(7) Sterile filtration. Unlike the process of inactivating microorganisms through high temperatures, filtration is a method of reducing microbial load through “removal.” Filtration is often performed at different stages of the sterile product manufacturing process. For products with aseptic filling, filtration sterilization is usually used as the last step before filling semi-finished products. Filtration methods have been widely used in the production of sterile liquid preparations and in the aseptic processing of gases.

An important prerequisite for filtration is to conduct porosity and integrity testing of filter membranes, filter elements, etc. The currently commonly used sterile filter element has a pore size of 0.22μm [2], and the integrity testing methods mainly include bubble point detection, forward flow detection and water intrusion detection. Common main causes of filter failure are: incorrect shell assembly (high frequency); defective or defective filter elements; membrane failure (low frequency); microbial growth in the filter itself.

(8) Biological purification. Equipment such as isolators used for aseptic filling should be biologically decontaminated. The most common method is to use hydrogen peroxide vapor. Since hydrogen peroxide vapor has no penetrating ability, EU regulators do not classify it as a disinfection process.

Vaporized Hydrogen Peroxide (VHP) is a commonly used isolation technology. A common VHP preparation method is to vaporize liquid hydrogen peroxide (at 120°C) to obtain a mixture of VHP and water vapor. As a “drying” process, the concentration of VHP is maintained below a given condensation point, which depends on the area temperature. Compared with other gas detergents, hydrogen peroxide decomposes into water and oxygen, which is safer and leaves no residue during the purification process.

The selection of a VHP method must take into account the physical properties of the equipment being purified, which generally require it to be relatively smooth, impermeable to water, and shaped to allow all surfaces to be exposed to steam. Key parameters evaluated include hydrogen peroxide vapor concentration, humidity, temperature and vapor residence time.

(8) Deviation. Generally speaking, the approved process should be strictly followed during the production process, and deviations from the process procedures or SOP should be avoided as much as possible. Any deviation from the original production process, quality standards, operating procedures, etc. should be truthfully recorded, and a detailed investigation should be carried out to evaluate the impact of the deviation on the quality of the produced products. At the same time, a detailed investigation should be conducted to find out the root cause of the deviation and take measures. Appropriate corrective and preventive measures to avoid recurrence of this situation.

(9) Other aspects. In addition to the above key concerns, other factors affecting the filling process need to be considered, especially those aspects that may affect the assessment of sterility assurance, such as shutdown records, production line cleaning records, equipment and room cleaning records and equipment calibration status, any impact on production Process changes, etc.

Part 4 Batch Record Management

Like other documents that make up the quality system, pharmaceutical batch records should comply with GMP principles. This philosophy refers to the use of clearly written procedures designed to prevent errors and allow tracking of all activities related to the production, testing and release of pharmaceutical products. To do this, the design, preparation, review and distribution of batch records must be managed in a controlled manner.

Furthermore, the document must have clear content: the title, nature and purpose should be clearly stated. They must be placed in an orderly manner and easy to inspect. Copied documents must be legible. As part of the process, documentation must be regularly reviewed and evaluated and kept up to date. When a document is revised, the system must be operated to prevent inadvertent use of the superseded document (ie, only the current document can be used).

Batch records should be legible and recorded on suitable indelible media. Sufficient space must be provided for the record. Any corrections made to batch records must be signed and dated, and the correction must permit reading of the original information. Normally, the reason for the correction should be documented. Records must be maintained for each action taken so that all activities related to preclinical research, clinical trials, and the production and control of the product are traceable.

Where records are in the form of digital data, key records should be stored securely. That is, stored in a secure system with limited access only to authorized personnel. The storage location must ensure adequate protection against loss, destruction or counterfeiting, as well as damage due to fire, water, etc. At the same time, data should be backed up using tapes, microfilm, paper copies or other methods to ensure data security and facilitate access.

Part 5 Conclusion

Microbial control of sterile drugs is related to the final quality and safety of drugs. my country’s “Measures for the Supervision and Administration of Drug Production” lists sterile drugs as high-risk varieties and requires relevant drug supervision and administration departments to conduct compliance inspections of drug production management specifications on production companies every year [4]. The quality and safety of sterile drugs involves many aspects. To release them, it is necessary to focus on raw materials and excipients, microbial monitoring of the production process, production environment monitoring, and stable operation of public systems. Any deviations related to the production management of sterile products should be fully evaluated. , changes, evaluate their impact on product quality, and regularly carry out continuous process verification to ensure that all parameters and indicators in the entire production process are stable and controllable.